MXPA06000922A - Quinolinone derivatives as inhibitors of c-fms kinase - Google Patents

Abstract

The invention is directed to compounds of Formulae I and II:(I) (II) wherein R1, R2, R3, R5, R6, Y1, Y2, Y3, Y4 and X 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

QUINOLINONE DERIVATIVES AS INHIBITORS OF THE C-FMS KINASE REFERENCE TO RELATED REQUESTS This application is a non-provisional filing of the Provisional USSN 60 / 488,811, filed on July 22, 2003, now FIELD OF THE INVENTION The invention relates to novel compounds that function as inhibitors of the protein tyrosine kinase. More particularly, the invention relates to novel quinolinone derivatives, which function as inhibitors of the c-fms kinase.

BACKGROUND OF THE INVENTION Protein kinases are enzymes that serve as key components of the transduction pathways of the signal, catalyzing the transfer of the terminal phosphate of ATP to the hydroxy group of the tyrosine, serine and threonine protein residues. As a consequence, protein kinase inhibitors and substrates are valuable tools to assess the physiological consequences of protein kinase activation. It has been shown that overexpression or inappropriate expression of normal or mutant protein kinases in mammals plays significant roles in the development of many diseases, including cancer and diabetes. The protein kinases can be divided into two classes: those that preferentially phosphorylate the tyrosine residues (protein tyrosine kinases), and those which, preferably, phosphorylate serine and / or threonine residues (serine / threonine kinase proteins). The protein tyrosine kinases perform various functions that vary from growth stimulation and cell differentiation to stop cell proliferation. They can be classified as either receptor tyrosine kinase proteins or as intracellular tyrosine kinase proteins. The receptor tyrosine kinase proteins, which have an extracellular ligand binding domain and an intracellular catalytic domain with intrinsic tyrosine kinase activity, are distributed among 20 subfamilies. The family of epidermal growth factor receptor ("EGF") tyrosine kinases, which includes the HER-1, HER-2 / neu and HER-3 receptors, contains an extracellular binding domain, a transmembrane domain and a catalytic domain intracellular cytoplasmic. The receptor binding leads to the initiation of multiple intracellular tyrosine kinase-dependent phosphorylation processes, which ultimately result in the transcription of the oncogene. Breast, colorectal and prostate cancers have been linked to this family of receptors.

The insulin receptor ("IR") and the insulin-like growth factor I receptor ("IGF-1R") are structurally and functionally related, but exert different biological effects. The expression of IGF-1R has been associated with breast cancer. Platelet-derived growth factor receptors ("PDGF") mediate cellular responses that include proliferation, migration, and survival and include PDGFR, the germ cell factor receptor (c-kit), and c-fms. These receptors have been linked to diseases such as atherosclerosis, fibrosis and proliferative vitreoretinopathy. The fibroblast growth factor receptors ("FGR") consist of four receptors that are responsible for the production of blood vessels, the excrescence of the limbs and the growth and differentiation of numerous cell types. Vascular endothelial growth factor ("VEGF"), a potent mitogen of endothelial cells, is produced in high amounts by many tumors, including ovarian carcinomas. The known receptors for VEGF are designated VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4). A group of related receptors, tie-1 and tie-2 kinases, have been identified in vascular endothelial and hematopoietic cells. VEGF receptors have been linked to vasculogenesis and angiogenesis.

Intracellular tyrosine kinase proteins are also known as non-receptor tyrosine kinase proteins. More than 24 such kinases have been identified and classified into 11 subfamilies. The serine / threonine kinase proteins, as cellular tyrosine kinase proteins, are predominantly intracellular. Diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, rheumatoid arthritis, cardiovascular disease and cancer are examples of pathogenic conditions that have been linked to the abnormal activity of protein tyrosine kinase. Thus, there is a need for selective and potent small molecule protein tyrosine kinase inhibitors. The Patents of E.U.A. Nos. 6,383,790; 6,346,625; 6,235,746; 6,100,254 and the PCT International Applications WO 01/47897, WO 00/27820 and WO 02/068406 are indicative of recent attempts to synthesize such inhibitors.

BRIEF DESCRIPTION OF THE INVENTION The invention addresses the current need for selective and potent protein tyrosine kinase inhibitors, providing potent c-fms kinase inhibitors. One embodiment of the invention is directed to novel compounds of Formula I: (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is -H, C6 alkyl, cycloalkyl, aryl, aralkyl , heteroaryl, heteroaralkyl, -CORa, -COORa, -CONRaRb or -SO2Ra, R2 is phenyl, naphthyl or biaryl, each of which may be optionally substituted with one or more of C-? -6 alkyl, amino, aminoalkyl , heteroaryl, halogen, hydroxy, -CF3l alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2 , -SO2Ra, -SO3R, -SO2NRaRb, -N = C (Ra) -NRbRc, -CH2NRaRbl-CH2NRaRbNRcRd, -NRaSO2Rb, -NRaCONRbRc, or -CH2N (CH2CH2) 2NRa; or a mono- or 8- to 10-membered heteroaromatic or heterocyclic ring bicyclic, having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more C? 6, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb) -N02l -S02Ra > -SO3Ra, -SO2NRaRb, -N = C (Ra) -NRbRc, -CH2NRaRbl-CH2NRaRbNRcRd, -NRaSO2Rb, -NRaCONRbRc, -N (Ra) CON (Rb) -alkyl-Rc or -CH2N (CH2CH2) 2NRa; R3 is phenyl, naphthyl, biaryl or cycloalkyl, each of which may be optionally substituted with one or more of C-? 6 alkyl, C2-6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3 , alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2, -SRa, -SO2Ra, - NRaSO2Rb, -SO3Ra or -SO2NRaRb; or a 5- to 7-membered heterocyclic ring having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C? _ alkyl, C 2-6 alkenyl, amino, aminoalkyl , heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, - NO2, -SRa, -SO2Ra, -NRaSO2Rb, -SO3Ra or -SO2NRaRb; or a bicyclic mono- or 8- to 10-membered 5- to 7-membered heteroaromatic ring having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C 1-6 alkyl, alkenyl C2-6, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRbl- N (Ra) CORb, -N02l -SRa, -SO2Ra, -NRaSO2Rb, -SO3Ra or -SO2NRaRb; X is O, S, N (Ra) N (Ra) (Rb), N (Ra) N (Rb) CORc; and Y1, Y2, Y3 and Y4 are independently -C (R4) - or -N-, wherein each R4 is independently -H, C6-6 alkyl, C2-6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa > -CONRaRb, -N (Ra) CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, -N (Ra) SO2R or wherein two independent R4 substituents, taken together with Y1 = Y2, Y2 = Y3 or Y3 = Y4, form an aryl or heteroaryl ring of 5-7 membered cyclic, heterocyclic , which contains 0-3 heteroatoms selected from N, O or S, which may be optionally substituted with -H, C? -6 alkyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl , heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaR, -N (Ra) CORb, -NO2, -SO2Ra, -N (Ra) SO2Rb , -S03Ra or -SO2NRaRb, wherein Ra, Rb, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, can be substituted with one or more of the following: -SO2NH2. SO2-alkyl or -C02-alkyl. In another embodiment, the invention is directed to the novel compounds of Formula II:.

(ID or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is -H, C1-6 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -CORa, -COORa, -CONRaRb or -SO2Ra , R 2 is a 5- to 7-membered heterocyclic or heteroaromatic ring, having one to three heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C 1-6 alkyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2 , -SO2Ra, -NRaSO2Rb, -SO3Ra or -SO2NRaRb; R5, R6 and R7 are independently C alquilo _6 alkyl, C2.6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, meta-hydroxy, para-hydroxy, meta-methoxy, para-methoxy, C2 alkoxy. 5, -CF3, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -SRa, -S02Ra, -NRaSO2Rb) -S03Ra or -S02NRaRb; X is O, S, N (Ra) N (Ra) (Rb), N (Ra) N (Rb) CORc; and Y1, Y2, Y3 and Y4 are independently -C (R4) - or -N-, wherein each R4 is independently -H, Cj-6 alkyl, C2-6 alkenyl, amino, aminoalkyl , halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, - CONRaRb, -N (Ra) CORb, -NO2, -SO2Ra, -SO3Ra or -SO2NRaRb, -N (Ra) SO2Rb or wherein two independent R4 substituents, taken together with Y1 = Y2, Y2 = Y3 or Y3 = Y4, form an aryl or heteroaryl ring of 5-7 membered cyclic, heterocyclic , which contains 0-3 heteroatoms selected from N, O or S, which may be optionally substituted with -H, C 1-5 alkyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF 3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2, -SO2Ra, -NRaSO2Rb, -SO3Ra or - S02NRaRb, wherein Ra, Rb, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, may be substituted with one or more than the following: -SO2NH2, S02-aikyl or -CO2-alkyl, with the proviso that R2 is not an isoxazoline, pyrazoline or benzimidazole ring and the condition that if Y2 is -C (R4), then R4 is not a heteroaromatic of |. The compounds of Formulas I and II are especially potent inhibitors of the protein tyrosine kinase c-fms. The invention also relates to methods for inhibiting tyrosine kinase protein activity in a mammal by administering a therapeutically effective amount of at least one compound of Formula I or II.

