CN101405278A - Novel heterocyclic NF-kB inhibitors - Google Patents

Novel heterocyclic NF-kB inhibitors Download PDF

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CN101405278A
CN101405278A CNA2007800092336A CN200780009233A CN101405278A CN 101405278 A CN101405278 A CN 101405278A CN A2007800092336 A CNA2007800092336 A CN A2007800092336A CN 200780009233 A CN200780009233 A CN 200780009233A CN 101405278 A CN101405278 A CN 101405278A
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alkyl
halo
hydroxy alkylene
amino
group
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约翰·莱班
哈拉尔德·施米特
克里斯蒂娜·沃尔夫
斯蒂凡诺·彼格拉罗
安德烈亚斯·伍兹克
罗尔夫·卡尔尤斯
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4SC AG
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4SC AG
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Priority claimed from US11/375,259 external-priority patent/US7601745B2/en
Priority claimed from PCT/EP2006/002396 external-priority patent/WO2007016979A2/en
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Publication of CN101405278A publication Critical patent/CN101405278A/en
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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Abstract

The present invention relates to compounds of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, wherein A is NR<2>, S or O; R<3a> is H, OH, SH, NH2, -C(NR<7>)NR<7'>R<8>, -(CH2)paryl, -(CH2)pNR<7>R<8>, -C(O)NR<7>R<8>, -N=CR<7>R<8>, -NR<7>C(O)R<8>, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; R<3> is H, -C(0)NR<a>R<b>, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR<4'>OR<5'>, NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, hetero-cycloalkyl, hydroxyalkyl, or haloalkyloxy; X is NR<2'>, O, or S; Z is N or CR<2'>.

Description

Novel heterocyclic NF-kB inhibitors
The present invention relates to general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) the possible acceptable salt of medicine that forms with acid or alkali of compound or its steric isomer or its or the medicine acceptable prodrugs of these compounds.Compound of the present invention can and be particularly useful for treatment and the unusual and hyper-proliferative diseases associated of the middle cell of Mammals (especially human) as medicine.Particularly, its to be used for the treatment of with the T cell hyperproliferation be the disease of feature.The present invention relates to be suitable for to treat the compound of the disease (for example cancer, immunity or inflammatory conditions and viral infection) that can treat by the cellular pathways of regulating in the eukaryote, relate to the method for preparing these compounds, and relate to its purposes.
The T Cell Homeostasis is vital to keeping immunotolerance.The defective of T Cell Homeostasis can cause autoimmune disease.Autoimmune disease comprises on a large scale different clinically entity, its shared etiology, the immunne response of misguided, self-conductance.This immunne response can also be the result of organ transplantation.Evidence has shown the main effect of T cytoactive in autoimmune disease.It is the measuring method (Killestein, J.et al.J.Neuroimmunol.133,217-24,2002) of widely used measurement immunological competence that propagation in the measurement T lymphocyte is replied.
We use the on-radiation technology to come the outer T cell proliferation (Messele, T.et al.Clinical and Diagnostic Laboratory Immunology 687-692,2000) of measuring body.Separating periphery blood monocytic cell (PBMC) from the human blood that obtains by the aspiration contributor.Use HISTOPAQUE to isolate PBMC by the centrifuging in the ACCUSPIN pipe.Stimulate PBMC and measure cell proliferation in conjunction with the ELISA test kit with PHA with Luo Shi colorimetry BromUridin.
By multiple signal pathway, for example T cell or TNF receptor signal are controlled the adjusting (Chen, G.et al.Science 296,1634-1635,2002) of immunne response.Find the target of activated compound in order further to characterize us in the T cell proliferation test, we have tested the ability of compound inhibition human protein enzyme body.
Neutral protein hydrolytic activity main in cytosol and karyon is a proteasome, and it is 20S (700kDa) particulate with multiple peptidase activity.Immunity system uses the continuous circulation of the cell protein that passes through ubiquitin-proteasome pathway with proteic appearance (Dantuma, N.P.et al.Nat.Biotechnol.2000,18 (5), 538-43 in the screening abnormal cells; Goldberg, AL.et al.Nature357,375,1993).Ubiquitin-proteasome pathway plays crucial effects to regulating the NF-kB activity, and it is the reason that causes inhibitor I κ B-α degraded.For by target with through proteasome degraded, I κ B-α must be at first at serine residue 32 and 36 places through the selectivity phosphorylation, pass through general peptideization (Chen, ZJ.et al.Cell 84,853-862,1996 then; Brown, K.et al.Science 267,1485,1995).NF-κ B is a kind of transcription factor, and it regulates transcribe (Baeuerle, PA.et al.Cell 87,1,13-20,1996) that relate to a series of important gene in the inflammatory response.Proteasome inhibitor hinders the degraded of I κ B-α and the activation (Traeckner et al.EMBOJ.13,5433,1994) of NF-κ B.
The document of description proteasome inhibitor is (Adams in summary, J.et al.Ann.Rev.Med.Chem.31,279-288,1996) and among the patent US 6117887, US 5834487, WO00/004954, WO 00/04954, WO 00/170204, WO 00/33654, WO 00/64863, WO 00/114324, WO 99/15183, WO 99/37666 describe.
Here, we describe and have the chemical entity that proteasome suppresses active novelty.
NF-κ B (nuclear Factor-Kappa B) as homodimer or heterodimer, in nonactive title complex, be arranged in the rel family eukaryotic transcription factor of tenuigenin.There is (D.Thanos et al.Cell 80,529,1995) in it mainly as the heterodimer of being made up of p50 and p65 subunit, combine with the arrestin of the I κ B family that is generally I κ B-α.NF-κ B responds to the different stimulated source and activates, and described stimulus comprises inflammatory cytokine, UV radiation, Buddhist ripple ester, bacterium and virus infection.Because phosphorylation and I κ B-α albumen is by the Degradation of proteasome (P.A.Baeuerleet al.Annu.Rev.Immunol.12,141,1995) subsequently, hormesis has triggered NF-κ B by the release among the I κ B.In case it is released, NF-κ B then is transferred to nucleus, it combines with DNA at specific kB site in nucleus, and induce transcribing of several genes, these genes encodings relate to the albumen of control immunity and inflammatory response, comprise interleukin, TNF-α, NO-synthase and cyclooxygenase 2 (S.Grimm et al.J.Biochem.290,297,1993).Therefore, NF-κ B is considered to immunity and the early stage conditioning agent of inflammatory response and relevant with the pathogenesis of the control of cell proliferation and multiple human diseases, described disease is rheumatoid arthritis (H.Beker et al.Clin.Exp.Immunol.99 for example, 325,1995), local asphyxia (A.Salminen et al.Biochem.Biophys.Res.Comm.212,939,1995), arteriosclerosis (A.S.Baldwin, Annals Rev.Immunol.212,649,1996) and AIDS.To the restraining effect of the genetic transcription of NF-κ B mediation can by to the inhibition of the phosphorylation of arrestin I κ B, to the inhibition of I κ B degraded, to the inhibition of NF-κ B (p50/p65) nuclear transposition, to NF-κ b form dna in conjunction with or the DNA that mediates of the NF-κ B inhibition of transcribing realize (J.C.Epinat et al.Oncogene 18,6896,1999).
The present invention relates to the acceptable salt of medicine or its medicine acceptable prodrugs or steric isomer that general formula (Ia) compound or itself and acid or alkali form.
Wherein
R is hydrogen, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
R 1Be alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
X is CO, CS or SO 2
Y is CO, CS or SO 2
Z is NR 2', S or O;
R 2' be H, alkyl ,-C (O) NR 7,-C (O) R e, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R cBe H, OH, SH, NROR independently 1, NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7' represent H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl independently;
R 8Be H, NH 2, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R eRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, aryl, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4'-benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl or heteroaryl;
R 4', R 4", R 5' represent independently H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl
P is 1 to 6;
Q is 1 to 6;
R 2Be independently
Figure A20078000923300211
R 5Be H, COR independently 6, CO 2R 6, SOR 6, SO 2R 6, SO 3R 6, alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkylamine ,-NR 7COR 6, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 6Be H, alkyl, cyclic hydrocarbon radical, amino, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, aryl or heteroaryl independently;
Wherein
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched, the C of straight or branched to 5 carbon atoms 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl, they can be randomly by one or more substituent R ' replace;
Described C1-C 6Alkyl, C2-C 6Thiazolinyl and C2-C 6The alkynyl part can be selected from-CH3、-C 2H 5、 -CH＝CH 2、-C≡CH、-C 3H 7、-CH(CH 3) 2、-CH 2-CH＝CH 2、-C(CH 3)＝CH 2、 -CH＝CH-CH 3、-C≡C-CH 3、-CH 2-C≡CH、-C 4H 9、-CH 2-CH(CH 3) 2、 -CH(CH 3)-C 2H 5、-C(CH 3) 3、-C 5H 11、-C 6H 13、-C(R”) 3、-C 2(R’) 5、-CH 2-C(R’) 3、 -C 3(R’) 7、-C 2H 4-C(R’) 3、-C 2H 4-CH＝CH 2、-CH＝CH-C 2H 5、-CH＝C(CH 3) 2、 -CH 2-CH＝CH-CH 3、-CH＝CH-CH＝CH 2、-C 2H 4-C≡CH、-C≡C-C 2H 5、 -CH 2-C≡C-CH 3、-C≡C-CH＝CH 2、-CH＝CH-C≡CH、-C≡C-C≡CH、 -C 2H 4-CH(CH 3) 2、-CH(CH 3)-C 3H 7、-CH 2-CH(CH 3)-C 2H 5、 -CH(CH 3)-CH(CH 3) 2、-C(CH 3) 2-C 2H 5、-CH 2-C(CH 3) 3、-C 3H 6-CH＝CH 2， -CH＝CH-C 3H 7、-C 2H 4-CH＝CH-CH 3、-CH 2-CH＝CH-C 2H 5、 -CH 2-CH＝CH-CH＝CH 2、-CH＝CH-CH＝CH-CH 3、-CH＝CH-CH 2-CH＝CH 2、 -C(CH 3)＝CH-CH＝CH 2、-CH＝C(CH 3)-CH＝CH 2、-CH＝CH-C(CH 3)＝CH 2、 -CH 2-CH＝C(CH 3) 2、C(CH 3)＝C(CH 3) 2、-C 3H 6-C≡CH、-C≡C-C 3H 7、 -C 2H 4-C≡C-CH 3、-CH 2-C≡C-C 2H 5、-CH 2-C≡C-CH＝CH 2、 -CH 2-CH＝CH-C≡CH、-CH 2-C≡C-C≡CH、-C≡C-CH＝CH-CH 3、 -CH＝CH-C≡C-CH 3、-C≡C-C≡C-CH 3、-C≡C-CH 2-CH＝CH 2、 -CH＝CH-CH 2-C≡CH、-C≡C-CH 2-C≡CH、-C(CH 3)＝CH-CH＝CH 2、 -CH＝C(CH 3)-CH＝CH 2、-CH＝CH-C(CH 3)＝CH 2、-C(CH 3)＝CH-C≡CH、 -CH＝C(CH 3)-C≡CH  、-C≡C-C(CH 3)＝CH 2、-C 3H 6-CH(CH 3) 2、 -C 2H 4-CH(CH 3)-C 2H 5、-CH(CH 3)-C 4H 9、-CH 2-CH(CH 3)-C 3H 7、 -CH(CH 3)-CH 2-CH(CH 3) 2、-CH(CH 3)-CH(CH 3)-C 2H 5、 -CH 2-CH(CH 3)-CH(CH 3) 2、-CH 2-C(CH 3) 2-C 2H 5、-C(CH 3) 2-C 3H 7、 -C(CH 3) 2-CH(CH 3) 2、-C 2H 4-C(CH 3) 3、-CH(CH 3)-C(CH 3) 3、-C 4H 8-CH＝CH 2、 -CH＝CH-C 4H 9、-C 3H 6-CH＝CH-CH 3、-CH 2-CH＝CH-C 3H 7、 -C 2H 4-CH＝CH-C 2H 5、-CH 2-C(CH 3)＝C(CH 3) 2、-C 2H 4-CH＝C(CH 3) 2、 -C 4H 8-C≡CH、-C≡C-C 4H 9、-C 3H 6-C≡C-CH 3、-CH 2-C≡C-C 3H 7、 -C 2H 4-C≡C-C 2H 5；
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 to 8 carbon atoms, preferred 4 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by the E group, and E is O, S, SO, SO 2, N or NR ", R " as hereinbefore defined; Described C 3-C 8The cyclic hydrocarbon radical part can be selected from-encircle-C 3H 5,-ring-C 4H 7,-ring-C 5H 9,-ring-C 6H 11,-ring-C 7H 13,-ring-C 8H 15, morpholine-4-base, piperazinyl, 1-alkyl piperazine-4-base;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined; The preferred methoxyl group of described-oxyl group, oxyethyl group, isopropoxy, tert.-butoxy or pentyloxy;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement; Described halo hydrocarbyl group is preferred-C (R 10) 3,-CR 10(R 10') 2,-CR 10(R 10') R 10" ,-C 2(R 10) 5,-CH 2-C (R 10) 3,-CH 2-CR 10(R 10') 2,-CH 2-CR 10(R 10') R 10" ,-C 3(R 10) 7Or-C 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement; Described halo-oxyl group is preferred-OC (R 10) 3,-OCR 10(R 10') 2,-OCR 10(R 10') R 10" ,-OC 2(R 10) 5,-OCH 2-C (R 10) 3,-OCH 2-CR 10(R 10') 2,-OCH 2-CR 10(R 10') R 10" ,-OC 3(R 10) 7Or-OC 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is chlorine, bromine, fluorine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined; The preferred benzyl of described aryl, phenyl ,-neighbour-C 6H 4-R ' ,--C 6H 4-R ' ,-right-C 6H 4-R ', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl;
Heteroaryl groups represents to contain heteroatomic five yuan or the hexa-member heterocycle group that at least one is selected from O, N or S.This heterocyclic group can condense with other aromatic ring.For example, this group can be selected from thiadiazoles, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base benzoxazole-2-base benzoxazole-4-base benzoxazole-5-base, benzoisoxazole-3-base, benzoisoxazole-4-base, benzoisoxazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, benzisothiazole-3-base, benzisothiazole-4-base, benzisothiazole-5-base, 1,2,5-thiadiazoles-3-base, the 1-imidazolyl, the 2-imidazolyl, 1,2,5-thiadiazoles-4-base, the 4-imidazolyl, benzoglyoxaline-4-base, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyranyl, the 3-pyranyl, the 4-pyranyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl, 2,4-dimethoxy-6-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 2-pyrazinyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,5-triazole-6-base, 2,4-dimethoxy-1,3,5-triazole-6-base, 1H-tetrazolium-2-base, 1H-tetrazolium-3-base, tetrazyl, acridyl, furazan, indazolyl, phenazinyl, carbazyl phenoxazine, indolizine, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl, the 1-pseudoindolyl, the 3-pseudoindolyl, the 4-pseudoindolyl, the 5-pseudoindolyl, the 6-pseudoindolyl, the 7-pseudoindolyl, the 2-indolinyl, the 3-indolinyl, the 4-indolinyl, the 5-indolinyl, the 6-indolinyl, the 7-indolinyl, benzo [b] furyl, the benzo furazan, benzimidazole thiophanate is for furazan, benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base, benzotriazole-7-base, phentriazine, benzo [b] thiophenyl, benzimidazolyl-2 radicals-Ji, the 1H-benzimidazolyl-, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, benzothiazolyl, quinazolyl, quinoxalinyl, cinnolines, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydrochysene-isoquinolyl, purine, 2, the 3-naphthyridine, pteridine, sulfo-four benzazoles, sulfo-three benzazoles, isothiazole and pyrazine, isothiazole and pyrimidine, method for preparation of pyrazolotriazine, pyrazolopyrimidine, tetramethylene sulfide also [3,4-d] imidazoles-2-ketone, pyrazolo [5,1-c] [1,2,4] triazine, 2,3-dihydrobenzo [1,4]-dioxin-2-base, 2,3-dihydrobenzo [1,4]-dioxin-3-base, 2,3-dihydrobenzo [1,4]-dioxin-5-base, 2,3-dihydrobenzo [1,4]-dioxin-6-base, 2,6-dimethoxypyridin-3-base, 2,6-dimethoxypyridin-4-base, Imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazo-triazine, the triazolo triazine, Triazolopyridine, Triazolopyrazine, triazolo pyrimidine or 4-[1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furan [2,3-c] pyridin-4-yl, 1-furan [2,3-c] pyridine-5-base, 1-furan [2,3-c] pyridin-3-yl or Triazolopyridazines group.This heterocyclic group can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
The present invention relates to the acceptable salt of medicine or its medicine acceptable prodrugs or steric isomer that general formula (Ib) compound or itself and acid or alkali form.
Wherein
R 1Be-C (O) R 7,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8Or-C (S) R 7
R 9Represent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, aryl, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4'-benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl ,-(CH 2) pNR 7COR 8Or heteroaryl;
R 4Be H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
Perhaps R 1And R 4And connected X-shaped become 3 yuan to 8 yuan, saturated or to undersaturated monocycle of small part or polycyclic member ring systems, wherein at least one annular atoms is the heteroatoms that is selected from O, N, S, and described ring randomly has one or more substituent R 9
X is N or CR 2';
Y is CO, CS or SO 2
Z is NR 2", S or O;
R 2" be H, alkyl ,-C (O) NR 7,-C (O) R e, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 2' be H, alkyl ,-C (O) NR 4' ,-C (O) R 4', cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 4', R 4", R 5' represent independently H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
R aBe H, OH, SH, NH independently 2, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R bBe H, OH, SH, NH independently 2, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R cBe H, OH, SH, NR independently 4' OR 5', NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7' represent H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl independently;
R 8Be H, NH 2, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R eRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, aryl or heteroaryl;
R 2Be independently
Figure A20078000923300271
A is N, O or CR 2';
R 5Be H, SOR independently 7, SO 2R 7, SO 3R 7,-C (O) R 7,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8,-C (S) R 7,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 7', alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkyl amino, hydroxy alkylene amino, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
N is 0 to 2;
Wherein
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched, the C of straight or branched to 5 carbon atoms 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl, they can be randomly by one or more substituent R ' replace;
Described C1-C 6Alkyl, C2-C 6Thiazolinyl and C2-C 6The alkynyl part can be selected from-CH3、-C 2H 5、 -CH＝CH 2、-C≡CH、-C 3H 7、-CH(CH 3) 2、-CH 2-CH＝CH 2、-C(CH 3)＝CH 2、 -CH＝CH-CH 3、-C≡C-CH 3、-CH 2-C≡CH、-C 4H 9、-CH 2-CH(CH 3) 2、 -CH(CH 3)-C 2H 5、-C(CH 3) 3、-C 5H 11、-C 6H 13、-C(R”) 3、-C 2(R’) 5、-CH 2-C(R’) 3、 -C 3(R’) 7、-C 2H 4-C(R’) 3、-C 2H 4-CH＝CH 2、-CH＝CH-C 2H 5、-CH＝C(CH 3) 2、 -CH 2-CH＝CH-CH 3、-CH＝CH-CH＝CH 2、-C 2H 4-C≡CH、-C≡C-C 2H 5、 -CH 2-C≡C-CH 3、-C≡C-CH＝CH 2、-CH＝CH-C≡CH、-C≡C-C≡CH、 -C 2H 4-CH(CH 3) 2、-CH(CH 3)-C 3H 7、-CH 2-CH(CH 3)-C 2H 5、 -CH(CH 3)-CH(CH 3) 2、-C(CH 3) 2-C 2H 5、-CH 2-C(CH 3) 3、-C 3H 6-CH＝CH 2、 -CH＝CH-C 3H 7、-C 2H 4-CH＝CH-CH 3、-CH 2-CH＝CH-C 2H 5、 -CH 2-CH＝CH-CH＝CH 2、-CH＝CH-CH＝CH-CH 3、-CH＝CH-CH 2-CH＝CH 2、 -C(CH 3)＝CH-CH＝CH 2、-CH＝C(CH 3)-CH＝CH 2、-CH＝CH-C(CH 3)＝CH 2、 -CH 2-CH＝C(CH 3) 2、C(CH 3)＝C(CH 3) 2、-C 3H 6-C≡CH、-C≡C-C 3H 7、 -C 2H 4-C≡C-CH 3、-CH 2-C≡C-C 2H 5、-CH 2-C≡C-CH＝CH 2、 -CH 2-CH＝CH-C≡CH、-CH 2-C≡C-C≡CH、-C≡C-CH＝CH-CH 3、 -CH＝CH-C≡C-CH 3、-C≡C-C≡C-CH 3、-C≡C-CH 2-CH＝CH 2、 -CH＝CH-CH 2-C≡CH、-C≡C-CH 2-C≡CH、-C(CH 3)＝CH-CH＝CH 2、 -CH＝C(CH 3)-CH＝CH 2、-CH＝CH-C(CH 3)＝CH 2、-C(CH 3)＝CH-C≡CH、 -CH＝C(CH 3)-C≡CH、-C≡C-C(CH 3)＝CH 2、-C 3H 6-CH(CH 3) 2、 -C 2H 4-CH(CH 3)-C 2H 5、-CH(CH 3)-C 4H 9、-CH 2-CH(CH 3)-C 3H 7、 -CH(CH 3)-CH 2-CH(CH 3) 2、-CH(CH 3)-CH(CH 3)-C 2H 5、 -CH 2-CH(CH 3)-CH(CH 3) 2、-CH 2-C(CH 3) 2-C 2H 5、-C(CH 3) 2-C 3H 7、 -C(CH 3) 2-CH(CH 3) 2、-C 2H 4-C(CH 3) 3、-CH(CH 3)-C(CH 3) 3、-C 4H 8-CH＝CH 2、 -CH＝CH-C 4H 9、-C 3H 6-CH＝CH-CH 3、-CH 2-CH＝CH-C 3H 7、 -C 2H 4-CH＝CH-C 2H 5、-CH 2-C(CH 3)＝C(CH 3) 2、-C 2H 4-CH＝C(CH 3) 2、 -C 4H 8-C≡CH、-C≡C-C 4H 9、-C 3H 6-C≡C-CH 3、-CH 2-C≡C-C 3H 7、 -C 2H 4-C≡C-C 2H 5；
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 to 8 carbon atoms, preferred 4 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by the E group, and E is O, S, SO, SO 2, N or NR ", R " as hereinbefore defined; Described C 3-C 8The cyclic hydrocarbon radical part can be selected from-encircle-C 3H 5,-ring-C 4H 7,-ring-C 5H 9,-ring-C 6H 11,-ring-C 7H 13,-ring-C 8H 15, morpholine-4-base, piperazinyl, 1-alkyl piperazine-4-base;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined; The preferred methoxyl group of described-oxyl group, oxyethyl group, isopropoxy, tert.-butoxy or pentyloxy;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement; Described halo hydrocarbyl group is preferred-C (R 10) 3,-CR 10(R 10') 2,-CR 10(R 10') R 10" ,-C 2(R 10) 5,-CH 2-C (R 10) 3,-CH 2-CR 10(R 10') 2,-CH 2-CR 10(R 10') R 10" ,-C 3(R 10) 7Or-C 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement; Described halo-oxyl group is preferred-OC (R 10) 3,-OCR 10(R 10') 2,-OCR 10(R 10') R 10" ,-OC 2(R 10) 5,-OCH 2-C (R 10) 3,-OCH 2-CR 10(R 10') 2,-OCH 2-CR 10(R 10') R 10" ,-OC 3(R 10) 7Or-OC 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is chlorine, bromine, fluorine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined; The preferred benzyl of described aryl, phenyl ,-neighbour-C 6H 4-R ' ,--C 6H 4-R ' ,-right-C 6H 4-R ', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl;
Heteroaryl groups represents to contain heteroatomic five yuan or the hexa-member heterocycle group that at least one is selected from O, N or S.This heterocyclic group can condense with other aromatic ring.For example, this group can be selected from thiadiazoles, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base benzoxazole-2-base benzoxazole-4-base benzoxazole-5-base, benzoisoxazole-3-base, benzoisoxazole-4-base, benzoisoxazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, benzisothiazole-3-base, benzisothiazole-4-base, benzisothiazole-5-base, 1,2,5-thiadiazoles-3-base, the 1-imidazolyl, the 2-imidazolyl, 1,2,5-thiadiazoles-4-base, the 4-imidazolyl, benzoglyoxaline-4-base, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyranyl, the 3-pyranyl, the 4-pyranyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl, 2,4-dimethoxy-6-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 2-pyrazinyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,5-triazole-6-base, 2,4-dimethoxy-1,3,5-triazole-6-base, 1H-tetrazolium-2-base, 1H-tetrazolium-3-base, tetrazyl, acridyl, furazan, indazolyl, phenazinyl, carbazyl phenoxazine, indolizine, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl, the 1-pseudoindolyl, the 3-pseudoindolyl, the 4-pseudoindolyl, the 5-pseudoindolyl, the 6-pseudoindolyl, the 7-pseudoindolyl, the 2-indolinyl, the 3-indolinyl, the 4-indolinyl, the 5-indolinyl, the 6-indolinyl, the 7-indolinyl, benzo [b] furyl, the benzo furazan, benzimidazole thiophanate is for furazan, benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base, benzotriazole-7-base, phentriazine, benzo [b] thiophenyl, benzimidazolyl-2 radicals-Ji, the 1H-benzimidazolyl-, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, benzothiazolyl, quinazolyl, quinoxalinyl, cinnolines, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydrochysene-isoquinolyl, purine, 2, the 3-naphthyridine, pteridine, sulfo-four benzazoles, sulfo-three benzazoles, isothiazole and pyrazine, isothiazole and pyrimidine, method for preparation of pyrazolotriazine, pyrazolopyrimidine, tetrahydrochysene-thieno-[3,4-d] imidazoles-2-ketone, pyrazolo [5,1-c] [1,2,4] triazine, Imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazo-triazine, the triazolo triazine, 2,3-dihydrobenzo [1,4]-dioxin-2-base, 2,3-dihydrobenzo [1,4]-dioxin-3-base, 2,3-dihydrobenzo [1,4]-dioxin-5-base, 2,3-dihydrobenzo [1,4]-dioxin-6-base, 2,6-dimethoxypyridin-3-base, 2,6-dimethoxypyridin-4-base, Triazolopyridine, Triazolopyrazine, triazolo pyrimidine, 4-[1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furan [2,3-c] pyridin-4-yl, 1-furan [2,3-c] pyridine-5-base, 1-furan [2,3-c] pyridin-3-yl or Triazolopyridazines group.This heterocyclic group can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
The present invention relates to the acceptable salt of medicine or its medicine acceptable prodrugs or steric isomer that general formula (Ic) compound or itself and acid or alkali form.
