EP2016057A1 - Inhibiteurs de la c-fms kinase - Google Patents

Inhibiteurs de la c-fms kinase

Info

Publication number
EP2016057A1
EP2016057A1 EP06758435A EP06758435A EP2016057A1 EP 2016057 A1 EP2016057 A1 EP 2016057A1 EP 06758435 A EP06758435 A EP 06758435A EP 06758435 A EP06758435 A EP 06758435A EP 2016057 A1 EP2016057 A1 EP 2016057A1
Authority
EP
European Patent Office
Prior art keywords
cyano
amide
imidazole
enyl
cyclohex
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.)
Withdrawn
Application number
EP06758435A
Other languages
German (de)
English (en)
Inventor
Mark R. Player
Nand Baindur
Benjamin M. Brandt
Naresh Chadha
Raymond J. Patch
Davoud Asgari
Taxiarchis Georgiadis
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 EP2016057A1 publication Critical patent/EP2016057A1/fr
Withdrawn legal-status Critical Current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

Definitions

  • the invention relates to novel compounds that function as protein tyrosine kinase inhibitors. More particularly, the invention relates to novel compounds that function as inhibitors of c-fms kinase.
  • Protein kinases are enzymes that serve as key components of signal transduction pathways by catalyzing the transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine and threonine residues of proteins.
  • protein kinase inhibitors and substrates are valuable tools for assessing the physiological consequences of protein kinase activation.
  • the overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been demonstrated to play significant roles in the development of many diseases, including cancer and diabetes.
  • Protein kinases can be divided into two classes: those which preferentially phosphorylate tyrosine residues (protein tyrosine kinases) and those which preferentially phosphorylate serine and/or threonine residues (protein serine/threonine kinases). Protein tyrosine kinases perform diverse functions ranging from stimulation of cell growth and differentiation to arrest of cell proliferation. They can be classified as either receptor protein tyrosine kinases or intracellular protein tyrosine kinases.
  • the receptor protein tyrosine kinases which possess an extracellular ligand binding domain and an intracellular catalytic domain with intrinsic tyrosine kinase activity, are distributed among 20 subfamilies.
  • Receptor tyrosine kinases of the epidermal growth factor ("EGF') family which includes HER-I, HER-2/neu and HER-3 receptors, contain an extracellular binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain. Receptor binding leads to the initiation of multiple intracellular tyrosine kinase dependent phosphorylation processes, which ultimately results in oncogene transcription.
  • Breast, colorectal and prostate cancers have been linked to this family of receptors.
  • Insulin receptor IR
  • insulin-like growth factor I receptor IGF-IR
  • IGF-IR insulin-like growth factor I receptor
  • Platelet derived growth factor (“PDGF') receptors mediate cellular responses that include proliferation, migration and survival and include PDGFR, the stem cell factor receptor (c-kit) and c-fms. These receptors have been linked to diseases such as atherosclerosis, fibrosis and proliferative vitreoretinopathy.
  • Fibroblast growth factor (“FGR”) receptors consist of four receptors which are responsible for the production of blood vessels, for limb outgrowth, and for the growth and differentiation of numerous cell types.
  • VEGF Vascular endothelial growth factor
  • Ht-I VEGFR-I
  • KDR VEGFR-2
  • VEGFR-3 VEGFR-3
  • a related group of receptors, tie-1 and tie-2 kinases, have been identified in vascular endothelium and hematopoietic cells.
  • VEGF receptors have been linked to vasculogenesis and angiogenesis.
  • Intracellular protein tyrosine kinases are also known as non-receptor protein tyrosine kinases. Over 24 such kinases have been identified and have been classified into 11 subfamilies. The serine/threonine protein kinases, like the cellular protein tyrosine kinases, are predominantly intracellular.
  • Diabetes, angiogenesis, psoriasis, restenosis, ocular diseases, schizophrenia, rheumatoid arthritis, cardiovascular disease and cancer are exemplary of pathogenic conditions that have been linked with abnormal protein tyrosine kinase activity. Thus, a need exists for selective and ,potent small-molecule protein tyrosine kinase inhibitors.
  • the invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase.
  • One embodiment of the invention is directed to the novel compounds of Formula I:
  • A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more Of -C 1-6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR 3 , -CONR a R b , -N(R a )COR b , -NO 2 , -
  • R 2 and R 3 are independently
