WO2004096795A2 - C-fms kinase inhibitors - Google Patents
C-fms kinase inhibitors Download PDFInfo
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- WO2004096795A2 WO2004096795A2 PCT/US2004/012729 US2004012729W WO2004096795A2 WO 2004096795 A2 WO2004096795 A2 WO 2004096795A2 US 2004012729 W US2004012729 W US 2004012729W WO 2004096795 A2 WO2004096795 A2 WO 2004096795A2
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- phenyl
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- carboxylic acid
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- 0 **/C(/CCCCCC1)=C1\N(*)** Chemical compound **/C(/CCCCCC1)=C1\N(*)** 0.000 description 3
- OYECAJPUPWFCSL-UHFFFAOYSA-N Nc(cccc1)c1N1CCCCC1 Chemical compound Nc(cccc1)c1N1CCCCC1 OYECAJPUPWFCSL-UHFFFAOYSA-N 0.000 description 1
- SXINBFXPADXIEY-UHFFFAOYSA-N [O-][N+](c1ccc(C=O)[o]1)=O Chemical compound [O-][N+](c1ccc(C=O)[o]1)=O SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 description 1
- JYKWPPFMIWMTPT-UHFFFAOYSA-N [O-][N+](c1ccc(CNc(cccc2)c2N2CCCCC2)[o]1)=O Chemical compound [O-][N+](c1ccc(CNc(cccc2)c2N2CCCCC2)[o]1)=O JYKWPPFMIWMTPT-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- A—HUMAN NECESSITIES
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
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- 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
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- 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
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- 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
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Definitions
- the invention relates to novel compounds that function as protein tyro sine 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. As a consequence, 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-1, 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.
- EGF epidermal growth factor
- HER-1 epidermal growth factor
- 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 ('TR”) and insulin-like growth factor I receptor (“IGF-1R”) are structurally and functionally related
- 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.
- PDGF Platelet derived growth factor
- 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
- ovarian carcinomas a potent mitogen of endothelial cells
- VEGFR-1 Flt-1
- VEGFR-2 VEGFR-2
- KDR VEGFR-3
- Flt-4 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.
- U.S. Patent Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and PCT International Applications WO 01/47897, WO 00/27820 and WO 02/068406 are indicative of recent attempts to synthesize such 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, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -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 a , -CN, -C(NH)NH 2 , -COORa, -CONR a R b , -N(R a )COR b , -NO 2 , -SO ⁇ , -SO 3 R a or -SO 2 NR a
- 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 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -COOR a ,
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SOsR, or -SO 2 NR a R b ; or
- Ra and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl 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 -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 a , -CN,
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 ,
- Ri is -H, aryl, -CORa, -COR a , -COOR a , -CONR a R b , -SO 2 R a or -SO 2 NR a R b ;
- R 2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens;
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1- alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SOsR, or -SO 2 NR a R ; or
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- A is a 5- to 6-membered 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, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido,
- Y is direct bond, -CH 2 -, -CH 2 CH 2 -, -CE CH-, -NR a -, -O-, -S-, -SO-, -SO 2 -, -CH 2 O-,
- R 2 and R 3 are independently -H, -C 1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -COR a , -COR a ,
- R 2 and R 3j 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 a , -CONR a R , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2 NR a R b ,
- R 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 a , -CN, -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SOiNRaRi,
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- the compounds of Formulae I and II are especially potent inhibitors of the c- fms protein tyrosine kinase.
- the compounds of Formula 111 are expected to exhibit similar inhibitory potencies.
- the invention also relates to methods of inhibiting protein tyrosme 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 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 a ,
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -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 a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 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 a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2 NR a R b
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1- alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SO 3 R a or -SO 2 NR a R b ; or
- 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 -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 a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R , -N(R a )COR b , -NO 2 , -SO 2 R a , -SO 3 R a or
- a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -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 a , -CN,-C(NH)NH 2 , -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 Ra, -SO 3 R a or -SO 2 NR
- Ri is -H, aryl, -COR a , -COR a , -COOR a , -CONR a R b , -SO 2 R a or -SO 2 NR a R b ;
- R 2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens;
- W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C 1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF 3 , alkoxy, aryloxy, arylalkoxy, -OCF 3 , -COR a , -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -NHCOR a R b , -NHSO 2 R a , -NO 2 , -SOR a , -SO 3 R a or -SO 2 NR a R b ; or
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- A is a 5- to 6-membered 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, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3 , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a ,
- 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 ⁇ - 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 a , -CONR a R b , -N(R a )COR , -NO 2 , -SO 2 R a , -SO 3 R a or -SO 2 NR a R b , and
- -H, -C 1-6 alkyl 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 a , -CN,
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- Preferred compounds of Formula I are those wherein A is phenyl; R ⁇ is -H; and
- R 2 and R 3 taken together with the attached nitrogen, form a piperidine, piperazine, morpholine, thiomorpho ne, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or imidazoline 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, -COOR a , -CONR a R b , -N(R a )COR b , -NO 2 , -SO 2 R a
- R a and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
- Particularly preferred compounds of Formula I are those wherein
- A is phenyl
- R ⁇ is -H; R 2 and R , 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 1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF 3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -COR a , -CN, -C(NH)NH 2 , -COORa, -CONR a R , -N(R a )COR b , -NO
- 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 a , -CONR 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
- Ri 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, -CORa, -CN, -C(NH)NH 2 , -COOR a , -CONR a R b , -
- Ra and R b are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl. It is expected that the preferred compounds of Formula III will have similar or identical R 2 and R 3 substituents as compared to the preferred compounds of Formulae I and II.
- 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-piperidin-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-phenyl)-amide; 5- nitro-furan-2-carboxylic acid [2-
- 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.
- 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 tyrosme 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 transfonned 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.
- 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 and imidazolinyl.
- 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, py ⁇ olyl, 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 C 1-6 alkyl group containing an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.
- heteroarylkyl refers to a C 1-6 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.