Figure A20078000923300301
Wherein
R 1Represent H, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
X is CO, CS or SO 2
Y is CO, CS or SO 2
Z is NR 2", S or O;
R 2" be H, alkyl ,-C (O) NR 7,-C (O) R e, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 4', R 4", R 5' represent independently H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
M is 0 to 4;
R is 0 or 1;
T is 0 or 1;
S is 0 or 1;
R bBe H, OH, SH, NR independently 4' OR 5', NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R cBe H, OH, SH, NR independently 4' OR 5', NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7' represent H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl independently;
R 8Be H, NH 2, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R eRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, aryl or heteroaryl;
R 3Be H, OH, SH, NR independently 4' OR 5', NH 2, hydroxy alkylene amino, alkyl amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched, the C of straight or branched to 5 carbon atoms 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl, they can be randomly by one or more substituent R ' replace;
Described C1-C 6Alkyl, C2-C 6Thiazolinyl and C2-C 6The alkynyl part can be selected from-CH3、-C 2H 5、 -CH＝CH 2、-C≡CH、-C 3H 7、-CH(CH 3) 2、-CH 2-CH＝CH 2、-C(CH 3)＝CH 2、 -CH＝CH-CH 3、-C≡C-CH 3、-CH 2-C≡CH、-C 4H 9、-CH 2-CH(CH 3) 2、 -CH(CH 3)-C 2H 5、-C(CH 3) 3、-C 5H 11、-C 6H 13、-C(R”) 3、-C 2(R’) 5、-CH 2-C(R’) 3、 -C 3(R’) 7、-C 2H 4-C(R’) 3、-C 2H 4-CH＝CH 2、-CH＝CH-C 2H 5、-CH＝C(CH 3) 2、 -CH 2-CH＝CH-CH 3、-CH＝CH-CH＝CH 2、-C 2H 4-C≡CH、-C≡C-C 2H 5、 -CH 2-C≡C-CH 3、-C≡C-CH＝CH 2、-CH＝CH-C≡CH、-C≡C-C≡CH、 -C 2H 4-CH(CH 3) 2、-CH(CH 3)-C 3H 7、-CH 2-CH(CH 3)-C 2H 5、 -CH(CH 3)-CH(CH 3) 2、-C(CH 3) 2-C 2H 5、-CH 2-C(CH 3) 3、-C 3H 6-CH＝CH 2、 -CH＝CH-C 3H 7、-C 2H 4-CH＝CH-CH 3、-CH 2-CH＝CH-C 2H 5、 -CH 2-CH＝CH-CH＝CH 2、-CH＝CH-CH＝CH-CH 3、-CH＝CH-CH 2-CH＝CH 2、 -C(CH 3)＝CH-CH＝CH 2、-CH＝C(CH 3)-CH＝CH 2、-CH＝CH-C(CH 3)＝CH 2、 -CH 2-CH＝C(CH 3) 2、C(CH 3)＝C(CH 3) 2、-C 3H 6-C≡CH、-C≡C-C 3H 7、 -C 2H 4-C≡C-CH 3、-CH 2-C≡C-C 2H 5、-CH 2-C≡C-CH＝CH 2、 -CH 2-CH＝CH-C≡CH、-CH 2-C≡C-C≡CH、-C≡C-CH＝CH-CH 3、 -CH＝CH-C≡C-CH 3、-C≡C-C≡C-CH 3、-C≡C-CH 2-CH＝CH 2、 -CH＝CH-CH 2-C≡CH、-C≡C-CH 2-C≡CH、-C(CH 3)＝CH-CH＝CH 2、 -CH＝C(CH 3)-CH＝CH 2、-CH＝CH-C(CH 3)＝CH 2、-C(CH 3)＝CH-C≡CH、 -CH＝C(CH 3)-C≡CH  、-C≡C-C(CH 3)＝CH 2、-C 3H 6-CH(CH 3) 2、 -C 2H 4-CH(CH 3)-C 2H 5、-CH(CH 3)-C 4H 9、-CH 2-CH(CH 3)-C 3H 7、 -CH(CH 3)-CH 2-CH(CH 3) 2、-CH(CH 3)-CH(CH 3)-C 2H 5、 -CH 2-CH(CH 3)-CH(CH 3) 2、-CH 2-C(CH 3) 2-C 2H 5、-C(CH 3) 2-C 3H 7、 -C(CH 3) 2-CH(CH 3) 2、-C 2H 4-C(CH 3) 3、-CH(CH 3)-C(CH 3) 3、-C 4H 8-CH＝CH 2、 -CH＝CH-C 4H 9、-C 3H 6-CH＝CH-CH 3、-CH 2-CH＝CH-C 3H 7、 -C 2H 4-CH＝CH-C 2H 5、-CH 2-C(CH 3)＝C(CH 3) 2、-C 2H 4-CH＝C(CH 3) 2、 -C 4H 8-C≡CH、-C≡C-C 4H 9、-C 3H 6-C≡C-CH 3、-CH 2-C≡C-C 3H 7、 -C 2H 4-C≡C-C 2H 5；
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 to 8 carbon atoms, preferred 4 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by the E group, and E is O, S, SO, SO 2, N or NR ", R " as hereinbefore defined; Described C 3-C 8The cyclic hydrocarbon radical part can be selected from-encircle-C 3H 5,-ring-C 4H 7,-ring-C 5H 9,-ring-C 6H 11,-ring-C 7H 13,-ring-C 8H 15, morpholine-4-base, piperazinyl, 1-alkyl piperazine-4-base;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined; The preferred methoxyl group of described-oxyl group, oxyethyl group, isopropoxy, tert.-butoxy or pentyloxy;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement; Described halo hydrocarbyl group is preferred-C (R 10) 3,-CR 10(R 10') 2,-CR 10(R 10') R 10" ,-C 2(R 10) 5,-CH 2-C (R 10) 3,-CH 2-CR 10(R 10') 2,-CH 2-CR 10(R 10') R 10" ,-C 3(R 10) 7Or-C 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement; Described halo-oxyl group is preferred-OC (R 10) 3,-OCR 10(R 10') 2,-OCR 10(R 10') R 10" ,-OC 2(R 10) 5,-OCH 2-C (R 10) 3,-OCH 2-CR 10(R 10') 2,-OCH 2-CR 10(R 10') R 10" ,-OC 3(R 10) 7Or-OC 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is chlorine, bromine, fluorine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined; The preferred benzyl of described aryl, phenyl ,-neighbour-C 6H 4-R ' ,--C 6H 4-R ' ,-right-C 6H 4-R ', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl;
Heteroaryl groups represents to contain heteroatomic five yuan or the hexa-member heterocycle group that at least one is selected from O, N or S.This heterocyclic group can condense with other aromatic ring.For example, this group can be selected from thiadiazoles, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base benzoxazole-2-base benzoxazole-4-base benzoxazole-5-base, benzoisoxazole-3-base, benzoisoxazole-4-base, benzoisoxazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, benzisothiazole-3-base, benzisothiazole-4-base, benzisothiazole-5-base, 1,2,5-thiadiazoles-3-base, the 1-imidazolyl, the 2-imidazolyl, 1,2,5-thiadiazoles-4-base, the 4-imidazolyl, benzoglyoxaline-4-base, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyranyl, the 3-pyranyl, the 4-pyranyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl, 2,4-dimethoxy-6-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 2-pyrazinyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,5-triazole-6-base, 2,4-dimethoxy-1,3,5-triazole-6-base, 1H-tetrazolium-2-base, 1H-tetrazolium-3-base, tetrazyl, acridyl, furazan, indazolyl, phenazinyl, carbazyl phenoxazine, indolizine, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl, the 1-pseudoindolyl, the 3-pseudoindolyl, the 4-pseudoindolyl, the 5-pseudoindolyl, the 6-pseudoindolyl, the 7-pseudoindolyl, the 2-indolinyl, the 3-indolinyl, the 4-indolinyl, the 5-indolinyl, the 6-indolinyl, the 7-indolinyl, benzo [b] furyl, the benzo furazan, benzimidazole thiophanate is for furazan, benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base, benzotriazole-7-base, phentriazine, benzo [b] thiophenyl, benzimidazolyl-2 radicals-Ji, the 1H-benzimidazolyl-, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, benzothiazolyl, quinazolyl, quinoxalinyl, cinnolines, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydrochysene-thieno-[3,4-d] imidazoles-2-ketone, pyrazolo [5,1-c] [1,2,4] triazine, tetrahydro isoquinolyl, purine, 2, the 3-naphthyridine, pteridine, sulfo-four benzazoles, sulfo-three benzazoles, isothiazole and pyrazine, isothiazole and pyrimidine, method for preparation of pyrazolotriazine, pyrazolopyrimidine, Imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazo-triazine, the triazolo triazine, Triazolopyridine, Triazolopyrazine, triazolo pyrimidine, 2,3-dihydrobenzo [1,4]-dioxin-2-base, 2,3-dihydrobenzo [1,4]-dioxin-3-base, 2,3-dihydrobenzo [1,4]-dioxin-5-base, 2,3-dihydrobenzo [1,4]-dioxin-6-base, 2,6-dimethoxypyridin-3-base, 2,6-dimethoxypyridin-4-base, 4-[1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furan [2,3-c] pyridin-4-yl, 1-furan [2,3-c] pyridine-5-base, 1-furan [2,3-c] pyridin-3-yl or Triazolopyridazines group.This heterocyclic group can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
The invention still further relates to the acceptable salt of medicine or its medicine acceptable prodrugs or steric isomer that general formula (III) compound or itself and acid or alkali form.
Figure A20078000923300351
Wherein
R 1Be-C (O) R 7a,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8Or-C (S) R 7b
R 2Be H, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl,
Perhaps R 1And R 2And connected N atom or C atom form together 3 yuan to 8 yuan, saturated or to undersaturated monocycle of small part or polycyclic member ring systems, on the wherein said ring at least one or a plurality of carbon atom are the heteroatomss that is selected from O, N or S, and described ring can be by one or more substituent R 9Replace;
R 4aBe H, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
R 3Be H ,-C (O) NR aR b, halogen, alkyl, halo alkyl, aryl, heteroaryl, OH, SH, NR 4' OR 5', NH 2, hydroxy alkylene amino, alkyl amino,-oxyl, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene or halo-oxyl;
R 4Be H, OH, SH, NH 2,-oxyl, halo-oxyl, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 5Be halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R aBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R bRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl, halogen, halo alkyl, halo-oxyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxy alkylene, hydroxyl-cyclic hydrocarbon radical, hydroxy alkylene amino, heterocycle alkyl, aryl or heteroaryl;
R 4', R 4", R 5' be independently H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl, halo alkyl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7', R 8Be H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, arylamino, heteroaryl or aryl independently;
R 7aBe cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, heteroaryl or aryl;
R 7bBe H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, heteroaryl or aryl;
A is CO or SO 2
X is NR 2', O or S;
Z is N or CR 2';
R 2' be H, alkyl ,-C (O) NR 7,-C (O) R b, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
R 9Represent independently H ,-CN ,-OH ,-SH,-oxyl, sulfenyl ,-CO 2R 4' ,-C (O) R 4a,-C (O) NR 7R 8,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, halogen, halo alkyl, alkyl amino ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxyl cyclic hydrocarbon radical, hydroxy alkylene amino, halo-oxyl, heterocycle alkyl ,-(CH 2) pNR 7COR 8, aryl or heteroaryl;
Wherein
If not explanation in addition, C 1-C 6Alkyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched to 5 carbon atoms, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, C 2-C 6Alkenyl group is represented the C of straight or branched 2-C 6Thiazolinyl, preferred 2 straight or brancheds to 6 carbon atoms, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched, the C of straight or branched to 6 carbon atoms 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl group, they can be randomly by one or more substituent R ' replace;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 to 8 carbon atoms, preferred 4 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group as hereinbefore defined; Described C 3-C 8The cyclic hydrocarbon radical part can be selected from-encircle-C 3H 5,-ring-C 4H 7,-ring-C 5H 9,-ring-C 6H 11,-ring-C 7H 13,-ring-C 8H 15
The heterocyclic hydrocarbon basis representation contains 2 to 10 carbon atoms and at least one is selected from the heteroatomic non-aromatic ring system of O, N or S, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group as hereinbefore defined; Preferred heterocycle hydrocarbyl group is morpholine-4-base, piperazinyl, 1-alkyl piperazine-4-base, piperidyl, pyrrolidyl, azepan-1-base;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined; The preferred methoxyl group of described-oxyl group, oxyethyl group, isopropoxy, tert.-butoxy or pentyloxy;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement; Described halo hydrocarbyl group is preferred-C (R 10) 3,-CR 10(R 10') 2,-CR 10(R 10') R 10" ,-C 2(R 10) 5,-CH 2-C (R 10) 3,-CH 2-CR 10(R 10') 2,-CH 2-CR 10(R 10') R 10" ,-C 3(R 10) 7Or-C 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement; Described halo-oxyl group is preferred-OC (R 10) 3,-OCR 10(R 10') 2,-OCR 10(R 10') R 10" ,-OC 2(R 10) 5,-OCH 2-C (R 10) 3,-OCH 2-CR 10(R 10') 2,-OCH 2-CR 10(R 10') R 10" ,-OC 3(R 10) 7Or-OC 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined; The preferred benzyl of described aryl, phenyl ,-neighbour-C 6H 4-R ' ,--C 6H 4-R ' ,-right-C 6H 4-R ', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl, R ' is as hereinbefore defined;
The arylamino group is represented HN-aryl or N-diaryl group, and described aromatic yl group as hereinbefore defined;
Heteroaryl groups represents to contain heteroatomic five yuan or the hexa-member heterocycle group that at least one is selected from O, N or S.This heterocyclic group can condense with other aromatic ring.For example, this group can be selected from thiadiazoles, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base benzoxazole-2-base benzoxazole-4-base benzoxazole-5-base, benzoisoxazole-3-base, benzoisoxazole-4-base, benzoisoxazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, benzisothiazole-3-base, benzisothiazole-4-base, benzisothiazole-5-base, 1,2,5-thiadiazoles-3-base, the 1-imidazolyl, the 2-imidazolyl, 1,2,5-thiadiazoles-4-base, the 4-imidazolyl, benzoglyoxaline-4-base, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyranyl, the 3-pyranyl, the 4-pyranyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl, 2,4-dimethoxy-6-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 2-pyrazinyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,5-triazole-6-base, 2,4-dimethoxy-1,3,5-triazole-6-base, 1H-tetrazolium-2-base, 1H-tetrazolium-3-base, tetrazyl, acridyl, furazan, indazolyl, phenazinyl, carbazyl phenoxazine, indolizine, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl, the 1-pseudoindolyl, the 3-pseudoindolyl, the 4-pseudoindolyl, the 5-pseudoindolyl, the 6-pseudoindolyl, the 7-pseudoindolyl, the 2-indolinyl, the 3-indolinyl, the 4-indolinyl, the 5-indolinyl, the 6-indolinyl, the 7-indolinyl, benzo [b] furyl, the benzo furazan, benzimidazole thiophanate is for furazan, benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base, benzotriazole-7-base, phentriazine, benzo [b] thiophenyl, benzimidazolyl-2 radicals-Ji, the 1H-benzimidazolyl-, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, benzothiazolyl, quinazolyl, quinoxalinyl, cinnolines, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydrochysene-thieno-[3,4-d] imidazoles-2-ketone, pyrazolo [5,1-c] [1,2,4] triazine, 2,3-dihydrobenzo [1,4]-dioxin-2-base, 2,3-dihydrobenzo [1,4]-dioxin-3-base, 2,3-dihydrobenzo [1,4]-dioxin-5-base, 2,3-dihydrobenzo [1,4]-dioxin-6-base, 2,6-dimethoxypyridin-3-base, 2,6-dimethoxypyridin-4-base, tetrahydro isoquinolyl, purine, 2, the 3-naphthyridine, pteridine, sulfo-four benzazoles, thio group three benzazoles, isothiazole and pyrazine, isothiazole and pyrimidine, method for preparation of pyrazolotriazine, pyrazolopyrimidine, Imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazo-triazine, the triazolo triazine, Triazolopyridine, Triazolopyrazine, triazolo pyrimidine, 4-[1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furan [2,3-c] pyridin-4-yl, 1-furan [2,3-c] pyridine-5-base, 1-furan [2,3-c] pyridin-3-yl or Triazolopyridazines group.This heterocyclic group can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
Following compound is by being excluded in the general formula (III):
Figure A20078000923300401
Wherein
R 1The aryl alkyl of heteroaryl, aryl alkyl or replacement of representing aryl, heteroaryl, the replacement of hydrogen, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl, replacement independently;
R 2Expression-NR independently 3R 4,
Figure A20078000923300411
R 3Represent independently alkyl, cyclic hydrocarbon radical,-oxyl, alkylamine ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl,
R 4Represent alkyl, cyclic hydrocarbon radical,-oxyl, alkylamine, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
R 5Represent H, COR independently 6, CO 2R 6, SOR 6, SO 2R 6, SO 3R 6, alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkylamine ,-NR 7COR 6, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 6Represent independently H, alkyl, cyclic hydrocarbon radical ,-NH 2, alkylamine, aryl or heteroaryl;
R 7Represent independently H, alkyl, cyclic hydrocarbon radical,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, aryl or heteroaryl;
P is 0 or 1;
Q is 0 or 1;
X is CO or SO 2
The invention still further relates to the acceptable salt of medicine or its medicine acceptable prodrugs or steric isomer that general formula (Ih) compound or itself and acid or alkali form,
Figure A20078000923300412
Wherein
A is NR 2', S or O;
T is 0 to 4;
R is 0 or 1;
R 2aBe H, OH, SH, NH independently 2, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R 3aBe H, OH, SH, NH 2,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 1Be-C (O) R 7a,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8Or-C (S) R 7b
R 2Be H, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino or heteroaryl;
Perhaps R 1And R 2And connected N atom or C atom form together 3 yuan to 8 yuan, saturated or to undersaturated monocycle of small part or polycyclic member ring systems, on the wherein said ring at least one or a plurality of carbon atom are the heteroatomss that is selected from O, N or S, and described ring can be by one or more substituent R 9Replace;
R 4aBe H, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
R 3Be H ,-C (O) NR aR b, halogen, alkyl, halo alkyl, aryl, heteroaryl, OH, SH, NR 4' OR 5', NH 2, hydroxy alkylene amino, alkyl amino,-oxyl, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene or halo-oxyl;
R aBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R bRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl, halogen, halo alkyl, halo-oxyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxy alkylene, hydroxyl-cyclic hydrocarbon radical, hydroxy alkylene amino, heterocycle alkyl, aryl or heteroaryl;
R 4', R 4", R 5' be independently H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl, halo alkyl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7', R 8Be H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, arylamino, heteroaryl or aryl independently;
R 7aBe cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, heteroaryl or aryl;
R 7bBe H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, heteroaryl or aryl;
X is NR 2', O or S;
Z is N or CR 2';
R 2' be H, alkyl ,-C (O) NR 7,-C (O) R b, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
R 9Represent independently H ,-CN ,-OH ,-SH,-oxyl, sulfenyl ,-CO 2R 4' ,-C (O) R 4a,-C (O) NR 7R 8,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, halogen, halo alkyl, alkyl amino ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxyl cyclic hydrocarbon radical, hydroxy alkylene amino, halo-oxyl, heterocycle alkyl ,-(CH 2) pNR 7COR 8, aryl or heteroaryl;
Wherein
If not explanation in addition, C 1-C 6Alkyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched to 5 carbon atoms, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, C 2-C 6Alkenyl group is represented the C of straight or branched 2-C 6Thiazolinyl, preferred 2 straight or brancheds to 6 carbon atoms, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched, the C of straight or branched to 6 carbon atoms 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl group, they can be randomly by one or more substituent R ' replace;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 to 8 carbon atoms, preferred 4 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group, and R ' as hereinbefore defined; Described C 3-C 8The cyclic hydrocarbon radical part can be selected from-encircle-C 3H 5,-ring-C 4H 7,-ring-C 5H 9,-ring-C 6H 11,-ring-C 7H 13,-ring-C 8H 15
