CN1902198A - Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment - Google Patents
Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment Download PDFInfo
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- CN1902198A CN1902198A CN 200480038144 CN200480038144A CN1902198A CN 1902198 A CN1902198 A CN 1902198A CN 200480038144 CN200480038144 CN 200480038144 CN 200480038144 A CN200480038144 A CN 200480038144A CN 1902198 A CN1902198 A CN 1902198A
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Abstract
The present invention relates to pharmaceutical compositions for the treatment or prevention of viral infections comprising as an active principle at least one imidazo[4,5-c]pyridine prodrug having the general Formula (A) wherein the substituents are described in the specification. The invention also relates to processes for the preparation and screening of compounds according to the invention having above mentioned general Formula and their use in the treatment or prophylaxis of viral infections.
Description
Invention field
The present invention relates to the imidazo [4 of a series of novelties, 5-c] pyridine compounds, their preparation method, their purposes and their purposes in the medicine of preparation treatment or prophylaxis of viral infections in treatment or prophylaxis of viral infections, infection in particular for the virus of flaviviridae and pico+ribonucleic acid+virus section causes more preferably is used for the infection that is caused by hepatitis C virus (HCV).
Background of invention
Flaviviridae is made up of 3 genus: pestivirus, arboviruses belong to and Hepacivirus, and still the hepatitis G virus of uncertain genus (HGV/GBV-C) is also contained in wherein.Pestivirus, for example classical Pig Fever virus (CSFV), bovine viral diarrhea virus (BVDV) and edge disease virus (Border Disease Virus, BDV) can cause the infection of domestic animal (being respectively pig, ox and sheep), and cause worldwide a large amount of financial loss.BVDV is the prototype representative of pestivirus, its ubiquity also causes the clinical manifestation of certain limit, comprise: miscarriage, teratogeny, breathing problem, chronic wasting disease, immunity system function hinder and are subject to secondary virus and infectation of bacteria, also can cause the acute fatal disease.The tire ox can be by the BVDV persistent infection, and these animals all can continue to carry virus (remain viremic) all the life, and become lasting virus disseminating source in herd.
Use vaccine successfully to control the plague virus disease to some extent in some countries.In other countries, the method control plague virus illness outbreak that adopts animal to reject and butcher.
Estimate 1,700,000,000 people (account for world population 3%) are arranged in the world wide by the HCV chronic infection according to the World Health Organization.These chronic carrier have the danger that develops into liver cirrhosis and/or liver cancer.In the follow-up investigation of 10-20, the patient of 20-30% develops into liver cirrhosis, and the 1-5% among them can develop into liver cancer between the several years subsequently.It is to use interferon (or form of its PEGization) separately or with itself and virazole coupling that the treatment that only can adopt is at present selected.Yet, only in about 40% patient, observes and continue to reply, and treatment is with severe side effect.Therefore, press for the potent and selective depressant that HCV duplicates, HCV infects with treatment.
In addition, the research of the specific inhibitor that duplicates for HCV be subjected to always can not be in cell culture fluid the obstruction of this fact of (effectively) breeding HCV.Because HCV and pestivirus belong to same Viraceae, and have many similarities (genomic composition, similar gene product and replicative cycle), adopted model and the surrogate of pestivirus as HCV.For example, (HCV) is closely related for BVDV and hepatitis C virus, is used as in the drug development that infects at HCV and substitutes virus.
It is reported compound 3-[((2-dipropyl amino) ethyl) sulphur]-5H-1,2,4-triazine also [5,6-b] indoles can selectivity suppresses the duplicating of BVDV and other pestivirus (Baginski SG etc., Proc.Natl.Acad.Sci.U.S.A.2000 July 5; 97 (14): 7981-6).At present, also there is not to be used to control the treatment plan of the infection that pestivirus causes.
Coxsackie virus belongs to the enterovirus genus of pico+ribonucleic acid+virus section.They cause one group of heterogeneous infection, comprising: herpangina, aseptic meningitis, common cold sample syndrome, non--spinal paralytic poliomyelitis sample syndrome, epidemic pleurodynia (acute, heat generation, be generally epidemic communicable disease), hand-foot-and-mouth syndrome, children and adult's pancreatitis and serious myocarditis.
At present; only to pleconaril (3-13; 5-dimethyl-different the azoles of 4-[[3-methyl-5-base] propyl group] phenyl)-5-(Trifluoromethyl-1; 2,4- diazole)) and enviroxime (2-amino-1-(sec.-propyl alkylsulfonyl)-6-benzoglyoxaline phenyl ketoxime) treatment enterovirus infection carried out clinical study.Pleconaril is so-called " viral capsid function-inhibitor "; Enviroxime then can stop formation rna replicon intermediate.Enviroxime only reaches limited clinical and virusology effect in some researchs, and does not have effect in other respects.In some researchs, observed the clinical response of pleconaril, but this compound still fails to obtain the approval of Food and Drug Administration's (hearing on March 18th, 2002).
Relevant announcement comprises: United States Patent (USP) 4,914,108; 4,988,707; 4,990,518; 5,137,896; 5,208,242; 5,227,384; 5,302,601; 5,374,638; 5,405,964; 5,438,063; 5,486,525; 6,479,508; With U.S. Patent Publication No. US 2003/0108862 Al, Canadian Patent 2423800 Al, German Patent 4211474 Al, 4236026,4309969,4318813, European patent EP 0 138 552 A2, EP0 706 795 A2, EP 1 132 381 Al, English Patent 2158440 A, PCT patent publication No. WO 00/20416, WO 00/39127, WO 00/40583, WO 03/007945 Al, WO 03/010140 A2, WO 03/010141A2, WO 93/02080, WO 93/14072, WO 96/11192, WO 96/12703, WO 99/27929; Akamatsu etc., " new effective route of benzimidizole derivatives solid phase synthesis (New Efficient Route forSolid-Phase Synthesis of Benzimidazole Derivatives) ", 4:475-483, J.COMB.CHEM, 2002, Cleve etc., " Derivate des Imidazo[4.5-b]-undlmidazo[4.5-c] pyridins ", 747:158-171, JUSTUS LIEBIGS ANNALEN DERCHEMICA, 1971; Kiyama etc. " novel non-peptide class angiotensin II acceptor antagonist: synthetic and assessment (Synthesis and Evaluation ofNovel Nonpeptide Angiotensin II Receptor Antagonists:Imidazo[4; 5-c] pyridine Derivatives with an Aromatic Substituent) " with imidazo [4; 5-c] pyridine derivate of aromatic substituent, 43 (3): 450-60, CHEM PHARM BULL, 1995; Mederski etc., " the synthetic and structure ownership (Synthesis and Structural Assignment of SomeN-substituted Imidazopyridine Derivatives) of the imidazopyridine derivatives that some N-replace ", 48 (48): 10549-58, TETRAHEDRON, 1992; Yutilov etc., 23 (1): 56-9, KHIMIKO-FARMATSEVTICHESKII ZHURNAL, 1989.This paper is included on the equal expressivity of announcement ground in all quoted passages of herein listing as a reference in, and it can make that with reference to degree these announcements are relevant with the content of this paper.
Existence is for the demand of the compound with antiviral and other desired characteristic (biological example availability, effectiveness, nontoxicity, optimization clearance rate, drug effect etc.).Particularly, need have the active compound of selection in the virus of pico+ribonucleic acid+virus section for having virus (comprise hepatitis C virus) and the family dependents of military personel in the liberated areas of the family dependents of military personel in the liberated areas in flaviviridae.With this specification sheets do as a whole consider after, these and other objects of the present invention are conspicuous for those skilled in the art.
Summary of the invention
Compound with general formula (A) is provided in an embodiment of the invention, and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and dotted line to have represented at least 3, chosen wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio (thioalkyl), C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, they are separately randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11Or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio (alkylthio), halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S)
R9, SH, aryl, aryloxy, arylthio (arylthio), arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy (cycloalkyloxy), C
3-10Cycloalkyl sulfenyl (cycloalkylthio), C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be selected from: aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl-N (R
10)-or heterocyclic radical, wherein, each described substituting group can be randomly by at least one R
17Replace, prerequisite is for cycloalkenyl group, its pair key not with nitrogen adjacency, and R
3-M-Q is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by amino acid whose carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by this amino acid whose amino amino-acid residue, CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
13And R
14Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12,-C (=S) R
12Or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be M-Q-independently, wherein, M is for randomly by one or more R
19The ring that replaces, and Q is key or M is connected to R
3Linking group, described linking group comprises 1-10 atom and randomly by one or more R
19Replace;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-18Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O ,-NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12Or-C (=S) R
12
R
22Be selected from: hydrogen ,-OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
1-18Alkoxyl group ,-NR
23R
24, aryl, C
3-10Cycloalkyl and C
4-10Cycloalkenyl group;
R
23And R
24Be independently selected from: hydrogen, C
1-18Alkyl or by R
22N and C
2-3The heterocyclic radical that alkyl forms together, this heterocyclic radical randomly replace by OH, aryl or by the amino-acid residue that amino acid whose carboxyl connects;
R
25And R
26Do not exist or be independently selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, aryl, heterocyclic radical, wherein, each group can be chosen wantonly independently and be replaced by 1-4 group that is selected from down group: C
1-6Alkyl, C
1-6Alkoxyl group, halogen, CH
2OH, benzyloxy and OH; And
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
Compound with general formula (A) is provided in another embodiment of the present invention, and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and this at least 3 of dotted line representative, to choose wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio (thioalkyl), C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11, or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R then
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be randomly by at least one R
17The heterocyclic radical that replaces, however prerequisite is randomly by at least one R
17The R that replaces
3Be not pyridyl or 5-chlorothiophene base, and prerequisite is R
3-MQ is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, heterocyclic radical, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by the amino acid carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by this amino acid whose amino amino-acid residue, CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
13And R
14Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12,-C (=S) R
12Or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Haloalkyl, C
2-18Haloalkenyl group, C
2-18Halo alkynyl, C
1-18Halogenated alkoxy, C
1-18Halogenated alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, CO
2H, CO
2R
18, NO
2, NR
7R
8, haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl, alkoxy aryl, alkylthio-aryl, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each described aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl, alkoxy aryl, alkylthio-aryl, heterocyclic radical or C
1-18Hydroxyalkyl is randomly by one or more R
19Replace;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O ,-NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12, the heterocyclic radical that replaces of carboxyl ester or-C (=S) R
12
R
22Be selected from: hydrogen ,-OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
1-18Alkoxyl group ,-NR
23R
24, aryl, C
3-10Cycloalkyl and C
4-10Cycloalkenyl group;
R
23And R
24Be independently selected from: hydrogen, C
1-18Alkyl or by R
22N and C
2-3The heterocyclic radical that alkyl forms together, this heterocyclic radical randomly replace by OH, aryl or by the amino-acid residue that amino acid whose carboxyl connects;
R
25And R
26Do not exist or be independently selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, aryl, heterocyclic radical, wherein, each group can be chosen wantonly independently and be replaced by 1-4 group that is selected from down group: C
1-6Alkyl, C
1-6Alkoxyl group, halogen, CH
2OH, benzyloxy and OH; And
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
Compound with general formula (A) is provided in an embodiment of the invention, and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and this at least 3 of dotted line representative, to choose wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio, C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11Or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be randomly by at least one R
17The heterocyclic radical that replaces, prerequisite is R
3-M-Q is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by its carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by this amino acid whose amino amino-acid residue, CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
13And R
14Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12,-C (=S) R
12Or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be M-Q-, wherein M is for randomly by one or more R
19The C that replaces
3-10Cycloalkyl, and Q is a key or randomly by one or more R
19The C that replaces
1-10Alkyl;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18,
SH,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O, NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12Or-C (=S) R
12
R
22Be selected from: hydrogen,
-OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
1-18Alkoxyl group ,-NR
23R
24, aryl, C
3-10Cycloalkyl and C
4-10Cycloalkenyl group;
R
23And R
24Be independently selected from: hydrogen, C
1-18Alkyl or by R
22N and C
2-3The heterocyclic radical that alkyl forms together, this heterocyclic radical randomly replace by OH, aryl or by the amino-acid residue that amino acid whose carboxyl connects;
R
25And R
26Do not exist or be independently selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, aryl, heterocyclic radical, wherein, each group can be chosen wantonly independently and be replaced by 1-4 group that is selected from down group: C
1-6Alkyl, C
1-6Alkoxyl group, halogen, CH
2OH, benzyloxy and OH; And
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
Compound with formula (B) is provided in another embodiment of the present invention,
In the formula:
It is to be adjacent to each other that the optional two keys of dotted line representative, prerequisite do not have two two keys, and dotted line is represented two keys of at least 3, optional 4; R
1, R
2, R
3, R
4, R
5, R
25, R
26, X and Y as mentioned above.
Formula (B) compound is provided in an embodiment of the invention, and wherein, Y is singly-bound and R
1Be aryl.
Formula (B) compound is provided in another embodiment of the present invention, and wherein, X is C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene.
Formula (B) compound is provided in another embodiment of the present invention, wherein, R
3Be heterocyclic radical.
Formula (B) compound is provided in another embodiment of the present invention, wherein, R
3For by R
17The heterocyclic radical that replaces, R
17In Q be that key and M are aryl.
Formula (B) compound is provided in another embodiment of the present invention, and wherein, Y is singly-bound and R
1Be phenyl.
Formula (B) compound is provided in another embodiment of the present invention, wherein, R
3For by R
17Replace the De isoxazole, R
17In Q be that key and M are aryl.
Formula (B) compound is provided in another embodiment of the present invention, wherein, R
3For by R
17Replace the De isoxazole, R
17In Q be that key and M are phenyl.
Formula (C) compound is provided in another embodiment of the present invention,
In the formula, R
1, R
2, R
3, R
4, R
5, R
25, R
26, X and Y as mentioned above.
Formula (C) compound is provided in an embodiment of the invention, and wherein, Y is a singly-bound, and R
1Be aryl.
Formula (C) compound is provided in another embodiment of the present invention, and wherein, X is C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene.
Formula (C) compound is provided in another embodiment of the present invention, wherein, R
3Be heterocyclic radical.
Formula (C) compound is provided in another embodiment of the present invention, wherein, R
3For by R
17The heterocyclic radical that replaces, R
17In Q be that key and M are aryl.
Formula (C) compound is provided in another embodiment of the present invention, and wherein, Y is a singly-bound, and R
1Be phenyl.
Formula (C) compound is provided in another embodiment of the present invention, wherein, R
3For by R
17Replace the De isoxazole, R
17In Q be that key and M are aryl.
Formula (C) compound is provided in another embodiment of the present invention, wherein, for by R
17Replace the De isoxazole, R
17In Q be that key and M are phenyl.
Formula (A) compound can be randomly with pharmacology on acceptable excipient composition.
Formula (A) compound is needed the object (human or animal) of antiviral therapy with the treatment significant quantity, be specially and be used to suppress flavivirus and pico+ribonucleic acid+virus, the especially infection of BVDV, HCV and Coxsackie virus, grow and duplicate.
The invention still further relates to a kind of method of screening antiviral compound, described method comprises the antiviral activity that formula (A) compound is provided and measures described compound.
The meta-bolites that also comprises formula (A) compound in the scope of the present invention, this metabolite are to obtain by the method that gives object with formula (A) compound and reclaim meta-bolites from described object.
The present invention also comprises a kind of structure-active method that is used for mensuration formula (A) compound analogue,
Substituting group wherein is definition to some extent in WO 2004/005286, and described method comprises:
(A) preparation has formula (A) compound that a substituting group does not disclose at least in WO 2004/005286; With
(B) the whose anti-HCV activity of determination step (a) compound.
Detailed Description Of The Invention
" alkyl " is meant saturated hydrocarbyl portion, and that this part can be is acyclic, the combination of cyclic or non-annularity and circular part.Described non-annularity part can comprise 1-3 carbon atom, and each ring can comprise 3-6 carbon atom (for example, 3-methylcyclohexyl).In this definition, term " cycloalkyl " is meant cyclic saturated hydrocarbyl part.The example of " alkyl " comprising: methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, 2-methyl isophthalic acid-propyl group (isobutyl-), 2-butyl (sec-butyl) 2-methyl-2-propyl group (tertiary butyl), 1-amyl group (n-pentyl), the 2-amyl group, the 3-amyl group, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl isophthalic acid-butyl, the 2-methyl-1-butene base, the 1-hexyl, the 2-hexyl, the 3-hexyl, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 3-methyl-3-amyl group, 2-methyl-3-amyl group, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, suberyl, encircle octyl group etc., or have the C of 7-10 carbon atom
7-10The polycyclic saturated hydrocarbon base, for example: norborneol alkyl, fenchyl, trimethylammonium three suberyl or adamantyl.
" thiazolinyl " is meant that at least one position is the hydrocarbyl portion of unsaturated double-bond, and wherein, that this part can be is acyclic, the combination of cyclic or non-annularity and circular part.Described non-annularity part can comprise 1-3 carbon atom, and each circular part can comprise 3-6 carbon atom.The position of unsaturated double-bond can be in non-annularity part, circular part.In the part of combination, in each several part, all can contain the position of unsaturated double-bond with non-annularity and circular part.In this definition, term " cycloalkenyl group " is meant the hydrocarbyl portion of cyclic unsaturated double-bond.The example of term " thiazolinyl " includes but not limited to: vinyl (CH=CH
2), allyl group (CH
2CH=CH
2), cyclopentenyl (C
5H
7), 5-hexenyl (CH
2CH
2CH
2CH
2CH=CH
2), 1-ring penta-1-thiazolinyl, 1-ring penta-2-thiazolinyl, 1-ring penta-3-thiazolinyl, 1-hexamethylene-1-thiazolinyl, 1-hexamethylene-2-thiazolinyl and 1-hexamethylene-3-thiazolinyl.Two keys can randomly be cis or transconfiguration.
" alkynyl " is meant that at least one position is unsaturated triple-linked hydrocarbyl portion, and wherein, that this part can be is acyclic, the combination of cyclic or non-annularity and circular part.Described non-annularity part can comprise 1-3 carbon atom, and each circular part can comprise 7 or more a plurality of carbon atom.In this definition, term " cycloalkynyl radical " is meant the unsaturated triple-linked hydrocarbyl portion of cyclic.The example of term " alkynyl " includes but not limited to :-C ≡ CH ,-CH
2C ≡ CH ,-CH
2C ≡ C-cyclohexyl or-CH
2-cycloheptyne base.
The prefix " Asia " that is connected with alkyl, thiazolinyl, alkynyl (being equivalent to the suffix " ene " in the English) is meant that these groups have at least two positions to be substituted.This polyvalent alkyl includes but not limited to: methylene radical (CH
2-), ethylene (CH
2CH
2-), trimethylene (CH
2CH
2CH
2-), tetramethylene (CH
2CH
2CH
2CH
2-), vinylene (CH=CH-) ,-C ≡ C-, inferior proyl (CH
2C ≡ C-) and the inferior pentynyl (CH of 4-
2CH
2CH
2C ≡ CH-).
" aryl " is meant the aryl that contains one or more rings, is generally 1,2 or 3 ring, contains 4-6 carbon atom in each ring, is generally 5-6 carbon atom.
" arylalkyl ", " aryl alkenyl " and " aromatic yl polysulfide yl " are meant alkyl, the alkenyl or alkynyl that hydrogen atom (being generally hydrogen atom on end or the sp3 carbon atom) is replaced by aryl respectively.Typical arylalkyl includes but not limited to: benzyl, 2-diphenylphosphino ethane-1-base, 2-phenyl ethene-1-base, naphthyl methyl, 2-naphthyl ethane-1-base, 2-naphthyl ethene-1-base, naphtho-benzyl, 2-naphtho-diphenylphosphino ethane-1-base etc.
As sugg, carbocyclic ring randomly is monocycle or multi-loop system.Usually, the alkyl of formula (A) compound is monocyclic.The monocycle carbocyclic ring comprises 3-6 annular atoms usually, is more typically to comprise 5 or 6 annular atomses.Two ring carbocyclic rings comprise 7-12 annular atoms usually, for example are arranged as two ring [4,5], [5,5], [5,6] or [6,6] system, or comprise 9 or 10 annular atomses, and they are arranged as two ring [5,6] or [6,6] systems.
If the carbonatoms to alkyl does not specify, then carbonatoms is generally 1-18, except the carbonatoms in the unsaturated alkyl is generally 2-18, and is 6-10 in the aryl.
" heterocyclic radical " or " heterocycle " is meant heteroatomic any 4,5,6,7,8 or 9 yuan monocycle or the condensed ring system that comprises one or more O of being selected from, N or S.Heterocycle is optional to be complete aromaticity, saturated fully or comprise the heterocycle of the unsaturated position of one or more intra-annular (being generally two keys).Multicomponent heterocycle (multiple heterocyclicrings, one or more ring contains heteroatoms) is bridge joint or volution.Usually, heterocycle is an aromaticity, and they are generally monocycle.The heterocyclic example comprises: oxaza alkyl (oxazacyloalkyl), morpholinyl, dioxane alkyl (dioxacycloalkyl), sulfo-cycloalkenyl group (thiacycloalkyl), pyridyl, the dihydropyridine base, tetrahydro pyridyl (piperidyl), thiazolyl, tetrahydrochysene thiophenyl (tetrahydrothiophenyl), furyl, thienyl, pyrryl, pyranyl, pyrazolyl, pyrazolidyl, pyrazolinyl, imidazolyl, tetrazyl, benzofuryl, thianaphthenyl, indyl, indolinyl (indolenyl), quinolyl, isoquinolyl, benzimidazolyl-, piperidyl, piperazinyl, pyrrolidyl, 2-pyrrolidyl (2-pyrrolidonyl), pyrrolinyl, tetrahydrofuran base, two-tetrahydrofuran base, THP trtrahydropyranyl, two-THP trtrahydropyranyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, the octahydro isoquinolyl, the azocine base, triazinyl, 6H-1,2,5-thiadiazine base, 2H, 6H-1,5,2-dithiazine base, thianthrenyl, pyranyl, isobenzofuran-base, benzopyranyl, xanthenyl, phenoxathiin base (phenoxathinyl), the 2H-pyrryl, isothiazolyl, different thiazolidine base (isothiazoledinyl) isoxazolyl oxazolinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrrolidyl, pyrrolinyl, the indolizine base, pseudoindoyl, the 3H-indyl, the 1H-indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, the cinnoline base, pteridyl, the 4aH-carbazyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, pyrimidyl, the phenanthroline base, phenazinyl, phenothiazinyl, furazan base phenoxazinyl, the isochroman base, chromanyl, imidazolidyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperazinyl, indolinyl, iso-dihydro-indole-group, quinuclidinyl oxazolidinyl, the benzotriazole base, the benzoisoxazole base, oxindole base benzoxazole quinoline base, benzothienyl, benzothiazolyl and isatinoyl.Other suitable heterocycle illustration to some extent in the Nomenclature of Organic Compound (Adv.Chem.Ser.126 (1974) 49-64 pages or leaves) of the Nomenclature ofOrganic Chemistry (Sections A-H (1979) 53-76 pages or leaves) of Rigaudy etc. and Fletcher etc.
