# Patent

## Title
C-fms kinase inhibitors

## 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.

## Background
PRIORITY CLAIM
This application claims benefit under 35 U.S.C. § 119(e) to Provisional Application No. 60/465,204, filed Apr. 25, 2003.


FIELD OF THE INVENTION
The invention relates to novel compounds that function as protein tyrosine kinase inhibitors. More particularly, the invention relates to novel compounds that function as inhibitors of c-fms kinase.
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 (“IR”) 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. Pat. 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:




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)CORb, —NO2, —SO2Ra, —SO3Ra or —SO2NRaRb;
    
    
    R1 is
    
        —H, aryl, —CORa, —CORa, —COORa, —CONRaRb, —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, —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)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 C1-4 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, —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:




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)CORb, —NO2, —SO2Ra, —SO3Ra or —SO2NRaRb;
    
    
    R1 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, —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:




or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein

    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, —CONRaRb, —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—;
    
    
    R1 is
    
        —H, aryl, —CORa, —CORa, —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)CORb, —NO2, —SO2Ra, —SO3Ra or —SO2NRaRb, 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.

    
    


The compounds of Formulae I and II are especially potent inhibitors of the c-fms protein tyrosine kinase. The compounds of Formula III are expected to exhibit similar inhibitory potencies.
The invention also relates to methods of inhibiting protein tyrosine kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, II or III.


DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to the novel compounds of Formula I:




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)CORb, —NO2, —SO2Ra, —SO3Ra or —SO2NRaRb;
    
    
    R1 is
    
        —H, aryl, —CORa, —CORa, —COORa, —CONRaRb, —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, —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)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 C1-4 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, —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:




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)CORb, —NO2, —SO2Ra, —SO3Ra or —SO2NRaRb;
    
    
    R1 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, —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:




or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein

    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, —CONRaRb, —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—;
    
    
    R1 is
    
        —H, aryl, —CORa, —CORa, —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)CORb, —NO2, —SO2Ra, —SO3Ra or —SO2NRaRb, 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.

    
    


Preferred compounds of Formula I are those wherein

    A is phenyl;
    R1 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)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;
    R1 is —H;
    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, —C(NH)NH2, —COORa, —CONRaRb, —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 —SO2NRaRb,

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;
    R1 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 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-1-yl-phenyl)-amide; isoxazole-5-carboxylic acid (2-piperidin-1-yl-phenyl)-amide 5-nitro-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidin-1-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid [2-(3-methyl-piperidin-1-yl)-phenyl]-amide; 4-nitro-pyridine-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid (2-morpholin-4-yl-phenyl)-amide; 5-chloro-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid [2-(trans-2,6-dimethyl-morpholin-4-yl)-phenyl]-amide; 3-nitro-N-(2-piperidin-1-yl-phenyl)-benzamide; 5-bromo-furan-2-carboxylic acid (2-piperidin-1-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-1-yl-phenyl)-amide; 5-(2-piperidin-1-yl-phenylcarbamoyl)-furan-2-carboxylic acid; isoxazole-5-carboxylic acid (2-morpholin-4-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide; 5-nitro-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-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-1-yl)-phenyl]-amide; 5-nitro-furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide; 5-nitro-furan-2-carboxylic acid (2-azepan-1-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidin-1-yl-phenyl)-amide; 5-cyano-furan 2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide; 5-cyano-furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide; 5-cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-phenyl}-amide; 5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-1-yl)-phenyl]-amide; 5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide; 5-cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-1-yl)-5-hydroxymethyl-phenyl]-amide; 5-cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-5-hydroxymethyl-phenyl}-amide; 5-cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-1-yl)-phenyl]-amide; 4-nitro-1H-pyrrole-2-carboxylic acid [2-(4-ethyl-piperidin-1-yl)-phenyl]-amide; 4-nitro-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide; 4-nitro-1H-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-1-yl)-phenyl]-amide; 4-nitro-1H-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidin-1-yl)-phenyl]-amide; 4-nitro-1H-pyrrole-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-5-hydroxymethyl-phenyl}-amide; 4-cyano-1H-pyrrole-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide; 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-ethyl-piperidin-1-yl)-phenyl]-amide; 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide; 4-cyano-1H-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-1-yl)-phenyl]-amide; 4-cyano-1H-pyrrole-2-carboxylic acid [5-hydroxymethyl-2-(4-ethyl-piperidin-1-yl)-phenyl]-amide; 4-cyano-1H-pyrrole-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-5-hydroxymethyl-phenyl}-amide; 5-cyano-furan-2-carboxylic acid (5-methylsulfonamidomethyl-2-piperidin-1-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-guanidinomethyl-2-piperidin-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-1-yl-phenyl)-amide; 5-cyano-furan-2-carboxylic acid (5-cyano-2-piperidin-1-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-1-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-1,1,2-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 tyrosine kinase is c-fms.
The invention is considered to include the enantiomeric, diastereomeric and tautomeric forms of all compounds of Formulae I, II and III as well as their racemic mixtures. 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 transformed into active drugs by in vivo enzymatic or chemical processes.
1. 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, pyrrolyl, quinolinyl, thiazolyl and thienyl.
The term “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 Formula 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 III 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”) morpholine resin (Aldrich) (50 mg, 0.14 mmol), followed by the addition of a solution of 5-nitro-furan-2-carbonyl chloride (Lancaster) (15 mg, 0.086 mmol) in dioxane (0.5 mL). The reaction was heated to 70° 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-1-yl-phenyl)-amide