  • R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or.heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido,.-COR a , -CN, -COOR 3 , -C0NR a R b , -N(R 3 )C0R b , -NO 2 , -SO 2 R 3 , -SO 3 R 3 or -SO 2 NR 3 Ri 3 ,
  • W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more Of C 1-4 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR 3 , -CN, - C(NH)NH 2 , -COOR 3 , -C0NR a R b , -NHC0R a R b , -NHSO 2 R 3 , -NO 2 , -SOR 3 , -SO 3 R 3 or
  • -SO 2 NR 3 R 1 ; or a 5- to 6-membered mono- or a 8- to 10-membered bicyclic heterocyclic or heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, ' halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , ⁇ -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR 3 , -CN, -C(NH)NH 2 , -COOR 3 , -CONR 3 Rb, -N(R 3 )CORb, -NO 2 , -SO 2 R 3 , -SO
  • R a and Rb are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • the invention is directed to the novel compounds of Formula II:
  • A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more Of -Ci -6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN, -C(NH)NH 2 , -COOR 3 , -C0NR a R b , -N(R a )C0R b , -NO 2 ,
  • R 2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens or lower alkyl groups, preferably 1 or 2 methyl groups;
  • W is phenyl; naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1-4 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR 3 , -CN, - C(NH)NH 2 , -COOR 3 , -C0NR a R b , -NHC0R a R b , -NHSO 2 R 3 , -NO 2 , -SOR 3 , -SO 3 R 3 or
  • A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -Ci -6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN, -C(NH)NH 2 , -COOR 3 , -C0NR a R b , -N(R 3 )CORb, -NO 2 , -SO 2
  • R 1 is
  • R 2 and R 3 are independently
  • R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -C0R a , -CN, -COOR 3 , -CONR 3 R 1 ,, -N(R a )COR b , -NO 2 , -SO 2 R 3 , -SO 3 R 3
  • R 4 Is one or more of -H, -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN, -COOR 3 , -CONR 3 R b , -N(R 3 )CORb, -NO 2 , -SO 2 R 8 , -SO 3 R 3 or -SO 2 NR 3 Rb,
  • Ra and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • the compounds of Formulae I and II are especially potent inhibitors of the c-fms protein tyrosine kinase.
  • the compounds of Formula III are expected to exhibit similar inhibitory potencies.
  • the invention also relates to methods of inhibiting protein tyrosine kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, II or III.
  • A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C L6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR 3 , -CONR a R b , -N(R 3 )CORb, -NO 2 , -SO 2 R
  • R 2 and R 3 are independently
  • R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR 3 , -CN, -COOR 3 , -C0NR 3 R b , -N(R a )C0R b , -NO 2 , -SO 2 R 3 , -SO 3 R 3 or -SO 2 NR a R b ; and
  • W is phenyl, naphthyl or biphenyl, each, of which may be optionally substituted with one or more of Ci -4 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, - C(NH)NH 2 , -COOR 3 , -C0NR a R b , -NHC0R a R b , -NHSO 2 R 3 , -NO 2 , -SOR 3 , -SO 3 R 3 or
  • R 3 and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C 1- 6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN, -C(NH)NH 2 , -COOR 3 , -C0NR a R b , -N(R 3 )CORb, -NO 2 , -SO 2 R
  • R 2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens or lower alkyl groups, preferably 1 or 2 methyl groups;
  • W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1-4 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , a ⁇ koxy, aryloxy, arylalkoxy, -OCF 3 , -COR 3 , -CN, - C(NH)NH 2 , -COOR a , -CONR a R b , -NHC0R a R b , -NHSO 2 R 3 , -NO 2 , -SOR 3 , -SO 3 R 3 or
  • R 3 and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -Ci -6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -N(R 3 )CORb, -NO 2 , -SO
  • R 2 and R 3 are independently -H, -Ci -6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -COR a , -COR 3 , -COOR 3 , -CONR 3 Rb, -SO 2 R 3 or -SO 2 NR 8 Rb; or
  • R 2 and R 3 taken together with the attached nitrogen, form a 5- to 7-membered heterocyclic or heteroaromatic ring containing from one to three heteroatoms selected from N, O or S, which may be optionally substituted with -Ci -6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkyl amino, -OCO-alkylamido, -COR 3 , -CN, -COOR 3 , -C0NR a R b , -N(R a )COR b , -NO 2 , -SO 2 R 3 , -SO 3 R 3 or -SO 2 NR 3 Rb, and
  • R 4 Is one or more of -H, -Cj -6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN, -COOR 3 , -CONR 3 Rb, -N(R 3 )CORb, -NO 2 , -SO 2 R 3 , -SO 3 R 3 or -SO 2 NR 3 R b ,
  • R 3 and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • Preferred compounds of Formula I are those wherein
  • A is phenyl