DETAILED DESCRIPTION OF THE INVENTION The invention is directed to the novel compounds of Formula I: (i) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is -H, C-? 6 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -CORa, -COORa, -CONRaRb or -SO2Ra, R2 is phenyl, naphthyl or biaryl, each of which may be optionally substituted with one or more of Ci-β alkyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl , heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2, -SO2Ra, -SO3R; -SO2NRaR, -N = C (Ra) -NRbRc, -CH2NRaRb, -CH2NRaRbNRcRd, -NRaSO2Rb, -NRaCONRbRc, or -CH2N (CH2CH2) 2NRa; or a mono- or 8- to 10-membered heteroaromatic or heterocyclic ring bicyclic, having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more C? -6, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2, -SO2Ra, -SO3Ra, -SO2NRaRb, -N = C (Ra) -NRbRc, -CH2NRaRb, -CH2NRaRbNRcRd, -NRaSO2Rb, -NRaCONRbRc, -N (Ra) CON (Rb) -alkyl -Rc or -CH2N (CH2CH2) 2NRa; R3 is phenyl, naphthyl, biaryl or cycloalkyl, each of which may be optionally substituted with one or more of C6-6 alkyl) C2-6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2, -SRa, -SO2Ra, -NRaS02Rb , -SO3Ra or -SO2NRaRb; or a 5- to 7-membered heterocyclic ring having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C-? 6 alkyl, C 2-6 alkenyl, amino , aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb , -NO2, -SRa, -SO2Ra, -NRaSO2Rb, -SO3Ra or -SO2NRaRb; or a bicyclic mono- or 8- to 10-membered 5- to 7-membered heteroaromatic ring having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more C-.e alkyl, C2-6 alkenyl. amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb. -N (Ra) CORb, -N02, -SRa, -SO2Ra, -NRaSO2Rb, -SO3Ra or -SO2NRaR; X is O, S, N (Ra) N (Ra) (Rb), N (Ra) N (Rb) CORc; and Y1, Y2, Y3 and Y4 are independently -C (R4) - or -N-, wherein each R4 is independently -H, C6-6 alkyl, C2-6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3l -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -NO2, -S02Ra, -S03Ra or -SO2NRaRb, -N (Ra) SO2Rb or wherein two independent R4 substituents, taken together with Y1 = Y2, Y2 = Y3 or Y3 = Y4, form an aryl or heteroaryl ring of 5-7 membered cyclic, heterocyclic , which contains 0-3 heteroatoms selected from N, O or S, which may be optionally substituted with -H, C -.-6 alkyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb) -N (Ra) CORb, -NO2, -SO2Ra, -N (Ra) SO2Rb, -SO3Ra or -SO2NRaRb, wherein Ra, Rb, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, it may be substituted with one or more of the following: -SO2NH2, S2-a-alkyl or -CO2-alkyl. In another embodiment, the invention is directed to the novel compounds of Formula II: (p) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is -H, C1-6 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -CORa, -COORa, -CONRaR or - SO2Ra, R2 is a 5- to 7-membered heterocyclic or heteroaromatic ring, having one to three heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C1-6alkyl, amino, aminoalkyl , heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, - N02, -S02Ra, -NRaS02Rb, -SO3Ra or -S02NRaRb; R5, R6 and R7 are independently alkyl of C -.-6, C2.6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, meta-hydroxy, para-hydroxy, meta-methoxy, para-methoxy, alkoxy C2.5, -CF3, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb) -N02, -SRa, -S02Ra, -NRaS02R, -SO3Ra or -SO2NRaRb; X is O, S, N (Ra) N (Ra) (R), N (Ra) N (Rb) CORc; and Y1, Y2, Y3 and Y4 are independently -C (R4) - or -N-, wherein each R4 is independently -H, C6-6 alkyl, C2-6 alkenyl, amino, aminoaicyl, halogen, hydroxy, hydroxyalkyl, -CF3lalkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRbl PhCF3, -OCF3, -OCO-alkyl, -CORa > -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -S02Ra, -S03Ra or -S02NRaRbl -N (Ra) S02Rb or wherein two independent R4 substituents, taken together with Y1 = Y2, Y2 = Y3 or Y3 = Y4, form a 5- to 7-membered aryl or heteroaryl ring cyclic, heterocyclic, containing 0-3 heteroatoms selected from N, O or S, which may be optionally substituted with -H, C? -6 alkyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -S02Ra, -NRaS02Rb, -S03Ra or - S02NRaRb, wherein Ra, Rb, Rc and R are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, may be substituted with one or more than the following: -S02NH2, S02-alkyl or -C02-alkyl, with the proviso that R2 is not an isoxazoline, pyrazoline or benzimidazole ring and with the condition that if Y2 is -C (R4), then R4 is not a heteroaromatic of). Preferred compounds of Formula I are those wherein R 1 is -H; R 2 is a 5- to 7-membered heterocyclic or heteroaromatic ring, having one to three heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C 1-6 alkyl, amino, aminoalkyl, heteroaryl , halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -S02Ra, -S03Ra or -S02NRaRb; R3 is a 5- to 7-membered heterocyclic ring having from one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C? .6 alkyl, C2-6 alkenyl, amino , aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRbl -N (Ra) CORb, -N02, -SRa, -S02Ra, -S03Ra or -S02NRaRb; or phenyl or cycloalkyl, each of which may be optionally substituted with one or more of C? _6 alkyl, C2.6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, -hydroxy, -CF3, alkoxy, aryl, arachidyl , heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -SRa, -S02Ra, -S03Ra or -S02NRaRb; X is O; and Y \ Y2, Y3 and Y4 are -C (R4) -, wherein each R4 is independently -H, C-? 6 alkyl, C2.6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl , -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRbl -N (Ra) CORb, -N02, -S02Ra, -S03Ra or -S02NRaRb, -N (Ra) S02Rb or wherein Ra, Rb, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, may be substituted with one or more of the following: -S02NH2, S02-alkyl or -C02-alkyl. Preferred compounds of Formula II are those wherein R1 is -H; R2 is a 5- to 7-membered heterocyclic or heteroaromatic ring, having one to three heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C-? 6alkyl, amino, aminoalkyl , heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, - N02l -S02Ra, -S03Ra or -S02NRaRb; X is O; and Y1, Y2, Y3 and Y4 are -C (R4) -, wherein each R4 is independently -H, Ci-β alkyl, C2-6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, - CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb) -N (Ra) CORb, -N02, -S02Ra, -S03Ra or -S02NRaRb, -N (Ra) S02Rb, wherein Ra, Rb and Rc are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, with the proviso that R2 is not a isoxazoline ring, pyrazoline or benzimidazole, and with the proviso that if Y2 is -C (R4), then R4 is not a heteroaromatic of Ci. More preferred compounds of Formula I include, but are not limited to, 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (pyridin-4-yl) -1H-quinolin-2-one.; 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (pyridin-3-yl) -1 H -quinolin-2-one; 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (pyridin-2-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-piperidin-1-yl-1 H -quinolin-2-one; 6-Chloro-4-cycloheptyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4-cyclohex-1-enyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4-cyclohep-1-enyl-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one and the pharmaceutically acceptable salts thereof. More preferred compounds of Formula II include, but are not limited to, 6-chloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one; 6-bromo-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 6-bromo-3- (3-methyl-isoxazol-5-yl) -4- (2-fluorophenyl) -1H-quinolin-2-one; 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (2-fluorophenyl) -1H-quinolin-2-one; 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (3-hydroxyphenyl) -1 H -quinolin-2-one; 6-chloro-3- (3-ethyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (3- (2-phenyl) ethyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one; 6-chloro-3- (3-isopropyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one; 3- (3-tert-Butyl-isoxazol-5-yl) -6-chloro-4-phenyl-1H-quinolin-2-one; 6-chloro-3- (4-methyl-4,5-dihydro-oxazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (4-isopropyl-4,5-dihydro-oxazol-2-yl) -4-phenyl-1H-quinolin-2-one; 6-chloro-3- (4-isobutyl-4,5-dihydro-oxazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 3- (4-tert-Butyl-4,5-dihydro-oxazol-2-yl) -6-chloro-4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (4-methyl-oxazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (4-ethyl-oxazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (4-isopropyl-oxazol-2-yl) -4-phenyl-1H-quinolin-2-one; 6-chloro-3- (4-isobutyl-oxazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 3- (4-tert-Butyl-oxazol-2-yl) -6-chloro-4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (2-methyl-2H-tetrazol-5-yl) -4-phenyl-1H-quinolin-2-one; 6-chloro-3- (2-ethyl-2H-tetrazol-5-yl) -4-phenyl-1H-quinolin-2-one; 6-chloro-3- (2-isopropyl-2H-tetrazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (1 H -imidazol-4-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (1-methyl-1H-imidazol-4-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (1-ethyl-1 H-imidazol-4-yl) -4-phenyl-1 H -quinolin-2-one; 6-chloro-3- (1-isopropyl-1 H -imidazol-4-yl) -4-phenyl-1 H -quinolin-2-one; 3- (5-bromo-pyridin-3-yl) -6-chloro-4-phenyl-1 H-quinolin-2-one; 6-chloro-4-phenyl-3-pyridin-3-yl-1 H-quinolin-2-one; 6-Nitro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 3- (1-benzyl-1 H- [1,2,3] triazol-4-yl) -6-chloro-4-phenyl-1 H -quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxylic acid; 6-chloro-4-phenyl-3-pyridin-4-yl-1 H-quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-vinyl-phenyl) -1,2-dihydro-quinoline-6-carbonitrile; 4- (4-Ethyl-phenyl) -3- (3-methy1-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinolin-6-carbonitrile; 6-Chloro-4- (4-ethyl-phenyl] -3- (3H-imidazol-4-yl) -1H-quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoIin-6-carbonitrile; 3- (3H-lmidazol-4-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile; 6-Chloro-4-phenyl-3-. { 3 - [(2-pyrroiidin-1-yl-ethylamino) -methyl] -isoxazol-5-yl} -1H-quinolin-2-one and the pharmaceutically acceptable salts thereof. The invention also relates to methods for inhibiting protein tyrosine kinase activity in a mammal by administering a therapeutically effective amount of at least one compound of Formula I or II. A preferred tyrosine kinase is c-fms. The invention is considered to include the enantiomeric, diastereomeric and tauromeric forms of all the compounds of Formulas I and II, as well as their racemic mixtures. In addition, some of the compounds represented by Formulas I and II can be prodrugs, that is, derivatives of a drug acting which possesses delivery capabilities and superior therapeutic values as compared to the drug acting. The prodrugs are transformed into active drugs by enzymatic or chemical procedures in vivo.

I. Definitions The term "alkyl" refers to both straight chain 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 "alkenyl" refers to an alkyl group of up to 12 carbon atoms containing at least one unsaturation; Examples include, but are not limited to, vinyl and allyl. The term "cycloalkyl" refers to a saturated or partially unsaturated ring, composed of 3 to 8 carbon atoms. Alkyl substituents may be present in the ring. Examples include cyclopropyl, 1,1-dimethylcyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl and cyclohexenyl. The term "heterocyclyl" refers to a non-aromatic (i.e., saturated or partially unsaturated) ring, composed of 3 to 7 carbon atoms and at least one heteroatom selected from N, O or S. Alkyl substituents may be present in 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 an alkyl group of C-α-6 containing a heterocyclyl substituent. Examples include dihydropyranylethyl and 2-morpholinylpropyl. The term "hydroxyalkyl" refers to at least one hydroxyl group attached to any carbon atom or along the alkyl chain.