To PS-HOBt resin (0.1 mmol) was added anhydrous dichloromethane (“DCM”) (1 mL) followed by pyridine (0.5 mmol) and isoxazole-5-carbonyl chloride (Lancaster) (0.3 mmol). The mixture was shaken at room temperature for 3 h and was then filtered. The resin was washed successively with tetrahydrofuran (“THF”) (3×) and DCM (3×) and dried in vacuo. To this acylated resin was added a solution of 2-piperidinoaniline (Lancaster) (0.05 mmol, 0.5 eq) in anhydrous THF (1 mL) and the mixture was shaken at room temperature for 16 h. The mixtue was then filtered and the resin washed with THF and DCM as described above. The combined filtrate and washings were concentrated under reduced pressure to yield the product. Yield: 100%. MS: 272 (M+1). LC/MS purity: 100%. 1HNMR (CDCl3, 300 MHz): δ 8.2 (d, 1H), 7.85 (t, 2H), 7.55 (m, 1H), 7.4 (m, 2H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 4H).

EXAMPLE 2-A
5-Nitro-furan-2-carboxylic acid (2-piperidin-1-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 (CDCl3, 300 MHz): δ 8.2 (d, 1H), 7.85 (d, 1H), 7.55 (m, 1H), 7.4 (m, 3H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 6H).

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 (“DIC”) (0.66 mmol) in DCM. The mixture was shaken at room temperature for 3 h and filtered. The resin was washed with DMF (3×), THF (3×) and DCM (3×) 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 (CDCl3, 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-1-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 hydrochloride (“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 MgSO4, 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 (CDCl3, 300 MHz): δ 9.75 (br s, 1H), 8.45 (d, 1H), 7.22-7.05 (m, 4H), 6.50 (d, 1H), 3.00-2.80 (m, 4H), 1.95-1.80 (m, 4H), 1.75-1.60 (m, 2H).

EXAMPLE 4-A
5-(2-Piperidin-1-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 H2O/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 (“HCl”) solution (1 N). The product, which precipitated out as a white solid, was filtered, washed with H2O and dried under high vacuum to afford pure product. MS: 315 (M+1). 1H NMR (DMSO-d6, 300 MHz): δ 13.60 (br s, 1H), 9.90 (s, 1H), 8.25 (dd, 1H), 7.36 (dd, 2H), 7.35-7.25 (m, 1H), 7.20-7.10 (m, 2H), 2.85-2.65 (m, 4H), 1.85-1.65 (m, 4H), 1.65-1.45 (m, 2H).