  • R 2 and R 3 taken together with the attached nitrogen, form a piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or imidazoline ring which may be optionally substituted with -C ⁇ alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR 3 , -CN, -COOR 3 , -CONR 3 Rb, -N(R 3 )CORb, -NO 2 , -SO 2 R 3 , -SO 3 R 3 or -SO
  • R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
  • A is phenyl
  • R 1 is -H
  • R 2 and R 3 taken together with the attached nitrogen, form a piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or imidazoline ring which may be optionally substituted with -Ci -6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR 3 , -CN, -C(NH)NH 2 , -COOR 3 , -C0NR a R b , -N(R a )C0R b , -NO 2
  • W is a phenyl, furan, thiophene, isoxazole, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring which may be optionally substituted with -Ci -6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO- alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR 3 , -CN, -C(NH)NH 2 , -COOR 3 , -C0NR a R b ,
  • R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
  • Preferred compounds of Formula II are those wherein A is phenyl
  • R 1 is -H
  • W is a phenyl, furan, thiophene, isoxazole, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring which may be optionally substituted with -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO- alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -C(NH)NH 2 , -COOR 2 , -C0NR a R b ,
  • R 3 and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
  • A is phenyl, pyridinyl, pyridazinyl, or piperidinyl; wherein
  • A can be optionally substituted with one or more of -C 1-6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN 5 -C(NH)NH 2 , -COOR 3 ,
  • R 1 is -H
  • X is -CO-
  • Y is a direct link
  • R 2 is cycloalkyl, heterocyclyl, or heteroaryl; particularly preferred as R 2 are the moieties cyclohexenyl, dimethylcyclohexenyl, methylimidazolyl, piperidinyl, and methylpiperidinyl;
  • W is imidazolyl, optionally substituted with one or two -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido,
  • W is imidazolyl optionally substituted with one or two of the following: -C 1-6 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano, or -CONR 3 R b ;
  • R 3 and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • A is phenyl, pyridinyl, pyridazinyl, or piperidinyl; wherein
  • A can be optionally substituted with one or more of -C 1-6 alkyl, -C 2-6 alkenyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, alkylsulfonamidoalkyl, guanidinoalkyl, heteroaryl, alkoxyheteroaryl, aminoheteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aminoaryl, aminoaryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR 3 , -CN 5 -C(NH)NH 2 , -
  • R 1 is -H
  • X is -CO-
  • Y is a direct link
  • R 2 is cyclohexenyl, dimethylcyclohexenyl, methylimidazolyl, piperidinyl, or methylpiperidinyl;
  • W is imidazolyl optionally substituted with one or two of the following:-C 1-6 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano, or -C0NR a R b ;
  • R a and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl. Even more preferred are compounds of Formula II wherein
  • A is phenyl, or pyridinyl
  • A can be unsubstituted or optionally substituted with bromo, amino, aminoalkyl, aminoaryl, hydroxyalkyl, alkoxyalkyl, pyridinyl, N-oxypyrindinyl, methoxy pyrindinyl, -COR 3 , -CONR 3 Rb, -arylNSO 2 R 3 ; -alkyl SO 2 NR a R b; -SO 2 R 3 , tetrazolyl, alkyltetrazolyl, or alkyltetrazolylalkyl NR 3 R b ;
  • R 1 is -H
  • X is -CO-
  • Y is a direct link
  • R 2 is cyclohexenyl, dimethylcyclohexenyl, methylimidazolyl, piperidinyl, or methylpiperidinyl;
  • W is imidazolyl optionally substituted with one or two of the following:-Ci -6 alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, cyano, or -CONR 3 Ri,;
  • R 3 and R b are independently hydrogen, alkyl, carboxyl, alkylcarboxyl, hydroxyalkyl,cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl.
  • the most preferred compounds of Formula I include, but are not limited to, 5-nitro-furan- 2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; isoxazole-5-carboxylic acid (2-piperidin-l- yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidm-l-yl-phenyl)- amide; 5-nitro-furan-2-carboxylic acid [2-(3-methyl-piperidin-l-yl)-phenyl]-amide; 4-nitro- pyridine-2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid (2- morpholin-4-yl-phenyl)-amide; 5-chloro-furan-2-carboxylic acid (2-piperidin-l-yl)- amide; 5-nitro-furan-2-carboxylic
  • the most preferred compounds of Formula II include 5-nitro-furan-2-carboxylic acid [2- (2-chloro-l,l,2-trifluoro-ethylsulfanyl)-phenyl] -amide; 5-nitro-furan-2-carboxylic acid (2- ethoxyphenyl)-amide and pharmaceutically acceptable salts thereof.