The term "aminoalkyl" refers to at least one primary or secondary amino group attached to any carbon atom along the alkyl chain. The term "alkoxyalkyl" refers to at least one alkoxy group attached to any carbon atom of the alkyl chain. The term "polyalkoxyalkyl" refers to the long chain alkoxy compounds, and include polyethylene glycols of discrete or monodisperse sizes. The term "thioalkyl" refers to at least one sulfur group attached to any carbon atom of the alkyl chain. The sulfur group can be in any oxidation state and includes sulfoxides, sulfones and sulfates. The term "carboxyalkyl" refers to at least one carboxylate group attached to any carbon atom of the alkyl chain. The term "carboxylate group" includes carboxylic acids and alkyl, cycloalkyl, aryl or aralkyl carboxylate ester. The term "heteroaromatic" or "heteroaryl" refers to aromatic ring systems of 5-7 mono members or 8-10 bicyclic members, any ring of which may consist of one to four heteroatoms selected from N, O or S, in where the nitrogen and sulfur atoms can exist in any allowed oxidation states. 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 an alkyl group of C 6 -6 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 permitted oxidation states. The term "alkoxy" refers to straight or branched chain radicals of up to 12 carbon atoms, unless otherwise indicated, attached 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. The alkyl substituents may be optionally present in the ring. Examples include benzene, biphenyl and naphthalene. The term "aralkyl" refers to an alkyl group of C-? 6 which contains an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl. The term "heteroaralkyl" refers to a C 1-6 alkyl group that contains a heteroaryl substituent. Examples include furylmethyl and pyridylpropyl.

The term "aryloxy" refers to an oxygen atom attached to an aryl substituent. Examples include phenoxy and benzyloxy. The term "arylalkoxy" refers to an alkoxy group attached to an aryl substituent. Examples include phenylmethyl ether. The term "acyl" refers to the group -C (0) Ra, wherein Ra is alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. An "acylating agent" adds the group -C (0) Ra to a molecule. The term "sulfonyl" refers to the group -S (0) 2Ra, wherein Ra is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl. A "sulfonating agent" adds the group -S (0) 2Ra to a molecule.

II. Therapeutic Uses The compounds of Formulas I and II represent potent novel inhibitors of the protein tyrosine kinases, such as c-fms, and may be useful in the prevention and treatment of disorders resulting from the actions of these kinases. The invention also provides methods for inhibiting a tyrosine kinase protein comprising contacting the tyrosine kinase protein with an effective inhibitory amount of at least one of the compounds of Formula I or II. A preferred tyrosine kinase is c-fms. In an embodiment for inhibiting a tyrosine kinase protein, at least one of the compounds of Formula 1 or 11 is combined with a known tyrosine kinase inhibitor. In various embodiments of the invention, the tyrosine kinase proteins inhibited by the compounds of Formulas I and II, are located in the cells, in a mammal or in vitro. In the case of mammals, including humans, they are administered a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I or II. The invention further provides methods for treating cancer in mammals, including humans, by administering a therapeutically effective amount of a pharmaceutically acceptable composition of at least one compound of Formula I or II. Exemplary cancers include, but are not limited to, breast cancer, colon cancer, stomach cancer, capillary cell leukemia, and non-small lung carcinoma. In one embodiment of the invention, an effective amount of at least one compound of Formula I or II is administered in combination with an effective amount of a chemotherapeutic agent. The invention also provides methods for treating cardiovascular and inflammatory diseases in mammals, including humans, by administering a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I or II. Examples of diseases that can be treated effectively include glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor-related angiogenesis, restenosis, schizophrenia, and Alzheimer's dementia. When used as inhibitors of the protein tyrosine kinase, the compounds of the invention can 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 a dose single or divided daily. The dose administered may be affected by factors such as the route of administration, health, weight and age of the recipient, the frequency of treatment and the presence of concurrent and unrelated treatments. The compounds of Formulas I and II can 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 Formulas I and II 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, camphorrate, dodecyl sulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Basic 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, groups containing basic nitrogen may be quatemized with, for example, alkyl halides. The pharmaceutical compositions of the invention can be administered by any means that achieve their intended purpose. Examples include administration by the parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternately or concurrently, the administration can be by oral route. Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble forms, for example, water-soluble salts, acid solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and complexes including cyclodextrin. lll. Preparation Methods The exemplary synthetic routes for generating the quinolinones of the invention are described below.

REACTION SCHEME 1 Reaction Scheme 1 illustrates the preparation methods of the compounds of formulas I and II. The appropriate functionality of the amino ketones of the compounds of formula 1-1 can be introduced into the amino ketones of formula 1-2 before the formation of the quinolone. In cases where Z is a halogen such as bromine, iodine or chlorine, it can be converted to a cyano group using catalysis methods with palladium catalysis or, more preferably, copper cyanide in DMF at temperatures varying from 120- 180 ° C. Halogens can also be converted to acetylenes or alkenes using palladium catalyzed coupling methods.

The treatment of an amino-ketone of formula 1-2 with a carboxylic acid in a suitable reaction medium containing a coupling reagent generates an amide of formula 1-3. Suitable coupling reagents include PyBrOP, oxalyl chloride, phosphorus oxychloride and EDCI with or without an additive such as HOBt or DMAP. The preferred coupling agent is EDCI in DCM or PyBrOP. The compounds of formula 1-4 are then obtained via cyclization promoted by a base of the compounds of formula 1-3. Suitable bases are piperidine, DMAP or NEt3 in a reaction medium such as DCM, DMF or toluene. Preferably, the cyclization is conducted in toluene containing piperidine at temperatures ranging from 25 ° C to 110 ° C. In addition, it is recognized that the quinolones of formula 1-4 can be further modified to provide compounds of formula 1-5. Examples include, in a non-exclusive manner: when R4 of formula 1-4 is a nitro group, it can be reduced to an amino group using standard techniques, such as H2 with Pd on carbon, and then the amine is reacted with reagents such as carboxylic anhydride or acid chlorides to provide the compounds of formula 1-5, wherein R4 is N-acyl; a sulfonyl chloride to provide the compounds of formula 1-5, wherein R4 is N-sulfonamide; and the aldehydes and ketones in the presence of a reducing agent such as sodium triacetoxyborohydride to provide the compounds of formula 1-5, wherein R4 is N-alkyl. When R4 of formula 1-4 is a halide such as bromine, iodine or chlorine, reactions may include Suzuki couplings with boronic acids to provide compounds of formula 1-5, wherein R4 is alkyl, aryl or heteroaryl; palladium catalyzed cyanation reactions to provide compounds of formula 1-5, wherein R 4 is cyano; and when R4 of formula 1-4 is a bromine or iodine, halogen-metal exchange reactions wherein the quinolone NH, is first deprotonated with an aprotic base such as i-PrMgCI, followed by the exchange of lithium-bromine using n-butyllithium and quenching with several electrophiles such as dimethyl disulfide to provide the compounds of formula 1-5, wherein R 4 is S-Me when the electrophile is dimethyl disulfide. When R4 of formula 1-4 is a vinyl alkene, the alkene can be oxidized to the diol (J. Org. Chem. 1992, 57, 2768), and further manipulated by oxidation with sodium periodate to provide an aldehyde. The aldehyde can be reacted with amines under reaction conditions to provide alkyl amines or oxidized to the carboxylic acid with sodium chlorite or reduced to an alcohol with sodium borohydride. In the cases where R2 of formula 1-4 is an amino-heterocycle, such as a 3-amino-isoxazol-5-yl, the amino group can be subjected to the reactions described above for the compounds of formula 1-4, wherein R 4 is an amino group to provide compounds of formula 1-5, wherein R 4 is a 3-amino-substituted isoxazol-5-yl; and in addition, it can be reacted with formamide such as N, N-dimethylformamide or amides such as N, N-dimethylacetamide in the presence of methanesulfonyl chloride to provide the compounds of formula 1-5, wherein R4 is isoxazol-5-yl 3-N-amidino substituted.

In the cases where R2 of the compounds of formula 1-4 is a carboxylic acid ester, the ester can be hydrolyzed with HCl in dioxane to provide the carboxylic acid derivative, which can then be reacted with ethanolamines according to standard procedures for providing compounds of formula 1-5, wherein R 2 is a substituted 4 or 5 oxazol-2-yl derivative.

REACTION SCHEME 2 2-3 Reaction Scheme 2 illustrates alternative methods of preparing the compounds of formulas I and II. The treatment of an aniline of the formula 2-1 with a carboxylic acid in the presence of POCI3 in a suitable reaction medium generates a 2-chloroquinoline of the formula 2-2. Suitable reaction media are toluene or DCM, or the reaction can be carried out in POCI3 without an additional solvent. Preferably, the reaction is carried out in POCI3 at temperatures ranging from 25 ° C to 110 ° C.

Hydrolysis of the compounds of formula 2-2 provides the compounds of formula 2-4. Suitable reagents include aqueous hydrochloric acid or acetic acid and water. The preferred reaction condition is acetic acid containing 20% water at 120 ° C. The compounds of formula 2-2 can also be modified to provide compounds of formula 2-3. For example, when R4 of formula 2-2 is a nitro group, it can be reduced to an amino group using iron and ammonium chloride. The amino group can then be reacted with aryl or heteroaryl iodides or bromides using palladium catalyzed coupling methods to provide the compounds of formula 2-3, wherein R 4 is N-heteroaryl or N-aryl. The compounds 2-3 can then be hydrolyzed to compounds 2-4, using the methods described for the compounds of formula 2-2.

REACTION SCHEME 3 3-1 3-2 3-3 3-4 3-5 Reaction Scheme 3 illustrates different methods for the preparation of ortho-amino ketones, which are the raw materials for the compounds of formulas I and II. Some of these compounds are either commercially available or accessible by methods known in the literature or can be prepared using the following methods. In formula i, amine 3-1 is shown with a protective group directed in the ortho position, such as trimethyl acetyl. Deprotonation with a strong base such as n-BuLi, sec-BuLi or ter-BuLi or the exchange of metal halides of a substituted or unsubstituted halo aryl amine suitably protected with a suitable organometallic reagent such as BuLi and the intercept of the resulting organometallic species with R3L such as acyl halide, acylamide or anhydride, introduces an acyl portion. Where L is understood to be a leaving group such as chlorine or -NMe (OMe). The subsequent deprotection generates the ortho-amino ketones 3-2; preferred examples of the 3-2 have a Y (1"4) as nitrogen In the formula ii, the compounds 3-3 are reacted with acid chlorides such as acetyl chloride or benzoyl chloride in the presence of a base such as pyridine to provide the 4-oxazinones The subsequent reaction with Grignard reagents, followed by hydrolysis of the resulting amide with sodium hydroxide, provides the amino-ketones 3-5 Formula III illustrates the synthesis of the ortho amino ketones by Friedel-Crafts acylation of an aryl or heteroaryl amines substituted or unsubstituted with suitable acylating agents, R3L such as heteroaryl or aryl cyanides, anhydrides and acyl halides in the presence of a suitable catalyst such as Lewis acids .