EXAMPLE 5
Procedure for Preparation of Reduced Amides
5-(Nitro-furan-2-ylmethyl)-(2-piperidin-1-yl-phenyl)-amine




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 (CDCl3, 300 MHz): δ 7.25 (d, 1H), 7.15-6.95 (m, 2H), 6.75 (t, 1H), 6.55 (d, 1H), 5.4 (bs, 1H), 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-yl)-phenyl]-amide
A. 2-Cyano-5-furancarboxylic acid




To a solution of 2-fornyl-5-furancarboxylic acid (0.28 g, 2.0 mol) in pyridine (5.0 mL) was added hydroxylamine hydrochloride (“NH2OH.HCl”) (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 (3×30 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 (3×30 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 (3×50 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, 1H), 7.75 (d, 1H), 7.40 (d, 1H). IR (neat): (cm−1) 3200, 2250, 1053, 1025, 1006.

B. 4-(4-Methyl-piperidin-1-yl)-3-nitro-phenyl]-methanol




A stirred suspension of (4-fluoro-3-nitro-phenyl)-methanol (171 mg, 1 mmol), 4-methyl piperidine (95 mg, 0.96 mmol) PS morpholine (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 chromatography to give [4-(4-methyl-piperidin-1-yl)-3-nitro-phenyl]-methanol (i). 1H NMR (CDCl3, 300 MHz): δ 7.8 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.6 (s, 2H), 3.2 (d, 2H), 2.8 (dd, 2H), 1.8-1.3 (m, 5H), 1.0 (d, 3H).

C. 5-Cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-1-yl)-phenyl]-amide




A suspension of 5% Pd/C (5.0 mg, 2.3×10−3 mmol), [4-(4-methyl-piperidin-1-yl)-3-nitro-phenyl]-methanol (i) (95 mg, 0.38 mmol), acetic acid (“HOAc”) (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-1-yl)-phenyl]-methanol was used in the next step without further purification. A suspension of [3-amino-4-(4-methyl-piperidin-1-yl)-phenyl]-methanol, 5-cyano-2-furoyl chloride (64 mg, 0.44 mmol), PS morpholine (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-1-yl)-phenyl]-amide. MS: 340 (M+1), 1H NMR (CDCl3, 300 MHz): δ 9.9 (s br, 1H), 8.4 (s, 1H), 7.3 (s, 1H), 7.25-7.1 (m, 3H), 4.7 (s, 2H), 3.0 (m, 2H), 2.8 (m, 2H), 1.9, (d, 2H), 1.8-1.4 (m, 3H), 1.1 (d, 3H).

EXAMPLE 7
Procedure for Preparation of Biarylamides
5-Phenyl-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide




5-Bromo-furan-2-carboxylic acid (2-piperidin-1-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 chromatography to afford the pure product. Yield: 75%. MS: 347 (M+1). 1H NMR (CDCl3, 300 MHz): δ 9.90 (br s, 1H), 8.50 (d, 1H), 7.82 (d, 2H), 7.50-7.28 (m, 4H), 7.24-7.05 (m, 3H), 6.82 (d, 1H), 3.00-2.80 (m, 4H), 1.95-1.80 (m, 4H), 1.75-1.60 (m, 2H).

EXAMPLE 8
Procedure for Extension of Aromatic Rings Through Amination
5-Phenylamino-furan-2-carboxylic 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)-1,1′-binaphthyl (“BINAP”) (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 III
4-Oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]guinoline-2-carbonitrile




5-Cyano-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide (200 mg) is dissolved in a mixture of benzene (180 mL) and ethanol (20 mL). The solution is irradiated with a 100 W high pressure Hg Lamp at room temperature for 10 h, according to the method described by Kanoka and Itoh [Synthesis, 36 (1972)]. The solvent is removed in vacuo and the residue is purified by preparative thin layer chromatography (“TLC”) (silica gel) to yield the pure product.

