CN101466686A - C-FMS kinase inhibitor - Google Patents

C-FMS kinase inhibitor Download PDF

Info

Publication number
CN101466686A
CN101466686A CNA2006800549949A CN200680054994A CN101466686A CN 101466686 A CN101466686 A CN 101466686A CN A2006800549949 A CNA2006800549949 A CN A2006800549949A CN 200680054994 A CN200680054994 A CN 200680054994A CN 101466686 A CN101466686 A CN 101466686A
Authority
CN
China
Prior art keywords
imidazoles
thiazolinyl
hexamethylene
phenyl
cyano group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2006800549949A
Other languages
Chinese (zh)
Inventor
M·R·普莱尔
N·拜恩杜尔
B·M·布兰德特
N·查哈
R·J·佩奇
D·阿斯加里
T·乔治亚迪斯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of CN101466686A publication Critical patent/CN101466686A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention is directed to compounds of Formula II: wherein A, R1, R2, R3, R4, X, Y and W are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase.

Description

The C-FMS kinase inhibitor
Invention field
The present invention relates to the new compound that function is a protein tyrosine kinase inhibitor.Specifically, the present invention relates to the new compound that function is the c-fms kinase inhibitor.
Background of invention
Protein kinase be by the catalysis terminal phosphate from ATP be transferred to proteinic tyrosine, Serine and threonine residues hydroxyl and as the enzyme of signal transduction pathway key ingredient.Therefore, kinases inhibitor and substrate are the effective tools of estimating protein kinase activatory physiological action.Verified, normal or mutain kinases crossing in Mammals express or the inappropriate development that is expressed in numerous disease in play an important role, described disease comprises cancer and diabetes.
Protein kinase can be divided into two classes: those (albumen serine/threonine kinases) of those (protein tyrosine kinases) of preferential phosphorylated tyrosine residue and preferential phosphorylation Serine and/or threonine residues.Protein tyrosine kinase has from stimulate cell growth and breaks up the multiple function that stops cell proliferation.They can be categorized as receptor protein tyrosine kinase or intracellular protein Tyrosylprotein kinase.Receptor protein tyrosine kinase has extracellular ligand in conjunction with the territory with have catalytic domain in the cell of intrinsic tyrosine kinase activity, and receptor protein tyrosine kinase is divided into 20 subclass.
The receptor tyrosine kinase of Urogastron (＂ EGF ') family comprises the extracellular in conjunction with territory, membrane-spanning domain and cell endoplasm catalytic domain, and Urogastron (＂ EGF ') family comprises HER-1, HER-2/neu and HER-3 acceptor.Receptors bind causes a plurality of intracellular tyrosine kinases dependency phosphorylation processes to begin to start, and this finally causes oncogene to be transcribed.Mammary cancer, colorectal carcinoma and prostate cancer are related with this family's acceptor.
Insulin receptor (＂ IR ＂) is relevant on 26S Proteasome Structure and Function with insulin-like growth factor I receptor (＂ IGF-IR ＂), but brings into play different biological effects.IGF-IR cross express relevant with mammary cancer.
The receptor-mediated cell response that comprises propagation, migration and existence of platelet-derived somatomedin (＂ PDGF '), and comprise PDGFR, STEM CELL FACTOR acceptor (c-kit) and c-fms.These acceptors and disease-related connection, described disease is atherosclerosis, fibrosis and proliferative vitreoretinopathy for example.
Fibroblast growth factor (＂ FGR ＂) acceptor is made up of to the growth of outgrowth and many cell types and four kinds of acceptors of differentiation responsible vasculogenesis, four limbs.
Vascular endothelial growth factor (＂ VEGF ＂) is a kind of effective endothelial cell division element, is generated with the amount that improves by the many tumours that comprise ovarian cancer.Known vegf receptor is named as VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4).In blood vessel endothelium and hematopoietic cell, identified one group of relevant acceptor, tie-1 and tie-2 kinases.Vegf receptor is associated with vascularization and blood vessel.
The intracellular protein Tyrosylprotein kinase also is called non-receptor protein tyrosine kinase.There have been 24 kinds of such kinases of surpassing to be identified and be categorized as 11 subclass.The same with the cell protein tyrosine kinase enzyme, serine/threonine protein kitase mainly is present in the cell.
Diabetes, blood vessel generation, psoriatic, restenosis, illness in eye, schizophrenia, rheumatoid arthritis, cardiovascular disorder and cancer are the pathogenic disease states of example, and it is associated with unusual protein tyrosine kinase activity.Therefore, exist the effective demand of small molecular protein tyrosine kinase inhibitor optionally.United States Patent (USP) the 6th, 383,790; 6,346,625; 6,235,746; 6,100, No. 254 and PCT International Application No. WO 01/47897, WO 00/27820 and WO02/068406 have described the recent trial of synthetic this inhibitor.
Summary of the invention
The present invention has solved at present the effective demand of protein tyrosine kinase inhibitor optionally by effective c-fms kinase inhibitor is provided.One embodiment of the invention relate to new compound or its solvate, hydrate, tautomer or the pharmacologically acceptable salts of following formula I:
Figure A200680054994D00111
Wherein:
A is
Phenyl, naphthyl or xenyl, it is warp-C randomly separately 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-CORa ,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 7-unit that is selected from N, O or S single-or the hetero-aromatic ring or the bicyclic heterocycle of 8-to 10-unit dicyclo, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, guanidine alkylation, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bIn one or more replacements;
R 1Be
-H, aryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR b
X is
-CO-,-C (=NH)-,-CS-,-CON (R a)-,-CS (NR a)-,-SO 2-or-CR aR b-;
R 2And R 3Be independently
-H ,-C 1-6Alkyl, aryl, cycloalkyl, heterocyclic radical, heteroaryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR bOr
R 2And R 3Form with the nitrogen that is connected
Have 1 to 3 heteroatomic 5-to 7-unit's heterocycle or hetero-aromatic ring that is selected from N, O or S, it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace; And
W is
Phenyl, naphthyl or xenyl, it separately can be randomly through C 1-4Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryloxy, alkoxy aryl ,-OCF 3,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-NHCOR aR b,-NHSO 2R a,-NO 2,-SOR a,-SO 3R aOr-SO 2NR aR bIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 6-unit's list or 8-to 10-unit's bicyclic heterocycle or hetero-aromatic ring that is selected from N, O or S, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R wherein aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
In one embodiment, the present invention relates to new compound or its solvate, hydrate, tautomer or the pharmacologically acceptable salts of Formula Il:
Figure A200680054994D00141
Wherein:
A is
Phenyl, naphthyl or xenyl, it is warp-C randomly separately 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-CORa ,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 7-unit that is selected from N, O or S single-or the hetero-aromatic ring or the bicyclic heterocycle of 8-to 10-unit dicyclo, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, guanidine alkylation, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bIn one or more replacements;
R 1Be
-H, aryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR b
X is
-CO-,-C (=NH)-,-CS-,-CON (R a)-,-CS (NR a)-,-SO 2-or-CR aR b-;
Y is
-S-,-SO-,-SO 2-,-O-or direct key;
R 2Be
Alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, its separately can be randomly through one or more halogens or low alkyl group, preferred 1 or 2 methyl substituted; And
W is
Phenyl, naphthyl or xenyl, it separately can be randomly through C 1-4Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryloxy, alkoxy aryl ,-OCF 3,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-NHCOR aR b,-NHSO 2R a,-NO 2,-SOR a,-SO 3R aOr-SO 2NR aR bIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 6-unit's list or 8-to 10-unit's bicyclic heterocycle or hetero-aromatic ring that is selected from N, O or S, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
Another embodiment of the present invention relates to compound or its solvate, hydrate, tautomer or the pharmacologically acceptable salts of Formula Il I:
Figure A200680054994D00161
Wherein:
A is
Phenyl, naphthyl or xenyl, it is warp-C randomly separately 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aIn one or more replacements;
X is
-CO-,-C (=NH)-,-SO 2-or-CS-;
Y is
Direct key ,-CH 2-,-CH 2CH 2-,-CH=CH-,-NR a-,-O-,-S-,-SO-,-SO 2-,-CH 2O-,-OCH 2-,-NR aCH 2-,-CH 2NR a-,-CONR a-or-NR aCO-;
R 1Be
-H, aryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR b
R 2And R 3Independently be
-H ,-C 1-6Alkyl, aryl, cycloalkyl, heterocyclic radical, heteroaryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR bOr
R 2And R 3Form with the nitrogen that is connected
Have 1 to 3 heteroatomic 5-to 7-unit's heterocycle or hetero-aromatic ring that is selected from N, O or S, it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace; And
R 4Be
-H ,-C 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, guanidine alkylation, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bIn one or more,
R aAnd R bIndependent is hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl.
The compound of formula I and II is effective especially c-fms protein tyrosine kinase inhibitor.The expection of formula III compound shows similar inhibition and tires.
The compound that the invention still further relates at least a formula I, II by the administering therapeutic significant quantity or III suppresses the method for mammalian proteins tyrosine kinase activity.
Detailed Description Of The Invention
The present invention relates to new compound or its solvate, hydrate, tautomer or the pharmacologically acceptable salts of following formula I:
Figure A200680054994D00181
Wherein:
A is
Phenyl, naphthyl or xenyl, it is warp-C randomly separately 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 7-unit that is selected from N, O or S single-or the hetero-aromatic ring or the bicyclic heterocycle of 8-to 10-unit dicyclo, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, guanidine alkylation, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bIn one or more replacements;
R 1Be
-H, aryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR b
X is
-CO-,-C (=NH)-,-CS-,-CON (R a)-,-CS (NR a)-,-SO 2-or-CR aR b-;
R 2And R 3Be independently
-H ,-C 1-6Alkyl, aryl, cycloalkyl, heterocyclic radical, heteroaryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR bOr
R 2And R 3Form with the nitrogen that is connected
Have 1 to 3 heteroatomic 5-to 7-unit's heterocycle or hetero-aromatic ring that is selected from N, O or S, it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace; And
W is
Phenyl, naphthyl or xenyl, it separately can be randomly through C 1-4Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryloxy, alkoxy aryl ,-OCF 3,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-NHCOR aR b,-NHSO 2R a,-NO 2,-SOR a,-SO 3R aOr-SO 2NR aR bIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 6-unit's list or 8-to 10-unit's bicyclic heterocycle or hetero-aromatic ring that is selected from N, O or S, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R wherein aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
In another embodiment, the present invention relates to new compound or its solvate, hydrate, tautomer or the pharmacologically acceptable salts of Formula Il:
Wherein:
A is
Phenyl, naphthyl or xenyl, it is warp-C randomly separately 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 7-unit that is selected from N, O or S single-or the hetero-aromatic ring or the bicyclic heterocycle of 8-to 10-unit dicyclo, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, guanidine alkylation, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bIn one or more replacements;
R 1Be
-H, aryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR b
X is
-CO-,-C (=NH)-,-CS-,-CON (R a)-,-CS (NR a)-,-SO 2-or-CR aR b-;
Y is
-S-,-SO-,-SO 2-,-O-or direct key;
R 2Be
Alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, its separately can be randomly through one or more halogens or low alkyl group, preferred 1 or 2 methyl substituted; And
W is
Phenyl, naphthyl or xenyl, it separately can be randomly through C 1-4Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryloxy, alkoxy aryl ,-OCF 3,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-NHCOR aR b,-NHSO 2R a,-NO 2,-SOR a,-SO 3R aOr-SO 2NR aR bIn one or more replacements; Or
Have 1 to 4 heteroatomic 5-to 6-unit's list or 8-to 10-unit's bicyclic heterocycle or hetero-aromatic ring that is selected from N, O or S, and warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
Another embodiment of the present invention relates to compound or its solvate, hydrate, tautomer or the pharmacologically acceptable salts of Formula Il I:
Wherein:
A is
Phenyl, naphthyl or xenyl, it is warp-C randomly separately 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aIn one or more replacements;
X is
-CO-,-C (=NH)-,-SO 2-or-CS-;
Y is
Direct key ,-CH 2-,-CH 2CH 2-,-CH=CH-,-NR a-,-O-,-S-,-SO-,-SO 2-,-CH 2O-,-OCH 2-,-NR aCH 2-,-CH 2NR a-,-CONR a-or-NR aCO-;
R 1Be
-H, aryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR b
R 2And R 3Independently be
-H ,-C 1-6Alkyl, aryl, cycloalkyl, heterocyclic radical, heteroaryl ,-COR a,-COR a,-COOR a,-CONR aR b,-SO 2R aOr-SO 2NR aR bOr
R 2And R 3Form with the nitrogen that is connected
Have 1 to 3 heteroatomic 5-to 7-unit's heterocycle or hetero-aromatic ring that is selected from N, O or S, it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace; And
R 4Be
-H ,-C 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, guanidine alkylation, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bIn one or more,
R aAnd R bIndependent is hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl.
Preferred formula I compound is those compounds wherein as described below:
A is a phenyl;
R 1Be-H; And
R 2And R 3Form piperidines, piperazine, morpholine, thiomorpholine, tetramethyleneimine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or tetrahydroglyoxaline ring with the nitrogen that is connected, it can be chosen wantonly through-C 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R wherein aAnd R bBe hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl independently.
Particularly preferred formula I compound is those compounds wherein as described below:
A is a phenyl;
R 1Be-H;
R 2And R 3Form piperidines, piperazine, morpholine, thiomorpholine, tetramethyleneimine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or tetrahydroglyoxaline ring with the nitrogen that is connected, it can be chosen wantonly through-C 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R 3) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace, and
W is phenyl, furans, thiophene, isoxazole, pyrroles, oxazole, thiazole, imidazoles, pyrazoles, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring, and it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R wherein aAnd R bBe hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl independently.
Preferred formula II compound is those compounds wherein as described below:
A is a phenyl;
R 1Be-H; And
W is phenyl, furans, thiophene, isoxazole, pyrroles, oxazole, thiazole, imidazoles, pyrazoles, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring, and it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace,
R wherein aAnd R bBe hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl independently.
Particularly preferably be formula II compound wherein as described below:
A is phenyl, pyridyl, pyridazinyl or piperidyl; Wherein
A is warp-C randomly 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aOr-alkyl SO 2NR aR bIn one or more replacements;
R 1Be-H;
X is-CO-;
Y is direct key;
R 2Be cycloalkyl, heterocyclic radical or heteroaryl;
Particularly preferably be R 2Be cyclohexenyl, dimethyl cyclohexenyl, methylimidazolyl, piperidyl and methyl piperidine base section;
W is an imidazolyl, its randomly through one or two-C 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace;
Particularly preferably being W is imidazolyl, its randomly replacement of one or two in following radicals :-C 1-6Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano group or-CONR aR b
And
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
Formula II compound more preferably wherein as described below:
A is phenyl, pyridyl, pyridazinyl or piperidyl; Wherein
A is warp-C randomly 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aOr-alkyl SO 2NR aR bIn one or more replacements;
R 1Be-H;
X is-CO-;
Y is direct key;
R 2Be cyclohexenyl, dimethyl cyclohexenyl, methylimidazolyl, piperidyl or methyl piperidine base;
W is an imidazolyl, its randomly replacement of one or two in following radicals :-C 1-6Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano group or-CONR aR b
And
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
Even formula II compound more preferably wherein as described below:
A is phenyl or pyridyl; Wherein
A can be unsubstituted, perhaps optional through bromo, amino, aminoalkyl group, aminoaryl, hydroxyalkyl, alkoxyalkyl, pyridyl, N-nitrogen oxide indenyl (N-oxypyrindinyl), methoxyl group indyl (methoxy pyrindinyl) ,-COR 3,-CONR aR b,-aryl NSO 2R a-alkyl SO 2NR aR b-SO 2R a, tetrazyl, alkyl tetrazyl or alkyl tetrazyl alkyl NR aR bReplace;
R 1Be-H;
X is-CO-;
Y is direct key;
R 2Be cyclohexenyl, dimethyl cyclohexenyl, methylimidazolyl, piperidyl or methyl piperidine base;
W is an imidazolyl, its randomly replacement of one or two in following radicals :-C 1-6Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano group or-CONR aR b
And
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
Be contemplated that preferred formula III compound has and preferred formula I and the same or analogous R of formula II compound 2And R 3Substituting group.
Most preferred formula I compound includes but not limited to 5-nitro-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; Isoxazole-5-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-nitro-furans-2-carboxylic acid (5-hydroxymethyl-2-piperidines-1-base-phenyl)-acid amides; 5-nitro-furans-2-carboxylic acid [2-(3-methyl-piperidines-1-yl)-phenyl]-acid amides; 4-nitro-pyridine-2-carboxylic acids (2-piperidines-1-base-phenyl)-acid amides; 5-nitro-furans-2-carboxylic acid (2-morpholine-4-base-phenyl)-acid amides; 5-chloro-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-nitro-furans-2-carboxylic acid [2-(trans-2,6-dimethyl-morpholine-4-yl)-phenyl]-acid amides; 3-nitro-N-(2-piperidines-1-base-phenyl)-benzamide; 5-bromo-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-ethanoyl--thiophene-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-nitro-furans-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholine-4-yl)-phenyl]-acid amides; 4-nitro-2H-pyrazoles-3-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-formyl radical-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-(2-piperidines-1-base-phenyl amino formyl radical)-furans-2-carboxylic acid; Isoxazole-5-carboxylic acid (2-morpholine-4-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 5-nitro-furans-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 5-nitro-furans-2-carboxylic acid [2-(4-methyl-piperazine-1-yl)-phenyl]-acid amides; 5-nitro-furans-2-carboxylic acid [2-(4-hydroxy-piperdine-1-yl)-phenyl]-acid amides; 5-nitro-furans-2-carboxylic acid [2-(4-hydroxymethyl-piperidines-1-yl)-phenyl]-acid amides; 5-nitro-furans-2-carboxylic acid (2-azepan-1-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid (5-hydroxymethyl-2-piperidines-1-base-phenyl)-acid amides; 5-cyano group-furans 2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 5-cyano group-furans-2-carboxylic acid [2-(4-hydroxymethyl-piperidines-1-yl)-phenyl]-acid amides; 5-cyano group-furans-2-carboxylic acid 2-[4-(2-hydroxyl-ethyl)-piperidines-1-yl]-phenyl }-acid amides; 5-cyano group-furans-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 5-cyano group-furans-2-carboxylic acid [5-hydroxymethyl-2-(4-hydroxymethyl-piperidines-1-yl)-phenyl]-acid amides; 5-cyano group-furans-2-carboxylic acid [2-(4-ethyl-piperidines-1-yl)-5-hydroxymethyl-phenyl]-acid amides; 5-cyano group-furans-2-carboxylic acid 2-[4-(2-hydroxyl-ethyl)-piperidines-1-yl]-5-hydroxymethyl-phenyl }-acid amides; 5-cyano group-furans-2-carboxylic acid [2-(4-ethyl-piperidines-1-yl)-phenyl]-acid amides; 4-nitro-1H-pyrroles-2-carboxylic acid [2-(4-ethyl-piperidines-1-yl)-phenyl]-acid amides; 4-nitro-1H-pyrroles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 4-nitro-1H-pyrroles-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 4-nitro-1H-pyrroles-2-carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidines-1-yl)-phenyl]-acid amides; 4-nitro-1H-pyrroles-2-carboxylic acid 2-[4-(2-hydroxyl-ethyl)-piperidines-1-yl]-5-hydroxymethyl-phenyl)-acid amides; 4-cyano group-1H-pyrroles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides; 4-cyano group-1H-pyrroles-2-carboxylic acid [2-(4-ethyl-piperidines-1-yl)-phenyl]-acid amides; 4-cyano group-1H-pyrroles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 4-cyano group-1H-pyrroles-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides; 4-cyano group-1H-pyrroles-2-carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidines-1-yl)-phenyl]-acid amides; 4-cyano group-1H-pyrroles-2-carboxylic acid 2-[4-(2-hydroxyl-ethyl)-piperidines-1-yl]-5-hydroxymethyl-phenyl }-acid amides; 5-cyano group-furans-2-carboxylic acid (5-sulfonyloxy methyl amine methyl-2-piperidines-1-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid (5-guanidine radicals methyl-2-piperidines-1-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid [5-(4-methyl-piperazine-1-ylmethyl)-2-piperidines-1-base-phenyl]-acid amides; 5-cyano group-furans-2-carboxylic acid (4-fluoro-2-piperidines-1-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid (4-chloro-2-piperidines-1-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid (5-cyano group-2-piperidines-1-base-phenyl)-acid amides; 5-cyano group-furans-2-carboxylic acid 5-[(2,3-dihydroxyl-propyl group amino)-methyl]-2-piperidines-1-base-phenyl }-acid amides; 5-nitro-2H-pyrazoles-3-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides and pharmacologically acceptable salts thereof.
Most preferred formula II compound comprises 5-nitro-furans-2-carboxylic acid [2-(2-chloro-1,1,2-three fluoro-ethyl sulfane bases)-phenyl]-acid amides; 5-nitro-furans-2-carboxylic acid (2-ethoxyl phenenyl)-acid amides and pharmacy acceptable salt thereof.
Even preferred formula II compound comprises 4-cyano group-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-methoxyl group-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(pyridin-3-yl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides, trifluoroacetate; 4-cyano group-5-(1-hydroxyl-1-methyl-ethyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4-ethanoyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4-formamyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-formamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides, trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-sulfonyl methane amino-biphenyl-4-yl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-5-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfonyl methane-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxyl-ethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid (6-hexamethylene-1-thiazolinyl-benzo [1,3] dioxole-5-yl)-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(3-methyl-3H-imidazol-4 yl)-phenyl]-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-pyridin-3-yl)-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfamyl-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-sulfamyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-sulfamyl-ethyl)-phenyl]-acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sulfamyl-phenyl)-acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-dimethylamino alkylsulfonyl biphenyl-4-yl)-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(dimethyl-hexamethylene-1-thiazolinyl)-6-(1-hydroxyl-1-methyl-ethyl)-pyridin-3-yl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid [4-[2-(2-dimethylamino-ethyl)-2H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides; 5-cyano group-1-(2-dimethylamino-ethyl)-1H-imidazoles-2-carboxylic acid 2-hexamethylene-1-thiazolinyl-4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-yl]-phenyl }-acid amides; [4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzoyl]-1-L-glutamic acid; 3H-imidazoles-2,4-dicarboxylic acid 4-acid amides 2-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }; 3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }; 2-cyano group-3H-imidazoles-4-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-yl)-the acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid (3-piperidines-1-base-pyridazine-4-yl)-acid amides; 4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenylformic acid; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-formyl-dimethylamino-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; With 5-cyano group-1-H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-ethyl)-phenyl]-acid amides.
In the above-claimed cpd, most preferably following compound:
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-methoxyl group-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate;
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides;
5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(pyridin-3-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfonyl methane-phenyl]-acid amides;
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxyl-ethyl)-phenyl]-acid amides;
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides trifluoroacetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl-acid amides trifluoroacetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-sulfamyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-sulfamyl-ethyl)-phenyl]-acid amides trifluoroacetate;
4-cyano group-1H-imidazoles-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-yl)-the acid amides trifluoroacetate; With
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides.
Even most preferred is following compound:
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate;
5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group-phenyl]-acid amides; With
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides.
The compound that the invention still further relates at least a formula I, II by the administering therapeutic significant quantity or III suppresses the method for protein tyrosine kinase activity in the Mammals.Preferred Tyrosylprotein kinase is c-fms.
Think enantiomerism, diastereo-isomerism and the tautomeric form of all compounds of the present invention includes formula I, II or III and their racemic mixture.In addition, some can be prodrugs in the compound of being represented by formula I, II or III,, compare the derivative of the active medicine with better delivery capability and therapeutic value with active medicine that is.Prodrug is transformed into active medicine by body endoenzyme or chemical process.
I. definition
Unless otherwise, term " alkyl " refers to the straight chain and the branched group of maximum 12 carbon atoms, and include but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl, heptyl, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl and dodecyl.
Term ＂ cycloalkyl ＂ refers to the ring of the saturated or fractional saturation that is made of 3 to 8 carbon atoms.Alkyl substituent can be chosen wantonly and be present on the ring.Example comprises cyclopropyl, 1,1-dimethylcyclobutyl, 1,2,3-trimethylammonium cyclopentyl, cyclohexyl and cyclohexenyl and dimethyl cyclohexenyl.
Term ＂ heterocyclic radical ＂ is selected from the non-fragrance that the heteroatoms of N, O or S constitutes (that is, saturated or part is unsaturated) ring by 3 to 7 carbon atoms and at least one.Alkyl substituent can randomly be present on the ring.Example comprises tetrahydrofuran base, dihydro pyranyl, piperidyl, 2,5-lupetidine base, morpholinyl, piperazinyl, thio-morpholinyl, pyrrolidyl, pyrrolinyl, pyrazolidyl, pyrazolinyl, imidazolidyl, imidazolinyl and tetrazyl.
Term ＂ heterocyclic radical alkyl ＂ refers to contain the substituent C of heterocyclic radical 1-6Alkyl.Example comprises dihydro pyranyl ethyl and 2-morpholinyl propyl.
Term ＂ hydroxyalkyl ＂ refers to any carbon atom bonding at least one hydroxyl and the alkyl chain.
Term ＂ aminoalkyl group ＂ refers to any carbon atom bonding at least one uncle or secondary amino group and the alkyl chain.
Term ＂ alkoxyalkyl ＂ refers to any carbon atom bonding at least one alkoxyl group and the alkyl chain.
The poly-alkoxyalkyl ＂ of term ＂ refers to the long-chain alkoxy based compound, and comprises the polyoxyethylene glycol of discrete (discreet) or single dispersion size.
Term ＂ sulfane base ＂ refers to any carbon atom bonding at least one methylthio group and the alkyl chain.Methylthio group can be any state of oxidation, and comprises sulfoxide, sulfone and sulfuric ester.