Not strict for the position on the heterocycle that provides with The compounds of this invention rest part tie point, but those skilled in the art can identify and has best compound stability and/or be easy to synthetic the position of substitution.The heterocycle that carbon connects is connecting with upper/lower positions usually: 2,3,4,5 or 6 of pyridine; 3,4,5 or 6 of pyridazine; 2,4,5 or 6 of pyrimidine; 2,3,5 or 6 of pyrazine; Furans, tetrahydrofuran (THF), thiophene (thiofuran), thiophene (thiophene), pyrroles or Pyrrolidine 2,3,4 or 5; Oxazole, imidazoles or thiazole 2,4 or 5; Isoxazole, pyrazoles or isothiazole 3,4 or 5; 2 or 3 of aziridine; 2,3 or 4 of azetidine; 2,3,4,5,6,7 or 8 of quinoline; Or 1,3,4,5,6,7 or 8 of isoquinoline 99.9.More generally, the heterocycle of carbon connection comprises: 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
Nitrogen heterocyclic ring connects on nitrogen or carbon, connects on carbon atom usually.These comprise, for example: 1 of aziridine, 1-'-aziridino, 1-azelidinyl, 1-pyrryl, 1-imidazolyl, 1-pyrazolyl, piperidino, 2-pyrroline, 3-pyrroline, 2-tetrahydroglyoxaline, 3-tetrahydroglyoxaline, 9-carbazole, 4-morpholine, 9-α or β-Ka Lin, 2-isoindole, 2-pyrazoline and 3-pyrazoline, and similarly: azetidine, pyrroles, tetramethyleneimine, piperidines, piperazine, indoles, pyrazoline, indoline, imidazoles, imidazolidine, 1H-indazole and isoindoline.Those skilled in the art knows these and other nitrogen heterocyclic ring, and their link position is selectable.
Sulfur heterocyclic ring connects by carbon or sulphur.They comprise oxidation state, for example-S (=O) (=O).Usually, contain N heterocyclic mode and connect to be similar at formula (A) compound.
" alkoxyl group ", " cycloalkyl oxy ", " aryloxy ", " alkoxy aryl ", " oxa-ring ", " alkylthio ", " sulfo-cycloalkyl (thiocycloalkyl) ", " arylthio " and " alkylthio-aryl " are meant that alkyl, cycloalkyl, aryl or arylalkyl pass through singly linked substituting group with Sauerstoffatom or sulphur atom respectively, such as but not limited to: methoxyl group, oxyethyl group, propoxy-, butoxy, thio-ethyl, sulphomethyl, phenoxy group, benzyloxy, sulfydryl phenmethyl etc.
" halogen " is meant any atom that is selected from down group: fluorine, chlorine, bromine and iodine.
Any appointment substituting group of finding in a more than position in the reply The compounds of this invention carries out independent selection.
When a certain group of explanation is replaced by " one or more " other group, typically refer to 1-3 substituting group, be generally 1,2 or 3 substituting group.
Those skilled in the art will be appreciated that also compound of the present invention can exist by multiple different protonation state, and this state depends on their environment pH except other factors.Though the structural formula that this paper provided has only been described a kind of in the multiple possible protonation state of compound, be to be understood that these structures just in order to illustrate, and the present invention being not limited to any concrete protonation state---any and whole protonated form of described compound all falls within the scope of this invention.
Amino acid
" amino acid " refers to be derived from and has chemical formula H
2N-CHR
28The group of the molecule of-COOH, wherein R
28It is side-chain radical with natural existence or known synthesizing amino acid.Described amino acid is randomly had the alkyl replacement of 1-8 carbon usually at its one or more carboxyls or amino place, and with after compound rest part of the present invention is connected, these groups can be positioned on the side chain or free at amino acid.
Randomly, described amino-acid residue is a hydrophobic residue, as single-or two-alkyl or aryl amino acid, cycloalkylamino acid etc.Choose wantonly, this residue does not contain sulfydryl or guanidine radicals substituting group.
Naturally occurring amino-acid residue is present in plant, animal or the microorganism, especially in their protein.Most of polypeptide are made up of such natural amino acid residue usually basically.These amino acid are: glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, Serine, Threonine, halfcystine, methionine(Met), L-glutamic acid, aspartic acid, Methionin, hydroxylysine, arginine, Histidine, phenylalanine, tyrosine, tryptophane, proline(Pro), l-asparagine, glutamine and oxyproline.In addition, also comprise alpha-non-natural amino acid, for example valanine, phenylglycocoll and homoarginine.
Usually, on any position in the parent molecule only one by aminoacid replacement, although introduce amino acid also within the scope of the present invention in permission position more than 1.Usually; amino acid whose alpha-amino group or α-carboxyl are connected to the remainder of molecule; that is, carboxyl in the amino acid side chain or amino-as be not used in and parent compound forms amido linkage (although needing these groups are protected) during synthetic binding substances (conjugate).
Under acid (pH＜3) or alkalescence (pH＞10) condition, amino acid ester in vivo or external optional be hydrolyzable.Randomly, they are stable basically in people's intestines and stomach, but blood or in intracellular environment by enzymic hydrolysis.
R
28Be C
1-C
6Alkyl or quilt are selected from down the C of the group replacement of group
1-C
6Alkyl: amino, carboxyl, acid amides, carboxyl (and aforesaid ester), hydroxyl, C
6-C
7Aryl, guanidine radicals, imidazolyl, indyl, sulfydryl, sulfoxide and/or alkyl phosphate.R
28Also can be nitrogen, it is with amino acid α-form proline residue.Yet, R
28What be generally above to be disclosed naturally exists amino acid whose side-chain radical, for example: H ,-CH
3,-CH (CH
3)
2,-CH
2-CH (CH
3)
2,-CHCH
3-CH
2-CH
3,-CH
2-C
6H
5,-CH
2CH
2-S-CH
3,-CH
2OH ,-CH (OH)-CH
3,-CH
2-SH ,-CH
2-C
6H
4OH ,-CH
2-CO-NH
2,-CH
2-CH
2-CO-NH
2,-CH
2-COOH ,-CH
2-CH
2-COOH ,-(CH
2)
4-NH
2With-(CH
2)
3-NH-C (NH
2)-NH
2R
28Also comprise 1-guanidine radicals third-3-base, benzyl, 4-hydroxybenzyl, imidazol-4 yl, indol-3-yl, p-methoxy-phenyl and ethoxyl phenenyl.
Exemplary embodiment
R
1Be generally by 1,2 or 3 R
6The aryl or the aromatic heterocycle that replace, wherein, R
6Be halogen, C
1-C
18Alkoxyl group; Or C
1-C
18Haloalkyl.Usually, R
1Be the phenyl that is replaced by 1,2 or 3 halogen (being generally fluorine).
Y is generally singly-bound, O, C
1-6Alkylidene group, C
2-6Alkenylene, C
2-6Alkynylene, or be selected from O, S or NR for containing 1-3 (being generally 1)
11A heteroatomic above-mentioned group.Example comprises :-O (CH
2)
1-5-,-(CH
2)
1-4-O-(CH
2)
1-4-,-S-(CH
2)
1-5-,-(CH
2)
1-4-S-(CH
2)
1-4-,-NR
11-(CH
2)
1-5-,-(CH
2)
1-4-NR
11-(CH
2)
1-4Or C
3-10Cycloalkylidene (cycloalkylidene).Usually, Y is-OCH
2-,-CH
2O-, C
1-2Alkylidene group, C
2-3Alkenylene, C
2-3Alkynylene, O or key, but be generally a key.
Usually, YR
1Be not H, unsubstituted C
3-10Cycloalkyl or C
1-6Among the alkyl any.Usually, YR
1The phenyl of (being generally trihalomethyl group) that replaces for halogen or halogenated methyl (and usually on an ortho position or a position 1 or 2 substituting group arranged).
X is generally alkylidene group, alkenylene or alkynylene, is generally alkylidene group, perhaps has heteroatoms in the chain, is generally the described alkyl of O or S.Example comprises :-CH
2-,-CH (CH
3)-,-CH
2-CH
2-,-CH
2-CH
2-CH
2,-CH
2-CH
2-CH
2-CH
2,-(CH
2)
2-4-O-(CH
2)
2-4-,-(CH
2)
2-4-S-(CH
2)
2-4-,-(CH
2)
2-4NR
10-(CH
2)
2-4-, C
3-10Cycloalkylidene, C
2-6Alkenylene (for example-CH=CH-CH
2-) and C
2-6Alkynylene.Usually, X is a methylene radical.
R
3Be generally aryl or heterocycle, be generally the aromaticity heterocycle.Usually comprise 1,2 or 3 N, S or O atom in this heterocyclic ring, be connected with X by ring carbon atom usually, and contain 4-6 (often being 5) total annular atoms usually.This R
3Aryl or heterocycle are often by 1,2 or 3 (being generally 1) R
17Replace.R
3It randomly is not indyl.
Work as R
3By R
17During replacement, R
17Be generally by one or more (being generally 1,2 or 3) R
19The heterocycle or the aryl that replace.
R in some embodiments of the present invention
17Be M-Q.M is ring.Here be meant any cyclic organic structure, no matter be carbocyclic ring or heterocycle, no matter be saturated, unsaturated or aromaticity or monocycle or condensed ring system.M is selected from constitutionally stable lopps in biosystem.Usually, M is aryl or aromaticity heterocycle, and wherein, heterocycle as defined above.
Q is a spacer groups and optional.Usually it is not a cyclic, and does not cover and comprise maximum 3 atoms (being generally C, O or S, often is C or O).
R
17Usually be selected from down group: C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl; Alkoxy aryl (optional is benzyloxy); Alkylthio-aryl (optional is benzylthio-); Heterocycle; C
1-18Hydroxyalkyl, but be generally aryl or heterocycle, and wherein, each described aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl, alkoxy aryl, alkylthio-aryl or heterocyclic radical are randomly by one or more R
19Replace.R
17Be usually located at the far-end of X.Randomly, R
17Be not C (O) R
18
R
9And R
18Be generally H, OH or alkyl.R
18Optional is not NR
15R
16
R
5Be generally H.
R
6Be generally halogen.Randomly, R
6Be not C (O) R
18
R
7, R
8, R
10, R
11, R
13, R
14, R
15, R
16, R
20, R
21, R
23And R
24Usually be H or C independently
1-18Alkyl.
R
12And R
22Usually be OH or alkyl independently.
R
19Be generally H; C
1-18Alkyl; C
2-18Thiazolinyl; C
2-18Alkynyl; C
1-18Alkoxyl group; Alkene oxygen base; Alkynyloxy group; C
1-18Alkylthio; C
3-10Cycloalkyl; C
4-10Cycloalkenyl group; C
4-10Cycloalkynyl radical; Halogen; OH; CN; The cyano group alkyl, NO
2NR
20R
21Haloalkyl; Halogenated alkoxy; C (=O) R
18C (=O) OR
18O thiazolinyl C (=O) OR
18-O alkyl C (=O) NR
20R
21Aryl; Heterocycle;-O alkyl OC (=O) R
18C (=O) N (C
1-6Alkyl), (O) (C of N (H) S (O)
1-6Alkyl); Alkoxy aryl; Aryloxy; Alkoxy aryl and arylalkyl; They are not substituted separately or are replaced by one or more groups that are selected from down group :=O; NR
20R
21CN; Alkoxyl group; Heterocycle; Haloalkyl-or the heterocycle of alkyl-replacement; Be connected to R by alkyl, alkoxyl group alkoxy or halogen
17Heterocycle.At this as substituent R
18Usually be not H.R
19Usually be halogen, N (R independently
20R
21), the alkyl or the alkoxyl group of alkoxy or halogen-replacement.
R
25And R
26Usually do not exist, but if present, be generally cyclopentyl or cyclohexyl.If compound is at R
25Or R
26Be substituted, then R
2Or R
4Be selected from: (=O), (=S) and (=NR
27), be generally=O.
M is generally the ring of aromaticity, is generally monocycle or two condensed rings, and contains 4-10 atom.Usually, M is an alkyl, but also can randomly comprise 1-3 N, O and/or S heteroatoms.
Q is generally hydrocarbon chain, Chang Weizheng or secondary thiazolinyl, and it randomly comprises at least one oxygen or thioesters.Usually Q is a 1-6 atom, often is 1-3.Q is not usually by R
19Replace, if but by R
19Replace, then Q is generally by 1 R
19Replace.Go up substituent R as Q
19Be generally halogen, nitro or cyano group.Substituting group randomly indicates key or does not indicate key.No matter whether indicate key, (bond indication), if substituting group is polyvalent (based on its position in the indication structure), substituting group then any and that all may be orientated all is as expected.
Haloalkyl or halogenated alkoxy are generally-CF
3Or-OCF
3
The invention provides formula (A) compound of following formula structure,
Such as the method (for example the part B in the embodiment part " is used to measure antiviral and method cell growth inhibiting activity ") of being instructed in full with specification sheets mensuration, it has antiviral activity.The preparation of this compound has been stated in religion in specification sheets full text, for example in embodiment 6.
The present invention also provides formula (A) compound of following formula,
Such as the method (for example the part B in the embodiment part " is used to measure antiviral and method cell growth inhibiting activity ") of being instructed in full with specification sheets mensuration, it has antiviral activity.The preparation of this compound has been stated in religion in specification sheets full text, for example in embodiment 8A.
Formula (A) has been described optional singly-bound or two key.Should be understood that these keys exist, thus the aromaticity of the formula of keeping (A) core, and promptly these structural formulas will comprise all possible tautomer.For example, if suc as formula shown in and R
25Or R
26Bonded ring N links to each other with lateral (flanking) ring carbon atom by two keys, then R
25Or R
26To not exist.From another point of view, if suc as formula shown in and R
25Or R
26Bonded N atom only links to each other with lateral carbon atom by singly-bound, then can have R
25Or R
26In this case, regulate aromaticity, for example R wherein by other substituting group
2Or R
4Be oxo.
As used herein, term " prodrug " is meant after giving biosystem, as the result of spontaneous chemical reaction, enzymatic chemical reaction, photolysis and/or metabolic chemical reaction and produce the compound of medicine (being activeconstituents).Therefore, prodrug is the covalent modification analogue or the potential form of therapeutical active compound.
Prodrug
Some compound herein can be as the prodrug effect when being replaced by the suitable functional group (functionality) through selecting.These unsettled functional groups separate from the downtrod compound of activity in cell on systematicness ground in metabolic process, this separation is carried out (Bulldgaard by hydrolysis, enzymatic lysis or by some other method, Hans, " Designand Application of prodrugs " (1991) in Textbook of Drug Design and Development one book, P.Krogsgaard-Larsen and H.Bundgaard compiles.Harwood Academic Publishers, the 113-191 page or leaf).These prodrug moieties can be used for strengthening that solubleness, absorptivity and lipotropy are sent to optimize medicine, bioavailability and drug effect.Therefore, " prodrug " is the covalency improvement analogue of therapeutical active compound.Certainly, prodrug moiety itself can have therapeutic activity.
Exemplary prodrug moiety comprises: the responsive or unsettled carboxylic acid (CO to hydrolysis
2H) ester class (CO
2R ') or have other functional group of the acid proton that is incorporated into imidazo of the present invention [4,5-c] pyridine compounds.This type of R ' group responsive to hydrolysis or unsettled ester class can comprise: (i) acyloxy methyl ester ,-CH
2OC (=O) R
9a(ii) acyloxy methyl carbonic-CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
6Alkyl, C
1-C
6The alkyl that replaces, C
6-C
20Aryl or C
6-C
20The aryl that replaces.The prodrug moiety that also can be used as The compounds of this invention near variant of acyloxy alkyl ester, alkoxy-carbonyl oxy alkyl ester (carbonic ether) strengthens oral administration biaavailability.Acyloxy methyl ester R group be exemplified as the pivaloyl group Oxymethoxy, (POM)-CH
2OC (=O) C (CH
3)
3Acyloxy methyl carbonic prodrug moiety be exemplified as pivaloyl group oxygen ylmethyl carbonic ether, (POC)-CH
2OC (=O) OC (CH
3)
3Cleavable (cleavable) part that can be used as prodrug functional group randomly is connected on the compound of the present invention in any open ended site, for example R
3And any substituting group.
The compound of getting rid of
The present invention has got rid of all compounds that clearly disclose (excluded ranges constitutes effective novelty or inventive step/apparent property defective for this reference to the application) (also having got rid of the compound that is disclosed in the patent families in any referenced patent) in any prior art reference from the compound that the application sets forth, and can make the application's claim losing novelty or not creative step or be conspicuous any other compound according to the application law.
As institute's requirement, the present invention has got rid of the compound of following general formula (A):
(a) substituent X, Y, R
1, R
2, R
3, R
4, R
5In arbitrary be cynnematin, or wherein substituent X, Y, R
1, R
2, R
3, R
4, R
5Being the azabicyclo group, more specifically is also [4.2.0] oct-2-ene-8-ketone of 5-thia-1-aza-bicyclo;
(b) this compound is bromination 5-(2-piperidines-1-base-ethyl)-2-(4-hydroxy phenyl)-1H-imidazo [4,5-c] pyridine-5-(X=ethyl, Y=key, R
1The phenyl that=contraposition is replaced by OH, R
2=H, R
3=piperidyl, and R
4, R
5=H) (such as embodiment 52 among the EP 1132381 announcement);
(c) this compound be 4-[5-(2-14-[is two-(4-fluorophenyl)-methyl]-piperazine-1-yl-ethyl)-5H-imidazo [4,5-c] pyridine-2-yl] phenol (X=ethyl, Y=key, R
1The phenyl that=contraposition is replaced by OH, R
2=H, R
3=have 2 heteroatomic heterocycles of N, wherein, an involved CH of N (phenyl)
2Arylalkyl replace, and wherein each phenyl all has F in contraposition) (such as embodiment 54 among the EP 1132381 announcement);
(d) this compound be 4-[5-(3-{4-[is two-(4-fluorophenyl)-methyl]-piperazine-1-yl-propyl group) 5H-imidazo [4,5-c] pyridine-2-yl] phenol (X=butyl, Y=key, R
1The phenyl that=contraposition is replaced by OH, R
2=H, R
3=have 2 heteroatomic heterocycles of N, wherein, an involved CH of N (phenyl)
2Arylalkyl replace, and wherein each phenyl all has F in contraposition) (such as embodiment 55 among the EP 1132381 announcement);
(e) this compound is 5-(phenyl methyl)-5H-imidazo [4,5-c] pyridine, and wherein, phenyl is by CONR
15R
16Replace R
16C for side chain
3Alkyl, and R
16Be phenyl (X=-CH
2-; The Y=key; R
1=hydrogen; R
2=H; R
3=by 1 C (=O) R
18The phenyl that replaces, wherein, R
18Be NR
15R
16, and R
15And R
16C for side chain
6Alkyl; R
4=H) (as US 5,302,601 embodiment 35 discloses);
(f) this compound is 6-(5H-imidazo [4,5-c] pyridine-5-base-methyl)-N-(1 methylethyl)-N-phenyl-3-pyridine carboxamides (X=-CH
2-; The Y=key; R
1=hydrogen; R
2=H, R
3=by 1 R
6The pyridine that replaces, wherein, R
6=1 C=OR
18, R
18Be NR
15R
16, R wherein
15=sec.-propyl, and R
16=phenyl) (as US 4,990,518 embodiment 6 discloses);
(g) this compound is following compound: wherein, and X=-CH
2-; The Y=key; R
1=hydrogen; R
2=H, R
3=5-6 unit heterocycle is specially pyridyl or furyl, and it is by 1 R
17Replace, wherein, R
17=C (=O) R
18, and R
18=NR
15R
16, R
15And R
16Perhaps be C
1-18Alkyl (being specially methyl, ethyl or sec.-propyl), C
2-18Thiazolinyl (being specially the 2-methacrylic) or for C
3-10Cycloalkyl (being specially cyclopentyl or cyclohexyl) (as US 4,990,518 announcements);
(h) this compound is following compound: wherein, and X=-CH
2-; The Y=key; R
1=hydrogen; R
2=H, R
3=5-6 unit heterocycle is specially pyridyl or furyl, and it is by 1 R
17Replace, wherein, R
17=C (=O) R
18, and R
18=C
3-10Cycloalkyl or C
4-10Cycloalkenyl group.