REACTION SCHEME 4 Reaction Scheme 4 illustrates the preparation of the compounds of formula I and II, wherein R2 is a 1-substituted-triazol-4-yl derivative (4-2) or a 3-substituted -soxazole-5- derivative ilo (4-4). Treatment of the compounds of formula 4-1 with an azide in the presence of sodium ascorbate and copper sulfate in a suitable reaction medium provides the compounds of formula 4-2. The suitable reaction medium is 50% aqueous t-butanol at temperatures of 50-100 ° C. The treatment of the compounds of formula 4-1 with oximes in the presence of sodium hypochloride at 0-25 ° C in a suitable reaction medium such as DCM, provides compounds of formula 4-3, which can be cyclized as described in Reaction Scheme 1, to provide compounds of formula 4-4.

REACTION SCHEME 5 Reaction Scheme 5 illustrates the functionalization of a heterocyclic portion at the C-3 position. The unmasked hydroxyl functional group can be oxidized with suitable oxidizing agents such as Dess-Martin periodinane, Mn02, PDC, PCC, Swem reagent or Cr03 to provide either an aldehyde or a carboxylic acid, depending on the reagent of choice. The acids can be reacted, after activation with reagents known to someone skilled in the art, with compounds containing primary or secondary amines to obtain the corresponding amides. The aldehydes can be subjected to reductive amination with suitable primary or secondary amines in the presence of a reducing agent, such as sodium triacetoxy borohydride, to introduce the amino substituted functionalities.

REACTION SCHEME 6 6-6 Reaction Scheme 6 illustrates a general procedure for the synthesis of quinolones with diversity at position 4. Compound 6-1 is reacted with two equivalents of alkyl halide, for example, benzyl bromide in a solvent organic, such as acetonitrile, in the presence of a base, such as NaH to provide compound 6-2. The amino group in compound 6-2 is coupled with an acylating agent, such as (3-methyl-isoxazol-5-yl) -acetic acid, in the presence of POCI3 to form the product 6-3. The cyclization is carried out with a base such as NaH in an aprotic solvent, such as DMF, followed by conversion of the 4-hydroxy group to a triflate or a bromide, using the appropriate reagents, such as either triflic anhydride or POBr3. to provide compound 6-4. The reaction of Suzuki with a boronic acid or a boronic ester, such as phenylboronic acid or 4- (4,4,5,5-tetramethyl-1,2,2-dioxaboroyl-2-yl) benzonitrile, in the presence of a palladium catalyst such as Pd (PPh3) 4 and an appropriate base, such as Na 2 CO 3, provides compound 6-5. Alternatively, the triflate group or the bromo group in compound 6-4 can be replaced by a nucleophilic agent, for example, magnesium dicyclohexyl chloride, to form compound 6-5. Compound 6-4 can also react with an amine such as piperidine in an organic solvent, such as tetrahydrofuran, to form compound 6-5. The protecting group in compound 6-5, such as a benzyl group, is removed under strong acidic conditions, for example, using methanesulfonic acid to provide compound 6-6.

REACTION SCHEME 7 Reaction Scheme 7 now illustrates a Suzuki reaction that can introduce substituents at position 4 in the less protected quinolones. Compound 7-1 is treated with an acylating agent, such as (3-methyl-isoxazol-5-yl) -acetic acid, in the presence of a coupling reagent, such as POCI3 to form the product 7-2. Cyclization with a base such as t-BuOK in an aprotic solvent, such as DMSO, is followed by reaction with a triflating agent such as N-phenyltrifluoromethanesulfonimide to provide a compound 7-3. The reaction of Suzuki with a boronic acid, such as phenylboronic acid in the presence of a palladium catalyst such as Pd (PPh3) and an appropriate base, such as Na2CO3, provides compound 7-4.

EXAMPLE 1 General procedure for the synthesis of quinolone and naphthyridinone by cyclocondensation To a mixture of substituted acetic acid (1 mmol) and amino ketone (1 mmol), POCI3 (3 mL) was added. The resulting mixture was heated at 70 ° C under N2 for 12 hours. POCI3 was removed and the residue was dried in vacuo for 1 hour. The residue was then dissolved in HOAc (98% acid, 2% water) (2 mL) and NH 4 AC (77 mg, 1 mmol) was added and heated at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and the HOAc was removed. The resulting residue was purified on silica with an appropriate solvent system.

EXAMPLE 2 General procedure for the synthesis of quinolone and naphthyridinone by cyclocondensation To a mixture of 2-substituted acetic acid (1.5 mmol) and amino ketone (1 mmol), DIEA (0.7 mL, 4 mmol) in THF (10 mL), PyBrop (730 mg, 1.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. If the LC / MS and / or the TLC of the reaction mixture indicated the complete formation of the expected fully cyclized product, the solvents were removed and the product was isolated by chromatography on silica with an appropriate solvent system. If incomplete cyclization was detected, toluene (10 mL) and piperidine (1 mL) were added to the reaction mixture and the resulting mixture was heated to 70 ° C until the complete formation of the expected quinolone was observed, by LC / MS. The solvents then removed and the product was isolated in the usual manner.

EXAMPLE 3 3- (3-Methyl-isoxazol-5-yl, -4-phenyl-1 H-H, 51-naphthyridin-2-one EXAMPLE 3a, 3-Amino-pyridin-2-yl, -phenyl-methanone To a solution of 3-amino-2-bromopyridine (860 mg, 5 mmol) in CH2Cl2 (10 mL) and Et3N (0.86 mL, 6.2 mmol), trimethyl acetyl chloride (0.67 mL, 5.5 mL) was added dropwise. mmoles) under N2 at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours and poured into water (10 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified on silica (20% EtOAc / hexanes). Yield 88%; 1 H-NMR (CDCl 3; 400 MHz) d 8.72 (dd, Ji = 8.16, J2 = 1.8 Hz, 1H), 8.1 (broad s, 2H), 7.22 (dd, J? = 8.16, J2 = 4.6 Hz, 1H) , 1.38 (s, 9H). To a solution of the above compound (2.5 g, 10 mmol) in THF (40 mL) at -78 ° C, BuLi (10 mL, 25 mmol, 2.5 M solution) was added. The resulting mixture was stirred at -78 ° C for 1 hour and a solution of the N-methoxy-N-methyl-benzamide (2.47 g, 15 mmol) in THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight and poured into ice water (50 mL) and extracted with CH2Cl2 (3x20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The obtained residue was dissolved in 3N aqueous HCl (20 mL) and MeOH (10 mL). The resulting mixture was heated at 100 ° C for 16 hours and allowed to cool to room temperature and neutralized with saturated aqueous NaHCO 3. The precipitated product was collected by purification with suction and purified on silica (20% EtOAc: hexanes). Performance 39%. 1 H-NMR (CDCl 3, 400 MHz) d 8.04 (dd, J = 4.16, J2 = 1.44 Hz, 1 H), 7.93 (m, 2 H), 7.3-7.6 (m, 3 H), 7.23 (m, 1 H), 7.17 (d, J = 4.1 Hz, 1H), 6.1 (broad s, 2H). The title compound was prepared from (3-methyl-isoxazol-5-yl) -acetic acid and (3-amino-pyridin-2-yl) -phenyl-methanone (Example 3a) according to general procedure 1; Performance 48%.

EXAMPLE 4 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1 H-Pl, 6, naphthyridin-2-one EXAMPLE 4a (4-Amino-pyridin-3-yl) -phenyl-methanone Prepared from 2,2-dimetii-N- (4-pyridinyl) propanamide and N-methoxy-N-methyl-benzamide according to procedure 6a. 1 H-NMR (CDCl 3, 400 MHz) d 8.59 (s, 1H), 8.23 (d, J = 5.84 Hz, 1H), 7.70-7.26 (m, 5H), 6.4-6.5 (broad s, 2H), 6.61 ( d, J = 5.84 Hz, 1H). The title compound was prepared from (3-methyl-isoxazol-5-yl) -acetic acid and (4-amino-pi.ridin-3-yl) -phenyl-methanone (Example 4a) of according to procedure 1; Performance 59%.

EXAMPLE 5 6-C »oro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-f1.81naphthyridin-2-one EXAMPLE ßa (2-Amino-5-chloro-pyridin-3-yl) -phenyl-r-tannate Prepared by reacting the lithiated 2,2-dimethyl-N- (5-chloropyridin-2-yl) propanamide (as described in the literature, J. Org. Chem., 48 (20), 3401-8,1983) with N-methoxy-N-methyl-benzamide, followed by the acid catalyzed deprotection as described in the previous example.

Performance 54%. d 8.20 (d, J = 2.44 Hz, 1H), 7.86 (d, J = 2.44 Hz, 1H), 7.4-7.6 (m, 5H), 6.80 (broad s, 2H). The title compound was prepared from (3-methyl-isoxazol-5-yl) -acetic acid and (2-amino-5-chloro-pyridin-3-yl) -phenyl-methanone (example 5a) according to with procedure 1; Performance 56%.