Term ＂ carboxyalkyl ＂ refers to any carbon atom bonding at least one hydroxy-acid group (carboxylate group) and the alkyl chain.Term ＂ hydroxy-acid group ＂ comprises carboxylic acid and alkyl, cycloalkyl, aryl or aralkyl carboxylicesters.
Term ＂ heteroaromatic ＂ or ＂ heteroaryl ＂ refer to 5-to 7-unit single-or 8-to 10-unit Bicyclic loop systems, its arbitrary ring can comprise 1 to 4 heteroatoms that is selected from N, O or S, wherein the state of oxidation that nitrogen-atoms and sulphur atom can any permissions exists.Example comprises benzimidazolyl-, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, quinolyl, thiazolyl and thienyl.
Term ＂ heteroaralkyl ＂ refers to have the substituent C of heteroaryl 1-6Alkyl.Example comprises furyl ethyl and 2-quinolyl propyl group.
Term ＂ heteroatoms ＂ refers to nitrogen-atoms, Sauerstoffatom or sulphur atom, and wherein the state of oxidation that nitrogen and sulphur atom can any permissions exists.
Unless otherwise, term ＂ alkoxyl group ＂ refers to the straight or branched group and the Sauerstoffatom bonding of maximum 12 carbon atoms.Example comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy and butoxy.
The monocycle or the Bicyclic loop systems that contain 6 to 12 carbon in the term ＂ aryl ＂ finger ring.Alkyl substituent can randomly be present on the ring.Example comprises benzene, biphenyl and naphthalene (napththalene).
Term ＂ aralkyl ＂ refers to contain the C of aryl substituent 1-6Alkyl.Example comprises benzyl, phenylethyl or 2-naphthyl methyl.
Term ＂ heteroaralkyl ＂ refers to contain the substituent C of heteroaryl 1-6Alkyl.Example comprises furyl methyl and pyridyl propyl group.
Term ＂ aryloxy ＂ refers to and aryl substituent bonded Sauerstoffatom.Example comprises phenoxy group and benzyloxy.
Term ＂ alkoxy aryl ＂ refers to and aryl substituent bonded alkoxyl group.Example comprises phenyl methyl ether.
Term ＂ acyl group ＂ refers to group-C (O) R a, R wherein aBe alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.＂ acylating agent ＂ is molecule interpolation-C (O) R aGroup.
Term ＂ alkylsulfonyl ＂ refers to group-S (O) 2R a, R wherein aBe hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.＂ sulfonyl agent ＂ is molecule interpolation-S (O) 2R aGroup.
II. therepic use
Novel effective protein proteins Tyrosylprotein kinase (for example c-fms) inhibitor of formula I, II and III compounds represented, and can be used to prevent and treat the illness that causes by these kinases.
The present invention also provides the method for arrestin Tyrosylprotein kinase, comprises protein tyrosine kinase is contacted with at least a formula I, II or the III compound of effective inhibitory amount.Preferred Tyrosylprotein kinase is c-fms.In an embodiment of arrestin Tyrosylprotein kinase, at least a formula I, II or III compound combine with known tyrosine kinase inhibitor.
In different embodiments of the present invention, the protein tyrosine kinase that is suppressed by formula I, II and III compound is arranged in mammalian body or cell in vitro.Comprising under people's the Mammals situation that at least a formula I, the II of administering therapeutic significant quantity or the pharmacy of III compound can be accepted form.
The pharmacy that the present invention further provides at least a formula I, II by the administering therapeutic significant quantity or III compound can be accepted composition and treat the mammiferous method for cancer that comprises the people.Exemplary cancer includes but not limited to mammary cancer, colorectal carcinoma, cancer of the stomach, hairy cell and non-small cell carcinoma.In one embodiment of the invention, the chemotherapeutics of at least a formula I, the II of significant quantity or III compound and significant quantity is co-administered.
The present invention also provides by the pharmacy of at least a formula I, the II of administering therapeutic significant quantity or III compound can accept the method that form is treated the mammiferous cardiovascular and inflammatory diseases that comprises the people.The disease example that can effectively be treated comprises blood vessel generation, restenosis, schizophrenia and the Alzheimer that glomerulonephritis, rheumatoid arthritis, psoriatic, diabetes, tumour are correlated with.
When the protein tyrosine kinase inhibitor, The compounds of this invention can with about 0.5mg to about 10g, preferably about 0.5mg extremely the significant quantity in about 5g dosage range use with single or the per daily dose that separates.The dosage of being used is subjected to following factor affecting: the existence of the state of health of route of administration, acceptor, body weight and age, therapeutic frequency and while and independent treatment.
Formula I, II and III compound can be mixed with the pharmaceutical composition that comprises any known pharmaceutical acceptable carrier.Exemplary carrier includes but not limited to any suitable solvent, dispersion agent, dressing, antibacterium and anti-mycotic agent and isotonic agent.The Exemplary excipients that also can become formulation component comprises weighting agent, tackiness agent, disintegrating agent and lubricant.
The pharmaceutically acceptable salt of formula I, II and III compound comprises can be from conventional non-toxic salt or quaternary ammonium salt inorganic or organic acid or alkali generation.The example of this acid salt comprises acetate, adipate, benzoate, benzene sulfonate, Citrate trianion, camphorate, dodecyl sulfate, hydrochloride, hydrobromate, lactic acid salt, maleate, mesylate, nitrate, oxalate, pivalate, propionic salt, succinate, vitriol and tartrate.Alkali salt comprises ammonium salt, an alkali metal salt (for example sodium salt and sylvite), alkaline earth salt (for example calcium salt and magnesium salts), organic alkali salt (for example dicyclohexyl amine salt and with for example arginic salt of amino acid).And alkaline nitrogen-containing group can be used for example alkylogen quaternary baseization.
Pharmaceutical composition of the present invention can be used by any way of realizing its intended purposes.Example comprises by parenteral, subcutaneous, intravenously, intramuscular, intraperitoneal, uses through skin, oral cavity or eye approach.Alternatively or side by side, using can be by Orally administered.The preparation that suitable parenteral is used comprise the active compound of water-soluble form (for example water-soluble salt) aqueous solution, acidic solution, basic solution, dextrose-aqueous solution, etc. ooze sugar soln and cyclodextrin inclusion complexes.
III. preparation method
Formula I, II and III compound can be combined to by the solid phase carrier method or by solution and prepare.The exemplary route of synthesis that is used to generate acid amides of the present invention has hereinafter been described.
Embodiment 1 (general procedure of acid amides preparation)
5-nitro-furans-2-carboxylic acid phenyl acid amides
Figure A200680054994D00381
Aniline (10mg, 0.069mmol) De diox (0.5mL) solution polystyrene (＂ PS ＂) morpholine resin (Aldrich) (50mg, 0.14mmol) handle, add 5-nitro-furans-2-carbonyl chloride (Lancaster) (15mg, 0.086mmol) De diox (0.5mL) solution subsequently.Reactant is heated to 70 ℃ and stir 2h.(25mg 0.12mmol) handles and is heated to 70 ℃ and continues other 2h reactant with PS triamine (Aldrich).Filter and produce the product of wanting, productive rate 80%.
Embodiment 2 (program 2 of acid amides preparation)
Isoxazole-5-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides
Figure A200680054994D00382
Add anhydrous methylene chloride (＂ DCM ＂) (1mL) to PS-HOBt resin (0.1mmol), (0.5mmol) is with isoxazole-5-carbonyl chloride (Lancaster) (0.3mmol) to add pyridine subsequently.Mixture filters then at room temperature jolting 3h.Resin uses tetrahydrofuran (THF) (＂ THF ＂) (3x) and DCM (3x) washing successively, and vacuum-drying.(mixture is at room temperature jolting 16h for 0.05mmol, anhydrous THF (1mL) solution 0.5eq) to add the basic aniline (Lancaster) of 2-piperidines-1-to this acidylate resin.Filtering mixt is used THF and DCM washing resin as mentioned above then.The filtrate and the elutant concentrating under reduced pressure that merge generate product.Productive rate: 100%.MS:272 (M+1) .LC/MS purity: 100%. 1HNMR(CDCl 3，300MHz)：δ?8.2(d，1H)，7.85(t，2H)，7.55(m，1H)，7.4(m，2H)，3.8-3.2(bm，4H)，2.7-1.9(bm，4H)。
Embodiment 2-A
5-nitro-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides
Figure A200680054994D00391
Prepare compound according to the program of describing among the embodiment 2 from 5-nitro-furans-2-carbonyl chloride and 2-piperidines-1-base aniline.Productive rate: 100%.MS:316 (M+1) .LC/MS purity: 100%. 1HNMR(CDCl 3，300MHz)：δ?8.2(d，1H)，7.85(d，1H)，7.55(m，1H)，7.4(m，3H)，3.8-3.2(bm，4H)，2.7-1.9(bm，6H)。
Embodiment 3 (acid amides preparation procedure 3)
5-nitro-thiophene-2-carboxylic acid (2-piperidines-1-base-phenyl))-acid amides
Figure A200680054994D00392
Add the DCM solution of 2mL pyridine (0.09mmol) and the N of 0.6mL carboxylic acid (0.23mmol), dinethylformamide (＂ DMF ＂) solution to PS-HOBt resin (0.15mmol).Mixture adds 0.4mL1 then room temperature jolting 5 minutes, 3-DIC (＂ DIC ＂) DCM solution (0.66mmol).Mixture is in room temperature jolting 3h and filtration.Resin washs with DMF (3 x), THF (3 x) and DCM (3 x), and vacuum-drying.Add 2-piperidines-1-base aniline (0.075mmol to this acyl group resin; 0.5 anhydrous THF (1mL) solution equivalent), mixture is jolting 16h at room temperature.Filtering reaction thing then, resin is with THF and DCM washing.Filtrate that merges and elutant vacuum concentration are to generate product.MS：332(M+1)。LC/MS:100% purity. 1H?NMR(CDCl 3，300MHz)：δ?7.95(d，2H)，7.5(m，2H)，7.2(m，2H)，2.85(m，4H)，1.8-1.6(bm，4H)，1.5(bm，2H)。
Embodiment 4 (program 4 of acid amides preparation)
5-bromo-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides
Figure A200680054994D00401
5-bromine furancarboxylic acid (Aldrich) (1.0mmol), 2-piperidines-1-base aniline (1.0mmol), I-hydroxybenzotriazole hydrate (＂ HOBT ＂) (1.2mmol) and triethylamine (＂ Et 3N ＂) DCM (2mmol) (10mL) solution at room temperature stirred 10 minutes.Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (＂ EDCI ＂) then (1.2mmol), the orange solution that obtains stirs and spends the night.Reaction mixture saturated sodium bicarbonate (＂ NaHCO 3＂) solution (10mL) is handled, and extracts with DCM.The organic layer that merges is through MgSO 4Drying, and concentrating under reduced pressure is generated as the crude product of orange solids.Through the silica gel chromatography purifying, produce pure yellow product, productive rate 85%.MS：349(M+1). 1H?NMR(CDCl 3，300MHz)：δ?9.75(br?s，IH)，8.45(d，1H)，7.22-7.05(m，4H)，6.50(d，1H)，3.00-2.80(m，4H)，1.95-1.80(m，4H)，1.75-1.60(m，2H)。
Embodiment 4-A
5-(2-piperidines-1-base-phenyl amino formyl radical)-furans-2-carboxylic acid
Figure A200680054994D00402
5-formyl radical-pyromucic acid (TCI) (1.0mmol), 2-piperidines-1-base aniline (1.0mmol), HOBT (1.2mmol) and Et 3DCM (10mL) solution of N (2mmol) was stirring at room 10 minutes.Add EDCI (1.2mmol) then, the orange solution that obtains stirs and spends the night.Reaction mixture saturated sodium bicarbonate (＂ NaHCO 3＂) solution (10mL) is handled, and extracts with DCM.The organic layer that merges is through MgSO 4Drying, and concentrating under reduced pressure is generated as the crude product of orange solids.Through the silica gel chromatography purifying, produce acid amides aldehyde product, productive rate 80%.Aldehyde product (1mmol) is dissolved in and contains yellow soda ash (＂ Na 2CO 3＂) the H2O/ glycol dimethyl ether of (2mol) (＂ DME ＂) (2:1,5mL).In independent bottle (separate flask), potassium permanganate (＂ KMnO 4＂) (1.3mmol) is dissolved in H 2O (5mL), and under 45 ℃, slowly be added in the reaction flask.Reactant at room temperature stirs and spends the night, and filters by plug of celite, uses hydrochloric acid (＂ HCl ＂) solution (1N) to be acidified to pH3 to 4 then.The product that is settled out as white solid after filtration, H 2O washing and high vacuum dry are to provide pure products.MS：315(M+1). 1H?NMR(DMSO-d 6，300MHZ)：δ?13.60(br?s，IH)，9.90(s，1H)，8.25(dd，1H)，7.36(dd，2H)，7.35-7.25(m，1H)，7.20-7.10(m，2H)，2.85-2.65(m，4H)，1.85-1.65(m，4H)，1.65-1.45(m，2H)。
Embodiment 5 (preparation procedure of reductive acid amides)
5-(nitrofuran-2-ylmethyl)-(2-piperidines-1-base-phenyl) amine
Figure A200680054994D00411
2-piperidines-1-base aniline (1mmol), 5-nitro-furans-2-formaldehyde (1.1mmol) and sodium triacetoxy borohydride (＂ NaBH (OAc) 3＂) anhydrous DCM (10mL) solution of (2mmol) at room temperature stirs 16h.Then, mixture is the sodium hydroxide of water, dilution (the ＂ NaOH ＂) aqueous solution, water and salt water washing successively, then through MgSO 4Drying is filtered and concentrating under reduced pressure.By fast silica gel chromatogram purifying oil residues, generate product.MS:301 (M+1) .LC/MS purity: 100%. 1H?NMR(CDCl 3，300MHz)：δ?7.25(d，1H)，7.15-6.95(m，2H)，6.75(t，1H)，6.55(d，1H)，6.4(d，1H)，5.4(bs，1H)，4.45(s，2H)，2.8(bm，4H)，1.8-1.5(bm，6H)。
Embodiment 6 (preparation of 5-cyano group-furans-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides)
A.2-cyano group-5-furancarboxylic acid
(0.28g, pyridine 2.0mol) (5.0mL) solution adds oxammonium hydrochloride (＂ NH to 2-formyl radical-5-furancarboxylic acid 2OH-HCl ＂) (0.27g, 4.0mol).Mixture is heated to 85 ℃, adds diacetyl oxide (4.0ml) then.Reaction mixture stirs 3h at 85 ℃, is cooled to 60 ℃ and pour in the water (25mL).Mixture is cooled to room temperature and stirs spend the night (pH value of solution is through being measured as 5-6).Impurity extracts with 4/1 DCM/ aqueous isopropanol (3 x 30mL).It is about 9 to pH then water layer to be alkalized with NaOH solution (2N), and pyridine extracts with 4/1DCM/ Virahol (3 x 30mL) solution.Then that acidified aqueous solution is about 2 to pH, product extracts with 3/1DCM/ aqueous isopropanol (3 x 50mL).The organic extracting solution that merges is through MgSO 4Drying, evaporating solvent obtain being light brown solid pure products, productive rate 90%. 1H NMR (DMSO-d 6): δ 13.80 (bs, 1H), 7.75 (d, 1H), 7.40 (d, 1H) .IR (pure): (cm -1) 3200,2250,1053,1025,1006.
B.4-(4-methyl-piperidines-1-yl)-3-nitro-phenyl]-methyl alcohol
Figure A200680054994D00422
(4-fluoro-3-nitro-phenyl)-methyl alcohol (171mg, 1mmol), the 4-methyl piperidine (95mg, 0.96mmol) the PS morpholine (400mg, 1mmol) and the suspension of the stirring of chloroform (3mL) 50 ℃ the heating 2 hours.Reactant on diatomite, evaporate and by purification by flash chromatography to generate [4-(4-methyl-piperidines-1-yl)-3-nitro-phenyl]-methyl alcohol (i). 1H?NMR(CDCl 3，300MHz)：δ?7.8(s，1H)，7.4(d，1H)，7.1(d，1H)，4.6(s，2H)，3.2(d，2H)，2.8(dd，2H)，1.8-1.3(m，5H)，1.0(d，3H)。
C.5-cyano group-furans-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides
Figure A200680054994D00431
5%Pd/C (5.0mg, 2.3 x 10 -3Mmol), [4-(4-methyl-piperidines-1-yl)-3-nitro-phenyl]-methyl alcohol (i) (95mg, 0.38mmol), acetate (＂ HOAc ＂) (23mg, 0.38mmol), the suspension of methyl alcohol (1mL) and ethyl acetate (4mL) stirs 3h in nitrogen atmosphere.Reactant after filtration, vacuum concentration, [3-amino-4-(4-methyl-piperidines-1-yl)-the phenyl]-methyl alcohol that obtains need not to be further purified and is used for next step.[3-amino-4-(4-methyl-piperidines-1-yl)-phenyl]-methyl alcohol, 5-cyano group-2-furoyl chloride (64mg, 0.44mmol), the PS morpholine (600mg, 1.50mmol) and the suspension of DCM (10mL) stirring at room 30 minutes.Reactant evaporates on diatomite, generates 5-cyano group-furans-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides by the column chromatography purifying.MS：340(M+1)， 1H?NMR(CDCl 3，300MHz)：δ?9.9(s?br，1H)，8.4(s，1H)，7.3(s，1H)，7.25-7.1(m，3H)，4.7.(s，2H)，3.0(m，2H)，2.8(m，2H)，1.9，(d，2H)，1.8-1.4(m，3H)，1.1(d，3H)。
Embodiment 7 (preparation procedure of diaryl acid amides)
5-phenyl-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides
Figure A200680054994D00432
5-bromo-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides (1.0mmol), phenyl-boron dihydroxide (1.2mmol), 1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II) [＂ Pd (dppf) 2Cl 2＂] (Aldrich) (0.05mmol) and Na 2CO 3(3.0mmol) be dissolved in THF/H 2O solution (4:1,5mL; Argon is saturated), and be heated to 80 ℃ of 5h.After being cooled to room temperature, mixture concentrating under reduced pressure, the residue that obtains by the silica gel chromatography purifying so that pure products to be provided.Productive rate: 75%.MS：347(M+1). 1H?NMR(CDCl 3，300MHz)：δ?9.90(br?s，1H)，8.50(d，1H)，7.82(d，2H)，7.50-7.28(m，4H)，7.24-7.05(m，3H)，6.82(d，1H)，3.00-2.80(m，4H)，1.95-1.80(m，4H)，1.75-1.60(m，2H)。
Embodiment 8 (extending the program of aromatic nucleus by amination)
5-phenyl amino-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides
Figure A200680054994D00441
Toluene (7.5mL) solution to 5-bromo-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides (1.0mmol) adds aniline (1.3mmol), three (dibenzalacetones), two palladiums (O) (＂ Pd 2Dba ＂) (Aldrich) (0.05mmol), 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (＂ BINAP ＂) (0.1mmol) and potassium tert.-butoxide (＂ t-BuOK ＂) (1.5mmol), the mixture that obtains refluxes and spends the night.Then reactant is cooled to room temperature, passes silicon-dioxide plug and concentrated.The burgundy residue provides product by the HPLC purifying.Productive rate: 40%.MS：362(M+1).
Embodiment 9 (preparation procedure 1 of formula III compound)
4-oxo-6-piperidines-1-base-4,5-dihydro-furan be [2,3-c] quinoline-2-formonitrile HCN also
Figure A200680054994D00442
5-cyano group-furans-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides (200mg) is dissolved in the mixture of benzene (180mL) and ethanol (20mL).According to Kanoka and Itoh[Synthesis, 36 (1972)] method of describing, solution at room temperature shines 10h with 100W high pressure Hg lamp.Solvent removed in vacuo, residue is by preparation thin-layer chromatography (＂ TLC ＂) (silica gel) purifying, to generate pure product.
Embodiment 10 (preparation procedure 2 of formula III compound)
4-oxo-6-piperidines-1-base-4,5-dihydro-furan be [2,3-c] quinoline-2-formonitrile HCN also
Figure A200680054994D00451
2-nitro-3-toluene bromide (1.8g, 8.3mmol), (10mL is 101mmol) with the vlil 56h of diox (85mL) for piperidines.Reaction after filtration, concentrate and on diatomite, evaporate.Silica gel chromatography produces 1-(3-methyl-2-nitro-phenyl)-piperidines (i).
Under 0 ℃, the THF solution of 1-(3-methyl-2-nitro-phenyl)-piperidines (i) lithium diisopropylamine (＂ LDA ＂) (1 equivalent), oxalic acid diethyl ester (1.05 equivalent) processing subsequently.Make reactant in 90 minutes, be warming up to room temperature.Reactant water and ether dilution, distribution, water layer washs with ether.The organic layer that merges is through MgSO 4Dry, filtration and concentrated.Chromatography produces 3-, and (2-nitro-3-piperidines-1-base-phenyl)-2-oxo-ethyl propionate (ii).
Figure A200680054994D00461
Under 0 ℃, 3-(2-nitro-3-piperidines-1-base-phenyl)-2-oxo-ethyl propionate THF solution (ii) potassium ethylate (＂ KOEt ＂) (1 equivalent), pyruvic acid bromine ethyl ester (1.05 equivalent) processing subsequently.Make reactant in 90 minutes, be warming up to room temperature.Reactant water and ether dilution, distribution, water layer washs with ether.The organic layer that merges is through MgSO 4Dry, filtration and concentrated.Chromatography produces 3-(2-nitro-3-piperidines-1-base-phenyl)-2, and 5-dioxo-diethylene adipate (iii).
Figure A200680054994D00462
3-(2-nitro-3-piperidines-1-base-phenyl)-2,5-dioxo-diethylene adipate THF solution is (iii) handled with acetate (＂ HOAc ＂), and at room temperature stirs 4h.Reactant is handled with zinc powder (10 equivalent), and stirs extra 2h.Reactant dilutes with DCM, half saturated brine and distributes.The saturated NaHCO of organic layer 3Solution washing, MgSO 4Drying is filtered and is concentrated.Chromatography produces 4-oxo-6-piperidines-1-base-4, and also [2,3-c] quinaldic acid's ethyl ester (iv) for the 5-dihydro-furan.
Figure A200680054994D00471
4-oxo-6-piperidines-1-base-4,5-dihydro-furan also [2,3-c] quinaldic acid's ethyl ester DCM solution are (iv) handled with diisobutyl aluminium hydride (＂ DIBAL-H ＂) down at 0 ℃, and make it be warming up to room temperature.Reactant also distributes with saturated sodium tartrate potassium solution quencher.Organic layer is through MgSO 4Dry, filter and with violent (the ＂ MnO of titanium dioxide 2＂) handle.After stirring 16h under the room temperature, reactant after filtration and concentrate and produce 4-oxo-6-piperidines-1-base-4, also [2,3-c] quinoline-2-formaldehyde is (v) for the 5-dihydro-furan.
Figure A200680054994D00472
4-oxo-6-piperidines-1-base-4,5-dihydro-furan also [2,3-c] quinoline-2-formaldehyde (Virahol v) (＂ iPrOH ＂) solution is at room temperature handled with ammonia.After 90 minutes, reactant MnO 2Handle and stir other 16h.Reactant evaporates after filtration and on diatomite.Silica gel chromatography provides 4-oxo-6-piperidines-1-base-4, and the 5-dihydro-furan is [2,3-c] quinoline-2-formonitrile HCN also.
Embodiment 11
4-cyano group-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00481
A) 1-(2-TMS-ethoxyl methyl)-1H-imidazoles-4-formonitrile HCN
Figure A200680054994D00482
Be equipped with imidazoles-4-formonitrile HCN (0.50g, 5.2mmol) (synthetic, 677,2003), 2-(trimethyl silyl) ethoxyl methyl chlorine (SEMCl) (0.95mL, 5.3mmol), K 2CO 3(1.40g, 10.4mmol) and the flask of acetone (5mL) at room temperature stir 10h.Mixture dilutes with EtOAc (20mL), and water (20mL) and salt solution (20mL) washing, and organic layer is through MgSO 4Dry.From 20-g SPE post (silicon-dioxide) wash-out crude product, what obtain 0.80g (70%) is the titled reference compound of water white oil with 30% EtOAc/ hexane.Mass spectrum (CI (CH 4), m/z): C 10H 17N 3OSi calculated value 224.1 (M+H), actual measurement 224.1.
B) 2-bromo-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-4-formonitrile HCN
Figure A200680054994D00483
To 1-(2-TMS-ethoxyl methyl)-1H-imidazoles-4-formonitrile HCN (0.70g, 3.1mmol) CCl of (prepared in step before) 4(10mL) solution adds N-bromosuccinimide (NBS) (0.61g, 3.4mmol) and azepine two (isopropyl cyanide) (AIBN) (cat), mixture is at 60 ℃ of heating 4h.Reactant is used NaHCO with EtOAc (30mL) dilution 3The washing of (2 x 30mL), salt solution (30mL), organic layer is through Na 2SO 4Dry back concentrates.Use the 30%EtOAc/ hexane from 20-g SPE post (silicon-dioxide) wash-out titled reference compound, obtain 0.73g (77%) yellow solid.Mass spectrum (CI (CH 4), m/z): C 10H 16BrN 3OSi calculated value 302.0/304.0 (M+H), actual measurement 302.1/304.1.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid, ethyl ester
Figure A200680054994D00491
Under-40 ℃, to 2-bromo-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-4-formonitrile HCN (0.55g, 1.8mmol) tetrahydrofuran (THF) (THF) of (in the preparation of step before) (6mL) solution drip THF (1mL) solution of 2M i-PrMgCl.Reactant stirred 10 minutes at-40 ℃, was cooled to-78 ℃ then, and interpolation cyanoformic acid ethyl ester (0.30g, 3.0mmol).Make reactant reach room temperature, stir 1h.The saturated NH of reactant 4The quencher of the Cl aqueous solution is with EtOAc (20mL) dilution, with salt solution (2 x 20mL) washing.Organic layer is through Na 2SO 4Drying concentrates then.Use 30% EtOAc/ hexane from 20-g SPE post (silicon-dioxide) wash-out titled reference compound, obtain 0.40g (74%) water white oil.Mass spectrum (ESI, m/z): C 13H 21N 3O 3The Si calculated value, 296.1 (M+H), actual measurement 296.1.
D) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite
Figure A200680054994D00492
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid, ethyl ester (0.40g, 1.3mmol) ethanol (3mL) solution of (in the preparation of step before) adds 6M KOH solution (0.20mL) solution, reactant stirs after 10 minutes and concentrates, and obtains 0.40g (100%) and is the titled reference compound of yellow solid. 1H-NMR (CD 3OD; 400MHz) δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). mass spectrum (ESI-neg, m/z): C 11H 16KN 3O 3The Si calculated value, 266.1 (M-K), actual measurement 266.0.
E) 4-bromo-2-hexamethylene-1-thiazolinyl-aniline
Figure A200680054994D00501
To 4-bromo-2-iodo-aniline (2.00g, 6.71mmol), 2-hexamethylene-1-thiazolinyl-4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane (1.40g, 6.71mmol) and Pd (PPh 3) 4(4-diox mixture adds 2.0M Na for 388mg, 1 of 40mL 0.336mmol) 2CO 3The aqueous solution (26.8mL, 53.7mmol).Argon gas stirs 5h down for following 80 ℃, and reactant is cooled to room temperature.Mixture is handled with EtOAc (100mL), uses H 2O (3 x 30mL) and salt solution (20mL) washing.Organic layer drying (Na 2SO 4) and vacuum concentration.Residue obtains 1.47g (87%) and is the titled reference compound of light brown oil by purification by flash chromatography on the silica gel (10-20%EtOAc/ hexane).Mass spectrum (ESI, m/z): C 12H 14The BrN calculated value, 252.0 (M+H), actual measurement 252.0.
F) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00502
To 4-bromo-2-hexamethylene-1-thiazolinyl-aniline (in the preparation of step before, 1.23g, 4.88mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 1.49g, 4.88mmol) and bromo tripyrrole alkane-1-base phosphonium hexafluorophosphate (PyBroP) (2.27g, 4.88mmol) at 25mL N, the mixture in the dinethylformamide (DMF) adds N, N-diisopropylethylamine (DIEA) (2.55mL, 14.6mmol).After stirring 16h under the room temperature, mixture is handled with 100mL EtOAc, uses H 2O (2 x 30mL), salt solution (30mL) washing, and dry (Na 2SO 4).Organic solvent is evaporated, and residue obtains 2.21g (90%) and is the titled reference compound of white solid by purification by flash chromatography on the silica gel (5-10% EtOAc/ hexane). 1H-NMR(CDCl 3；400MHz)：δ?9.70(s，1H)，8.26(d，1H，J＝8.6Hz)，7.78(s，1H)，7.36(dd，1H，J＝8.6，2.3Hz)，7.31(d，1H，J＝2.3Hz)，5.94(s，2H)，5.86(m，1H)，3.66(t，2H，J＝8.3Hz)，2.19-2.33(m，4H)，1.75-1.88(m，4H)，0.97(t，2H，J＝8.3Hz)，0.00(s，9H)。
G) 4-cyano group-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides (at the preparation of step before, 1.20mg, 10mL DCM (CH 2.39mmol) 2Cl 2) solution interpolation 0.30mL EtOH, add 5.0mL trifluoroacetic acid (TFA) subsequently.Behind the stirring at room 3h, mixture is handled with the 20mL n-propyl alcohol, and vacuum concentration.Residue grinds with DCM, is the titled reference compound of white solid so that 853mg (96%) to be provided. 1H-NMR (DMSO-d 6400MHz): δ 9.80 (s, 1H), 8.30 (s, 1H), 7.94 (d, 1H, J=8.6Hz), 7.50 (dd, 1H, J=8.6,2.3Hz), 7.39 (d, 1H, J=2.3Hz), 5.80 (m, 1H), 2.12-2.25 (m, 4H), 1.61-1.77 (m, 4H). mass spectrum (ESI, m/z): C 17H 15BrN 4The O calculated value, 371.0 (M+H), actual measurement 371.0.
Embodiment 12
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides
Figure A200680054994D00511
Under-78 ℃, argon gas, (2mLTHF solution 0.135mmol) adds isopropylmagnesium chloride (71 μ L for preparation in embodiment 11 steps (g), 50.0mg to 4-cyano group-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides, 0.14mmol, 2.0M).The mixture heating up that obtains stirred 15 minutes to room temperature, was cooled to-78 ℃ again.(1.7M), the mixture that obtains stirred 5 minutes at-78 ℃ for 240 μ L, 0.405mmol to add tert-butyl lithium to mixture.(0.40mL, 0.68mmol), reactant is warming up to room temperature, and stirs 1h under argon gas to add acetone then.The mixture saturated NH of 1mL 4H is used in Cl, 40mL EtOAc processing subsequently 2O (10mL), salt solution (5mL) washing, and dry (Na 2SO 4).Removal of solvent under reduced pressure is carried out flash chromatography (1-2% MeOH/DCM) to residue subsequently on silica gel, obtain 32.1mg (68%) and be the titled reference compound of white solid. 1H-NMR (CDCl 3400MHz): δ 11.88 (s, 1H), 9.58 (s, 1H), 8.29 (d, 1H, J=8.6Hz), 7.74 (s, 1H), 7.42 (dd, 1H, J=8.6,2.2Hz), 7.35 (d, 1H, J=2.2Hz), 5.87 (m, 1H), 2.23-2.34 (m, 4H), 1.73-1.90 (m, 4H), 1.79 (s, 1H, OH), 1.61 (s, 6H). mass spectrum (ESI, m/z): C 20H 22N 4O 2Calculated value 351.2 (M+H), actual measurement 351.0.
Embodiment 13
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-methoxyl group-1-methyl-ethyl)-phenyl]-acid amides
To (the preparation in embodiment 12 of 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides, 18.0mg, 0.0514mmol) 1mLDCM solution add the vitriol oil (50 μ L), add 50 μ L MeOH subsequently.The mixture that obtains at room temperature stirs 0.5h, uses the saturated NaHCO of 10mL then 3The aqueous solution is handled.Mixture extracts with EtOAc (2 x 20mL).The organic layer H that merges 2O (10mL), salt solution (10mL) washing and dry (Na 2SO 4).After the removal of solvent under reduced pressure residue is carried out flash chromatography on silica gel (1%MeOH/DCM), obtain 8.2mg (44%) and be the titled reference compound of white solid. 1H-NMR(CDCl 3；400MHz)：δ?12.31(s，1H)，9.65(s，1H)，8.30(d，1H，J＝8.6Hz)，7.76(s，1H)，7.35(dd，1H，J＝8.6，2.3Hz)，7.25(d，1H，J＝2.3Hz)，5.88(m，1H)，3.11(s，3H)，2.23-2.37(m，4H)，1.75-1.90(m，4H)，1.55(s，6H)。
Embodiment 14
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate
Figure A200680054994D00531
A) 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-azido--1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides
Under 0 ℃ of argon gas, to 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides (preparation among the embodiment 12,15.0mg, 0.0428mmol) and NaN 3(27.8mg, 0.428mmol) mixture in the 1mL chloroform add TFA (49 μ L, 0.642mmol).The mixture that obtains is 0 ℃ of stirring 1h under argon gas.After 30mL EtOAc processing, the saturated NaHCO of mixture 3The aqueous solution (10mL), salt solution (10mL) washing, and dry (Na 2SO 4).Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (0-5% EtOAc/DCM) to residue subsequently, obtains 13.6mg (84%) and is the titled reference compound of white solid.Mass spectrum (ESI, m/z): C 20H 21N 7The O calculated value, 376.2 (M+H), actual measurement 376.0.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate
To 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-azido--1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides (in the preparation of step before, 13.6mg, 0.0362mmol) and zinc (9.5mg, 0.15mmol) interpolation of the mixture in 1mL THF acetate (0.20mL).The mixture that obtains is stirring at room 3h under argon gas.Remove solid by diatomite filtration, the filtrate vacuum concentration obtains light brown oil.Mixture grinds with DCM (2 x 4mL).Solvent is by removing by filter, and solid vacuum-drying obtains 13.5mg (91%) and is the titled reference compound of white solid. 1H -NMR(CD 3OD；400MHz)：δ?8.27(s，1H)，7.70(s，1H)，7.43(d，1H，J＝7.3Hz)，7.29(s，1H)，5.81(m，1H)，2.11-2.37(m，4H)，1.91(s，3H)，1.59-1.84(m，4H)，1.71(s，6H)。
Embodiment 15
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate
Figure A200680054994D00541
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(5, the 5-dimethyl-own borine of [1,3,2] dioxane-2-yl)-phenyl]-acid amides
Figure A200680054994D00542
To (the preparation in embodiment 11 steps (f) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides, 201mg, 0.400mmol), two neo-pentyl oxyacetic acid two boron (bis (neopentyl glycolato) diboron) (108mg, 0.480mmol) and Pd (dppf) Cl 2(29.3mg, 0.0400mmol) at 4mL1, the mixture interpolation KOAc in the 4-diox (118mg, 1.20mmol).The mixture that obtains is 80 ℃ of stirring 10h under argon gas.After being cooled to room temperature, mixture is handled with 50mL EtOAc, uses H 2O (3x 10mL) and salt solution (10mL) washing.Organic layer drying (Na 2SO 4) and vacuum concentration.Residue obtains 144mg (67%) and is the titled reference compound of white solid by flash chromatography on silica gel purifying (DCM): 1H-NMR (CDCl 3400MHz): δ 9.84 (s, 1H), 8.35 (d, 1H, J=8.2Hz), 7.76 (s, 1H), 7.70 (dd, 1H, J=8.2,1.4Hz), 7.60 (d, 1H, J=1.4Hz), 5.95 (s, 2H), 5.82 (m, 1H), 3.76 (s, 4H), 3.65 (t, 2H, J=8.1Hz), 2.22-2.35 (m, 4H), 1.68-1.92 (m, 4H), 1.01 (s, 6H), 0.96 (t, 2H, J=8.1Hz), 0.01 (s, 9H).
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides
Figure A200680054994D00551
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(5,5-dimethyl-[1,3,2] the own borine of dioxane-2-yl)-phenyl]-acid amides is (in the preparation of step before, 32.0mg, 0.0600mmol), 5-bromo-pyridine-2-base amine (10.4mg, 0.0660mmol) and Pd (PPh 3) 4(7.0mg, 0.0060mmol) at 1.0mL1, the mixture in the 4-diox adds 2.0M Na 2CO 3The aqueous solution (0.24mL, 0.48mmol).The mixture that obtains is 80 ℃ of stirring 6h under argon gas.After being cooled to room temperature, mixture is handled with 30mL EtOAc, uses H 2O (3 x 15mL) and salt solution (10mL) washing.Organic layer drying (Na 2SO 4) and vacuum concentration.Residue obtains 24mg (78%) and is the titled reference compound of white solid by flash chromatography on silica gel purifying (2-3% MeOH/DCM): and mass spectrum (ESI, m/z): C 28H 34N 6O 2The Si calculated value, 515.3 (M+H), actual measurement 515.2.
C) 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides (in the preparation of step before, 22mg, 0.043mmol) 1.5mL DCM solution add 50 μ L EtOH, add 0.50mLTFA subsequently.The solution that obtains at room temperature stirred 1 day.Reactant is handled and vacuum concentration with the 20mL n-propyl alcohol.Residue obtains 17mg (77%) and is the titled reference compound of white solid by flash chromatography on silica gel purifying (3-5% MeOH/DCM). 1H-NMR (CD 3OD; 400MHz): δ 8.37 (dd, 1H, J=8.5,1.9Hz), 8.27 (ddd, 1H, J=9.3,2.3,1.9Hz), 8.11 (m, 1H), 8.03 (m, 1H), 7.54 (ddd, 1H, J=8.5,2.3,1.9Hz), 7.45 (m, 1H), 7.11 (br d, 1H, J=9.3Hz), 5.90 (m, 1H), 2.25-2.35 (m, 4H), 1.76-1.93 (m, 4H). mass spectrum (ESI, m/z): C 22H 20N 6The O calculated value, 385.2 (M+H), actual measurement 385.1.
Embodiment 16
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides
A) 4-(1-oxidation-pyridin-4-yl)-aniline
To 4-chloro-pyridine 1-oxide compound (389mg, 3.00mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-aniline (712mg, 3.15mmol) and Pd (PPh 3) 4(347mg, 0.30mmol) at 20mL1, the mixture in the 4-diox adds 2.0MNa 2CO 3The aqueous solution (3.0mL, 6.00mmol).The mixture that obtains 80 ℃ of stirring 24h under argon gas are cooled to room temperature then.After the 50mL brine treatment, mixture extracts with DCM (10 x 30mL).The organic layer vacuum concentration that merges, and by flash chromatography on silica gel purifying (2-6%MeOH/DCM), obtain 280mg (50%) and be the titled reference compound of white solid. 1H-NMR (CDCl 3400MHz): δ 8.24 (d, 2H, J=7.3Hz), 7.46 (d, 2H, J=7.3Hz), 7.43 (d, 2H, J=8.6Hz), 6.77 (d, 2H, J=8.6Hz). mass spectrum (ESI, m/z): C 11H 10N 2O, calculated value 187.1 (M+H), actual measurement 187.1.
B) 2-bromo-4-(1-oxidation-pyridin-4-yl)-aniline
Figure A200680054994D00571
Under argon gas, to 0 ℃ 4-(1-oxidation-pyridin-4-yl)-aniline (in the preparation of step before, 200mg, 20mL 4:1DCM/MeOH solution 1.07mmol) adds N-bromosuccinimide (NBS) (191mg, 10mL DCM solution 1.07mmol).Mixture stirs 1h down at 0 ℃.With the saturated NaHCO of 20mL 3After the aqueous solution and the 20mL brine treatment, mixture extracts with DCM (5 x 50mL).The organic layer vacuum concentration that merges also passes through flash chromatography on silica gel purifying (2-6% MeOH/DCM), obtains 248mg (87%) and is the titled reference compound of white solid.
1H-NMR (CDCl 3400MHz): δ 8.20 (d, 2H, J=7.4Hz), 7.67 (d, 1H, J=2.1Hz), 7.40 (d, 2H, J=7.4Hz), 7.35 (dd, 1H, J=8.4,2.1Hz), 6.84 (d, 1H, J=8.4Hz), 3.90-4.60 (br s, 2H). mass spectrum (ESI, m/z): C 11H 9BrN 2The O calculated value, 265.0 (M+H), actual measurement 265.1.
C) 2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-aniline
Figure A200680054994D00572
To 2-bromo-4-(1-oxidation-pyridin-4-yl)-aniline (in the preparation of step before, 240mg, 0.905mmol), tetrahydrobenzene-1-ylboronic acid (126mg, 0.996mmol) and Pd (PPh 3) 4(105mg, 0.091mmol) at 9mL1, the mixture in the 4-diox adds 2.0M Na 2CO 3The aqueous solution (3.62mL, 7.24mmol).The mixture that obtains is 80 ℃ of stirring 8h under argon gas, are cooled to room temperature then.After the 20mL brine treatment, mixture extracts with DCM (4 x 20mL).The organic layer that merges is through vacuum concentration, and by flash chromatography on silica gel purifying (2-5%MeOH/DCM), obtains 241mg (100%) and be the titled reference compound of faint yellow solid.
1H-NMR (CDCl 3400MHz): δ 8.18 (d, 2H, J=7.3Hz), 7.44 (d, 2H, J=7.3Hz), 7.30 (dd, 1H, J=8.4,2.2Hz), 6.76 (d, 1H, J=8.4Hz), 5.80 (m, 1H), 3.0-4.2 (br s, 2H), and 2.17-2.28 (m, 4H), 1.68-1.82 (m, 4H). mass spectrum (ESI, m/z): C 17H 18N 2The O calculated value, 267.1 (M+H), actual measurement 267.1.
D) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides
Figure A200680054994D00581
To 2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-(embodiment 17 for aniline, step (c), 107mg, 0.40mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (embodiment 11 steps (d), 129mg, 0.42mmol) and PyBroP (187mg, 0.42mmol) mixture in 4mL DMF add DIEA (209 μ L, 1.20mmol).The mixture that obtains is stirring at room 5h under argon gas.After 50mL EtOAc processing, mixture H 2O (2 x 10mL), salt solution (10mL) washing and dry (Na 2SO 4).Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (1-5% MeOH/DCM) to residue subsequently, obtains 86mg (42%) and is the titled reference compound of light yellow oil.
1H-NMR (CDCl 3400MHz): δ 9.84 (s, 1H), 8.51 (d, 1H, J=8.7Hz), 8.25 (d, 2H, J=7.2Hz), 7.81 (s, 1H), 7.52 (m, 3H), 7.41 (d, 1H, J=2.3Hz), 5.96 (s, 2H), 5.92 (m, 1H), 3.68 (t, 2H, J=8.3Hz), 2.25-2.37 (m, 4H), 1.70-1.94 (m, 4H), 0.99 (t, 2H, J=8.3Hz), 0.012 (s, 9H). mass spectrum (ESI, m/z): C 28H 33N 5O 3The Si calculated value, 516.2 (M+H), actual measurement 516.1.
E) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides (in the preparation of step before, 40mg, 0.078mmol) 3mL DCM solution add 0.10mL EtOH, add 1mLTFA subsequently.The solution that obtains at room temperature stirs 2h.Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (3-5% MeOH/DCM) to residue subsequently, obtains 29.3mg (98%) and is the titled reference compound of white solid.
1H-NMR (1:1CDCl 3/ CD 3OD; 400MHz): δ 8.50 (d, 1H, J=8.7Hz), 8.29 (d, 2H, J=7.3Hz), 7.81 (s, 1H), 7.68 (d, 2H, J=7.3Hz), 7.58 (dd, 1H, J=8.7,2.3), 7.47 (d, 1H, J=2.3Hz), 5.94 (m, 1H), 2.26-2.39 (m, 4H), and 1.79-1.94 (m, 4H). mass spectrum (ESI, m/z): C 22H 19N 5O 2Calculated value, 386.1 (M+H), actual measurement 386.1.
Embodiment 17
5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides
Figure A200680054994D00591
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxo-pyridin-4-yl)-phenyl]-acid amides (preparation in embodiment 16 steps (e), 14mg, 0.036mmol), iron powder (10mg, 0.18mmol) and NH 4(19mg .036mmol) mixture in 4mL ethanol stirs 5h at 80 ℃ to Cl, is cooled to room temperature then.Use 20mL H 2After O handled, mixture extracted with EtOAc (3 x 20mL).The organic layer that merges, obtains 10.1mg (69%) and is the titled reference compound of white solid by flash chromatography on silica gel purifying (1-2% MeOH/DCM) through vacuum concentration:
1H-NMR (CDCl 3400MHz): δ 8.57 (d, 2H, J=6.3Hz), 8.49 (d, 1H, J=8.7Hz), 7.89 (s, 1H), 7.63-7.68 (m, 3H), 7.54 (d, 1H, J=2.0Hz), 5.94 (m, 1H), and 2.27-2.39 (m, 4H), 1.80-1.94 (m, 4H). mass spectrum (ESI, m/z): C 22H 19N 5The O calculated value, 370.2 (M+H), actual measurement 370.1.
Embodiment 18
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides
A) 3-bromopyridine 1-oxide compound
Figure A200680054994D00602
The 3-bromopyridine (158mg, 1.00mmol) and perhydrit (658mg, 2.5mL formic acid solution 7.00mmol) at room temperature stirs 16h.The mixture H that obtains 2O (30mL) handles, and extracts with DCM (3 x 15).Organic layer drying (the Na that merges 2SO 4) and concentrate, obtain 87mg (50%) and be the titled reference compound of water white oil.Mass spectrum (ESI, m/z): C 5H 4The BrNO calculated value, 174.0 (M+H), actual measurement 174.2.
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides
Figure A200680054994D00603
Titled reference compound is by embodiment 15, the Suzuki coupling program preparation of step (b), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(5,5-dimethyl-own the borine of [1,3,2] dioxane-2-yl)-phenyl]-acid amides (preparation in embodiment 15 steps (a), 53.5mg, 0.100mmol) and 3-bromopyridine 1-oxide compound (in step preparation before, 20.9mg, 0.120mmol).Silica gel chromatography (1-3%MeOH/DCM) provides and has been the titled reference compound of water white oil (49mg, 95%).Mass spectrum (ESI, m/z): C 28H 33N 5O 3The Si calculated value, 516.2 (M+H), actual measurement 516.1.
C) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides
Titled reference compound is by the program preparation of embodiment 15 steps (c), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides (in step preparation before, 49mg, 0.095mmol).Silica gel chromatography (1-4% MeOH/DCM) provides and has been the titled reference compound of white solid (35mg, 96%).
1H-NMR (DMSO-d6; 400MHz): δ 9.85 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.21 (ddd, 1H, J=6.5,1.5,0.8Hz), 8.17 (d, 1H, J=8.5Hz), 7.69-7.72 (m, 2H), 7.62 (d, 1H, J=2.3), 7.49 (dd, 1H, J=8.0,6.5Hz), 5.86 (m, 1H), 2.16-2.33 (m, 4H), 1.64-1.81 (m, 4H). mass spectrum (ESI, m/z): C 22H 19N 5O 2Calculated value, 386.2 (M+H), actual measurement 386.1.
Embodiment 19
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-3-yl-phenyl)-acid amides
Figure A200680054994D00611
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxo-pyridin-3-yl)-phenyl]-acid amides (preparation in embodiment 18 steps (c), 18.0mg, 0.0467mmol), iron powder (13.0mg, 0.234mmol) and NH 4Cl (25.0mg, 0.467mmol) the 80 ℃ of stirring 6h under argon gas of the mixture in 4.0mL EtOH.After being cooled to room temperature, mixture is handled with salt solution (20mL), and extracts with DCM (4 x 15mL).Organic layer drying (the Na that merges 2SO 4) and vacuum concentration.Residue obtains 15.0mg (87%) and is the titled reference compound of white solid by flash chromatography on silica gel purifying (1-3% MeOH/DCM).
1H-NMR (CDCl 3400MHz): δ 12.61 (s, 1H), 9.65 (s, 1H), 8.61 (m, 1H), 8.50 (d, 1H, J=8.5Hz), 7.90 (ddd, 1H, J=7.9,1.9,1.9Hz), 7.75 (s, 1H), 7.54 (dd, 1H, J=8.5,2.1Hz), 7.42 (d, 2H, J=2.1Hz), 7.38 (dd, 1H, J=7.9,4.8Hz), 5.94 (m, 1H), 2.27-2.37 (m, 4H), 1.78-1.93 (m, 4H). mass spectrum (ESI, m/z): C 22H 19N 5The O calculated value, 370.2 (M+H), actual measurement 370.1.
Embodiment 20
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides
Figure A200680054994D00621
A) 2-bromo-pyridine 1-oxide compound
Figure A200680054994D00622
The 2-bromopyridine (158mg, 1.00mmol) and perhydrit (658mg, 7.00mmol) solution in 2.5mL formic acid at room temperature stirs 16h.The mixture H that obtains 2O (30mL) handles and extracts with DCM (3 x 15).Organic layer drying (the Na that merges 2SO 4) and concentrate, obtain 96mg (55%) and be the titled reference compound of brown oil.Mass spectrum (ESI, m/z): C 5H 4The BrNO calculated value, 174.0 (M+H), actual measurement 174.2.
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides
Figure A200680054994D00623
Titled reference compound is by the Suzuki coupling program preparation of embodiment 15 steps (b), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(5,5-dimethyl-[1,3,2] the own borine of dioxane-2-yl)-phenyl]-acid amides (preparation in embodiment 15 steps (a), 53.5mg, 0.100mmol) and 2-bromopyridine 1-oxide compound (in step preparation before, 20.9mg, 0.120mmol).Silica gel chromatography (1-3%MeOH/DCM) provides and has been the titled reference compound of water white oil (49mg, 95%).Mass spectrum (ESI, m/z): C 28H 33N 5O 3The Si calculated value, 516.2 (M+H), actual measurement 516.0.
C) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides
Titled reference compound is by the program preparation of embodiment 15 steps (c), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides (in step preparation before, 49mg, 0.095mmol).Silica gel chromatography (1-4%MeOH/DCM) provides and has been the titled reference compound of light blue solid (35mg, 96%).
1H-NMR (DMSO-d6; 400MHz): δ 12.66 (s, 1H), 9.59 (s, 1H), 8.53 (d, 1H, J=5.4Hz), 7.79 (d, 1H, J=7.8Hz), 7.64 (s, 1H), 7.43-7.59 (m, 4H), 7.35 (br s, 1H), 5.79 (m, 1H), 2.01-2.47 (m, 4H), 1.70-1.89 (m, 4H). mass spectrum (ESI, m/z): C 22H 19N 5O 2Calculated value, 386.2 (M+H), actual measurement 386.1.
Embodiment 21
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides
Figure A200680054994D00631
The program preparation of titled reference compound by embodiment 19, used 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides (preparation in embodiment 20 steps (c), 18mg, 0.047mmol).Silica gel chromatography (1-3%MeOH/DCM) provides and has been the titled reference compound of white solid (5.2mg, 30%).
1H-NMR (CDCl 3400MHz): δ 11.85 (s, 1H), 9.69 (s, 1H), 8.71 (br s, 1H), 8.48 (d, 1H, J=8.1Hz), and 7.86-7.98 (m, 2H), 7.65-7.83 (m, 3H), 7.24 (m, 1H), 5.93 (m, 1H), and 2.24-2.40 (m, 4H), 1.76-1.92 (m, 4H). mass spectrum (ESI, m/z): C 22H 19N 5The O calculated value, 370.2 (M+H), actual measurement 370.1.
Embodiment 22
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides
A) 2-hexamethylene-1-thiazolinyl-4-sec.-propyl-aniline
Figure A200680054994D00642
To 2-bromo-4-sec.-propyl-aniline (214mg, 1.00mmol), hexanaphthene-1-ene boric acid (139mg, 1.10mmol) and Pd (PPh 3) 4(116mg, 0.100mmol) at 5mL1, the mixture in the 4-diox adds 2.0M Na 2CO 3The aqueous solution (4.0mL, 8.0mmol).The mixture that obtains is 80 ℃ of stirring 8h under argon gas, are cooled to room temperature then.H is handled and used to reactant with EtOAc (20mL) 2O (2 x 10mL) and salt solution (10mL) washing.Organic layer is through Na 2SO 4Dry also vacuum concentration.Residue obtains 205mg (95%) and is the titled reference compound of light brown oil by flash chromatography on silica gel (DCM) purifying.Mass spectrum (ESI, m/z): C 15H 21The N calculated value, 216.2 (M+H), actual measurement 216.1.
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides
Figure A200680054994D00651
To 2-hexamethylene-1-thiazolinyl-4-sec.-propyl-aniline (in the preparation of step before, 30.0mg, 0.139mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (preparation in embodiment 11 steps (d), 43.0mg, 0.141mmol) and PyBroP (65.0mg, 0.139mmol) mixture in 1.5mL DMF add DIEA (73 μ L, 0.417mmol).The mixture that obtains is stirring at room 16h under argon gas.After the 30mLEtOAc processing, mixture H 2O (2 x 10mL), salt solution (10mL) washing and dry (Na 2SO 4).Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (DCM) to residue subsequently, obtains 55.4mg (86%) and is the titled reference compound of water white oil.Mass spectrum (ESI, m/z): C 26H 36N 4O 2The Si calculated value, 465.3 (M+H), actual measurement 464.9.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides (in the preparation of step before, 50.0mg, 0.108mmol) 6mLDCM solution add 0.20mL EtOH, add 2mL TFA subsequently.The solution that obtains is at stirring at room 2h.Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (1-4%EtOAc/DCM) to residue subsequently, obtains 29.5mg (82%) and is the titled reference compound of white solid.
1H-NMR (CDCl 3400MHz): δ 12.77 (s, 1H), 9.64 (s, 1H), 8.23 (d, 1H, J=8.5Hz), 7.75 (s, 1H), 7.19 (dd, 1H, J=8.5,2.1Hz), 7.07 (d, 1H, J=2.1Hz), 5.86 (m, 1H), 2.91 (m, 1H), 2.22-2.36 (m, 4H), 1.70-1.89 (m, 4H), 1.27 (d, 6H, J=7.0Hz). mass spectrum (ESI, m/z): C 20H 22N 4The O calculated value, 335.2 (M+H), actual measurement 335.0.
Embodiment 23
4-cyano group-1H-imidazoles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides, trifluoroacetate
Figure A200680054994D00661
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides
Figure A200680054994D00662
To 2-piperidines-1-base-aniline (63.5mg, 0.360mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 100mg, 0.327mmol) and PyBroP (152mg, 0.327mmol) at 4mL1, mixture interpolation DIEA in the 2-ethylene dichloride (171 μ L, 0.981mmol).Behind the stirring at room 16h, mixture is handled with 50mL EtOAc, uses H under argon gas 2O (2 x 10mL) and salt solution (10mL) washing.Organic layer (the Na that is dried 2SO 4) and vacuum concentration.Residue obtains 118mg (85%) and is the titled reference compound of white solid by flash chromatography on silica gel (5-10% EtOAc/ hexane) purifying.Mass spectrum (ESI, m/z): C 22H 31N 5O 2The Si calculated value, 426.2 (M+H), actual measurement 426.1.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides, trifluoroacetate
The program preparation of titled reference compound by embodiment 22 steps (c), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides (in step preparation before, 110mg, 0.258mmol).Silica gel chromatography (1-3%MeOH/DCM) provides and has been the titled reference compound of white solid (85mg, 80%).
1H-NMR (CDCl 3400MHz): δ 9.94-10.87 (brs, 3H), 8.00 (m, 1H), 7.80 (s, 1H), 7.30-7.39 (m, 3H), 2.99-3.34 (m, 4H), 1.87-2.06 (m, 4H), 1.54-1.83 (m, 2H). mass spectrum (ESI, m/z): C 16H 17N 5The O calculated value, 296.1 (M+H), actual measurement 296.1.
Embodiment 24
4-cyano group-5-(1-hydroxyl-1-methyl-ethyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00671
A) 4-cyano group-5-(1-hydroxyl-1-methyl-ethyl)-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00672
Under-78 ℃ of argon gas, to (the preparation in embodiment 11 steps (f) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides, 50.0mg, 0.100mmol) 1mLTHF solution add isopropylmagnesium chloride (55 μ L, 0.11mmol 2.0M is in THF).The mixture that obtains is warming up to room temperature and stirred 15 minutes, cools back-78 ℃.Add n-Butyl Lithium (2.0M is in hexanaphthene for 55 μ L, 0.11mmol) to mixture, the mixture that obtains is-78 ℃ of stirring 0.5h under argon gas.(30 μ L, 0.40mmol), reactant is warming up to room temperature, and stirs 16h under argon gas to add acetone.With the saturated NH4Cl aqueous solution of 5mL, 30mL EtOAc processing subsequently, mixture H 2O (10mL), salt solution (5mL) washing and dry (Na 2SO 4).Solvent evaporated under reduced pressure, residue obtains 40.0mg (84%) and is the titled reference compound of white solid by flash chromatography on silica gel (5-10% EtOAc/ hexane) purifying.Mass spectrum (ESI, m/z): C 26H 35BrN 4O 3The Si calculated value, 559.2 (M+H), actual measurement 558.9.
B) 4-cyano group-5-(1-hydroxyl-1-methyl-ethyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
4-cyano group-5-(1-hydroxyl-1-methyl-ethyl)-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides is (in step preparation before, 40.0mg, 0.0715mmol) and tetrabutyl ammonium fluoride (357 μ L, 0.357mmol, 1.0M in THF) solution in 2.0mL THF under argon gas 50 ℃ stir 16h, reflux and stir 3h.After being cooled to room temperature, mixture is handled with EtOAc (40mL), with the saturated NH4Cl aqueous solution (5mL), salt solution (10mL) washing and dry (Na 2SO 4).The organic layer vacuum concentration, residue obtains 26mg (84%) and is the titled reference compound of white solid by flash chromatography on silica gel (5-10%EtOAc/DCM) purifying.
1H-NMR (CDCl 3400MHz): δ 11.79 (s, 1H), 9.55 (s, 1H), 8.23 (d, 1H, J=8.6Hz), 7.42 (dd, 1H, J=8.6,2.3Hz), 7.33 (d, 1H, J=2.3Hz), 5.87 (m, 1H), 5.08 (s, 1H), and 2.16-2.34 (m, 4H), 1.83 (s, 6H), and 1.71-1.88 (m, 4H). mass spectrum (ESI, m/z): C 20H 21BrN 4O 2Calculated value, 429.1 (M+H), actual measurement 428.9.
Embodiment 25
4-cyano group-1H-imidazoles-2-carboxylic acid (4-ethanoyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00681
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-ethanoyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00682
4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides (preparation in embodiment 11 steps (f), 100mg, 0.199mmol), tributyl (1-vinyl ethyl ether base) tin (86.3mg, 0.239mmol) and Pd (PPh 3) 2Cl 2(10.5mg, 0.0149mmol) at 2mL1, the mixture in the 4-diox is 90 ℃ of stirring 2h under argon gas.After being cooled to room temperature, reactant is handled with EtOAc (40mL), with 15% aqueous citric acid solution (2 x 10mL), H 2O (10mL) and salt solution (10mL) washing.Organic layer is through Na 2SO 4Dry also vacuum concentration.Residue obtains 80.1mg (86%) and is the titled reference compound of light brown oil by flash chromatography on silica gel (10-20% EtOAc/ hexane) purifying.Mass spectrum (ESI, m/z): C 25H 32N 4O 3The Si calculated value, 465.2 (M+H), actual measurement 465.1.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid (4-ethanoyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Titled reference compound is by the program preparation of embodiment 15 steps (c); used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-ethanoyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides (in step preparation before; 40.0mg, 0.0862mmol).Silica gel chromatography (10%EtOAc/DCM) provides and has been the titled reference compound of white solid (26.2mg, 91%).
1H-NMR (CDCl 3400MHz): δ 11.59 (s, 1H), 9.79 (s, 1H), 8.50 (d, 1H, J=8.6Hz), 7.92 (dd, 1H, J=8.6,2.0Hz), 7.82 (d, 1H, J=2.0Hz), 7.78 (s, 1H), 5.92 (m, 1H), 2.62 (s, 3H), 2.23-2.39 (m, 4H), and 1.77-1.94 (m, 4H). mass spectrum (ESI, m/z): C 19H 18N 4O 2Calculated value, 335.1 (M+H), actual measurement 335.1.
Embodiment 26
4-cyano group-1H-imidazoles-2-carboxylic acid (4-formamyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Figure A200680054994D00691
A) 4-amino-3-bromo-benzamide
Figure A200680054994D00692
Under 0 ℃, (1.00g is 7.34mmol) at 50mL 1:4CH to 4-amino-benzamide 3Suspension among the CN/DCM is added on 20mL 1:1 CH 3N-bromosuccinimide among the CN/DCM (NBS) (1.31g, 7.34mmol).Mixture is warming up to room temperature and stirs 16h under argon gas.After 100mL EtOAc processing, mixture H 2O (2 x 30mL), salt solution (20mL) washing and dry (Na 2SO 4).The vacuum-evaporation organic solvent, residue grinds with DCM, obtains 1.45g (92%) and is the titled reference compound of faint yellow solid.Mass spectrum (ESI, m/z): C 7H 7BrN 2The O calculated value, 215.0 (M+H), actual measurement 215.1.
B) 4-amino-3-hexamethylene-1-thiazolinyl-benzamide
Figure A200680054994D00701
The Suzuki coupling program preparation of titled reference compound by embodiment 11 steps (e), used 4-amino-3-bromo-benzamide (in step preparation before, 500mg, 2.32mmol) and hexanaphthene-1-ene boric acid (322mg, 2.56mmol).Purifying obtains the titled reference compound (382mg, 76%) into yellow solid to mixture by grinding with DCM.Mass spectrum (ESI, m/z): C 13H 16N 2The O calculated value, 217.1 (M+H), actual measurement 217.2.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-formamyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
Titled reference compound is by the program preparation of embodiment 11 steps (f), used 4-amino-3-hexamethylene-1-thiazolinyl-benzamide (in step preparation before, 100mg, 0.462mmol) and (preparation in embodiment 11 steps (d) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium, 155mg, 0.509mmol).Silica gel chromatography (1-2% MeOH/DCM) provides and has been the titled reference compound of white solid (210mg, 98%).Mass spectrum (ESI, m/z): C 24H 31N 5O 3The Si calculated value, 466.2 (M+H), actual measurement 466.1.
D) 4-cyano group-1H-imidazoles-2-carboxylic acid (4-formamyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-formamyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides (in the preparation of step before, 200mg, 0.430mmol) solution in 6mL DCM adds 2mL TFA.Behind stirring at room 3h, mixture is handled and vacuum concentration with the 20mL n-propyl alcohol.Residue obtains 88.0mg (61%) and is the titled reference compound of white solid by flash chromatography on silica gel (4-6% MeOH/DCM) purifying.
1H-NMR (CD 3OD; 400MHz): δ 8.41 (d, 1H, J=8.6Hz), 8.03 (s, 1H), 7.81 (dd, 1H, J=8.6,2.3Hz), 7.74 (d, 1H, J=2.3Hz), 5.89 (m, 1H), 2.20-2.38 (m, 4H), 1.71-1.95 (m, 4H). mass spectrum (ESI, m/z): C 18H 17N 5O 2Calculated value, 336.1 (M+H), actual measurement 336.1.
Embodiment 27
4-cyano group-1H-imidazoles-2-carboxylic acid [4-formamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00711
A) 4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzamide
Figure A200680054994D00712
Titled reference compound is by the Suzuki coupling program preparation of embodiment 11 steps (e), used (the preparation in embodiment 16 steps (a) of 4-amino-3-bromo-benzamide, 62.4mg, 0.289mmol) and 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4,4,5,5-tetramethyl--[1,3,2] the dioxane pentaborane (75.0mg, 0.318mmol).Silica gel chromatography (0-2% MeOH/DCM) provides and has been the titled reference compound of faint yellow solid (55mg, 78%).Mass spectrum (ESI, m/z): C 15H 20N 2The O calculated value, 245.2 (M+H), actual measurement 245.2.
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-formamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00721
Titled reference compound is by the program preparation of embodiment 11 steps (f), used 4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzamide is (in the preparation of step before, 51.0mg, 0.209mmol) and (preparation in embodiment 11 steps (d) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium, 70.2mg, 0.230mmol).Silica gel chromatography (0-2% MeOH/DCM) provides and has been the titled reference compound of white solid (91mg, 94%).Mass spectrum (ESI, m/z): C 26H 35N 5O 3The Si calculated value, 494.3 (M+H), actual measurement 494.1.
C) 4-cyano group-1H-imidazoles-2-carboxylic acid [4-formamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Titled reference compound is by the program preparation of embodiment 24 steps (b); used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-formamyl-2-(4; 4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides is (in the preparation of step before; 100mg; 0.203mmol) and tetrabutyl ammonium fluoride (1.01mL; 1.01mmol 1.0M is in THF).Silica gel chromatography (5%MeOH/DCM) provides and has been the titled reference compound of white solid (14.1mg, 19%).
1H-NMR (CD 3OD; 400MHz): δ 8.42 (d, 1H, J=8.6Hz), 8.00 (s, 1H), 7.81 (dd, 1H, J=8.6,2.3Hz), 7.75 (d, 1H, J=2.3Hz), 5.81 (m, 1H), 2.28-2.40 (m, 2H), 2.04-2.17 (m, 2H), 1.63 (t, 2H, J=6.3Hz), 1.11 (s, 6H). mass spectrum (ESI, m/z): C 20H 21N 5O 2Calculated value, 364.2 (M+H), actual measurement 364.1.
Embodiment 28
4-cyano group-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides, trifluoroacetate
Figure A200680054994D00731
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides
To (the preparation in embodiment 11 steps (f) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides, 30mg, 0.060mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-and aniline (14.4mg, 0.066mmol) and Pd (PPh 3) 4(7mg, 0.006mmol) at 1mL1, the mixture in the 4-diox adds 2.0M Na 2CO 3The aqueous solution (0.24mL, 0.48mmol).The mixture that obtains is 80 ℃ of stirring 3h under argon gas, are cooled to room temperature then.After 50mL EtOAc processing, mixture H 2O (2 x 20mL), salt solution (10mL) washing and dry (Na 2SO 4).Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (20% EtOAc/ hexane) to residue subsequently, obtains 16mg (85%) and is the titled reference compound of white solid.