- 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 a , 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 Fo ⁇ nula 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 HI 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. Also, 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.
- each well received 10 ⁇ L of a 1:1:3 mixture of anti-phosphotyrosine antibody, 10X, PTK green tracer, 10X (vortexed), FP dilution buffer, respectively (all from PanVera, cat. # P2837).
- the plate was covered, incubated for 30 min at room temperature and the fluorescence polarization was read on the Analyst.
- the instrument settings were: 485 nm excitation filter; 530 nm 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 IC 50 values are averages of three independent measurements.
- Table 1 lists representative compounds of Formulae I and II of the invention. TABLE 1
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Abstract
The invention is directed to compounds of formulae (I), (II) and (III), 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
c-fms Kinase Inhibitors
Inventors
Mark R. Player, Nand Baindur, Benjamin M. Brandt, Naresh Chadl a, Raymond J. Patch, Davoud Asgari, and Taxiarchis Georgiadis
Related Applications
This application claims the benefit of U.S. Provisional Application 60/406,033 (filed August 27, 2002) and U.S. Provisional Application 60/384,171 (filed May 31, 2002) both of which are hereby incorporated by reference in their entirety.
Field of the Invention
The invention relates to novel compounds that function as protein tyro sine kinase inhibitors. More particularly, the invention relates to novel compounds that function as inhibitors of c-fms kinase.
Background of the Invention
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. As a consequence, 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-1, 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 ('TR") and insulin-like growth factor I receptor ("IGF-1R") are structurally and functionally related but exert distinct biological effects. IGF-1R over-expression has been associated with breast cancer.
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. Vascular endothelial growth factor ("VEGF"), a potent mitogen of endothelial cells, is produced in elevated amounts by many tumors, including ovarian carcinomas.
The known receptors for VEGF are designated as VEGFR-1 (Flt-1), VEGFR-2
(KDR), VEGFR-3 (Flt-4). 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. U.S. Patent Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and PCT International Applications WO 01/47897, WO 00/27820 and WO 02/068406 are indicative of recent attempts to synthesize such inhibitors.
Summary of the Invention
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:
-SO2NRaR ; or
a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO^, -SO3Ra or -SO2NRaRb;
-H, aryl, -CORa, -CORa, -COORa, -CONRaR , -SO2Ra or -SO2NRaRb; X is
-CO-, -C(=NH)-, -CS-, -CON(Ra)-, -CS(NRa)-, -SO2- or -CRaRb-;
R2 and R3 are independently
-H, -C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -CORa, -CORa, -COORa,-CONRaR , -SO2Ra or -SO2NRaR ; or
R2 and R3; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa,
-CONRaRb, -N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ; and
W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -NHCORaRb, -NHSO2Ra, -NO2, -SORa, -SOsR, or -SO2NRaRb; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO- alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR ,
-N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
In another embodiment, the invention is directed to the novel compounds of Formula II:
II or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein
A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN,
-C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or
-SO2NRaRb; or
a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3,
-OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)COR , -NO2,
-SO2Ra, -SO3Ra or -SO2NRaRb;
Ri is -H, aryl, -CORa, -CORa, -COORa, -CONRaRb, -SO2Ra or -SO2NRaRb;
Xis
-CO-, -C(=NH)-, -CS-, -CON(Ra)-, -CS(NRa)-, -SO2- or -CRaRb-;
Y is
-S-, -SO-, -SO2-, -O- or direct link;
R2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens; and
W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1- alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -NHCORaRb, -NHSO2Ra, -NO2, -SORa, -SOsR, or -SO2NRaR ; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO- alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
Yet another embodiment of the invention is directed to the compounds of Formula III:
-CORa,-CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb;
X is -CO-, -C(=NH)-, -SO2- or -CS-;
Y is direct bond, -CH2-, -CH2CH2-, -CE CH-, -NRa-, -O-, -S-, -SO-, -SO2-, -CH2O-,
-OCH2-, -NRaCH2-, -CH2NRa-, -CONRa- or -NRaCO-;
Rt is
-H, aryl, -CORa, -CORa, -COORa, -CONRaRb, -SO2Ra or -SO2NRaR ;
R2 and R3 are independently -H, -C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -CORa, -CORa,
-COORa,-CONRaRb, -SO2Ra or -SO2NRaR ; or
R2 and R3j 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, and
R is one or more of -H, -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy,
aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SOiNRaRi,,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
The compounds of Formulae I and II are especially potent inhibitors of the c- fms protein tyrosine kinase. The compounds of Formula 111 are expected to exhibit similar inhibitory potencies. The invention also relates to methods of inhibiting protein tyrosme kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, II or III.