  • Even more preferred compounds of Formula II include 4-Cyano-lH-imidazole-2- carboxylic acid (4-bromo-2-cyclohex-l-enyl-phenyl)-amide; 4-Cyano-lH-imidazole-2- carboxylic acid P-cyclohex-l-enyM-Q-hydroxy-l-methyl-ethyty-pheny ⁇ -amide; 4-Cyano-lH- imidazole-2-carboxylic acid [2-cyclohex- 1 -enyl-4-( 1 -methoxy- 1 -methyl-ethyl)-phenyl]-amide; 4-Cyano- lH-imidazole-2-carboxylic acid [4-( 1 -amino- 1 -methyl-ethyl)-2-cyclohex- 1 -enyl- phenyl] -amide, acetic acid salt; 4-Cyano-lH-imidazole-2-carboxy
  • the invention also relates to methods of inhibiting protein tyrosine kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, II or III.
  • a .preferred tyrosine kinase is c-fms.
  • the invention is considered to include the enantiomeric, diastereomeric and tautomeric forms of all compounds of Formulae I, II and III as well as their racemic mixtures.
  • some of the compounds represented by Formulae I, II and III may be prodrugs, i.e., derivatives of an acting drug that possess superior delivery capabilities and therapeutic value as compared to the acting drug. Prodrugs are transformed into active drugs by in vivo enzymatic or chemical processes.
  • alkyl refers to both linear and branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, ',2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • cycloalkyl refers to a saturated or partially unsaturated ring composed of from 3 to 8 carbon atoms. Alkyl substituents may optionally be present on the ring. Examples include cyclopropyl, 1,1-dimethyl cyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl and cyclohexenyl and dimethylcyclohexenyl.
  • heterocyclyl refers to a nonaromatic (i.e. saturated or partially unsaturated) ring composed of from 3 to 7 carbon atoms and at least one heteroatom selected from N, O or S.
  • Alkyl substituents may optionally be present on the ring. Examples include tetrahydrofuryl, dihydropyranyl, piperidyl, 2,5-dimethypiperidyl, morpholinyl, piperazinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl imidazolinyl and tetrazolyl.
  • heterocyclylalkyl refers to a C 1-6 alkyl group containing a heterocyclyl substituent. Examples include dihydropyranylethyl and 2-morpholinylpropyl.
  • hydroxyalkyl refers to at least one hydroxyl group bonded to any carbon atom along an alkyl chain.
  • aminoalkyl refers to at least one primary or secondary amino group bonded to any carbon atom along an alkyl chain.
  • alkoxyalkyl refers to at least one alkoxy group bonded to any carbon atom along an alkyl chain.
  • polyalkoxyalkyl refers to long-chain alkoxy compounds and includes polyethylene glycols of discreet or monodispersed sizes.
  • thioalkyl refers to at least one sulfur group bonded to any carbon atom along an alkyl chain. The sulfur group may be at any oxidation state and includes sulfoxides, sulfones and sulfates.
  • carboxyalkyl refers to at least one carboxylate group bonded to any carbon atom along an alkyl chain.
  • carboxylate group includes carboxylic acids and alkyl, cycloalkyl, aryl or aralkyl carboxylate esters.
  • heteroaryl refers to 5- to 7-membered mono- or 8- to 10- membered bicyclic aromatic ring systems, any ring of which may consist of from one to four heteroatoms selected from N, O or S where the nitrogen and sulfur atoms can exist in any allowed oxidation state.
  • Examples include benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl and thienyl.
  • heteroarylkyl refers to a C 1-6 alkyl group having a heteroaryl substituent. Examples include furylethyl and 2-quinolinylpropyl.
  • heteroatom refers to a nitrogen atom, an oxygen atom or a sulfur atom wherein the nitrogen and sulfur atoms can exist in any allowed oxidation states.
  • alkoxy refers to straight or branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, bonded to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.
  • aryl refers to monocyclic or bicyclic aromatic ring systems containing from 6 to 12 carbons in the ring. Alkyl substituents may optionally be present on the ring. Examples include benzene, biphenyl and napththalene.
  • aralkyl refers to a Ci -6 alkyl group containing an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.
  • heteroarylkyl refers to a Ci -6 alkyl group containing a heteroaryl substituent. Examples include furylmethyl and pyridylpropyl.
  • aryloxy refers to an oxygen atom bound to an aryl substituent. Examples include phenoxy and benzyloxy.
  • arylalkoxy refers to an alkoxy group bound to an aryl substituent. Examples include phenylmethyl ether.
  • acyl refers to the group -C(O)R a , where R a is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.
  • An “acylating agent” adds the -C(O)R a group to a molecule.
  • sulfonyl refers to the group -S(O) 2 R 8 , where R a is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl.
  • a "sulfonylating agent” adds the -S(O) 2 R a group to a molecule.