1H-NMR (CDCl 3400MHz): δ 9.76 (s, 1H), 8.37 (d, 1H, J=8.6Hz), 7.78 (s, 1H), 7.43-7.47 (m, 3H), 7.35 (d, 1H, J=2.1Hz), 6.84 (d, 2H, J=8.5Hz), 5.97 (s, 2H), 5.89 (m, 1H), 3.67 (t, 2H, J=8.2Hz), 2.25-2.34 (m, 4H), 1.77-1.90 (m, 4H), 0.98 (t, 2H, J=8.2Hz), 0.01 (s, 9H). mass spectrum (ESI, m/z): C 29H 35N 5O 2Si, calculated value, 514.3 (M+H), actual measurement 514.1.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides, trifluoroacetate
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides (in step preparation before, 25mg, 0.049mmol) solution in 1.5mL DCM adds 0.050mL EtOH, adds 0.50mL TFA subsequently.The solution that obtains is at stirring at room 3h.Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (3-5% MeOH/DCM) to residue subsequently, obtains 17.2mg (71%) and is the titled reference compound of yellow solid.
1H-NMR (1:1CDCl 3/ CD 3OD; 400MHz): δ 8.38 (d, 1H, J=8.4Hz), 7.84 (s, 1H), 7.63 (d, 2H, J=8.6Hz), 7.50 (dd, 1H, J=8.4,2.3Hz), 7.40 (d, 1H, J=2.3Hz), 7.24 (d, 2H, J=8.6Hz), 5.92 (m, 1H), 2.27-2.37 (m, 4H), and 1.79-1.92 (m, 4H). mass spectrum (ESI, m/z): C 23H 21N 5The O calculated value, 384.2 (M+H), actual measurement 384.1.
Embodiment 29
4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-sulfonyl methane amino-biphenyl-4-yl)-acid amides
Figure A200680054994D00741
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-sulfonyl methane amino-biphenyl-4-yl)-acid amides
To (the preparation in embodiment 28 steps (a) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides, 28.1mg, 0.0547mmol) mixture in 0.5mL DCM adds pyridine (13 μ L, 0.16mmol), add subsequently methane sulfonyl chloride (5.1 μ L, 0.066mmol).Under the argon gas behind the stirring at room 16h, the mixture concentrating under reduced pressure.Residue obtains 31mg (95%) and is the titled reference compound of white solid by flash chromatography on silica gel (2-4% EtOAc/DCM) purifying.
1H-NMR (CDCl 3400MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.6Hz), 7.79 (s, 1H), 7.58 (d, 2H, J=8.6Hz), 7.48 (dd, 1H, J=8.6,2.3Hz), 7.37 (s, 1H), 7.29 (d, 2H, J=8.6Hz), 6.64 (s, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.68 (t, 2H, J=8.2Hz), 3.05 (s, 3H), 2.24-2.38 (m, 4H), 1.75-1.93 (m, 4H), 0.99 (t, 2H, J=8.2Hz), 0.01 (s, 9H). mass spectrum (ESI, m/z): C 30H 37N 5O 4The SSi calculated value, 592.2 (M+H), actual measurement 591.6.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-sulfonyl methane amino-biphenyl-4-yl)-acid amides
Titled reference compound is by the program preparation of embodiment 11 steps (g), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-sulfonyl methane amino-biphenyl-4-yl)-acid amides (in step preparation before, 29.5mg, 0.0498mmol).Silica gel chromatography (5-10% EtOAc/DCM) provides and has been the titled reference compound of white solid (10.1mg, 44%).
1H-NMR (CD 3OD; 400MHz): δ 8.29 (d, 1H, J=8.6Hz), 8.01 (s, 1H), 7.60 (d, 2H, J=8.6Hz), 7.53 (dd, 1H, J=8.4,2.0Hz), 7.42 (d, 1H, J=2.0Hz), 7.33 (d, 2H, J=8.6Hz), 5.89 (m, 1H), 2.98 (s, 3H), 2.23-2.38 (m, 4H), and 1.77-1.93 (m, 4H). mass spectrum (ESI, m/z): C 24H 23N 5O 3The S calculated value, 462.2 (M+H), actual measurement 461.9.
Embodiment 30
4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides
Figure A200680054994D00761
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides
Titled reference compound is by the program preparation of embodiment 28 steps (a), used (the preparation in embodiment 11 steps (f) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides, 19mg, 0.038mmol) and phenyl-boron dihydroxide (5.1mg, 0.042mmol).Silica gel chromatography (5-10% EtOAc/ hexane) provides and has been the titled reference compound of white solid (16mg, 85%).
1H-NMR (CDCl 3400MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.5Hz), 7.78 (s, 1H), 7.59 (m, 2H), 7.52 (dd, 1H, J=8.5,2.1Hz), 7.44 (m, 2H), 7.41 (d, 1H, J=2.1Hz), 7.33 (m, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.67 (t, 2H, J=8.3Hz), 2.26-2.36 (m, 4H), 1.75-1.93 (m, 4H), 0.98 (t, 2H, J=8.3Hz), 0.01 (s, 9H). mass spectrum (ESI, m/z): C 29H 34N 4O 2The Si calculated value, 499.3 (M+H), actual measurement 498.8.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides
Titled reference compound is by the program preparation of embodiment 11 steps (g), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides (in step preparation before, 16mg, 0.032mmol).Silica gel chromatography (2-3%EtOAc/DCM) provides and has been the titled reference compound of white solid (7.1mg, 60%).
1H-NMR (1:1CDCl 3/ CD 3OD; 400MHz): δ 8.36 (d, 1H, J=8.6Hz), 7.88 (s, 1H), and 7.59-7.62 (m, 2H), 7.54 (dd, 1H, J=8.6,2.3Hz), 7.42-7.46 (m, 3H), 7.34 (m, 1H), 5.92 (m, 1H), and 2.29-2.37 (m, 4H), 1.79-1.94 (m, 4H). mass spectrum (ESI, m/z): C 23H 20N 4The O calculated value, 369.2 (M+H), actual measurement 369.1.
Embodiment 31
4-cyano group-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00771
A) 1-[4-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-3-nitro-phenyl]-ethyl ketone
Figure A200680054994D00772
The Suzuki coupling program preparation of titled reference compound by embodiment 11 steps (e), used 1-(4-bromo-3-nitro-phenyl)-ethyl ketone (347mg, 1.42mmol) and 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid (254mg, 1.65mmol).Silica gel chromatography (5-15% EtOAc/ hexane) provides and has been the titled reference compound of light green oil (385mg, 99%).Mass spectrum (APCI, m/z): C 16H 19NO 3Calculated value, 274.1 (M+H), actual measurement 274.0.
B) 1-[3-amino-4-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-ethyl ketone
Figure A200680054994D00781
1-[4-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-3-nitro-phenyl has been used in the program preparation of titled reference compound by embodiment 19]-ethyl ketone (in step preparation before, 382mg, 1.40mmol), iron powder (391mg, 7.00mmol) and NH 4Cl (749mg, 14.0mmol).Silica gel chromatography (5-20%EtOAc/ hexane) provides and has been the titled reference compound of faint yellow solid (263mg, 77%).Mass spectrum (ESI, m/z): C 16H 21The NO calculated value, 244.2 (M+H), actual measurement 244.2.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00782
Titled reference compound is by the program preparation of embodiment 11 steps (f), used 1-[3-amino-4-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-ethyl ketone is (in the preparation of step before, 243mg, 1.00mmol) and (preparation in embodiment 11 steps (d) of 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium, 321mg, 1.05mmol).Silica gel chromatography (5-15%EtOAc/ hexane) provides and has been the titled reference compound of white solid (415mg, 84%).Mass spectrum (ESI, m/z): C 27H 36N 4O 3The Si calculated value, 493.3 (M+H), actual measurement 493.0.
D) 4-cyano group-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Titled reference compound is by the program preparation of embodiment 11 steps (g); used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4; 4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides is (in the preparation of step before; 200mg, 0.406mmol).Silica gel chromatography (5-15%EtOAc/DCM) provides and has been the titled reference compound of white solid (134mg, 91%).
1H-NMR (CDCl 3400MHz): δ 12.85 (s, 1H), 9.75 (s, 1H), 9.13 (d, 1H, J=1.8Hz), 8.18 (d, 1H, J=2.5Hz), 7.75 (dd, 1H, J=8.1,1.8Hz), 7.32 (d, 1H, J=8.1Hz), 5.86 (m, 1H), 2.67 (s, 3H), 2.28-2.35 (m, 2H), 2.08-2.19 (m, 2H), 1.62 (t, 2H, J=6.3Hz), 1.13 (s, 6H). mass spectrum (ESI, m/z): C 21H 22N 4O 2Calculated value, 363.2 (M+H), actual measurement 363.2.
Embodiment 32
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-5-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides
Figure A200680054994D00791
Under argon gas-78 ℃; to 4-cyano group-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4; 4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides (preparation in embodiment 31 steps (d); 30.0mg; 0.0828mmol) solution in 2mL THF adds methylmagnesium-chloride (58 μ L; 0.17mmol 3.0M is in THF).The mixture heating up that obtains is to room temperature and stir 0.5h.With the saturated NH of 10mL 4The Cl aqueous solution, subsequently use the 10mL brine treatment after, mixture extracts with EtOAc (2x 20mL).The organic layer that merges is through Na 2SO 4Dry.The solvent vapourisation under reduced pressure, residue obtains 29.0mg (93%) and is the titled reference compound of white solid by flash chromatography on silica gel purifying (2-3% MeOH/DCM).
1H-NMR (DMSO-d6; 400MHz): δ 14.22 (s, 1H), 9.76 (s, 1H), 8.32 (s, 1H), 8.12 (d, 1H, J=1.8Hz), 7.25 (dd, 1H, J=8.1,1.8Hz), 7.14 (d, 1H, J=8.1Hz), 5.65 (m, 1H), 2.16-2.29 (m, 2H), 1.87-1.98 (m, 2H), 1.47 (t, 2H, J=6.2Hz), 1.43 (s, 6H), 0.99 (s, 6H). mass spectrum (ESI, m/z): C 22H 26N 4O 2Calculated value, 379.2 (M+H), actual measurement 379.0.
Embodiment 33
4-cyano group-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00801
A) 4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-aniline
Figure A200680054994D00802
4-bromo-2-iodo-aniline (873mg, 2.93mmol), 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid (496mg, 3.22mmol), Pd (PPh 3) 4(169mg is 0.147mmol) with 2.0M Na 2CO 3(11.7mL, 23.4mmol) at 20mL1, the mixture in the 4-diox is 80 ℃ of stirring 12h under argon gas for the aqueous solution.After being cooled to room temperature, reactant is handled with EtOAc (50mL), and uses H 2O (25mL) and salt solution (20mL) washing.Organic layer drying (Na 2SO 4) and vacuum concentration.Residue obtains 770mg (91%) and is the titled reference compound of water white oil by flash chromatography on silica gel (5% EtOAc/ hexane) purifying.Mass spectrum (ESI, m/z): C 14H 18The BrN calculated value, 280.1 (M+H), actual measurement 280.1.
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00811
To 4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-aniline is (in the preparation of step before, 770mg, 2.75mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (preparation in embodiment 11 steps (d), 840mg, 2.75mmol) and PyBroP (1.28g, 2.75mmol) mixture in 20mL DMF add DIEA (1.44mL, 8.25mmol).The mixture that obtains is stirring at room 16h under argon gas.After 80mL EtOAc processing, mixture H 2O (2 x 20mL), salt solution (20mL) are handled and dry (Na 2SO 4).Removal of solvent under reduced pressure is carried out flash chromatography on silica gel (5-10% EtOAc/ hexane) to residue subsequently, obtains 1.28g (88%) and is the titled reference compound of white solid.Mass spectrum (ESI, m/z): C 25H 33BrN 4O 2The Si calculated value, 529.2 (M+H), actual measurement 528.9.
C) 4-cyano group-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Titled reference compound is by the experimental arrangement preparation of embodiment 11 steps (g), used 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides is (in the preparation of step before, 350mg, 0.661mmol).Titled reference compound (253mg, 96%) obtains to be white solid.
1H-NMR (CDCl 3400MHz): δ 8.19 (d, 2H, J=8.8Hz), 7.50 (d, 2H, J=8.8Hz), 6.23 (m, 1H), 4.12 (m, 2H), 3.66 (m, 2H), 2.54 (m, 2H), 1.49 (s, 9H). mass spectrum (ESI, m/z): C 19H 19BrN 4The O calculated value, 399.1 (M+H), actual measurement 399.1.
Embodiment 34
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides
Figure A200680054994D00821
The experimental arrangement preparation of titled reference compound by embodiment 12, used 4-cyano group-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides (in step preparation before, 200mg, 0.501mmol).Flash chromatography on silica gel (1-4% MeOH/DCM) provides and has been the titled reference compound of white solid (101mg, 53%).
1H-NMR (CDCl 3400MHz): δ 12.52 (s, 1H), 9.68 (s, 1H), 8.29 (d, 1H, J=8.6Hz), 7.72 (d, 1H, J=2.3Hz), 7.42 (dd, 1H, J=8.6,2.2Hz), 7.35 (d, 1H, J=2.2Hz), 5.78 (m, 1H), 2.64 (s, 1H, OH), 2.30 (m, 2H), 2.11 (m, 2H), 1.62 (s, 6H), 1.59 (t, 2H, J=6.5Hz), 1.11 (s, 6H). mass spectrum (ESI, m/z): C 22H 26N 4O 2Calculated value, 379.2 (M+H), actual measurement 379.3.
Embodiment 35
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group)-phenyl]-acid amides
Under-40 ℃, to 4-cyano group-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides (preparation in embodiment 11 steps (g)) (0.10g, 0.27mmol) solution in 1.5mLTHF adds 0.15mL i-PrMgCl (0.30mmol, the solution of 2M in THF), stirred solution 15 minutes under this temperature.Then mixture is cooled to-78 ℃, adds 2,2-dimethyl-oxyethane (0.12mL, 1.3mmol), add subsequently the boron trifluoride etherate (0.044mL, 0.35mmol) and tert-butyl lithium (0.41mL, 0.69mmol, the 1.7M solution in pentane).-78 ℃ are stirred after 30 minutes the saturated NH of mixture 4Cl (10mL) quencher is extracted with EtOAc (2x 10mL), and organic layer is through Na 2SO 4Dry and concentrated.Use the 50%EtOAc/ hexane from 20-g SPE post wash-out titled reference compound, obtain 0.015g (15%) white solid:
1H-NMR (DMSO-d6,400MHz): δ 14.25 (s, 1H), 9.71 (s, 1H), 8.33 (s, 1H), 7.84 (d, J=8.2Hz, 1H), 7.14 (dd, J=8.2,1.9Hz, 1H), 7.06 (d, J=1.9Hz, 1H), 5.74 (s, 1H), 4.63 (t, J=5.2Hz, 1H), 3.61 (m, 2H), 2.70 (t, J=7.0Hz, 2H), 2.23-2.11 (m, 4H), 1.76-1.62 (m, 4H). mass spectrum (ESI, m/z): C 21H 24N 4O 2Calculated value, 365.2 (M+H), actual measurement 365.1.
Embodiment 36
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfonyl methane-phenyl]-acid amides
Figure A200680054994D00831
A) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-methyl sulphur alkyl-phenyl]-acid amides
Titled reference compound has used dimethyl disulphide as electrophilic reagent according to the general procedure preparation of embodiment 12.Mass spectrum (ESI, m/z): C 20H 22N 4The OS calculated value, 367.1 (M+H), actual measurement 367.0.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfonyl methane-phenyl]-acid amides
To 4-cyano group-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-4-methyl sulphur alkyl-phenyl]-acid amides (30mg, 0.082mmol) solution in 2mL DCM add the m-chloro-peroxy benzoic acid (77%, 55mg, 0.25mmol), mixture is at stirring at room 3h.Reactant dilutes with 15mL EtOAc, and uses NaHCO 3The washing of (2 x 15mL) and salt solution (15mL) is through Na 2SO 4Dry and concentrated.Titled reference compound from 5-g SPE post wash-out purifying, obtains 23mg (70%) white solid with the 50%EtOAc/ hexane.
1H NMR (CDCl 3, 400MHz): δ 11.18 (br s, 1H), 9.70 (br s, 1H), 8.62 (d, J=8.7Hz, 1H), 7.88 (dd, J=2.2,8.7Hz, 1H), 7.77 (d, J=2.2Hz, 1H), 7.76 (s, 1H), 5.86 (m, 1H), 3.10 (s, 3H), 2.32 (m, 2H), 2.12 (m, 2H), 1.62 (m, 2H), 1.12 (s, 6H). mass spectrum (ESI, m/z): C 20H 22N 4O 3The S calculated value, 399.1 (M+H), actual measurement 399.0.
Embodiment 37
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxyl-ethyl)-phenyl]-acid amides
Figure A200680054994D00841
A) 2-(4-amino-3-bromo-phenyl)-ethanol
Figure A200680054994D00842
(5.10g, 37.2mmol) (6.60g, 37.1mmol), mixture is in stirred overnight at room temperature for the interpolation of the solution in 37mL DMF NBS to 2-(4-amino-phenyl)-ethanol.Reactant dilutes with 100mL water, and extracts with EtOAc (3 x 100mL).Organic layer is with salt solution (200mL) washing and through Na 2SO 4Dry.Titled reference compound with 50%EtOAc/ hexane wash-out, obtains 5.10g (64%) white solid by the flash chromatography on silica gel purifying.Mass spectrum (ESI, m/z): C 8H 10The BrNO calculated value, 216.0 (M+H), actual measurement 216.1.
B) 2-(4-amino-3-hexamethylene-1-thiazolinyl-phenyl)-ethanol
Figure A200680054994D00851
Titled reference compound prepares by 2-(4-amino-phenyl)-ethanol (preparing in the step before) and the Suzuki coupling of 1-tetrahydrobenzene-1-base-boric acid according to the program of embodiment 44 steps (b).Mass spectrum (ESI, m/z): C 14H 19The NO calculated value, 218.1 (M+H), actual measurement 218.1.
C) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxyl-ethyl)-phenyl]-acid amides
Titled reference compound, carries out the SEM deprotection according to the program of embodiment 11 steps (g) subsequently and prepares by coupling 2-(4-amino-3-hexamethylene-1-thiazolinyl-phenyl)-ethanol (preparing in the step before) and 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) according to the program of embodiment 42 steps (c).
1H-NMR (CD 3OD, 400MHz): δ 8.10 (d, J=8.3Hz, 1H), 8.02 (s, 1H), 7.17 (dd, J=8.3,1.9Hz, 1H), 7.08 (d, J=1.9Hz, 1H), 5.82 (s, 1H), 3.77 (t, J=7.0Hz, 2H), 2.82 (t, J=7.0Hz, 2H), 2.31-2.25 (m, 4H), and 1.90-1.76 (m, 4H). mass spectrum (ESI, m/z): C 19H 20N 4O 2Calculated value, 337.2 (M+H), actual measurement 337.1
Embodiment 38
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides
Figure A200680054994D00852
This compound is according to the preparation of the program among the embodiment 37, and with 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid substitutes 1-tetrahydrobenzene-1-base-boric acid in step (b).
1H-NMR (CDCl 3.400MHz): δ 12.62 (s, 1H), 9.65 (s, 1H), 8.26 (d, J=8.3Hz, 1H), 7.68 (s, 1H), 7.19 (dd, J=8.3,1.8Hz, 1H), 7.07 (d, J=1.8Hz, 1H), 5.75 (s, 1H), 3.92 (t, J=6.4Hz, 2H), 2.88 (t, J=6.4Hz, 2H), 2.30-2.23 (m, 2H), 2.11-2.06 (m, 2H), 1.57 (t, J=6.3Hz, 2H), 1.09 (s, 6H). mass spectrum (ESI, m/z): C 21H 24N 4O 2Calculated value, 365.2 (M+H), actual measurement 365.0.
Embodiment 39
5-cyano group-1H-imidazoles-2-carboxylic acid (6-hexamethylene-1-thiazolinyl-benzo [1,3] dioxole-5-yl)-acid amides
Figure A200680054994D00861
A) 6-hexamethylene-1-thiazolinyl-benzo [1,3] dioxole-5-base amine
Figure A200680054994D00862
Titled reference compound is according to the program of embodiment 44 steps (g), by Suzuki coupling 6-bromo-benzo [1,3] dioxole-5-base amine (Bioorganic ﹠amp; Medicinal Chemistry (2002), 10 (11), 3395-3400) and tetrahydrobenzene-1-ylboronic acid and preparing.Mass spectrum (ESI, m/z): C 13H 15NO 2Calculate 218.1 (M+H), actual measurement 218.1.
B) 5-cyano group-1H-imidazoles-2-carboxylic acid (6-hexamethylene-1-thiazolinyl-benzo [1,3] dioxole-5-yl)-acid amides
Titled reference compound passes through according to the program coupling 6-hexamethylene-1-thiazolinyl-benzo [1 in embodiment 42 steps (c); 3] dioxole-5-base amine (preparing in the step before) and 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) carry out the SEM deprotection according to the program in embodiment 11 steps (g) subsequently and prepare.
1H-NMR (DMSO-d 6, 400MHz): δ 14.23 (s, 1H), 9.67 (s, 1H), 8.31 (s, 1H), 7.48 (s, 1H), 6.78 (s, 1H), 6.01 (s, 2H), 5.69 (s, 1H), 2.20-2.05 (m, 4H), 1.71-1.57 (m, 4H). mass spectrum (ESI, m/z): C 18H 16N 4O 3Calculated value, 337.1 (M+H), actual measurement 337.0.
Embodiment 40
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(3-methyl-3H-imidazol-4 yl)-phenyl]-acid amides trifluoroacetate
Figure A200680054994D00871
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-phenyl]-acid amides
Figure A200680054994D00872
Titled reference compound is by preparing according to the program coupling 2-amino-benzene boric acid pinacol ester in embodiment 32 steps (c) and 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)).Mass spectrum (ESI, m/z): C 23H 33BN 4O 4The Si calculated value, 469.2 (M+H), actual measurement 468.9.
B) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(3-methyl-3H-imidazol-4 yl)-phenyl]-acid amides trifluoroacetate
Titled reference compound by according in embodiment 44 steps (b) program Suzuki coupling 4-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid; 4; 5; 5-tetramethyl--[1; 3; 2] dioxane pentaborane-2-yl)-phenyl]-acid amides (preparing in the step before) and 5-iodo-1-methyl isophthalic acid H-imidazoles, prepare according to the program SEM deprotection in embodiment 11 steps (g) subsequently.
1H-NMR (DMSO-d 6, 400MHz): δ 14.20 (s, 1H), 10.44 (s, 1H), 9.09 (s, 1H), 8.32 (s, 1H), 7.76 (d, J=7.6Hz, 1H), 7.64 (d, J=1.3Hz, 1H), 7.63-7.55 (m, 2H), 7.44 (m, 1H), 3.69 (s, 3H). mass spectrum (ESI, m/z): C 15H 12N 6The O calculated value, 293.1 (M+H), actual measurement 293.0.
Embodiment 41
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides trifluoroacetate
Figure A200680054994D00881
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides
Figure A200680054994D00882
1.00g (7.09mmol) DMF (5mL) solution of 1-fluoro-2-nitro-benzene is handled with 2.52mL (21.3mmol) 4-methyl-piperidines, and is heated to 60 ℃ and continues 15 minutes.Mixture washs with EtOAc (50mL) dilution and water (6 x 30mL).Organic layer drying (MgSO 4) and vacuum concentration.250mg (1.14mmol) part residue is absorbed into THF (5mL) and uses 15mg 10% Pd/C (Degussa model E101-NE/W, Aldrich, the water of 50% weight) at H 2(1 atm) handles down.When this reaction finished, mixture was gone into 24.5mg (0.147mmol) PyBroP, 30.0mg (0.0980mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) and the suspension of 51.0 μ L (0.295mmol) DIEA in THF (5mL) through the diatomite direct filtration.Mixture is with argon cleaning and at stirring at room 16h.Add extra 24.5mg (0.147mmol) PyBroP, 30.0mg (0.0980mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) and 51.0 μ L (0.295mmol) DIEA, mixture stirs 2h.Mixture dilutes with EtOAc (10mL), water (1 x 10mL) and saturated NaHCO 3The aqueous solution (1 x 10mL) washing, dry (MgSO 4) and vacuum concentration be the titled reference compound of white solid so that 153mg (30%) to be provided: mass spectrum (ESI, m/z): C 23H 33N 5The Si calculated value, 440.2 (M+H), actual measurement 440.0.
B) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides trifluoroacetate
153mg (0.348mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides (in step preparation before) is at CH 2Cl 2Solution (5mL) is handled with EtOH (1) and TFA (1mL), mixture heating up to 40 ℃ lasting 2h and room temperature maintenance 2 days.Mixture is concentrated into drying, is absorbed into CH 2Cl 2(5mL), use EtOH (1) and TFA (1.00mL) at room temperature treatment 7h.Mixture is by vacuum concentration.Residue is absorbed into MeOH (2.5mL) and 10% acetonitrile solution (7.5mL) to form suspension.Solid is the titled reference compound of white solid with the acetone grinding of minimum so that 50.7mg (34%) to be provided also after filtration:
1H-NMR (CD 3OD; 400MHz): δ 8.35-8.32 (m, 1H), 8.03 (s, 1H), 7.29-7.26 (m, 1H), 7.15-7.12 (m, 2H), 3.09-2.99 (m, 2H), 2.81-2.74 (m, 2H), and 1.85-1.80 (m, 2H), 1.72-1.56 (m, 3H), 1.09 (d, 3H, J=6.0Hz). mass spectrum (ESI, m/z): C 17H 19N 5The O calculated value, 310.2 (M+H), actual measurement 310.0.
Embodiment 42
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides trifluoroacetate
Figure A200680054994D00901
A) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-3-nitro-pyridine
894mg (3.78mmol) 4,4-dimethyl-hexamethylene-1-ene boric acid and 0.500g (3.15mmol) the 2-chloro-3-nitro-pyridine solution in toluene (20mL) and EtOH (10mL) 12.6mL (25.2mmol) 2.0M Na 2CO 3The aqueous solution is handled.Mixture places under the argon gas through ultrasonic degasification, with 364mg (0.315mmol) Pd (PPh 3) 4Handle, and be heated to 80 ℃ of lasting 2h.Mixture is cooled to room temperature, with EtOAc (50mL) dilution, and uses saturated NaHCO 3The aqueous solution (1 x 40mL) and water (1 x 40mL) washing.Water layer extracts with EtOAc (40mL), the organic layer of the merging (MgSO that is dried 4) and vacuum concentration.Use CH 2Cl 2Provide 446mg (61%) to be the titled reference compound of yellow solid to the residue silica gel chromatography:
1?H-NMR(CDCl 3；400MHz)：δ?8.73(dd，1H，J＝4.8，1.6Hz)，8.02(dd，1H，J＝8.4，1.6Hz)，7.32(m，1H)，5.83(sept，1H，J＝2.0Hz)，2.50-2.44(m，2H)，1.98-1.93(m，2H)，1.56(t，2H，J＝6.0Hz)，1.00(s，6H).
B) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl amine
Figure A200680054994D00903
90.0mg (0.387mmol) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-and the solution of 3-nitro-pyridine (in step preparation before) in EtOH (10mL) and water (5mL) AcOH (3) and the processing of 121mg (2.17mmol) Fe powder, be heated to 70 ℃ of lasting 1.5h then.The saturated NaHCO of mixture 3The aqueous solution (20mL) quencher is also used CH 2Cl 2(3 x 40mL) extracts.Organic layer drying (the MgSO that merges 4) and vacuum concentration be the titled reference compound of amber glass body so that 80.0mg (100%) to be provided: mass spectrum (ESI, m/z): C 13H 18N 2Calculated value, 203.2 (M+H), actual measurement 203.2.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides
Figure A200680054994D00911
80.0mg (0.395mmol) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl amine (in step preparation before) is at CH 2Cl 2Solution (10mL) is handled with 277mg (0.593mmol) PyBroP, 133mg (0.435mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) and 207 μ L (1.19mmol) DIEA.Mixture is used CH at stirring at room 17h 2Cl 2(20mL) dilution and water (1 x 10mL) washing.Water layer CH 2Cl 2(1 x 10mL) extracts, the organic layer drying (MgSO of merging 4) and vacuum concentration.Use 25% EtOAc-hexane on 10-g Isolute SPE post, residue to be carried out silica gel chromatography, provide 95mg (53%) to be the titled reference compound of white solid:
1H-NMR(CDCl 3；400MHz)：δ?9.92(br?s，1H)，8.72(dd，1H，J＝8.0，1.6Hz)，8.37(dd，1H，J＝4.4，1.6Hz)，7.77(s，1H)，7.23-7.18(m，1H)，6.00-5.94(m，1H)，5.93(s，2H)，3.70-3.63(m，2H)，2.51-2.43(m，2H)，2.18-2.11(m，2H)，1.61(t，2H，J＝6.4Hz)，1.12(s，6H)，1.00-0.94(m，2H)，0.00(s，9H).
D) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides trifluoroacetate
95.0mg (0.210mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides (in step preparation before) is at CH 2Cl 2Solution (15mL) is handled with MeOH (1) and TFA (1mL).Mixture is in stirring at room 2 days, solvent vacuum-evaporation.Use 25% EtOAc-hexane on 20-g Isolute SPE post, to carry out silica gel chromatography to residue, and use 0.1% TFA/H 210-80% CH among the O 3CN carries out RP-HPLC (C18), 30 minutes, provides 36.0mg (39%) to be the titled reference compound of white solid:
1H-NMR (CD 3OD; 400MHz): δ 9.02 (dd, 1H, J=8.4,1.6Hz), 8.44 (dd, 1H, J=5.2,1.6Hz), 8.06 (s, 1H), and 7.76-7.71 (m, 1H), 6.22 (sept, 1H, J=2.0Hz), 2.50-2.43 (m, 2H), 2.18-2.13 (m, 2H), 1.65 (t, 2H, J=6.4Hz), 1.11 (s, 6H). mass spectrum (ESI, m/z): C 18H 19N 5The O calculated value, 322.1 (M+H), actual measurement 322.1.
Embodiment 43
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-pyridin-3-yl)-acid amides trifluoroacetate
Figure A200680054994D00921
A) 2-hexamethylene-1-thiazolinyl-3-nitro-pyridine
Figure A200680054994D00922
1.00g (6.31mmol) solution of 2-chloro-3-nitro-pyridine in toluene (50mL) and EtOH (25mL) 1.58g (7.57mmol) 2-hexamethylene-1-thiazolinyl-4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane and 25.2mL (50.4mmol) 2.0M Na 2CO 3The aqueous solution is handled.Mixture places under the argon gas through ultrasonic degasification, with 729mg (0.631mmol) Pd (PPh 3) 4Handle, be heated to 80 ℃ of lasting 16h.Mixture washs with EtOAc (100mL) dilution and water (1 x 75mL).Organic layer drying (MgSO 4) and vacuum concentration.Use CH 2Cl 2On 50-g VarianMegaBond Elut SPE post, residue is carried out silica gel chromatography, provides 497mg (39%) to be the titled reference compound of yellow solid:
1H-NMR(CD 3OD；400MHz)：δ?8.70(dd，1H，J＝5.2，1.6Hz)，8.20(dd，1H，J＝8.4，1.6Hz)，7.51-7.46(m，1H)，5.81(sept，1H，J＝2.4Hz)，2.44-2.37(m，2H)，2.19-2.12(m，2H)，1.84-1.76(m，2H)，1.74-1.66(m，2H).
B) 2-hexamethylene-1-thiazolinyl-pyridin-3-yl amine
Figure A200680054994D00931
497.0mg (2.43mmol) solution of 2-hexamethylene-1-thiazolinyl-3-nitro-pyridine (in step preparation before) in EtOH (10mL) and water (5mL) is handled with AcOH (6) and 679mg (12.2mmol) iron powder, is heated to 75 ℃ of lasting 19h.Mixture washs with EtOAc (30mL) dilution and water (1 x 20mL).Organic layer drying (MgSO 4) and vacuum concentration, provide 365mg (86%) to be the titled reference compound of faint yellow solid: mass spectrum (ESI, m/z): C 11H 14N 2Calculated value, 175.1 (M+H), actual measurement 175.2.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-pyridin-3-yl)-acid amides
Figure A200680054994D00932
365mg (2.10mmol) 2-hexamethylene-1-thiazolinyl-pyridin-3-yl amine (in step preparation before) is at CH 2Cl 2Solution (10mL) is at room temperature handled 3h with 1.46g (3.14mmol) PyBroP, 704mg (2.30mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) and 1.09mL (6.28mmol) DIEA.Mixture CH 2Cl 2(20mL) dilution, and use saturated NaHCO 3The aqueous solution (1 x15mL) washing.Organic layer drying (MgSO 4) and vacuum concentration.Use 1%MeOH-CH 2Cl 2On 50-g Varian MegaBond Elut SPE post, residue is carried out silica gel chromatography, provides 615mg (69%) to be the titled reference compound of white solid:
1H-NMR(CDCl 3；400MHz)：δ?9.86(br?s，1H)，8.69(dd，1H，J＝8.0，1.6Hz)，8.37-8.34(m，1H)，7.78(s，1H)，7.22-7.17(m，1H)，6.05(sept，1H，J＝1.6Hz)，5.93(s，2H)，3.68-3.63(m，2H)，2.45-2.39(m，2H)，2.37-2.30(m，2H)，1.91-1.77(m，4H)，1.00-0.95(m，2H)，0.00(s，9H).
D) 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-pyridin-3-yl)-acid amides trifluoroacetate
615mg (1.45mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-pyridin-3-yl)-acid amides (in step preparation before) is at CH 2Cl 2Solution (12mL) is at room temperature handled 3.5h with MeOH (100 μ L) and TFA (3mL).Add MeOH (5mL), vacuum concentration then to mixture.Use is at 0.1%TFA/H 210-80% CH among the O 3CN carries out RP-HPLC (C18) to residue, 30 minutes, provides 177mg (30%) to be the titled reference compound of white solid:
1H-NMR (CD 3OD; 400MHz): δ 9.03 (dd, 1H, J=8.4,1.6Hz), 8.45 (dd, 1H, J=5.2,1.6Hz), 8.07 (s, 1H), 7.81-7.74 (m, 1H), 6.36-6.29 (m, 1H), and 2.49-2.34 (m, 4H), 1.97-1.79 (m, 4H). mass spectrum (ESI, m/z): C 16H 15N 5The O calculated value, 294.1 (M+H), actual measurement 294.1.
Embodiment 44
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-phenyl]-acid amides
Figure A200680054994D00951
A) 2-bromo-4-(morpholine-4-alkylsulfonyl)-aniline
Figure A200680054994D00952