Detailed Description of the Invention 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa,
-CN,-C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ; or
a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be
optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ;
Ri is
-H, aryl, -CORa, -CORa, -COORa, -CONRaR , -SO2Ra or -SO2NRaR ;
X is
-CO-, -C(=NH)-, -CS-, -CON(Ra)-, -CS(NRa)-, -SO2- or -CRaRb-;
R2 and R3 are independently
-H, -C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -CORa, -CORa, -COORa,-CONRaRb, -SO2Ra or -SO2NRaR ; or
R2 and R3; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb; and
W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1- alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -NHCORaRb, -NHSO2Ra, -NO2, -SORa, -SO3Ra or -SO2NRaRb; 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 -C1-6 alkyl, amino, aminoalkyl,
hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO- alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
In another embodiment, the invention is directed to the novel compounds of Formula II:
II or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or
-SO2NRaR ; or
a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN,-C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb;
Ri is
-H, aryl, -CORa, -CORa, -COORa, -CONRaRb, -SO2Ra or -SO2NRaRb;
X is
-CO-, -C(=NH)-, -CS-, -CON(Ra)-, -CS(NRa)-, -SO2- or -CRaRb-;
Y is
-S-, -SO-, -SO2-, -O- or direct link;
R2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted with one or more halogens; and
W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -NHCORaRb, -NHSO2Ra, -NO2, -SORa, -SO3Ra or -SO2NRaRb; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO- alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR ,
-N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
Yet another embodiment of the invention is directed to the compounds of Formula III:
-CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or
-SO2NRaRb;
X is
-CO-, -C(=NH)-, -SO2- or -CS-
Y is direct bond, -CH2-, -CH2CH2-, -CH=CH-, -NRa-, -O-, -S-, -SO-, -SO2-, -CH2O- -OCH2-, -NRaCH2-, -CH2NRa-, -CONRa- or -NRaCO-;
-H, aryl, -CORa, -CORa, -COORa, -CONRaRb, -SO2Ra or -SO2NRaR ;
R2 and R3 are independently
-H, -C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -CORa, -CORa, -COORa,-CONRaRb, -SO2Ra or -SO2NRaRb; or
R2 and R3; 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 -Cι-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy,-OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, and
is one or more of -H, -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN,
-COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
Preferred compounds of Formula I are those wherein A is phenyl; Rγ is -H; and
R2 and R3, taken together with the attached nitrogen, form a piperidine, piperazine, morpholine, thiomorpho ne, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine or imidazoline ring which may be optionally substituted with -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
Particularly preferred compounds of Formula I are those wherein
A is phenyl;
Rι is -H;
R2 and R , 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF , -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb; and
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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO- alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
Preferred compounds of Formula II are those wherein
A is phenyl;
Ri is -H; and
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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO- alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ,
wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
It is expected that the preferred compounds of Formula III will have similar or identical R2 and R3 substituents as compared to the preferred compounds of Formulae I and II.
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-piperidin-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-phenyl)-amide; 5- nitro-furan-2-carboxylic acid [2-(trans-2,6-dimethyl-mo holin-4-yl)-phenyl] -amide; 3-nitro-N-(2-piperidin-l-yl-phenyl)-benzamide; 5-bromo-iuran-2-carboxylic acid (2- piperidin-l-yl-phenyl)-amide; 5-acetyl-thiophene-2-carboxylic acid (2-piperidin-l-yl- phenyl)-amide; 5-nitro-furan-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)- phenyl]-amide; 4-nitro-2H-pyrazole-3-carboxylic acid (2-piperidin-l-yl-phenyl)- amide; 5-formyl-furan-2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; 5-(2- piperidin-l-yl-phenylcarbamoyl)-furan-2-carboxylic acid; isoxazole-5-carboxylic acid (2-moφholin-4-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (2-piperidin-l-yl- phenyl)-amide; 5-nitiO-furan-2-carboxylic acid [2-(4-methyl-piperidin-l-yI)-phenyι]- amide; 5-nitro-furan-2-carboxylic acid [2-(4-methyl-piperazin-l-yl)-phenyl]-amide; 5-nitro-furan-2-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-phenyl] -amide; 5-nitro- furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-l-yl)-phenyl]-amide; 5-nitro- furan-2-carboxylic acid (2-azepan-l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidin-l-yl-phenyl)-amide; 5-cyano-furan 2-carboxylic acid [2-(4-methyl-piperidin-l-yl)-phenyl]-amide; 5-cyano-furan-2-carboxylic acid [2- (4-hydroxymethyl-piperidin-l-yl)-phenyl]-amide; 5-cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l-yl]-phenyl}-amide; 5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-l-yl)-phenyl]-amide; 5-cyano-furan-2- carboxylic acid [5-hydroxymethyl-2-(4-hydroxymethyl-piperidin-l-yl)-phenyl]- amide; 5-cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-l-yl)-5-hydroxymethyl- phenylj-amide; 5-cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l- yl]-5-hydroxymethyl-phenyl} -amide; 5-cyano-furan-2-carboxylic acid [2-(4-ethyl-
piperidin-l-yl)-phenyl] -amide; 4-nitro-lH-pyrrole-2-carboxylic acid [2-(4-ethyl- piperidin-l-yl)-phenyl]-amide; 4-nitro-lH-pyrrole-2-carboxylic acid [2-(4-methyl- piperidin-l-yl)-phenyl]-amide; 4-nitro-lH-pyπole-2-carboxylic acid [5- hydroxymethyl-2-(4-methyl-piperidin-l-yl)-phenyl]-amide; 4-nitro-lH-pyrrole-2- carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidin-l-yl)-phenyl]-amide; 4-nitro- lH-pyrrole-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l-yl]-5- hydroxymethyl-phenyl} -amide; 4-cyano-lH-pyrrole-2-carboxylic acid (2-piperidin-l- yl-phenyl)-amide; 4-cyano-lH-pyrrole-2-carboxylic acid [2-(4-ethyl-piperidin-l-yl)- phenyl] -amide; 4-cyano-lH-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-l-yl)- phenyl]-amide; 4-cyano-lH-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4- methyl-piperidin-l-yl)-phenyl] -amide; 4-cyano-lH-pyrrole-2-carboxylic acid [5- hydroxymethyl-2-(4-ethyl-piperidin-l-yl)-phenyl] -amide; 4-cyano-lH-pyrrole-2- carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l-yl]-5-hydroxymethyl-phenyl}- amide; 5-cyano-furan-2-carboxylic acid (5-methylsulfonamidomethyl-2-piperidin-l- yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-guanidinomethyl-2-piperidin-l- yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid [5-(4-methyl-piperazin-l- ylmethyl)-2-piperidin-l-yl-phenyl]-amide; 5-cyano-furan-2-carboxylic acid (4-fluoro- 2-piperidin-l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (4-chloro-2- piperidin-l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-cyano-2-piperidin- l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid {5-[(2,3-dihydroxy- propylamino)-methyl]-2-piperidin-l-yl-phenyl}-amide; 5-nitro-2H-pyrazole-3- carboxylic acid (2-piperidin-l-yl-phenyl)-amide and pharmaceutically acceptable salts thereof.
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.
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 tyrosme 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. In addition, 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 transfonned into active drugs by in vivo enzymatic or chemical processes.
I. Definitions
The term "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.
The term "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. The term "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 and imidazolinyl.