EXAMPLE 10
Procedure 2 for Preparation of the Compounds of Formula III
4-Oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbonitrile




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).





A solution of 1-(3-methyl-2-nitro-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 MgSO4, filtered and concentrated. Chromatography gives 3-(2-nitro-3-piperidin-1-yl-phenyl)-2n-oxo-propionic acid ethyl ester (ii).





A solution of 3-(2-nitro-3-piperidin-1-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-1-yl-phenyl)-2,5-dioxo-hexanedioic acid di ethyl 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 (“HOAc”) 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-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carboxylic acid ethyl ester (iv).





A solution of 4-oxo-6-piperidin-1-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 (“DIBAL-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-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbaldehyde (v).





A solution of 4-oxo-6-piperidin-1-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. Chromatography on silica gel affords 4-oxo-6-piperidin-1-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 BioSystems). 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 (3DP) 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, 10×, PTK green tracer, 10× (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







% Inhibition


COMPOUND
IC50 (uM)
(at 10 μM)











A
100 


 






A
100 


 






A
97


 






A
99


 






A
99


 






A
100 


 






B
61


 






A
92


 






A
100 


 






A
98


 






A
100 


 






A
91


 






A
89


 






A
 99*


 






A
96


 






B
50


 






A
100 


 






B
90


 






B
89


 






B
88


 






B
87


 






B
80


 






B
77


 






B
68


 






B
60


 






B
72


 






B
61


 






B
56


 






B
24


 






B
86


 






B
 90*


 






A
 97*


 






A
ND


 






A
 90*


 






A
 94*


 






A
100*


 






A
 94*


 






A
 93*


 






A
 95*


 






B
 50*


 






A
 93*





A: <1 μM


B: >1 μM


*= % Inhibition @ 2 μM


ND: not determined

## Claims

1. A compound of Formula I:




or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein
A is phenyl, 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;
R1 is —H;
X is —CO—, or —CS—;
R2 and R3, taken together with the attached nitrogen, form a piperidine, or pyrrolidine 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,
and wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;
and
W is furyl 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.

2. A compound of claim 1, which is one of
5-nitro-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide;
5-nitro-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidin-1-yl-phenyl)-amide;
5-nitro-furan-2-carboxylic acid [2-(3-methyl-piperidin-1-yl)-phenyl]-amide;
5-chloro-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide;
5-bromo-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide;
5-formyl-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide;
5-nitro-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide;
5-nitro-furan-2-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-phenyl]-amide;
5-nitro-furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide;
5-cyano-furan-2-carboxylic acid (5-hydroxymethyl-2-piperidin-1-yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-phenyl]-amide;
5-cyano-furan-2-carboxylic acid [2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide;
5-cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-phenyl}-amide;
5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-methyl-piperidin-1-yl)-phenyl]-amide;
5-cyano-furan-2-carboxylic acid [5-hydroxymethyl-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide;
5-cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-1-yl)-5-hydroxymethyl-phenyl]-amide;
5-cyano-furan-2-carboxylic acid {2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-5-hydroxymnethyl-phenyl}-amide;
5-cyano-furan-2-carboxylic acid [2-(4-ethyl-piperidin-1-yl)-phenyl]-amide;
5-cyano-furan-2-carboxylic acid (5-methylsulfonamidomethyl-2-piperidin-1-yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid (5-guanidinomethyl-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-1-yl-phenyl)-amide;
5-cyano-furan-2-carboxylic acid (5-cyano-2-piperidin-1-yl-phenyl)-amide; and
5-cyano-furan-2-carboxylic acid {5-[(2,3-dihydroxy-propylamino)-methyl]-2-piperidin-1-yl-phenyl}-amide.