The solution of 250mg (0.918mmol) 4-(4-nitro-benzenesulfonyl)-morpholine in MeOH (15mL) uses 20mg 10% Pd/C (Degussa model E101-NE/W, Aldrich, 50% weight water) at H 2(1atm) handle down.Mixture is at stirring at room 1.5h, and through diatomite filtration.Filter cake washs with MeOH, the filtrate vacuum concentration.Residue is absorbed into CH 2Cl 2(10mL), be cooled to 0 ℃, and under this temperature, handled 25 minutes with 124mg (0.698mmol) NBS.Mixture CH 2Cl 2(15mL) dilution and with saturated NaHCO 3The aqueous solution (1 x10mL) washing.Organic layer drying (MgSO 4) and vacuum concentration.Use 40-50% EtOAc-hexane on 50-g Varian MegaBond Elut SPE post residue to be carried out silica gel chromatography, it is filbert solid titled reference compound that 50.0mg (17%) is provided: and mass spectrum (ESI, m/z): C 10H 13N 2O 3The SBr calculated value, 321.0 (M+H), actual measurement 320.9/322.8.
B) 2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-aniline
Figure A200680054994D00953
50.0mg (0.156mmol) solution of 2-bromo-4-(morpholine-4-alkylsulfonyl)-aniline (in the preparation of step before) in toluene (4mL) and EtOH (2mL) is with 623 μ L (1.25mmol) 2.0M Na 2CO 3The aqueous solution and 20.6mg (0.163mmol) hexamethylene-1-ene boric acid is handled.Mixture places under the argon gas through ultrasonic degasification, with 12.6mg (0.0109mmol) Pd (PPh 3) 4Handle, and be heated to 80 ℃ of lasting 3.5h.Mixture is cooled to room temperature, stirs 16h, with EtOAc (10mL) dilution, and uses saturated NaHCO 3The aqueous solution (1 x 10mL) and salt solution (1 x 10mL) washing.Organic layer drying (MgSO 4) and vacuum concentration.Use 25-50% EtOAc-hexane on 25-g Varian MegaBond Elut SPE post, residue to be carried out silica gel chromatography, provide 20.0mg (40%) to be the titled reference compound of pale solid: mass spectrum (ESI, m/z): C 16H 22N 2O 3The S calculated value, 323.1 (M+H), actual measurement 323.1.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-phenyl]-acid amides
Figure A200680054994D00961
24.0mg (0.0785mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) is at CH 2Cl 2Suspension was handled 5 minutes with 6.40 μ L (0.0785mmol) pyridines (5mL).Mixture is cooled to 0 ℃, adds 5.70 μ L (0.0785mmol) SOCl 2, be warming up to room temperature subsequently, stirred 30 minutes.20.0mg (0.0620mmol) (12.0 μ L are 0.0854mmol) at CH for 2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-aniline (in step preparation before) and triethylamine 2Cl 2Solution (1mL) is handled with acyl chloride solution, and at stirring at room 7h.Mixture CH 2Cl 2(10mL) dilution and water (1 x 10mL) washing.Organic layer drying (MgSO 4) and vacuum concentration, provide 15.0mg (37%) to be the titled reference compound of brown solid: mass spectrum (ESI, m/z): C 27H 37N 5O 5The SSi calculated value, 572.2 (M+H), actual measurement 572.0.
D) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-phenyl]-acid amides
15.0mg (0.0262mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-phenyl]-acid amides (in step preparation before) is at CH 2Cl 2Solution (5mL) is handled with MeOH (1) and TFA (1mL).Mixture at room temperature stirs 2h, vacuum evaporating solvent.Use is at 0.1%TFA/H 210-80% CH among the O 3CN carries out RP-HPLC (C18) residue is carried out purifying, 30 minutes, provides 3.4mg (29%) to be the titled reference compound of white solid:
1H-NMR (CD 3OD; 400MHz): δ 8.62 (d, 1H, J=8.8Hz), 8.07 (s, 1H), 7.72 (dd, 1H, J=8.8,2.0Hz), 7.57 (d, 1H, J=2.0Hz), 6.01-5.96 (m, 1H), 3.77-3.70 (m, 4H), 3.02-2.95 (m, 4H), 2.40-2.30 (m, 4H), 1.97-1.82 (m, 4H). mass spectrum (ESI, m/z): C 21H 23N 5O 4The S calculated value, 442.2 (M+H), actual measurement 441.9.
Embodiment 45
4-cyano group-1H-imidazoles-2-carboxylic acid [(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfamyl-phenyl]-acid amides
Figure A200680054994D00971
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-tertiary butyl sulfamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D00972
Solution 253mg (1.07mmol) 2-(4 of 300mg (0.976mmol) 4-amino-3-bromo-N-tert.-butylbenzene sulphonamide (preparation in embodiment 48 steps (a)) in toluene (8mL) and EtOH (4mL), 4-dimethyl-hexamethylene-1-thiazolinyl)-4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane and 3.90mL (7.81mmol) 2.0M Na 2CO 3Handle.Mixture places under the argon gas through ultrasonic degasification, with 113mg (0.0976mmol) Pd (PPh 3) 4Handle, and be heated to 80 ℃ of lasting 6h.Mixture washs with EtOAc (30mL) dilution and water (2 x 20mL).Organic layer drying (MgSO 4) and vacuum concentration.Use 1-4% MeOH-CH 2Cl 2On 50-gVarian MegaBond Elut SPE post residue is carried out silica gel chromatography, it is the flint glass shape solid 4-amino-N-tertiary butyl-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzsulfamide that 158mg (48%) is provided.215mg (0.704mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) is at CH 2Cl 2Suspension (10mL) was handled 5 minutes with 60.0 μ L (0.704mmol) pyridines.Then with mixture with 51.4 μ L (0.704mmol) SOCl 2At room temperature handled 30 minutes.158mg (0.0470mmol) 4-amino-N-tertiary butyl-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzsulfamide (before preparing in this step) is at CH 2Cl 2Solution (5mL) is handled with acyl chloride solution, and at room temperature stirs 17h.Mixture CH 2Cl 2(30mL) dilution and use saturated NaHCO 3The aqueous solution (1 x 20mL) washing.Organic layer drying (MgSO 4) and vacuum concentration.Use 1% MeOH-CH 2Cl 2On 50-g Varian MegaBond Elut SPE post, residue is carried out silica gel chromatography, provides 100.0mg (17%) to be the titled reference compound of white solid:
1H-NMR(CDCl 3；400MHz)：δ?9.95(br?s，1H)，8.55(d，1H，J＝8.8Hz)，7.78(dd，1H，J＝8.8，2.4Hz)，7.78(s，1H)，7.69(d，1H，J＝2.4Hz)，5.92(s，2H)，5.84-5.80(m，1H)，4.55(br?s，1H)，3.68-3.62(m，2H)，2.32-2.24(m，2H)，2.14-2.08(m，2H)，1.63-1.56(m，2H)，1.23(s，9H)，1.11(s，6H)，1.00-0.94(m，2H)，0.00(s，9H).
B) 4-cyano group-1H-imidazoles-2-carboxylic acid [(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfamyl-phenyl]-acid amides
100mg (0.171mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-tertiary butyl sulfamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides (in step preparation before) is at CH 2Cl 2Solution (10mL) is at room temperature handled 18h with 62.0 μ LEtOH, 67.0 μ L (0.616mmol) phenylmethylethers and TFA (750 μ L).Add EtOH (3mL), mixture is concentrated, and residue stands above-mentioned condition once more, except using 900 μ LTFA, accepts 1.70mL TFA then for the third time.Solvent vacuum-evaporation.Use is at 0.1% TFA/H 220-100% CH among the O 3CN carries out RP-HPLC (C18) residue is carried out purifying, 30 minutes, provides 27.7mg (41%) to be the titled reference compound of white solid:
1H-NMR(CD 3OD；400MHz)：δ?8.40(d，1H，J＝8.8Hz)，7.92(s，1H)，7.71(dd，1H，J＝8.8，2.4Hz)，7.62(d，1H，J＝2.4Hz)，5.80-5.73(m，1H)，2.30-2.21(m，2H)，2.08-1.99(m，2H)，1.60-1.50(m，2H)，1.02(s，6H).
Embodiment 46
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-sulfamyl-ethyl)-phenyl]-acid amides
Figure A200680054994D00991
A) 2-[4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the ethyl sulfonic acid tert-butylamides
Figure A200680054994D00992
The solution 321mg (1.36mmol) 4 of 380mg (1.13mmol) 2-(4-amino-3-bromo-phenyl)-ethyl sulfonic acid tert-butylamides (preparation in embodiment 47 steps (a)) in toluene (10mL) and EtOH (5mL), 4-dimethyl hexamethylene-1-ene boric acid and 4.53mL (9.06mmol) 2.0M Na 2CO 3The aqueous solution is handled.Mixture places under the argon gas through ultrasonic degasification, with 131mg (0.113mmol) Pd (PPh 3) 4Handle, and be heated to 80 ℃ of lasting 19h.Mixture washs with EtOAc (30mL) dilution and water (1 x 20mL).Organic layer drying (MgSO 4) and vacuum concentration.Use 1% MeOH-CH 2Cl 2On 50-g Varian MegaBond Elut SPE post, residue is carried out silica gel chromatography, obtain 267mg (64%) and be the titled reference compound of pale solid: mass spectrum (ESI, m/z): C 20H 32N 2O 2The S calculated value, 365.2 (M+H), actual measurement 365.2.
B) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-(2-(tertiary butyl sulfamyl)-ethyl)-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D01001
267mg (0.732mmol) 2-[4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-ethyl sulfonic acid tert-butylamides (in the preparation of step before) is at CH 2Cl 2Solution (10mL) is handled with 512mg (1.10mmol) PyBroP, 246mg (0.806mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) and 383 μ L (2.20mmol) DIEA.Mixture at room temperature stirs 3h, uses CH 2Cl 2(20mL) dilution, and use saturated NaHCO 3The aqueous solution (1 x 15mL) washing.Organic layer drying (MgSO 4) and vacuum concentration.Use 25% EtOAc-hexane on 50-g VarianMegaBond Elut SPE post, residue to be carried out silica gel chromatography, provide 311mg (69%) to be the titled reference compound of white solid:
1H-NMR(CDCl 3；400MHz)：δ?9.73(br?s，1H)，8.32(d，1H，J＝8.4Hz)，7.76(s，1H)，7.13(dd，1H，J＝8.4，2.0Hz)，7.02(d，1H，J＝2.0Hz)，5.94(s，2H)，5.77-5.72(m，1H)，4.07(br?s，1H)，3.69-3.62(m，2H)，3.35-3.27(m，2H)，3.14-3.06(m，2H)，2.31-2.23(m，2H)，2.12-2.07(m，2H)，1.58(t，2H，J＝6.4Hz)，1.34(s，9H)，1.10(s，6H)，1.00-0.94(m，2H).
C) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-sulfamyl-ethyl)-phenyl]-acid amides
311mg (0.506mmol) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-(2-tertiary butyl sulfamyl-ethyl)-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides (in step preparation before) is at CH 2Cl 2Solution (6mL) is handled with EtOH (175 μ L), phenylmethylether (80.0uL) and TFA (1.8mL).The 3.5th and 26h add extra TFA (each 0.5mL).Mixture at room temperature stirs common 48h.Add MeOH (3mL), the mixture vacuum concentration, residue is by using at 0.1% TFA/H 220-100% CH among the O 3The RP-HPLC of CN (C18) purifying 30 minutes provides 70.5mg (32%) to be the titled reference compound of white solid:
1H-NMR (CD 3OD; 400MHz): δ 8.17 (d, 1H, J=8.0Hz), 8.01 (s, 1H), 7.21 (dd, 1H, J=8.0,2.0Hz), 7.13 (d, 1H, J=2.0Hz), 5.79-5.73 (m, 1H), 3.40-3.34 (m, 1H), and 3.16-3.07 (m, 2H), 2.37-2.29 (m, 2H), and 2.13-2.07 (m, 2H), 1.65-1.57 (m, 2H), 1.10 (s, 6H). mass spectrum (ESI, m/z): C 21H 25N 5O 3The S calculated value, 428.2 (M+H), actual measurement 428.1.
Embodiment 47
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-sulfamyl-ethyl)-phenyl]-acid amides trifluoroacetate
Figure A200680054994D01011
A) 2-(4-amino-3-bromo-phenyl)-ethyl sulfonic acid tert-butylamides
Figure A200680054994D01012
Under 0 ℃, to tert-BuNH 2(15.6mL, 148mmol) the solution portions in THF (50mL) add 2-(4-nitro-phenyl)-ethyl sulfonyl chloride (WO 2006010079,1.9g, 7.6mmol).The mixture that obtains at room temperature stirs 24h.Vacuum is removed solvent, and residue is absorbed into DCM (50mL) and cold 0.5N HCl (50mL).Separated, the dry (Na of organic layer 2SO 4) and concentrate to obtain 2-(4-nitro-phenyl)-ethyl sulfonic acid tert-butylamides (1.3g, 62%), it need not to be further purified and directly uses.
2-(4-nitro-phenyl)-ethyl sulfonic acid tert-butylamides (in above-mentioned steps, prepare, 633mg, 2.21mmol) under inflation pressure (balloon pressure) in EtOH (20mL) hydrogenation 12h, used 10% Pd/C (100mg).Reaction mixture is through diatomite filtration and concentrated, and to obtain 2-(4-amino-phenyl)-ethyl sulfonic acid tert-butylamides (536mg, 95%), it need not to be further purified and directly uses.
4-[2-(2-methyl-propane-2-alkylsulfonyl)-ethyl]-(prepare in above-mentioned steps, 536mg 2.09mmol) is dissolved in CH to aniline 3CN/DCM (2:1) (10mL) and be cooled to 0 ℃.Portions interpolation NBS (345mg, 1.93mmol).Reaction mixture at room temperature stirred 15 minutes and vacuum concentration.The residue that obtains is absorbed into DCM (20mL) and uses saturated NaHCO 3(10mL) with 10% Na 2S 2O 3(10mL) washing.Organic layer is separated, dry and concentrated to obtain 2-(4-amino-3-bromo-phenyl)-ethyl sulfonic acid tert-butylamides (665mg, 95%).Mass spectrum (ESI, m/z): C 12H 19BrN 2O 2The S calculated value, 335.0,336.0 (M+H), actual measurement 335.2,336.2.
B) 2-(4-amino-3-hexamethylene-1-thiazolinyl-phenyl)-ethyl sulfonic acid tert-butylamides
Figure A200680054994D01021
Titled reference compound uses hexamethylene-1-ene boric acid (117mg according to the Suzuki coupling program of embodiment 44 steps (b), 0.931mmol) and 2-(4-amino-3-bromo-phenyl)-ethyl sulfonic acid tert-butylamides (in the preparation of step before, 250mg, 0.745mmol) preparation, and on silicon-dioxide purifying (20% EtOAc/ hexane) (228mg, 91%).
1H-NMR(CDCl 3；400MHz)：δ?6.87(dd，1H，J＝8.0，2.1Hz)，6.82(d，1H，J＝2.1Hz)，6.64(d，1H，J＝8.0Hz)，5.72(br?s，1H)，4.12(s，1H)，3.82(brs，2H)，3.28(m，2H)，2.96(m，2H)，2.19-2.23(m，4H)，1.62-1.82(m，4H)，1.31(s，9H).
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-(2-tertiary butyl sulfamyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides
Figure A200680054994D01031
Under 0 ℃, (0.746mmol) (66 μ L, 0.81mmol) suspension in DCM (5mL) adds SOCl to pyridine for preparation in embodiment 11 steps (d), 228mg to 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite 2(60 μ L, 0.81mmol).The mixture that obtains is at stirring at room 1h, and under 0 ℃, be transferred to 2-(4-amino-3-hexamethylene-1-thiazolinyl-phenyl)-ethyl sulfonic acid tert-butylamides (in step preparation before, 228mg, 0.670mg) and pyridine (66 μ L, 0.81mmol) mixture in DCM (5mL).The mixture that obtains is in stirred overnight at room temperature.Add water (20mL) then, separated, the dry (Na of organic layer 2SO 4) and concentrate.The residue that obtains on silicon-dioxide purifying (20-50% EtOAc/ hexane) to obtain titled reference compound (271mg, 68%).Mass spectrum (ESI, m/z): C 29H 43N 5O 4The SSi calculated value, 586.2 (M+H), actual measurement 586.0.
D) 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-sulfamyl-ethyl)-phenyl]-acid amides trifluoroacetate
(preparing in the step before to 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-(2-tertiary butyl sulfamyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides; 275mg, 0.470mmol) solution in DCM (5mL) adds EtOH (140 μ L), phenylmethylether (51 μ L) and TFA (1.5mL).The solution that obtains at room temperature stirs 6h.The extra 0.35mL TFA that adds, the mixture that obtains at room temperature stirs and spends the night.Reaction mixture is concentrated, and residue stands RP-HPLC, uses at 0.1%TFA/H 220% to 100%CH among the O 3The CN wash-out, 20 minutes, the C18 post was to provide titled reference compound (26.6mg, 11%).
1H-NMR (DMSO-d6; 400MHz): δ 9.72 (s, 1H), 8.31 (s, 1H), 7.85 (d, 1H, J=8.4Hz), 7.17 (d, 1H, J=8.4Hz), 7.10 (s, 1H), 6.82 (s, 2H), 5.72 (br s, 1H), 3.23 (m, 2H), 2.92 (m, 2H), 2.1-2.29 (m, 4H), 1.62-1.75 (m, 4H); Mass spectrum (ESI, m/z): C 19H 21N 5O 3The S calculated value, 400.1 (M+H), actual measurement 400.1.
Embodiment 48
5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sulfamyl-phenyl)-acid amides trifluoroacetate
Figure A200680054994D01041
A) 4-amino-N-tertiary butyl-3-hexamethylene-1-thiazolinyl-benzsulfamide
Figure A200680054994D01042
To the 4-amino-N-tertiary butyl-benzsulfamide (J.Med.Chem. (2003), 46 (16), 3463-3475,228mg, 1.00mmol) solution in DCM (10mL) add NBS (178mg, 1.00mmol).The mixture that obtains at room temperature stirs 30 minutes, and uses saturated NaHCO 3(10mL) with 10% Na 2S 2O 3The aqueous solution (10mL) washing.Organic layer is separated, dry and concentrated to obtain the 4-amino-3-bromo-N-tertiary butyl-benzsulfamide (163mg, 53%).
4-amino-N-the tertiary butyl-3-hexamethylene-1-thiazolinyl-benzsulfamide uses hexamethylene-1-ene boric acid (63mg according to the Suzuki coupling program of embodiment 44 steps (b), 0.50mmol) and the 4-amino-3-bromo-N-tertiary butyl-benzsulfamide (123mg, 0.400mmol, as above preparation) preparation, to obtain the 4-amino-N-tertiary butyl-3-hexamethylene-1-thiazolinyl-benzsulfamide (87mg, 70%) in silicon-dioxide purifying (30% EtOAc/ hexane) back.Mass spectrum (ESI, m/z): C 16H 24N 2O 2The S calculated value, 309.1 (M+H), actual measurement 309.1.
B) 5-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-methyl-propane-2-sulfuryl amino)-phenyl]-acid amides
Figure A200680054994D01051
As described in embodiment 47 steps (c), 4-amino-N-tertiary butyl-3-hexamethylene-1-thiazolinyl-benzsulfamide (is being prepared in the step before, 276mg, 0.896mmol) (in embodiment 11 steps (d), prepare 328mg with 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite, 0.896mmol) coupling, behind silicon-dioxide purifying (20-50% EtOAc/ hexane), provide titled reference compound (319mg, 64%).
1H-NMR(CDCl 3；400MHz)：δ?9.92(s，1H)，8.51(d，1H，J＝8.6Hz)，7.8(s，1H)，7.78(dd，1H，J＝8.6，2.2Hz)，7.7(d，1H，J＝2.2Hz)，5.92(s，2H)，5.89(br?s，1H)，4.85(br?s，1H)，3.63(m，2H)，2.18-2.39(m，4H)，1.87-1.91(m，4H)，1.22(s，9H)，0.94(m，2H)，0.01(s，9H).\
C) 5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sulfamyl-phenyl)-acid amides trifluoroacetate
(preparing in the step before to 5-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-methyl-propane-2-sulfuryl amino)-phenyl]-acid amides; 319mg, 0.572mmol) solution in DCM (5mL) adds EtOH (170 μ L), phenylmethylether (65 μ L) and TFA (1.8mL).The solution that obtains at room temperature stirs 6h.Add extra 0.45mL TFA, the mixture that obtains at room temperature stirs and spends the night.Reaction mixture is concentrated, and residue stands RP-HPLC, uses at 0.1%TFA/H 220% to 100%CH among the O 3The CN wash-out, 20 minutes, the C18 post was to provide titled reference compound (70mg, 25%).
1H-NMR (DMSO-d6; 400MHz): δ 9.91 (s, 1H), 8.35 (s, 1H), 8.15 (d, 1H, J=8.5Hz), 7.73 (dd, 1H, J=8.5,2.2Hz), 7.63 (d, 1H, J=2.2Hz), 7.3 (s, 2H), 5.83 (brs, 1H), 2.1-2.3 (m, 4H), 1.62-1.73 (m, 4H); Mass spectrum (ESI, m/z): C 17H 17N 5O 3The S calculated value, 372.1 (M+H), actual measurement 372.0.
Embodiment 49
5-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-dimethylamino alkylsulfonyl biphenyl-4-yl)-acid amides
Figure A200680054994D01061
A) 4 '-amino-biphenyl-4-sulfonic acid dimethylformamide
Figure A200680054994D01062
Add 4-bromo-N to round-bottomed flask, N-dimethyl-benzsulfamide (in step preparation before, 539mg, 2.28mmol), 4-aminophenyl boric acid (500mg, 2.28mmol), Pd (OAc) 2(51mg, 0.22mmol), K 3PO 4(967mg, 4.56mmol) and 2-(dicyclohexyl-phosphine)-biphenyl (319mg, 0.910mmol).Packing into to flask, (10mL) is with diox (10mL), and is heated to 90 ℃ under argon gas for toluene.Behind the 5h, reactant vacuum concentration, residue be by 10-g silica gel SPE-column purification, uses DCM, 10% MeOH-DCM wash-out subsequently, obtains 67mg (10%) and be the titled reference compound of brown solid.Mass spectrum (ESI, m/z): C 14H 16N 2O 2The S calculated value, 277.0 (M+H), actual measurement 277.1.
B) 4 '-amino-3 '-bromo-biphenyl-4-sulfonic acid dimethylformamide
Titled reference compound according to the program of embodiment 16 steps (b) from 4 '-amino-biphenyl-4-sulfonic acid dimethylformamide (in step preparation before, 337mg, 1.21mmol) preparation (142mg, 33%).Mass spectrum (ESI, m/z): C 14H 15BrN 2O 2The S calculated value, 355.0 (M+H), actual measurement 354.8.
C) 4 '-amino-3 '-hexamethylene-1-thiazolinyl-biphenyl-4-sulfonic acid dimethylformamide
Figure A200680054994D01072
Titled reference compound according to the program of embodiment 34 steps (b) from 4 '-amino-3 '-bromo-biphenyl-4-sulfonic acid dimethylformamide (in step preparation before, 124mg, 0.340mmol) preparation (64mg, 53%).Mass spectrum (ESI, m/z): C 20H 24N 2O 2The S calculated value, 357.1 (M+H), actual measurement 357.1.
D) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-dimethylamino alkylsulfonyl-biphenyl-4-yl)-acid amides
Figure A200680054994D01073
Titled reference compound according to the program of embodiment 11 steps (f) from 4 '-amino-3 '-hexamethylene-1-thiazolinyl-biphenyl-4-sulfonic acid dimethylformamide is (in step preparation before, 64mg, 0.17mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 60mg, 0.19mmol), PyBroP (117mg, 0.350mmol) and DIEA (69. μ L, 0.39mmol) preparation (84mg, 70%).Mass spectrum (ESI, m/z): C 31H 39N 5O 4The SSi calculated value, 606.2 (M+H), actual measurement 605.9.
E) 5-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-dimethylamino alkylsulfonyl-biphenyl-4-yl)-acid amides
Titled reference compound (is preparing the step from 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-dimethylamino alkylsulfonyl-biphenyl-4-yl)-acid amides before according to the program of embodiment 11 steps (g); 82mg; 0.13mmol) preparation (47mg, 76%).
1H-NMR (DMSO-d 6400MHz): δ 9.82 (s, 1H), 8.35 (d, 1H, J=1.2Hz), 8.18 (m1H), 7.95 (d, 2H, J=8.3Hz), 7.78 (d, 2H, J=7.9Hz), 7.70 (m, 1H), 7.59 (s, 1H), 5.85 (m, 1H), 2.63 (s, 6H), 2.30-2.18 (m, 4H), and 1.77-1.67 (m, 4H). mass spectrum (ESI, m/z): C 25H 25N 5O 3The S calculated value, 476.1 (M+H), actual measurement 476.0.
Embodiment 50
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-phenyl]-acid amides
A) 2-methoxyl group-5-(4-nitro-phenyl)-pyridine
Titled reference compound according to the program of embodiment 44 steps (b) from 4,4,5,5-tetramethyl--2-(4-nitro-phenyl)-[1,3,2] dioxane pentaborane (899mg, 3.60mmol), 5-bromo-2-methoxyl group-pyridine (616mg, 3.28mmol) and Pd (PPh 3) 4(380mg, 0.360mmol) preparation (615mg, 94%).Mass spectrum (ESI, m/z): C 12H 10N 2O 3Calculated value, 231.0 (M+H), actual measurement 231.2.
B) 4-(6-methoxyl group-pyridin-3-yl)-aniline
2-methoxyl group-5-(4-nitro-phenyl)-pyridine (in the preparation of step before, 102mg, 0.443mmol) and the mixture of 5% Pd-C (80mg) at 1atm H 2In 4mL EtOH, stir 4h down, then through diatomite filtration and vacuum concentration, so that 73mg (82%) to be provided titled reference compound.Mass spectrum (ESI, m/z): C 12H 12N 2The O calculated value, 201.0 (M+H), actual measurement 201.3.
C) 2-bromo-4-(6-methoxyl group-pyridin-3-yl)-aniline
Titled reference compound according to the program of embodiment 16 steps (b) from 4-(6-methoxyl group-pyridin-3-yl)-aniline (in step preparation before, 73mg, 0.36mmol) and NBS (65mg 0.36mmol) prepares (20mg, 20%).Mass spectrum (ESI, m/z): C 12H 11BrN 2The O calculated value, 279.0 (M+H), actual measurement 279.2.
D) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-aniline
Figure A200680054994D01101
Titled reference compound according to the program of embodiment 44 steps (b) from 2-bromo-4-(6-methoxyl group-pyridin-3-yl)-aniline (in step preparation before, 20mg, 0.07mmol), 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid (14mg, 0.086mmol), Pd (PPh 3) 4(8.0mg, 0.007mmol) and 2MNa 2CO 3(0.28mL, 0.56mmol) preparation (16mg, 76%).Mass spectrum (ESI, m/z): C 20H 24N 2The O calculated value, 309.1 (M+H), actual measurement 309.2.
E) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-phenyl]-acid amides
Figure A200680054994D01102
Titled reference compound according to the program of embodiment 11 steps (f) from 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-aniline is (in the preparation of step before, 16.4mg, 0.0530mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 23mg, 0.074mmol), PyBroP (40mg, 0.084mmol) and DIEA (23 μ L, 0.13mmol) preparation (20mg, 68%).Mass spectrum (ESI, m/z): C 31H 39N 5O 3The Si calculated value, 558.2 (M+H), actual measurement 558.3.
F) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-phenyl]-acid amides
Figure A200680054994D01111
Titled reference compound according to the program of embodiment 11 steps (g) from 4-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-phenyl]-acid amides is (in the preparation of step before, 20mg, 0.035mmol) preparation (15mg, 100%).
1H-NMR (DMSO-d 6400MHz): δ 9.78 (s, 1H), 8.47 (d, 1H, J=2.3Hz), 8.26 (s, 1H), 8.12 (d, 1H, J=8.4Hz), 8.02 (dd, 1H, J=8.4,2.4Hz), 7.60 (m, 1H), 7.48 (d, 1H, J=1.9Hz), 6.90 (d, 1H, J=8.6Hz), 5.72 (m, 1H), 3.19 (s, 3H), 2.29 (m, 2H), 1.97 (m, 2H), 1.50 (m, 2H), 1.00 (s, 6H). mass spectrum (ESI, m/z): C 25H 25N 5O 2Calculated value, 428.2 (M+H), actual measurement 428.2.
Embodiment 51
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(dimethyl-hexamethylene-1-thiazolinyl)-6-(1-hydroxyl-1-methyl-ethyl)-pyridin-3-yl]-acid amides
Figure A200680054994D01112
A) 6-bromo-2-iodo-pyridin-3-yl amine
To the 6-bromo-pyridin-3-yl amine that stirs (10.2g, 0.0580mol) and Ag 2SO 4(18.1g, 0.0580mol) solution in EtOH (150mL) adds I 2(7.59g 0.0580mol), stirs reactant and spends the night.At this moment, add hexane (200mL), the gained mixture is through diatomite filtration.Solvent removed in vacuo is dissolved in CHCl 3(200mL), use saturated Na 2S 2O 3The aqueous solution (100mL), water (1 x 100mL) washing, dry (Na 2SO 4).Solvent vacuum concentration, residue are dissolved in hot EtOAc (100mL), filter, and handle with hexane (100mL).Filtration obtains 11.2g (65%) and is the titled reference compound of white crystalline material.
1H-NMR(CDCl 3；400MHz)：δ?7.10(d，1H，J＝8.2Hz)，6.74(d，1H，J＝8.2Hz)，4.06(br?s，2H).
B) 6-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl amine
Figure A200680054994D01121
Titled reference compound according to the program of embodiment 44 steps (b) from 6-bromo-2-iodo-pyridin-3-yl amine (in step preparation before, 348mg, 1.17mmol), 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid (198mg, 1.28mmol), Pd (PPh 3) 4(135mg is 0.117mol) with 2M Na 2CO 3(15.2mL, 30.5mmol) preparation (417mg, 46%).
1H-NMR(CDCl 3；400MHz)：δ?7.06(d，1H，J＝8.3Hz)，6.85(d，1H，J＝8.3Hz)，5.95(m，1H)，3.86(brs，2H)，2.43-2.39(m，2H)，1.99-1.97(m，2H)，1.51(t，2H，J＝6.4Hz)，0.99(s，6H).
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides
Figure A200680054994D01122
Titled reference compound according to the program of embodiment 11 steps (f) from 6-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl amine is (in the preparation of step before, 60mg, 0.21mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 91.0mg, 0.290mmol), PyBroP (157mg, 0.330mmol) and DIEA (91.0 μ L, 0.520mmol) preparation (84mg, 78%).
1H-NMR(CDCl 3；400MHz)：δ?9.91(s，1H)，8.64(d，1H，J＝8.6Hz)，7.79(s，1H)，7.38(d，1H，J＝8.6Hz)，6.00(m，1H)，5.92(s，2H)，3.67(m，2H)，2.46(m，2H)，2.14(m，2H)，1.62(t，2H，J＝6.3Hz)，1.12(s，6H)，0.98(m，2H).
D) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-6-(1-oxyethyl group-vinyl)-pyridin-3-yl]-acid amides
Figure A200680054994D01131
To contain 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides (in the preparation of step before, 32mg, 0.060mmol), Pd (PPh 3) 4(7mg, 0.006mmol) and tributyl-(1-oxyethyl group-vinyl)-stannane (30mg, 0.080mmol) round-bottomed flask adds DMF (0.7mL), and the solution that obtains is spent the night 100 ℃ of stirrings.Reactant dilutes with EtOAc (25mL), water (2 x25mL) washing, dry (Na 2SO 4) and vacuum concentration.Residue obtains the titled reference compound of 12mg (43%) for oil by preparation TLC (20%EtOAc-hexane) purifying.Mass spectrum (ESI, m/z): C 28H 39N 5O 3The Si calculated value, 522.2 (M+H), actual measurement 522.3.
E) 5-cyano group-1H-imidazoles-2-carboxylic acid [6-ethanoyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides
Figure A200680054994D01141
Titled reference compound according to the program of embodiment 11 steps (g) from 5-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-6-(1-oxyethyl group-vinyl)-pyridin-3-yl]-acid amides is (in the preparation of step before, 12mg, 0.023mmol) preparation (4.4mg, 52%).Mass spectrum (ESI, m/z): C 20H 21N 5O 2Calculated value, 364.1 (M+H), actual measurement 364.1.
F) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(dimethyl-hexamethylene-1-thiazolinyl)-6-(1-hydroxyl-1-methyl-ethyl)-pyridin-3-yl]-acid amides
To 5-cyano group-1H-imidazoles-2-carboxylic acid [6-ethanoyl-2-(4; 4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides (in step preparation before, 6mg, (3M is in THF for THF 0.016mmol) (1mL) solution interpolation MeMgBr; 41 μ L, 0.072mmol).After 20 minutes, add other 2.5 normal MeMgBr, make reactant be warming up to room temperature and use saturated NaHCO 3The aqueous solution (2mL) quencher.Slurry filters and vacuum concentration through 5-g Sep-PakSPE post.Crude product is by silica gel chromatography (250-mg, 3-mL Supelco Si pipe, gradient CHCl 3-2%CHCl 3-MeOH) purifying obtains 2.6mg (43%) and is the titled reference compound of white solid.
1H-NMR (CD 3OD; 400MHz): δ 8.44 (d, 1H, J=8.5Hz), 7.90 (s, 1H), 7.42 (d, 1H, J=8.5Hz), 5.86 (s, 1H), 2.39-2.37 (m, 2H), 1.99-1.94 (m, 2H), 1.51 (t, 1H, J=6.3Hz), 1.43 (s, 6H), 0.99 (s, 6H). mass spectrum (ESI, m/z): C 21H 25N 5O 2Calculated value, 380.2 (M+H), actual measurement 380.1.
Embodiment 52
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4 ', 4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides
Figure A200680054994D01151
A) (4-amino-3-bromo-phenyl)-acetonitrile
Figure A200680054994D01152
(1.45g, 10.9mmol) (1.95g 10.9mmol) handles (dripping with adding funnel) to the solution in acetonitrile (10mL) to 4-aminophenyl acetonitrile with the NBS in the acetonitrile (10mL) down at 0 ℃.Make reactant be warming up to room temperature, then vacuum concentration.Crude product is dissolved in EtOAc (50mL), with saturated NaHCO 3The aqueous solution (2 x 50mL) washing and dry (Na 2SO 4).Solvent removed in vacuo provides to be incarnadine solid titled reference compound (2.12g, 92%).Mass spectrum (ESI, m/z): C 8H 7BrN 2Calculated value, 210.9 (M+H), actual measurement 211.0.
B) [4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acetonitrile
Figure A200680054994D01153
Titled reference compound according to the program of embodiment 34 steps (b) from (4-amino-3-bromo-phenyl)-acetonitrile (in step preparation before, 805mg, 3.81mmol), 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid (705mg, 4.57mmol), Pd (PPh 3) 4(440mg is 0.380mmol) with 2M Na 2CO 3(15.2mL, 30.5mmol) preparation (417mg, 46%).
1H-NMR(CDCl 3；400MHz)：δ?6.89(1H，dd，J＝8.1，2.0Hz)，6.84(1H，d，J＝2.0Hz)，6.59(d，1H，J＝8.1Hz)，5.60(m，1H)，3.71(br?s，2H)，2.19-2.15(m，2H)，1.90-1.88(m，2H)，1.45-1.42(m，2H)，0.92(s，6H).
C) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-tin trimethyl alkyl-1H-tetrazolium-5-ylmethyl)-aniline
Figure A200680054994D01161