The term "heterocyclylalkyl" refers to a C1-6 alkyl group containing a heterocyclyl substituent. Examples include dihydropyranylethyl and 2- morpholinylpropyl.
The term "hydroxyalkyl" refers to at least one hydroxyl group bonded to any carbon atom along an alkyl chain.
The term "aminoalkyl" refers to at least one primary or secondary amino group bonded to any carbon atom along an alkyl chain.
The term "alkoxyalkyl" refers to at least one alkoxy group bonded to any carbon atom along an alkyl chain. The term "polyalkoxyalkyl" refers to long-chain alkoxy compounds and ' includes polyethylene glycols of discreet or monodispersed sizes.
The term "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.
The term "carboxyalkyl" refers to at least one carboxylate group bonded to any carbon atom along an alkyl chain. The term "carboxylate group" includes carboxylic acids and alkyl, cycloalkyl, aryl or aralkyl carboxylate esters.
The term "heteroaromatic" or "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, pyπolyl, quinolinyl, thiazolyl and thienyl.
The tenn "heteroaralkyl" refers to a C1-6 alkyl group having a heteroaryl substituent. Examples include furylethyl and 2-quinolinylpropyl.
The term "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.
The term "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.
The term "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.
The term "aralkyl" refers to a C1-6 alkyl group containing an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.
The term "heteroaralkyl" refers to a C1-6 alkyl group containing a heteroaryl substituent. Examples include furylmethyl and pyridylpropyl.
The term "aryloxy" refers to an oxygen atom bound to an aryl substituent. Examples include phenoxy and benzyloxy. The term "arylalkoxy" refers to an alkoxy group bound to an aryl substituent.
Examples include phenylmethyl ether.
The term "acyl" refers to the group -C(O)Ra, where Ra is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. An "acylating agent" adds the -C(O)Ra group to a molecule.
The term "sulfonyl" refers to the group -S(O)2Ra, where Ra is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. A "sulfonylating agent" adds the -S(O)2Ra group to a molecule.
II. Therapeutic Uses
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. In one embodiment of inhibiting a protein tyrosine kinase, at least one of the compounds of Formula I, II or III is combined with a known tyrosine kinase inhibitor. In various embodiments of the invention, 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. In one embodiment of the invention, 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 Foπnula I, II or III. Example of diseases that may be effectively treated include glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia and Alzheimer's dementia.
When employed as protein tyrosine kinase inhibitors, 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 HI include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases. Examples of such 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. Also, the basic nitrogen-containing groups may be quaternized with, for example, alkyl halides.
The pharmaceutical 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.
III. Methods of Preparation 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.
EXAMPLE 1 (General Procedure for Preparation of Amides) 5-Nitro-furan-2-carboxylic acid phenylamides
A solution of aniline (10 mg, 0.069 mmol) in dioxane (0.5 mL) was treated with polystyrene ("PS") moφholine resin (Aldrich) (50 mg, 0.14 mmol), followed by the addition of a solution of 5-nifro-furan-2-carbonyl chloride (Lancaster) (15 mg, 0.086 mmol) in dioxane (0.5 mL). The reaction was heated to 70 °C and agitated for 2 h. The reaction was treated with PS trisamine (Aldrich) (25 mg, 0.12 mmol) and heated to 70 °C for an additional 2 h. Filtration gave the desired product in > 80 % yield.
EXAMPLE 2 (Procedure 2 for Preparation of Amides) Isoxazole-5-carboxylic acid (2-piperidin-l-yl-phenviy amide
EXAMPLE 2-A 5-Nitro-furan-2-carboxylic acid (2-piperidin-l-yl-phenyl -amide
The compound was prepared according to the procedure described in Example 2 from 5-nitro-furan-2-carbonyl chloride and 2-piperidinoaniline. Yield: 100 %. MS: 316 (M+1). LC/MS purity: 100 %. 1HNMR (CDCI3, 300 MHz): δ 8.2 (d, IH), 7.85 (d, IH), 7.55 (m, IH), 7.4 (m, 3H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 6H).
EXAMPLE 3 (Procedure 3 for Preparation of Amides) 5-Nitro-thiophene-2-carboxylic acid (2-piperidin- 1 -yl-phenyl )-amide
To PS-HOBt resin (0.15 mmol) was added 2 mL of a solution of pyridine (0.09 mmol) in DCM and 0.6 mL of a solution of the carboxylic acid (0.23 mmol) in N, N-dimethyl formamide ("DMF"). The mixture was shaken at room temperature for 5 min before the addition of 0.4 mL of a solution of 1,3-diisopropylcarbodiimide ("DIG") (0.66 mmol) in DCM. The mixture was shaken at room temperature for 3 h and filtered. The resin was washed with DMF (3 x), THF (3 x) and DCM (3 x) and dried in vacuo. To this acyl resin was added a solution of 2-piperidinoaniline (0.075 mmol; 0.5 eq) in anhydrous THF (1 mL) and the mixture was shaken at room temperature for 16 h. The reaction was then filtered and the resin washed with THF and DCM. The combined filtrate and washings were concentrated in vacuo to yield the product. MS: 332 (M+1). LC/MS: 100 % purity. 1H NMR (CDC13, 300 MHz): 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).
EXAMPLE 4 (Procedure 4 for Preparation of Amides) 5-Bromo-furan-2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide
A solution of 5-bromofuroic acid (Aldrich) (1.0 mmol), 2-piperdinoaniline (1.0 mmol), 1-hydroxybenzotriazole hydrate ("HOBT") (1.2 mmol), and triethylamine ("Et3N") (2 mmol) in DCM (10 mL) was stirred for 10 min at room temperature. 1-
(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de ("EDCI") (1.2 mmol) was then added and the resulting orange solution was stirred overnight. The reaction mixture was treated with saturated sodium bicarbonate ("NaHCO3") solution (10 mL) and extracted with DCM. The combined organic layers were dried over MgSO , and concentrated under reduced pressure to afford the crude product as an orange solid. Purification by silica gel chromatography afforded the pure yellow product in 85 % yield. MS: 349 (M+1). 1H NMR (CDC13, 300 MHz): δ 9.75 (br s, IH), 8.45 (d, IH), 7.22-7.05 (m, 4H), 6.50 (d, IH), 3.00-2.80 (m, 4H), 1.95-1.80 (m, 4H), 1.75-1.60 (m, 2H).