The heterocyclic hydrocarbon basis representation contains 2 to 10 carbon atoms and at least one is selected from the heteroatomic non-aromatic ring system of O, N or S, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group as hereinbefore defined; Preferred heterocycle hydrocarbyl group is morpholine-4-base, piperazinyl, 1-alkyl piperazine-4-base, piperidyl, pyrrolidyl, azepan-1-base;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined; The preferred methoxyl group of described-oxyl group, oxyethyl group, isopropoxy, tert.-butoxy or pentyloxy;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement; Described halo hydrocarbyl group is preferred-C (R 10) 3,-CR 10(R 10') 2,-CR 10(R 10') R 10" ,-C 2(R 10) 5,-CH 2-C (R 10) 3,-CH 2-CR 10(R 10') 2,-CH 2-CR 10(R 10') R 10" ,-C 3(R 10) 7Or-C 2H 4-C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement; Described halo-oxyl group is preferred-OC (R 10) 3,-OCR 10(R 10') 2,-OCR 10(R 10') R 10" ,-OC 2(R 10) 5,-OCH 2C (R 10) 3,-OCH 2CR 10(R 10') 2,-OCH 2CR 10(R 10') R 10" ,-OC 3(R 10) 7Or-OC 2H 4C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined; The preferred benzyl of described aryl, phenyl ,-neighbour-C 6H 4-R ' ,--C 6H 4-R ' ,-right-C 6H 4-R ', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl, R ' is as hereinbefore defined;
The arylamino group is represented HN-aryl or N-diaryl group, and described aromatic yl group as hereinbefore defined;
Heteroaryl groups represents to contain heteroatomic five yuan or the hexa-member heterocycle group that at least one is selected from O, N or S.This heterocyclic group can condense with other aromatic ring.For example, this group can be selected from thiadiazoles, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base benzoxazole-2-base benzoxazole-4-base benzoxazole-5-base, benzoisoxazole-3-base, benzoisoxazole-4-base, benzoisoxazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, benzisothiazole-3-base, benzisothiazole-4-base, benzisothiazole-5-base, 1,2,5-thiadiazoles-3-base, the 1-imidazolyl, the 2-imidazolyl, 1,2,5-thiadiazoles-4-base, the 4-imidazolyl, benzoglyoxaline-4-base, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyranyl, the 3-pyranyl, the 4-pyranyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl, 2,4-dimethoxy-6-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 2-pyrazinyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,5-triazole-6-base, 2,4-dimethoxy-1,3,5-triazole-6-base, 1H-tetrazolium-2-base, 1H-tetrazolium-3-base, tetrazyl, acridyl, furazan, indazolyl, phenazinyl, carbazyl phenoxazine, indolizine, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl, the 1-pseudoindolyl, the 3-pseudoindolyl, the 4-pseudoindolyl, the 5-pseudoindolyl, the 6-pseudoindolyl, the 7-pseudoindolyl, the 2-indolinyl, the 3-indolinyl, the 4-indolinyl, the 5-indolinyl, the 6-indolinyl, the 7-indolinyl, benzo [b] furyl, the benzo furazan, benzimidazole thiophanate is for furazan, benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base, benzotriazole-7-base, phentriazine, benzo [b] thiophenyl, benzimidazolyl-2 radicals-Ji, the 1H-benzimidazolyl-, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, benzothiazolyl, quinazolyl, quinoxalinyl, cinnolines, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydrochysene-thieno-[3,4-d] imidazoles-2-ketone, pyrazolo [5,1-c] [1,2,4] triazine, 2,3-dihydrobenzo [1,4]-dioxin-2-base, 2,3-dihydrobenzo [1,4]-dioxin-3-base, 2,3-dihydrobenzo [1,4]-dioxin-5-base, 2,3-dihydrobenzo [1,4]-dioxin-6-base, 2,6-dimethoxypyridin-3-base, 2,6-dimethoxypyridin-4-base, tetrahydro isoquinolyl, purine, 2, the 3-naphthyridine, pteridine, sulfo-four benzazoles, sulfo-three benzazoles, isothiazole and pyrazine, isothiazole and pyrimidine, method for preparation of pyrazolotriazine, pyrazolopyrimidine, Imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazo-triazine, the triazolo triazine, Triazolopyridine, Triazolopyrazine, triazolo pyrimidine, 4-[1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furan [2,3-c] pyridin-4-yl, 1-furan [2,3-c] pyridine-5-base, 1-furan [2,3-c] pyridin-3-yl, and Triazolopyridazines group.This heterocyclic group can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
Following compound is by being excluded in the general formula (Ih):
Figure A20078000923300471
Wherein
R 1The aryl alkyl of heteroaryl, aryl alkyl or replacement of representing aryl, heteroaryl, the replacement of hydrogen, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl, replacement independently;
R 2Expression-NR independently 3R 4,
Figure A20078000923300472
R 3Represent independently alkyl, cyclic hydrocarbon radical,-oxyl, alkylamine ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 4Represent alkyl, cyclic hydrocarbon radical,-oxyl, alkylamine, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
R 5Represent H, COR independently 6, CO 2R 6, SOR 6, SO 2R 6, SO 3R 6, alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkylamine ,-NR 7COR 6, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 6Represent independently H, alkyl, cyclic hydrocarbon radical ,-NH 2, alkylamine, aryl or heteroaryl;
R 7Represent independently H, alkyl, cyclic hydrocarbon radical,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, aryl or heteroaryl;
P is 0 or 1;
Q is 0 or 1;
X is CO or SO 2
Following substituting group preferred independent or combination in general formula (Ih):
The preferred S of X or O, more preferably S.
R 3aPreferred H.
In preferred embodiments, Z is CR 2' and R 1And R 2And connected C atom forms 6 yuan of saturated rings.In another embodiment preferred, Z is N and R 1And R 2And connected N atom forms 6 yuan of saturated rings.
R 9Preferred heteroaryl, aryl or benzyl, more preferably heteroaryl.R 9Also more preferably Thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolo pyrimidine.Even more preferably, R 9It is Thienopyrimidine.
T preferred 0.
R preferred 1.
R 2aPreferred OH, alkyl, aryl or heteroaryl, more preferably alkyl, especially methyl.
The invention still further relates to the acceptable salt of medicine or its medicine acceptable prodrugs or steric isomer that general formula (II) compound or itself and acid or alkali form,
Figure A20078000923300481
Wherein
R 1Be-C (O) R 7,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8Or-C (S) R 7
R 2Be H, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, alkyl amino, hydroxy alkylene amino or heteroaryl;
Perhaps R 1And R 2And connected N atom or C atom form together 3 yuan to 8 yuan, saturated or to undersaturated monocycle of small part or polycyclic member ring systems, on the wherein said ring at least one or a plurality of carbon atom are the heteroatomss that is selected from O, N or S, and described ring can be by one or more substituent R 9Replace;
R 3Be H ,-C (O) NR aR b, halogen, alkyl, halo alkyl, aryl, heteroaryl, OH, SH, NR 4' OR 5', NH 2, hydroxy alkylene amino, alkyl amino,-oxyl, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene or halo-oxyl;
R aBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R bRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeterocycle, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl, halogen, halo alkyl, halo-oxyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxy alkylene, hydroxy alkylene amino, aryl, heterocycle alkyl or heteroaryl;
R 6Be halogen ,-C (O) R 7,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8,-C (S) R 7,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 7', alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7', R 8Be independently H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-NH aryl, heteroaryl or aryl;
A is CO or SO 2
X is NR 2', O or S;
Y is N, CR 2If ' or Y be O then do not have R 6
Z is N or CR 2'; If Z is CH then X is O or NR 2'
R 2' be H, alkyl ,-C (O) NR 2,-C (O) R b, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
N is 0 to 2;
P is 1 to 6;
Q is 1 to 6;
R 9Represent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4a,-C (O) NR 7R 8,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, alkyl amino,-oxyl, sulfenyl, halogen, halo alkyl, halo-oxyl, hydroxy alkylene amino, hydroxy alkylene, hydroxyl cyclic hydrocarbon radical, aryl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl ,-(CH 2) pNR 7COR 8Or heteroaryl;
R 4', R 4", R 5' be independently H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 4aBe H, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
Wherein
If not explanation in addition, C 1-C 6Alkyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched to 5 carbon atoms, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, C 2-C 6Alkenyl group is represented the C of straight or branched 2-C 6Thiazolinyl, preferred 2 straight or brancheds to 6 carbon atoms, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, preferred 1 straight or branched, the C of straight or branched to 6 carbon atoms 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl group, they can be randomly by one or more substituent R ' replace;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
Heterocycle is represented heterocycle hydrocarbyl group or heteroaryl groups;
The cyclic hydrocarbon radical group represents to contain 3 to 8 carbon atoms, preferred 4 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group, and R ' as hereinbefore defined; Described C 3-C 8The cyclic hydrocarbon radical part can be selected from-encircle-C 3H 5,-ring-C 4H 7,-ring-C 5H 9,-ring-C 6H 11,-ring-C 7H 13,-ring-C 8H 15
The heterocyclic hydrocarbon basis representation contains 2 to 10 carbon atoms and at least one is selected from the heteroatomic non-aromatic ring system of O, N or S, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group as hereinbefore defined; Preferred heterocycle hydrocarbyl group is morpholine-4-base, piperazinyl, 1-alkyl piperazine-4-base, piperidyl, pyrrolidyl, azepan-1-base;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined; The preferred methoxyl group of described-oxyl group, oxyethyl group, isopropoxy, tert.-butoxy or pentyloxy;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement; Described halo hydrocarbyl group is preferred-C (R 10) 3,-CR 10(R 10') 2,-CR 10(R 10') R 10" ,-C 2(R 10) 5,-CH 2-C (R 10) 3,-CH 2-CR 10(R 10') 2,-CH 2-CR 10(R 10') R 10" ,-C 3(R 10) 7Or-C 2H 4-C (R 10) 3, R wherein 10, R 10", R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement; Described halo-oxyl is preferred-OC (R 10) 3,-OCR 10(R 10') 2,-OCR 10(R 10') R 10" ,-OC 2(R 10) 5,-OCH 2C (R 10) 3,-OCH 2CR 10(R 10') 2,-OCH 2CR 10(R 10') R 10" ,-OC 3(R 10) 7Or-OC 2H 4C (R 10) 3, R wherein 10, R 10', R 10" represent F, Cl, Br or I, preferred F;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined; The preferred benzyl of described aryl, phenyl ,-neighbour-C 6H 4-R ' ,--C 6H 4-R ' ,-right-C 6H 4-R ', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl, R ' is as hereinbefore defined;
Heteroaryl groups represents to contain heteroatomic five yuan or the hexa-member heterocycle group that at least one is selected from O, N or S.This heterocyclic group can condense with other aromatic ring.For example, this group can be selected from thiadiazoles, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base benzoxazole-2-base benzoxazole-4-base benzoxazole-5-base, benzoisoxazole-3-base, benzoisoxazole-4-base, benzoisoxazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, benzisothiazole-3-base, benzisothiazole-4-base, benzisothiazole-5-base, 1,2,5-thiadiazoles-3-base, the 1-imidazolyl, the 2-imidazolyl, 1,2,5-thiadiazoles-4-base, the 4-imidazolyl, benzoglyoxaline-4-base, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyranyl, the 3-pyranyl, the 4-pyranyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl, 2,4-dimethoxy-6-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, the 2-pyrazinyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,3,5-triazole-6-base, 2,4-dimethoxy-1,3,5-triazole-6-base, 1H-tetrazolium-2-base, 1H-tetrazolium-3-base, tetrazyl, acridyl, furazan, indazolyl, phenazinyl, carbazyl phenoxazine, indolizine, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl, the 1-pseudoindolyl, the 3-pseudoindolyl, the 4-pseudoindolyl, the 5-pseudoindolyl, the 6-pseudoindolyl, the 7-pseudoindolyl, the 2-indolinyl, the 3-indolinyl, the 4-indolinyl, the 5-indolinyl, the 6-indolinyl, the 7-indolinyl, benzo [b] furyl, the benzo furazan, benzimidazole thiophanate is for furazan, benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base, benzotriazole-7-base, phentriazine, benzo [b] thiophenyl, benzimidazolyl-2 radicals-Ji, the 1H-benzimidazolyl-, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, benzothiazolyl, quinazolyl, quinoxalinyl, cinnolines, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydrochysene-thieno-[3,4-d] imidazoles-2-ketone, pyrazolo [5,1-c] [1,2,4] triazine, 2,3-dihydrobenzo [1,4]-dioxin-2-base, 2,3-dihydrobenzo [1,4]-dioxin-3-base, 2,3-dihydrobenzo [1,4]-dioxin-5-base, 2,3-dihydrobenzo [1,4]-dioxin-6-base, 2,6-dimethoxypyridin-3-base, 2,6-dimethoxypyridin-4-base, tetrahydro isoquinolyl, purine, 2, the 3-naphthyridine, pteridine, sulfo-four benzazoles, sulfo-three benzazoles, isothiazole and pyrazine, isothiazole and pyrimidine, method for preparation of pyrazolotriazine, pyrazolopyrimidine, Imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazo-triazine, the triazolo triazine, Triazolopyridine, Triazolopyrazine, triazolo pyrimidine, 4-[1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furan [2,3-c] pyridin-4-yl, 1-furan [2,3-c] pyridine-5-base, 1-furan [2,3-c] pyridin-3-yl or Triazolopyridazines group.This heterocyclic group can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
In a preferred embodiment of the invention, in general formula (Ia) compound, Z is S, and Y is CO, and X is CO, and R is H, R cBe H and R 1Be aryl, benzyl or heteroaryl, R 2Be
Figure A20078000923300531
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In a preferred embodiment of the invention, in general formula (Ia) compound, Z is O, and Y is CO, and X is CO, and R is H, R cBe H and R 1Be aryl, benzyl or heteroaryl, R 2Be
Figure A20078000923300532
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In a preferred embodiment of the invention, in general formula (Ib) compound, Z is S, and Y is CO, X and R 1And R 4Form piperidine ring together, R aAnd R bBe H, R cBe H or methyl, R 2Be
Figure A20078000923300533
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In a preferred embodiment of the invention, in general formula (Ib) compound, Z is O, and Y is CO, X and R 1And R 4Form piperidine ring together, R aAnd R bBe H, R cBe H or methyl, R 2Be
Figure A20078000923300534
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In another preferred embodiment, in general formula (Ic) compound, r is 1, and Y is CO, and Z is O, and t is 0, and s is 1, and X is CO, R cBe H, methyl, ethyl, methoxyl group, alkyl amino, morpholinyl, N methyl piperazine, CF 3Or OCF, R 2Be
Figure A20078000923300535
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In another preferred embodiment, in general formula (Ic) compound, r is 1, and Y is CO, and Z is S, and t is 0, and s is 0, R cBe H, methyl, ethyl, methoxyl group, alkyl amino, morpholinyl, N methyl piperazine, CF 3Or OCF, R 2Be
Figure A20078000923300536
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In another preferred embodiment, in general formula (Ic) compound, r is 1, and Y is CO, and Z is S, and t is 0, and s is 1, and X is CO, R cBe H, methyl, ethyl, methoxyl group, alkyl amino, morpholinyl, N methyl piperazine, CF 3Or OCF, R 2Be
Figure A20078000923300541
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In another preferred embodiment, in general formula (Ic) compound, r is 1, and Y is CO, and Z is O, and t is 0, and s is 0, and Rc is H, methyl, ethyl, methoxyl group, alkyl amino, morpholinyl, N methyl piperazine, CF 3Or OCF, R 2Be
Figure A20078000923300542
And R 5Randomly be aryl, benzyl or the heteroaryl that replaces.
In general formula (III) compound, the preferred embodiments of the invention are general formula (IIIa) compound
R 3, R 4, R 5, R 7aWith Z as hereinbefore defined.
Preferably, R 3Be H, Me, OMe, CF 3, OCF 3, Cl, OH or SH, more preferably H, Me, OMe, CF 3, OCF 3, more preferably H also.
Preferably, Z is N.
Preferably, R 4Be H.
Preferably, R 7aBe aryl or heteroaryl, more preferably aryl, also more preferably phenyl.Further preferably, R 7aBy one or two substituent R ' replace, more preferably by a substituent R ' replace.In particularly preferred embodiments, R 7aIt is the 2-Trifluoromethoxyphen-l.In another particularly preferred embodiment, R 7aIt is the 2-p-methoxy-phenyl.In another particularly preferred embodiment, R 7aIt is the 2-chloro-phenyl-.And in another particularly preferred embodiment, R 7aIt is the 2-aminomethyl phenyl.
Preferably, R 5Be aryl or heteroaryl, more preferably heteroaryl.Described heteroaryl preferably contains 2 nitrogen-atoms and preferred especially 2-imidazolyl or 2-benzimidazolyl-, also more preferably 2-benzimidazolyl-.In another embodiment preferred, described heteroaryl contains 1 nitrogen-atoms and 1 sulphur atom and preferred especially 2-thiazolyl or 2-[4-morpholinodithio base, also more preferably 2-[4-morpholinodithio base.Described heteroaryl is further preferably by 1 to 4 substituent R ' replace, more preferably by 1 or 2 substituent R ' replace.In particularly preferred embodiments, R 5Be 5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji.In another particularly preferred embodiment, R 5Be 5,6-dimethyl-1H-benzothiazole-2-base.
Preferably, R ' is-SO 2-alkyl ,-NO 2, halogen ,-CO 2H ,-OH, halo-oxyl,-oxyl or alkyl.R ' is preferred especially: methylsulfonyl, nitro, fluorine, chlorine, bromine, carboxyl, hydroxyl, trifluoromethoxy, methoxyl group, oxyethyl group, methyl, ethyl or trifluoroethyl.
In an embodiment preferred, X is O.In another embodiment preferred, X is S.Also in another embodiment preferred, X is NR 2'.
In the preferred embodiment of general formula (IIIa) compound, R 3Be H, methyl, methoxyl group, CF 3Or OCF 3R 4, R 5, R 7aAs defined above; X is NR 2', O or S; And Z as defined above.
In general formula (III) compound, another preferred embodiment of the present invention is general formula (IIIa) compound, R 7a=-NH-aryl.
In general formula (III) compound, another preferred embodiment of the present invention is general formula (IIIb) compound,
Figure A20078000923300551
Wherein
R 3Be H, methyl, methoxyl group, CF 3Or OCF 3R 5As defined above; X is NR 2', O or S; If Z is N then X is NR 2', O or S; If Z is CR 2' then X be O; Y ' is O or NR 2', R 2' as hereinbefore defined.