  • the compounds of Formulae I, II and III represent novel potent inhibitors of protein tyrosine kinases, such as c-fms, and may be useful in the prevention and treatment of disorders resulting from actions of these kinases.
  • the invention also provides methods of inhibiting a protein tyrosine kinase comprising contacting the protein tyrosine kinase with an effective inhibitory amount of at least one of the compounds of Formula I, II or III.
  • a preferred tyrosine kinase is c-fms.
  • at least one of the compounds of Formula I, II or III is combined with a known tyrosine kinase inhibitor.
  • the protein tyrosine kinases inhibited by the compounds of Formulae I, II and III are located in cells, in a mammal or in vitro. In the case of mammals, which includes humans, a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I, II or III is administered.
  • the invention further provides methods of treating cancer in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable composition of least one compound of Formula I, II or III.
  • exemplary cancers include, but are not limited to, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma.
  • an effective amount of at least one compound of Formula I, II or III is administered in combination with an effective amount of a chemotherapeutic agent.
  • the invention also provides methods of treating cardiovascular and inflammatory diseases in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I, II or III.
  • diseases that may be effectively treated include glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia and Alzheimer's dementia.
  • the compounds of the invention may be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g, in single or divided daily doses.
  • the dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.
  • the compounds of Formulae I, II and III may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers.
  • Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
  • Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
  • the pharmaceutically-acceptable salts of the compounds of Formulae I, II and III include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
  • acid addition salts include acetate, ⁇ adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, ⁇ hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts and salts with amino acids such as arginine.
  • the basic nitrogen-containing groups may be quaternized with, for example, alkyl halides.
  • compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
  • suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
  • the compounds of Formulae I, II and III may be prepared by either solid phase support methodology or by solution-phase synthesis. Exemplary synthetic routes for generating amides of the invention are described below.
  • PS trisamine dioxane / 70 0 C A solution of aniline (10 mg, 0.069 mmol) in dioxane (0.5 niL) was treated with polystyrene ("PS") niorpholine resin (Aldrich) (50 mg, 0.14 mmol), followed by the addition of a solution of 5-nitro-furan-2-carbonyl chloride (Lancaster) (15 mg, 0.086 mmol) in dioxane (0.5 mL). The reaction was heated to 70 0 C and agitated for 2 h. The reaction was treated with PS trisamine (Aldrich) (25 mg, 0.12 mmol) and heated to 70 0 C for an additional 2 h. Filtration gave the desired product in > 80 % yield. [0059] EXAMPLE 2 (Procedure 2 for Preparation of Amides)
  • N-bromosuccinimide N-bromosuccinimide
  • AIBN azobis(isobutyronitrile)
  • Example 18 4-Cyano- lH-imidazole-2-carboxylic acid [2-cyclohex- 1 -enyl-4-( 1 -oxy-pyridin-3-yl)-phenyl] - amide
  • the title compound was prepared by the procedure of Example 19, using 4-cyano-lH- imidazole-2-carboxylic acid [2-cyclohex-l-enyl-4-(l-oxy-pyridin-2-yl)-phenyl] -amide (as prepared in Example 20, step (c), 18 mg, 0.047 mmol).
  • Silica gel chromatography (1-3 % MeOH/DCM) afforded the title compound (5.2 mg, 30 %) as a white solid.
  • the title compound was prepared by the procedure of Example 15, step (c) using 4- cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid (4-acetyl-2- cyclohex-l-enyl-phenyl)-amide (as prepared in the previous step, 40.0 mg, 0.0862 mmol).
  • Silica gel chromatography (10 % EtOAc/DCM) afforded the title compound (26.2 mg, 91 %) as a white solid.
  • N-bromosuccinimide N-bromosuccinimide
  • the title compound was prepared by the procedure of Example 24, step (b) using 4- cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid [4-carbamoyl-2- (4,4-dimethyl-cyclohex-l-enyl)-phenyl]-amide (as prepared in the previous step, 100 mg, 0.203 mmol) and tetrabutylammonium fluoride (1.01 mL, 1.01 mmol, 1.0 M in THF). Silica gel chromatography (5 % MeOH/DCM) afforded the title compound (14.1 mg, 19 %) as a white solid.