EXAMPLE 4-A 5-(2-Piperidin-l-yl-phenylcarbamoyl -furan-2-carboxylic acid
A solution of 5-formyl-2-furancarboxylic acid (TCI) (1.0 mmol), 2- piperidinoaniline (1.0 mmol), HOBT (1.2 mmol), and Et3N (2 mmol) in DCM (10 mL) was stirred for 10 min at room temperature. EDCI (1.2 mmol) was then added and the resulting orange solution was stirred overnight. The reaction mixture was treated with saturated NaHCO3 solution (10 mL) and extracted with DCM. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure to afford the crude product as an orange solid. Purification by silica gel chromatography afforded the amidoaldehyde product in 80 % yield. The aldehyde product (1 mmol) was dissolved in H O/dimethoxyethane ("DME") (2:1, 5 mL) containing sodium carbonate ("Na2CO3") (2 mol). In a separate flask, potassium permanganate ("KMnO4") (1.3 mmol) was dissolved in H2O (5 mL) and was slowly added to the reaction flask at 45 °C. The reaction was stirred overnight at room temperature, filtered through a plug of celite, and then acidified to a pH of 3 to 4 using a hydrochloric acid ("HCI") solution (I N). The product, which precipitated out as a white solid, was filtered, washed with H O and dried under high vacuum to
afford pure product. MS: 315 (M+1). 1H NMR (DMSO-d6, 300 MHz): δ 13.60 (br s, IH), 9.90 (s, IH), 8.25 (dd, IH), 7.36 (dd, 2H), 7.35-7.25 (m, IH), 7.20-7.10 (m, 2H), 2.85-2.65 (m, 4H), 1.85-1.65 (m, 4H), 1.65-1.45 (m, 2H).
EXAMPLE 5 (Procedure for Preparation of Reduced Amides) 5-(TS[itro-furan-2-ylmethyl)-(2-piperidm-l-yl-phenylVamine
A solution of 2-piperidinoaniline (1 mmol), 5-nitro-furan-2-carbaldehyde (1.1 mmol) and sodium triacetoxyborohydride ("NaBH(OAc)3") (2 mmol) in anhydrous
DCM (10 mL) was stirred 16 h at room temperature. The mixture was then washed successively with water, dilute aqueous sodium hydroxide ("NaOH"), water and brine before being dried over MgSO4, filtered and concentrated under reduced pressure.
Purification of the residual oil by flash silica gel chromatography yielded the product.
MS : 301 (M+1). LC/MS purity: 100 %. 1H NMR (CDC13, 300 MHz): δ 7.25 (d,
IH), 7.15-6.95 (m, 2H), 6.75 (t, IH), 6.55 (d, IH), 6.4 (d, IH), 5.4 (bs, IH), 4.45 (s,
2H), 2.8 (bm, 4H), 1.8-1.5 (bm, 6H).
EXAMPLE 6 (Preparation of 5-Cyano-furan-2-carboxylic acid [5-hydroxymethyl-2- (4-methyl-piperidin- 1 -yι)-phenyl]-amide)
A. 2-Cvano-5-furancarboxylic acid
To a solution of 2-formyl-5-furancarboxylic acid (0.28 g, 2.0 mol) in pyridine (5.0 mL) was added hydroxylamine hydrochloride ("NH2OHΗCl") (0.27 g, 4.0 mol). The mixture was heated to 85 °C before the addition of acetic anhydride (4.0 ml). The
reaction mixture was stirred at 85 °C for 3 h, cooled to 60 °C and poured into water (25 mL). The mixture was cooled to room temperature and stirred overnight (the pH of the solution was measured to be 5-6). The impurities were extracted with a solution of 4/1 DCM/isopropanol (3 x 30 mL). The aqueous layer was then basified with NaOH solution (2 N) to a pH of about 9, and the pyridine was extracted with a solution of 4/1 DCM isopropanol (3 x 30 mL). The aqueous solution was then acidified to a pH of about 2 and the product was extracted with a solution of 3/1 DCM/isopropanol (3 x 50 mL). The combined organic extracts were dried over MgSO4, and the solvent was evaporated to afforded the pure product as a light brown solid in 90 % yield. 1H NMR (DMSO-d6): δ 13.80 (bs, IH), 7.75 (d, IH), 7.40 (d, IH). TR (neat): (cm"1) 3200, 2250, 1053, 1025, 1006.
B. 4-(4-Methyl-piperidin-l-yl -3-nitro-phenyl1-methanol
A stirred suspension of (4-fluoro-3-nitro-phenyl)-methanol (171 mg, 1 mmol), 4-methyl piperidine (95 mg, 0.96 mmol) PS moφholine (400 mg, 1 mmol), and chloroform (3 mL) was heated at 50 °C for 2 hrs. The reaction was evaporated onto celite and purified by flash cliromatography to give [4-(4-methyl-piperidin-l-yl)-3- nitro-phenyl]-methanol (i). 1H NMR (CDC13, 300 MHz): δ 7.8 (s, IH), 7.4 (d, IH), 7.1 (d, 1 H), 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-furan-2-carboxylic acid [5-hvdroxymethyl-2- 4-methyl-ρiperidin- 1 - vD-phenyl] -amide
PS - Morpholine
A suspension of 5 % Pd/C (5.0 mg, 2.3 x 10" mmol), [4-(4-methyl-piperidin- l-yl)-3-nitro-phenyl]-methanol (i) (95 mg, 0.38 mmol), acetic acid ("HO Ac") (23 mg, 0.38 mmol), methanol (1 mL) and ethyl acetate (4 mL) was stirred in an atmosphere of hydrogen for 3 h. The reaction was filtered, concentrated in vacuo and the resulting [3-amino-4-(4-methyl-piperidin-l-yl)-phenyl]-methanol was used in the next step without further purification. A suspension of [3-amino-4-(4-methyl-piperidin-l- yl)-phenyl] -methanol, 5-cyano-2-furoyl chloride (64 mg, 0.44 mmol), PS moφholine (600 mg, 1.50 mmol), and DCM (10 mL) was stirred at room temperature for 30 min. The reaction was evaporated onto celite, and purified by column chromatography to give 5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-l-yl)- phenyl]-amide. MS: 340 (M + 1), 1H NMR (CDC13, 300 MHz): δ 9.9 (s br, IH), 8.4 (s, IH), 7.3 (s, IH), 7.25-7.1 (m, 3H), 4.7 (s, 2H), 3.0 (m, 2 H), 2.8 (m, 2H), 1.9, (d, 2H), 1.8-1.4 (m, 3H), 1.1 (d, 3H).