[4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acetonitrile (preparing in the step before, 417mg, 1.73mmol) (428mg, 2.08mmol) mixture in toluene (8mL) is by reflux 40h with nitrine trimethylammonium stannane.Make reactant be cooled to room temperature, filter then.Throw out 20mL toluene wash, and vacuum-drying is the titled reference compound of white solid so that 410mg (53%) to be provided.Mass spectrum (ESI, m/z): C 16H 21N 5Calculated value, 284.1 (M-SnMe 3+ 2H), actual measurement 284.1.
D) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides
Figure A200680054994D01162
Titled reference compound according to the program of embodiment 11 steps (f) from 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-tin trimethyl alkyl-1H-tetrazolium-5-ylmethyl)-aniline is (in the preparation of step before, 280mg, 0.626mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 267mg, 1.56mmol), PyBroP (466mg, 1.00mmol) and DIEA (273 μ L, 1.56mmol) preparation (128mg, 38%).
1H-NMR(CDCl 3；400MHz)：δ?9.72(s，1H)，8.27(d，1H，J＝8.3Hz)，7.76(s，1H)，7.19(m，1H)，7.12(s，1H)，5.94(s，2H)，5.70(s，1H)，4.29(s，2H)，3.66-3.64(m，2H)，2.27-2.25(m，2H)，2.07-2.06(m，2H)，1.56-1.51(m，2H)，1.09(s，6H)，0.99-0.94(m，2H)，0.01(s，9H).
E) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides
Titled reference compound according to the program of embodiment 11 steps (g) from 4-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides is (in the preparation of step before, 128mg, 0.240mmol) preparation (21mg, 22%).
1H-NMR (CD 3OD; 400MHz): δ 8.15 (d, 1H, J=8.1Hz), 7.97 (s, 1H), 7.17 (d, 1H, J=8.1Hz), 7.12 (s, 1H), 5.71 (s, 1H), 4.25 (s, 2H), 2.27 (m, 2H), 2.05 (m, 2H), 1.56 (t, 2H, J=6.2Hz). mass spectrum (ESI, m/z): C 21H 22N 8The O calculated value, 403.1 (M+H), actual measurement 403.0.
Embodiment 53
5-cyano group-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate
Figure A200680054994D01171
A) 5-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D01181
4-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides (preparation in embodiment 52 steps (d), 78mg, 0.14mmol) and hydrochloric acid (2-chloro-ethyl)-dimethyl-amine (63mg, 0.43mmol) solution in DMF (1mL) is with DIEA (128 μ L, 0.73mmol) handle, then at 100 ℃ of heating 1h.Make reactant be cooled to room temperature, with EtOAc (25mL) dilution, water (2 x 10mL) washing then.Organic phase drying (Na2SO 4) and vacuum concentration.By preparation TLC (10% MeOH-CHCl 3) purifying, obtain 19mg (22%) titled reference compound.Mass spectrum (ESI, m/z): C 31H 45N 9O 2The Si calculated value, 604.3 (M+H), actual measurement 604.1.
B) 5-cyano group-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate
Titled reference compound according to the program of embodiment 11 steps (g) from 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides is (in the preparation of step before, 19mg, 0.031mmol) preparation (18mg, 99%).
1H-NMR (CD 3OD; 400MHz): δ 8.20 (dd, 1H, J=7.5,1.3Hz), 7.99 (s, 1H), 7.20-7.19 (m, 2H), 5.74 (m, 1H), 4.79 (t, 2H, J=6.1Hz), 4.39 (s, 2H), 3.64 (t, 2H, J=6.1Hz), 2.96 (s, 6H), 2.31-2.27 (m, 2H), 2.05 (m, 2H), 1.57 (t, 2H, J=6.3Hz), 1.07 (s, 6H). mass spectrum (ESI, m/z): C 25H 31N 9The O calculated value, 474.2 (M+H), actual measurement 474.0.
Embodiment 54
5-cyano group-1H-imidazoles-2-carboxylic acid [4-[2-(2-dimethylamino-ethyl)-2H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate
Figure A200680054994D01191
A) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-[2-(2-dimethylamino-ethyl)-2H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D01192
4-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides (preparation in embodiment 42 steps (b), 78mg, 0.14mmol) and hydrochloric acid (2-chloro-ethyl)-dimethyl-amine (63mg, 0.43mmol) solution in DMF (1mL) is with DIEA (128 μ L, 0.73mmol) handle, then at 100 ℃ of heating 1h.Make reactant be cooled to room temperature, with EtOAc (25mL) dilution, water (2 x 10mL) washing then.Organic phase drying (Na 2SO 4) and vacuum concentration.By preparation tlc (10% MeOH-CHCl 3) purifying, obtain 21mg (24%) titled reference compound.Mass spectrum (ESI, m/z): C 31H 45N 9O 2The Si calculated value, 604.3 (M+H), actual measurement 604.1.
B) 5-cyano group-1H-imidazoles-2-carboxylic acid [4-[2-(2-dimethylamino-ethyl)-2H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate
Titled reference compound according to the program of embodiment 11 steps (g) from 5-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-2H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides is (in the preparation of step before, 21mg, 0.031mmol) preparation (18.5mg, 93%).
1H-NMR (CD 3OD; 400MHz): δ 8.16 (1H, J=8.3Hz), 7.98 (s, 1H), 7.23 (dd, 1H, J=8.3,2.0Hz), 7.17 (d, 1H, J=2.0Hz), 5.71 (m, 1H), 5.13 (t, 2H, J=5.9Hz), 4.25 (s, 2H), 2.98 (s, 6H), 2.28 (m, 2H), 2.06 (m, 2H), 1.57 (t, 2H, J=6.2Hz), 1.07 (s, 6H). mass spectrum (ESI, m/z): C 25H 31N 9The O calculated value, 474.2 (M+H), actual measurement 474.0.
Embodiment 55
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides
Figure A200680054994D01201
A) (4-amino-3-hexamethylene-1-thiazolinyl-phenyl)-acetonitrile
Figure A200680054994D01202
Titled reference compound according to the program of embodiment 44 steps (b) from (4-amino-3-bromo-phenyl)-acetonitrile (preparation embodiment 42 steps (a), 668mg, 3.16mmol), tetrahydrobenzene-Ji tetramethyl ethylene ketone boric acid ester (790mg, 3.79mmol), Pd (PPh 3) 4(365mg, 0.31mmol) and 2MNa 2CO 3(15.2mL, 12.6mmol) preparation (226mg, 34%).
1H-NMR(CDCl 3；400MHz)：δ6.88(dd，1H，J＝8.1，1.9Hz)，6.84(d，1H，J＝1.9Hz)，6.58(d，1H，J＝8.1Hz)，5.67(m，1H)，3.73(br?s，2H)，3.53(s，2H)，2.14-2.08(m，4H)，1.72-1.58(m，4H).
B) 2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-aniline
Figure A200680054994D01211
Titled reference compound according to the program of embodiment 52 steps (c) from (4-amino-3-hexamethylene-1-thiazolinyl-phenyl)-acetonitrile toluene (4mL) (in step preparation before, 103mg, 0.485mmol) and azido-trimethylammonium stannane (105mg, 0.510mmol) preparation, then by preparation TLC (10% MeOH-CHCl 3) be further purified, be the titled reference compound of white solid so that 40mg (39%) to be provided.Mass spectrum (ESI, m/z): C 14H 17N 5Calculated value, 256.1 (M+H), actual measurement 256.1.
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides
Titled reference compound according to the program of embodiment 11 steps (f) from 2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-aniline (in step preparation before, 40mg, 0.15mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 67mg, 0.21mmol), PyBroP (116mg, 0.249mmol) and DIEA (68 μ L, 0.39mmol) preparation (60mg, 76%).Mass spectrum (ESI, m/z): C 25H 32N 8O 2The Si calculated value, 505.2 (M+H), actual measurement 504.9.
D) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides
Titled reference compound according to the program of embodiment 11 steps (g) from 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides (in step preparation before, 56mg, 0.11mmol) preparation (22mg, 53%).
1H NMR (CD 3OD; 400MHz): δ 8.16 (d, 1H, J=8.3Hz), 8.00 (s, 1H), 7.19 (dd, 1H, J=8.3,2.0Hz), 7.12 (d, 1H, J=2.0Hz), 5.81 (m, 1H), 4.28 (s, 2H), 2.27-2.23 (m, 4H), 1.93-1.76 (m, 4H). mass spectrum (ESI, m/z): C 19H 18N 8The O calculated value, 375.1 (M+H), actual measurement 375.1.
Embodiment 56
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides
Figure A200680054994D01221
A) 4-amino-3-bromo-benzonitrile
Titled reference compound according to the program of embodiment 16 steps (b) from the 4-aminobenzonitrile (2.04g, 17.2mmol) and NBS (3.07g, 17.2mmol) preparation (2.53g, 75%).Mass spectrum (ESI, m/z): C 7H 5BrN 2Calculated value, 196.9 (M+H), actual measurement 196.7.
Figure A200680054994D01222
B) 4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzonitrile
Figure A200680054994D01231
Titled reference compound according to the program of embodiment 44 steps (b) from 4-amino-3-bromo-benzonitrile (in step preparation before, 1.0g, 5.0mmol), 4,4-dimethyl tetrahydrobenzene-1-ylboronic acid (938mg, 6.07mmol), Pd (PPh 3) 4(585mg is 0.506mmol) with 2M Na 2CO 3(20.2mL, 40.5mmol) preparation (284mg, 25%).Mass spectrum (ESI, m/z): C 15H 18N 2Calculated value, 227.1, actual measurement 227.3.
C) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-tin trimethyl alkyl-1H-tetrazolium-5-yl)-aniline
Figure A200680054994D01232
Titled reference compound according to the program of embodiment 52 steps (c) from 4-amino-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-(in step preparation before, 245mg is 1.08mmol) with azido-trimethylammonium stannane (246mg for benzonitrile, 1.19mmol) preparation (363mg, 78%).Mass spectrum (ESI, m/z): C 15H 19N 5Calculated value, 270.1 (M-SnMe 3+ 2H), actual measurement 270.1.
D) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides
Figure A200680054994D01241
Titled reference compound according to the program of embodiment 11 steps (f) from 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-tin trimethyl alkyl-1H-tetrazolium-5-yl)-aniline is (in the preparation of step before, 150mg, 0.347mmol), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (in embodiment 11 steps (d) preparation, 148mg, 0.480mmol), PyBroP (259mg, 0.555mmol) and DIEA (151 μ L, 0.867mmol) preparation (103mg, 57%).Mass spectrum (ESI, m/z): C 26H 34N 8O 2The Si calculated value, 519.2, actual measurement 519.1.
F) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides
Titled reference compound according to the program of embodiment 11 steps (g) from 5-cyano group-1-(2-TMS-ethoxyl methyl)-[2-(4 for 1H-imidazoles-2-carboxylic acid, 4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides is (in the preparation of step before, 103mg, 0.198mmol) preparation (39.7mg, 52%).
1H-NMR (DMSO-d 6400MHz): δ 9.81 (s, 1H), 8.32 (s, 1H), 8.21 (d, 1H, J=8.4Hz), 7.93 (m, 1H), 7.85 (d, 1H, J=1.1Hz), 5.78 (m, 1H), 2.32-2.30 (m, 2H), 2.01 (m, 2H), 1.54 (t, 2H, J=6.0Hz), 1.04 (s, 6H). mass spectrum (ESI, m/z): C 20H 20N 8The O calculated value, 389.1 (M+H), actual measurement 389.1.
Embodiment 57
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides
Figure A200680054994D01251
A) 4-amino-3-hexamethylene-1-thiazolinyl-benzonitrile
Titled reference compound according to the program of embodiment 44 steps (b) from 4-amino-3-bromo-benzonitrile (preparation embodiment 46 steps (a), 466mg, 2.36mmol), tetrahydrobenzene-1-ylboronic acid (354mg, 2.80mmol), Pd (PPh 3) 4(272mg is 0.236mmol) with 2M Na 2CO 3(9.4mL, 18mmol) preparation (245mg, 52%).Mass spectrum (ESI, m/z): C 13H 14N 2Calculated value, 199.1 (M+H), actual measurement 199.2.
B) 2-hexamethylene-1-thiazolinyl-4-(1-tin trimethyl alkyl-1H-tetrazolium-5-yl)-aniline
Figure A200680054994D01253
Titled reference compound according to the program of embodiment 52 steps (c) from 4-amino-3-hexamethylene-1-thiazolinyl-benzonitrile (in step preparation before, 245mg, 0.123mmol) and azido-trimethylammonium stannane (267mg, 1.29mmol) preparation (320mg, 64%).Mass spectrum (ESI, m/z): C 13H 15N 5Calculated value, 242.1 (M-SnMe 3+ 2H), actual measurement 242.2 (M+H).
C) 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides
Figure A200680054994D01261
Titled reference compound prepares from 2-hexamethylene-1-thiazolinyl-4-(1-tin trimethyl alkyl-1H-tetrazolium-5-yl)-aniline (in step preparation before), 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid potassium (preparation embodiment 11 steps (d)), PyBroP and DIEA according to the program of embodiment 11 steps (f).Mass spectrum (ESI, m/z): C 24H 30N 8O 2The Si calculated value, 491.2, actual measurement 491.1.
E) 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides
Titled reference compound prepares from 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides (in step preparation before) according to the program of embodiment 11 steps (g).
1H-NMR (DMF-d 7400MHz): δ 10.07 (s, 1H), 8.55 (s, 1H), 8.46 (d, 1H, J=8.4Hz), 8.18 (dd, 1H, J=8.4,2.0Hz), 8.07 (d, 1H, J=2.0Hz), 6.09 (m, 1H), 2.47-2.39 (m, 4H), 2.00-1.88 (m, 4H). mass spectrum (ESI, m/z): C 18H 16N 8The O calculated value, 361.1, actual measurement 361.1.
Embodiment 58
5-cyano group-1-(2-dimethylamino-ethyl)-1H-imidazoles-2-carboxylic acid 2-hexamethylene-1-thiazolinyl-4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-yl]-phenyl }-acid amides
Figure A200680054994D01271
(DMF 0.10mmol) (0.5mL) solution adds K for preparation in embodiment 57 steps (e), 37mg to 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides 2CO 3(42mg, 0.30mmol), add subsequently 2-chloro-ethyl-dimethyl-amine hydrochlorate (18mg, 0.12mmol).Reactant is heated to 70 ℃.Behind the 3h, (14.6mg 0.102mmol), adds K subsequently to add 2-chloro-ethyl-dimethyl-amine once more 2CO 3(28mg, 0.20mmol), the mixture that obtains is heated to 100 ℃.Behind the 1h, (18mg, 0.12mmol) and DIEA (35 μ L, 0.20), the mixture that obtains spends the night 100 ℃ of stirrings to add 2-chloro-ethyl-dimethyl-amine.Mixture is poured EtOAc (20mL) into and is used saturated NaHCO 3The aqueous solution (2 x 10mL) washing.Organic layer drying (Na 2SO 4) and vacuum concentration.Residue is by preparation TLC (15% MeOH-CHCl 3) purifying, obtain 10.7mg (21%) and be the titled reference compound of white solid.
1H-NMR (CDCl 3400MHz): δ 9.85 (s, 1H), 8.44 (d, 1H, J=8.5Hz), 7.98 (dd, 1H, J=8.5,2.0Hz), 7.89 (d, 1H, J=1.9Hz), 7.66 (s, 1H), 5.84 (m, 1H), 4.67 (t, 2H, J=6.7Hz), 4.60 (t, 2H, J=5.9Hz), 2.92 (t, 2H, J=6.7Hz), 2.68 (t, 2H, J=5.9Hz), 2.25 (s, 6H), 2.22 (s, 6H), 1.81-1.73 (m, 8H). mass spectrum (ESI, m/z): C 26H 34N 10The O calculated value, 503.2, actual measurement 503.2.
Embodiment 59
[4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzoyl]-L-L-glutamic acid
Figure A200680054994D01281
Filling 4-[(4-cyano group-1H-imidazoles-2-carbonyl in the flask)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenylformic acid (36mg, 99 μ mol) (preparation among the embodiment 65), 1-L-glutamic acid diethyl ester hydrochloride (26mg, 120 μ mol), N-(3-dimethylamino-propyl group)-N '-ethyl carbodiimide (23mg, 120 μ mol), I-hydroxybenzotriazole (13mg, 99 μ mol), DIEA (38mg, 300 μ mol) and 0.3mL DCM, stir 8h under the room temperature.Mixture is used NaHCO with 20mL EtOAc dilution 3The washing of (2 x 20mL) and salt solution (20mL), organic layer drying (Na 2SO 4) and concentrate.Residue is dissolved in 2mL EtOH, adds the 7N KOH aqueous solution (43 μ L, 300 μ mol), and reactant at room temperature stirs 8h.Use 2N TFA solution to regulate pH to 2, titled reference compound uses at 0.1% TFA/H by the RP-HPLC purifying 2The linear gradient of 30% to 50% acetonitrile among the O, 10 minutes, the C18 post obtained 25mg (52%) white solid.
1H-NMR (CD 3OD, 400MHz): δ 8.35 (d, J=8.6Hz, 1H), 7.92 (s, 1H), 7.72 (dd, J=8.6,2.1Hz, 1H), 7.66 (d, J=2.1Hz, 1H), 5.74 (m, 1H), 4.54 (m, 1H), 2.39 (t, J=7.4Hz, 2H), 2.30-2.16 (m, 3H), 2.07-1.95 (m, 3H), 1.54 (t, J=6.3Hz, 2H), 1.03 (s, 6H). mass spectrum (ESI, m/z): C 25H 27N 5O 6Calculated value, 494.2 (M+H), actual measurement 494.1.
Embodiment 60
3H-imidazoles-2,4-dicarboxylic acid 4-acid amides 2-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }
Figure A200680054994D01282
A) 4-formamyl-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid
To 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid, ethyl ester (preparation in embodiment 11 steps (c)) (2.0g, 6.8mmol) 15mL EtOH solution add 5N NaOH (2.0mL, 10mmol), reactant is at stirring at room 8h.Mixture is concentrated, and (3.4mL, 6.8mmol), mixture is heated to 90 ℃ of lasting 1h to add water (20mL) and 2N KOH then.Mixture cools off in ice bath, uses 3N HCl to regulate pH to 4, filters and collects white precipitate (ppt), and drying obtains 1.5g (77%) titled reference compound under the vacuum.Mass spectrum (ESI, m/z): C 11H 19N 3O 4The Si calculated value, 286.1 (M+H), actual measurement 285.8.
B) 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-aniline
Figure A200680054994D01292
Titled reference compound according to the program of embodiment 44 steps (b) by Suzuki coupling 2-bromaniline and 4,4-dimethyl-1-tetrahydrobenzene-1-ylboronic acid and preparing.Mass spectrum (ESI, m/z): C 14H 19The N calculated value, 202.1 (M+H), actual measurement 202.1.
C) 3H-imidazoles-2,4-dicarboxylic acid 4-acid amides 2-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }
Titled reference compound is by the program coupling 2-(4 according to embodiment 42 steps (c); 4-dimethyl-hexamethylene-1-thiazolinyl)-and aniline (preparing in the step before) and 4-formamyl-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (preparation in embodiment 43 steps (a)), carry out the SEM deprotection according to embodiment 61 steps (f) subsequently and prepare.
1H-NMR (DMSO-d 6, 400MHz): δ 13.83 (s, 1H), 9.61 (s, 1H), 8.23 (dd, J=7.5,1.5Hz, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 7.38 (ddd, J=7.5,7.5,1.5Hz, 1H), 7.30 (dd, J=7.5,1.5Hz, 1H), 7.22 (ddd, J=7.5,7.5,1.5Hz, 1H), 7.02 (s, 1H), 5.80 (m, 1H), 2.33 (m, 2H), 2.08 (m, 2H), 1.58 (t, J=6.2Hz, 2H), 1.08 (s, 6H). mass spectrum (ESI, m/z): C 19H 22N 4O 2Calculated value, 339.2 (M+H), actual measurement 339.2.
Embodiment 61
3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }
Figure A200680054994D01301
A) 1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-formaldehyde
1H-imidazoles-2-formaldehyde (1.1g, 11mmol), salt of wormwood (3.0g, 23mmol) and SEM-Cl (2.4mL, 14mmol) mixture in 10mL acetone is heated to 60 ℃ of lasting 8h.Mixture dilutes with EtOAc (100mL), and uses NaHCO 3The washing of (2 x 100mL) and salt solution (100mL), organic layer drying (Na 2SO 4) and concentrate.Titled reference compound is by using 50% EtOAc from 20-g SPE post wash-out and purifying obtains 1.5g (58%) water white oil.
1H-NMR(CDCl 3，400MHz)：δ?9.82(s，1H)，7.38(d，J＝1.0Hz，1H)，7.34(d，J＝1.0Hz，1H)，5.78(s，2H)，3.55(m，2H)，0.94(m，2H)，-0.02(s，9H).
B) 1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-formonitrile HCN
Figure A200680054994D01303
To 1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-formaldehyde (1.5g, 6.6mmol) 5mL MeOH solution adds azanol (0.6mL, 9.1mmol, 50% aqueous solution), reactant concentrates then stirring at room 10 minutes.Residue is dissolved in 10mL DCM and 5mL pyridine, and cools off in ice bath.(4.2g, 20mmol), reactant at room temperature stirs 8h to add trifluoroacetic anhydride to this mixture.Mixture is concentrated, and is dissolved in EtOAc (50mL) then, uses NaHCO 3The washing of (2 x 50mL) and salt solution (50mL).Organic layer drying (Na 2SO 4) and concentrate, obtaining 1.2g (81%) brown oil, purity is enough to be used in next step.
1H-NMR (CDCl 3, 400MHz): δ 7.28 (s, 2H), 5.48 (s, 2H), 3.56 (m, 2H), 0.96 (m, 2H), 0.00 (s, 9H). mass spectrum (APCI, m/z): C 10H 17N 3OSi224.1 (M+H), actual measurement 223.6.
C) 2-cyano group-3-(2-TMS-ethoxyl methyl)-3H-imidazoles-4-carboxylic acid, ethyl ester
Figure A200680054994D01311
Under-50 ℃, to 2,2,6, (0.365mL, 4mLTHF solution 2.17mmol) adds n-Butyl Lithium (2M is in pentane for 1.08mL, 2.17mmol) to 6-tetramethyl--piperidines, and mixture was stirred 10 minutes at 0 ℃.Mixture is cooled to-50 ℃, add 1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-formonitrile HCN (preparing in the step before) (0.440g, 1.97mmol) 2mL THF solution, reactant stirs 1h down at-50 ℃, add then Vinyl chloroformate (0.210mL, 2.17mmol).After 10 minutes, under-50 ℃, reactant is with salt solution (20mL) quencher, and with EtOAc (2 x 20mL) extraction, the organic layer (Na that is dried 2SO 4) and concentrate.Titled reference compound uses 20% EtOAc/ hexane from 20-g SPE post wash-out, obtains 0.280g (48%) water white oil.
1H-NMR (CDCl 3, 400MHz): δ 7.81 (s, 1H), 5.89 (s, 2H), 4.40 (q, J=7.1Hz, 2H), 3.65 (m, 2H), 1.41 (t, J=7.1Hz, 3H), 0.96 (m, 2H), 0.00 (s, 9H). mass spectrum (ESI, m/z): C 13H 21N 3O 3The Si calculated value, 296.1 (M+H), actual measurement 295.5.
D) 2-formamyl-3-(2-TMS-ethoxyl methyl)-3H-imidazoles-4-carboxylic acid
Figure A200680054994D01321
To 2-cyano group-3-(2-TMS-ethoxyl methyl)-3H-imidazoles-4-carboxylic acid, ethyl ester (preparing in the step before) (0.28g, 10mL 50% EtOH/H 0.95mmol) 2O solution adds 2N KOH solution, and (0.95mL, 1.9mmol), mixture at room temperature stirs 8h.Use 3N HCl to regulate pH to 4, collecting precipitation is also dry, obtains 0.24g (88%) white solid.
1H-NMR (DMSO-d 6, 400MHz): δ 13.39 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.29 (s, 2H), 3.57 (t, J=7.8Hz, 2H), 0.87 (t, J=7.8Hz, 2H), 0.00 (s, 9H). mass spectrum (ESI, m/z): C 11H 19N 3O 4The Si calculated value, 286.1 (M+H), actual measurement 285.8.
E) 3-(2-TMS-ethoxyl methyl)-3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }
Titled reference compound prepares by coupling 2-formamyl-3-(2-TMS-ethoxyl methyl)-3H-imidazoles-4-carboxylic acid (preparing in the step before) and 2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-aniline (preparation in embodiment 60 steps (b)) according to the program of embodiment 42 steps (c).Mass spectrum (ESI, m/z): C 25H 36N 4O 3The Si calculated value, 469.2 (M+H), actual measurement 469.0.
F) 3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }
3-(2-TMS-ethoxyl methyl)-3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides } (90mg, 0.19mmol) (preparing in the step before) solution in the 0.5mL EtOH and the 0.5mL 6N HCl aqueous solution is heated to 80 ℃ of lasting 3h.Solution is cooled to room temperature, and precipitation is filtered, and uses H 2O and cold MeOH washing obtain 47mg (72%) white solid.
1H-NMR (CD 3OD, 400MHz): δ 8.24 (m, 1H), 7.84 (s, 1H), 7.30-7.10 (m, 3H), 5.74 (m, 1H), 2.31 (m, 2H), 2.09 (m, 2H), 1.60 (t, J=6.3Hz, 2H), 1.10 (s, 6H). mass spectrum (ESI, m/z): C 19H 22N 4O 2Calculated value, 339.2 (M+H), actual measurement 339.2.
Embodiment 62
2-cyano group-3H-imidazoles-4-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides
Figure A200680054994D01331
To 3-(2-TMS-ethoxyl methyl)-3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides } (80mg, 0.17mmol) (preparation in embodiment 61 steps (e)) suspension interpolation 0.4mL Phosphorus Oxychloride in 2mL toluene, mixture is heated to 80 ℃ and continues 30 minutes.Mixture is concentrated, and residue is dissolved in EtOAc (20mL), uses NaHCO 3The washing of (2 x 20mL) and salt solution (20mL), organic layer drying (Na 2SO 4) and concentrate.Titled reference compound is by using 2% MeOH/DCM from 5-gSPE post wash-out and purifying obtains 7.0mg (13%) white solid.
1H-NMR (CD 3OD, 400MHz): δ 8.24 (dd, J=7.6,1.6Hz, 1H), 7.94 (s, 1H), 7.27 (ddd, J=7.6,7.6,1.6Hz, 1H), 7.18 (dd, J=7.6,1.6Hz, 1H), 7.12 (ddd, J=7.6,7.6,1.6Hz, 1H), 5.74 (m, 1H), 2.31 (m, 2H), 2.09 (m, 2H), 1.60 (t, J=6.3Hz, 2H), 1.10 (s, 6H). mass spectrum (ESI, m/z): C 19H 20N 4O 2Calculated value, 321.2 (M+H), actual measurement 321.2.
Embodiment 63
4-cyano group-1H-imidazoles-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-yl)-the acid amides trifluoroacetate
Figure A200680054994D01341
(4.74g, toluene 0.03mol) (50mL) solution adds Na to 2-chloro-3-nitropyridine 2CO 3(3.39g, 32.0mmol) with 4, the 4-lupetidine (J.Org.Chem., 47 (20), 3890, (1982), 3.3g, 0.033mmol).The mixture that obtains stirs 1h and vacuum concentration at 50 ℃.Add water (20mL) and EtOAc (50mL) then.Organic layer is separated, dry and concentrated, obtains 4,4-dimethyl-3 '-nitro-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl, it directly carries out as catalytic hydrogenation as described in embodiment 47 steps (a) and obtains 4,4-dimethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-Ji amine (4.1g, 67%).Mass spectrum (ESI, m/z): C 12H 19N 3Calculated value, 206.1 (M+H), actual measurement 206.2.
As described in embodiment 32 steps (c); 4; 4-dimethyl-3; 4; 5; 6-tetrahydrochysene-2H-[1; 2 '] bipyridyl-3 '-Ji amine (in above-mentioned steps, preparing) and 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (in embodiment 11 steps (d), preparing) coupling, obtain 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (4,4-dimethyl-3; 4; 5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-yl)-acid amides; it carries out the SEM deprotection as described in embodiment 47 steps (d), obtain titled reference compound.
1H-NMR (DMSO-d6; 400MHz): δ 14.4 (s, 1H), 9.72 (s, 1H), 8.39 (m, 2H), 8.11 (dd, 1H, J=4.8,1.7Hz), 7.13 (dd, 1H, J=4.8,1.7Hz), 3.02 (m, 4H), 1.56 (m, 4H), 1.01 (s, 6H); Mass spectrum (ESI, m/z): C 17H 20N 6The O calculated value, 325.1 (M+H), actual measurement 325.2.
Embodiment 64
5-cyano group-1H-imidazoles-2-carboxylic acid (3-piperidines-1-base-pyridazine-4-yl)-acid amides
(1-methyl sulfane base-2-nitro-vinyl)-(WO 2000016766 for piperidines for 1-, 202mg, 1.00mmol) and hydrazine (30 μ L, 1.0mmol) reaction generation (2-nitro-1-piperidines-1-base-vinyl)-hydrazine in EtOH, it is according to literature method (Tett.Lett.41,3619, (1977)) similarly program be converted into 4-nitro-3-piperidines-1-base-pyridazine.
4-nitro-3-piperidines-1-base-pyridazine (preparing in above-mentioned steps) carries out catalytic hydrogenation (described in embodiment 47 steps (a)) then, generates 3-piperidines-1-base-pyridazine-4-base amine.Mass spectrum (ESI, m/z): C 9H 14N 4Calculated value, 179.1 (M+H), actual measurement 178.9.
As described in embodiment 42 steps (c); 3-piperidines-1-base-pyridazine-4-base amine (in above-mentioned steps, preparing) and 4-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid sylvite (preparation in embodiment 11 steps (d)) coupling; obtain 5-cyano group-1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-carboxylic acid (3-piperidines-1-base-pyridazine-4-yl)-acid amides; it carries out the SEM deprotection as described in embodiment 47 steps (d), obtain titled reference compound.
1H-NMR (DMSO-d6; 400MHz): δ 9.79 (br s, 1H), 9.03 (d, 1H, J=4Hz), 8.50 (s, 1H), 8.43 (d, 1H, J=4Hz), 3.21 (m, 4H), 1.71-1.86 (m, 6H); Mass spectrum (ESI, m/z): C 14H 15N 7The O calculated value, 298.1 (M+H), actual measurement 298.1.
Embodiment 65
4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenylformic acid
A) 4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-ethyl benzoate
Figure A200680054994D01361
Titled reference compound uses ethyl cyanoformate to prepare as electrophilic reagent according to the program of embodiment 12.Mass spectrum (ESI, m/z): C 22H 24N 4O 3Calculated value, 393.2 (M+H), actual measurement 393.2.
B) 4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenylformic acid
To 4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-ethyl benzoate (50mg, 0.13mmol) 1mL EtOH solution add the 2N KOH aqueous solution (0.20mL, 0.10mmol), mixture be heated to 60 ℃ of lasting 6h.Use the 2N TFA aqueous solution to regulate pH to 2, titled reference compound uses at 0.1% TFA/H by the RP-HPLC purifying 2The linear gradient elution of 30% to 50% acetonitrile among the O, through 10 minutes, the C18 post obtained 40mg (87%) white solid.
1H-NMR (CD 3OD, 400MHz): δ 8.48 (d, J=8.6Hz, 1H), 8.04 (s, 1H), 7.96 (dd, J=8.6,2.0Hz, 1H), 7.85 (d, J=2.0Hz, 1H), 5.85 (m, 1H), 2.40-2.32 (m, 2H), 2.17-2.13 (m, 2H), 1.66 (t, J=6.3Hz, 2H), 1.15 (s, 6H). mass spectrum (APCI, m/z): C 20H 20N 4O 3Calculated value, 363.2 (M-H), actual measurement 363.4.
Following embodiment is according to the program preparation of embodiment before, and is as follows:
Figure A200680054994D01371
IV. result
A kind of autophosphorylation fluorescence polarization competition immunoassay is used to measure selected formula I and tiring that relevant c-fms that the II compound shows suppresses.Be determined in the black 96-hole microplate (LJL BioSystems) and carry out.The mensuration damping fluid that uses is 100mM HEPES, and pH 7.5,1mM DTT, 0.01% (v/v) tween 20.Compound is containing before be about to measuring in the mensuration damping fluid of 4%DMSO and is diluting.Add 5 μ L compounds to every hole, add 3 μ L mixtures subsequently, described mixture contains 33nM c-fms (3DP) and 16.7mMMgCl in measuring damping fluid 2(Sigma).Start kinase reaction by the 5mM ATP (Sigma) that in measuring damping fluid, adds 2 μ L.The ultimate density of measuring is 10nMc-fms, 1mM ATP, 5mMMgCl 2, 2% DMSO.Carry out control reaction in each plate: in positive and negative control hole, measure damping fluid (4%DMSO) alternative compounds; In addition, the positive control hole receives the 50mM EDTA of 1.2 μ L.
Described plate was at room temperature hatched 45 minutes.Hatching when finishing, (at this moment, EDTA is not added into the positive control hole with the 50mMEDTA quencher of 1.2 μ L in reaction; See above).After hatching in 5 minutes, each hole receives the 1:1:3 mixture 10 μ L of the green tracer 10X of anti-phosphotyrosine antibody 10X, PTK (through the vortex vibration), FP dilution buffer agent (all from PanVera, catalog number (Cat.No.) P2837) respectively.Described plate is through covering, and incubated at room 30 minutes reads fluorescence polarization numerical value on the analyser (Analyst).Instrument is set to: the 485nm exciter filter; 530nm launches spectral filter; Z height: middle part, hole; G-factor: 0.93.Under these conditions, fluorescence polarization value positive and negative control is respectively about 300 and 150, and is used for determining that 100% and 0% of c-fms reaction suppresses.The IC that is reported 50Value is the mean value of three independent tests.
Table 1 has been listed representational formula I of the present invention and II compound.
Table 1
Figure A200680054994D01391
Figure A200680054994D01401
Figure A200680054994D01421
Figure A200680054994D01431
Figure A200680054994D01441
Figure A200680054994D01451
Figure A200680054994D01461
Figure A200680054994D01471
A：<1μM
B：>1μM
*=% inhibition @2 μ M
ND: undetermined
Measure the IC-50 of the compound of embodiment 11-68 in a similar manner.
Preferred embodiment 12,13,14,15,16,17,18,19,20,21,22,34,35,36,37,38,41,42,46,47,63 and 67 compound show activity when being lower than 1 μ M.