(i) this compound is 2,6-two (1,1,-dimethyl ethyl)-4-[[2-(5H-imidazo-[4,5-c] pyridine-5-yl) ethyl] sulphur]-phenol hydrate and/or 2,6-two (1,1,-dimethyl ethyl)-and 4-[[2-(5H-imidazo-[4,5-c] pyridine-5-yl) propyl group] sulphur]-phenol hydrate (X=CH
2-CH
2-; The Y=key; R
1=hydrogen, R
2=H, R
3=by 3 R
6The arylthio (thioaryl) that replaces, wherein, R
6The side chain C of position between=2
4The OH of alkyl and contraposition) (such as among the embodiment 6 of WO 96/12703 announcement);
(j) this compound is 5-[2-(phenylbenzene-4-base oxygen)-ethyl]-5H-imidazo [4,5-c] pyridine (X=CH
2CH
2, Y=key, R
1=hydrogen, R
2=H, R
3=in contraposition by a R
17The phenoxy group that replaces, wherein, R
17=benzyl; R
4=H) (such as among the WO 96/11192 announcement);
(k) this compound is 5-[2-(4-phenoxy group-phenoxy group)-ethyl]-5H-imidazo [4,5-c] pyridine (X=CH
2CH
2, Y=key, R
1=hydrogen, R
2=H, R
3=in contraposition by a R
17The phenoxy group that replaces, wherein, R
17=phenoxy group; R
4=H) (such as among the WO 96/11192 announcement);
(1) this compound is [5-(4-luorobenzyl)-5H-imidazo [4,5-c] pyridine-2-yl]-methylamine (X=CH
2, Y=NR
11, wherein, R
11=methyl, R
1=R
2=H, R
3=in contraposition by a R
17The phenyl that replaces, wherein R
6Be F, R
4=H, R
5=H) (such as among the EP 76530 announcement);
(m) this compound is 2, two (1,1 ,-dimethyl ethyl)-4-[[3-(5H-imidazo-[4, the 5-c] pyridine-5-yl) propyl group of 6-] sulphur]-phenol hydrate (X=CH
2-CH
2-CH
2, the Y=key; R
1=hydrogen, R
2=H, R
3=by three R
6The thiophenyl that replaces, wherein, R
6The side chain C of position between=2
4The OH of alkyl and contraposition) (such as WO 96/12703 announcement);
(n) this compound is 5-[2-(4-phenyl methoxyl group-phenoxy group)-ethyl]-5H-imidazo [4,5-c] pyridine (X=CH
2CH
2, Y=key, R
1=hydrogen, R
2=H, R
3=in contraposition by a R
17The phenoxy group that replaces, wherein, R
17=benzyloxy) (such as WO 96/11192 announcement);
(o) this compound is 5-[3-(4-phenoxy group-phenoxy group)-propyl group]-5H-imidazo [4,5-c] pyridine (X=CH
2CH
2CH
2, Y=key, R
1=hydrogen, R
2=H, R
3=in contraposition by a R
6The phenoxy group that replaces, wherein, R
6=the phenoxy group that replaced by F in contraposition; R
4=H) (such as WO 96/11192 announcement);
(p) this compound is 5-{2-[4-(4-fluorophenoxy)-phenoxy group]-ethyl }-5H-imidazo [4,5-c] pyridine (X=CH
2CH
2, Y=key, R
1=hydrogen, R
2=H, R
3=in contraposition by a R
6The phenoxy group that replaces, wherein, R
6=the phenoxy group that replaced by F in contraposition; R
4=
H) (such as WO 96/11192 announcement);
(q) this compound is 5-[3-(4-phenyl methyl-phenoxy group)-propyl group]-5H-imidazo [4,5-c] pyridine (X=CH
2CH
2CH
2, Y=key, R1=hydrogen, R2=H, R
3=in contraposition by a R
6The phenoxy group that replaces, wherein, R
6=benzyl; R
4=H) (such as WO 96/11192 announcement);
(r) this compound is (1H-indol-3-yl)-[3-(2-methyl-5H-imidazo [4,5-c] pyridine-5-carbonyl)-phenyl]-ketone (X=-(C=O)-or SO
2, Y=CH
2, R
1=H, R
2=H, R
3=by a R
6The phenyl that replaces, wherein, R
6Be C (=O) R
18, R
18Be indoles) (as US 5,486,525 announcements);
(s) this compound is 4 or 3-[(2-methyl-5H-imidazo [4,5-c] pyridine-5-yl) methyl]-phenylformic acid alkyl ester or 5-[4 or 3-(alkoxy carbonyl-phenyl)-methyl]-2-methyl-5H-imidazo [4,5-c] pyridine, be specially 4 or 3-[(2-methyl-5H-imidazo [4,5-c] pyridine-5-yl) methyl) methyl esters (X=CH
2, Y=CH
2, R
1=H, R
2=H, R
3=in contraposition or a position by a R
17The phenyl that replaces, wherein, R
17Be (C=O) R
18, the R18=alkoxyl group) and (as US 5,486,525 announcements);
(t) this compound is the 5-[(fluorophenyl) methyl]-2-amino-5-H-imidazo [4,5-c] pyridine (XR
3=luorobenzyl, Y=NR
11, R
11=methyl, R
1=H, R
2, R
3, R
4=H) (as US 5,137,896 announcements);
(u) this compound is ((5-[4-(fluorophenyl) methyl]-5-H-imidazo [4,5-c]-pyridine-2-yl) methyl)-carbamate, methyl esters (XR
3=luorobenzyl, Y=C (=O) R
12, R
12=methyl, R
1=H, R
2, R
3, R
4=H) (as US 5,137,896 disclose);
(v) this compound is 5-(4-Chlorophenylmethyl)-2-(piperidines-1-ylmethyl)-5H-imidazo [4,5-c] pyridine and dihydrochloride (XR thereof
3=benzyl chloride base, Y=-CH
2-, R
1=piperidyl) (as Justus Liebigs Annalen derChemie (1971), 747,158-171 discloses);
(w) this compound is 5-(4-Chlorophenylmethyl)-2-(4-methyl-piperazine-1-ylmethyl)-5H-imidazo [4,5-c] pyridine (XR
3=benzyl chloride base, Y=-CH
2-, R
1=piperazinyl, R
6=methyl) (as Journal of theChemical Society[section B]: Physical Organic (1966), 4,285-291 discloses);
(x) compound is specially Cleve etc., the compound 9 that " Liebigs Ann.Chem.747:158-171 (1971) " the 160th page;
(y) compound is specially the compound 19 and 20 in " Chem.Pharm.Bull.43 (3): 450-460 (1995) " such as Kiyama; And
(z) compound is specially the compound 14 of " Tet.Lt. " 48 (48): 10549-10558 (1992) such as Medereslci.
Compound of the present invention is randomly got rid of aforesaid those general formulas (A) compound, wherein, and (a) YR
1Phenyl for being replaced by OH in contraposition, or (b) be H, unsubstituted C
3-10Cycloalkyl, or C
1-6Alkyl.
Compound of the present invention is randomly got rid of aforesaid those general formulas (A) compound, wherein, and R
1Be not H, Y is not NR
11, R
11Be C
1-6Alkyl or methyl, and/or YR
1Be not monomethyl amino.
Compound of the present invention is randomly got rid of aforesaid those general formulas (A) compound, wherein, and R
1For by a R
6The phenyl that replaces, R
6Be C (=O) R
18, R
18Be tert.-butoxy.
Compound of the present invention is randomly got rid of aforesaid those general formulas (A) compound, wherein, and R
1Be not piperidyl, and be not by methyl substituted piperazinyl.
Compound of the present invention is got rid of the compound that WO 2004/005286 is disclosed, and is specially compound listed in its table 8.
Compound of the present invention is randomly got rid of following compound: XR
3Definition and United States Patent (USP) 5,302, the substructure-(CH in the comparable announcement of 601 the 1st hurdles the 49th row-Di 2 hurdles the 38th row and any patent families thereof
2) n-Y-C (O)-N (R
1) (R
2) identical, the announcement in these patents is included this paper in as a reference.
Compound of the present invention is randomly got rid of R
5Be included in any substituting group that is designated as " Ar " among the WO 00/39127, be specially aryl, aryl phenoxy group or benzyl.
Compound of the present invention does not randomly comprise the compound among the embodiment of following patent: United States Patent (USP) 5,302,601 embodiment 35, United States Patent (USP) 4,990, embodiment 6 in 518, United States Patent (USP) 4,988,707 embodiment 1-5, United States Patent (USP) 5,208,241 embodiment 1-5, United States Patent (USP) 5,137,896 embodiment 39, pyridine benzimidazole compounds among the WO99/27929, United States Patent (USP) 5,227,384 embodiment 1-20 and 45, the embodiment 3 and/or 11 of WO96/12703, and/or the compound 340A of WO 96/11192,347C, 349C, 351C, 355C and/or 356C.
Compound of the present invention is randomly got rid of XR
3Be equal to United States Patent (USP) 4,990, listed substructure-(CH in the 41st row-Di 2 hurdles, 518 the 1st hurdles the 24th row
2)
n-Het-C (O)-N (R
1) (R
2).
Compound of the present invention do not comprise in the background of invention above in the listed patent the compound that disclosed among the compound, Chemical Abstracts acc no.1987:18435 and the Chemical Abstracts acc no.1983:594812 that clearly disclose.
Compound of the present invention does not comprise Justus Liebigs Annalen der Chemie (1971), 747,158-171 or the Journal of the Chemical Society[section B]: PhysicalOrganic (1966), 4, among the 285-291 the compound that clearly discloses.
Randomly, compound of the present invention is got rid of YR
1Be United States Patent (USP) 5,486, the capable R that is appointed as of 525 the 5th hurdle 22-38
13One of substituting group, and/or R
2And/or R
5Be United States Patent (USP) 5,486, the capable compound of concentrating one of specified substituting group of 525 the 5th hurdle 38-53.
Randomly, compound of the present invention is got rid of the compound in any patent families of any announcement or the patent of mandate (especially in the patent of quoting in this mandate).
At last, compound of the present invention is also randomly got rid of the methylene radical analogue of the aforementioned known compound of getting rid of in the scope of the invention.Should understand the compound of randomly getting rid of and also comprise its esters.
Purposes
Compound of the present invention or have a large amount of purposes by the metabolite that these compounds produce in vivo.They can be used on fields such as immunology, chromatographic science, diagnostics and treatment.
With formula (A) but compound and immunogenic polypeptide engage with as inducing the generation specificity to combine the reagent of the antibody of this polypeptide, this compound or their meta-bolites (it has kept the epi-position of immune identification, i.e. the site of antibodies).Therefore, these immunogenic compositions can be used as that preparation is used for diagnosing, the antibody of quality control etc. or the intermediate of test formula (A) compound or their new meta-bolites.This compound can be used for producing the antibody of anti-other non-immunogenic polypeptide, this be since this compound as the haptens site stimulate can with the immune response of the conjugated protein generation cross reaction of unmodified.
The binding substances of formula (A) compound and immunogenic polypeptide (for example albumin or keyhole hemocyanin) is often used as antigen.This polypeptide with supply with amino acid whose same loci on combine.Above-mentioned meta-bolites can keep the immune cross-reactivity with the roughly the same degree of compound of the present invention.Therefore, antibody of the present invention can with without the protection compound of the present invention combine, and not with through the protection compound combine.Perhaps, this meta-bolites can with through the compound of protection and/or combine with this meta-bolites and can not combine with compound of the present invention through protecting, or can be specifically arbitrary or whole in conjunction with among the three.Substantial cross reaction will can not take place with naturally occurring material in ideal antibody.Substantive cross reaction (Substantial cross-reactivity) is the reaction that can make the effective distrubed test result of specific analyte under the fc-specific test FC condition.
Immunogen of the present invention comprises compound of the present invention, and described compound can the required epi-position of submission when combining with immunogenic substance.In full text of the present invention, this combination is meant that covalent attachment is to form immunogenic conjugates (at where applicable) or the mixture of non-covalent bond material or above-mentioned combination.Immunogenic substance comprises: adjuvant, for example freund's adjuvant; Immunogenic protein, for example virus, bacterium, yeast, plant and animal polypeptide, especially keyhole hemocyanin, serum albumin, bovine thyroglobulin or Trypsin inhibitor SBTI and immunogenicity polysaccharide.Usually, the crosslinking reaction agent of multifunctional by using (being generally two senses) makes the compound with required epi-position structure combine with immunogenic polypeptide or polysaccharide covalent.Being used to prepare the immunogenic method of haptens is conventional in essence, also should use be used for haptens is attached to any method of immunogenic polypeptide etc. up to now, and consider to can be used on precursor or the hydrolysate possibility of the antibody of crosslinked functional group and the generation unknown epitope specificity opposite with immunogenic substance.
Usually polypeptide chain is connected on away from being identified on the site of epi-position on the The compounds of this invention.
Mode with routine prepares this binding substances.For example, linking agent N-hydroxy-succinamide, succinyl oxide or alkyl N=C=N alkyl (alkN=C=Nalk) are used to prepare binding substances of the present invention.This binding substances comprises by key or has 1-100, is generally 1-25, is more typically the linking group of 1-10 carbon atom, the compound of the present invention that is connected with immunogenic substance.By methods such as chromatograms, this connector is separated from parent material and by product, sterile filtration and bottling store then.
Usually animal is carried out the immunity of anti-immunogenic conjugates or derivative, and prepare antiserum(antisera) or monoclonal antibody in a conventional manner.
Compound of the present invention can be used as in the preparation affinity adsorbing base affinity (being generally hydrophobicity) partly, connector or spacer.Randomly with the insoluble matrix covalent attachment and be used for the affinity chromatography partition method, this depends on the character of compound group, for example the compound that has aryl side can be used to prepare hydrophobic affinity post with compound of the present invention.
They also can be in the preparation of immobilized enzyme as the connector and the spacer that are used for process control, or as connector and spacer in the immunoassay agent preparation.The functional group that compound comprised of this paper is suitable for as carrying out crosslinked site with desired substance.For example, conventional is that affinity reagent is combined with insoluble matrix, and described affinity reagent is for example hormone, peptide, antibody, medicine etc.Use these insoluble reagent in a known manner, with from the preparation, test sample and other the impure mixture that make absorption affinity reagent in conjunction with counterpart.Similarly, immobilized enzyme is used to be easy to reclaim the catalyzed conversion of enzyme.When the preparation diagnostic reagent, with two functional compounds analyte is linked to each other with detectable group usually.
For diagnostic purpose, available detectable part (biological example element, radio isotope, enzyme etc.) is carried out mark to compound of the present invention.Known realization is to the Appropriate technology of formula (A) compound mark, and after this specification sheets integral body is considered, these technology will be conspicuous for technicians.For example, a site that is suitable for mark is R
17Or R
19
Yet, having more representational is that compound of the present invention is used for the treatment of or prophylaxis of viral infections, for example yellow fever virus, dengue fever virus, hepatitis B virus, hepatitis G virus, typicalness Pig Fever virus or edge disease virus infect, but more particularly be used for the treatment of or virus infection, especially HCV and the BVDV of prevention of flavivirus section or pico+ribonucleic acid+virus section.
Can give mammalian object (comprising the people) with one or more therapeutic compounds of the present invention by any mode well known in the art, promptly by oral, nose interior, subcutaneous, intramuscular, intracutaneous, intravenously, intra-arterial, gi tract are outer or mode administration such as conduit insertion.The treatment significant quantity of described one or more compounds is growth-inhibiting amounts of flavivirus or pico+ribonucleic acid+virus.More preferably, it duplicates formula (A) compound of amount of suppression or flavivirus or pico+ribonucleic acid+virus enzyme amount of suppression for flavivirus or pico+ribonucleic acid+virus.It is believed that this is equivalent to guarantee that blood plasma level is about 1 μ g/ml-100mg/ml, randomly is the amount of 10mg/ml.This selected value is by administration of human every kg body weight every day 0.001-60mg, preferred 0.01-10mg, more preferably the dosage of 0.1-1mg obtains.These are the starting points that are used for the preferred dose of definite The compounds of this invention.Accurately amount will depend on many factors known to the skilled, and these factors comprise: the bioavailability of compound, whether it comprises, and prodrug is functional, its metabolism and distribution and its effectiveness etc. in object.Usually be necessary in clinical adjustment to determine suitable dosage, and this point is known to those of ordinary skills.The treatment significant quantity of one or more compounds of the present invention randomly can be divided into several subunits every day, or give every day or surpass a world at interval to give, this depends on the state of an illness that will treat, patient's situation and the character of The compounds of this invention.
As the routine in this area, can by analyze between each medicine interactional quantitatively, adopt Chou etc. at the intermediate value principle of effect (median effect principle) described in Adv Enzyme Reg. (1984) 22:27 or with the test that includes but not limited to isobologram (as Elion etc. at J.Biol.Chem. (1954) 208:477-488 and Baba etc. described in Antimicrob.Agents Chemother. (1984) 25:515-517), use EC
50Come calculating section inhibition concentration (fractional inhibitory concentration) to assess the synergy of pharmaceutical composition.
Can be included in the antiviral composition or the suitable antiviral agent that gives jointly in a course of treatment comprises, for example: interferon alpha, virazole, fall within EP1162196, WO 03/010141, compound in the scope that WO 03/007945 and WO 03/010140 are disclosed, fall within the compound in WO 00/204425 and other patent or their scope that patent family application disclosed, dosage is the 1-99.9 weight % that accounts for The compounds of this invention, preferred 1-99 weight %, more preferably 5-95 weight %, this dosage can be determined at an easy rate by those skilled in the art.Need not this type of common administered agents is formulated in the formulation identical with compound of the present invention.The course of treatment that gives object formula (A) compound, can randomly they be given the object in the course of treatment separately.
The present invention also provides veterinary composition, and said composition comprises at least a activeconstituents as defined above and carrier for animals thereof, for example is used for the treatment of BVDV.Carrier for animals is the material that is used to give the purpose of composition, and it is an acceptable vehicle in inertia or the veterinary field, and can be compatible with compound of the present invention.Can be oral, outside gi tract or by other required approach, give these veterinary compositions.
Salt
As used herein, term " pharmacy acceptable salt " refers to the non-toxic salt form by the therapeutic activity of formula (A) compound formation.Such salt can comprise the salt that suitable positively charged ion (as basic metal and alkaline-earth metal ions or ammonium and quaternary ammonium ion) is obtained with acid anion part (normally carboxylic acid) chemical combination.The compounds of this invention can have a plurality of positive charges or negative charge.The net charge of The compounds of this invention can be for just or for negative.Usually can adopt the synthetic and/or separation method that obtains this compound to introduce any associating counter ion.Typical counter ion include but not limited to: ammonium, sodium, potassium, lithium, halogen, acetate moiety, trifluoroacetic acid root etc. and their mixture.Be understood that any associating counter ion kind is not a key feature of the present invention, the present invention includes and the associating compound of any kind counter ion.In addition, because The compounds of this invention can various multi-form existence, the present invention not only is intended to comprise and the associating compound form of counter ion (for example dried salt), also comprise not with the associating form of counter ion (as, the aqueous solution or organic solution).Usually, can make metal-salt by metal hydroxides and The compounds of this invention are reacted.The example of Zhi Bei metal-salt is by this way: contain Li
+, Na
+, Ca
2+, Mg
2+And K
+Salt.Can make more insoluble salt from the solution of more diffluent salt, separate out by adding suitable metallic compound.In addition, can form salt in the acid groups by some organic acid and mineral acid are joined alkali center (being generally amine) or join.The example of this suitable acid comprises, for example: and mineral acid, as haloid acid (example hydrochloric acid or Hydrogen bromide), sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid, as acetate, propionic acid, oxyacetic acid, phenylformic acid, 2 hydroxy propanoic acid, 2-oxo propionic acid, lactic acid, fumaric acid, tartrate, pyruvic acid, toxilic acid, propanedioic acid, oxysuccinic acid, Whitfield's ointment (that is 2 hydroxybenzoic acid), para-aminosalicylic acid, ethylenehydrinsulfonic acid, lactobionic acid, succsinic acid, oxalic acid and citric acid; Organic sulfonic acid is as methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid and tosic acid; And mineral acid, for example hydrochloric acid, sulfuric acid, phosphoric acid and thionamic acid; C
1-C
6Alkylsulphonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, cyclohexane sulfamic acid etc.Preferred salt comprises: mesylate and hydrochloride.
Compound of the present invention comprises the solvate by formula (A) compound and salt formation thereof, hydrate for example, alcoholate etc.Composition as herein described comprises the compound of the present invention and the zwitterionic form thereof of unionization form and combines the hydrate forms of formation with the water of stoichiometry.
Also comprise formula (A) compound and one or more aforesaid amino acids formed salt in the scope of the invention.Described amino acid has the side chain with basic group or acidic-group usually, as Methionin, and arginine or L-glutamic acid, or have the side chain of neutral group, and as glycine, Serine, Threonine, L-Ala, Isoleucine or leucine.
Also can use not as the salt of acid of being accepted on the physiology or alkali, for example, be used for preparation or purifying formula (A) compound., derived from physiologically acceptable acid or alkali whether all salt all within the scope of the invention no matter.
Isomers
As used herein, term " isomers " is meant all possible isomeric form of formula (A) compound, comprises change and stereochemical form, but does not comprise positional isomers.Usually, structure shown in this article is only enumerated a kind of change form or the resonance form of compound, but also comprises other corresponding configuration.Except as otherwise noted, the chemical symbol of compound (designation) refers to the mixture of all possible form of three-dimensional chemical isomer, described mixture comprises all diastereomers and enantiomorph (because formula (A) compound can have one or more chiral centres), and stereochemistry isomer pure or enrichment.More specifically, three-dimensional center can have R-or S-configuration, and two key or triple bond can randomly be cis-or transconfiguration.
The isomeric form of the enrichment of The compounds of this invention is meant substantially the not individual isomer of other enantiomeric form of this compound or diastereo-isomerism form.Particularly, term " enrichment on the stereoisomerism " or " the chirality enrichment " are meant that the single stereoisomers ratio is at least about 80% (promptly, a kind of isomer of at least 90% and maximum 10% other possible isomer), preferably at least 90%, more preferably at least 94%, at least 97% compound most preferably.Term " enantiomer-pure " and " diastereisomericallypure pure " contain can not detection level any other isomer.
Can finish separation by standard method known in the art to steric isomer.Can be by method as use optical activity resolution reagent, with a kind of Chiral Separation of The compounds of this invention is not have its opposite enantiomorph (" stereochemistry of carbon compound " basically, " Stereochemistry of Carbon Compounds " (1962), E.L.Eliel, McGraw Hill; Lochmuller, C.H., (1975) J.Chromatogr., 113:(3) 283-302).The separation of isomer can be undertaken by any suitable method in the mixture, described method comprises: (1) and chipal compounds form the diastereo-isomerism salt of ionic, and it is separated by fractional crystallization or other method, (2) form the diastereo-isomerism compound with chiral derivatizing agent, separate this diastereomer, and be translated into pure enantiomorph, or (3) under the chirality condition, directly enantiomer separation.For method (1), can be by chiral base (as vauqueline, quinine, ephedrine, brucine, a-methyl-b-phenyl-ethyl amine (Amphetamine) etc.) and the asymmetric compound reaction formation diastereomeric salt that has acidic functionality (as carboxylic acid and sulfonic acid) with enantiomer-pure.