EXAMPLE 7 (Procedure for Preparation of Biarylamides) 5-Phenyl-furan-2-carboxylic acid ("2-piperidin-l-yl-phenylVamide
5-Bromo-furan-2-carboxylic acid (2-piperidin-l-yl-phenyl)-amide (1.0 mmol), phenylboronic acid (1.2 mmol), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) ["Pd(dppf)2Cl2"] (Aldrich) (0.05 mmol) and Na2CO3 (3.0 mmol) were dissolved in a solution of THF/H2O (4:1, 5 mL; saturated with argon) and heated to 80 °C for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the resulting
residue was purified by silica gel cliromatography to afford the pure product. Yield: 75 %. MS: 347 (M+1). 1H NMR (CDC13, 300 MHz): δ 9.90 (br s, IH), 8.50 (d, IH), 7.82 (d, 2H), 7.50-7.28 (m, 4H), 7.24-7.05 (m, 3H), 6.82 (d, IH), 3.00-2.80 (m, 4H), 1.95-1.80 (m, 4H), 1.75-1.60 (m, 2H).
EXAMPLE 8 (Procedure for Extension of Aromatic Rings Through Animation) 5-Phenylamino-furan-2-carboxylie acid (2-piperidin- 1 -yl-phenyl -amide
To a solution of 5-bromo-furan-2-carboxylic acid (2-piperidin- 1-yl-phenyl)- amide (1.0 mmol) in toluene (7.5 mL) was added aniline (1.3 mmol), tris(dibenzylidineacetone)dipalladium(0) ("Pd2dba") (Aldrich) (0.05 mmol), 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl ("BLNAP") (0.1 mmol), and potassium tert- butoxide ("t-BuOK") (1.5 mmol), and the resulting mixture was refluxed overnight. The reaction was then cooled to room temperature, passed through a plug of silica and concentrated. Purification of the dark brown residue by HPLC afforded the product. Yield: 40 %. MS: 362 (M+1).
EXAMPLE 9 (Procedure 1 for Preparation of the Compounds of Formula IH) 4-Oxo-6-piperidin-l-yl-4,5-dihvdro-furo|"2,3-clquinoline-2-carbonitrile
EXAMPLE 10 (Procedure 2 for Preparation of the Compounds of Formula III) 4-Oxo-6-piperidin-l-yl-4,5-dihvdro-furo[2,3-clquinoline-2-carbonitrile
(i)
A solution of 2-nitro-3-bromotoluene (1.8 g, 8.3 mmol), piperidine (10 mL, 101 mmol), and dioxane (85 mL) was heated to reflux for 56 h. The reaction was filtered, concentrated and evaporated onto Celite. Chromatography on silica gel gave 1 -(3-methyl-2-nitro-phenyl)-piperidine (i).
(i) (ϋ)
A solution of l-(3-methyl-2-mtro-phenyl)-piperidine (i) in THF is treated with lithium diisopropylamide ("LDA") (1 eq), followed by diethyl oxalate (1.05 eq), at 0 °C. The reaction is allowed to warm to room temperature over 90 min. The reaction is diluted with water and ether, partitioned, and the aqueous layer is washed with ether. The combined organic layers are dried over MgSO , filtered and concentrated. Chromatography gives 3-(2-nitro-3-piperidin-l-yl-phenyl)-2-oxo-propionic acid ethyl ester (ii).
(ii) (iii)
A solution of 3-(2-nitro-3-piperidin-l-yl-phenyl)-2-oxo-propionic acid ethyl ester (ii) in THF is treated with potassium ethoxide ("KOEt") (1 eq), followed by bromoethyl pyruvate (1.05 eq), at 0 °C. The reaction is allowed to warm to room temperature over 90 min. The reaction is diluted with water and ether, partitioned, and the aqueous layer is washed with ether. The combined organic layers are dried over MgSO4, filtered and concentrated. Chromatography gives 3-(2-nitro-3-piperidin- l-yl-phenyl)-2,5-dioxo-hexanedioic acid diethyl ester (iii).
A solution of 3-(2-nitro-3-piperidin- 1 -yl-phenyl)-2,5-dioxo-hexanedioic acid diethyl ester (iii) in THF is treated with acetic acid ("HO Ac") and is stirred at room temperature for 4 h. The reaction is treated with zinc dust (10 eq) and is stirred for an additional 2 h. The reaction is diluted with DCM, half saturated brine, and partitioned. The organic layer is washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated. Chromatography gives 4-oxo-6-piperidin-l-yl-4,5- dihydro-furo[2,3-c]quinoline-2-carboxylic acid ethyl ester (iv).
(iv) (v)
A solution of 4-oxo-6-piperidin-l-yl-4,5-dihydro-furo[2,3-c]quinoline-2- carboxylic acid ethyl ester (iv) in DCM at 0 °C is treated with diisobutylaluminum hydride ("DLBAL-H") and is allowed to warm to room temperature. The reaction is quenched with a saturated solution of sodium potassium tartrate and partitioned. The organic layer is dried over MgSO4, filtered and treated with manganese dioxide ("MnO2"). After stirring for 16 h at room temperature, the reaction is filtered and is concentrated to give 4-oxo-6-piperidin-l-yl-4,5-dihydro-furo[2,3-c]quinoline-2- carbaldehyde (v).