  • the title compound was prepared by the procedure of Example 11 , step (g) using 4- cyano- 1 -(2-trimethylsilanyl-ethoxymethyl)- lH-imidazole-2-carboxylic acid (3-cyclohex- 1 -enyl- 4'-methanesulfonylamino-biphenyl-4-yl)-amide (as prepared in the previous step, 29.5 mg, 0.0498 mmol).
  • Silica gel chromatography (5-10 % EtOAc/DCM) afforded the title compound (10.1 mg, 44 %) as a white solid.
  • Example 28 The title compound was prepared by the procedure of Example 28, step (a) using 4- cyano-1 -(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid (4-bromo-2- cyclohex-l-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 19 mg, 0.038 mmol), and phenylboronic acid (5.1 mg, 0.042 mmol).
  • Silica gel chromatography (5-10 % EtOAc/hexane) afforded the title compound (16 mg, 85 %) as a white solid.
  • the title compound was prepared by the procedure of Example 11, step (g) using A- cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid (3-cyclohex-l-enyl- biphenyl-4-yl)-amide (as prepared in the previous step, 16 mg, 0.032 mmol).
  • Silica gel chromatography (2-3 % EtOAc/DCM) afforded the title compound (7.1 mg, 60 %) as a white solid.
  • the title compound was prepared by the procedure of Example 11, step (g) using 4- cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid [5-acetyl-2-(4,4- dimethyl-cyclohex-l-enyl)-phenyl]-amide (as prepared in the previous step, 200 mg, 0.406 mmol).
  • Silica gel chromatography (5-15 % EtOAc/DCM) afforded the title compound (134 mg, 91 %) as a white solid.
  • the title compound was prepared by the experimental procedure of Example 11, step (g) using 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid [4-bromo-2- (4,4-dimethyl-cyclohex-l-enyl)- ⁇ heriyl]-amide (as prepared in the previous step, 350 mg, 0.661 mmol).
  • the title compound (253 mg, 96 %) was obtained as a white solid.
  • the title compound was prepared by the experimental procedure of Example 12 using 4- cyano- 1 H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-l -enyl)-phenyl]- amide (as prepared in the previous step, 200 mg, 0.501 mmol). Flash chromatography on silica gel (1-4 % MeOH/DCM) afforded the title compound (101 mg, 53 %) as a white solid.
  • the title compound was prepared by coupling 2-(4-amino-3-cyclohex-l-enyl-phenyl)- ethanol (prepared in the previous step) and 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH- imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 42, step (c) followed by SEM deprotection according to the procedure in Example 11, step (g).
  • the title compound was prepared by coupling 6-cyclohex-l-enyl-benzo[l,3]dioxol-5- ylamine (prepared in the previous step) and 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH- imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 42, step (c) followed by SEM deprotection according to the procedure in Example 11, step (g).
  • the mixture was degassed via sonication, placed under Ar, treated with 113 mg (0.0976 mmol) of Pd(PPh 3 ) 4 , and heated to 80 °C for 6 h.
  • the mixture was diluted with EtOAc (30 mL) and washed with water (2 x 20 mL).
  • the organic layer was dried (MgSO 4 ) and concentrated in vacuo.
  • 2-(4-Nitro-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in the step above, 633 mg, 2.21 mmol) was hydrogenated under balloon pressure in EtOH (20 mL) using 10 % PdVC (100 mg) for 12 h.
  • the reaction mixture was filtered through Celite and concentrated to obtain 2-(4-amino-phenyl)-ethanesulfonic acid tert-butylamide (536 mg, 95 %) which was used directly without further purification.
  • the title compound was prepared according to the Suzuki coupling procedure of Example 44, step (b) using cyclohex-1-enyl boronic acid (117 mg, 0.931 mmol) and 2-(4-amino-3-bromo- phenyl)-ethanesulfonic acid tert-butylamide (as prepared in the previous step, 250 mg, 0.745 mmol) and purified on silica (20 % EtOAc/hexanes) (228 mg, 91 %).
  • 4-Amino-N-tert-butyl-3-cyclohex-l-enyl-benzenesulfonamide was prepared according to the Suzuki coupling procedure of Example 44, step (b) using cyclohex-l-enyl boronic acid (63 mg, 0.50 mmol) and 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (123 mg, 0.400 mmol, as prepared above) to obtain 4-amino-N-tert-butyl-3-cyclohex-l-enyl-benzenesulfonamide (87 mg, 70%) after purification on silica (30 % EtOAc/ hexanes).
  • the title compound was prepared from 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH- imidazole-2-carboxylic acid (3-cyclohex-l-enyl-4'-dimethylsulfamoyl-biphenyl-4-yl)-amide (as prepared in the previous step, 82 mg, 0.13 mmol) according to the procedure in Example 11, step (g) (47 mg, 76 %).
  • the title compound was prepared from 4-cyano-l-(2-trimethylsilanyl- ethoxymethyl)-lH-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-l-enyl)-4-(6- methoxy-pyridin-3-yl)-phenyl] -amide (as prepared in the previous step, 20 mg, 0.035 mmol) according to the procedure in Example 11, step (g) (15 mg, 100 % ).