Can randomly impel diastereomeric salt to separate by fractional crystallization or chromatography of ions.Be the optical isomer of separation of ammonia based compound, add chiral carboxylic acids or sulfonic acid (as camphorsulfonic acid, tartrate, amygdalic acid or lactic acid) and can cause forming diastereomeric salt.Perhaps, by using method (2), the material that needs to split can form diastereomer to (Eliel with a kind of enantiomorph reaction of chipal compounds, E. and Wilen, S. (1994). " stereochemistry of organic compound " (Stereochemistry of Organic Compounds), John Wiley; Sons, Inc., 322 pages).The method that forms diastereomeric compound can be: make chiral derivatizing agent (as the menthyl derivatives) reaction of asymmetric compound and enantiomer-pure, separate diastereomer then and with its hydrolysis, obtain the xanthene of free enantiomorph enrichment.The method of measuring optical purity comprises the chiral ester for preparing racemic mixture, as menthyl ester or Mosher ester, a-methoxyl group-a-(trifluoromethyl) phenylacetic acid ester (JacobIII. (1982) J.Org.Chem.47:4165), and NMR spectrum analyzed to confirm existing of two kinds of rotation diastereomers.Can (Hoye, T. WO96/15111), separate with reverse-phase chromatography and the stable diastereomer of emanating by positive according to atropisomerrism body (atropisomeric diastereomer) naphthyl-isoquinoline 99.9 separation method.According to method (3), can adopt chiral stationary phase that the racemic mixture of two kinds of asymmetric enantiomorphs is separated by chromatogram.Suitable chiral stationary phase is for example polyose, particularly Mierocrystalline cellulose or straight chain starch derivative.Commercially available polysaccharide base chiral stationary phase is: ChiralCeI
TMCA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak
TMAD, AS, OP (+) and OT (+).The suitable eluent or the moving phase that are used for being used with described polysaccharide base chiral stationary phase are (as ethanol with alcohols, Virahol etc.) (" the chirality liquid chromatography (LC) " such as hexanes of modification, " Chiral Liquid Chromatography " (1989) W.J.Lough compiles, Chapmanand Hall, New York; Okamoto, (1990)." optical resolution of the dihydropyridine enantiomorph that the phenylcarbamate of polysaccharide is carried out as chiral stationary phase by high performance liquid chromatography ", " Optical resolutionof dihydropyridine enantiomers by High-performance liquid chromatographyusing phenylcarbamates of polysaccharides as a chiral stationary phase ", J.of Chromatogr.513:375-378).
Meta-bolites
The present invention also provides the interior metabolism product of compound as herein described, and the announcement degree is novel and non-obvious for this type of product with respect to prior art.This type of product can be available from compound after the administration for example, and oxidation, reduction, hydrolysis, amidation, esterification etc. mainly are to be produced by enzymic process.Therefore, the present invention includes the novel and non-obvious compound that produces by the method that comprises following steps: compound of the present invention is contacted one period that is enough to obtain the meta-bolites of described compound with Mammals.Usually, can differentiate these products as follows: the The compounds of this invention of preparation radio-labeling (as C14 or H3), with detectable dosage (as greater than about 0.5mg/kg) it is passed through parenteral administration animal (for example rat, mouse, cavy, monkey or people), give the sufficiently long time carrying out metabolism (being generally about 30 seconds-30 hours), and from urine, blood or biological sample, separate its converted product.Because these products are through mark, they are easy to separate (other material is can come isolating in conjunction with the antibody of the epi-position that exists in the metabolite by using).The method of available routine is determined the structure of this meta-bolites, for example analyzes by MS or NMR.Usually, can adopt the method identical to analyze meta-bolites with conventional medicament metabolism research well known to those skilled in the art.As long as do not find these converted products in vivo in addition,, they can be used for the diagnositc analysis of The compounds of this invention therapeutic dose yet even they itself do not have antiviral activity.
Preparation
Can be randomly that compound of the present invention is formulated together with conventional pharmaceutical carriers and vehicle, the selection of described carrier and vehicle will be carried out according to the practice of routine.Tablet can contain vehicle, glidant, weighting agent, tackiness agent etc.Aqueous formulation prepares with sterile form, by other administration except that oral administration the time, generally is isoosmotic.Preparation is optional can to comprise vehicle, those vehicle of in " handbook of pharmaceutical excipients " (" Handbookof Pharmaceutical Excipients ", 1986), enumerating for example, and comprise: xitix and other antioxidant; Sequestrant is as EDTA; Carbohydrate is as dextrin, hydroxy alkyl cellulose, hydroxyalkyl methylcellulose gum, stearic acid etc.
Subsequently, as used herein, term " pharmaceutically acceptable carrier " refers to active ingredient formulated together, so that activeconstituents is easy to use or be distributed to and needs treatment part dissolving, dispersion or the diffusion of described composition (for example by) and/or make it be easy to store, transport or handle and can not damage any material or the material of activeconstituents effect.Pharmaceutically acceptable carrier can be the gas of solid or liquid or compressed formation liquid, and promptly the present composition is suitable for enriched material, emulsion, solution, granule, pulvis, sprays, aerosol, suspensoid, ointment, creme, tablet, pill or powder type use.
The pharmaceutical carrier that is applicable to described pharmaceutical composition and preparation thereof is well known to those skilled in the art, in the present invention its selection is not particularly limited.They also comprise additive, as: wetting agent, dispersion agent, tackiness agent, tackiness agent, emulsifying agent, solvent, Drug coating, antiseptic-germicide and anti-mycotic agent (for example phenol, Sorbic Acid, butylene-chlorohydrin), isotonic agent (as sugar or sodium-chlor) etc., prerequisite is that these additives are consistent with medicinal practice, and promptly carrier and additive can not produce permanent damage to Mammals.Can prepare pharmaceutical composition of the present invention by any known way, for example pass through in a step or a plurality of step with active ingredient and carrier uniform mixing, dressing and/or pulverizing, if be fit to also can add other additive (for example tensio-active agent) through selecting.Also can be prepared, for example, promptly make the microcapsule that are used for controlled release or slowly-releasing active ingredient for obtaining to typically have a diameter from the microspheres form of about 1-10gm by micronization.
Can be used for the suitable tensio-active agent (being also referred to as emulgent or emulsifying agent) of pharmaceutical composition of the present invention, is the non-ionic type with well emulsify, dispersion and/or wettability, cationic and/or anionic material.Suitable aniorfic surfactant had both comprised water miscible soap, comprised water miscible synthetic tensio-active agent again.Suitable soap is higher fatty acid (C
10-C
22) an alkali metal salt or alkaline earth salt, the unsubstituted or ammonium salt that replaces, as oleic acid or stearic sodium salt or sylvite or can be available from the sodium salt or the sylvite of the natural acid mixture of Oleum Cocois or tallow oil.Synthetic surfactant comprises: polyacrylic sodium salt or calcium salt; Fat sulfonate or fat sulphate; Sulphonated benzimidazole derivative and alkylaryl sulphonate.Fat sulfonate or vitriol is basic metal or alkaline-earth metal salt form normally; the alkyl of 8-22 carbon atom or the ammonium salt or the unsubstituted ammonium salt of acyl substituted are arranged; sodium salt or calcium salt as lignosulfonic acid or dodecyl sodium sulfonate; or available from the mixture of the aliphatic alcohol sulfate of natural acid, the affixture of the basic metal of sulfuric acid or sulphonate or alkaline earth salt (as Sodium Lauryl Sulphate BP/USP) and Fatty Alcohol(C12-C14 and C12-C18) sulfonic acid/oxyethane.Suitable sulphonated benzimidazole derivative preferably contains 8-22 carbon atom.The example of alkylaryl sulphonate is sodium salt, calcium salt or the pure amine salt of dodecyl sodium sulfonate or dibutyl-naphthene sulfonic acid or naphthalene-sulfonic acid/formaldehyde condensation products.Corresponding phosphoric acid salt is fit to too, as the salt of phosphoric acid ester, to nonylphenol and the affixture or the phosphatide that contain oxyethane and/or propylene oxide.The suitable phosphatide that is used for this purpose is natural (being derived from the animal or plant cell) or synthetic kephalin or Yelkin TTS type phosphatide, as, phosphatidylethanolamine, phosphatidylserine, phosphatidyl glycerol, lysolecithin, Val, dioctyl phosphatidyl-choline, two palmityl phosphatidyl-choline, and their mixture.
Suitable ionic surfactant pack is drawn together: the polyethoxylated of following material and poly-propoxylated derivative: alkylphenol, Fatty Alcohol(C12-C14 and C12-C18), lipid acid, the aliphatic amine or the acid amides that contain at least 12 carbon atoms in the molecule, alkylated aromatic sulfonic acid salt (alkylarenesulphonate) and dialkyl sulfosuccinates, as aliphatic series and alicyclic alcohol, the polyglycol ether derivative of saturated and unsaturated fatty acids and alkylphenol, described derivative preferably partly contain 3-10 ethylene glycol ether group and 8-20 carbon atom and at moieties 6-18 carbon atom are arranged at (aliphatic series) hydrocarbon of alkylphenol.Other suitable nonionogenic tenside is the water-soluble affixture that contains the second diamino polypropylene glycol of 1-10 carbon atom in polyethylene oxide and polypropylene glycol, the alkyl chain, and this affixture contains 20-250 ethylene glycol ether group and/or 10-100 propylene glycol group.Such compound contains 1-5 ethylene glycol unit usually in each propylene glycol unit.The representative example of nonionogenic tenside is nonylphenol-polyethoxyethanols, Viscotrol C polyglycolic acid ether (polyglycolic ether), poly(propylene oxide)/polyethylene oxide affixture, tributyl benzene oxygen polyethoxyethanols, polyoxyethylene glycol and octylphenoxy polyethoxy ethanol.The anhydrate fatty acid ester (as the polyoxyethylene sorbitol olein that anhydrates) of sorbyl alcohol (polyethylene sorbitan), the fatty acid ester of glycerine, the fatty acid ester of the sorbyl alcohol that anhydrates, the fatty acid ester of sucrose and the fatty acid ester of tetramethylolmethane of poly-ethylidene also is suitable nonionogenic tenside.
Suitable cationic surfactants comprises quaternary ammonium salt, particularly halogenated quaternary ammonium salt, and it has 4 and chooses wantonly by the alkyl of the phenyl of halogen, phenyl, replacement or hydroxyl replacement; For example, following quaternary ammonium salt: contain for as substituent at least one C8-C22 alkyl of N-(as hexadecyl, lauryl, palmityl, myristyl, oil base etc.), and as the quaternary ammonium salt of other substituent unsubstituted or halogenated low alkyl group, benzyl and/or hydroxy lower alkyl.
Be fit to this purpose the tensio-active agent more detailed description can referring to for example " McCutcheon ' stain remover and emulsifying agent annual report " (" McCutcheon ' s Detergents and Emulsifiers Annual " (MCPublishing Crop., Ridgewood, New Jersey, 1981), " Tensid-Taschenbucw '; second edition (Hanser Verlag; Vienna; 1981) and " tensio-active agent encyclopedia " (" Encyclopaedia of Surfactants "; (Chemical Publishing Co.; New York, 1981).
Can give acceptable salt on compound of the present invention and the physiology thereof (below be referred to as activeconstituents) to need treatments symptom suitable way by any, suitable route of administration comprises: oral, rectum, nasal cavity, local (comprising eye, oral cavity and hypogloeeis), vagina and non-enteron aisle (comprising in subcutaneous, intramuscular, intravenously, intracutaneous, the sheath and epidural administration).Preferred route of administration can change according to the person's that for example is subjected to the medicine situation.
Although can give activeconstituents separately, preferably present with pharmaceutical dosage forms.Preparation of the present invention is no matter veterinary drug and human all comprise at least a aforesaid activeconstituents, with one or more its pharmaceutically acceptable carrier and other optional therapeutic component.Carrier is " acceptable " preferably, and it is compatible and can not be subjected to the medicine to it person is harmful to mean other composition of itself and preparation.Preparation comprises those preparations that are suitable for oral, rectum, nasal cavity, part (comprising oral cavity and hypogloeeis), vagina or non-enteron aisle (comprising in subcutaneous, intramuscular, intravenously, intracutaneous, the sheath and epidural) administration.Said preparation can be presented with unit dosage routinely, and can be by any known method preparation of pharmaceutical field.Such method comprises makes activeconstituents and this step of carrier combinations that constitutes one or more ancillary components.Usually by activeconstituents and liquid or finely divided solid carrier or both are evenly mixed closely, if necessary product shaping is prepared described preparation then.
Be fit to preparation of the present invention (discrete) unit existence individually of oral administration, as capsule, cachet or tablet, they contain the activeconstituents of predetermined amount separately; As powder or particle; As solution in waterborne liquid or the non-aqueous liquid or suspension; Or as O/w emulsion or water-in-oil emulsion.Activeconstituents ball, electuary or paste form greatly exists.
Can suppress or the molded tablet for preparing with one or more ancillary components by optional.Can prepare compressed tablets to optional compacting of the activeconstituents of free-flowing form (as powder or particle) by in suitable equipment with tackiness agent, lubricant, inert diluent, sanitas, tensio-active agent or dispersant.Can carry out the molded molded tablet for preparing to mixture by in suitable equipment with the moistening powdered compound of inert liquid diluent.Can randomly carry out dressing or indentation, and can be mixed with the tablet that activeconstituents is wherein provided slowly-releasing or controlled release tablet.Infection to eyes or other outside organization (as mouth and skin), can randomly 0.075-20%w/w (be included in the activeconstituents of 0.1-20% for example to contain, increment with 0.1%w/w increases, as 0.6%w/w, 0.7%w/w etc.), preferred 0.2-15%w/w, most preferably the local application's cream or the cream of 0.5-10%w/w activeconstituents are used said preparation.When being mixed with ointment, activeconstituents can be used with paraffin or the immiscible ointment matrix of water.Perhaps, activeconstituents and oil-in-water frost matrix can be mixed with creme.If desired, the water of cream base for example can comprise the polyvalent alcohol of 30%w/w at least, the alcohol that promptly has two or more hydroxyls is as propylene glycol, 1,3 butylene glycol, N.F,USP MANNITOL, sorbyl alcohol, glycerine and polyoxyethylene glycol (comprising PEG400) and their mixture.Topical preparation need comprise the compound that energy enhanced activity composition sees through skin or absorption of other involved area or infiltration.The example of such transdermal enhancer comprises dimethyl sulfoxide (DMSO) and related analogs.
The oil phase of emulsion of the present invention is made of by known way known component.Although oil phase only comprises a kind of emulsifying agent (being also referred to as emulgent), need comprise at least a emulsifying agent and oily or fatty and oily both mixture of fat.Also comprise lipophilic emulsifier when randomly, comprising hydrophilic emulsifier as stablizer.Also preferably not only comprise oil but also comprise fat.Constitute so-called emulsifying wax by one or more emulsifying agents jointly when existing or not having one or more stablizers, and described wax constitutes so-called oil in water emulsion cream base matter with oil ﹠ fat, this matrix forms the oily disperse phase of creme.
Because activeconstituents is extremely low in the solubleness of most of oil that may be used for pharmaceutical emulsion, so select to be applicable to the oily or fatty of preparation according to the required makeup performance that will reach.Therefore, creme should be chosen wantonly to (non-staining) of non-oil, non-staining and can wash product, and has suitable consistency to avoid it from pipe or other container leakage.Can use straight or branched, list-or binary alkyl ester, as two-dissident, two acid esters, stearic acid isocetyl ester, propylene glycol coconut fatty acid diester, Isopropyl myristate, decyl oleate, Wickenol 111, butyl stearate, palmitinic acid 2-ethylhexyl or be called the mixture of the branched ester of Crodamol CAP, preferred back three kinds of esters.According to required performance, these esters can be used singly or in combination.Perhaps, can use high-melting-point lipid, as paraffinum molle alba and/or whiteruss or other mineral oil.
The pharmaceutical preparation that is suitable for the topical administration eye also comprises eye drop, and wherein, activeconstituents dissolves or is suspended in the suitable carriers (especially for the aqueous solvent of activeconstituents).Activeconstituents is optional with 0.5-20%, preferred 0.5-10%, and preferably the concentration of about 1.5%w/w is present in the preparation.The preparation that is fit to the topical administration oral area comprises lozenge, and it is included in activeconstituents in the flavoured base, and described seasonings is generally sucrose and gum arabic or tragacanth; Pastille, it is included in activeconstituents in the inert base, and described inert base is for example gelatinum and glycerine or sucrose and gum arabic; And collutory, it is included in activeconstituents in the suitable liquid vehicle.
The preparation that is used for rectal administration can be used as suppository form and exists, described suppository contain suitable for example comprise theobroma oil or salicylate matrix.Be applicable to that the carrier in the preparation of intranasal administration is a solid, it comprises granularity and (comprises the 20-500 micron for for example 20-500 micron, 5 microns of increments, as 30 microns, 35 microns etc.) coarse meal, its mode administration to get with snuffing promptly sucks by nasal cavity fast from the container that powder is housed of being close to nose.The carrier that is used for the appropriate formulation of nasal spray for example or nasal drops administration is a liquid, and this preparation comprises the aqueous solution or the oily solution of activeconstituents.Can be suitable for the preparation of aerosol administration according to the ordinary method manufacturing, and can transmit with other therapeutical agent.
The preparation that is applicable to vagina administration can be vaginal suppository, tampon (tampon), creme, gel, paste, foams or sprays, except that comprising activeconstituents, also comprises suitable carrier known in the art.
The preparation that is applicable to parenterai administration comprises water-based and non-aqueous aseptic injectable solution, and it can comprise antioxidant, buffer reagent, fungistat and make preparation and be subjected to the medicine the isoosmotic solute of person's blood; And water-based and non-aqueous aseptic suspension agent, it can comprise suspension agent and thickening material.This preparation can be present in unitary dose or the multi-dose container, for example Mi Feng ampoule and bottle, and can under freeze-dried (freeze dried) condition, store, only need add at once before use aseptic liquid vehicle, for example water for injection.Interim injection solution of the sterilized powder of available aforementioned type, particle and tablet preparation and suspension.
Preferred unit dose formulations be contain per daily dose or as indicated above unit day time dosage (sub-dose) or those preparations of the activeconstituents of its suitable divided dose.
Should be understood that the composition except above mentioning especially, preparation of the present invention can comprise the conventional reagent in other this area according to the type of the preparation of being discussed, and for example is applicable to those comprised seasoningss of oral administration.
The compounds of this invention can be used for providing the pharmaceutical preparation (" controlled release preparation ") that contains as the controlled release of one or more The compounds of this invention of activeconstituents, wherein, may command and regulate the release of activeconstituents is with the administration frequency that reduces given The compounds of this invention or improve its pharmacokinetics or toxicity profile.Can be applicable to the controlled release preparation of oral administration according to the ordinary method manufacturing, wherein discrete unit comprises one or more The compounds of this invention.
Can comprise the assign to persistence of activeconstituents effect in the control combination thing of other one-tenth.Therefore, by selecting suitable polymer support, for example polyester, polyamino acid, Polyvinylpyrolidone (PVP), vinyl-vinyl acetate copolymer, methylcellulose gum, carboxymethyl cellulose, protamine sulfates etc. can obtain controlled release composition.Can also be by activeconstituents being added control drug release speed and active persistence in the polymer beads (for example minigel), described polymkeric substance is for for example: hydrogel, poly(lactic acid), Walocel MT 20.000PV, polymethylmethacrylate and other above-mentioned polymkeric substance.These class methods comprise the colloid drug delivery system, as liposome, microballoon, micro emulsion, nanoparticle, Nano capsule etc.According to route of administration, pharmaceutical composition may needing protection property dressing.The pharmaceutical dosage form that is applicable to injection comprises its aseptic aqueous solution or dispersion liquid and sterilized powder for interim preparation usefulness.The typical carriers that is used for this purpose comprises biocompatible aqueous buffer, ethanol, glycerine, propylene glycol, polyoxyethylene glycol etc. and their mixture.
In view of this fact, promptly when being used in combination several activeconstituentss, they will their combination therapy effect directly give simultaneously the Mammals that will treat, and correspondent composition can also comprise separately but in adjacent storage column or the medicine box or the packaged form existence of separating two kinds of components in the lattice.In back one situation, each activeconstituents can be mixed with the mode of the route of administration that is suitable for being different from other composition thus, as a kind of composition wherein can be oral or the non-gastrointestinal preparation form, and other composition then is ampoule form or the aerosol form that is used for intravenous injection.
Synthetic method
Use a series of chemical reactions well known to those skilled in the art to come preparation formula (A) compound, and set up the method and the further example of the described compound of preparation simultaneously.The method that further describes only is as an example, and does not mean limiting the scope of the invention.
The invention still further relates to the method for preparing the present composition.Prepare described composition by available technology in any organic synthesis.Many these type of technology are technology well known in the art.Yet many known technology describe in detail in following document to some extent: " methodology of organic synthesis summary " (" Compendium of OrganicSynthetic Methods " (John Wiley ﹠amp; Sons, NewYork) volume 1, Ian T.Harrison and ShuyenHarrison, 1971; Volume 2, Ian T.Harrison and Shuyen Harrison, 1974; Volume 3, LouisS.Hegedus and Leroy Wade, 1977; Volume 4, Leroy G.Wade, Jr., 1980; Volume 5, Leroy G.Wade, Jr., 1984; With volume 6, Michael B.Smith; And March, J., " senior organic chemistry " third edition (" Advanced Organic Chemistry, Third Edition ", (John Wiley ﹠amp; Sons, New York, 1985)), " comprehensive organic synthesis.Selection in the modern organic chemistry, strategy and effectiveness " (" ComprehensiveOrganic Synthesis.Selectivity，Strategy & Efficiency in Modern OrganicChemistry。Volume 9 ", Barry M.Trost chief editor (Pergamon Press, New York, 1993 printings)).