In general formula (III) compound, another preferred embodiment of the present invention is general formula (IIIc) compound,
Figure A20078000923300561
Wherein
R 11, R 12Represent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl hydroxy alkylene, hydroxyl cyclic hydrocarbon radical, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl, aryl alkyl or heterocycle; R 4', R 4", R 5' as hereinbefore defined; R 3Be H, methyl, methoxyl group, CF 3Or OCF 3X is NR 2', O or S; R 4As hereinbefore defined;
R 7And R 7' as hereinbefore defined; R 11', R 12' represent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl hydroxy alkylene, hydroxyl cyclic hydrocarbon radical, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl, aryl alkyl or heterocycle; And R 4', R 4", R 5' as hereinbefore defined.
In general formula (III) compound, the preferred embodiment of the present invention is general formula (IIId) compound,
Figure A20078000923300571
Wherein
R 3Be H, methyl, methoxyl group, CF 3Or OCF 3X is NR 2', O or S; R 4As hereinbefore defined; R 7And R 7' as hereinbefore defined; Y " and R 11', R 12' such as in the above general formula (IIIc) definition; Y ' is O or NR 2' and R 2' as hereinbefore defined.
In general formula (III) compound, another preferred embodiment of the present invention is general formula (IIIe) compound,
Wherein
R 3, R 4And R 5As hereinbefore defined; X is O or S; R 11And R 12Such as in the above general formula (IIIc) definition; And if Z is N, X is NR 2', O or S; If Z is CH, X is O.
In general formula (III) compound, another preferred embodiment of the present invention is general formula (IIIf) compound,
Figure A20078000923300581
Wherein
Z is N or CH; R 3Be H, methyl, methoxyl group, CF 3Or OCF 3X is NR 2', O or S; R 4As hereinbefore defined; R 7And R 7' as hereinbefore defined; R 2' as hereinbefore defined; Y " and R 11, R 11', R 12, R 12' such as in the above general formula (IIIc) definition.
The preferred embodiment of the invention is general formula (Iha) compound,
Figure A20078000923300582
Wherein
R 1Be COR 7a
R 2And R 3aBe H;
A is NH;
R 7As hereinbefore defined;
Z is N;
X is NR 2', O or S;
R 3Be H, methyl, ethyl, methoxyl group, amine, alkylamine, morpholinyl, N methyl piperazine, CF 3Or OCF 3
T is 0;
R is 1; And
R 2aRandomly be aryl, benzyl or the heteroaryl that replaces.
In general formula (Ih) compound, another embodiment preferred of the present invention is general formula (Iha) compound, wherein R 7aRandomly be aryl, benzyl or the heteroaryl that replaces.
In general formula (Ih) compound, another embodiment preferred of the present invention is general formula (Ihb) compound,
Figure A20078000923300591
Wherein
R 3aBe H;
A is NH;
X is NR 2', O or S;
Y ' is O or NR 2';
R 2' as hereinbefore defined;
R 3Be H, methyl, ethyl, methoxyl group, amine, alkylamine, morpholinyl, N methyl piperazine, CF 3Or OCF 3
T is 0;
R is 1; And
R 2aRandomly be aryl, benzyl or the heteroaryl that replaces.
In general formula (Ihb), following substituting group preferred independent or combination:
The preferred CR of Z 2'.
The preferred NR of Y ' 2'.In an embodiment preferred, the NR of Y ' 2' in R 2' preferably replace or unsubstituted heteroaryl.In another embodiment preferred, the NR of Y ' 2' in R 2' be aryl.Also in another embodiment preferred, the NR of Y ' 2' in R 2' be benzyl.In a more preferred embodiment, the NR of Y ' 2' in R 2' be pyrimidine or triazine.In another preferred embodiment, the NR of Y ' 2' in R 2' be that replace or unsubstituted bicyclic heteroaryl, more preferably Thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolo pyrimidine, also more preferably Thienopyrimidine.
In preferred embodiments, X is S.In another embodiment preferred, X is O.Also in another embodiment preferred, X is NR 2'.
R 3Preferred H.
R 2aPreferred aryl groups or heteroaryl, more preferably phenyl.
In general formula (Ih) compound, another preferred embodiment of the present invention is general formula (Ihe) compound,
Figure A20078000923300601
Wherein
R 3aBe H; A is NH; X is NR 2', O or S;
R 11And R 12Represent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl hydroxy alkylene, hydroxyl cyclic hydrocarbon radical, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl, aryl alkyl or heterocycle;
R 4', R 4", R 5' as hereinbefore defined;
R 2' as hereinbefore defined;
R 3Be H, methyl, ethyl, methoxyl group, amine, alkylamine, morpholinyl, N methyl piperazine, CF 3Or OCF 3
T is 0;
R is 1; And
R 2aRandomly be aryl, benzyl or the heteroaryl that replaces.
In general formula (Ihe), following substituting group preferred independent or combination:
The preferred CR of Z 2'.
In preferred embodiments, X is S.In another embodiment preferred, X is O.Also in another embodiment preferred, X is NR 2'.
R 11Preferably-H ,-CN ,-OH, halogen, halo alkyl, halo-oxyl, more preferably-CN.
R 12Preferred H.
R 2aPreferred aryl groups or heteroaryl, more preferably phenyl.
In general formula (II) compound, the preferred embodiment of the invention is general formula (IIa) compound,
Figure A20078000923300611
Wherein
R 1And R 2As hereinbefore defined; Z as hereinbefore defined; X is O or S; R 3Be H, methyl, methoxyl group, CF 3Or OCF 3R 11And R 12Such as in the above general formula (IIIc) definition.
In general formula (II) compound, the preferred embodiment of the present invention is general formula (IIb) compound,
Figure A20078000923300621
Wherein
R 1And R 2As hereinbefore defined; Z as hereinbefore defined; X is O or S; R 3Be H, methyl, methoxyl group, CF 3Or OCF 3
In general formula (II) compound, another preferred embodiment of the present invention is general formula (IIc) compound,
Figure A20078000923300622
Wherein
X is O or S; R 3Be H, methyl, methoxyl group, CF 3Or OCF3; Y ' is NR 2'.
In general formula (II) compound, another preferred embodiment of the present invention is general formula (IId) compound,
Figure A20078000923300631
Wherein
Z as hereinbefore defined; R 3Be H, methyl, methoxyl group, CF 3Or OCF 3R 11, R 11' and R 12, R 12' as hereinbefore defined.
In addition, the invention provides the method for preparing The compounds of this invention, for example general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) preparation method of compound.
Can obtain general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound by several different methods.
Can prepare piperidin-4-yl-thiazole-4-carboxyl methane amide by the several different methods of describing in the document.Such example is as Houben-Weyl, suitable 2 described in 2002,730, the oxidation of 5-thiazoline.Thiazoline also can be synthetic by the method described in the same reference document, or by You, S., Razavi, H., Kelly, J.W.Angew.Chem.2003,115,87 or Katritzky, AR., Cai, C, Suzuki, K., Singh, SK.J.Org.Chem.2004,69, the method described in the reference of 811-814 and these two pieces of papers is synthetic.Other method is at Yasuchika, S.et al.Heterocycles, and Vol.57, No.5 describes in 2002.
On heterocycle, have more the general formula of multi-substituent (II), (Ic) and (III) compound can obtain by the method described in the following document: Organic Syntheses, Coll, Vol.9, p.155; And Vol.74, p.229; J.Org.Chem., 1975, Vol.40, No.10,1521; J.Am.Chem.Soc.96:19/1974 September 18; J.Org.Chem., 1990,55,4484-4487; ChemischeBerichte 1968,101 (1), 302-307; Agricultural Chemistry and Biotechnology, 2002,45 (1), 37-42.
The substituent a kind of possible synthetic method of the benzoglyoxaline of the replacement of general formula (III) is at Synthesis, and 2006,4, describe among the 597-602.
A kind of possible synthetic method (referring to scheme 1) of general formula (IIIa, c and IIa, b) compound is included under the classical acid amides coupling condition, for example HBTU, iPr 2NEt, DMF, 0 ℃ to room temperature, make logical formula V compound and the reaction of general formula (VI) compound with acquisition intermediate (VII).Another selection of this step can be (V) and with (VI) corresponding acyl chloride reaction to obtain (VII).In second step, compound (VII) with the saponification of 1M NaOH solution, is almost obtained the acid of expecting (VIII) quantitatively.This step also can realize under acidic conditions.At last, with above-mentioned steps 1 similarly, another acid amides coupling step (with primary amine or secondary amine) is finished the synthetic of type (IIIa, c and IIa and b) compound.
Figure A20078000923300641
Synthesizing of scheme 1 type (IIIa, c) and (IIa, b) derivative
Relating to structure (IIIb, d, e, f) compound and structure (IIc, d) compound can be synthetic according to the method shown in the scheme 2.Here, heterocycle (IX) obtains bicyclic diester (XI) with bromo compound (X) by affine substitution reaction, and the saponification under condition standard and known of this bicyclic diester is acid (XII) then, finishes this with another as above scheme 1 described coupling step and synthesizes.
Figure A20078000923300651
Synthesizing of the derivative of scheme 2 types (IIIb, d, e, f) and (IIc, d), wherein Z=N
If Z=CH, according to the scheme of scheme 3 general introduction easily composite structure be the compound of (IIIb, d, e, f) and (IIc, d) type, wherein, heterocycle (XIII) is converted into compound (XV) by the cyclocondensation step.After the saponification reaction, (XVI) obtained desired product (IIIb, d, e, f) or (IIc, d) with the amine coupling.
Figure A20078000923300661
The derivative of scheme 3 types (IIIb, d, e, f) and (IIc, d) synthetic, Z=CH
2 bit strips at thiazole ring have the substituent The compounds of this invention of piperidin-4-yl for example to pass through as following scheme preparation.This synthetic route has partly been described in WO 2004/058750.
Figure A20078000923300662
2-(1-(tertbutyloxycarbonyl) piperidin-4-yl) thiazole-4-carboxylic acid can be by being converted into suitable R with HBTU, DIPEA coupling in DMF 1Acid amides.Different R 1Amine is commercially available or can easily synthesizes.The Boc protecting group can be removed under standard conditions, for example handles 2 hours to 3 hours with usefulness 4N HCl in TFA processing 2 hours to 3 hours or the Zai diox under 0 ℃.Then, the acyclic derivatives HCl salt of deprotection can followingly be converted into corresponding amide, urea and N-heterocyclic analogs.
The piperidinyl compounds that urea replaces can be by synthesizing with commercially available isocyanic ester coupling in the presence of DIPEA.The piperidinyl compounds of heterocyclic substituted can be synthetic by standard method, for example in the presence of alkali with chloro-substituted heterocyclic ring coupling accordingly.Perhaps, the piperidinyl compounds of heterocyclic substituted can obtain by palladium mediated cross-coupling.As more selection, Tetrahydrothienopyriderivatives derivatives can pass through HBTU coupling method and piperidinyl compounds coupling.
2 bit strips at thiazole ring have another route of the substituent The compounds of this invention of piperidin-4-yl shown in following scheme.
Figure A20078000923300671
Can under standard conditions, remove the Boc protecting group, for example under 0 ℃, handle 2 hours to 3 hours with usefulness 4N HCl in TFA processing 2 hours to 3 hours or the Zai diox.Then, the acyclic derivatives HCl salt of deprotection can be converted into the corresponding N heterocyclic analogs by aforesaid several different methods.
For above general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound, term " steric isomer " is meant suitable/anti-or E/Z isomery.More specifically, the possible two keys that are present in the various substituting groups of The compounds of this invention can be E or Z configuration.These pure or impure geometrical isomers form general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) intact part of compound individually or with form of mixtures.Term " steric isomer " also comprise produce by the existence of one or more symmetry axis in the molecule and/or symmetry centre and cause light beam rotation, independent or as whole isomeric forms of mixture.More specifically, it comprises pure or as the enantiomer and the diastereomer of form of mixtures.
The general formula that uses according to the present invention (Ia), (Ib), (Ic), (Ih), (II) or (III) compound can form salt with mineral acid or organic acid or alkali.The example of the acceptable salt of medicine includes but not limited to nontoxic inorganic salt or organic salt, for example derived from the acetate of acetate, aconitate derived from equisetic acid, ascorbate salt derived from xitix, benzoate derived from benzic acid, cinnamate derived from styracin, Citrate trianion derived from citric acid, embonate derived from pamoic acid, enanthate derived from enanthic acid, formate derived from formic acid, fumarate derived from fumaric acid, glutaminate derived from L-glutamic acid, oxyacetate derived from oxyacetic acid, muriate derived from hydrochloric acid, derived from hydrobromic bromide, lactic acid salt derived from lactic acid, maleate derived from toxilic acid, mesylate derived from methylsulfonic acid, naphthalene-2-sulfonic acid salt derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphoric acid salt derived from phosphoric acid, phthalate derived from phthalic acid, derived from salicylic salicylate, sorbate derived from Sorbic Acid, derived from stearic stearate, succinate derived from succsinic acid, derived from vitriolic vitriol, derived from tartaric tartrate, derived from the right-tosylate of right-toluenesulphonic acids and other.Such salt can produce by the method that well known to a person skilled in the art and describe in the prior art.
Be not regarded as acceptable other the salt of medicine, for example derived from the oxalate of oxalic acid, can be suitable for as producing general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) intermediate of compound or the acceptable salt of its medicine or its medicine acceptable prodrugs or its steric isomer.
As implied above, the present invention comprises the acceptable salt of medicine, also comprises to allow general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound appropriate separation or crystalline salt, for example with the salt of Chiral Amine gained.
Above general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound also comprise the prodrug of these compounds.Term used herein " prodrug " is meant such compound: in case when being given the patient, himself not pharmaceutical activity (" prodrug "), but in vivo, promptly in the object that compound gives, it chemically and/or biologically is converted into the form (general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound) of its pharmaceutical activity.Prodrug comprises, for example, compound of the present invention, wherein, hydroxyl, amine or mercapto groups form hydroxyl, amine or sulfydryl with decomposing when giving the patient arbitrary group combines.Therefore, the representative instance of prodrug includes but not limited to acetate/ester, formate/ester and the benzoate/ester derivative of alcohol, sulfydryl and the amine functional group of The compounds of this invention.In addition, (situation COOH) can be used ester, for example methyl esters, ethyl ester, dibasic acid esters etc. for carboxylic acid.Ester can be self active and/or be can be in the body of human body hydrolysis under the condition.
Compound of the present invention and medicine prepared therefrom be generally used for treating the cell proliferation illness, be used for the treatment of or epidemic prevention disease and disease condition (for example inflammatory diseases, nerve immunity disease, autoimmune disorder or other).
The compounds of this invention can be used for treating the disease that is caused by malignant cell propagation, for example solid tumor, leukemia and lymphoma.Therefore, the system change that The compounds of this invention and medicine prepared therefrom are generally used for regulating cell activation, cell proliferation, cell survival, cytodifferentiation, cell cycle, cell maturation and necrocytosis or are used for inducing metabolism, for example variation in sugar, lipid or the Proteometabolism.It can also be used to keep cell and produce, be included in cell depleting or the growth of the hemocyte after the cytoclasis that causes owing to for example toxic agent, radiation, immunotherapy, growth defect, malnutrition, malabsorption, immunoregulatory abnormality, anaemia etc. and produce (short hemoposieis), perhaps be used to provide tissue generation and the therapeutic control of degraded and the therapeutic correction of cell and organizational protection and hemocyte stable state.
These diseases and disease condition include but not limited to cancer, for example neoplastic hematologic disorder (leukemia for example, lymphoma, myelomatosis) or (mammary gland for example of solid tumor, prostate gland, liver, bladder, lung, esophagus, stomach, colorectum, apparatus urogenitalis, stomach and intestine, skin, pancreas, brain, the uterus, colon, H﹠N portion, uterine neck and ovary, melanoma, astrocytoma, small cell lung cancer, glioma, rodent cancer and squamous cell carcinoma, as Kaposi sarcoma and osteosarcomatous sarcoma) or be used for the treatment of by suppressing the disease that one or more kinases and/or Phosphoric acid esterase are treated or alleviated.Compound of the present invention and medicine prepared therefrom are particularly useful for treating prostate cancer, melanoma, ovarian cancer and multiple myeloma.
" treatment " among the present invention means cure diseases wholly or in part or alleviates disease or stop the progress of given disease.
Therefore, in one embodiment, the present invention relates to general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound or the acceptable salt of its medicine or medicine acceptable prodrugs or steric isomer, if desired, being used for the treatment of or preventing hyper-proliferative with keratinocyte and/or T cell in generation with suitable adjuvant and additive is purposes in the medicament of disease of feature, described disease is inflammatory conditions and immune disorders especially, preferably is selected from Addison's disease, alopecia areata, ankylosing spondylitis, hemolytic anemia, pernicious anemia, aphtha, aphthous stomatitis, sacroiliitis, the arteriosclerotic illness, osteoarthritis, rheumatoid arthritis, aspermiogenese, bronchial asthma, autoimmunity asthma, the autoimmune hemolytic anemia disease, black Qi Teshi disease, sarcoidosis, inflammatory bowel, Burkitt lymphoma, Crohn's disease, choroiditis, ulcerative colitis, celiac disease, cryoglobulinemia, dermatitis herpetiformis, dermatomyositis, the type i diabetes of insulin-dependent, juvenile diabetes, idiopathic diabetes insipidus, insulin-dependent diabetes mellitus, the autoimmunity demyelinating disease, dupuytren's contracture, encephalomyelitis, allergic encephalitis, phacoanaphylactic endophthalmitis, allergy enteritis, auto immune enteropathy syndrome, ENL, idiopathic facial palsy, chronic fatigue syndrome, rheumatic fever (febris rheumatica), glomerulonephritis, goodpasture's syndrome, Graves disease, Hei-lining Er Shi disease, Hashimoto's disease, Hashimoto thyroiditis, sudden hearing disappearance, sensorineural hearing loss, chronic hepatitis, Hodgkin, paroxysmal hemoglobinuria, hypogonadism, Crohn, iritis, leukopenia, leukocytosis, lupus erythematosus disseminatus, systemic lupus erythematous, lupus erythematosus,cutaneous, lymphogranuloma malignum, infectious monocytosis, myasthenia gravis, transverse myelitis, the primary idiopathic myxedema, nephrosis, sympathetic ophthalmia, granulomatous orchitis, pancreatitis, pemphigus, pemphigus vulgaris, polyarteritis nodosa, the primary chronic polyarthritis, polymyositis, acute polyneuroradiculitis, psoriasis, purpura, PG, quervain's thyroiditis, Reiter syndrome, sarcoidosis, the ataxia sclerosis, progressive systemic sclerosis, scleritis, sclerodesmia, multiple sclerosis, disseminated sclerosis disease, acquired splenatrophy, the infertility that causes by antisperm antibody, thrombopenia, primary thrombocytopenic purpura, thymoma, acute anterior uveitis, vitiligo, such as xerodermosteosis and AIDS, HIV, the disease that SCID is relevant with epstein-Barr virus, with virus (AIDS or EBV) relevant B cell lymphoma, such as leishmanial parasitosis, and the immunosuppressive disease state of the virus infection after transplanting such as allograft, AIDS, cancer, the chronic active hepatitis diabetes, toxic shock syndrome, TSS or food poisoning.
Compound of the present invention and medicine prepared therefrom especially can be used for treating autoimmune disease and inflammatory diseases, for example rheumatoid arthritis, multiple sclerosis, inflammatory bowel (especially colitis and Crohn's disease), inflammatory dermatosis (especially neurodermatitis and psoriasis) and lupus erythematosus.
In addition, the present invention relates to treatment or prophylactic method, it comprises (Ia) of significant quantity, (Ib), (Ic), (Ih), (II) or (III) compound or the acceptable salt of its medicine or medicine acceptable prodrugs or steric isomer administration.
The present invention also provides pharmaceutical composition, and it comprises the general formula (Ia), (Ib), (Ic), (Ih), (II) of free form or acceptable salt of medicine and medicine acceptable prodrugs form or (III) compound and for this reason medicine acceptable diluent or carrier.
In preferred embodiments, the present invention relates to general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound or the acceptable salt of its medicine or medicine acceptable prodrugs or steric isomer, if desired, be used for the treatment of or prevent purposes in the dermopathic medicine that T cell wherein works with suitable adjuvant and additive in generation, described tetter especially preferably is selected from psoriasis, atopic dermatitis, alopecia areata, alopecia capitis totalis, inferior whole alopecia (alopecia subtotalis), alopecia universalis, dispersivity alopecia (alopecia diffusa), lupus erythematosus,cutaneous, lichen planus, dermatomyositis, atopic eczema, local scleroderma, sklerodermia, psoriasis, head psoriasis (psoriasis capitis), guttate psoriasis, abnormality psoriasis (psoriasis inverse), snakelike alopecia areata, androgenetic alopecia, the supersensitivity contact eczema, the pungency contact eczema, contact eczema, pemphigus vulgaris, lobate pemphigus, pemphigus vegetans, cicatricial mucosal pemphigoid (scarring mucosalpemphigoid), bullous pemphigoid, mucus pemphigoid (mucous pemphigoid), dermatitis, dermatitis herpetiformis dermatitis herpetiformis (dermatitis herpetiformis duhring), urticaria, necrobiosis lipoidica, erythema nodosum, Vidal lichen (lichen vidal), prurigo simplex, prurigo nodularis, prurigo temporanea, linear IgA dermatosis, polymorphism daylight tetter, sun erythema, lichen albus of Von Zumbusch, skin rash, drug rash, the chronic progressive external purpura, dyshidrotic eczema, eczema, the fixed drug rash, the photoallergy skin reaction, eriorale haplolichen (lichen simplexeriorale), dermatitis and " graft versus host disease (GVH disease) ", acne, acne erythematosa, scarring, keloid and vitiligo.
In addition, compound of the present invention can be used in the disease that treatment is caused by the ischemic and/or the reperfusion injury of the part of organ and/or health, the part of described organ and/or health is selected from heart, brain, the periphery limbs, kidney, liver, spleen or lung, and/or wherein said endothelial function disturbance and the infraction that is selected from such as myocardial infarction, the disease of critical limb ischemia is relevant, and/or wherein said endothelial function disturbance be selected from ischemic disease, the disease of myocardial infarction or organ ischemic disease is relevant, described ischemic disease is the peripheral arterial occlusive disease for example, as serious shank local asphyxia; Described organ such as kidney, spleen, brain, lung.