(v)
A solution of 4-oxo-6-piperidin-l-yl-4,5-dihydro-furo[2,3-c]quinoline-2- carbaldehyde (v) in isopropanol ("iPrOH") is treated with ammonia gas at room temperature. After 90 min, the reaction is treated with MnO2 and stirred for an additional 16 h. The reaction is filtered and evaporated onto celite. Cliromatography on silica gel affords 4-oxo-6-piperidin-l-yl-4,5-dihydro-furo[2,3-c]quinoline-2- carbonitrile.
IV. Results
An autophosphorylation, fluorescence polarization competition immunoassay was used to determine the potency for c-fms inhibition exhibited by selected compounds of Formulae I and II. The assay was performed in black 96-well microplates (LJL Bio Systems). The assay buffer used was 100 mM HEPES, pH 7.5, 1 mM DTT, 0.01 % (v/v) Tween-20. Compounds were diluted in assay buffer containing 4 % DMSO just prior to the assay. To each well, 5 μL of compound were added followed by the addition of 3 μL of a mix containing 33 nM c-fms (3 DP) and 16.7 mM MgCl2 (Sigma) in assay buffer. The kinase reaction was initiated by adding 2 μL of 5 mM ATP (Sigma) in assay buffer. The final concentrations in the assay were 10 nM c-fms, 1 mM ATP, 5 mM MgCl2, 2 % DMSO. Control reactions were ran in each plate: in positive and negative control wells, assay buffer (made 4 % in DMSO) was substituted for the compound; in addition, positive control wells received 1.2 μL of 50 mM EDTA.
The plates were incubated at room temperature for 45 min. At the end of the incubation, the reaction was quenched with 1.2 μL of 50 mM EDTA (EDTA was not added to the positive control wells at this point; see above). Following a 5-min incubation, each well received 10 μL of a 1:1:3 mixture of anti-phosphotyrosine antibody, 10X, PTK green tracer, 10X (vortexed), FP dilution buffer, respectively (all from PanVera, cat. # P2837). The plate was covered, incubated for 30 min at room temperature and the fluorescence polarization was read on the Analyst. The instrument settings were: 485 nm excitation filter; 530 nm 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 IC50 values are averages of three independent measurements.
Table 1 lists representative compounds of Formulae I and II of the invention.
TABLE 1
A: <1 μM
B: >1 μM
* = % Inhibition @ 2 μM
ND: not determined
Claims
The claimed invention is:
1. A compound of Formula I:
A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb; or a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SOzRa, -SO3Ra or -SO2NRaR ; Rx is
-H, aryl, -CORa, -CORa, -COORa, -CONRaR , -SO2Ra or -SO2NRaRb;
X is
-CO-, -C(=NH)-, -CS-, -CON(Ra)-, -CS(NRa)-, -SO2- or -CRaRb-;
R2 and R3 are independently
-H, -C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -CORa, -CORa, -COORa,-CONRaR , -SO2Ra or -SO2NRaR ; or R2 and R3; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa,
-CONRaR , -N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ; and
is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF3, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -NHCORaR , -NHSO2Ra, -NO2, -SORa, -SO3Ra or -SO2NRaR ; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO- alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
A compound of Formula II:
II or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein
A is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ; or a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with one or more of -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)COR , -NO2,
-SO2Ra, -SO3Ra or -SO2NRaR ;
-H, aryl, -CORa, -CORa, -COORa, -CONRaRb, -SO2Ra or -SO2NRaRb;
X is
-CO-, -C(=NH)-, -CS-, -CON(Ra)-, -CS(NRa)-, -SO2- or -CRaRb-
Y is
-S-, -SO-, -SO -, -O- or direct link; R2 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which maybe optionally substituted with one or more halogens; and
W is phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, halogen, hydroxy, -CF3, alkoxy, aryloxy, arylalkoxy, -OCF , -CORa, -CN, - C(NH)NH2,-COORa, -CONRaR , -NHCORaR , -NHSO2Ra, -NO2, -SORa, -SO3Ra or -SO2NRaRb; 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO- alkylamino, -OCO-alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
A compound of Formula III:
A is
a 5- to 6-membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa,
-CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaR ;
X is -CO-, -C(=NH)-, -SO2- or -CS-;
Y is direct bond, -CH2-, -CH2CH2-, -CH=CH-, -NRa-, -O-, -S-, -SO-, -SO2-, -CH2O-, -OCH2-, -NRaCH2-, -CH2NRa-, -CONRa- or -NRaCO-;
Rπs
-H, aryl, -CORa, -COR,, -COORa, -CONRaRb, -SO2Ra or -SO2NRaRb;
R2 and R3 are independently -H, -C1-6 alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, -CORa, -CORa,
-COORa,-CONRaRb, -SO2Ra or -SO2NRaRb; or
R2 and R3) 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaR , and
R4 is one or more of -H, -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, sulfonamidoalkyl, guanidinoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
4. A compound according to claim 1, wherein
A is phenyl; R\ is -H; and
R2 and R3, 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and R are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
5. A compound according to claim 4, wherein
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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO- alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaR , -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
6. A compound according to claim 2, wherein A is phenyl;
Ri is -H; and
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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO- alkylamido, -CORa, -CN, -C(NH)NH2, -COORa, -CONRaRb, -N(Ra)CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and R are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
7. A compound according to claim 3, wherein Ri is -H; and
R2 and R3, 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 -C1-6 alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, halogen, hydroxy, - CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -OCO-alkylamino, -OCO-alkylamido, -CORa, -CN, -COORa, -CONRaRb, -N(Ra)COR , -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
8. A compound of claim 1 , which is one of