EXAMPLE 6 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1 H-f1, 8, naphthyridin-2-one EXAMPLE 6a (2-Amino-pyridin-3-iO-phenyl-methanone) BuLi (10.0 mL, 25 mmol) was added to a solution of 2,2-dimethyl-N- (2-pyridinyl) propanamide (1.78 g, 10.00 mmol) at -78 ° C under N2. 2. 5M in hexane). The resulting mixture was allowed to warm to 0 ° C and was stirred for 4 hours. Then, a solution of the N-methoxy-N-methyl-benzamide (2.47 g, 15 mmol) in THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight and poured into ice water (50 mL) and extracted with CH2Cl2 (3x20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The obtained residue was dissolved in 3N aqueous HCl (20 mL) and MeOH (10 mL) and heated at 100 ° C for 16 hours. The reaction mixture was allowed to cool to room temperature and neutralized with saturated aqueous NaHCO3. The precipitated product was collected by purification with suction and purified on silica (20% EtOAc: hexane). Yield 53%. 1 H-NMR (CDCl 3, 400 MHz) d 8.26 (dd, J 4. 4.76, J2 = 1.88 Hz, 1H), 7.79 (dd, J 7. 7.80, J2 = 1.88 Hz, 1H), 7.78-7.28 (m, 5H) , 6.86 (broad s, 2H), 6.62 (dd, J ^ 8.24, J2 = 4.76 Hz, 1H). The title compound was made from (3-methyl-isoxazol-5-yl) -acetic acid and (2-amino-pyridin-3-yl) -phenyl-methanone (Example 6a) according to procedure 1; Performance 67%.

EXAMPLE 7 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1 H-, 1.71naphthyridin-2-one EXAMPLE 7a _3-Amino-pyridin-4-yl) -phenyl-methanone As described in the previous example, the title compound was prepared from 2,2-dimethyl-N- (3-pyridinyl) propanamide and N-methoxy-N-methyl-benzamide. 1 H-NMR (CDCl 3, 400 MHz) d 8.29 (s, 1 H), 7.93 (d, J = 5.18 Hz, 1 H), 7.40-7.62 (m, 5 H), 7.23 (d, J = 5.18 Hz, 1 H), 5.83 (broad s, 2H). The title compound was prepared from (3-methyl-isoxazol-5-yl) -acetic acid and (3-amino-pyridin-4-yl) -phenyl-methanone (Example 7a) according to procedure 1; Performance 66%.

EXAMPLE 8 ß-Bromo-3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1H-ri.81naphthyridin-2-one EXAMPLE 8a (2-Amino-5-bromo-pyridin-3? O-phenyl-methanone To a solution of (2-amino-pyridin-3-yl) -phenyl-methanone (Example 6a) (198.2 mg, 1 mmol) in CH 3 CN (2 mL) under N 2 was added NBS (195 mg, 1.1 mmol). The resulting solution was stirred at room temperature for 12 hours and concentrated. The residue was dissolved in CH2Cl2 and washed with water (10 mL), aqueous NaHCO3 and 10% aqueous Na2S203 (10 mL). The organic layer was separated, dried (Na2SO) and concentrated. The residue was then purified on silica (20% EtOAc: hexanes). Performance 43%. 1 H-NMR (CDCl 3, 400 MHz) d 8.27 (d, J = 2.44 Hz, 1 H), 7.84 (d, J = 2.44 Hz, 1 H), 7.4-7.6 (m, 5H), 6.87 (broad s, 2H). The title compound was prepared from (3-methyl-isoxazol-5-yl) -acetic acid and (2-amino-5-bromo-pyridin-3-yl) -phenyl-methanone (Example 8a) according to with the procedure 1. Performance 29%.

EXAMPLE 9 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-ri, 71-naphthyridin-2-one EXAMPLE 9a (5-Arnino-2-chloro-pyridin-4-yl-phen-methanone Prepared (as described in the previous example) by reacting the lithiated 2,2-dimethyl-N- (6-chloropyridin-3-yl) propanamide (as described in J. Org. Chem., 55 (15), 4744 , 1990) with N-methoxy-N-methyl-benzamide, followed by acid-catalysed deprotection. Performance 44%. 1 H-NMR (CDCl 3, 400 MHz) d 8.08 (s, 1 H), 7.70-7.26 (m, 5H), 7. 29 (s, 1H), 5.9 (s broad, 2H). The title compound was prepared from (3-methyl-isoxazol-5-yl) -acetic acid and (5-amino-2-chloro-pyridin-4-yl) -phenyl-methanone (Example 9a), according to the procedure for example 2, yield 71%.

EXAMPLE 10 6-Chloro-3- (3-methyl-benzo, b.thiophen-2-yl, -4-phenyl-1H-quinolin-2-one) From benzo [b] thiophen-2-yl-acetic acid and (2-amino-5-chloro-phenyl) -phenyl-methanone according to general procedure 2. Yield 38%.

EXAMPLE 11 6-Chloro-4-phenyl-3-thiophen-2-yl-1H-quinolin-2-one From thiophen-2-yl-acetic acid and (2-amino-5-chloro-phenyl) -phenyl-methanone according to general procedure 2. Yield 55%.

EXAMPLE 12 6-Chloro-4-phenyl-3- (1 H-pyrroD-2-H-1 H-quinolin-2-one) From pyrrol-2-yl-acetic acid (Synthetic Communications, 19, (13-14), 2585, 1989) and (2-amino-5-chloro-phenyl) -phenyl-methanone according to the general procedure 2. Yield 12%.

EXAMPLE 13 6-Chloro-4-phenyl-3-pyrazol-1-yl-1 H-quinolin-2-one From 2- (1H-pyrazol-1-yl-acetic acid and (2-amino-5-chloro-phenyl) -phenyl-methanone according to general procedure 2. Yield 49% > EXAMPLE 14 6-Chloro-3. 4-diphenyl-1 H-quinolin-2-one From phenylacetic acid and (2-amino-5-chloro-phenyl) -phenyl-methanone according to general procedure 2. Yield 53%.

EXAMPLE 15 6-Chloro-3-r (5-morpholin-4-carbonyl) 1H-pyrrol-2-n-4-phenyl-1H-quinolin-2-one EXAMPLE 15a Acid r5- (Morpholin-4-carboniQ-1 H-pyrrole-2-in-acetic) Triphosgene (1.64 g, 5.5 mmol) was added to the ethyl ester of (1H-pyrrol-2-yl) -acetic acid (prepared following the general procedure described in J. Org. Chem., 59 (18), 5230-5234, 1994) (841.0 mg, 5.5 mmol) in toluene (50 mL). The resulting mixture was heated at 100 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature and morpholine (1 mL) and EtsN (1 mL) were added. The resulting mixture was stirred at room temperature overnight and concentrated. The residue obtained was subjected to chromatography on silica (50-100% EtOAc: Hexane) to obtain [5- (Morpholin-4-carbonyl) -1H-pyrrol-2-yl-acetic acid ethyl ester. Performance 43%. 1 H-NMR (CDCl 3, 400 MHz) d 10.46 (broad s, 1 H), 6.43 and 6.08 (dd, J? = 3.6, J2 = 2.68, 1 H each), 4.1 (c, J = 7.16, 2H) , 3.85 and 3.73 (m, 4H each), 3.67 (s, 2H), 1.25 (t, J = 7.16, 3H). The above compound (266 mg, 1 mmol) was dissolved in MeOH (5 mL). NaOH 1 (3 mL) was added to this solution. The resulting mixture was stirred at room temperature overnight and the MeOH was removed in vacuo. Then water (10 mL) was added and the reaction mixture was acidified with HOAc. The product was extracted with 5% MeOH: CH2Cl2 (5x10 mL). The organic layers were combined and dried (Na2SO4) and concentrated to obtain [5- (morpholin-4-carbonyl) -1H-pyrrol-2-yl] -acetic acid. Performance 73%. d 11.28 (s broad, 1H), 6.42 and 5.95 (dd, ^ = 3.3, J2 = 2.48, 1H each), 3.69 and 3.61 (m, 4H each), 3.60 (s, 2H). The title compound was prepared from [5- (morpholin-4-carbonyl) -1H-pyrrol-2-yl] -acetic acid (Example 15a) and (2-amino-5-chloro-phenyl) -phenyl -metanone according to the general procedure 2. Yield 41%.

EXAMPLE 16 6-Chloro-3- (5-methyl-2H-pyrazol-3-yl, -4-phenylamine-quinofin-2-one) Synthesized from 5-methyl-2H-pyrazol-3-yl-acetic acid and (2-amino-5-chloro-phenyl) -phenyl-methanone according to general procedure 2. Yield 23%.

EXAMPLE 17 3-f 1-Benzyl-1 H-imidazol-2-yl) -6-chloro-4-phenyl-1 H-quinolin-2-one Synthesized from (1-benzyl-1H-imidazol-2-yl) -acetic acid (Tetrahedron Letters, 37 (51), 9259, 1996) and (2-amino-5-chloro-phenyl) -phenyl -metanone according to the general procedure 2. Performance 43%.

EXAMPLE 18 6-Chloro-3- (5-methyl-isoxazol-3-yl) -4-phenyl-1H-quinolin-2-one Synthesized from (5-methyl-isoxazol-3-yl) -acetic acid (J. Med. Chem., 34 (2), 518, 1991) and (2-amino-5-chloro-phenyl) -phenyl -Metanone according to the general procedure 2. Performance 69%.

EXAMPLE 19 6-Chloro-4-phenyl-3-pyridin-2-i H-quinolin-2-one Synthesized from (2-pyridyl) -acetic acid and (2-amino-5-chloro-phenyl) -phenyl-methanone according to general procedure 2. Yield 23%.

EXAMPLE 20 4- (4-Ethyl-phenol) -3- (2-methyl-thiazol-4-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile Synthesized from (2-methyI-thiazol-4-yl) -acetic acid and 4-Amino-3- (4-ethyl-benzoyl) -benzonitrile according to general procedure 2. Yield 27%.

EXAMPLE 21 6-Chloro-3-3 3-hydroxymethyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one EXAMPLE 21a Preparation of the acid, 3- (tert-butyl-dimethylsilanyloxy-pyroxy [-isoxazole-5-yl-acetic acid] A solution of 3- (tert-butyl-dimethylsilanyloxymethyl) -5-methyl-xoxazo (US 5464848) (13 g, 57 mmol) and TMEDA (1.2 mL, 7.9 mmol) in THF (150 mL) was cooled to -78 ° C and BuLi (25 mL, 62.6 mmol, 2.5M solution) was added in 5 minutes. The resulting mixture was stirred at -78 ° C for 45 minutes and CO 2 (g) was bubbled into the reaction mixture until the orange color disappeared. The reaction mixture was stirred at -78 ° C for a further 30 minutes and saturated NH 4 Cl (10 mL) was added followed by water (25 mL). The reaction mixture was allowed to warm to room temperature and extracted with CH2Cl2 (5x20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue obtained was dried in vacuo to obtain [3- (tert-butyl-dimethylsilanyloxymethyl) -isoxazol-5-yl] -acetic acid and was used directly in the next step without purification. Performance 68%. d 4.77 (s, 2H), 3.89 (s, 2H), 0.92 (s, 9H).