Compound of the present invention can also be used for prevention and treatment nervous system disorders or illness (with brain or neural system diseases associated or illness), includes but not limited to alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Lewy body, amyotrophic lateral sclerosis, apoplexy, epilepsy, multiple sclerosis, myasthenia gravis, huntington's chorea, mongolism, nerve deafness and Meniere.Other nervous system disorders and illness are conspicuous for those skilled in the art and are included in and are used for definition of the present invention.Compound of the present invention and medicine prepared therefrom are particularly useful for treating apoplexy, reperfusion injury and alzheimer's disease.
Compound of the present invention can also be used for the disease that humans and animals is caused by protozoal infections.This class livestock or the pathogenic protozoon of people preferably push up intracellular reactive parasite, especially trypanosoma, plasmodium, leishmania, babesia and Taylor worm, Cryptosporidium, sarcocystis section, amoeba worm, coccidium and the Trichomonadida of multiple door or Sarcomastigophora.The quartan malaria that vivax malaria that these active substances or corresponding medicine be particularly suitable for treating the estivoautumnal fever that caused by plasmodium falciparum, caused by Plasmodium vivax or Plasmodium ovale and treatment are caused by malariae.The leishmaniasis of the coccidiosis that it also is suitable for treating the toxoplasmosis that caused by toxoplasma gondii, caused by for example Isospora belli, the intestines sarcosporidiasis that causes by the sarcocystis suihominis, the dysentery that causes by entamoeba histolytica, the cryptosporidiosis that causes by Cryptosporidium parvum, the chagas disease that causes by schizotrypanum cruzi, the nona that causes by Bu Shi trypanosoma rhodesiense or Bu Shi castellanella gambiense, epidermis and internal organ and other form.It also is suitable for treatment and infects the pathogenic protozoic animal of livestock, and the pathogenic protozoon of described livestock for example causes the pathogenic agent of East Coast fever, theileria parva; Cause the pathogenic agent of domestic animal tsetse fly disease in Africa, trypanosoma confusum the Congo subspecies or trypanosoma uniforme every other day subspecies, trypanosoma bocagei nominate subspecies; Cause the trypanosoma bocagei Yi Shi subspecies of surra; Cause the pathogenic agent of texas fever in domestic animal and the buffalo, Babesia bigemina; Cause the pathogenic agent of this parasitosis of BABEI of European Niu Babeisi parasitosis and dog, cat and sheep, babesia bovis; Cause the pathogenic agent of the sarcosporidiasis of sheep, domestic animal and pig, the sheep dog lives sarcocystis and Sarcocystis ovifelis; Cause the pathogenic agent of domestic animal and birds cryptosporidiosis, Cryptosporidium; Cause in rabbit, domestic animal, sheep, goat, pig and the birds, especially pathogenic agent, eimeria and the isospora of the coccidiosis in chicken and the turkey.The compounds of this invention especially is preferred for treating coccidiosis or malaria infection, perhaps is used to prepare the medicine or the feed that are used for the treatment of these diseases.This treatment can be preventative or curative.When the treatment malaria, The compounds of this invention can combine with other anti-malarial reagent.
Compound of the present invention can also be used to prevent and/or treat the infectious diseases that is caused by bacterium and virus or the like, comprise in the Mammals, comprise the opportunistic infection among the mankind.Described method comprises with the amount that effectively prevents and/or treats described infectious diseases and/or opportunistic infection and gives at least a general formula of Mammals (Ia), (Ib), (Ic), (Ih), (II) or (III) compound and/or the acceptable salt of its medicine.
Described infectious diseases can be selected from AIDS, hydatid disease,alveolar (AHD, hydatidosis), loeschiasis (infection due to Entamoeba histolytica), infection by Angiostrongylus, anisakiasis, anthrax, this parasitosis of BABEI (babesia infection), the pouch ciliate infects (balantidiasis), Baylisascaris infects (racoon roundworm), Schistosoma (schistosomiasis), blastocystis infects (blastomycosis), Boreliosis, botulism, Brainerd diarrhoea (Brainerd Diarrhea), brucellosis, BSE (bovine spongiform encephalopathy), moniliosis, capillariasis (capillaria infection), CFS (chronic fatigue syndrome), chagas disease (American trypanosomiasis), varicella (varicella zoster virus), infection involving chlamydia pneumoniae, cholera, chronic fatigue syndrome, CJD (Creutzfeldt-Jakob disease), clonorchiasis (Clon infection), CLM (cutaneous larva migrans, hookworm infection), coccidioidomycosis, conjunctivitis, coxsackie virus A16 (hand foot mouth disease), torulosis, Cryptosporidium infects (cryptosporidiosis), culex (west nile virus carrier), cutaneous larva migrans (CLM), circle sorosphere parasitosis (circle sorosphere insect infection), cysticercosis (neural cysticercosis), cytomegalovirus infection (CMV), step on leather/singapore hemorrhagic fever, Diplopylidium infects (the flea tapeworm of dog and cat), the Ebola virus hemorrhagic fever, hydatidosis (hydatid disease,alveolar), encephalitis, infection by Entamoeba coli, unbecoming infection by Entamoeba, entamoeba hartmanni infects, infection due to Entamoeba histolytica's (loeschiasis), entamoeba polecki infects, oxyuriasis (retrofection), enterovirus infection (non-poliomyelitis), epstein-Barr virus infects, coli-infection, the infection of food borne transmission, foot and mouth disease, mycotic dermatitis, gastroenteritis, A family streptococcicosis, B family streptococcicosis, infect the disease that causes by staphylococcus (streptococcus aureus and other staphylococcus kind), infect the disease that causes by Pseudomonas aeruginosa and other pseudomonas kind, the onion burkholderia infects, Hansen's disease (leprosy), Hantavirus pulmonary syndrome, head louse is infected (pediculosis), Helicobacter pylori infection, hemopathy, the Heng Dela virus infection, hepatitis, zoster (Herpes Zoster) (zoster (Shingles)), HIV infects, the human ehrlichiosis, the human parainfluenza virus infects, influenza, isosporiasis (isospora infection), lassa fever, leishmaniasis, kala-azar (kala-azar, infections with leishmaniasis), leprosy, lice (body louse, head louse, crab louse), Lyme disease, marburg hemorrhagic fever, measles, meningitis, mosquito-borne disease, mycobacterium avium mixture (MAC) infects, Naegleria infects, nosocomial infection, the avirulence Entamoeba intestinalis infects, onchocerciasis (river is blind), opisthorchiasis (Opisthorchis infection), microvirus infects, pestilence, PCP (pneumocystis carinii pneumonia), poliomyelitis, Q heat, rabies, respiratory syncytial virus (RSV) infects, rheumatic fever, Rift valley fever, river blind (onchocerciasis), rotavirus infection, roundworm infection, salmonellosis, Salmonella enteritidis, scabies, shigellosis, zoster, nona, smallpox, streptococcal infection, tapeworm (Tapeworm) infects (tapeworm (Taenia) infection), tetanus, toxic shock syndrome, pulmonary tuberculosis, ulcer (peptic ulcer disease), rift valley fever, vibrio parahemolyticus infection, Vibrio vulnificus infects, viral hemorrhagic fever, wart, water-borne communicable disease, west nile virus infects (west nile encephalitis), Whooping cough, yellow jack.Compound of the present invention and medicine prepared therefrom are used in particular for treating virus disease, for example hepatitis B, hepatitis C, influenza infection (especially influenza a virus infection), AIDS (HIV infection) and human papillomaviral infection.
Compound of the present invention and medicine prepared therefrom also are used in particular for treating atherosclerosis.
Compound of the present invention and medicine prepared therefrom also are used for the treatment of osteoporosis especially.
In one embodiment, the present invention relates to that compound of the present invention or composition be used for the treatment of or prevent with the cell hyperproliferation in preparation is purposes in the medicine of disease of feature.
In one embodiment, the present invention relates to compound of the present invention or composition is used for the treatment of or prevents by the purposes in the medicament of the local asphyxia of the part of organ and/or health and/or the disease that reperfusion injury causes in preparation, the part of described organ and/or health is selected from heart, brain, the periphery limbs, kidney, liver, spleen and lung, and/or wherein said endothelial function disturbance and the infraction that is selected from such as myocardial infarction, the disease of critical limb ischemia is relevant, and/or wherein said endothelial function disturbance be selected from ischemic disease, diseases such as myocardial infarction or organ ischemic disease are relevant.
In one embodiment, the present invention relates to compound of the present invention or composition and be used for the treatment of or prevent purposes in the medicament of nervous system disorders or illness in preparation, described nervous system disorders or illness are selected from alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Lewy body, amyotrophic lateral sclerosis, apoplexy, epilepsy, multiple sclerosis, myasthenia gravis, huntington's chorea, mongolism, nerve deafness and Meniere.
General formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound and the acceptable salt of medicine thereof can itself as therapeutical agent, with mutual form of mixtures or with pharmaceutical dosage forms to animal, preferred mammal, and be specially the mankind, dog and chicken and carry out administration, described pharmaceutical preparation allows in the intestines or intestines use outward, and comprise at least a general formula (Ia), (Ib), (Ic), (Ih), (II) of effective dose or (III) compound or its salt add vehicle and additive that common medicine is harmless as activeconstituents.General formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound can also be with the form administration of its salt, described salt can obtain by single compound is separately reacted with physiologically acceptable bronsted lowry acids and bases bronsted lowry.
Contain general formula of the present invention (Ia), (Ib), (Ic), (Ih), (II) or (III) compound medicine production and use and can carry out according to known pharmaceutical methods.
When the form that when the general formula of the present invention (Ia) that is used for the treatment of, (Ib), (Ic), (Ih), (II) or (III) compound can undressed compound is carried out administration, preferably with one or more adjuvants, vehicle, carrier, damping fluid, thinner and/or other conventional pharmaceutical auxiliary agent, randomly, introduce this activeconstituents with the form of physiologically acceptable salt in pharmaceutical composition.Such salt of described compound can be anhydrous or solvation.
In preferred embodiments, the invention provides and contain general formula of the present invention (Ia), (Ib), (Ic), (Ih), (II) or (III) compound or the acceptable salt of its medicine or its medicine acceptable prodrugs or its steric isomer, together with its one or more medicine acceptable carriers, and randomly, other treats and/or prevents the medicine of composition.Carrier must be " acceptable " mean with preparation in other composition be compatible and harmless to its acceptor.
Medicine of the present invention can be suitable for oral, rectum, segmental bronchus, intranasal, part, oral cavity, hypogloeeis, through the medicine of skin, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal intravenously, intra-arterial, the brain, intraocular injection or injection) administration, or be suitable for by inhalation or insufflation administration, comprise pulvis and liquid aerosol administration, or pass through the medicine of the form of slow-releasing system administration.The suitable example of slow-releasing system comprises the solid hydrophobic polymkeric substance semipermeability matrix that contains The compounds of this invention, and described matrix can be the form of setting goods, for example film or microcapsule.
Therefore, compound of the present invention can be inserted medicament forms and unitary dose thereof together with adjuvant, carrier or the thinner of routine.Such form comprises solid form, especially the form of tablet, filled capsules, pulvis and pill; And liquid form, especially moisture or water-free solution, suspension, emulsion, elixir and the capsule of filling same substance, it all can be used for the suppository of oral, rectal administration and is used for parenteral sterile injectable solution.Such medicine and unit dosage thereof can comprise the conventional ingredient of conventional ratio, contain or do not contain extra active compound or key element, and such unit dosage can comprise the activeconstituents with the corresponding any suitable effective dose of intended dose scope every day that will use.
Available compound of the present invention can be with multiple oral or parenteral dosage forms administration.For those skilled in the art apparently, following formulation can comprise general formula of the present invention (Ia), (Ib), (Ic), (Ih), (II) or (III) compound or the acceptable salt of its medicine or steric isomer as active ingredient.
For by general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) compound medicament, the medicine acceptable carrier can be solid or liquid.But the preparation of solid form comprises pulvis, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and it can also be as thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or packaged material.
In pulvis, described carrier is the ground solid in the mixture that forms with the ground active ingredient.In tablet, described active ingredient and the carrier with necessary adhesive capacity are with suitable mixed and be compressed the shape and size that are required.Suitable carriers is magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt point paraffin, cocoa wet goods.Terms " formulation " is intended to comprise active compound and as the preparation that the packaged material of capsular carrier is provided, wherein contain or carrier-free described active ingredient suppressed by vector around and therefore combine with it.Equally, also comprise cachet and lozenge.Tablet, pulvis, capsule, pill, cachet and lozenge can use as the solid form that is suitable for oral administration.
In order to prepare suppository, at first will be such as the fusing of the low melt point paraffin of fatty glyceride mixt or theobroma oil, then with described active ingredient homodisperse therein, for example by stirring.Then the impouring of fused uniform mixture is made things convenient in the mould of size, therefore cooling also solidifies.The composition that is suitable for vagina administration can be rendered as vaginal suppository, tampon, emulsifiable paste, gel, paste, foams or sprays, wherein also contains suitable carriers as known in the art except activeconstituents.Liquid preparation comprises solution, suspension and emulsion, for example water or water-propylene glycol solution.For example, the liquid preparation of parenteral injection can be formulated as the solution in the aqueous solution of polyglycol solution.
Therefore, general formula of the present invention (Ia), (Ib), (Ic), (Ih), (II) or (III) compound can be formulated as be used for administered parenterally (for example by injection, as bolus injection or continue perfusion) and can be rendered as in ampoule, prefilled syringe, low capacity perfusion or with the unit dosage of sanitas in multi-dose container that adds.Described composition can be taked such as the suspension in oiliness carrier or aqueous carrier, solution or emulsion form, and can comprise the prescription reagent such as suspension agent, stablizer and/or dispersion agent.Perhaps, described activeconstituents can powder form be used suitable carriers before use, for example aseptic, pyrogen-free water preparation, and described pulvis obtains by the aseptic separation of sterile solid or by freeze-drying from solution.
Can be by water-soluble appropriate colouring agent, spices, stablizer and the thickening material of adding as required then of active ingredient be prepared and is suitable for the oral aqueous solution.Can be suitable for oral aqueous suspension, described cohesive material for example natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine or other known suspension agent by the ground active ingredient is scattered in to prepare in the water together with cohesive material.
The preparation that also comprises solid form, plan is translated into the liquid absorption member that is used for oral administration before use soon.Such liquid form comprises solution, suspension and emulsion.Except active ingredient, these preparations also can comprise tinting material, spices, stablizer, buffer reagent, synthetical and natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc.
In an embodiment of the present invention, described pharmaceutical topical application or whole body used or by these two kinds of approach in conjunction with application.
In particularly preferred embodiment of the present invention, with described pharmaceutical topical application.Reduced possible side effect like this and the treatment of necessity has been limited in the zone of those infection.
Preferably, with described medication preparation be the forms such as emulsifiable paste, liposome, carrier, paste or pulvis of ointment, gel, gypsum, emulsion, lotion, foam, mixed phase or amphipathic emulsion system (oil/water-water/oily mixed phase).
For example, ointment and emulsifiable paste can and add suitable thickening and/or jelling agent and preparing with water-based or butyrous alkali.Lotion can and also comprise one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material usually with the preparation of water-based or butyrous alkali.
Be suitable for that topical drug delivery composition comprises in mouth: lozenge, it comprises promoting agent in being generally the fragrance matrix of sucrose and Sudan Gum-arabic or tragacanth; Pastille, it comprises activeconstituents in the inert base such as gelatin and glycerine or sucrose and Sudan Gum-arabic; And mouth wass, it comprises composition alive in suitable liquid carrier.
By ordinary method, for example use dropper, transfer pipet or atomizer, solution or suspension directly are applied to nasal cavity.Can single dose or the multiple doses form described composition is provided.For the situation of the multiple doses form of dropper or transfer pipet, this can give solution suitable, that preestablish volume or suspension by the patient and realize.For the situation of atomizer, this can realize by the method for for example measuring atomisation pump (metering atomising spray pump).
Administration to respiratory tract also can realize by the method for aerosol, wherein in pressurized package, provide described active ingredient with suitable propelling agent, described propelling agent is chlorofluorocarbon (CFC) for example, as Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Described aerosol also can contain tensio-active agent, for example Yelkin TTS expediently.Drug dose can be controlled by metering valve is provided.
Perhaps, can provide described activeconstituents by dry powder form, the powdered mixture of for example described compound of described dry powder in suitable powder matrix, described powder matrix for example lactose, starch, such as the starch derivative and the polyvinylpyrrolidone (PVP) of Vltra tears.Expediently, described powder carrier can form gel at nasal cavity.Described powder composition can unit dosage exists, and for example in capsule or cartridge case such as gelatin, or is present in the Blister Package, and the mode that powder can be by sucker is by this Blister Package administration.
In the composition of the plan that comprises intranasal compositions to respiratory tract administration, described compound has smaller particle size usually, for example 5 microns or the littler order of magnitude.Such particle diameter can obtain by means commonly known in the art, for example by micronization.
When needed, can use the composition that is adapted to provide the activeconstituents slowly-releasing.
Pharmaceutical preparation is preferably unit dosage form.In such form, preparation is subdivided into the unitary dose of the active ingredient that contains appropriate amount.Unit dosage form can be the preparation of encapsulation, and this packing contains discrete amount of formulation, for example the tablet that encapsulates in medicine bottle or ampoule, capsule and pulvis.Unit dosage form self can also be capsule, tablet, cachet or lozenge, and perhaps it can be any these dosage forms packing forms, suitable quantity.Composition is preferred for the tablet or the capsule of oral administration and is used for intravenous administration and continues dabbling liquid.
Make up a prescription and the more details of medicine-feeding technology be found in latest edition Remington ' sPharmaceutical Sciences (Lei Mingdun pharmacopedics) (Maack Publishing Co.Easton, Pa.).
Pharmaceutical composition also can comprise two or more general formulas (Ia), (Ib), (Ic), (Ih), (II) or (III) material of acceptable salt and other therapeutic activity on compound or its pharmacology.
Therefore, compound of the present invention can use or be used in combination with other active compound with the form of independent a kind of compound, for example use, thereby under one situation of back, noticed useful additional scale effect with the known drug regimen that can be used for treating aforementioned diseases.Appropriate vol to human administration can be 5mg to 500mg.
Can use in the pharmacy inert inorganic excipients or organic excipients to prepare described pharmaceutical preparation.For example, can use lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt to wait tablet and the hard gelatin capsule for preparing pill, tablet, dressing.The vehicle that is used for soft gelatin capsule and suppository is for example fat, wax, semisolid and liquid polyol, natural or sclerosis wet goods.The suitable vehicle that is suitable for producing solution and syrup is for example water, sucrose, Nulomoline, glucose, polyvalent alcohol etc.The suitable vehicle that is suitable for producing injection solution is for example water, alcohol, glycerine, polyvalent alcohol or vegetables oil.
Described dosage can change in wide range, and should be at the morbid state of the adaptation individuality under every kind of individual instances.To such use, suitable dosage will change according to administering mode, disease specific state and required effect to be treated.Yet the dose rates at about 1mg/kg to 100mg/kg the weight of animals, preferred 1mg/kg to 50mg/kg the weight of animals can obtain satisfied effect usually.Usually, be applicable to large mammal for example people's dose rates be about 10mg/ days to 3g/ days the order of magnitude, be administered once every day easily, with separate doses administration every day 2 to 4 times, or with the slowly-releasing form administration.
Usually, under the oral administration situation, the per daily dose of the about 10mg to 5000mg of each human individual, preferred 50mg to 500mg is suitable.Under the situation of other administering mode, per daily dose also is similar scope.Carry for the part, depend on skin perviousness, disease type and seriousness and depend on preparation type and frequency of administration, the active compound of different concns can be enough to cause result of treatment by topical application in the medicine.Preferably, the concentration of the active compound in medicine of the present invention or the acceptable salt of its medicine or neurological progression derivative or its steric isomer is 1 μ mol/l to 100mmol/l.
Comprise following embodiment and Tu with the explanation preferred embodiment of the invention.It will be understood by those skilled in the art that disclosed technology is represented technology that the present inventor finds, operational excellence in practice of the present invention in following examples, and therefore can be considered as the optimal way of its practice.Yet, it will be appreciated by those skilled in the art that the spirit and scope of the present invention that in disclosed specific embodiments, can make a lot of changes and state in not departing from as additional claim according to present disclosure.The reference of all references all is incorporated herein by reference.
Embodiment
Abbreviation: min, minute; H, hour; R.t., room temperature; T-, uncle-.
NMR spectrum: Bruker Avance 300MHz.Use the residual solvent peak as interior mark (DMSO-d 6, δ H=2.49; CD 3OD, δ H=3.31; CDCl 3, δ H=7.26; CD 3CN, δ H=1.93; (CD 3) 2CO, δ H=2.05), 300MHz ( 1H-NMR) write down spectrogram respectively.
Analyze LC/ESI-MS:2x Waters 600 multi-solvent delivery systems.50 μ l sample introduction circles.Chromatographic column, (Merck, Darmstadt), 50 * 4.6mm has 2 μ m prefilters (Merck) to Chromolith Speed ROD RP18e.Elutriant A, H 2O+0.1%HCO 2H; Elutriant B, MeCN.Gradient, 5%B to 100%B in the 5min; Flow velocity, 3ml/min.The single level Four bar of the WatersLCZ mass spectrograph that has electrospray ionization source.The MS method, MS8minPM-80-800-20V; Just/and negative ion mode scanning, m/z 80 to 800 in the 1s; Kapillary, 3.5kV; Awl voltage, 20V; Multiplier voltage, 400V; Probe and desolvation gas temperature are respectively 120 ℃ and 350 ℃.The two λ absorption photometric detectors of Waters2487 are set to 254nm.