5-nifro-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-piperidin-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-phenyl)-amide;
5-nitro-furan-2-carboxylic acid [2-(trans-2,6-dimethyl-morpholin-4-yl)-phenyl]- amide;
3-nitro-N-(2-piperidin-l-yl-phenyl)-benzamide;
5-bromo-furan-2-carboxylic acid (2-piperidin- l-yl-phenyl)-amide;
5-acetyl-thiophene-2-carboxylic acid (2-piperidin- 1 -yl-phenyl)-amide;
5-nitro-furan-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)-phenyl] -amide; 4-nitro-2H-pyrazole-3 -carboxylic acid (2-piperidin- 1 -yl-phenyl)-amide;
5-formyl-furan-2-carboxylic acid (2-piperidin- l-yl-phenyl)-amide;
5-(2-piperidin-l -yl-phenylcarbamoyl)-furan-2-carboxylic acid; isoxazole-5-carboxylic acid (2-morpholin-4-yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid (2-piperidin- l-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid [2-(4-methyl-piperidin-l-yl)-phenyl]-amide;
5-nitro-furan-2-carboxylic acid [2-(4-methyl-piperazin- 1 -yl)-phenyl]-amide;
5-nitro-furan-2-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-phenyl] -amide;
5-nitro-furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-l-yl)-phenyl]-amide;
5-nitro-furan-2-carboxylic acid (2-azepan-l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidin-l-yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin- 1 -yl)-phenyl]-amide;
-cyano-furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-l-yl)-phenyl] -amide; -cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l-yl]-phenyl}- amide; -cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-l-yl)- phenyl]-amide; -cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-hydroxymethyl-piperidin-l- yl)-phenyl]-amide; -cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-l-yl)-5-hydroxymethyl- phenyl]-amide; -cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l-yl]-5- hydroxymethyl-phenyl} -amide; -cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-l-yl)-phenyl] -amide; -nitro-lH-pyrrole-2-carboxylic acid [2-(4-ethyl-piperidin-l-yl)-phenyl]-amide; -nitro-lH-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-l-yl)-phenyl]-amide; -nitro-lH-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-l-yl)- phenyl] -amide; -nitro-lH-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidin-l-yl)- phenyl] -amide; -nitro- 1 H-pyrrole-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin- 1 -yl] -5- hydroxymethyl-phenyl} -amide; -cyano- 1 H-pyrrole-2-carboxylic acid (2-piperidin- 1 -yl-phenyl)-amide; -cyano- lH-pyrrole-2-carboxylic acid [2-(4-ethyl-piperidin- 1 -yl)-phenyl] -amide; -cyano- 1 H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin- 1 -yl)-phenyl]-amide; -cyano- lH-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-l-yl)- phenyl]-amide; -cyano- lH-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidin-l-yl)- phenyl] -amide; -cyano- lH-pyrrole-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-l-yl]-5- hydroxymethyl-phenyl} -amide; -cyano-furan-2-carboxylic acid (5-methylsulfonamidomethyl-2-piperidin-l-yl- phenyl)-amide; -cyano-furan-2-carboxylic acid (5-guanidinomethyl-2-pi eridin- 1 -yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid [5-(4-methyl-piperazin- 1 -ylmethyl)-2-piperidin- 1 -yl- phenyl] -amide; 5-cyano-furan-2-carboxylic acid (4-fluoro-2-piperidin- 1 -yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (4-chloro-2-piperidin-l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-cyano-2-piperidin-l-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid {5-[(2,3-dihydroxy-propylamino)-methyl]-2- piperidin- 1 -yl-phenyl} -amide; 5-nitro-2H-pyrazole-3-carboxylic acid (2-piperidin-l-yl-phenyl)-amide; and pharmaceutically acceptable salts thereof.
9. A compound of claim 2, which is one of 5-nitro-furan-2-carboxylic acid [2-(2-chloro- 1 , 1 ,2-trifluoro-ethylsulfanyl)-phenyl]- amide; 5-nitro-furan-2-carboxylic acid (2-ethoxyphenyl)-amide; and pharmaceutically acceptable salts thereof.
10. A pharmaceutical composition, comprising a compound of any one of claims 1 to 9 and a pharmaceutically acceptable carrier.
11. A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of any one of claims 1 to 9.
12. A method according to claim 11, wherein the protein tyrosine kinase is c-fms.
13. A method of treating inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 3.
14. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 3.
15. A method of treating cardiovascular disease in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 3.
16. A method of treating glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia or Alzheimer's dementia in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 3.
17. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of any one of claims 1 to 3.
18. A dosage form according to claim 17 adapted for parenteral or oral administration.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MXPA05011503A MXPA05011503A (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors. |
| EP04750617A EP1631560A2 (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors |
| JP2006513302A JP2007525460A (en) | 2003-04-25 | 2004-04-26 | c-fms kinase inhibitor |
| CA002536964A CA2536964A1 (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46520403P | 2003-04-25 | 2003-04-25 | |
| US60/465,204 | 2003-04-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2004096795A2 true WO2004096795A2 (en) | 2004-11-11 |
| WO2004096795A3 WO2004096795A3 (en) | 2005-03-10 |
Family
ID=33418203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2004/012729 Ceased WO2004096795A2 (en) | 2003-04-25 | 2004-04-26 | C-fms kinase inhibitors |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US7429603B2 (en) |
| EP (1) | EP1631560A2 (en) |
| JP (1) | JP2007525460A (en) |
| CA (1) | CA2536964A1 (en) |
| MX (1) | MXPA05011503A (en) |
| WO (1) | WO2004096795A2 (en) |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2004096795A3 (en) | 2005-03-10 |
| JP2007525460A (en) | 2007-09-06 |
| US20050004112A1 (en) | 2005-01-06 |
| CA2536964A1 (en) | 2004-11-11 |
| MXPA05011503A (en) | 2006-05-31 |
| US7429603B2 (en) | 2008-09-30 |
| EP1631560A2 (en) | 2006-03-08 |
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