The illustrative methods of the preparation present composition below is provided.These methods are for the character of these preparations is described, rather than in order to limit the scope of applicable method.
Usually, reaction conditions, for example temperature, reaction times, solvent, last handling process etc. are the common response condition of the concrete reaction that is used in this area carrying out.Reference material of quoting and the material of wherein quoting have comprised the detailed description to these conditions.Typical temperature is-100 to 200 ℃, and solvent is for dredging the solvent of protic or protic, and the reaction times is 10 seconds-10 days.Aftertreatment is made up of following steps usually: unreacted reagent is carried out quencher, distribute (extraction) then in water/organic hierarchical system, and separation contains product layer.
Usually under temperature, carry out oxidation and reduction reaction near room temperature (about 20 ℃), though for the reduction of metal hydride often is to carry out reducing under 0-100 ℃ the temperature, the solvent of reduction reaction is generally thin protic solvent, and the solvent of oxidizing reaction can be protic or thin protic solvent.Can regulate to obtain required conversion product the reaction times.
Usually carrying out condensation reaction under near the temperature of room temperature, also is very common though reduce temperature (0-100 ℃) in the condensation reaction of non-running balance control.Solvent can be protic (being generally in the running balance reaction) or thin protic (being generally in the reaction in kinetic control).
The synthetic technology of standard, for example removing byproduct of reaction and use anhydrous response condition (for example inert gas environment) by azeotropic is very conventional in the art, and can use it at where applicable.
General aspect to these illustrative methods is described hereinafter.For each product in the following method, can be before it be used for subsequent step, to its randomly separate, segregation and/or purifying.
It is abutment, mixing, reaction that term " treated ", " handle (treating) ", " handling (treatment) " are waited, make and react, make and be usually used in showing in its contact and this area so that one or more chemical units are converted into other term that the mode of one or more other chemical units is handled described one or more chemical units.This just mean this " handle compounds 1 " and be synonymous to " make compound 1 and compound 2 reactions ", " compound 1 contact with compound 2 ", " with compound 1 and compound 2 reactions " with compound 2 and be used in the organic synthesis field rationally showing that compound 1 " is handled through compound 2 ", other routine expression of " with compound 2 reactions ", " making compound 1 and compound 2 react " etc.
" processing " is meant the mode reasonable and commonly used that makes the organic chemical reagent reaction.Unless otherwise, concentration (the 0.01M-10M of normal use standard, be generally 0.1M-1M), (100 to 250 ℃ of temperature, be generally-78-150 ℃, be more typically-78-100 ℃, be more typically 0-100 ℃), reaction vessel (being generally glass, plastics, metal), solvent, pressure, atmosphere (usually air being used for oxygen and the insensitive reaction of water) etc. perhaps with the reaction of nitrogen or argon gas to oxygen and water sensitive.The known similar reacting knowledge in organic synthesis field can be used for being chosen in condition and the equipment that given method is used to handle.Particularly, the those of ordinary skill in organic synthesis field can carry out choose reasonable to condition and equipment on the basis of this area knowledge, reach the chemical reaction that carries out described method smoothly with expection.
Exemplary scheme and embodiment are changed the analogue of the concrete exemplary materials that can obtain above-mentioned generation.Can be suitable for carrying out these variations to the suitable methodology of organic synthesis of above quoting.
In exemplary scheme, it is favourable that reaction product is separated from a kind of other and/or parent material.The required product that adopts this area technology commonly used that each step or series of steps are produced separate and/or purifying (hereinafter referred to as separated) to the uniformity of required degree.Usually, this separation comprises heterogeneous extraction, crystallization from solvent or solvent mixture, distillation, distillation or chromatography.Chromatography can comprise any kind of method, for example comprises: size exclusion or ion-exchange chromatography; High, in or low pressure liquid chromatography, small-scale and preparation thin layer or thick layer chromatography, and small-scale thin layer and flash chromatography.
The separation method of other type comprises: with selecting to be used in conjunction with the reagent of required product, unreacted parent material, byproduct of reaction etc. or making isolating agent treated mixtures such as required product, unreacted parent material, byproduct of reaction.These reagent comprise sorbent material or sorbent material, as activated carbon, molecular sieve, Ion Exchange Medium etc.Perhaps, can be acid for this reagent of basic material, then is alkali for this reagent of acid material; Can be wedding agent, for example antibody, conjugated protein; Selectivity chelator, for example crown ether; Liquid/liquid ion extractuin reagent (liqid/liqidion extraction reagent, LIX) etc.
The character that the selection of suitable separation method is depended on related material.For example, the molecular weight in boiling point, distillation and the distillation, in chromatogram, whether have polar functional group, the stability of material in heterogeneous extraction in acidity and alkaline medium etc.Those skilled in the art can use these technology and obtain required separation as much as possible.
Also the proper method that is used to prepare mixture of the present invention can be found in WO 2004/005286, among the scheme 1-13 especially therein.
Scheme 1 is depicted as another synthetic route of 5-benzyl-2-phenyl-5H-imidazo [4,5-c] pyridine and analogue thereof.
Scheme 1:
Comprise the carboxylic acid reaction thing in the condensation ring-closure reaction that can be used for scheme 1 in the following table.The compound that produces will be at its YR
1The position has these sour residues.Randomly, can in the compound of arbitrary embodiment 2-7, find the nubbin of this molecule.
Comprise the alkylating reagent in the pyridyl alkyl reaction that can be used for scheme 1 in the following table.Herein, the residue of described alkylating reagent is positioned at the X R of The compounds of this invention
3The position.Randomly, can in the compound of arbitrary embodiment 2-7, find the nubbin of described compound.
Scheme 2 is depicted as the synthetic route of 5-diaryl methyl-2-phenyl-5H-imidazo [4,5-c] pyridine and 5-benzyl-2-diaryl-5H-imidazo [4,5-c] piperidines.
Scheme 2
Scheme 3 is depicted as the synthetic route of 5-(alkoxybenzyl)-2-phenyl-5H-imidazo [4,5-c] pyridine and 5-benzyl-2-alkoxybenzyl-5H-imidazo [4,5-c] pyridine.R, R ' and R " can be any alkyl, benzylic or assorted benzylic group.
Scheme 3
Known to those skilled in the art, can adopt the mode identical to synthesize similar compound by changing parent material, intermediate, solvent and condition with aforementioned schemes.
Embodiment
The A part
Compound is synthetic
Embodiment 1
2-(2, the 3-difluorophenyl)-3H-imidazo (4,5-c) pyridine
With Vanadium Pentoxide in FLAKES (24.56g) 50 ℃ of following stirring and dissolving in methylsulfonic acid (165.8mL).In above-mentioned solution, add 3, and the 4-diamino-pyridine (12.3g, 0.11mol) with 2, the 3-difluoro-benzoic acid (19.4g, 0.12mol).Reaction mixture was in 190 ℃ of heating 3 hours.Reaction is carried out three times.Reaction mixture is cooled to 50 ℃ and also under agitation pours in the ice.In this stage, all three batch reaction things merge.Reaction mixture neutralizes by under agitation adding NaOH, is 8 until pH.The solid matter that precipitation is separated out solution filters collection and air-dry.End product carries out recrystallization twice with the ethanol/water solvent, obtains 2-(2, the 3-difluorophenyl)-3H-imidazo (4,5-c) pyridine of 36g.1H 300Mhz (CD
3OD) sigma 7.3-7.42 (m, 1p); 7.43-7.58 (m, 1p); 7.70 (d, 1p); 8.0 (m, 1p); 8.34 (d, 1p); With 8.95 (s, 1p) .LC/MS value M/z=232.
According to above-mentioned step of instructing, and replace 2 with the 2-fluorobenzoic acid, the 3-difluoro-benzoic acid can make compound 2-(2-fluorophenyl)-3H-imidazo (4,5-c) pyridine.
Embodiment 2
5-((3-(4-chloro-phenyl-) isoxazole-5-base) methyl)-2-(2-fluorophenyl)-5H-imidazo (4,5-c) pyridine
(11.0g in DMF suspension 50.0mmol), adds the NaOH aqueous solution of 10% (w/v) at 2-(2-fluorophenyl)-3H-imidazo [4,5-c] pyridine.In the gained solution, add 5-(the chloromethyl)-3-be dissolved in DMF (4-chloro-phenyl-) isoxazole (and 13.68g, 60.0mmol).Reaction mixture at room temperature stirs, and adopts the LCMS monitoring per half an hour.LCMS is presented at after reaction gets nowhere between 2 hours control points and the 4 hours control points, termination reaction after 4 hours.Reactant elder generation water uses ethyl acetate (EtoAc) to grind (triturate) (3 *) again.The gained material by with the material heating for dissolving in MeOH, then carry out recrystallization with water precipitation.Carry out this re-crystallization step then repeatedly, ((3-(4-chloro-phenyl-) isoxazole-5-base) methyl)-2-(2-fluorophenyl)-(15.385g 38mmol), is white crystal to 5H-imidazo (4,5-c) pyridine, and productive rate is 74% to obtain 5-.1H300Mhz (d
6-DMSO) sigma 6.02 (s, 2p); 7.13 (s, 1p); 7.26-7.35 (m, 2p); 7.43-7.52 (m, 1p); 7.56 (d, 2p); (7.84 d, 1); 7.89 (d, 2p); (8.24 d, 1); 8.28-8.36 (m, 1p); With 9.19 (s, 1p) .LCMS value M/Z=405.31.
Embodiment 3A
5-(4-(trifluoromethoxy) benzyl)-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine
At first, in the DMF of 430ml, add 2-(2, the 3-difluorophenyl)-3H-imidazo (4,5-c) pyridine (20g, 86.6mmol).The part solid matter is not molten.10%NaOH (w/v) solution that in this solution, adds 43ml.Under high degree of agitation, undissolved material enters solution.Gained solution is divided into the 16.3ml of 30 equal portions, and the 2-of 3mmol (2, the 3-difluorophenyl)-3H-imidazo (4,5-c) pyridine (20g, 86.6mmol), the microwave reaction container of packing into.Add in each reaction vessel 1-(chloromethyl)-4-(trifluoromethoxy) benzene (693mg, 3mmol).Every part of reaction mixture was 110 ℃ of following microwave treatment 1 minute.After all microwave reactions finish, all reaction vessels merging (because the disruptive cause, a container loses) are three batches carry out aftertreatment.All batches vacuum is removed DMF, and the gained material adopts deionized water wash three times.The thick product of gained is dissolved in CH
2Cl
2, and with the SiO of 330g
2Post carries out purifying (Redisep (Isco) 0% to 0%/5 minute to 10%B/30 minute to 20%/5 minute), and the gained material carries out recrystallization with ethanol/water.Three batches obtain 14g, the 5-of 33.5mmol (4-(trifluoromethoxy) benzyl)-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine.1H 300Mhz (CD30D) sigma5.79 (s, 2p); 7.25-7.35 (m, 1p); 7.37 (d, 2p); 7.38-7.42 (m, 2p); 7.55 (d, 2p); 7.88-7.95 (m, 1p); 8.25 (d, 1p); With 9.05 (s, 1p) .LC/MS M/z=406.23.
Embodiment 3B
According to above-mentioned step of instructing, and, can make compound 5-(4-iodine benzyl)-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine with 1-(chloromethyl)-2,4 difluorobenzene replacement 1-(chloromethyl)-4-(trifluoromethoxy) benzene.
Embodiment 4
5-(2,4-two fluoro-xenyls) methyl-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine
5-(4-iodine benzyl)-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine (460mg, in DMF 1.03mmol) (10ml) solution, add the 2,4 difluorobenzene ylboronic acid (196mg, 1.24mmol).With Na
2CO
3Water-soluble, join in the DMF solution and stir.Then with Pd (PPh
3)
4Join in the DMF reaction mixture.Reaction mixture heated 2 minutes in microwave under 200 ℃.After extracting aftertreatment with ethyl acetate/water, thick product is used Isco 40g SiO in two batches
2Post (0 to 10%B/20 minute, A=CH
2Cl
2, B=MeOH, flow velocity=40ml/ minute) and carry out purifying respectively.The product component of purifying merges and concentrates.Gained solid CH
2The Cl/ hexane carries out recrystallization.The crystal high vacuum dry that collection obtains is spent the night, obtain productive rate and be 5-(2,4-two fluoro-xenyls) methyl-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine of 50% (223mg, 0.515mmol).1H300Mhz (CD30D) sigma 5.8 (s, 2p); 7.0-7.1 (m, 2p); 7.25-7.35 (m, 1p); 7.35-7.45 (m, 1p); 7.45-7.60 (m, 5p); 7.85 (d, 1p); 7.85-8.0 (m, 1p); 8.3 (d, 1p); With 9.10 (s, 1p) .LC/MS value M/z=434.18.
Embodiment 5
5-((3-(4-chloro-phenyl-) isoxazole-5-base) methyl)-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine
(10g in DMF solution 43.3mmol), adds the NaOH aqueous solution of 10% (w/v), then adds 5-(chloromethyl)-3-(4-chloro-phenyl-)-isoxazole (11.8g, 51.9mmol) DMF solution at the azepine benzoglyoxaline.Reaction mixture at room temperature stirred 7 hours, concentrated then.Solid matter is handled with EtOAc/ water, filters and collects.Solid matter water and EtoAc then grinds, and air-dry.Solid is further purified with the MeOH recrystallization, obtain 46.6% productive rate 5-((3-(4-chloro-phenyl-) isoxazole-5-base) methyl)-2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine (and 8.5g, 20.1mmol).1H300Mhz (DMSO-d6) sigma 6.03 (s, 2p); 7.12 (s, 1p); 7.25-7.35 (m, 1p); 7.44-7.53 (m, 1p); 7.55 (d, 2p); 7.88 (d, 3p); 8.11-8.18 (m, 1p); 8.24-8.29 (dd, 1p); With 9.23 (s, 1p) .LC/MS value M/z=423.34,425.22.
Embodiment 6
5-((3-(2,4-trifluoromethyl) isoxazole-5-base) methyl)-2-(2-fluorophenyl)-5H-imidazoles
And [4,5-c] pyridine
2,4-(two-trifluoromethyl) benzaldoxime
To be suspended in EtOH/ water (1: 2,230ml, in aromatic aldehyde 0.09M) (0.021mol), (1.58g 0.023mol), is cooled to 4 ℃ to add hydroxylamine hydrochloride.The NaOH aqueous solution of Dropwise 5 0%w/w in solution (4.13ml, 0.052mol).After the stirring at room 1.5 hours, reaction mixture carries out acidifying and uses CH with the 2N aqueous hydrochloric acid
2Cl
2Extract (3 * 50ml).Gained organic solution is washed dried over sodium sulfate with the saturated NaCl aqueous solution.Remove the thick product (5.3g, quantitative) that solvent obtains oxime, be directly used in subsequent step.
2,4-(two-trifluoromethyl) phenyl-chloride methyl-isoxazole
With 2, (9.75g 0.038mol) is suspended in CH to 4-(two-trifluoromethyl) benzaldoxime
2Cl
2(45ml, 0.85M) in, be cooled to 4 ℃.With propargyl chloride (2.72ml 0.038mol) adds in the reaction soln, then drip NaOCl (the 10-13% free chlorine, 37.6ml, 0.061mol).Reaction mixture stirred 15 minutes down at 4 ℃, reflux 3 hours.After being cooled to room temperature, reaction system is at CH
2Cl
2With distribute in the water.Organic layer separates, and the saturated NaCl aqueous solution washs, and sodium sulfate carries out drying.After removing solvent, the thick product of gained chloromethyl isoxazole is at silicon-dioxide column chromatography (10%CH
2Cl
2/ hexane) (6.5g purifies on 0.020mol).
5-((3-(2,4-trifluoromethyl) isoxazole-5-base) methyl)-2-(2-fluorophenyl)-5H-imidazo (4,5-c) pyridine
Imidazopyridine (14.28g in being suspended in DMF (40ml), 0.067mol) in, the NaOH aqueous solution of adding 10%w/w (32.2ml, 0.080mol), then add chloromethyl isoxazole (26.3g, DMF 0.020mol) (16ml) solution that abovementioned steps obtains.Stirred 12 hours under the room temperature, obtain brown solid behind the evaporating solvent.Thick product solid water (7 *) grinds, and carries out crystallization (2 *) with MeOH/ water, obtains pure title compound.
NMR；300Mhz D
6MSO
Chemical shift, multiplicity, proton number:
6.1，s，2
7.0，s，1
7.3，t，2
7.4-7.5，m，1
7.8-7.9，d，1
7.9-8.0，d，1
8.2-8.4，m，4
9.2，s，1
Embodiment 7
5-((3-(4-trifluoromethyl-2-fluorophenyl) isoxazole-5-base) methyl)-2-(2-fluorophenyl)
-5H-imidazo (4,5-c) pyridine
Isoxazole is synthetic
| Compound | MW | Quantity | Mole number | Equivalent |
| A | 207.13 | 9.3g | 0.044 | 1 |
| NaOCl (10% free chlorine) | 74.44 | 43.0ml | 0.44 | 1.6 |
| Propargyl chloride | 74.51 | 3.14ml | 0.044 | 1 |
| Methylene dichloride | 48.7ml |
" A " in methylene dichloride, 0 ℃ of fierce down stirring and adding NaOCl, then adds propargyl chloride at 0 ℃ of low suspension.Reactant stirred 5 minutes down at 0 ℃, and then reflux is 2 hours.Cool to room temperature is washed then, dried over sodium sulfate, and vacuum concentration obtains yellow solid.The gained solid carries out purifying on the compound flash chromatography (combiflash) of silicagel column, with 3-50% ethyl acetate-hexane wash-out, obtain the flash of light white solid of 4.5g.
| Compound | MW | Quantity | Mole number | Equivalent |
| A | 279.62 | 2.0g | 7.6 | 1.2 |
| B | 213.21 | 1.373g | 6.4 | 1 |
| The 10%w/v NaOH aqueous solution | 2.26ml | |||
| DMF | 13.73ml+6.56ml |
" B " is suspended among the 13.73mlDMF, adds the NaOH aqueous solution of 10% (w/v)." A " is dissolved in the DMF of 6.56ml, and gained solution under agitation joins in the above-mentioned system.Reactant was stirring at room 5 hours.The DMF vacuum concentration is removed, and gained solid water grinds twice and grinds with ethyl acetate.The gained solid carries out recrystallization with methanol-water, obtains the required compound of 533mg.
NMR (DMSO) value:
Chemical shift, multiplicity, proton number:
6.14，s，2
7.18，d，1
7.28-7.36，m，2
7.44-7.54，m，1
7.70-7.76，d，1
7.86-7.90，d，1
7.90-7.96，d，1
8.08-8.16，t，1
8.28-8.36，t，2
9.24，s，1
Embodiment 8A
5-((3-(2-trifluoromethyl-4-fluorophenyl)-isoxazole-5-bases) methyl))-2-(2-
Fluorophenyl)-5H-imidazo (4,5-c) pyridine
At azepine benzoglyoxaline (12.7g, 59.6mmol) DMF (120ml) solution in, NaOH (the 30.5ml that adds 10% (w/v), 76.6mmol) aqueous solution, then add 5-(chloromethyl)-3-(2-trifluoromethyl-4-fluorophenyl)-isoxazoles (21.3g, DMF 76.6mmol) (60ml) solution.Reaction mixture stirring at room 18 hours then concentrates.Adopt MeOH/ water to precipitate, filter and collect.Solid matter carries out recrystallization with the EtoAc/ hexane, obtains 5-((3-(2-trifluoromethyl-4-fluorophenyl) isoxazole-5-base) methyl)-2-(2-fluorophenyl)-5H-imidazo (4, the 5-c) pyridine of 69% productive rate.
The NMR value
300Mhz D
6MSO
Chemical shift, multiplicity, proton number:
6.15，s，2
6.91，s，1
7.3，t，2
7.42-7.52，m，1
7.65-7.9，m，2
7.84-7.9，m，2
8.22-8.45，m，2
9.19，s，1
Embodiment 8B
5-((3-(2-trifluoromethyl-4-fluorophenyl) isoxazole-5-base) methyl))-2-(2-fluorine
Phenyl)-5H-imidazo (4,5-c) pyridinium salt
Mesylate
5-((3-(2-trifluoromethyl-4-fluorophenyl) isoxazole-5-base) methyl))-2-(2-fluorophenyl)-5H-imidazo (4,5-c) pyridine free alkalis (200mg) pulping in 2.0ml acetone.Add methylsulfonic acid (42.6mg), mixture heating up is to～60 ℃.Adding the water yield slightly increases, up to forming solution (needing 110 μ l).The solution cool to room temperature also stirs and spends the night.The gained slurries cool off in ice bath, filter and use washing with acetone then.The gained solid is dry under 40 ℃, obtains the required salt of 149mg.213.1 ℃ of DSC heat absorptions.The NMR value is consistent with desired structure.
HCl salt
5-((3-(2-trifluoromethyl-4-fluorophenyl)-isoxazole-5-bases) methyl)-2-(2-fluorophenyl)-5H-imidazo (4,5-c) pyridine free alkalis (200mg) pulping in 2.0ml acetone.Add concentrated hydrochloric acid (46mg), mixture heating up is to～60 ℃.Add entry in thick slurry, adding the water yield slightly increases, up to forming solution (needing 100 μ l).The solution cool to room temperature also stirs and spends the night.Slurry cools off in ice bath, then filters and washing with acetone.The gained solid carries out drying at 40 ℃, obtains the required salt of 80mg.241.5 ℃ of DSC heat absorptions.The NMR value is consistent with desired structure.
Embodiment 8B
5-(the preparation of (3-(2-trifluoromethyl-4-fluorophenyl) isoxazole-5-base) methyl)-2-(2-fluorophenyl)-5H-imidazo (4,5-c) pyridinium salt
Arbitrary salt of embodiment 7B mixes with 1: 1 weight ratio with the starch of exsiccant pre-gelled.The mixture of 100mg loads in the regid gel capsule.
Other compound of the present invention is prepared by the method for steps A, C, D, E and F step.