Preparation HPLC-MS: have the Waters 600 multi-solvent delivery systems that prepare pump head.2000 μ l or 5000 μ l sample introduction circles.Chromatographic column, Waters X-Terra RP18,7 μ m, 19 * 150mm has 7 μ m, the X-Terra RP18 guard column of 19 * 10mm; Under the flow velocity of 20ml/min, use, perhaps YMC ODS-A,
Figure A20078000923300801
40 * 150mm has 7 μ m, the X-TerraRP18 guard column of 19 * 10mm; Under the flow velocity of 50ml/min, use.Supplementing solvent: MeCN-H 2O-HCO 2H80: 20: 0.05 (v: v: v).Elutriant A, H 2O+0.1%HCO 2H; Elutriant B, MeCN.Be adapted to sample, adopt the not synteny gradient of 5% to 100% elutriant B.Volume injected: 500 μ l-2000 μ l, depend on sample.The single level Four bar of the Waters ZQ mass spectrograph that has electrospray ionization source.Positive ion or negative ion mode scanning, m/z 80 to 800 in the 1s; Kapillary, 3.5kV or 3.0kV; Awl voltage, 20V; Multiplier voltage, 400V; Probe and desolvation gas temperature are respectively 120 ℃ and 350 ℃.Have (mass-triggered fraction collection) Waters fraction collector II that quality causes garbage collection.Waters 996 photodiode array detectors.
Synthesizing of 4-(methoxyl group-methyl-formamyl)-piperidines-1-carboxylic acid tert-butyl ester
With piperidines-1, (1.0eq 21.8mmol) is dissolved in 35ml exsiccant N, in the dinethylformamide to the 4-dicarboxylic acid list tert-butyl ester under inert conditions.Add O, N-dimethyl-hydroxylamine hydrochloride (1.03eq, 22.5mmol), benzotriazole-1-alcohol monohydrate (1.03eq, 22.5mmol) and triethylamine (1.5eq, 32.7mmol).Reaction mixture is chilled to 0 ℃, in 10 minutes time, add N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride (1.0eq, 21.8mmol) then with mixture at 0 ℃ of following vigorous stirring 1h and at r.t. vigorous stirring 18h.
Solvent removed in vacuo also is suspended in resistates in the 400ml ethyl acetate.Organic layer is also extracted 2 times with 100ml salt solution for 3 times with 100ml 1M citric acid, aqueous sodium carbonate extraction, use MgSO 4Dry also filtration.Except that desolvating and, obtaining 80% yield by the distillation purifying resistates.
Synthesizing of 4-formyl radical-piperidines-1-carboxylic acid tert-butyl ester
(1.0eq 16.4mmol) is dissolved in the 100ml exsiccant tetrahydrofuran (THF) with 4-(methoxyl group-methyl-formamyl)-piperidines-1-carboxylic acid tert-butyl ester under inert atmosphere.In the time of 1h, in this solution, dropwise adding lithium aluminum hydride (3.0eq, 49.6mmol) suspension in the 70ml dry tetrahydrofuran under-50 ℃.During adding mixture, temperature remains on-50 ℃, allows it to be warming up to 0 ℃ then in 3h.
This mixture is chilled to-78 ℃ also with the careful cancellation of 100ml 1M citric acid.This mixture is warming up to r.t. and uses the dilution of 400ml ethyl acetate.Separate each mutually and with water with 70ml ethyl acetate extraction 3 times.The organic layer that merges is also used 100ml salt solution extraction 2 times 3 times with 100ml 1M citric acid, aqueous sodium carbonate extraction, use MgSO 4Dry also filtration.Except that desolvating and, obtaining 85% yield by the distillation purifying resistates.
Synthesizing of 4-(4-ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidines-1-carboxylic acid tert-butyl ester
(1.0eq 13mmol) is dissolved in 40ml toluene with 4-formyl radical-piperidines-1-carboxylic acid tert-butyl ester under inert conditions.In this solution, add the L-ethylcysteine hydrochloride (1.6eq, 21mmol) and triethylamine (1.6eq, 21mmol).With this mixture backflow 14h.Remove the water of generation with Dean-Si Tuoke water trap.
Except that desolvating and resistates being dissolved in the 100ml ethyl acetate.Organic layer is also extracted 2 times with 50ml salt solution for 3 times with 50ml 1M citric acid, potassium bicarbonate aqueous solution extraction, use MgSO 4Dry also filtration.Except that desolvating and using 4: 1 gradient of PE/EA to come the purifying resistates by silica gel chromatography.Yield: 75%.
Synthesizing of 4-(4-ethoxycarbonyl-thiazol-2-yl)-piperidines-1-carboxylic acid tert-butyl ester
(1.0eq 8.7mmol) is dissolved in 160ml toluene with 4-(4-ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidines-1-carboxylic acid tert-butyl ester under inert conditions.In this solution, add MnO 2(15.0eq, 130mmol).To react and under agitation be heated to 70 ℃ and keep 5h.Wash filtering agent 3 times with this mixture of diatomite filtration and with 30ml toluene and ethyl acetate.The organic layer that vacuum distilling merges.Use 95: 5 gradient of DCM/MeOH to come the purifying resistates by silica gel chromatography.Yield: 30%.
The C-end is functionalized
(1.0eq 2.9mmol) is dissolved in the 40ml diox with 4-(4-ethoxycarbonyl-thiazol-2-yl)-piperidines-1-carboxylic acid tert-butyl ester under rare gas element.Under agitation dropwise add the 1.5ml 2NNaOH aqueous solution through 10min.At room temperature stir this mixture 2h then.
With 2N HCl neutralize this reaction and vaporising under vacuum solvent.Resistates is dissolved in the 50ml ethyl acetate.Organic layer is extracted 3 times with 10ml 1M citric acid and water, use MgSO 4Dry also filtration.Remove and desolvate and the vacuum-drying resistates.Yield: 95%.
Under inert conditions, 4-(4-carboxyl-thiazol-2-yl)-piperidines-1-carboxylic acid tert-butyl ester (1eq) is dissolved in exsiccant N,N-DIMETHYLACETAMIDE (0.03mmol/ml).In this solution, add arylamines or alkylamine (1eq), diisopropylethylamine (2eq) and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (2eq).Reaction mixture is stirred 12h under r.t..
Solvent removed in vacuo also is dissolved in ethyl acetate with resistates.Organic layer is extracted 3 times and extracts 2 times with salt solution with 1M citric acid, potassium bicarbonate aqueous solution, use MgSO 4Dry also filtration.Except that desolvating and using 95: 5 gradient of DCM/MeOH to come the purifying resistates by silica gel chromatography.Yield: 40% to 80%.
The N-end is functionalized
Under inert conditions, handle the substrate (concentration is 0.03mmol substrate in the 1mLHCl/ diox) of N protection and under r.t., stir 2h with 4M HCl/ diox.
Solvent removed in vacuo obtains the HCl salt of unhindered amina under situation about not being further purified.
Under inert conditions, this unhindered amina compound (1eq) is dissolved in exsiccant N,N-DIMETHYLACETAMIDE (0.03mmol/ml).In this solution, be sequentially added into aryl carboxylic acid or hydrocarbon carboxylic acids (1eq), diisopropylethylamine (2eq) and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (2eq), and reaction mixture stirred 12h under r.t..
Solvent removed in vacuo also is dissolved in ethyl acetate with resistates.Organic layer is extracted 3 times and extracts 2 times with salt solution with 1M citric acid, potassium bicarbonate aqueous solution, use MgSO 4Dry also filtration.Except that desolvating and using 95: 5 gradient of DCM/MeOH to come the purifying resistates by silica gel chromatography.Yield: 40% to 80%.
The type (III) and (II) universal synthesis method of compound
Type (IIIa), (IIIc), (IIa) and (IIb) synthetic operation of compound
With 7.3 * 10 -4Mol benzoic acid derivative (VI) is dissolved among the 5ml DMF and adds 1eq.H ü nig ' s alkali, with reaction mixture stirred for several minute, adds 1eq.HBTU then and restir 2min under r.t..Add 1eq.2-amino-thiazolyl--4-carboxylic acid, ethyl ester then, under uniform temp, this mixture stirring is spent the night.Then, by removing by filter solvent and resistates being dissolved in the 5ml diox once more, use 0.5ml 1M NaOH solution-treated then.After reacting completely, pH is reduced to 1-2, product of filtering-depositing (VII) and vacuum-drying with 1M HCl solution.For next step, intermediate (VII) is dissolved in 3ml DMF and adds 1eq.H ü nig ' s alkali, with reaction mixture stirred for several minute, add 1eq.HBTU then and restir 2min under r.t..The amine component that adds 1eq. then spends the night this mixture stirring under uniform temp.Then, by removing by filter solvent and thick product being dissolved in the 10ml ethyl acetate once more, with 10ml citric acid (1M solution), the saturated NaHCO of 10ml 3Solution and 10ml water washing 2 times.Then with organic phase evaporation and use MgSO 4Dried residue.Remove and desolvate, finish final purifying by aforesaid preparation HPLC then.
As second kind of variation of first step, can use 1.1eq.H ü nig ' s alkali that the corresponding chloride derivative of (VI) and 2-amino-thiazolyl--4-carboxylic acid, ethyl ester (1: 1) are reacted.
The synthetic operation of type (IIIb, d, e, f) and (IIc, d) compound
With 6.3 * 10 -4Mol 2-bromo-thiazole-4-carboxylic acid ethyl ester (X) and the various piperazines of 2.2eq. (IX) are dissolved in 10ml THF, and its backflow is spent the night.Solvent removed in vacuo is also by pTLC (PE/EE2/1) purifying resistates then.
With aforesaid type (IIIa) and (IIIc) synthesis step of compound finish reaction second the step and the 3rd step.
For the synthetic schemes of type (IIIb, d, e, f and IIc, the d) compound of Z=CH, referring to WO 2004/058750.
The exemplary compounds of general formula of the present invention (Ia) includes, but are not limited to following:
Compound Title Quality LC/(+)- ESI-MS： Biological activity 1)
74 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (7-fluoro-2,3-dihydro-benzo [1,4] dioxin-5-yl)-acid amides 619 620 [M+H] + ++
75 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (2,3-dihydro-benzo [1,4] dioxin-6-yl)-acid amides 601 602 [M+H] + ++
76 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (5-Methyl-2-trifluoromethyl-furans-3-yl)-acid amides 615 616 [M+H] + ++
77 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (2-thiophene-2-base-ethyl)-acid amides 577 578 [M+H] + +++
78 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid Isopropamide 509 510 [M+H] + +
79 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (2-trifluoromethoxy-phenyl)-acid amides 627 628 [M+H] + +++
80 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (3-methoxyl group-phenyl)-acid amides 573 574 [M+H] + +
81 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (3,4,5-trimethoxy-phenyl)-acid amides 633 634 [M+H] + ++
114 4-(4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carbonyl)-phenyl cyanide 568 569 [M+H] + +
134 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid phenyl acid amides 543 544 [M+H] + +
142 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (3-fluoro-phenyl)-acid amides 561 562 [M+H] + ++
143 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperidines-1-carboxylic acid (4-fluoro-phenyl)-acid amides 561 562 [M+H] + +
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
["+" expression 50% to 80% suppresses, and " ++ " expression 80% to 90% and " +++" expression 90% to 100% suppress]
The exemplary compounds of general formula of the present invention (Ib) includes, but are not limited to following:
Compound Title Quality LC/(+)- ESI-MS： Biological activity 1)
103 2-{5-methyl-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-yl }-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl ketone 640 641 [M+H] + ++
128 1-[4-(3-chloro-phenyl)-piperazine-1-yl]-2-{5-methyl-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-yl }-ethyl ketone 606 607 [M+H] + +++
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
["+" expression 50% to 80% suppresses, and " ++ " expression 80% to 90% and " +++" expression 90% to 100% suppress]
The exemplary compounds of general formula of the present invention (Ic) includes, but are not limited to following:
Compound Title Quality LC/(+)- ESI-MS： Biological activity 1)
150 [1-(5-chloro-2-methylamino-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-yl]-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-yl }-ketone 654 655 [M+H] + ++
160 1-{4-[4-(6,7-dihydroxyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-thiazol-2-yl]-piperidines-1-yl }-2-(4-fluoro-phenyl)-ethyl ketone 495 496 [M+H] + +
161 1-{4-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-thiazol-2-yl]-piperidines-1-yl }-2-(4-fluoro-phenyl)-ethyl ketone 523 524 [M+H] + +
163 1-{4-[4-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-thiazol-2-yl]-piperidines-1-yl }-2-(4-fluoro-phenyl)-ethyl ketone 463 464 [M+H] + +
232 1-{4-[4-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-thiazol-2-yl]-piperidines-1-yl }-2-(4-fluoro-phenyl)-ethyl ketone 537 538 [M+H] + +
233 1-{4-[4-(6,7-dihydroxyl-1-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-thiazol-2-yl]-piperidines-1-yl }-2-(4-fluoro-phenyl)-ethyl ketone 509 510 [M+H] + +
234 1-{4-[4-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-thiazol-2-yl]-piperidines-1-yl }-2-(4-fluoro-phenyl)-ethyl ketone 537 538 [M+H] + +
235 1-(4-{4-[1-(5-chloro-2-methylamino-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl]-thiazol-2-yl }-piperidines-1-yl)-2-(4-fluoro-phenyl)-ethyl ketone 602 603 [M+H] + +
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
["+" expression 50% to 80% suppresses, and " ++ " expression 80% to 90% and " +++" expression 90% to 100% suppress]
The exemplary compounds of general formula of the present invention (II) includes, but are not limited to following:
Compound Title Quality LC/(+)- ESI-MS： Biological activity 1)
3 N-{4-[4-(4-fluoro-phenyl)-piperazine-1-carbonyl]-thiazole-2-yl }-2-trifluoromethoxy-benzamide 494 495 [M+H] + ++
5 N-[5-(4-pyrimidine-2-base-piperazine-1-carbonyl)-thiazole-2-yl]-2-trifluoromethoxy-benzamide 478 479 [M+H] + +
15 2-methoxyl group-N-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-benzamide 490 491 [M+H] + +++
16 3-fluoro-4-trifluoromethyl-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl } the piperidin-4-yl methyl)-benzamide 643 644 [M+H] + ++
17 3-cyclopentyl-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-propionic acid amide 577 578 [M+H] + ++
18 2-trifluoromethoxy-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-benzamide 641 642 [M+H] + ++
19 4-cyano group-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-benzamide 582 583 [M+H] + ++
20 [4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-2-[4-(4-trifluoromethyl-phenyl)-piperazine-1-yl]-thiazole-4-yl }-ketone 569 570 [M+H] + ++
21 2-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 585 586 [M+H] + +
22 2-[4-(2-trifluoromethoxy-benzyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 599 600 [M+H] + +++
23 2-[4-(4-bromo-benzyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 593 594 [M+H] + +++
24 2-[4-(3-trifluoromethoxy-benzyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 599 600 [M+H] + +++
32 2-trifluoromethoxy-N-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-benzamide 544 545 [M+H] + +++
33 3-cyclopentyl-N-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-propionic acid amide 480 481 [M+H] + +++
34 3-fluoro-4-trifluoromethyl-N-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-benzamide 546 547 [M+H] + +++
37 3-cyclopentyl-1-(4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperazine-1-yl)-third-1-ketone 549 550 [M+H] + +++
38 2-[4-(2-methoxyl group-benzoyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 559 560 [M+H] + +++
39 2-[4-(2-trifluoromethoxy-benzoyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 613 614 [M+H] + +++
41 N-{4-[4-(3,4-two chloro-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-2-trifluoromethoxy-benzamide 544 545 [M+H] + +++
44 N-{4-[4-(2-methoxyl group-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-2-trifluoromethoxy-benzamide 506 507 [M+H] + ++
55 1-(2-trifluoromethoxy-phenyl)-3-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-urea 559 560 [M+H] + +++
58 N-[4-(4-diphenyl-methyl-piperazine-1-carbonyl)-thiazole-2-yl]-2-trifluoromethoxy-benzamide 566 567 [M+H] + ++
59 2-[4-(3,5-Bis-trifluoromethyl-benzoyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 665 666 [M+H] + +
60 2-[4-(3-fluoro-4-trifluoromethyl-benzoyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 615 616 [M+H] + +++
61 4-(4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperazine-1-carbonyl)-phenyl cyanide 554 555 [M+H] + +++
62 4-(4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperazine-1-ylmethyl)-phenyl cyanide 540 541 [M+H] + +++
63 4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperazine-1-carboxylic acid tertiary butyl ester 525 526 [M+H] + ++
64 (2-piperazine-1-base-thiazole-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 425 426 [M+H] + +
65 2-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 531 532 [M+H] + ++
66 1-[4-(4-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-piperazine-1-yl)-phenyl]-ethyl ketone 543 544 [M+H] + ++
67 [4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-thiazole-4-yl }-ketone 569 570 [M+H] + +
68 [2-(4-phenyl-Piperazine-1-yl)-thiazole-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 501 502 [M+H] + +
69 2-[4-(4-fluoro-phenyl)-piperazine-1-yl]-thiazole-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 519 520 [M+H] + ++
71 (4-diphenyl-methyl-piperazine-1-yl)-[2-(4-benzyl-piperazine-1-yl)-thiazole-4-yl]-ketone 537 538 [M+H] + +++
72 [2-(4-benzyl-piperazine-1-yl)-thiazole-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 515 516 [M+H] + +++
99 3-fluoro-4-trifluoromethyl-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-benzamide 642 643 [M+H] + +
100 3-cyclopentyl-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-propionic acid amide 576 577 [M+H] + +
101 2-trifluoromethoxy-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-benzamide 640 641 [M+H] + +
102 4-cyano group-N-(1-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl }-the piperidin-4-yl methyl)-benzamide 581 582 [M+H] + +
241 2-[1-(2,6-dimethoxy-pyrimidine-4-yl)-piperidines-4-yl]-5-methoxyl group-oxazoles-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 576 577 [M+H +] ++
242 2-[1-(4,6-dimethoxy-[1,3,5] triazine-2-yl)-piperidin-4-yl]-5-methoxyl group-oxazoles-4-yl }-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 577 578 [M+H +] ++
243 2-[1-(2,6-dimethoxy-pyrimidine-4-yl)-piperidines-4-yl]-5-methoxyl group-oxazoles-4-yl }-[4-(5-trifluoromethyl-benzotriazole-1-yl)-piperidines-1-yl]-ketone 616 617 [M+H +] ++
244 2-[1-(4,6-dimethoxy-[1,3,5] triazine-2-yl)-piperidin-4-yl]-5-methoxyl group-oxazoles-4-yl }-[4-(5-trifluoromethyl-benzotriazole-1-yl)-piperidines-1-yl]-ketone 617 618 [M+H +] ++
245 4-(4-{4-[4-(5-trifluoromethyl-benzotriazole-1-yl)-piperidines-1-carbonyl]-thiazol-2-yl }-piperazine-1-base-methyl)-phenyl cyanide 580 581 [M+H]+ ++
246 (2-morpholine-4-base-azoles-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone 410 411 [M+H]+ +
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
["+" expression 50% to 80% suppresses, and " ++ " expression 80% to 90% and " +++" expression 90% to 100% suppress]
The exemplary compounds of general formula of the present invention (III) includes, but are not limited to following:
Compound Title Quality LC/(+)- ESI-MS： Biological activity 1)
1 2-morpholine-4-base-thiazole-4-carboxylic acid (5,6-dimethyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 357 358 [M+H] + +
2 2-[3-(2-trifluoromethoxy-phenyl)-urea groups]-thiazole-4-carboxylic acid (the 1H-benzimidazolyl-2 radicals-yl)-acid amides 462 463 [M+H] + +
4 2-(2-fluoro-benzamido)-thiazole-4-carboxylic acid (5,6-dimethyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 409 410 [M+H] + +
6 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-3,4-two fluoro-benzamide 441 442 [M+H] + ++
7 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-4-fluoro-benzamide 423 424 [M+H] + ++
8 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-Evil azoles-2-yl }-2-trifluoromethoxy-benzamide 473 474 [M+H] + +++
9 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid (4-dimethylamino-[1,3,5] triazine-2-yl)-acid amides 453 454 [M+H] + +
10 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-4-bromo-benzamide 483 484 [M+H] + ++
11 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-2-methoxyl group-benzamide 435 436 [M+H] + ++
12 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-2-trifluoromethoxy-benzamide 489 490 [M+H] + +++
13 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-2-[4-(2-trifluoromethoxy-benzoyl)-piperazine-1-yl]-thiazole-4-carbonyl }-guanidine 558 559 [M+H] + +
14 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-[2-(2,3-dihydro-benzo [1,4] dioxin-2-yl)-thiazole-4-carbonyl]-guanidine 420 421 [M+H] + +
25 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid (5,6-dimethyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 475 476 [M+H] + +++
26 2-(3-fluoro-4-trifluoromethyl-benzamido)-azoles-4-carboxylic acid ethyl ester 536 537 [M+H] + +++
27 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-Evil azoles-2-yl }-3-fluoro-4-trifluoromethyl-benzamide 475 476 [M+H] + +++
30 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-[2-(4-benzyl-piperazine-1-yl)-thiazole-4-carbonyl]-guanidine 460 461 [M+H] + +++
31 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid (the 1H-benzimidazolyl-2 radicals-yl)-acid amides 447 448 [M+H] + +++
36 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl }-guanidine 557 558 [M+H] + +++