  • the title compound was prepared from 6-bromo-2-(4,4-dimethyl-cyclohex-l- enyl)-pyridin-3-ylamine (as prepared in the previous step, 60 mg, 0.21 mmol), potassium 4- cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylate (as prepared in Example 11, step (d), 91.0 mg, 0.290 mmol), PyBroP (157 mg, 0.330 mmol) and DIEA (91.0 ⁇ L, 0.520 mmol) according to the procedure in Example 11, step (f) (84 mg, 78 %).
  • the title compound was prepared from (4-amino-3-bromo-phenyl)-acetonitrile (as prepared in the previous step, 805 mg, 3.81 mmol), 4,4-dimethylcyclohexen-l-yl boronic acid (705 mg, 4.57 mmol), Pd(PPh 3 ) 4 (440 mg, 0.380 mmol), and 2M Na 2 CO 3 (15.2 mL, 30.5 mmol) according to the procedure in Example 34, step (b) (417 mg, 46 %).
  • the title compound was prepared from 2-(4,4-dimethyl-cyclohex-l-enyl)-4-(l- trimethylstannanyl-lH-tetrazol-5-ylmethyl)-phenylamine (as prepared in the previous step, 280 mg, 0.626 mmol), potassium 4-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2- carboxylate (as prepared in Example 11, step (d), 267 mg, 1.56 mmol), PyBroP (466 mg, 1.00 mmol) and DIEA (273 ⁇ L, 1.56 mmol) according to the procedure in Example 11, step (f) (128 mg, 38 %).
  • the title compound was prepared from 4-cyano-l-(2-trimethylsilanyl- ethoxymethyl)-lH-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-l-enyl)-4 ⁇ (lH- tetrazol-5-ylmethyl)-phenyl]-amide (as prepared in the previous step, 128 mg, 0.240 mmol) according to the procedure in Example 11, step (g) (21 mg, 22 %).
  • the title compound was prepared from 4-cyano-l-(2-trimethylsilanyl- ethoxymethyl)- 1 H-imidazole-2-carboxylic acid [4- [ 1 -(2-dimethyl amino-ethyl)- 1 H-tetrazol-5- ylmethyl]-2-(4,4-dimethyl-cyclohex-l-enyl)-phenyl]-amide (as prepared in the previous step, 19 mg, 0.031 mmol) according to the procedure in Example 11, step (g) (18 mg, 99 %).
  • the title compound was prepared from 5-cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH- imidazole-2-carboxylic acid [4- [ 1 -(2-dimethylamino-ethyl)-2H-tetrazol-5-ylmethyl]-2-(4,4- dimethyl-cyclohex-l-enyl)-phenyl]-amide (as prepared in the previous step, 21 mg, 0.031 mmol) according to the procedure in Example 11, step (g). (18.5 mg, 93 %).
  • the title compound was prepared from (4-amino-3-bromo-phenyl)-acetonitrile (as prepared in Example 42, step (a), 668 mg, 3.16 mmol), cyclohexen-yl pinacol boronic ester (790 mg, 3.79 mmol), Pd(PPh 3 ) 4 (365 mg, 0.31 mmol), and 2M Na 2 CO 3 (15.2 mL, 12.6 mmol) according to the procedure in Example 44, step (b) (226 mg, 34 %).
  • the title compound was prepared from 4-cyano-l-(2-trimethylsilanyl- ethoxymethyl)-lH-imidazole-2-carboxylic acid [2-cyclohex-l-enyl-4-(lH-tetrazol-5-ylmethyl)- phenyl] -aniide (as prepared in the previous step, 56 mg, 0.11 mmol) according to the procedure in Example 11, step (g) (22 mg, 53% ).
  • the title compound was prepared from 5-cyano-l-(2-trimethylsilanyl- ethoxymethyl)- 1 H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex- 1 -enyl)-4-( 1 H- tetrazol-5-yl)-phenyl] -amide (as prepared in the previous step, 103 mg, 0.198 mmol) according to the procedure in Example 11, step(g) (39.7 mg, 52 %).
  • the title compound was prepared by coupling 2-(4,4-dimethyl-cyclohex-l-enyl)- phenylamine (prepared in the previous step) and 4-carbamoyl-l-(2-trimethylsilanyl- ethoxymethyl)-lH-imidazole-2-carboxylic acid (as prepared in Example 43, step (a)) according to the procedure in Example 42, step (c), followed by SEM deprotection according to the procedure in Example 61, step (f).
  • 3-Piperidin-l-yl-pyridazin-4-ylamine (as prepared in above step) was coupled with 4- cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 11, step (d)), as described in Example 42, step (c) to afford 5-cyano-l-(2- trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxylic acid (3-piperidin-l-yl-pyridazin-4- yl)-amide which was subjected to SEM deprotection as described in Example 47, step (d) to afford the title compound.
  • the pH was adjusted to 2 with 2 N aq TFA and the title compound was purified by RP-HPLC eluting with a linear gradient of 30 % to 50 % acetonitrile in 0.1 % TFAZH 2 O over 10 min on a Cl 8 column giving 40 mg (87 %) of a white solid.
  • the instrument settings were: 485 nm excitation filter; 530 run emission filter; Z height: middle of well; G factor: 0.93. Under these conditions, the fluorescence polarization values for positive and negative controls were approximately 300 and 150, respectively, and were used to define the 100 % and 0 % inhibition of the c-fms reaction. The reported ICs 0 values are averages of three independent measurements.
  • Table 1 lists representative compounds of Formulae I and II of the invention.