Steps A: alkylation
For the compound that array format (array format) makes, the skeleton of 100um (scaffold) (herein being 2-(2,3-two fluoro-phenyl)-3H-imidazo (4,5-c) pyridine) is used for each reaction system.The 2-of all amounts (2,3-two fluoro-phenyl)-3H-imidazo (4,5-c) pyridine is dissolved among the DMF of q.s, obtains 500ul solution/reaction system.10% (w/v) NaOH/H that in every part of solution, adds 60 μ l
2O.Alkylating reagent is dissolved among the DMF with the concentration of 480 μ mol/mL, and 250 μ l gained solution are added each reaction system.Each reaction system was with carry out microwave radiation heating to 110 ℃ a minute.After the cooling, each reaction system is filtered by the 0.45um strainer.Every part of compound adopts 0.1%TFA/ water and 0.1%TFA/ acetonitrile to carry out purification based on quality grading as eluent on the reverse post of C-18.Every part of compound is confirmed with mass spectrum, with 254mn UV absorbance measurement purity.The HPLC fraction concentrates by centrifugal evaporation, and collecting amount is determined in weighing.
Step C:Suzuki boric acid
Aryl boric acid (1.2 equivalent) joins the DMF solution of 5-(4-iodine benzyl)-2-(2, the 3-difluorophenyl)-5H imidazo (4,5-c) pyridine (1 equivalent).With Na
2CO
3(2 equivalent) is dissolved in water, joins in the DMF solution and stirring.Then with Pd (PPh
3)
4(5 moles of %) joins the DMF reaction mixture.Reaction mixture heated two hours in 200 ℃ in microwave.Reaction mixture be applied to 1g solid-phase extraction column cylinder (extraction cartridge) (C-18) on, described post is with the methanol wash of 3 * 2ml.Elutriant filters by the strainer of 0.45um, is concentrated into dried.The gained material is dissolving again in DMF, carries out purifying with reverse hplc/MS.
Step D
The common step of preparation oxime
In the aromatic aldehyde that is suspended in EtOH/ water (1: 2), add hydroxylamine hydrochloride (1.1 equivalent), and be cooled to 4 ℃.The NaOH aqueous solution of Dropwise 5 0%w/w (2.5 equivalent) in this solution.After the stirring at room 1.5 hours, reaction mixture is with the acidifying of 2N aqueous hydrochloric acid and use CH
2Cl
2Extract.Organic solution is washed dried over sodium sulfate with the saturated NaCl aqueous solution.Remove solvent and obtain the thick product of oxime, be directly used in next step.
The common step of cycloaddition
Oxime is suspended in CH
2Cl
2And be cooled to 4 ℃.Propargyl chloride (1 equivalent) joins in the reaction soln, then drips NaOCl (free chlorine of 10-13%, 1 equivalent).Reaction mixture was in 4 ℃ of stirrings 15 minutes, and reflux is 3 hours then.After being cooled to room temperature, reaction system is at CH
2Cl
2And distribute between the water.Separate organic layer, wash with the saturated NaCl aqueous solution, sodium sulfate carries out drying.Except that after desolvating, thick product is by grinding (hexane) or passing through silicon oxide column chromatogram (10%CH
2Cl
2/ hexane) carries out purifying.
Alkylating common step
In being suspended in the imidazopyridine of DMF, drip the NaOH aqueous solution (1.2 equivalent) of 10%w/w, then add the chloromethyl isoxazole (1.2 equivalent) among the DMF.After the stirring at room 12 hours, solvent evaporates, and obtains the thick product of brown solid.Thick product solid water grinds, and methanol (2: 1) is carried out crystallization, obtains pure final product.
Step e: Suzuki bromide
Aromatic bromide (1.2 equivalent) is joined the DMF solution of 4-((2-(2, the 3-difluorophenyl)-5H-imidazo (4,5-c) pyridine-5-yl) methyl) phenyl-boron dihydroxide (1 equivalent).Na
2CO
3(2 equivalent) is dissolved in water, joins in the DMF solution and stirring.Then with Pd (PPh
3)
4(5 moles of %) joins this DMF reaction mixture.Microwave was in 200 ℃ of heating 2 minutes in the reaction mixture.Reaction mixture is applied on the 1g solid-phase extraction column cylinder (C-18), and described post is with the methanol wash of 3 * 2ml.Elutriant filters by the strainer of 0.45um, is concentrated into dried.The gained material is dissolving again in DMF, carries out purifying with reverse hplc/MS.
Step F
The preparation of xenyl array (biphenyl array)
At first in DMF, use aqueous sodium hydroxide solution as alkali reagent, handle 2-(2 with 1-brooethyl-4-iodobenzene (2), 3-two fluoro-phenyl)-3H-imidazo (4,5-c) pyridine (1), suitably replaced 4 '-[2-(2,3-two fluoro-phenyl)-imidazo (4,5-c) pyridine-5-ylmethyl]-xenyl-4-alcohol (5) skeleton.The 2-(2 of gained, 3-two fluoro-phenyl)-5-(4-iodine benzyl)-5H-imidazo (4,5-c) pyridine (3) (1 equivalent) is with three kinds of different 4-hydroxy phenyl boric acid ((4-hydroxy phenyl) boric acid that replace, 4-hydroxyl-2-(trifluoromethyl) phenyl-boron dihydroxide) and (4-hydroxy-2-methyl phenyl) boric acid) and (4-fluoro-2-hydroxyl) phenyl-boron dihydroxide (1.1 equivalent) (yellow soda ash under the Suzuki coupling condition, water, tetrakis triphenylphosphine palladium) handles under, suitably replaced 4 '-(2-(2, the 3-difluorophenyl)-imidazo (4,5-c) pyridine-5-ylmethyl)-biphenyl-4-is pure or (2-(2, the 3-difluorophenyl)-and imidazo (4,5-c) pyridine-5-ylmethyl) biphenyl-2-alcohol.Product precipitates in ethyl acetate, and medium glass filter filters, and washing obtains pure products (5).
The general formula for preparing for array way is the compound of (7), and 50 μ M skeletons (5) among the 250 μ LDMF are used for each reaction system.In each reaction system, add 1.4 normal cesium carbonates.The solution (0.05mmol) that adds the 0.4M of alkylating reagent (6) in DMF.Reaction system is in 60 ℃ of following joltings 4 hours, LC/MS analysis monitoring.Each reaction system is filtered with 0.45 μ M strainer, adopts 0.1%TFA/ water and 0.1%TFA/ acetonitrile to carry out purification based on quality grading as eluent on the reverse post of C-18.Every part of compound is confirmed with mass spectrum, is used in the UV absorbance measurement purity of 254nm.HPLC fraction vacuum concentration and weighing obtain the trifluoroacetate of product (7).
The compound and the part character thereof that prepare according to these steps and embodiment are described in following form.Substituting group with " C " expression is a methyl.
Obs.MW in the following table is meant observed molecular weight.
Embodiment 374
The isoxazole analogue
Ar=(replacement) phenyl, (replacement) heteroaryl (hetaryl)
X＝Br，Cl
374a's is synthetic
In the solution of the stirring of 50% ethanol (7ml), add ice (10g) and hydroxylamine hydrochloride (2.1000g) to 4-oxyethyl group-phenyl aldehyde (3.000g), then add 30% aqueous sodium hydroxide solution (3.5ml).After (1 hour) is finished in reaction, add hydrochloric acid and regulate pH to 1, suspension cools off in ice bath and filters.The thick product of oxime can not need purifying promptly to be used for next step.Perhaps, also can carry out recrystallization with diisopropyl ether and ethyl acetate mixture.Productive rate: 71%.
At propargyl chloride (655mg, 1 equivalent) and triethylamine (35mg, 0.1 in methylene dichloride equivalent) (9.5ml) solution, in 15 minutes and under the cooling, add 10% aqueous sodium hypochlorite solution (9.5ml successively, 1.5 equivalent), add oxime solution (1.40g ,～1.3M dichloromethane solution) then, then restir is 1 hour.Reaction is monitored by TLC (silica gel, the dichloromethane solution of eluent: 5%MeOH).Reaction is finished the afterreaction mixture with the dichloromethane extraction of 30ml 3 times.Merge organic phase, anhydrous sodium sulphate is carried out drying, reduction vaporization.Crude product 5-(chloromethyl)-3-(4-ethoxyl phenenyl)-isoxazoles carry out purifying by column chromatography (silica gel, ethyl acetate/petroleum ether=1: 9).Output: 1.1g.
3,4-diamino-pyridine (2.00g), 2, the mixture of 3-difluoro-benzoic acid (1 equivalent) and Tripyrophosphoric acid (50g) was in 180 ℃ of stirring heating 4 hours.Then mixture is cooled to room temperature, pours in ice/water.The gained mixture neutralizes by adding solid NaOH.Thick product 2-(2, the 3-difluorophenyl)-1 (3) H-imidazo (4,5-c) pyridine is collected by filtration, and washing is also dry.Be directly used in next step and do not need purifying.Productive rate: 88%.
2-(2, the 3-difluorophenyl)-1-(3) H-imidazo (4,5-c) pyridines (0.500g) are dissolved among the dry DMF (5ml), and gained solution is cooled to 0 ℃.Add 50% sodium hydroxide (1.5 equivalent), mixture was stirred 15 minutes.Then add 5-(chloromethyl)-3-(4-ethoxyl phenenyl)-isoxazoles (1.2 equivalent), the gained mixture at room temperature stirred 24 hours.At last, add entry (50ml), filter collecting precipitation, drying obtains thick product.
Carry out recrystallization with ethyl acetate; Clear crystal; Productive rate: 35%.
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.2Hz), 8.28 (dd, 1H, H6, J=6.6,1.2Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.6Hz), 7.77 (AA ' BB ', 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.07-7.00 (m, 3H, fragrant H), 6.02 (s, 2H, CH
2), 4.06 (q, 2H, OCH
2, J=6.9Hz), 1.32 (t, 3H, CH
3, J=6.9Hz).
Following examples are by being prepared with the similar method of above-mentioned steps:
374b
From the 4-methoxybenzaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.2Hz), 8.28 (dd, 1H, H6, J=6.6,1.2Hz), 8.15 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6Hz), 7.79 (AA ' BB ', 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.09-7.00 (m, 3H, fragrant H), 6.01 (s, 2H, CH
2), 3.80 (s, 3H, OCH
3).
374c
From the 4-tolyl aldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.24 (br s, 1H, H4), 8.29 (d, 1H, H6, J=6.7Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.7Hz), 7.58-7.27 (m, 6H, fragrant H), 7.00 (s, 1H ， isoxazole-H), 6.04 (s, 2H, CH
2), 2.41 (s, 3H, CH
3).
374d
From the 2-Furan Aldehydes
1H NMR (200MHz, DMSO-d
6) δ 9.24 (br s, 1H, H4), 8.28 (d, 1H, H6, J=6.7Hz), 8.15 (m, 1H, phenyl-H), 7.90-7.87 (m, 2H, fragrance H), 7.51 (m, 1H, phenyl-H), 7.32 (m, 1H, phenyl-H), 7.15 (d, 1H, furans-H, J=3.6Hz), 6.96 (s, 1H ， isoxazole-H), 6.68 (m, 1H, furans-H), 6.02 (s, 2H, CH
2).
374e
From thiophene-2-formaldehyde (t hiophene-2-carboxaldehyde)
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.6Hz), 8.27 (dd, 1H, H6, J=7.0,1.6Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=7.0Hz), 7.75-7.70 (m, 2H, fragrance H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.19 (dd, 1H, thiophene-H), 7.06 (s, 1H ， isoxazole-H), 6.02 (s, 2H, CH
2).
374f
From the dimethylamino benzaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.6Hz), 8.27 (dd, 1H, H6, J=7.0,1.6Hz Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=7.0Hz), 7.65 (AA ' BB ', 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 6.98 (s, 1H ， isoxazole-H), 6.76 (AA ' BB ', 2H, benzyl-H), 5.75 (s, 2H, CH
2), 2.95 (s, 6H, N (CH
3)
2)
374g
From 4-xenyl formaldehyde (4-biphenylcarboxaldehyde)
1H NMR (200MHz, DMSO-d
6) δ 9.25 (d, 1H, H4, J=1.6Hz), 8.30 (dd, 1H, H6, J=7.0,1.6Hz Hz), 8.16 (m, 1H, phenyl-H), and 7.98-7.70 (m, 7H, fragrant H), 7.57-7.26 (m, 5H, fragrant H), 7.18 (s, 1H ， isoxazole-H), 6.05 (s, 2H, CH
2).
374h
From the 4-bromobenzaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.6Hz), 8.28 (dd, 1H, H6, J=7.0,1.6Hz), 8.16 (m, 1H, phenyl-H), 7.90-7.68 (m, 4H, fragrant H), 7.51 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.15 (s, 1H ， isoxazole-H), 6.05 (s, 2H, CH
2).
374i
From 4-benzyloxy phenyl aldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.6Hz), 8.27 (dd, 1H, H6, J=7.0,1.6Hz Hz), 8.15 (m, 1H, phenyl-H), 7.90-7.76 (m, 3H, fragrant H), 7.57-7.26 (m, 7H, fragrant H), 7.15-7.05 (m, 3H, fragrant H), 6.01 (s, 2H, N-CH
2), 5.16 (s, 2H, O-CH
2).
374j
From 4-(methylthio group) phenyl aldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.2Hz), 8.28 (dd, 1H, H6, J=6.6,1.2Hz), 8.15 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6Hz), 7.79 (AA ' BB ', 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.38-7.25 (m, 3H, fragrant H), 7.10 (s, 1H ， isoxazole-H), 6.03 (s, 2H, CH
2), 2.51 (s, 3H, SCH
3).
374k
From 2-fluoro-4-methoxybenzaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.26 (d, 1H, H4, J=1.2Hz), 8.30 (dd, 1H, H6, J=6.6,1.2Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6Hz), 7.80 (m, 1H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.04-6.71 (m, 3H, fragrant H), 6.03 (s, 2H, CH
2), 3.82 (s, 3H, OCH
3).
374w
Preparation according to the method described above is from 4-chloro-2-fluorobenzaldehyde.
1H NMR (200MHz, DMSO-d
6) 9.26 (d, 1H, H4, J=1.4Hz), 8.30 (dd, 1H, H6, J=6.8,1.4Hz), 8.14 (m, 1H, phenyl-H), (7.90-7.87 m, 2H, fragrant H), 7.66 (dd, 1H, fragrant H, J=10.8,1.8Hz), 7.53-7.41 (m, 2H, fragrant H), 7.31 (m, 1H, phenyl-H), 7.10 (d, 1H isoxazole-H, J=2.7Hz), 6.06 (s, 2H, CH
2).
374l
From 4-propoxy-phenyl aldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.2Hz), 8.29 (dd, 1H, H6, J=6.6,1.2Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6Hz), 7.78 (AA ' BB ', 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.06-7.00 (m, 3H, fragrant H), 6.01 (s, 2H, CH
2), 3.97 (t, 2H, OCH
2, J=6.5Hz), 1.73 (hex, 2H, CH
2), 0.97 (t, 3H, CH3, J=7.3Hz).
374m
From the 4-phenoxy benzaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.25 (d, 1H, H4, J=1.2Hz), 8.29 (dd, 1H, H6, J=6.6,1.2Hz), 8.16 (m, 1H, phenyl-H), 7.92-7.83 (m, 3H, fragrant H), 7.58-7.05 (m, 10H, fragrant H), 6.04 (s, 2H, CH
2).
374n
From 1-methylpyrrole-2 formaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.2Hz), 8.28 (dd, 1H, H6, J=6.8,1.2Hz), 8.16 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.8Hz), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 6.98 (dd, 1H, the pyrroles-H), (6.92 s, 1H ， isoxazole H), 6.68 (dd, 1H, the pyrroles-H), 6.12 (dd, 1H, the pyrroles-H), 6.00 (s, 2H, CH
2).
374o
From 4-isopropyl benzene formaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.4Hz), 8.28 (dd, 1H, H6, J=7.0,1.4Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=7.0Hz), 7.76 (AA ' BB ', 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.05-6.98 (m, 3H, fragrant H), 6.01 (s, 2H, CH
2), 4.67 (hept, 1H, OCH, J=6.2Hz), 1.26 (d, 6H, (CH
3)
2, J=6.2Hz).
374p
Be prepared as above-mentioned method, from 5-chlorothiophene-2-formaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.4Hz), 8.27 (dd, 1H, H6, J=7.0,1.4Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=7.0Hz), 7.63 (d, 1H, thiophene-H, J=4.0Hz), 7.51 (m, 1H, phenyl-H), 7.37-7.24 (m, 2H, fragrant H), 7.07 (s, 1H ， isoxazole-H), 6.03 (s, 2H, CH
2).
374q
Be prepared as above-mentioned method, from 5-bromothiophene-2-formaldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.4Hz), 8.27 (dd, 1H, H6, J=6.6,1.4Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.6Hz), 7.59 (d, 1H, thiophene-H, J=3.6Hz), 7.50 (m, 1H, phenyl-H), 7.36-7.27 (m, 2H, fragrant H), 7.06 (s, 1H ， isoxazole-H), 6.02 (s, 2H, CH
2).
374r
Be prepared as above-mentioned method, from 4-butyl phenyl ether formaldehyde (getting) by the alkylation preparation of 4-hydroxy benzaldehyde.
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.2Hz), 8.28 (dd, 1H, H6, J=6.6,1.2Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.6Hz), 7.78 (AA ' BB ', 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.07-7.01 (m, 3H, fragrant H), 6.01 (s, 2H, CH
2), 4.01 (t, 2H, OCH
2, J=6.5Hz), 1.72 (m, 2H, CH
2), 1.42 (m, 2H, CH
2), 0.93 (t, 3H, CH
3, J=7.2Hz).
374s
Be prepared as above-mentioned method,, and use 2-(2-fluorophenyl)-1 (3) H-imidazo (4,5-c) pyridine to replace 2-(2, the 3-difluorophenyl)-1 (3) H-imidazo (4,5-c) pyridine from 4-propoxy-phenyl aldehyde.
1H NMR (200MHz, DMSO-d
6) 9.18 (d, 1H, H4, J=1.2Hz), 8.38-8.23 (m, 2H, fragrant H), 7.85 (d, 1H, H7, J=6.6Hz), 7.78 (AA ' BB ', 2H, benzyl-H), 7.54-7.25 (m, 3H, phenyl-H), 7.06-7.00 (m, 3H, fragrant H), 6.00 (s, 2H, CH
2), 3.98 (t, 2H, OCH
2, J=6.6Hz), 1.73 (hex, 2H, CH
2), 0.97 (t, 3H, CH
3, J=7.3Hz).
374t
From 4-allyloxy phenyl aldehyde
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.2Hz), 8.27 (dd, 1H, H6, J=6.7,1.2Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.7Hz), 7.79 (AA ' BB ', 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.09-7.00 (m, 3H, fragrant H), 6.15-5.98 (m, 3H), 5.45-5.24 (m, 2H), 4.62 (d, 2H, J=4.8Hz).
374u
5-(chloromethyl)-3-(4-chloro-phenyl-)-isoxazoles (2.00g), NCS (11.75g, 10 equivalents), the mixture heating up of Glacial acetic acid (35ml) and 20 vitriol oils refluxed 3 days.After being cooled to room temperature, add methylene dichloride (100ml), gained mixture water (2 * 100ml) and saturated sodium bicarbonate aqueous solution (2 * 100ml) extract.Organic phase is carried out drying and evaporation with anhydrous sodium sulphate.The thick product of gained carries out purifying (silica gel, eluent: petrol ether/ethyl acetate=19: 1) obtain the product of 1.14g by column chromatography.
Last step step is as mentioned previously carried out.Carry out recrystallization with ethyl acetate and alcohol mixture.Productive rate: 60%.
1H NMR (200MHz, DMSO-d
6) 9.20 (d, 1H, H4, J=1.4Hz), 8.25 (dd, 1H, H6, J=6.8,1.4Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.8Hz), 7.83 (AA ' BB ', 2H, benzyl-H), 7.66 (AA ' BB ', 2H, benzyl-H), 7.51 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 6.14 (s, 2H, CH
2).
374v
1H NMR (200MHz, DMSO-d
6) δ 9.18 (d, 1H, H4, J=1.4Hz), 8.22 (dd, 1H, H6, J=6.8,1.4Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.8Hz), 7.80 (AA ' BB ', 2H, benzyl-H), 7.65 (AA ' BB ', 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.30 (m, 1H, phenyl-H), 6.11 (s, 2H, CH
2).
To synthesize with the similar method of Lv Isoxazole derivative 374u, 4 normal NBS refluxed productive rate: 91% in 2.5 hours.
Embodiment 375
In the 4ml carbon tetrachloride solution of the 3-of 500mg methyl isophthalic acid-phenylpyrrole, in 70 ℃ of mixtures that add 678mg (1.2 equivalent) NBS and AIBN (62.3mg, 0.12 equivalent) in batches.The gained mixture continued reflux 15 minutes, was cooled to room temperature.Filter out precipitation, filtrate concentrates postprecipitation and obtains thick product (380mg), after filtration collection and the drying, need not purifying and is directly used in subsequent step.Final step method is as described above carried out.Use re-crystallizing in ethyl acetate.Productive rate: 35%.
Embodiment 376
Imidazo (4,5-c) pyridine-4-keto analog
The mixture of 4-chloro-3-nitro-pyridin-2-ones (1.00g), 4-(trifluoromethyl) benzyl chloride (1.226g), Anhydrous potassium carbonate (0.871g) and dry DMF (10ml) stirred under room temperature 24 hours.Then add entry (100ml), the gained sedimentation and filtration is collected, and washing is also dry.Productive rate: 4-chloro-3-nitro-1-(4-trifluoromethyl) benzyl-pyridin-2-ones of 58.2%.
4-chloro-3-nitro-1-(4-trifluoromethyl) benzyl-pyridin-2-ones (500mg) is dissolved in anhydrous THF (10ml).Add strong aqua (7.5ml), the gained mixture was in stirring at room 24 hours.Add entry (50ml), the gained sedimentation and filtration is collected, and washing is also dry.Productive rate: 4-amino-3-nitro-1-(4-trifluoromethyl) benzyl-pyridin-2-ones of 45.8%.