EXAMPLE 21b 3-r3- (tert-butyl-dimethyl-silanyloxymethip-isoxazole-5-ip-6-chloro-4-phenyl-1H-quinolin-2-one) Prepared from [3- (tert-butyl-dimethylsilanyloxymethyl) -isoxazol-5-yl] -acetic acid (Example 21a) and (2-amino-5-chloro-phenyl) -phenyl-methanone as described above) in THF (80 mL). Treatment of the resulting mixture with 1 N HCl (10 mL) was followed by stirring at room temperature (12 hours) and concentration. The obtained residue was triturated with ether (3X50 mL) and dried in vacuo to obtain the title compound according to general procedure 2.

Performance 43%.

EXAMPLE 22 5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-y0-isoxazole-3-carboxylic acid To a solution of 6-chloro-3- (3-hydroxymethyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one (Example 21) (353 mg, 1 mmol) in HOAc ( 1 mL), C.O3 (100 mg, 1 mmol) was added. The resulting mixture was stirred at 50 ° C for 3 hours. The reaction mixture was allowed to cool to room temperature and the HOAc was removed. The residue was subjected to reverse phase HPLC to obtain the title compound. Performance 21%.

EXAMPLE 23 6-Chloro-3-r (3-morpholin-4-carbonyl) isoxazole-5-in-4-phenyl-1H-quinolin-2-one To a solution of 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxylic acid (Example 22) (36.7 mg, 0.1 mmol), Morpholine (13 μL, 0.15 mmol) in DMF (1 mL) was added PyBrop (73 mg, 0.15 mmol) and DIEA (70 μL). The resulting mixture was stirred at room temperature overnight and concentrated. The obtained residue was purified on silica (0-5% MeOH: EtOAc) to obtain the title compound. Performance 41%.

EXAMPLE 24 General procedure for the elaboration of R2 To a solution of 6-chloro-3- (3-hydroxymethyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one (822 mg, 2.33 mmol) in CH3CN (8 mL) was added. added Dess-Martin periodinane (1.05 g, 2.47 mmol). The resulting mixture was stirred at room temperature for 3 hours and concentrated. Water (20 mL) was then added and the product was extracted with (5% MeOH: CH 2 Cl 2 3x50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was chromatographed on silica (30-80% EtOAc: Hexane) to obtain 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) - partially pure soxazole-3-carboxaldehyde. Yield 66%). 1 H-NMR (CDCl 3, 400 MHz) d 13.15 (s, 1 H), 10.09 (s, 1 H), 7.57-7.47 (m, 8H), 6.97 (s, 1 H). To a solution of the above aldehyde (35.1 mg, 0.1 mmol) and the corresponding amine (0.1 mmol) in dichloroethane (1 mL), HOAc (6 μL) was added. The resulting mixture was stirred at room temperature for 30 minutes and Na (OAc) 3BH (31.6 mg, 0.15 mmol) was added and stirred at room temperature for 12 hours and concentrated. The obtained residue was dissolved in MeOH (0.5 mL), filtered and purified by reverse phase HPLC using CH3CN: 0.1% TFA / water to obtain the expected product as its TFA salt.

EXAMPLE 25 6-Chloro-3-? 3- (4-methyl-piperazin-1-ylmethyl) -isoxazole-5-in-4-phenyl-1 H-quinolin-2-one From 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde and 1-methyl-piperazine, according to the procedure Yield 71%.

EXAMPLE 26 6-Chloro-4-phenyl-3- (3-r-2-piperidin-1-yl-ethylamino) -methin-isoxazol-5-yl) -1H-quinolin-2-one From 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde and 2-piperidin-1-yl-ethylamine in accordance with the procedure 24. Yield 53%.

EXAMPLE 27 2- (5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl-isoxazol-3-ylmethyl-amino-malonic acid dimethyl ester) From 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde and the 3-amino-pentandioic acid dimethyl ester, according to with procedure 24. Yield 27%.

EXAMPLE 28 6-Chloro-4-phenyl-3-. { 3-r (2-pyrrolidin-1-yl-ethylamine) -methin-isoxazol-5-yl) -1H-quinolin-2-one From 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -soxazole-3-carboxaldehyde and 2-pyrrolidin-1-yl-ethylamine , according to procedure 24. Yield 53%.

EXAMPLE 29 6-Chloro-3-f3-r (2-morpholin-4-yl-ethylamino) -methin-isoxazol-5-yl-phenyl-1H-quinolin-2-one From 5- (6-chloro-2-oxo-4-phene-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde and 2-morpholin-4-yl-ethylamine, according to procedure 24. Yield 37%.

EXAMPLE 30 6-Chloro-4-phenyl-3-r3- (4-pyridin-2-yl-piperazin-1-ylmethyl) -isoxazol-5-yn-1H-quinolin-2-one From 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde and 1-pyridin-2-yl-piperazine, in accordance with procedure 24. Yield 32%.

EXAMPLE 31 4-f (r5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazo-3-ylmethrin-aminol-methdiD-benzenesulfonamide From 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde and 4-aminomethyl-benzenesulfonamide, according to procedure 24. Yield 44% EXAMPLE 32 5- (6-Chloro-2-oxo-4-phenyl-1,2-d, 4-dichloroquinol-3-yl) -soxazole-3-carbonitrile To a solution of 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxaldehyde in MeOH (20 mL), aqueous NH 2 OH was added ( 1 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and water (20 mL) was added. The formed precipitate was then collected by purification with suction and dried in vacuo. The previous oxime (365 mg, 1 mmol) was dissolved in pyridine (10 mL) and acetic anhydride (0.3 mL, 2 mmol) was added. The resulting mixture was stirred overnight and concentrated. The obtained residue was purified with (30% EtOAc: Hexane) to obtain the title compound. Performance 67%.

EXAMPLE 33 Preparation of 6-Chloro-3- (1H-imidazol-2-yO-4-phenyl-1H-quinolin-2-one) A solution of 3- (1-benzyl-1H-imidazol-2-yl) -6-chloro-4-phenyl-1H-quinolin-2-one (110 mg) in a-chloroethylchloroformate (5 mL) was heated to 100 ° C for 2 hours. The reaction was evaporated and the resulting residue was dried in vacuo. The residue was dissolved in HOAc (5 mL) and H4AC (100 mg) was added. The reaction mixture was heated at 100 ° C for 12 hours. The solvents were removed and the title compound isolated by reverse phase HPLC. Performance 66%.

EXAMPLE 34 3- (5-bromo-pyridin-3-i0-6-chloro-4-phenyl-1H-quinoHn-2-one) A solution of 2-amino-5-chlorobenzophenone (230 mg, 1.00 mmol), 5-bromo-3-pyridineacetic acid (215 mg, 1.00 mmol) and 1- [3- (dimethylamino) propyl] -3 hydrochloride. Ethylcarbodiimide (EDCI) (230 mg, 1.20 mmol) in DCM (2.5 mL) was stirred overnight at room temperature. Then toluene (2.5 mL) and piperidine (0.2 mL) were added and the resulting solution was stirred at about 100 ° C, allowing the DCM to evaporate from the reaction mixture. After 2 hours, the reaction was allowed to cool and stirring continued at room temperature overnight. The precipitate that formed was filtered and washed with toluene. This crude product was dissolved in chloroform and extracted with water (4X), dried over potassium carbonate (K2CO3) and concentrated to provide the pure quinolinone product (285 mg, 69%). 1 H NMR (300 MHz, DMSO-d 6) d 12.4 (broad s, 1 H), 8.45 (d, 1 H, J = 3.0 Hz), 8.21 (d, 1 H, J = 1.3 Hz), 7.86 (t, 1 H, J = 1.5 Hz), 7.64 (dd, 1H, J = 8.9, 2.3 Hz, 1H), 7.46 (d, 1H, J = 8.6 Hz), 7.44-7.31 (m, 3H), 7.28-7.21 (m, 2H ), 6.94 (d, 1 H, J = 2.0 Hz). MS: 413.0 (M + H).

EXAMPLE 35 6-Chloro-4- (2-fluorophenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 34, in 40% yield. 1 H NMR (300 MHz, CDCl 3) d 11.35 (s, 1H), 7.60-7.43 (m, 5H), 7.38-7.12 (m, 2H), 6.76 (s, 1 H), 2.28 (s, 3H). MS: 355.0 (M + H).

EXAMPLE 36 6-Chloro-4-phenyl-3- (3-methyl-isoxazol-5-ip-1H-quinolin-2-one) Prepared according to the procedure described for Example 34, in 53% yield. 1 H NMR (300 MHz, DMSO-d 6) d 12.5 (broad s, 1 H), 7.66 (dd, 1 H, J = 8.9, 2.6 Hz), 7.51-7.42 (m, 4H), 7.31-7.24 (m, 2H), 6.91 (d, 1 H, J = 2.6 Hz), 6.49 (s, 1 H), 2.13 (s, 3H). MS: 337.2 (M + H).

EXAMPLE 37 6-Chloro-3- (3-methyl-isoxazol-5-ih-4-pyridin-2-yl-1H-quinolin-2-one) EXAMPLE 37a (2-Amino-5-chlorophenyl-pyridin-2-yl-methanone 3. 1M HC1 To a cooled (-40 ° C) solution of 2-bromopyridine (1.68 mL, 17.6 mmol) in tetrahydrofuran (THF) (30 mL), n-butyllithium (nBuLi) (9.7 mL, 19 mmol, 2 M) was added. in pentane) dropwise and the resulting mixture was stirred for 30 minutes. 2-Amino-5-chlorobenzoic acid (0.7 g, 4 mmol) was added and stirring continued at 0 ° C. After 2 hours, the mixture was quenched with trimethylchlorosilane (TMSCI) (10 mL), and hydrolyzed with 1N HCl (30 mL). The aqueous layer was separated from the organic phase, neutralized with 3N aqueous sodium hydroxide and extracted with ether (3 X 100 mL). The combined ether extracts were dried (Na 2 SO 4), filtered and purified by flash chromatography on silica gel [hexanes: ethyl acetate (7: 3)] to give (2-amino-5-chlorophenyl) -pyridin-2 il-methanone (0.71 g, 76%). The title compound was prepared according to the procedure described for Example 34, in 40% yield. H NMR (300 MHz, CDCl 3) d 11.87 (s, 1H), 8.76 (d, J = 4.8 Hz, 1 H), 7.92-7.79 (m, 1H), 7.58-7.48 (m, 1H), 7.48-7.40 (m, 1H), 7.36 (d, J = 9.6 Hz, 1H), 7.36 (d, J = 9.6 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 6.80 ( s, 1 H), 2.28 (s, 3H). MS: 338.0 (M + H).