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

L'invention concerne des composés de Formule II dans laquelle A, R1, R2, R3, R4, X, Y et W sont définis dans la description ainsi que des solvates, des hydrates, des tautomères ou des sels pharmaceutiquement acceptables de ceux-ci qui inhibent les protéine tyrosine kinases, notamment la c-fms kinase.
EP06758435A 2006-04-20 2006-04-20 Inhibiteurs de la c-fms kinase Withdrawn EP2016057A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2006/014886 WO2007123516A1 (fr) 2006-04-20 2006-04-20 Inhibiteurs de la c-fms kinase

Publications (1)

Publication Number Publication Date
EP2016057A1 true EP2016057A1 (fr) 2009-01-21

Family

ID=38625304

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06758435A Withdrawn EP2016057A1 (fr) 2006-04-20 2006-04-20 Inhibiteurs de la c-fms kinase

Country Status (6)

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

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007240400B2 (en) * 2006-04-20 2013-08-22 Janssen Pharmaceutica N.V. Method of inhibiting C KIT kinase
MX2009009304A (es) * 2007-03-01 2009-11-18 Novartis Ag Inhibidores de cinasa pim y metodos para su uso.
UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds
CN105753770A (zh) * 2015-05-27 2016-07-13 上海佐林生物医药有限公司 蛋白激酶抑制剂制备方法、中间体、制备方法及应用
US11083199B2 (en) 2017-01-10 2021-08-10 Bayer Aktiengesellschaft Heterocycle derivatives as pesticides
EP3821947A1 (fr) * 2019-11-13 2021-05-19 Libra Therapeutics, Inc. Agonistes heterocycliques de trpml1
WO2021144360A1 (fr) 2020-01-17 2021-07-22 F. Hoffmann-La Roche Ag Inhibiteurs csf-1r à petites molécules en utilisations thérapeutiques et cosmétiques

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050113566A1 (en) * 2003-04-25 2005-05-26 Player Mark R. Inhibitors of C-FMS kinase
US7427683B2 (en) * 2003-04-25 2008-09-23 Ortho-Mcneil Pharmaceutical, Inc. c-fms kinase inhibitors
JP2007525460A (ja) * 2003-04-25 2007-09-06 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド ｃ−ｆｍｓキナーゼ阻害剤
US7705042B2 (en) * 2004-10-22 2010-04-27 Janssen Pharmaceutica Nv Class of arylamide compounds useful as inhibitors of c-fms kinase
ES2611604T3 (es) * 2004-10-22 2017-05-09 Janssen Pharmaceutica Nv Inhibidores de la c fms quinasa

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007123516A1 *

Also Published As

Publication number Publication date
AU2006342509A1 (en) 2007-11-01
WO2007123516A1 (fr) 2007-11-01
JP2009534380A (ja) 2009-09-24
CA2649512A1 (fr) 2007-11-01
CN101466686A (zh) 2009-06-24

Similar Documents

Publication Publication Date Title
US7790724B2 (en) c-fms kinase inhibitors
EP2016070B1 (fr) Inhibiteurs de la c-fms kinase
EP1631560A2 (fr) Inhibiteurs de la kinase c-fms
CA2585053C (fr) Composes de n-acyl (hetero)aryl substitue en tant qu'inhibiteurs de la kinase c-fms
AU2005299476A1 (en) c-fms kinase inhibitors
WO2007123516A1 (fr) Inhibiteurs de la c-fms kinase
EP1807406A2 (fr) Inhibiteurs de la c-fms kinase
AU2005317870A1 (en) Pyridine carboxamide derivatives for use as anticancer agents
CA2702898A1 (fr) Inhibiteurs de la c-fms kinase
WO2007124318A1 (fr) Inhibiteurs de la c-fms kinase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20081120

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

RIN1 Information on inventor provided before grant (corrected)

Inventor name: GEORGIADIS, TAXIARCHIS

Inventor name: ASGARI, DAVOUD

Inventor name: PATCH, RAYMOND, J.

Inventor name: CHADHA, NARESH

Inventor name: BRANDT, BENJAMIN, M.

Inventor name: BAINDUR, NAND

Inventor name: PLAYER, MARK, R.

17Q First examination report despatched

Effective date: 20100325

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20100805