The mixture of 4-amino-3-nitro-1-(4-trifluoromethyl) benzyl-pyridin-2-ones (1.400g), saturated aqueous ammonium chloride (9.4ml), zinc powder (1.400g) and methyl alcohol (235ml) was in stirring at room 1 hour.Add zinc powder (1.400g) in addition again, gained mixture restir 23 hours.After the solvent evaporation, add entry (30ml), regulate pH to 8-9 by the NaOH that adds 2N.(3 * 30ml) extract the gained mixture, merge organic phase and wash (30ml), anhydrous sodium sulfate drying and evaporation with ethyl acetate.Productive rate: 53.4% 3,4-diaminostilbene-(4-trifluoromethyl) benzyl-pyridin-2-ones.
3,4-diaminostilbene-(4-trifluoromethyl) benzyl-pyridin-2-ones (0.200mg), 2, the mixture of 3-difluorobenzaldehyde (100mg), Sodium Pyrosulfite (0.134g) and N,N-dimethylacetamide (4.6ml) heated 24 hours down in 130 ℃.Then add entry (30ml), the gained sedimentation and filtration is collected, and washing is also dry.Thick product is through column chromatography (silica gel, eluent: methylene chloride=12/1) carry out purifying, then carry out recrystallization with diisopropyl ether and ethyl acetate.Productive rate: 16.8%.Fusing point: 279-283 ℃.
1H NMR (200MHz, DMSO-d
6) δ 13.05 (br s, 1H, NH), 7.88 (m, 1H, phenyl-H), 7.74-7.32 (m, 7H, fragrant H), 6.69 (br d, 1H, H7, J=6.0Hz), 5.34 (s, 2H, CH
2).
Embodiment 377
Synthesizing of 4-methyl analogue 377
The mixture of the methyl trioxy-rhenium (methyltrioxorhenium) of 2-(2, the 3-difluorophenyl)-1 (3) H-imidazo (4,5-c) pyridines (2.00g), 50mg, the methyl alcohol of 100ml and 30% aqueous hydrogen peroxide solution (4ml) was in stirring at room 4 days.Then, add methyl trioxy-rhenium and 30% aqueous hydrogen peroxide solution (4ml) of 50mg in addition, the gained mixture then stirred 2 days.After boiling off methyl alcohol, add entry (200ml), regulate pH to 9 by the NaOH that adds 2N.Gained precipitation filters, dry, carry out recrystallization with ethyl acetate (20ml) and ethanol (53ml) mixture, obtain 2-(2, the 3-difluorophenyl)-1-(3) H-imidazo (4, the 5-c) pyridine-5-oxide compound of 1.208g (56.5%).
2-(2, the 3-difluorophenyl)-1 (3) H-imidazo (4,5-c) pyridine-5-oxide compound (1.00g) is dissolved in exsiccant tetrahydrofuran (THF) (100ml), and argon shield drips MeMgBr solution (14ml, the diethyl ether solution of 3M) down.The gained mixture stirred under room temperature 1.5 hours.Slowly add water (100ml), pH regulator to 8.5.(3 * 70ml) extract ethyl acetate, and the organic phase of merging is carried out drying with anhydrous sodium sulphate, boil off 2-(2, the 3-difluorophenyl)-thick product of 4-methyl isophthalic acid (3) H-imidazo (4,5-c) pyridine that solvent obtains 0.630g (60%).Mixture with diisopropyl ether (20ml) and ethyl acetate (34ml) carries out recrystallization, obtains the pure 2-of 240mg (24.2%) (2, the 3-difluorophenyl)-4-methyl isophthalic acid (3) H-imidazo (4,5-c) pyridine.
Final step such as above-mentioned method are carried out.By column chromatography (silica gel, eluent: methylene chloride=20/1) carry out purifying.Productive rate: 22.4%.
1H NMR (200MHz, DMSO-d
6) δ 8.25 (d, 1H, H6, J=6.8Hz), 8.11 (m, 1H, phenyl-H), 7.89 (AA ' BB ', 2H, benzyl-H), 7.77 (d, 1H, H7, J=6.8Hz), 7.60-7.41 (m, 3H, fragrant H), 7.30 (m, 1H, phenyl-H), 7.12 (s, 1H ， isoxazole-H), 6.05 (s, 2H, CH
2), 3.05 (s, 3H, CH
3).
Embodiment 378
7 replace the synthetic of analogue
378a
3-methyl-4-nitropyridine 1-oxide compound (5.85g) is dissolved in Glacial acetic acid (115ml), in room temperature at Pa Er (Parr) hydrogenation apparatus (catalyzer: 220mg PtO
2* 2H
2O carried out hydrogenation 2.5 hours in 50psi).Then the elimination catalyzer boils off solvent.After adding the water of 150ml, the NaOH by adding 2N is with pH regulator to 12.Gained solution extracts 10 times with the methylene dichloride (containing 5% methyl alcohol) of 100ml.Merge organic phase, anhydrous sodium sulfate drying and evaporation obtain the 4-amino-3-picoline of 3.81g (83.6%).
Under ice-cooled, 4-amino-3-picoline (3.00g) is dissolved in the vitriol oil (36ml).Then drip nitrosonitric acid (4,72g).After the stirring at room 1 hour, solution was in 60 ℃ of heating 14 hours.After being cooled to room temperature, reaction mixture is poured in the ice, and gained solution is regulated pH to 13 by adding solid KOH.Precipitation is filtered, washing and dry.The 4-amino of productive rate: 1.198g (31.3%)-3-methyl-5-nitro pyridine.
The mixture heating up of 4-amino-3-methyl-5-nitro pyridine (1.198g), iron powder (1.748g), ethanol (52ml) and hydrochloric acid (13ml) refluxed 3 hours.After being cooled to room temperature, ethanol distillation is removed, and gained suspension is diluted with water to 50ml, regulates pH to 13 by the NaOH that adds 2N.(3 * 70ml) extract, and the organic phase of merging is carried out drying with anhydrous sodium sulphate, boil off solvent and obtain 3 of 0.579g (60%), 4-diamino-5-picoline with ethyl acetate.
With as above-mentioned method in PPA with 2, the 3-difluoro-benzoic acid carries out cyclization.Column chromatography is carried out purifying (silica gel, eluent: methylene chloride=12/1).Productive rate: 22.2%.
Last step is carried out with foregoing method.With ethyl acetate and alcohol mixture recrystallization.Productive rate: 42.9%378a.
1H NMR (200MHz, DMSO-d
6) δ 9.14 (d, 1H, H4, J=1.2Hz), 8.17-8.10 (m, 2H, fragrant H), 7.90 (AA ' BB ', 2H, benzyl-H), 7.60-7.42 (m, 3H, fragrant H), 7.32 (m, 1H, phenyl-H), 7.15 (s, 1H ， isoxazole-H), 5.99 (s, 2H, CH
2), 2.58 (s, 3H, CH
3).
Following compound is used with the similar method of above-mentioned steps and is prepared:
378b
1H NMR (200MHz, DMSO-d
6) δ 9.32 (d, 1H, H4, J=1.4Hz), 8.67 (d, 1H, H6, J=1.4Hz), 8.16 (m, 1H, phenyl-H), 7.78 (AA ' BB ', 2H, benzyl-H), 7.54 (m, 1H, phenyl-H), 7.34 (m, 1H, phenyl-H), 7.07-7.00 (m, 3H, fragrant H), 6.00 (s, 2H, CH
2), 4.07 (q, 2H, OCH
2, J=7.0Hz), 1.33 (t, 3H, CH
3, J=7.0Hz).
378c
1H NMR (200MHz, DMSO-d
6) δ 9.47 (d, 1H, H4, J=1.4Hz), 8.94 (d, 1H, H6, J=1.4Hz), 8.16 (m, 1H, phenyl-H), 7.89 (AA ' BB ', 2H, benzyl-H), 7.63-7.50 (m, 3H, fragrant H), 7.35 (m, 1H, phenyl-H), 7.16 (s, 1H ， isoxazole-H), 6.10 (s, 2H, CH
2).
378d
1H NMR (200MHz, DMSO-d
6) δ 9.30 (br s, 1H, H4), 8.66 (dd, 1H, H6, J=7.4,1.4Hz), 8.15 (m, 1H, phenyl-H), 7.89 (AA ' BB ', 2H, benzyl-H), 7.61-7.47 (m, 3H, fragrant H), 7.33 (m, 1H, phenyl-H), 7.16 (s, 1H ， isoxazole-H), 6.04 (s, 2H, CH
2).
Embodiment 379
1,2, the 4-oxadiazole
379a
The mixture heating up of 4-HOMOVERATRONITRILE (1.00g), hydroxylamine hydrochloride (0.785g), KOH (0.640g) and methyl alcohol (20ml) refluxed 3 hours.After being cooled to room temperature, the elimination precipitation, filtrate is evaporated.The gained residue is dissolved in the HCl (100ml) of 1N, and the solution that obtains extracts with diethyl ether (100ml).Water is by adding solid NaHCO
3Neutralize, diethyl ether extracts (2 * 100ml).Merge organic phase, anhydrous sodium sulphate is carried out drying, obtains the required amidoxime (amidoxime) of 450mg after the evaporation, and not needing further purifies directly uses.
Toluene (30ml) vlil of the anhydrous chloroacetic acid acid anhydride of (4-p-methoxy-phenyl) amidoxime of 700mg and 1.08g (1.5 equivalent) 3 hours.After being cooled to room temperature, reaction mixture water (twice of 50ml), saturated sodium bicarbonate solution (twice of 50ml) and water (50ml) successively extracts.At last, toluene is used anhydrous sodium sulfate drying mutually, obtains the Suo Xu oxadiazole of 660mg after the evaporation, and not needing further purifies directly uses.
Final step carries out (for example, with reference to the isoxazole analogue) with aforesaid method.Carry out recrystallization with ethyl acetate and alcohol mixture.Productive rate: 35%.
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.4Hz), 8.28 (dd, 1H, H6, J=6.8,1.4Hz), 8.15 (m, 1H, phenyl-H), 7.92-7.77 (m, 3H, fragrant H), 7.49 (m, 1H, phenyl-H), 7.33 (m, 1H, phenyl-H), 7.08-7.00 (m, 3H, fragrant H), 6.01 (s, 2H, CH
2), 3.80 (s, 3H, OCH
3).
379b
Be prepared with aforesaid method, from 4-methyl benzonitrile.
1H NMR (200MHz, DMSO-d
6) δ 9.23 (d, 1H, H4, J=1.4Hz), 8.31 (dd, 1H, H6, J=6.8,1.4Hz), 8.14 (m, 1H, phenyl-H), 7.93-7.78 (m, 3H, fragrant H), 7.50 (m, 1H, phenyl-H), 7.35-7.27 (m, 3H, fragrant H), 6.25 (s, 2H, CH
2), 2.35 (s, 3H, CH
3).
379c
With aforesaid method preparation, from pyridine-2-nitrile.
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.4Hz), 8.72 (ddd, 1H, pyridine-H), 8.32 (dd, 1H, H6, J=6.8,1.4Hz), 8.15 (m, 1H, phenyl-H), 8.00-7.90 (m, 3H, fragrant H), 7.64-7.27 (m, 3H, fragrant H), 6.30 (s, 2H, CH
2).
379d
With aforesaid method preparation, from 4-benzyl chloride nitrile.
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.4Hz), 8.31 (dd, 1H, H6, J=6.8,1.4Hz), 8.16 (m, 1H, phenyl-H), 7.96-7.90 (m, 3H, fragrant H), 7.60 (AA ' BB ', 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.34 (m, 1H, phenyl-H), 6.28 (s, 2H, CH
2).
379e
With aforesaid method preparation, from pyridine-4-nitrile.
1H NMR (200MHz, DMSO-d
6) δ 9.24 (d, 1H, H4, J=1.4Hz), 8.77 (AA ' BB ', 2H, pyridine-H2/6), 8.32 (dd, 1H, H6, J=7.0,1.4Hz), 8.15 (m, 1H, phenyl-H), 7.93 (d, 1H, H7, J=7.0Hz), 7.86 (AA ' BB ', 2H, pyridine-H3/5), 7.51 (m, 1H, phenyl-H), 7.32 (m, 1H, phenyl-H), 6.32 (s, 2H, CH
2).
The B part
Measure antiviral and method cell inhibitory activity
Cell and virus
Madin-Darbey Bovine Kidney (MDBK) cell remains on 37 ℃, the 5%CO of humidification
2Under the atmosphere, in the Eagle substratum (DMEM) of Dulbecco improvement, replenish described substratum with 5% foetal calf serum (DMEME-FCS) that does not conform to BVDV-.Adopt the antiviral activity of BVDV-1 (bacterial strain PE515) evaluation in the MDBK cell.
Anti--BVDV measures
In DMEM-FCS, inoculate the MDBK cell in the 96 porocyte culture plates, cell was reached after 24 hours converge (confluency).Then, remove substratum, add 5 times of diluents of a series of test compounds, cumulative volume is 100ul, afterwards, adds virus inoculation thing (100ul) in each hole.Used virus inoculation thing after 5 days, causes destroying more than 90% of cell monolayer 37 ℃ of hatchings.In each assay plate, comprise non-infected cells and receive virus but do not receive the cell of compound.After 5 days, remove substratum, in each hole, add the DMEM-FCS of 90 μ l and the MTS/PMS solution (Promega) of 10ul.After 2 hours, on microplate, read the optical density(OD) of each hole under 498nm 37 ℃ of hatchings.50% effective concentration (EC
50) value defined avoids taking place the compound concentration of virus-inductive cytopathic effect for protecting 50% cell monolayer.
Whose anti-HCV mensuration/replicon measures-1
The Huh-5-2 cell [has the cell strain that continues HCV replicon I389luc-ubi-neo/NS3-3 '/5.1; This replicon is the replicon that has the NS3-5B HCV polyprotein of Lampyridea luciferase-ubiquitin-neomycin phosphotransferase fusion rotein and EMCV-IRES driving] in RPMI substratum (Gibco), cultivate, be supplemented with 10% foetal calf serum in the described substratum, 2mM L-glutaminate (Life Technologies), the non-primary amino acid of 1x (Life Technologies); 100IU/ml penicillin and 100ug/ml Streptomycin sulphate and 250ug/ml G418 (Geneticin, Life Technologies).Cell is seeded in 96 hole View Plate with the density of 7000 cells/well
TM(Packard) in the substratum, except G418, described substratum contains the component identical with the above.Make cell attachment and hyperplasia 24 hours.At this moment, remove substratum, in lacking the substratum of G418, add a series of diluents of test compounds.Comprise interferon alpha 2a (500IU) conduct over against photograph.Plate is again in 37 ℃ and 5%CO
2Middle hatching 72 hours.HCV replicon being replicated in the Huh-5 cell produces luciferase activity in the cell.Luciferase activity can add the Steady-Glo luciferase assay reagent (Promega) of 50ul by the 1x Glo-lysis buffer reagent (Promega) that added 50 μ l in 15 minutes subsequently and measure.The activity of luciferase is with photometric determination, and the signal indication in each hole is the percentage ratio of culture of being untreated.The parallel culture of Huh-5-2 cell, be seeded in traditional 96-porocyte culture plate (Becton-Dickinson) with 7000 cells/well density, this culture is handled in a similar manner, and difference is not add Glo-lysis buffer reagent or Steady-Glo luciferase reagent.Adopt MTS method (Promega) to measure culture density in addition.
Come quantitative analysis HCV RNA by the Taqman real-time RT-PCR
The replicon cell is with 7.5 * 10
3Cells/well is in 37 ℃ and 5%CO
2In the 96-orifice plate, containing 10% foetal calf serum, in the minimum medium of Dulbecco ' the s improvement of 1% non-primary amino acid and 1mg/ml Geneticin.Behind the cell attachment 24 hours, in culture, add different dilution compounds.Plate hatching 5 days, at this moment, (Qiagen, Hilden Germany) extract RNA with Qiamp Rneazyi Kit.A 50 μ LPCR reactants comprise TaqMan EZ buffer reagent (50mmol/L N, N-two (hydroxyethyl) glycine, the 115mmol/L potassium acetate, EDTA O.01mmol/L, 60nmol/L 6-carboxyl-X-rhodamine and 8% glycerine, pH 8.2; Perkin Elmer Corp./Applied Biosystems), 300 μ mol/L deoxyadenosine triphosphates, 300 μ mol/L deoxyguanosine triphosphates, 300 μ mol/L dCTPs, 600 μ mol/L Deoxycytidine triphosphates, 200 μ mol/L forward primers (forward primer) [5 '-ccg gcT Acc TgcccA TTc], 200 μ mol/L reverse primers (reverse primer) [ccA GaT cAT ccT gAT cgAcAA G], 100 μ mol/L TaqMan probe[6-FAM-AcA Tcg cAT cgA gcg Agc AcgTAc-TAMRA], the 3mmol/L manganous acetate, 0.5U AmpErase uridylic-N-transglycosylase, 7.5U rTthDNA polysaccharase and 10 μ l RNA elutriants.Uridylic-N-transglycosylase is in 50 ℃ of initiate activations after 2 minutes, carries out RT 30 minutes in 60 ℃, and uridylic-N-transglycosylase carried out deactivation 5 minutes in 95 ℃ subsequently.PCR amplification subsequently comprises 40 circulations, and each circulation was annealed and spread 1 minute in 62 ℃ in ABI 7700 program detectors for 94 ℃ of sex change 20 seconds.To each PCR operation, use negative norm plate and positive template sample.This round-robin threshold value (Ct-value) is defined as the PCR cycle number that signal surpasses baseline, it define on the occasion of.If the Ct-value is＜50, think that this sample is for just.The result is expressed as genome equivalent (GE).
Anti-HCV mensuration/replicon measures-2
HCV replicon nutrient solution
The high sugar of DMEM w/ (or MEM)
1 * glutamine
1 * Sodium.alpha.-ketopropionate
10% heat-inactivated FBS
1 * microbiotic
Cell cultures is prepared
1, the freezing stock solution that in the substratum of 10-12ml, thaws.
2, add G418 (4-6 hour) and make cell attachment before.
3, add G418, to the last concentration is 200ug/ml (also can adopt higher concentration, but cell poor growth)
4, cell fission is that feasible growth in 1: 4 to 1: 6 is optimized
5, Nei Bu (In-house) replicon demonstrates and keeps luciferase signal～20 passages
The HCV replicon is measured
1, diluted chemical compound is in the HCV of 100ul replicon substratum (not containing G418).If compound dilutes, in medium, add DMSO (final DMSO concentration answers＜1%) in DMSO
If 2 cells reach converging of 80-90%, carry out trysinization with 1 * trypsinase
3, excessively trysinization.If trysinization is excessive, the easy grumeleuse of cell.
4, every hole adds 6 in 96 pore structures (format), 000-8,000 cell (G418 keeps (withheld) during the compound test).
5, in 37 ℃ of hatchings 3 days.Cell must be very near converging.
6, remove medium, with 1 * PBS washed cell.
7, remove PBS, add the cracking buffer reagent of 100 μ l Promega
8, hatched cell 5-20 minute in room temperature
9, in Microfluor Black Plate (VWR), add under the room temperature of 100 μ l luciferase substrate solution (Promega) extremely.
10, before being added to the luciferase substrate, lysate (lysate) is mixed (up-down vibration transfer pipet) fully.
11, the lysate that in the luciferase substrate solution, adds 75 μ l
12, on Top Count, read plate (Fusion LucB program～5 seconds readings)
13, the lysate of leaving over can freezingly be used for follow-up analysis.
Mensuration is to the cyto-inhibition of MDBK cell
Following mensuration medicine is to the effect with the MDBK cell of exponential growth.Cell is seeded in the density of 5000 cells/well in the plate in 96 holes of MEM substratum (Gibco), is supplemented with 10% foetal calf serum in the substratum, 2mM L-glutaminate (Life Technologies) and supercarbonate (Life Technologies).Cell cultures 24 hours adds a series of diluents of test compounds then.Culture was hatched 3 days again, adopted the effect of MTS method (Promega) quantitative evaluation cell growth then.The concentration that produces cell growth 50% inhibition is defined as 50% cell inhibition concentration (CC
50).
HCV CC50 measuring method
HCV replicon substratum
The high sugar of DMEM w/ (or MEM)
1 * glutamine
1 * Sodium.alpha.-ketopropionate
10% heat-inactivated FBS
1 * microbiotic
Cell cultures is prepared
1, the freezing stock solution that in the substratum of 10-12ml, thaws.
2, add G418 (4-6 hour) and make cell attachment before.
3, add G418, to the last concentration is 200ug/ml (also can adopt higher concentration, but cell poor growth)
4, cell fission is that feasible growth in 1: 4 to 1: 6 is optimized
5, Nei Bu replicon demonstrates and keeps luciferase signal～20 passages
The HCV replicon is measured
1, diluted chemical compound is in the HCV of 100ul replicon substratum (not containing G418).If compound dilutes, in substratum, add DMSO (ultimate density answers＜1%) in DMSO
If 2 cells reach converging of 80-90%, carry out trysinization with 1 * trypsinase
3, excessively trysinization.If trysinization is excessive, the easy grumeleuse of cell.
4, every hole adds 6 in 96 pore structures (format), 000-8,000 cell (G418 keeps (withheld) during the compound test).
5, in 37 ℃ of hatchings 3 days.Cell must be very near converging.
6, remove substratum, add the 0.2mg/mLMTT solution that in substratum, makes of 200 μ l.
7, hatching is 1.5-2 hour
8, remove substratum, add the DMSO of 150 μ l
9, in mixed at room temperature and hatched 5 minutes
10, read plate in 530nm reading the plate device.
The result
Find embodiment 2,3A, the EC50 of 4 and 5 compound in replicon mensuration 2 is respectively 0.01,0.02,0.01 and 0.0039 micromole, and the CC50 in the CC50 measuring method is respectively 26,34,19 and 10.8 (repeating (replicate) 13.4) micromole.
Basically all compounds demonstrate at least 1 micromolar activity in the table 1 in whose anti-HCV/replicon mensuration system.In addition, a lot of compounds have also shown anti--BVDV activity.