40 2-(2-trifluoromethoxy-benzamido)-azoles-4-carboxylic acid (5,6-dimethyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 459 460 [M+H] + +++
42 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid [6-(4-methyl-piperazine-1-yl)-benzothiazole-2-yl]-acid amides 562 563 [M+H] + +++
43 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid (5-nitro-1H-benzimidazolyl-2 radicals-yl)-acid amides 492 493 [M+H] + +++
45 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-2-cyclohexyl-benzamide 487 488 [M+H] + +++
46 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid (1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-acid amides 461 462 [M+H] + +++
47 2-(2-trifluoromethoxy-benzamido)-thiazole-4-carboxylic acid [5-(propane-1-alkylsulfonyl)-1H-benzimidazolyl-2 radicals-yl]-acid amides 553 554 [M+H] + +++
49 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 371 372 [M+H] + +++
51 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-4-trifluoromethyl-benzamide 473 474 [M+H] + +++
52 2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carboxylic acid [5-(propane-1-alkylsulfonyl)-1H-benzimidazolyl-2 radicals-yl]-acid amides 621 622 [M+H] + +++
53 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-2-fluoro-4-trifluoromethyl-benzamide 491 492 [M+H] + +++
54 1-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-3-(2-trifluoromethoxy-phenyl)-urea 504 505 [M+H] + +++
56 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-3-fluoro-4-trifluoromethyl-benzamide 491 492 [M+H] + +++
57 N-{4-[N '-(the 1H-benzimidazolyl-2 radicals-yl)-the guanidine radicals carbonyl]-thiazol-2-yl }-2,6-two fluoro-benzamide 441 442 [M+H] + +++
91 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 371 372 [M+H] + +
250 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carbonyl }-guanidine 484 485 [M+H]+ ++
251 N-benzothiazole-2-base-N '-2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carbonyl }-guanidine 501 502 [M+H]+ ++
252 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-2-[4-(4-cyano group-benzyl)-piperazine-1-yl]-thiazole-4-carbonyl }-guanidine 485 485 [M+H]+ +++
253 N-{2-[4-(4-cyano group-benzyl)-piperazine-1-yl]-thiazole-4-carbonyl }-N '-(4-methyl-thiazol-2-yl)-guanidine 466 467 [M+H]+ ++
254 N-(4-methyl-thiazol-2-yl)-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 352 353 [M+H]+ +
255 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 371 372 [M+H]+ +++
256 N-benzothiazole-2-base-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 388 389 [M+H]+ +++
257 N-(the 1H-benzimidazolyl-2 radicals-yl)-N '-(2-morpholine-4-base-azoles-4-carbonyl)-guanidine 355 356 [M+H]+ ++
258 N-benzoxazole-2-base-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 372 373 [M+H]+ ++
259 N-(2-morpholine-4-base-thiazole-4-carbonyl)-N '-(5-nitro-benzoxazoles-2-yl)-guanidine 417 418 [M+H]+ ++
260 N-(5-methyl-benzoxazoles-2-yl)-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 386 387 [M+H]+ +
261 N-(5-chloro-benzoxazole-2-yl)-N '-(2-morpholine-4-base-thiazole-4-carbonyl)-guanidine 406 407 [M+H]+ ++
262 N-{2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carbonyl }-N '-(4-methyl-thiazol-2-yl)-guanidine 465 466 [M+H]+ +
263 N-(6-chloro-1H-benzimidazolyl-2 radicals-yl)-N '-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl }-guanidine 591 592 [M+H]+ +++
264 N-(5,6-two chloro-1H-benzimidazolyl-2 radicals-yl)-N '-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl }-guanidine 625 626 [M+H]+ ++
265 2-morpholine-4-base-thiazole-4-carboxylic acid [4-(5-trifluoromethyl-benzothiazole-2-yl)-phenyl]-acid amides 490 491 [M+H]+
266 2-morpholine-4-base-thiazole-4-carboxylic acid (5-benzothiazole-2-base-pyridine-2-yl)-acid amides 423 424 [M+H]+
267 2-morpholine-4-base-thiazole-4-carboxylic acid (4-benzothiazole-2-base-2-fluoro-phenyl)-acid amides 440 441 [M+H]+
268 2-morpholine-4-base-thiazole-4-carboxylic acid (4-benzothiazole-2-base-2-trifluoromethoxy-phenyl)-acid amides 506 507 [M+H]+
269 2-(1-furan [2,3-c] pyridin-4-yl-piperidin-4-yl)-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 548 549 [M+H]+
270 2-[1-(4,6-dimethoxy-[1,3,5] triazine-2-yl)-piperidines-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 570 571 [M+H]+
271 2-[1-(4,6-dimethoxy-[1,3,5] triazine-2-yl)-piperidines-4-yl]-thiazole-4-carboxylic acid's (5-fluoro-benzothiazole-2-yl)-acid amides 501 502 [M+H]+
272 2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 546 547 [M+H +] ++
273 2-(1-thieno-[3,2-d] pyrimidine-4-base-piperidin-4-yl)-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 565 566 [M+H +] ++
274 2-[1-(4,6-dimethoxy-[1,3,5] triazine-2-yl)-piperidines-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 570 571 [M+H +] +++
275 2-[1-(6-trifluoromethyl-pyrimidine-4-yl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazolyl-2 radicals-yl)-acid amides 577 578 [M+H +] ++
276 2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-oxyethyl group-1H-benzimidazolyl-2 radicals-yl)-acid amides 486 487 [M+H]+ +
277 2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-chloro-1H-benzimidazolyl-2 radicals-yl)-acid amides 476 477 [M+H]+ ++
278 2-[1-(4-cyano group-benzyl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5,6-two chloro-1H-benzimidazolyl-2 radicals-yl)-acid amides 510 511 [M+H]+ ++
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
["+" expression 50% to 80% suppresses, and " ++ " expression 80% to 90% and " +++" expression 90% to 100% suppress]
The exemplary compounds of general formula of the present invention (Ih) includes, but are not limited to following:
Compound Title Quality LC/(+)- ESI-MS： [M+H] + Biological activity
279 2-(1-(2,6-dimethoxypyridin-4-yl) piperidines-4-yl)-N-(6-(thiophene-3-carbonyl)-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 575 576 +
280 2-(1-(thieno-[3,2-d] pyrimidine-4-yl) piperidines-4-yl)-N-(6-(thiophene-3-carbonyl)-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 571 572 +++
281 2-(1-(4,6-dimethoxy-1,3,5-triazines-2-yl) piperidines-4-yl)-N-(6-(thiophene-3-carbonyl)-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 576 577 +++
282 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(2,6-dimethoxypyridin-4-yl) piperidin-4-yl) thiazole-4-carboxamide 569 570 +++
283 N-(5-ethanoyl benzo [d] thiazol-2-yl)-2-(1-(thieno-[3,2-d] pyrimidine-4-yl) piperidin-4-yl) thiazole-4-carboxamide 520 521 +++
284 N-(5-(3-fluoro-4-anisoyl) benzo [d] thiazol-2-yl)-2-(1-(thieno-[3,2-d] pyrimidine-4-yl) piperidines-4-yl) thiazole-4-carboxamide 630 631 +
285 N-(5-(4-hydroxy 3-methoxybenzene formyl radical) benzo [d] thiazol-2-yl)-2-(1-(thieno-[3,2-d] pyrimidine-4-yl) piperidin-4-yl) thiazole-4-carboxamide 628 629 +
286 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(thiophene-2-base alkylsulfonyl) piperidin-4-yl) thiazole-4-carboxamide 577 578 ++
287 N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(6,7-dimethoxyquinazoline-4-yl) piperidines-4-yl) thiazole-4-carboxamide 619 620 +++
288 N-(5-(3-anisoyl) benzo [d] thiazole-2-yl)-2-(1-(thieno-[3,2-d] pyrimidine-4-yl) piperidin-4-yl) thiazole-4-carboxamide 612 613 +
289 2-(1-(7H-purine-6-yl) piperidin-4-yl)-N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 549 550 +++
290 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(2,6-dichloropyridine-4-base formamyl) piperidin-4-yl) thiazole-4-carboxamide 619 620 +++
291 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(4-cyanopyridine-2-yl) piperidin-4-yl) thiazole-4-carboxamide 533 534 +
292 N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(4,6-dimethoxy-1,3,5-triazines-2-yl) piperidin-4-yl) thiazole-4-carboxamide 570 571 +++
293 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(thieno-[3,2-d] pyrimidine-4-yl) piperidin-4-yl) thiazole-4-carboxamide 565 566 ++
294 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(6-(trifluoromethyl) pyrimidine-4-yl) piperidin-4-yl) thiazole-4-carboxamide 577 578 ++
295 N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(4-cyano group benzyl) piperidin-4-yl) thiazole-4-carboxamide 546 547 ++
296 2-(1-([1,2,4] triazolo [1,5-a] pyrimidin-7-yl) piperidines-4-yl)-N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 549 550 +++
297 N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(the 2-methylpyrazole is [1,5-a] pyrimidin-7-yl also) piperidin-4-yl) thiazole-4-carboxamide 562 563 +++
298 4-{4-[4-(5-benzoyl-1H-benzimidazolyl-2 radicals-Ji formamyl)-thiazol-2-yl]-piperidines-1-yl }-5-methyl-pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid methyl ester 620 621 +
299 Methyl 7-(4-(4-(5-benzoyl-1H-benzo [d] imidazoles-2-base formamyl) thiazol-2-yl) piperidines-1-yl)-[1,2,4] triazolo [1,5-a] pyrimidine-2-carboxylicesters 607 608 ++
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
[EC50 of "+" expression 30 μ M to 100 μ M, the EC50 of " ++ " expression 10 μ M to 30 μ M and " +++" expression are less than the EC50 of 10 μ M]
The exemplary compounds of general formula of the present invention (IIIa) includes, but are not limited to following:
Compound Title Quality LC/(+/-)- ESI-MS： [M+H] + ([M-H] -) Biological activity 1)
300 2-(Isonicotinamide base)-N-(6-(methyl sulphonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 459 460 +
301 2-cinnyl amido-N-(6-(methyl sulphonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 484 485 +
302 2-(furans-2-formamido group)-N-(6-(methyl sulphonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 448 449 +
303 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(furans-2-formamido group) thiazole-4-carboxamide 381 382 +
304 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(Isonicotinamide base) thiazole-4-carboxamide 392 393 +
305 2-cinnyl amido-N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 417 418 +
306 Ethyl 2-(2-(2-(trifluoromethoxy) benzamido) thiazole-4-formamido group)-1H-benzo [d] imidazoles-6-carboxylicesters 519 518 [M-H] - +++
307 Ethyl 2-(2-(2-(trifluoromethoxy) benzamido) thiazole-4-formamido group) benzo [d] thiazole-6-carboxylicesters 536 535 [M-H] - ++
308 2-(2-chlorobenzoyl amino)-N-(6-(phenyl sulfenyl)-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 506 505 [M-H] - +
309 N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(2-chlorobenzoyl amino) thiazole-4-carboxamide 501 500 [M-H] - ++
310 Ethyl 2-(2-(2-chlorobenzoyl amino) thiazole-4-formamido group) benzo [d] thiazole-6-carboxylicesters 486 485 [M-H] - +
311 2-(2-chlorobenzoyl amino)-N-(6-(trifluoromethyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 482 481 [M-H] - ++
312 2-(2-chlorobenzoyl amino)-N-(4-methoxyl group benzo [d] thiazol-2-yl) thiazole-4-carboxamide 444 443 [M-H]- ++
313 2-(2-chlorobenzoyl amino)-N-(6-methyl benzo [d] thiazol-2-yl) thiazole-4-carboxamide 428 427 [M-H]- +++
314 2-(2-chlorobenzoyl amino)-N-(6-nitro benzo [d] thiazol-2-yl) thiazole-4-carboxamide 459 458 [M-H]- ++
315 2-(2-chlorobenzoyl amino)-N-(6-oxyethyl group benzo [d] thiazol-2-yl) thiazole-4-carboxamide 458 457 [M-H]- +
316 2-(2-chlorobenzoyl amino)-N-(6-hydroxy benzo [d] thiazol-2-yl) thiazole-4-carboxamide 430 429 [M-H]- ++
317 2-(2-chlorobenzoyl amino)-N-(6-methoxyl group benzo [d] thiazol-2-yl) thiazole-4-carboxamide 444 443 [M-H]- ++
318 2-(2-chlorobenzoyl amino)-N-(4-methyl benzo [d] thiazol-2-yl) thiazole-4-carboxamide 428 427 [M-H]- +
319 2-(2-chlorobenzoyl amino)-N-(the 6-fluorobenzene is [d] thiazole-2-yl also) thiazole-4-carboxamide 432 431 [M-H]- +++
320 2-(2-chlorobenzoyl amino)-N-(the 6-chlorobenzene is [d] thiazole-2-yl also) thiazole-4-carboxamide 448 447 [M-H]- +
321 N-(the 6-bromobenzene is [d] thiazol-2-yl also)-2-(2-chlorobenzoyl amino) thiazole-4-carboxamide 493 492 [M-H]- +
322 2-(2-chlorobenzoyl amino)-N-(the 4-chlorobenzene is [d] thiazole-2-yl also) thiazole-4-carboxamide 448 447 [M-H]- +++
323 2-(2-chlorobenzoyl amino)-N-(5,6-dimethylbiphenyl [d] thiazol-2-yl) thiazole-4-carboxamide 442 441 [M-H]- ++
324 2-(2-chlorobenzoyl amino)-N-(6-(trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 498 497 [M-H]- +++
325 2-(2-chlorobenzoyl amino)-N-(6-(methyl sulphonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 492 491 [M-H]- +
326 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(1-(thiophene-2-yl) hexanaphthene formamido group) thiazole-4-carboxamide 479 478 [M-H]- +
327 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(1-benzyl ring propionamido) thiazole-4-carboxamide 431 430 [M-H]- +
328 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(2,5-thioxene-3-formamido group) thiazole-4-methane amide 425 424 [M-H]- +
329 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(tetrahydrofuran (THF)-3-formamido group) thiazole-4-carboxamide 385 386 +
330 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(5-methyl-2-(trifluoromethyl) furans-3-formamido group) thiazole-4-methane amide 463 462 [M-H]- +
331 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(2-(dimethylamino) kharophen) thiazole-4-carboxamide 372 373 +
332 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(5-(morpholinyl methyl) furans-2-formamido group) thiazole-4-carboxamide 480 479 [M-H]- +
333 2-(2-(2-methoxybenzoyl amino) thiazole-4-formamido group) benzo [d] thiazole-6-carboxylic acid 454 453 [M-H]- +++
334 2-(2-methoxybenzoyl amino)-N-(6-(phenyl sulfenyl)-1H-benzo [d] imidazoles-2-yl) thiazole-4-carboxamide 501 502 ++
335 N-(4-(5,6-dimethyl-1H-benzo [d] imidazoles-2-base formamyl) thiazol-2-yl) thieno-[2,3-b] pyrazine-6-methane amide 449 448 [M-H]- +++
336 N-(5,6-dimethyl-1H-benzo [d] imidazoles-2-yl)-2-(2-morpholinyl Isonicotinamide base) thiazole-4-carboxamide 477 476 [M-H]- +
337 Ethyl 2-(2-(2-methoxybenzoyl amino) thiazole-4-formamido group) benzo [d] thiazole-6-carboxylicesters 482 481 [M-H]- +
338 N-(5-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 496 495 [M-H]- +++
339 2-(2-methoxybenzoyl amino)-N-(6-(trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 494 493 [M-H]- +++
340 2-(2-methoxybenzoyl amino)-N-(6-(trifluoromethyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 478 477 [M-H]- +
341 2-(2-methoxybenzoyl amino)-N-(4-methoxyl group benzo [d] thiazol-2-yl) thiazole-4-carboxamide 440 441 +++
342 2-(2-methoxybenzoyl amino)-N-(6-methyl benzo [d] thiazol-2-yl) thiazole-4-carboxamide 424 423 [M-H]- +
343 2-(2-methoxybenzoyl amino)-N-(6-nitro benzo [d] thiazol-2-yl) thiazole-4-carboxamide 455 454 [M-H]- +
344 N-(6-oxyethyl group benzo [d] thiazol-2-yl)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 454 453 [M-H]- +
345 Tertiary butyl 4-(5,6-dimethyl-1H-benzo [d] imidazoles-2-base formamyl) thiazol-2-yl carbamate 387 388 +
346 N-(6-methyl isophthalic acid H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 461 462 +++
347 N-(5-oxyethyl group-1H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 491 492 +++
348 N-(6-fluoro-1H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 465 466 +++
349 N-(1-ethyl-1H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 475 476 +++
350 N-(5-nitro-1H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 492 493 +++
351 N-(5-methyl-7-(trifluoromethyl)-[1,2,4] triazolo [1,5-a] pyrimidine-2-base)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 531 532 +
352 N-(6-benzoyl-1H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-methane amide 551 552 +
353 N-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 461 462 +++
354 N-(6-hydroxy benzo [d] thiazol-2-yl)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 426 425 [M-H]- +++
355 2-(2-methoxybenzoyl amino)-N-(4-methyl benzo [d] thiazol-2-yl) thiazole-4-carboxamide 424 425 +++
356 N-(the 6-fluorobenzene is [d] thiazol-2-yl also)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 428 429 +++
357 N-(the 6-bromobenzene is [d] thiazol-2-yl also)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 488 487 [M-H]- +++
358 N-(the 6-chlorobenzene is [d] thiazol-2-yl also)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 444 445 +++
359 N-(the 4-chlorobenzene is [d] thiazol-2-yl also)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 444 445 +++
360 N-(5,6-dimethylbiphenyl [d] thiazol-2-yl)-2-(2-methoxybenzoyl amino) thiazole-4-carboxamide 438 439 +++
361 2-(2-methoxybenzoyl amino)-N-(6-(trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 494 495 +++
362 2-(2-methoxybenzoyl amino)-N-(6-(methyl sulphonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 488 489 +++
363 2-{[2-(2-trifluoromethoxy-benzamido)-thiazole-4-carbonyl]-amino }-benzothiazole-6-carboxylic acid ethyl ester 536 537 ++
364 N-(6-hydroxy benzo [d] thiazol-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 480 481 ++
365 N-(the 6-chlorobenzene is [d] thiazol-2-yl also)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 498 499 ++
366 N-(the 6-fluorobenzene is [d] thiazol-2-yl also)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 482 483 +++
367 N-(the 6-bromobenzene is [d] thiazol-2-yl also)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 542 543 +++
368 N-(the 7-chlorobenzene is [d] thiazol-2-yl also)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 498 499 +
369 N-(6-(methyl sulphonyl) benzo [d] thiazole-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-methane amide 542 541 [M-H]- ++
370 N-(6-nitro benzo [d] thiazol-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 509 510 +
371 N-(5-nitro benzo [d] thiazol-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 509 510 +
372 N-(5-methoxyl group benzo [d] thiazol-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 494 495 +
373 N-(7-methoxyl group benzo [d] thiazol-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 494 495 +
374 N-(5-oxyethyl group benzo [d] thiazol-2-yl)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 508 509 +
375 2-(2-(trifluoromethoxy) benzamido)-N-(5-(trifluoromethyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 532 533 +
376 2-(2-(trifluoromethoxy) benzamido)-N-(5-(trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 548 549 +
377 N-(the 5-fluorobenzene is [d] thiazol-2-yl also)-2-(2-(trifluoromethoxy) benzamido) thiazole-4-carboxamide 482 481 [M-H]- +
1)Biological data is meant the result who is obtained by the test of NF-κ B inflammation.
[EC50 of "+" expression 30 μ M to 100 μ M, the EC50 of " ++ " expression 10 μ M to 30 μ M and " +++" expression are less than the EC50 of 10 μ M]
Proteasome is measured:
Use super microplate reader of Tecan (Tecan Ultra plate reader) and the Chymotrypsin activity of measuring 20S proteasome (Immatics, T ü bingen) as the Suc-LLVT-AMC (Bachem) of substrate.In the hole of black 96 hole polypropylene boards, the various inhibitor that 2 μ l are dissolved in DMSO mix with 50 μ l substrate solutions (the 25mM HEPES of 20 ℃ of following pH 7.5,0.5mM EDTA and Suc-LLVT-AMC) (with suitable concentration), then by adding 150 μ l proteasome solution (1.3 μ g/ml 20S proteasomes among the 25mM HEPES of 20 ℃ of following pH 7.5,0.5mM EDTA, 0.033% (w/v) SDS) initiation reaction.Use fluorescent spectrometry (excitation wavelength: 360nm down at 30 ℃; Emission wavelength: 465nm) follow the tracks of substrate hydrolysis 20min, calculate initial velocity then and be expressed as the variation of relative fluorescence unit's p.s. (RFU).
In order to measure IC 50Value (50% suppresses required inhibitor concentration) is used at least 4 kinds of different inhibitor concentration.Each data point record 3 times.Use the suitable procedure matched curve.
The T lymphopoiesis is measured:
To being excited the restraining effect of peripheral blood lymphocytes (PBMC).
Pass through ACCUSPIN TMSystem The help of-1077 pipes separates PBMC from healthy volunteer's blood, with its washing and with 10 6Cell/ml is suspended in the Da Shi that contains 10% foetal calf serum and 2mM glutamine once more and revises in the Yi Shi substratum (Dulbecco ' s modifiedEagle ' s medium).In the presence of testing compound or blank carrier, with 2 μ g/ml phytoh(a)emagglutinin irritation cells 72 hours.4h before incubation period finishes adds 5-bromo-2 '-uracil deoxyriboside (BrdU) with the mark proliferative cell.After hatching, by the centrifuging isolated cell and remove culture supernatant.The immunosorbent that connects with enzyme is tested and is quantized bonded BrdU.In order to measure IC 50Value (50% suppresses required inhibitor concentration) is used at least 4 kinds of different inhibitor concentration.Each data point record 3 times.Use the suitable procedure matched curve.
Based on the result who in T lymphopoiesis test, obtains, compound of the present invention be suitable for treating inflammatory diseases or with the T cell associated diseases.
Inhibition to the inflammation of NF-κ B inductive:
In order to measure the antiphlogistic activity of compound, use from Cell Culture Service GmBH's
Figure A20078000923301002
NINA tests immediately.This test is based on the reorganization A549-NF-κ B-SEAP report cell of pre-inoculation in 96 hole flat undersides.Because the transfection reporter gene of SEAP (excretory embryo alkaline phosphatase) is to reply transcribing under the control of key element at NF-κ B-, the TNF-α stimulation that is expressed in of this pointer activates down.Can pass through chemiluminescent substrate
Figure A20078000923301003
Detect the secretion of SEAP in the nutrient solution clear liquid.The testing compound that suppresses the NF-kB activity demonstrates the SEAP activity of reduction and the luminous reading that reduces.