Claims (15)

1. the compound of a Formula Il or its solvate, hydrate, tautomer or pharmacologically acceptable salts:
Wherein A is phenyl, pyridyl, pyridazinyl or piperidyl;
A is warp-C randomly 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aOr-alkyl SO 2NR aR bIn one or more replacements;
R 1Be-H;
X is-CO-;
Y is direct key;
R 2Be cycloalkyl, heterocyclic radical or heteroaryl;
Particularly preferably be R 2Be cyclohexenyl, dimethyl cyclohexenyl, methylimidazolyl, piperidyl or methyl piperidine base;
W is an imidazolyl, and it is warp-C randomly 1-6Alkyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-the OCO-alkylamino ,-the OCO-alkylamidoalkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR bReplace;
Particularly preferably being W is imidazolyl, its randomly replacement of one or two in following radicals :-C 1-6Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano group or-CONR aR b
And
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
2. the formula II compound of claim 1, wherein
A is phenyl, pyridyl, pyridazinyl or piperidyl; And
A is warp-C randomly 1-6Alkyl ,-C 2-6Thiazolinyl, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, sulphonamide alkyl, alkyl sulfonamide alkyl, guanidine alkylation, heteroaryl, alkoxyl group heteroaryl, aminoheteroaryl, halogen, hydroxyl ,-CF 3, alkoxyl group, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, alkoxy aryl ,-OCF 3,-OCO-alkyl ,-COR a,-CN ,-C (NH) NH 2,-COOR a,-CONR aR b,-N (R a) COR b,-NO 2,-SO 2R a,-SO 3R aOr-SO 2NR aR b-aryl NSO 2R aOr-alkyl SO 2NR aR bIn one or more replacements;
R 1Be-H;
X is-CO-;
Y is direct key;
R 2Be cyclohexenyl, dimethyl cyclohexenyl, methylimidazolyl, piperidyl or methyl piperidine base;
W is an imidazolyl, its randomly replacement of one or two in following radicals :-C 1-6Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano group or-CONR aR b
And
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
3. the formula II compound of claim 1, wherein
A is phenyl or pyridyl; Wherein
A can be unsubstituted, perhaps optional through bromo, amino, aminoalkyl group, hydroxyalkyl, alkoxyalkyl, pyridyl, N-nitrogen oxide indenyl, methoxyl group indyl ,-COR 3,-CONR aR b,-aryl NSO 2R a-alkyl SO 2NR aR b-SO 2R a, tetrazyl, alkyl tetrazyl or alkyl tetrazyl alkyl NR aR bReplace;
R 1Be-H;
X is-CO-;
Y is direct key;
R 2Be cyclohexenyl, dimethyl cyclohexenyl, methylimidazolyl, piperidyl or methyl piperidine base;
W is an imidazolyl, its randomly replacement of one or two in following radicals :-C 1-6Alkyl, amino, aminoalkyl group, alkylamino alkyl, dialkyl aminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano group or-CONR aR b
And
R aAnd R bBe hydrogen, alkyl, carboxyl, alkyl carboxyl, hydroxyalkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclic radical or heteroaryl independently.
4. the compound of claim 1, it is 4-cyano group-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-methoxyl group-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(pyridin-3-yl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-piperidines-1-base-phenyl)-acid amides, trifluoroacetate; 4-cyano group-5-(1-hydroxyl-1-methyl-ethyl)-1H-imidazoles-2-carboxylic acid (4-bromo-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4-ethanoyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4-formamyl-2-hexamethylene-1-thiazolinyl-phenyl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-formamyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4 '-amino-3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides, trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-sulfonyl methane amino-biphenyl-4-yl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-biphenyl-4-yl)-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [5-ethanoyl-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-5-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfonyl methane-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxyl-ethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid (6-hexamethylene-1-thiazolinyl-benzo [1,3] dioxole-5-yl)-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(3-methyl-3H-imidazol-4 yl)-phenyl]-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-pyridin-3-yl)-acid amides trifluoroacetate; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(morpholine-4-alkylsulfonyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfamyl-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-sulfamyl-ethyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-sulfamyl-ethyl)-phenyl]-acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sulfamyl-phenyl)-acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid (3-hexamethylene-1-thiazolinyl-4 '-dimethylamino alkylsulfonyl biphenyl-4-yl)-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(6-methoxyl group-pyridin-3-yl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(dimethyl-hexamethylene-1-thiazolinyl)-6-(1-hydroxyl-1-methyl-ethyl)-pyridin-3-yl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid [4-[2-(2-dimethylamino-ethyl)-2H-tetrazolium-5-ylmethyl]-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-the acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-ylmethyl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides; 5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1H-tetrazolium-5-yl)-phenyl]-acid amides; 5-cyano group-1-(2-dimethylamino-ethyl)-1H-imidazoles-2-carboxylic acid 2-hexamethylene-1-thiazolinyl-4-[1-(2-dimethylamino-ethyl)-1H-tetrazolium-5-yl]-phenyl }-acid amides; [4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-benzoyl]-1-L-glutamic acid; 3H-imidazoles-2,4-dicarboxylic acid 4-acid amides 2-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }; 3H-imidazoles-2,4-dicarboxylic acid 2-acid amides 4-{[2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides }; 2-cyano group-3H-imidazoles-4-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-yl)-the acid amides trifluoroacetate; 5-cyano group-1H-imidazoles-2-carboxylic acid (3-piperidines-1-base-pyridazine-4-yl)-acid amides; 4-[(4-cyano group-1H-imidazoles-2-carbonyl)-amino]-3-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenylformic acid; 4-cyano group-1H-imidazoles-2-carboxylic acid [4-formyl-dimethylamino-2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; 4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides; With 5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-ethyl)-phenyl]-acid amides.
5. the compound of claim 4, it is
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-methoxyl group-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate;
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-4-yl)-phenyl]-acid amides;
5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(pyridin-3-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridine-2-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-sulfonyl methane-phenyl]-acid amides;
5-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxyl-ethyl)-phenyl]-acid amides;
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4-methyl-piperidines-1-yl)-phenyl]-acid amides trifluoroacetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-pyridin-3-yl]-acid amides trifluoroacetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-sulfamyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-sulfamyl-ethyl)-phenyl]-acid amides trifluoroacetate;
4-cyano group-1H-imidazoles-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-3 '-yl)-the acid amides trifluoroacetate; With
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-phenyl]-acid amides.
6. the compound of claim 5, it is
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(1-amino-1-methyl-ethyl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, acetate;
4-cyano group-1H-imidazoles-2-carboxylic acid [4-(6-amino-pyridine-3-yl)-2-hexamethylene-1-thiazolinyl-phenyl]-acid amides, trifluoroacetate;
5-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridin-4-yl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(1-oxidation-pyridin-3-yl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-pyridine-2-base-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid (2-hexamethylene-1-thiazolinyl-4-sec.-propyl-phenyl)-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(1-hydroxyl-1-methyl-ethyl)-phenyl]-acid amides;
4-cyano group-1H-imidazoles-2-carboxylic acid [2-hexamethylene-1-thiazolinyl-4-(2-hydroxy-2-methyl-propyl group)-phenyl]-acid amides; With
5-cyano group-1H-imidazoles-2-carboxylic acid [2-(4,4-dimethyl-hexamethylene-1-thiazolinyl)-4-(2-hydroxyl-ethyl)-phenyl]-acid amides.
7. pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier of claim 1.
8. the method for an arrestin tyrosine kinase activity, this method comprises makes described kinases contact with the compound of at least a claim 1 of effective inhibitory amount.
9. the method for claim 8, wherein said protein tyrosine kinase is c-fms.
10. method for the treatment of inflammation in mammals, this method are included as the compound of at least a claim 1 of described administration treatment significant quantity.
11. a method for the treatment of mammalian cancer, this method are included as the compound of at least a claim 1 of described administration treatment significant quantity.
12. a method for the treatment of the Mammals cardiovascular disorder, this method are included as the compound of at least a claim 1 of described administration treatment significant quantity.
13. a method for the treatment of relevant blood vessel generation, restenosis, schizophrenia or Alzheimer of Mammals renal glomerulus ephritis, rheumatoid arthritis, psoriatic, diabetes, tumour, this method are included as the compound of at least a claim 1 of described administration treatment significant quantity.
14. a pharmaceutical dosage form, it comprises pharmaceutically acceptable carrier and the about 0.5mg compound at least a claim 1 of about 10g.
15. the formulation of claim 14, it is suitable for parenteral or Orally administered.
CNA2006800549949A 2006-04-20 2006-04-20 C-FMS kinase inhibitor Pending CN101466686A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2006/014886 WO2007123516A1 (en) 2006-04-20 2006-04-20 C-fms kinase inhibitors