EXAMPLE 38 6-Chloro-3- (3-methyl-isoxazol-5-ip-4-pyridin-3-yl-1H-quinolin-2-one) EXAMPLE 38a .2-amino-5-chlorophenyl) -pyrid-4-yl-methanone A solution of 4-chloroaniline (1.3 g, 10 mmol) in dichloromethane (DCM) (15 mL) was added dropwise to a stirred solution of boron trichloride (BCI3) in heptane (1.0 M, 15 mmol) at 0 °. C, followed by the sequential addition of 4-cyanopyridine (1.2 g, 12 mmol) and aluminum trichloride (AICI3) (2.0 g, 15 mmol). The mixture was stirred at room temperature for 30 minutes, and then heated to reflux overnight. After cooling to room temperature, the reaction was carefully quenched with cold 2N HCl (60 mL), then heated at 80 ° C for 30 minutes. The mixture was extracted with DCM (2 X 50 mL). The separated aqueous layer was neutralized with 3N NaOH and extracted with DCM (3 X 50 mL). The organic layers were combined, dried (MgSO 4), filtered, concentrated and purified by flash chromatography on silica gel [hexanes: ethyl acetate (7: 3)] to provide (2-amino-5-chlorophenyl) ) -pyrid-4-yl-methanone as a yellow solid (1.4 g, 60%). The title compound was prepared according to the procedure described for Example 34, in 40% yield. 1 H NMR (300 MHz, DMSO-d 6) d 8.67 (dd, J = 2.5, 5.5 Hz, 1H), 8. 48-8.45 (m, 1H), 7.82-7.76 (m, 1H), 7.65 (dd, J = 3.8, 8.7 Hz, 1H), 7.56-7.50 (m, 1H), 7.45 (d, J = 8.0 Hz, 1 H), 6.88 (d, J = 3.0 Hz, 1H), 6.66 (s, 1 H), 2.15 (s, 3H). MS: 338. 1 (M + H).

EXAMPLE 39 6-Bromo-3- (3-methyl-isoxazol-5-yl, -4-phenyl-1H-quinolin-2-one) Prepared according to the procedure described for Example 34, in 55% yield. 1 H NMR (300 MHz, DMSO-d 6) d 12.54 (s, 1 H), 7.76 (dd, J = 3.6, 9.6 Hz, 1H), 7.51-7.44 (m, 3H), 7.38 (d, J = 9.3 Hz , 1 H), 7.30-7.23 (m, 2H), 7.05 (d, J = 2.1 Hz, 1H), 6.48 (s, 1H), 2.13 (s, 3H). MS: 381.0 (M + H).

EXAMPLE 40 6-Chloro-4- 3-hydroxyphenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one A mixture of 2-amino-5-chloro-3'-hydroxybenzophenone (0.1 g, 0.4 mmol), (3-methyl-isoxazol-5-yl) -acetyl chloride (1.18 mmol) [synthesized from the reaction between (3-Methyl-isoxazol-5-yl) -acetic acid hydrochloride and oxalyl chloride catalyzed by N, N-dimethylformamide in DCM], triethylamine (Et3N) (0.20 mL) and DCM (10 mL) was heated to reflux overnight. The mixture was then cooled to room temperature and concentrated and the residue was pued by flash chromatography on silica gel (5% methanol in DCM) to provide 6-chloro-4- (3-hydroxyphenyl) -3- (3 -methyl-isoxazol-5-yl) -1H-quinolin-2-one (99 mg, 70%). 1 H NMR (300 MHz, DMSO-d 6) d 9.68 (s, 1 H), 7.68-7.60 (m, 2 H), 7.43 (d, J = 10.0 Hz, 1 H), 7.25 (t, J = 10.0 Hz, 1 H) , 7.01-6.97 (m, 1 H), 6.88-6.80 (m, 1H), 6.68-6.59 (m, 1H), 6.47 (s, 1H), 2.15 (s, 3H). MS: 353.2 (M + H).

EXAMPLE 41 6-Chloro-3- (3-methyl-isoxazol-5-ip-4-pyridin-4-yl-1H-quinolin-2-one) A solution of (2-amino-5-chlorophenyl) -pyridin-4-yl-methanone (50 mg, 0.22 mmol) and (3-methyl-5-isoxazol-5-yl) -acetic acid (30 mg, 0.22 mmole) were dissolved in POCI3 (1 mL). The resulting solution was stirred at about 45 ° C for 5 hours. After cooling to room temperature, ethyl acetate (EtOAc) (10 mL) was added and the excess of POCI3 was carefully quenched with saturated aqueous NaHCO3 (until basic). After separating the two phases, the aqueous phase was extracted with EtOAc (3 X 10 mL) and the combined organic layers were dried over Na 2 SO 4 and concentrated. The resulting chloroquinoline was dissolved in 80% aqueous acetic acid or (HOAc) (2 mL) and heated in a microwave reactor (Smith Synthesizer) in a sealed tube at 140 ° C for 30 minutes. Concentration under reduced pressure provided the quinolinone product as the hydroacetate exits. 1 H NMR (300 MHz, DMSO-d 6) d 8.73-8.68 (m, 2H), 7.71-7.66 (m, 2H), 7.47 (d, J = 9.5 Hz, 1 H), 7.39-7.34 (m, 2H) , 6.86 (d, J = 4.3 Hz, 1 H), 6.69 (s, 1 H), 2.16 (s, 3H). MS: 338.0 (M + H).

EXAMPLE 42 6-l, 2-Dihydroxy-ethyl) -3-f 3-methyl-isoxazol-5-yl) -4-phenyl-1 H-quinolin-2-one (e) (a) To a solution of 2-amino-5-bromobenzophenone (0.69 g, 2.5 mmol) in dry ether (25 mL) was added anhydrous sodium carbonate (1.7 g, 16 mmol). The mixture was cooled to 0 ° C followed by the addition in portions of the tuoroacetic anhydride [(CF3CO) 20] (1.74 mL, 12.3 mmol). When the addition was complete, the mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was then partitioned between DCM (40 mL) and water (40 mL). The organic layer was dried (g S04), filtered and concentrated to give N- (2-benzoyl-4-bromophenyl) -2,2,2-tuoroacetamide (a) as a white solid (0.93 g, 100%) . (b) To a solution of the N- (2-benzoyl-4-bromophenyl) -2,2,2-tuoroacetamide (a) (0.37 g, 1.0 mmol) in dry degassed toluene (10 mL) was added a solution of tetracis (triphenyl-phosphine) palladium [Pd (PPh3) 4] in toluene (5 mL) under argon. The mixture was heated to reflux and tributyl (vinyl) tin (0.29 mL, 1 mmol) was added dropwise. After refluxing overnight, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was pued by flash chromatography on silica gel [hexanes: ethyl acetate (9: 1)] to give N- (2-benzoyl-4-vinylphenyl) -2,2,2-tuoro -acetamide (b) (0.22 g, 70%). 1 H NMR (300 MHz, CDCl 3) d 12.0 (s, 1 H), 8.62 (d, J = 10.9 Hz, 1 H), 7.80-7.60 (m, 5H), 7.60-7.43 (m, 2H), 6.65 (dd, J = 11, 19.6 Hz, 1 H), 5.69 (d, J = 19.6 Hz, 1H), 5.29 (d, J = 11 Hz, 1 H). MS: 320.2 (M + H). (c) N- (2-Benzoyl-4-vinyiphenyl) -2,2,2-tuoroacetamide (b) (0.32 g, 1. 0 mmol) was dissolved in a mixture of methanol (38 mL) and water (2.3 mL) and potassium carbonate (0.7 g, 5 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated. Water was added (20 mL) was added to the residue and the mixture was extracted with chloroform (3 X 50 mL). The combined organic layers were dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography on silica gel [hexanes: ethyl acetate (9: 1)] to yield 2-amino-5-vinylbenzophenone (c) (0.2 g, 90%). 1 H NMR (300 MHz, CDCl 3) d 7.70-7.60 (m, 2H), 7.60-7.40 (m, 5H), 6.72 (d, J = 10 Hz, 1H), 6.65 (dd, J = 11, 19.6 Hz, 1H), 6.16 (broad s, 2H), 5. 56 (d, J = 19.6 Hz, 1H), 5.03 (d, J = 11 Hz, 1H). MS: 224.2 (M + H). (d) A mixture of 2-amino-5-vinylbenzophenone (c) (0.1 g, 0.45 mmol), (3-methyl-isoxazol-5-yl) -acetyl chloride (0.9 mmol) [of Example 4], triethylamine (0.20 mL) and DCM (10 mL) was heated to reflux overnight.

After the mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography on silica gel (5% methanol in DCM) to provide 3- (3-methyl-isoxazol-5-yl) - 4-phenyl-6-vinyl-1 H-quinolin-2-one (d) (0.12 g, 81%). 1 H NMR (300 MHz, CDCl 3) d 12.68 (s, 1H), 7.74-7.65 (m, 1 H), 7.52-7.41 (m, 4H), 7.30-7.13 (m, 3H), 6.58 (dd, J = 11, 19.6 Hz, 1H), 6.45 (s, 1H), 5.62 (d, J = 19.6 Hz, 1H), 5.18 (d, J = 11 Hz, 1H), 2.27 (s, 3H). MS: 329.2 (M + H). (e) The AD-mixture ß was dissolved in 50% aqueous ter-butanol (10 mL) followed by 3- (3-methyl-isoxazol-5-yl) -4-phenyl-6-vinyl-1 H- quinolin-2-one (d) (60 mg, 0.18 mmol) and the resulting mixture was stirred at room temperature overnight. Sodium sulfite (0.3 g) was added and stirring continued until the solution cleared. The mixture was extracted with ethyl acetate (1 X 20 mL, 2 X 10 mL) and the combined organic layers were dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (5% methanol in DCM) to provide 6- (1,2-dihydroxy-ethyl) -3- (3-methyl-isoxazol-5-yl) -4- phenyl-1 H-quinolin-2-one (e) (66 mg, 100% o). 1 H NMR (300 MHz, DMSO-d 6) d 12.3 (s, 1 H), 7.56 (dd, J = 2.6, 6.9 Hz, 1 H), 7.49-7.41 (m, 3H), 7.37 (d, J = 8.6 Hz, 1H), 7.27-7.18 (m, 1 H), 7.09-7.04 (m, 1H), 6.41 (s, 1H), 5.25-5.20 (m, 1 H), 4.65 (dd, J = 6.4, 7.7 Hz, 1H), 4.46-4.36 (m, 1H), 2.12 (s, 3H). MS: 363.2 (M + H).