At 37 ℃, 5%CO 2Behind reactivate 18h under 90% relative humidity, before stimulating, cell is hatched 4.5h with the testing compound of 0.01 μ M height to 100 μ M with 2ng/mlTNF-α.After stimulating 22h, make the deactivation of endogenous Phosphoric acid esterase and provide with TNF-α
Figure A20078000923301004
Substrate 40min.Then by using the super plate reader of Tecan to measure the luminous SEAP activity of representing with relative light unit (RLU) that quantizes.Each data point writes down 4 times and calculates the EC50 value by fitting function and the ExcelSolver of Microsoft.

Claims (19)

1. the acceptable salt of medicine or its medicine acceptable prodrugs or its steric isomer that form of general formula (Ih) compound or itself and acid or alkali,
Figure A2007800092330002C1
Wherein
A is NR 2', S or O;
T is 0 to 4;
R is 0 or 1;
R 2aBe H, OH, SH, NH independently 2, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R 3aBe H, OH, SH, NH 2,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 1Be-C (O) R 7a,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8Or-C (S) R 7b
R 2Be H, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino or heteroaryl,
Perhaps R 1And R 2And connected N atom or C atom form together 3 yuan to 8 yuan, saturated or to undersaturated monocycle of small part or polycyclic member ring systems, on the wherein said ring at least one or a plurality of carbon atom are the heteroatomss that is selected from O, N, S, and described ring can be by one or more R 9Replace;
R 3Be H ,-C (O) NR aR b, halogen, alkyl, halo alkyl, aryl, heteroaryl, OH, SH, NR 4' OR 5', NH 2, hydroxy alkylene amino, alkyl amino,-oxyl, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene or halo-oxyl;
R aBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8, aryl ,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino or heteroaryl;
R bRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl, sulfenyl, halogen, halo alkyl, halo-oxyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4'-benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxy alkylene, hydroxyl-cyclic hydrocarbon radical, hydroxy alkylene amino, heterocycle alkyl, aryl or heteroaryl;
R 4', R 4", R 5' be independently H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl, halo alkyl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, heterocycle alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7', R 8Be H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, arylamino, heteroaryl or aryl independently;
R 7aBe cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, heteroaryl or aryl;
R 7bBe H, halogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, heteroaryl or aryl;
X is NR 2', O or S;
Z is N or CR 2';
R 2' be H, alkyl ,-C (O) NR 7,-C (O) R b, cyclic hydrocarbon radical, heterocycle alkyl, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
R 9Represent independently H ,-CN ,-OH ,-SH,-oxyl, sulfenyl ,-CO 2R 4' ,-C (O) R 4a,-C (O) NR 7R 8,-SO 2NR 4' ,-NR 4' R 5' ,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, halogen, halo alkyl, alkyl amino ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4'-benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, hydroxyl cyclic hydrocarbon radical, hydroxy alkylene amino, halo-oxyl, heterocycle alkyl ,-(CH 2) pNR 7COR 8, aryl or heteroaryl;
R 4aBe H, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
Wherein
If not explanation in addition, C 1-C 6Alkyl group is represented the C of straight or branched 1-C 6Alkyl, they can be randomly by one or more substituent R ' replace;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO2 ,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
If not explanation in addition, C 2-C 6Alkenyl group is represented the C of straight or branched 2-C 6Thiazolinyl, they can be randomly by one or more substituent R ' replace;
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, the C of straight or branched 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl group, they can be randomly by one or more substituent R ' replace; R ' as hereinbefore defined;
The cyclic hydrocarbon radical group represents to contain 3 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be by one or more substituent R ' replace; R ' as hereinbefore defined;
The heterocyclic hydrocarbon basis representation contains 2 to 10 carbon atoms and at least one is selected from the heteroatomic non-aromatic ring system of O, N or S, and the one or more carbon atoms on the wherein said ring can be replaced by R ' group as hereinbefore defined;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aromatic groups to 15 carbon atoms, and they can be randomly by one or more substituent R ' replace, wherein R ' is as hereinbefore defined;
The arylamino group is represented HN-aryl or N-diaryl group, and described aromatic yl group as hereinbefore defined;
Heteroaryl groups represent to contain at least one be selected from O, N or S heteroatomic five yuan to ten membered aromatic heterocycle groups, wherein said heterocyclic group can condense with another ring and described heterocyclic group or described fused rings all can be independently by one or more substituent R ' replace, wherein R ' is as hereinbefore defined;
Precondition is to get rid of following compound
Wherein
R 1The aryl alkyl of heteroaryl, aryl alkyl or replacement of representing aryl, heteroaryl, the replacement of hydrogen, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl, replacement independently;
R 2Expression-NR independently 3R 4,
Figure A2007800092330006C1
R 3Represent independently alkyl, cyclic hydrocarbon radical,-oxyl, alkylamine ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 4Represent alkyl, cyclic hydrocarbon radical,-oxyl, alkylamine, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
R 5Represent H, COR independently 6, CO 2R 6, SOR 6, SO 2R 6, SO 3R 6, alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkylamine ,-NR 7COR 6, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 6Represent independently H, alkyl, cyclic hydrocarbon radical ,-NH 2, alkylamine, aryl or heteroaryl;
R 7Represent independently H, alkyl, cyclic hydrocarbon radical,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, aryl or heteroaryl;
P is 0 or 1;
Q is 0 or 1;
X is CO or SO 2
2. the acceptable salt of medicine or its medicine acceptable prodrugs or its steric isomer that form of general formula (Ia) compound or itself and acid or alkali,
Figure A2007800092330006C2
R is hydrogen, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
R 1Be alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
X is CO, CS or SO 2
Y is CO, CS or SO 2
Z is NR 2', S or O;
R 2' be H, alkyl ,-C (O) NR 7,-C (O) R e, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R cBe H, OH, SH, NROR independently 1, NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7' represent H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl independently;
R 8Be H, NH 2, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R eRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, aryl, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4'-benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl or heteroaryl;
R 4', R 4", R 5' represent independently H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
R 2Be independently
R 5Be H, COR independently 6, CO 2R 6, SOR 6, SO 2R 6, SO 3R 6, alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkylamine ,-NR 7COR 6, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R 6Be H, alkyl, cyclic hydrocarbon radical, amino, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, aryl or heteroaryl independently;
Wherein
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, the C of straight or branched 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl, they can be by one or more substituent R ' replace; R ' as hereinbefore defined;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO2 ,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by group E, and E is O, S, SO, SO 2, N or NR ", R " as hereinbefore defined;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aromatic groups to 15 carbon atoms, and they can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined;
Heteroaryl groups represent to contain at least one be selected from O, N or S heteroatomic five yuan to ten membered aromatic heterocycle groups, wherein said heterocyclic group can condense with another ring and described heterocyclic group or described fused rings all can be independently by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
3. the acceptable salt of medicine or its medicine acceptable prodrugs or its steric isomer that form of general formula (Ib) compound or itself and acid or alkali,
Figure A2007800092330009C1
Wherein
R 1Be-C (O) R 7,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8Or-C (S) R 7
R 9Represent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, heteroaryl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, aryl, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4' benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl ,-(CH 2) pNR 7COR 8Or alkyl;
R 4Be H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
Perhaps R 1And R 4And connected X form together 3 yuan to 8 yuan, saturated or to undersaturated monocycle of small part or polycyclic member ring systems, wherein at least one annular atoms is the heteroatoms that is selected from O, N or S, and described ring randomly has one or more substituent R 9
X is N or CR 2';
Y is CO, CS or SO 2
Z is NR 2", S or O;
R 2" be H, alkyl ,-C (O) NR 7,-C (O) R e, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 2' be H, alkyl ,-C (O) NR 4' ,-C (O) R 4', cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 4', R 4", R 5' represent independently H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
R aBe H, OH, SH, NH independently 2, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R bBe H, OH, SH, NH independently 2, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl,-oxyl, alkyl amino, hydroxy alkylene amino, halogen, aryl or heteroaryl;
R cBe H, OH, SH, NR independently 4' OR 5', NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7' represent H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl independently;
R 8Be H, NH 2, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R eRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4'-benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, aryl or heteroaryl;
R 2Be independently
Figure A2007800092330011C1
A is N, O or CR 2';
R 5Be H, SOR independently 7, SO 2R 7, SO 3R 7,-C (O) R 7,-C (O) CHR 7R 8,-C (O) NR 7R 8,-C (O) OR 7,-R 7C (O) R 8,-C (S) R 7,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 7', alkyl, cyclic hydrocarbon radical,-oxyl ,-NH 2, alkyl amino, hydroxy alkylene amino, halogen ,-OH ,-SH, sulfenyl, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
N is 0 to 2;
Wherein
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, the C of straight or branched 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl group, they can be by one or more substituent R ' replace; R ' as hereinbefore defined;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO2 ,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by the E group, and E is O, S, SO, SO 2, N or NR ", R " as hereinbefore defined;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined;
Heteroaryl groups represent to contain at least one be selected from O, N, S heteroatomic five yuan to ten membered aromatic heterocycle groups, wherein said heterocyclic group can condense with another ring and described heterocyclic group or described fused rings all can be independently by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
4. the acceptable salt of medicine or its medicine acceptable prodrugs or its steric isomer that form of general formula (Ic) compound or itself and acid or alkali,
Figure A2007800092330012C1
Wherein
R 1Represent H, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl independently;
X is CO, CS or SO 2
Y is CO, CS or SO 2
Z is NR 2", S or O;
R 2" be H, alkyl ,-C (O) NR 7,-C (O) R e, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 4', R 4", R 5' represent independently H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, halogen, heteroaryl or aryl;
P is 1 to 6;
Q is 1 to 6;
M is 0 to 4;
R is 0 or 1;
T is 0 or 1;
S is 0 or 1;
R bBe H, OH, SH, NR independently 4' OR 5', NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R cBe H, OH, SH, NR independently 4' OR 5', NH 2, alkyl amino, hydroxy alkylene amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
R dBe H, halogen, alkyl ,-C (NR 7) NR 7' R 8,-(CH 2) pAryl ,-(CH 2) pNR 7R 8,-C (O) NR 7R 8,-N=CR 7R 8,-NR 7C (O) R 8, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R 7, R 7' represent H, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl independently;
R 8Be H, NH 2, alkyl, cyclic hydrocarbon radical, halo alkyl, hydroxy alkylene, hydroxy alkylene amino, alkyl amino, heteroaryl or aryl;
R eRepresent independently H ,-CN ,-OH ,-SH ,-CO 2R 4' ,-C (O) R 4' ,-SO 2NR 4' ,-NR 4' R 5' ,-C (O) NR 7R 8,-SO 2-alkyl ,-SO 2R 4', SO 3R 4' ,-N=CR 4' R 5' ,-NR 4' C (O) R 4" ,-NR 4'-CO-halo alkyl ,-NO 2,-NR 4'-SO 2-halo alkyl ,-NR 4'-SO 2-alkyl ,-NR 4'-CO-alkyl ,-NR 4' (CH 2) pHeteroaryl, alkyl, hydroxy alkylene, cyclic hydrocarbon radical, alkyl amino, hydroxy alkylene amino,-oxyl, sulfenyl ,-O (CH 2) p[O (CH 2) p] qOCH 3,-C (NR 4") NR 4' benzimidazolyl-,-C (NR 4") NR 4'-benzothiazolyl ,-C (NR 4") NR 4' benzoxazolyl, aryl or heteroaryl;
R 3Be H, OH, SH, NR independently 4' OR 5', NH 2, hydroxy alkylene amino, alkyl amino, halogen, CONR dR e,-oxyl, alkyl, cyclic hydrocarbon radical, hydroxy alkylene, halo alkyl, halo-oxyl, aryl or heteroaryl;
Wherein
If not explanation in addition, hydrocarbyl group is represented the C of straight or branched 1-C 6Alkyl, the C of straight or branched 2-C 6The C of thiazolinyl or straight or branched 2-C 6Alkynyl group, they can be by one or more substituent R ' replace; R ' as hereinbefore defined;
R ' be independently H ,-CO 2R " ,-CONHR " ,-CR " O ,-SO 2NR " ,-NR "-CO-halo alkyl ,-NO 2,-NR "-SO 2-halo alkyl ,-NR "-SO 2-alkyl ,-SO 2-alkyl ,-NR "-the CO-alkyl ,-CN, alkyl, cyclic hydrocarbon radical, alkyl amino,-oxyl ,-OH ,-SH, sulfenyl, hydroxy alkylene, hydroxy alkylene amino, halogen, halo alkyl, halo-oxyl, aryl or heteroaryl;
R " be H, halo alkyl, hydroxy alkylene, alkyl, cyclic hydrocarbon radical, aryl or heteroaryl independently;
The cyclic hydrocarbon radical group represents to contain 3 non-aromatic ring systems to 8 carbon atoms, and the one or more carbon atoms on the wherein said ring can be replaced by the E group, and E is O, S, SO, SO 2, N or NR ", R " as hereinbefore defined;
The-oxyl group is represented the O-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The sulfenyl group is represented the S-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
The halo hydrocarbyl group represents that described hydrocarbyl group as hereinbefore defined by the hydrocarbyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene group is represented the HO-hydrocarbyl group, and described hydrocarbyl group as hereinbefore defined;
Halo-oxyl group represents that described hydrocarbyl group as hereinbefore defined by the-oxyl group of 1 to 5 halogen atom replacement;
The hydroxy alkylene amino group is represented (HO-alkyl) 2-N-group or HO-alkyl-NH-group, described hydrocarbyl group is as hereinbefore defined;
The alkyl amino group is represented HN-alkyl or N-dialkyl group, and described hydrocarbyl group as hereinbefore defined;
Halogen group is fluorine, chlorine, bromine or iodine;
Aromatic yl group represents to have 5 aryl to 15 carbon atoms, and they can be by one or more substituent R ' replace, wherein R ' is as hereinbefore defined;
Heteroaryl groups represent to contain at least one be selected from O, N, S heteroatomic five yuan to ten membered aromatic heterocycle groups, wherein said heterocyclic group can condense with another ring and described heterocyclic group or described fused rings all can be independently by one or more substituent R ' replace, wherein R ' is as hereinbefore defined.
5. as the described compound of arbitrary claim in the claim 1 to 4 of medicine.
6. composition, it comprises the described compound of arbitrary claim and medicine acceptable carrier or thinner in the claim 1 to 4.
7. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or prevents with the cell hyperproliferation is the disease of feature.
8. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or prevents by the local asphyxia of the part of organ and/or health and/or the disease that reperfusion injury causes, the part of described organ and/or health is selected from heart, brain, the periphery limbs, kidney, liver, spleen and lung, and/or wherein said endothelial function disturbance and the infraction that is selected from such as myocardial infarction, the disease of critical limb ischemia is relevant, and/or wherein said endothelial function disturbance be selected from ischemic disease, myocardial infarction, diseases such as organ ischemic disease are relevant.
9. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or prevents nervous system disorders or illness, and described nervous system disorders or illness are selected from alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Lewy body, amyotrophic lateral sclerosis, apoplexy, epilepsy, multiple sclerosis, myasthenia gravis, huntington's chorea, mongolism, nerve deafness and Meniere.
10. compound as claimed in claim 7 or composition, wherein said disease is selected from psoriasis, atopic dermatitis, alopecia areata, alopecia capitis totalis, inferior whole alopecia, alopecia universalis, dispersivity alopecia (alopeciadiffusa), lupus erythematosus,cutaneous, lichen planus, dermatomyositis, atopic eczema, local scleroderma, sklerodermia, psoriasis, head psoriasis (psoriasis capitis), guttate psoriasis, abnormality psoriasis (psoriasis inverse), snakelike alopecia areata, androgenetic alopecia, the supersensitivity contact eczema, the pungency contact eczema, contact eczema, pemphigus vulgaris, lobate pemphigus, pemphigus vegetans, cicatricial mucosal pemphigoid (scarring mucosal pemphigoid), bullous pemphigoid, mucus pemphigoid (mucous pemphigoid), dermatitis, dermatitis herpetiformis dermatitis herpetiformis (dermatitis herpetiformis duhring), urticaria, necrobiosis lipoidica, erythema nodosum, Vidal lichen (lichen vidal), prurigo simplex, prurigo nodularis, prurigo temporanea, linear IgA dermatosis, polymorphism daylight tetter, sun erythema, lichen albus of Von Zumbusch, skin rash, drug rash, the chronic progressive external purpura, dyshidrotic eczema, eczema, the fixed drug rash, the photoallergy skin reaction, eriorale haplolichen (lichen simplex eriorale), dermatitis and " graft versus host disease (GVH disease) ", acne, acne erythematosa, scarring, keloid, vitiligo, the actinity seborrheic keratosis, such as epidermolytic hyperkeratosis, hyperkeratosis lenticularis perstans disease, keratosis pilaris disease or ichthyotic hyperkeratosis.
11. compound as claimed in claim 7 or composition, wherein said disease is selected from neoplastic hematologic disorder or solid tumor.
12. compound as claimed in claim 11 or composition, wherein said disease is selected from prostate cancer, melanoma, ovarian cancer or multiple myeloma.
13. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or prevents autoimmune disease or inflammatory diseases.
14. compound as claimed in claim 13 or composition, wherein said disease are rheumatoid arthritis, multiple sclerosis, inflammatory bowel, inflammatory dermatosis or lupus erythematosus.
15. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or preventing apoplectic, reperfusion injury and alzheimer's disease.
16. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or prevents virus disease.
17. compound as claimed in claim 16 or composition, wherein said virus disease are hepatitis B, hepatitis C, influenza infection, AIDS (HIV infection) and human papillomaviral infection.
18. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, its be used for the treatment of or prevention of arterial atherosis.
19. described compound of arbitrary claim or the described composition of claim 6 in the claim 1 to 4, it is used for the treatment of or preventing osteoporosis.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007115805A2 (en) * 2006-04-05 2007-10-18 European Molecular Biology Laboratory (Embl) Aurora kinase inhibitors
AU2008231705A1 (en) * 2007-03-27 2008-10-02 4Sc Ag Pharmaceutical composition comprising a cytokine
CA2699817A1 (en) * 2007-09-19 2009-03-26 4Sc Ag Benzimidazole nf- kappab inhibitors
DE102007047735A1 (en) * 2007-10-05 2009-04-09 Merck Patent Gmbh thiazole
CA2703106C (en) * 2007-10-24 2015-12-01 Astellas Pharma Inc. Azolecarboxamide derivatives as trka inhibitors
CA2707445A1 (en) * 2007-11-30 2009-06-11 Biota Scientific Management Pty Ltd Tetrahydro-isoquinoline ppat inhibitors as antibacterial agents
US8124616B2 (en) 2007-11-30 2012-02-28 Biota Scientific Management Pty Ltd Bicyclic PPAT inhibitors as antibacterial agents
EP2237774B1 (en) * 2007-12-21 2016-06-22 Merial Limited THE USE OF 6-HALOGENO-(1,2,4)-TRIAZOLO-(1,5-a)-PYRIMIDINE COMPOUNDS FOR COMBATING PESTS IN AND ON ANIMALS
BRPI0911497B8 (en) * 2008-05-05 2021-05-25 Merck Patent Gmbh nip thiazole derivatives, their manufacturing process, drug, pharmaceutical composition, and kit
AU2009316786A1 (en) * 2008-11-19 2010-05-27 Merck Sharp & Dohme Corp. Inhibitors of diacylglycerol acyltransferase
KR101051077B1 (en) * 2008-12-05 2011-07-21 한국화학연구원 2-piperazino-4,5-disubstituted-1,3-thiazole derivatives, preparation method thereof and therapeutic agent for inflammation-related diseases caused by spC receptor activity containing the same as an active ingredient
EP2376491B1 (en) 2008-12-19 2015-03-04 Cephalon, Inc. Pyrrolotriazines as alk and jak2 inhibitors
FR2969611B1 (en) * 2010-12-28 2013-02-08 Sanofi Aventis NOVEL THIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS AKT PHOSPHORYLATION INHIBITORS (PKB)
GB201401886D0 (en) 2014-02-04 2014-03-19 Lytix Biopharma As Neurodegenerative therapies
WO2022112205A1 (en) * 2020-11-25 2022-06-02 F. Hoffmann-La Roche Ag Aromatic bridged ring amide derivatives for the treatment and prophylaxis of hepatitis b virus infection

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL90337A0 (en) * 1988-05-24 1989-12-15 Pfizer Aromatic and heterocyclic carboxamide derivatives as antineoplastic agents
GB0230162D0 (en) * 2002-12-24 2003-02-05 Metris Therapeutics Ltd Compounds useful in inhibiting angiogenesis
WO2005079791A1 (en) * 2004-02-12 2005-09-01 Boehringer Ingelheim Pharmaceuticals, Inc. Thiophene -2- carboxylic acid - (1h - benzimidazol - 2 yl) - amide derivatives and related compounds as inhibitors of the tec kinase itk (interleukin -2- inducible t cell kinase) for the treatment of inflammation, immunological and allergic disorders
EP1797084A1 (en) * 2004-09-20 2007-06-20 4Sc Ag NOVEL HETEROCYCLIC NF-kB INHIBITORS

Cited By (4)

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CN109988121A (en) * 2019-04-28 2019-07-09 梯尔希（南京）药物研发有限公司 A kind of preparation method of Acotiamide derivative
CN109988121B (en) * 2019-04-28 2023-01-03 梯尔希（南京）药物研发有限公司 Preparation method of acotiamide derivative
WO2023056897A1 (en) * 2021-10-09 2023-04-13 浙江大学 Use of c-abl inhibitor in preparation of drug for preventing and/or treating amyotrophic lateralizing sclerosis

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