Publications (1)

Publication Number Publication Date
CN101466686A true CN101466686A (en) 2009-06-24

Family

ID=38625304

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2006800549949A Pending CN101466686A (en) 2006-04-20 2006-04-20 C-FMS kinase inhibitor

Country Status (6)

Country Link
EP (1) EP2016057A1 (en)
JP (1) JP2009534380A (en)
CN (1) CN101466686A (en)
AU (1) AU2006342509A1 (en)
CA (1) CA2649512A1 (en)
WO (1) WO2007123516A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753770A (en) * 2015-05-27 2016-07-13 上海佐林生物医药有限公司 Protein kinase inhibitor preparation method, protein kinase inhibitor intermediate, intermediate preparation method and application

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2008013528A (en) * 2006-04-20 2008-10-29 Jannsen Pharmaceutica N V Method of inhibiting c kit kinase.
MX2009009304A (en) * 2007-03-01 2009-11-18 Novartis Ag Pim kinase inhibitors and methods of their use.
UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds
AR113206A1 (en) 2017-01-10 2020-02-19 Bayer Cropscience Ag HETEROCYCLIC DERIVATIVES AS PESTICIDES
EP3821947A1 (en) * 2019-11-13 2021-05-19 Libra Therapeutics, Inc. Heterocyclic trpml1 agonists
WO2021144360A1 (en) 2020-01-17 2021-07-22 F. Hoffmann-La Roche Ag Small molecule csf-1r inhibitors in therapeutic and cosmetic uses

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7427683B2 (en) * 2003-04-25 2008-09-23 Ortho-Mcneil Pharmaceutical, Inc. c-fms kinase inhibitors
US20050113566A1 (en) * 2003-04-25 2005-05-26 Player Mark R. Inhibitors of C-FMS kinase
WO2004096795A2 (en) * 2003-04-25 2004-11-11 3-Dimensional Pharmaceuticals, Inc. C-fms kinase inhibitors
DE602005015742D1 (en) * 2004-10-22 2009-09-10 Janssen Pharmaceutica Nv AROMATIC AMIDES AS INHIBITORS OF C-FMS KINASE
PT1807077T (en) * 2004-10-22 2017-01-06 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753770A (en) * 2015-05-27 2016-07-13 上海佐林生物医药有限公司 Protein kinase inhibitor preparation method, protein kinase inhibitor intermediate, intermediate preparation method and application

Also Published As

Publication number Publication date
AU2006342509A1 (en) 2007-11-01
WO2007123516A1 (en) 2007-11-01
CA2649512A1 (en) 2007-11-01
EP2016057A1 (en) 2009-01-21
JP2009534380A (en) 2009-09-24

Similar Documents

Publication Publication Date Title
CN109563043B (en) Substituted pyridines as inhibitors of DNMT1
CN110167935B (en) 3-substituted propionic acids as alpha V integrin inhibitors
ES2611604T3 (en) C fms kinase inhibitors
JP2019532995A (en) Tau protein targeted PROTAC and related methods of use
CN1902196B (en) Thiazole derivative
JP5683489B2 (en) Piperidine-containing compounds and uses thereof
JP2022515879A (en) Heterocyclic compounds, intermediates, methods and applications thereof The present application applies to the Chinese patent application CN 2018116442319 with a filing date of December 29, 2018, and the Chinese patent application CN201910440214.3 with a filing date of May 24, 2019. Japan claims priority based on Chinese patent application CN200911016158.7 on October 24, 2019. In addition, the full text of the above Chinese patent application is incorporated in this application.
CN101466686A (en) C-FMS kinase inhibitor
CN108884077A (en) Glycosidase inhibitor
JP6795588B2 (en) Pyridinone dicarboxamide for use as a bromodomain inhibitor
US7790724B2 (en) c-fms kinase inhibitors
CN108884078A (en) Glycosidase inhibitor
CN114867727A (en) TAU protein targeting compounds and related methods of use
WO2012038743A1 (en) Pyrazolopyridines as inhibitors of the kinase lrrk2
CN101248062A (en) C-fms kinase inhibitors
JPWO2018102067A5 (en)
CN101472914A (en) Inhibitors of C-FMS kinase
AU2008279759A1 (en) Pyrazolo[1,5-a]pyrimidine derivatives
CN104837844B (en) The imidazopyrazine replaced as the pyrazoles of Casein kinase 1 D/E inhibitor
JP6449893B2 (en) Kynurenin-3-monooxygenase inhibitor, pharmaceutical composition, and methods of use thereof
TW201534606A (en) Aldosterone synthase inhibitors
JP2014511355A (en) Histone deacetylase inhibitors, compositions thereof and methods of use
CN111601807A (en) Exo-azaspiro inhibitors of MENIN-MLL interactions
AU2014367283A1 (en) Maleimide derivatives as modulators of WNT pathway
TW202304440A (en) Polycyclic derivative modulator, and preparation method therefor and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20090624