Claims (71)
1. compound with general formula (A), and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and dotted line to have represented at least 3, chosen wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio, C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11Or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be selected from: aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl-N (R
10)-or heterocyclic radical, wherein, each described substituting group can be randomly by at least one R
17Replace, prerequisite is for cycloalkenyl group, its pair key not with nitrogen adjacency, and R
3M-Q-is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by amino acid whose carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by amino acid whose amino amino-acid residue, the CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
4-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be M-Q-independently, wherein, M is for randomly by one or more R
19The ring that replaces, and Q is key or M is connected to R
3Linking group, described linking group comprises 1-10 atom and randomly by one or more R
19Replace.
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O ,-NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12Or-C (=S) R
12
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
2. compound with general formula (A), and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and this at least 3 of dotted line representative, to choose wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio, C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11, or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R then
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be randomly by at least one R
17The heterocyclic radical that replaces, however prerequisite is randomly by at least one R
17The R that replaces
3Be not pyridyl or 5-chlorothiophene base, and prerequisite is R
3-MQ is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, heterocyclic radical, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by amino acid whose carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by amino acid whose amino amino-acid residue, the CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Haloalkyl, C
2-18Haloalkenyl group, C
2-18Halo alkynyl, C
1-18Halogenated alkoxy, C
1-18Halogenated alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, CO
2H, CO
2R
18, NO
2, NR
7R
8, haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl, alkoxy aryl, alkylthio-aryl, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each described aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl, alkoxy aryl, alkylthio-aryl, heterocyclic radical or C
1-18Hydroxyalkyl is randomly by one or more R
19Replace;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O ,-NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12, the heterocyclic radical that replaces of carboxyl ester or-C (=S) R
12
R
25And R
26Do not exist or be independently selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, aryl, heterocyclic radical, wherein, each group can be chosen wantonly independently and be replaced by 1-4 group that is selected from down group: C
1-6Alkyl, C
1-6Alkoxyl group, halogen, CH
2OH, benzyloxy and OH; And
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
3. compound with general formula (A), and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and this at least 3 of dotted line representative, to choose wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio, C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11Or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be randomly by at least one R
17The heterocyclic radical that replaces, prerequisite is R
3-M-Q is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by amino acid whose carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
16R
16, aryl, by amino acid whose amino amino-acid residue, the CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be M-Q-, wherein M is for randomly by one or more R
19The C that replaces
3-10Cycloalkyl, and Q is a key or randomly by one or more R
19The C that replaces
1-10Alkyl;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O, NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12Or-C (=S) R
12
R
25And R
26Do not exist or be independently selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, aryl, heterocyclic radical, wherein, each group is optional to be replaced by 1-4 group that is selected from down group independently: C
1-6Alkyl, C
1-6Alkoxyl group, halogen, CH
2OH, benzyloxy and OH; And
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
4. as claim 1,2 or 3 described compounds, it is characterized in that R
3Be heterocyclic radical.
5. as claim 1,2 or 3 described compounds, it is characterized in that YR
1Be halogenophenyl.
6. compound as claimed in claim 5 is characterized in that, halogenophenyl is the ortho-fluorophenyl base.
7. as claim 1,2 or 3 described compounds, it is characterized in that R
3For by a R
17Replace the De isoxazolyl.
8. as claim 1,2 or 3 described compounds, it is characterized in that R
17For by 1,2 or 3 R
19The aryl or the aromatic heterocycle that replace.
9. as claim 1,2 or 3 described compounds, it is characterized in that YR
1Be not hydrogen, unsubstituted C
3-10Cycloalkyl or C
1-6One of alkyl.
10. compound as claimed in claim 9 is characterized in that YR
1Be not hydrogen.
11., it is characterized in that R as claim 1,2 or 3 described compounds
19Be trihalomethyl group, three halogenated methoxies, alkoxy or halogen.
12., it is characterized in that R as claim 1,2 or 3 described compounds
1For by 1,2 or 3 R
6The aromatic heterocycle or the aryl that replace, wherein, R
6Be halogen, C
1-18Alkoxyl group; Or C
1-18Haloalkyl.
13. compound as claimed in claim 12 is characterized in that, R
1Be the phenyl that is replaced by 1,2 or 3 halogen.
14., it is characterized in that halogen is a fluorine as claim 1,2 or 3 described compounds.
15., it is characterized in that Y is singly-bound, O, C as claim 1,2 or 3 described compounds
1-6Alkylidene group, C
2-6Alkenylene, C
2-5Alkynylene, or in the described group one comprises 1-3 and selects O, S or NR
11Heteroatoms.
16. compound as claimed in claim 15 is characterized in that, Y is-O (CH
2)
1-5-,-(CH
2)
1-4-O-(CH
2)
1-4-,-S-(CH
2)
1-5-,-(CH
2)
1-4-S-(CH
2)
1-4-,-NR
11-(CH
2)
1-5-,-(CH
2)
1-4-NR
11-(CH
2)
1-4Or C
3-10Cycloalkylidene.
17. compound as claimed in claim 15 is characterized in that, Y is-OCH
2-,-CH
2O-, C
1-2Alkylidene group, C
2-3Alkenylene, C
2-3Alkynylene, O or key.
18. compound as claimed in claim 15 is characterized in that, Y is a key.
19., it is characterized in that YR as claim 1,2 or 3 described compounds
1Be not H, unsubstituted C
3-10Cycloalkyl or C
1-C
6In the alkyl any.
20., it is characterized in that YR as claim 1,2 or 3 described compounds
1Be not H.
21. as claim 1,2 or 3 described compounds, YR
1Phenyl for halogen or halogenated methyl replacement.
22., it is characterized in that halogen or halogenated methyl are an ortho position or a position as claim 1,2 or 3 described compounds.
23., it is characterized in that X is selected from down group as claim 1,2 or 3 described compounds: alkylidene group, alkynylene or alkenylene, and described alkyl has N, O or S heteroatoms in the chain.
24., it is characterized in that X is an alkyl as claim 1,2 or 3 described compounds.
25. compound as claimed in claim 23 is characterized in that, X is selected from down group :-CH
2-,-CH (CH
3)-,-CH
2-CH
2-,-CH
2-CH
2-CH
2-,-CH
2-CH
2-CH
2-CH
2,-(CH
2)
2-4-O-(CH
2)
2-4-,-(CH
2)
2-4-S-(CH
2)
2-4-,-(CH
2)
2-4-NR
10-(CH
2)
2-4-, C
3-10Cycloalkylidene, C
2-6Alkenylene and C
2-6Alkynylene.
26., it is characterized in that X is a methylene radical as claim 1,2 or 3 described compounds.
27., it is characterized in that R as claim 1,2 or 3 described compounds
3For by 0-3 R
17The heterocycle or the aryl that replace.
28. compound as claimed in claim 27 is characterized in that, described heterocycle is an aromatic heterocycle.
29. compound as claimed in claim 28 is characterized in that, the described heterocycle that comprises 1,2 or 3 N, S or O atom in the ring is connected with X by ring carbon atom, and comprises 4-6 annular atoms altogether.
30., it is characterized in that R as claim 1,2 or 3 described compounds
3For by 1-3 R
19Replace the De isoxazolyl.
31., it is characterized in that R as claim 1,2 or 3 described compounds
17For further by 1-3 R
19The heterocycle or the aryl that replace.
32., it is characterized in that M is aryl or aromatic heterocycle as claim 1 or 3 described compounds.
33., it is characterized in that Q comprises 0-20 atom that is selected from C, O, S, N and H as claim 1 or 3 described compounds.
34., it is characterized in that M is for being selected from R as claim 1 or 3 described compounds
17Cyclic group.
35. compound as claimed in claim 2 is characterized in that, R
17Be selected from down group: C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl; Alkoxy aryl; Alkylthio-aryl; Heterocyclic radical; C
1-18Hydroxyalkyl, wherein, each described C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, arylalkyl; Alkoxy aryl; Alkylthio-aryl; Heterocyclic radical; C
1-18Hydroxyalkyl is not for replacing or by one or more R
19Replace.
36. compound as claimed in claim 2 is characterized in that, R
17Be selected from down group: aryl and heterocycle, and wherein said aryl or heterocycle are randomly by one or more R
19Replace.
37., it is characterized in that R as claim 1,2 or 3 described compounds
9And R
18Be H, OH or alkyl.
38., it is characterized in that R as claim 1,2 or 3 described compounds
5Be H.
39., it is characterized in that R as claim 1,2 or 3 described compounds
6Be halogen.
40., it is characterized in that R as claim 1,2 or 3 described compounds
7, R
8, R
10, R
11, R
15, R
16, R
20And R
21Be H or C independently
1-18Alkyl.
41., it is characterized in that R as claim 1,2 or 3 described compounds
12Be OH or alkyl.
42., it is characterized in that R as claim 1,2 or 3 described compounds
19Be selected from down group: H; C
1-18Alkyl; C
2-18Thiazolinyl; C
2-18Alkynyl; C
1-18Alkoxyl group; Alkene oxygen base; Alkynyloxy group; C
1-18Alkylthio; C
3-10Cycloalkyl; CC
4-10Cycloalkenyl group; C
4-10Cycloalkynyl radical; Halogen; OH; CN; The cyano group alkyl; NO
2NR
20R
21Haloalkyl; Halogenated alkoxy; C (=O) R
18C (=O) OR
18O thiazolinyl C (=O) OR
18-O alkyl C (=O) NR
20R
21Aryl; Heterocycle; O alkyl OC (=O)
18C (=O) N (C
1-6Alkyl), (O) (C of N (H) S (O)
1-6Alkyl); Alkoxy aryl; Aryloxy; Alkoxy aryl; And aralkyl; Wherein, each group is not for replacing or being replaced by one or more groups that are selected from down group :=O;-NR
20R
21CN; Alkoxyl group; Heterocyclic radical; Haloalkyl-or the heterocycle that replaces of alkyl; And by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects.
43. compound as claimed in claim 42 is characterized in that, R
19Be independently selected from down group: halogen, N (R
20R
21), alkoxyl group, haloalkyl and halogenated alkoxy.
44., it is characterized in that R as claim 1,2 or 3 described compounds
25And R
26Do not exist.
45., it is characterized in that described compound is at R as claim 1,2 or 3 described compounds
25Do not replace, and at R
26Replace, and R
2Or R
4Be selected from (=O), (=S) and (=NR
27).
46., it is characterized in that haloalkyl or halogenated alkoxy are-CF as claim 1,2 or 3 described compounds
3Or-OCF
3
47. a composition, described composition comprise pharmaceutically acceptable vehicle and claim 1,2 or 3 described compounds.
48. the compound with general formula (B), and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and dotted line to have represented at least 3, chosen wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio, C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11Or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be selected from: aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl-N (R
10)-or heterocyclic radical, wherein, each described substituting group can be randomly by at least one R
17Replace, prerequisite is for cycloalkenyl group, its pair key not with nitrogen adjacency, and R
3M-Q-is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by amino acid whose carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by amino acid whose amino amino-acid residue, the CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
16And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be M-Q-independently, wherein, M is for randomly by one or more R
19The ring that replaces, and Q is key or M is connected to R
3Linking group, described linking group comprises 1-10 atom and randomly by one or more R
19Replace;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O ,-NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12Or-C (=S) R
12
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
49. compound as claimed in claim 48 is characterized in that, Y is a singly-bound, and R
1Be aryl.
50. compound as claimed in claim 48 is characterized in that, X is C
1-10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene.
51. compound as claimed in claim 48 is characterized in that, R
3Be heterocyclic radical.
52. compound as claimed in claim 48 is characterized in that, R
3For by R
17The heterocyclic radical that replaces, wherein Q is that key and M are aryl.
53. compound as claimed in claim 48 is characterized in that, Y is a singly-bound, and R
1Be phenyl.
54. compound as claimed in claim 48 is characterized in that, R
3For by R
17Replace the De isoxazole, wherein Q is that key and M are aryl.
55. compound as claimed in claim 48 is characterized in that, R
3For by R
17Replace the De isoxazole, wherein Q is that key and M are phenyl.
56. the compound with general formula (C), and salt, tautomer, isomers and solvate,
In the formula:
It is to be adjacent to each other that two keys that dotted line representative is optional, prerequisite do not have two two keys, and dotted line to have represented at least 3, chosen wantonly be two keys of 4;
R
1Be selected from: hydrogen, aryl, heterocyclic radical, C
1-C
10Alkoxyl group, C
1-C
10Alkylthio, C
1-C
10Alkyl-amino, C
1-C
10Dialkyl-7-amino, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group and C
4-10Cycloalkynyl radical, wherein, each group is randomly by one or more R
6Replace;
Y is selected from: singly-bound, O, S (O) m, NR
11Or C
1-10Alkylidene group, C
2-10Alkenylene, C
2-10Alkynylene, wherein, each group can randomly comprise 1-3 heteroatoms that is selected from O, S or N;
R
2And R
4Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical, prerequisite is for working as R
25Or R
26One of when existing, R
2Or R
4Be selected from: (=O), (=S) and=NR
27
X is selected from: C
1-C
10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene, wherein, each group can comprise the heteroatoms of one or more O of being selected from, S, N, prerequisite be any this kind heteroatoms not with the ring in the N adjacency;
M is any integer of 0-2;
R
3Be selected from: aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl-N (R
10)-or heterocyclic radical, wherein, each described substituting group can be randomly by at least one R
17Replace, prerequisite is for cycloalkenyl group, its pair key not with nitrogen adjacency, and R
3M-Q-is not an xenyl;
R
5Be selected from: hydrogen; C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, halogen ,-OH ,-CN ,-NO
2,-NR
7R
8, halogenated alkoxy, haloalkyl ,-C (=O) R
9,-C (=O) OR
9,-C (=S) R
9, SH, aryl, aryloxy, arylthio, arylalkyl, C
1-18Hydroxyalkyl, C
3-10Cycloalkyl, C
3-10Cycloalkyl oxy, C
3-10Cycloalkyl sulfenyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical or heterocyclic radical;
R
6Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
1-18Alkylthio, C
1-18Alkyl sulfoxide, C
1-18Alkyl sulfone, C
1-18Halo-alkyl, C
2-18Halo-thiazolinyl, C
2-18Halo-alkynyl, C
1-18Halo-alkoxyl group, C
1-18Halo-alkylthio, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, C
7-10Cycloalkynyl radical, halogen, OH, CN, cyano group alkyl ,-CO
2R
18, NO
2,-NR
7R
8, C
1-18Haloalkyl, C (=O) R
18, C (=S) R
18, SH, aryl, aryloxy, arylthio, aryl sulfoxide, aryl sulfone, aryl sulfonamide, aryl (C
1-18) alkyl, aryl (C
1-18) alkoxyl group, aryl (C
1-18) alkylthio, heterocyclic radical, C
1-18Hydroxyalkyl, wherein, each group can be randomly by at least one R
19Replace;
R
7And R
8Be independently selected from: hydrogen, C
1-18Alkyl, C
1-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, heterocyclic radical ,-C (=O) R
12-C (=S) R
12, the amino-acid residue that connects by amino acid whose carboxyl, or R wherein
7And R
8Form heterocyclic radical with nitrogen;
R
9And R
18Be independently selected from: hydrogen, OH, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
1-18Alkoxyl group ,-NR
15R
16, aryl, by amino acid whose amino amino-acid residue, the CH that connects
2OCH (=O) R
9aOr CH
2OC (=O) OR
9a, wherein, R
9aBe C
1-C
12Alkyl, C
6-C
20Aryl, C
6-C
20Alkylaryl or C
6-C
20Aralkyl;
R
10And R
11Be independently selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, aryl ,-C (=O) R
12, heterocyclic radical or amino-acid residue;
R
12Be selected from down group: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
15And R
16Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group or amino-acid residue;
R
17Be M-Q-independently, wherein, M is for randomly by one or more R
19The ring that replaces, and Q is key or M is connected to R
3Linking group, described linking group comprises 1-10 atom and randomly by one or more R
19Replace;
R
19Be selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, C
1-18Alkoxyl group, C
2-18Alkene oxygen base, C
2-18Alkynyloxy group, C
1-18Alkylthio, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group, C
4-10Cycloalkynyl radical, halogen ,-OH ,-CN, cyano group alkyl ,-NO
2,-NR
20R
21, C
1-18Haloalkyl, C
1-18Halogenated alkoxy ,-C (=O) R
18,-C (=O) OR
18,-O thiazolinyl C (=O) OR
18,-O alkyl C (=O) NR
20R
21,-O alkyl OC (=O) R
18,-C (=S) R
18, SH ,-C (=O) N (C
1-6Alkyl) ,-(O) (C of N (H) S (O)
1-6Alkyl), aryl, heterocyclic radical, C
1-18Alkyl sulfone, aryl sulfoxide, aryl sulfonamide, aryl (C
1-18) alkoxyl group, aryloxy, aryl (C
1-8Alkyl) oxygen base, arylthio, aryl (C
1-18) alkylthio or aryl (C
1-18) alkyl, wherein, each group can randomly be replaced by one or more groups that are selected from down group :=O ,-NR
20R
21, CN, C
1-18Alkoxyl group, heterocyclic radical, C
1-18Haloalkyl, heterocyclic radical alkyl, by alkyl, alkoxyl group alkoxy or halogen and R
17The heterocyclic radical that connects;
R
20And R
21Be independently selected from: hydrogen, C
1-18Alkyl, C
2-18Thiazolinyl, C
2-18Alkynyl, aryl, C
3-10Cycloalkyl, C
4-10Cycloalkenyl group ,-C (=O) R
12Or-C (=S) R
12
R
27Be selected from: hydrogen, C
1-18Alkyl, C
3-10Cycloalkyl, (C
3-10Cycloalkyl)-C
1-6Alkyl, aryl and aryl C
1-18Alkyl.
57. compound as claimed in claim 56 is characterized in that, Y is a singly-bound, and R
1Be aryl.
58. compound as claimed in claim 56 is characterized in that, X is C
1-10Alkylidene group, C
2-10Alkenylene or C
2-10Alkynylene.
59. compound as claimed in claim 56 is characterized in that, R
3Be heterocyclic radical.
60. compound as claimed in claim 56 is characterized in that, R
3For by R
17The heterocyclic radical that replaces, wherein Q is that key and M are aryl.
61. compound as claimed in claim 56 is characterized in that, Y is a singly-bound, and R
1Be phenyl.
62. compound as claimed in claim 56 is characterized in that, R
3For by R
17Replace the De isoxazole, wherein Q is that key and M are aryl.
63. compound as claimed in claim 56 is characterized in that, R
3For by R
17Replace the De isoxazole, wherein Q is that key and M are phenyl.
64. a method, described method comprise that administration need be treated or the claim 1,2,3 of the antiviral significant quantity of object of prophylaxis of viral infections, 48 or 56 described compounds.
65., it is characterized in that described virus infection is an infection with hepatitis C virus as the described method of claim 64.
66. as the described method of claim 65, described method also comprises and gives object at least a other antiviral therapy agent.
67., it is characterized in that described other therapeutical agent is selected from down group: interferon alpha and virazole as the described method of claim 66.
Provide claim 1,2,3,48 or 56 described compounds 68. a method of screening antiviral compound, described method comprise, and measure the antiviral activity of described compound.
69., it is characterized in that described antiviral activity is to measure by anti-one or more activity that belong to the virus of flaviviridae and/or pico+ribonucleic acid+virus section of described compound as the described method of claim 68.
70. the structure-active method that is used for assessment formula (A) compound analogue,
Wherein, described substituting group in the WO 2004/005286 definition, described method comprises:
(c) prepare formula (A) compound that has at least a substituting group in WO 2004/005286, not disclose; And
(d) anti-HCV activity of determination step (a) compound.
71., it is characterized in that described substituting group is positioned at R as the described method of claim 70
3, R
2, R
4, R
26And/or R
5
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53229203P | 2003-12-22 | 2003-12-22 | |
| US60/532,292 | 2003-12-22 | ||
| US60/533,963 | 2004-01-02 | ||
| US60/590,989 | 2004-07-26 | ||
| US60/591,069 | 2004-07-26 | ||
| US60/590,990 | 2004-07-26 | ||
| US60/591,024 | 2004-07-26 |
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| CN200910132469.XA Division CN101538267B (en) | 2003-12-22 | 2004-12-21 | Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment |
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Family
ID=37657541
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| CN 200480038144 Pending CN1902198A (en) | 2003-12-22 | 2004-12-21 | Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment |
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|---|---|---|---|
| CN200910132469.XA Expired - Fee Related CN101538267B (en) | 2003-12-22 | 2004-12-21 | Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment |
Country Status (2)
| Country | Link |
|---|---|
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| SI (1) | SI1706403T1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102395579A (en) * | 2009-02-17 | 2012-03-28 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN110229150A (en) * | 2018-03-06 | 2019-09-13 | 沈阳药科大学 | Imidazo [4,5-c] pyridine derivatives and application thereof |
| CN115175909A (en) * | 2020-02-24 | 2022-10-11 | 鲁汶天主教大学 | Pyrrolopyridine and imidazopyridine antiviral compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0215293D0 (en) * | 2002-07-03 | 2002-08-14 | Rega Foundation | Viral inhibitors |
-
2004
- 2004-12-21 CN CN200910132469.XA patent/CN101538267B/en not_active Expired - Fee Related
- 2004-12-21 CN CN 200480038144 patent/CN1902198A/en active Pending
- 2004-12-21 SI SI200431858T patent/SI1706403T1/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102395579A (en) * | 2009-02-17 | 2012-03-28 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN102395579B (en) * | 2009-02-17 | 2014-03-12 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN110229150A (en) * | 2018-03-06 | 2019-09-13 | 沈阳药科大学 | Imidazo [4,5-c] pyridine derivatives and application thereof |
| CN115175909A (en) * | 2020-02-24 | 2022-10-11 | 鲁汶天主教大学 | Pyrrolopyridine and imidazopyridine antiviral compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| SI1706403T1 (en) | 2012-08-31 |
| CN101538267B (en) | 2015-04-29 |
| CN101538267A (en) | 2009-09-23 |
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