EXAMPLE 43 3- (3-Ethyl-5-oxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydroxyquinoline-6-carboxaldehyde (a) A mixture of 6-2-dihydroxy-ethyl) -3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H-quinolin-2-one (40 mg, 0.11 mmol), sodium periodate (94 mg, 0.44 mmoles), saturated aqueous sodium bicarbonate (0.2 mL) and DCM (5 mL) was stirred for 4 hours at room temperature, then filtered and concentrated. The residue was purified by flash chromatography on silica gel to provide 3- (3-methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydroquinoline-6-carboxaldehyde (a) as a white solid (31 mg, 85%).

EXAMPLE 44 3-, 3-Methylisoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydroquinol-6-carboxylic acid (b) 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxaldehyde (a) (16 mg, 0.05 mmol) was dissolved in tert-butanol (2 mL) followed by the sequential addition of a saturated aqueous solution of sodium phosphate monobasic (0.25 mL), 2-methyl-2-butene (0.05 mL) and sodium chlorite (NaCl02) (7 mg, 0.08 mmol). The mixture was stirred at room temperature for 3.5 hours and concentrated. The residue was dissolved in ethyl acetate (15 mL), dried (MgSO 4), filtered and concentrated to give the acid 3- (3-methylisoxazol-5-yl) -2-oxo-4-phenyl-1, 2-dihydroquinoline-6-carboxylic acid (b) as a white solid (17.3 mg, 100% o). 1 H NMR (300 MHz, CD 3 OD) d 8.19 (dd, J = 6.4, 8.0 Hz, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.51-7.43 (m, 4H), 7.31-7.23 (m, 2H), 6.33 (s, 1H), 2.18 (s, 3H). MS: 347.2 (M + H).

EXAMPLE 45 6-Hydroxymethyl-3- (3-methylisoxazol-5-yl) -4-phenyl-1H-quinolin-2-one © A mixture of 3- (3-methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxaldehyde (a) (33 mg, 0.11 mmol), sodium borohydride (NaBH) (4 mg, 0.1 mmol) in DCM (1 mL) and methanol (1 mL) was stirred at room temperature for 1.5 hours and then concentrated. To the residue was added DCM (10 mL) and water (1 mL). The organic layer was separated from the aqueous layer, dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography on silica gel to provide 6-hydroxymethyl-3- (3-methylisoxazol-5-yl) -4-phenyl-1H-quinolin-2-one (c) (33 mg, 90% ). 1 H NMR (300 MHz, CD 3 OD) d 7.65-7.58 (m, 1 H), 7.49-7.38 (m, 4 H), 7.30-7.20 (m, 3 H), 6.30 (s, 1 H), 4.51 (s, 2 H) , 2.17 (s, 3H). MS: 333.2 (M + H).

EXAMPLE 46 (General procedure for the preparation of 3- (3-alkyl-isoxazol-5-iP-quinolinones) 3- (3-tert-Butyl-isoxazol-5-yl) -6-chloro-4-phenyl-1 H-quinolin-2-one (b) (a) To a solution of 3-butionic acid (0.421 g, 5.01 mmol) in DMC anhydrous (10 mL) was added oxalyl chloride (0.48 mL, 5.5 mmol) and one drop of DMF. After stirring for 1 hour, 2-amino-5-chlorobenzophenone (1.16 g, 5.01 mmol) was added to the acid chloride recently generated at 0 ° C. The reaction mixture was stirred at 25 ° C for 15 minutes, and then refluxed for 30 minutes.

After cooling to room temperature, the solvent was evaporated to give a yellow oil, which was purified by flash chromatography (silica gel) to provide the but-3-ynoic acid (2-benzoyl-4-chlorophenyl) amide ( a) (1.33 g, 89%)) as a yellow solid. 1 H NMR (300 MHz, CDCl 3): d 11.25 (s, 1 H), 8.59 (d, J = 9.3 Hz, 1 H), 7.74-7.72 (m, 2 H), 7.72-7.61 (m, 1 H), 7.55- 7.26 (m, 4H), 3.41 (d, J = 2.7 Hz, 2H), 2.60 (t, J = 2.7 Hz, 1H). MS: 298 (M + H). (b) To an ice cooled solution of the but-3-inoic (2) (2-benzoyl-4-chlorophenyl) amide (a) (0.100 g, 0.336 mmole) in anhydrous DCM (7 mL), the oxime of 2,2-dimethylpropionaldehyde (0.204 g, 2.02 mmol) and a solution of sodium hypochlorite (3.50 mL). After stirring for 2 hours at 0 ° C, the reaction was heated to 25 ° C and stirred overnight. The organic layer was separated, dried (MgSO4) and concentrated to give N- (2-benzoyl-4-chlorophenyl) -2- (3-tert-butyl-isoxazoyl-5-yl) -acetamide as a yellow oil. . This ketoamide was dissolved in anhydrous toluene (4 mL) and treated with triethylamine (0.5 mL). After stirring for 12 hours at 25 ° C, the reaction mixture was evaporated to give the crude product as a yellow solid. Purification by flash chromatography afforded 3- (3-tert-butyl-isoxazol-5-yl) -6-chloro-4-phenyl-1H-quinolin-2-one (b) (0.10 g, 77%) yield ) as a white solid. 1 H NMR (300 MHz, CDCl 3): d 11.83 (s, 1 H), 7.52-7.45 (m, 4 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.26-7.20 (m, 3 H), 6.42 (s) , 1H), 1.26 (s, 9H). MS: 379 (M + H).

EXAMPLE 47 6-Chloro-3-, 3-isopropyl -soxazol-5-yl) -4-phenyl-1H-quinolin-2-one Prepared according to the procedure described for Example 46, in 74% yield. 1 H NMR (300 MHz, CDCl 3): d 12.77 (s, 1 H), 7.52-7.7.41 (m, 5H), 7. 26-7.20 (m, 3H), 3.00 (h, J = 6.9 Hz, 1 H), 1.22 (d, J = 6.9 Hz, 6H). MS: 365 (M + H).

EXAMPLE 48 6-Chloro-3- (3-phenethyl-isoxazole-5-yl, -4-phenylamine-quinolin-2-one) Prepared according to the procedure described for Example 46, in 75% yield. 1 H NMR (300 MHz, CDCl 3): d 12.23 (s, 1H), 7.53-7.46 (m, 4H), 7. 37 (d, J = 8.9 Hz, 1H), 7.32-7.21 (m, 6H), 7.19-7.15 (m, 2H), 6.38 (s, 1 H), 2.94 (s, 4H). MS: 427 (M + H).

EXAMPLE 49 (General procedure for the preparation of 3-fOxazol-2-D-Q-inolinones) 6-Chloro-3- (4-isobutyl-oxazol-2-p-4-phenyl-1H-quinolin-2-one (d) (a) A mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (200 mg, 0.61 mmol), 10% HCl (1 mL) and dioxane (3 mL) was heated to reflux for 48 hours. After cooling, water was added and the resulting precipitate was collected by filtration, washed with water and dried to provide 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid. (a) (143 mg, 78%). MS: 300.5 (M + H). To a suspension of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (a) (600 mg, 2 mmol) in DCM (10 mL), chloride was added. oxalyl (220 μL, 2.5 mmol), followed by a few drops of DMF. After stirring for 4 hours at room temperature, the mixture was concentrated to dryness and a portion of the crude acid chloride thus obtained (IR: 1780 cm "1) was used directly in the next step. (b) To a stirred suspension of 6-chloro-2-oxo-4-phenyl-1 chloride, 2-dihydro-quinoline-3-carboxylic acid (29 mg, 0.09 mmol) in DCM (0.5 mL) was added (S) - (+) - leucinol (30 μL, 0.23 mmol). Over the course of 5 minutes, the mixture became homogeneous and the reaction was terminated as determined by LCMS. Chloroform (2 mL) was added and the solution was extracted with 1N HCl (4X1 mL) and water (2X1 mL). The chloroform layer was purified directly by flash chromatography, eluting with chloroform, then chloroform / methanol (100: 1) → (50: 1) → (25.) To provide the (1-hydroxymethyl-3-methylbutyl) amide. 6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (b) (19 mg, 52%) as a white powder. MS: 399.2 (M + H). (c) To a mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (1-hydroxymethyl-3-methylbutyl) -amide (b) (30.0 mg, 0.075 mmole) in DCM (8.0 mL), thionyl chloride (31.0 μL, 0.40 mmole) was added at room temperature. The reaction was stirred for 0.5 hour at room temperature, cooled to 0 ° C, quenched with a cold solution of NaOH (1 N), and extracted with DCM (3 x 10 mL). The solvent was then removed in vacuo to provide 6-chloro-3- (4-isobutyl-4,5-dihydro-oxazol-2-yl) -4-phenyl-1H-quinolin-2-one (c) ( 25 mg, 87%). 1 H NMR (CDCl 3): d 12.60 (broad s, 1H), 7.55-7.35 (m, 7H), 7.20 (d, 1 H), 4.40 (t, 1H), 4.30-4.20 (m, 1H), 3.7 (t, 1 H), 1.60-1.50 (m, 1H), 1.20-1.00 (m, 2H), 0.80 (dd, 6H). MS: 381.3 (M + H). (d) A mixture of 6-chloro-3- (4-isobutyl-4,5-dihydro-oxazol-2-yl) -4-phenyl-1H-quinolin-2-one (c) (10.0 mg, 0.025 mmol) , Mn02 (15 mg) and CHCl3 (1.0 mL) in a sealed tube, was heated at 125 ° C for 45 minutes in a microwave reactor (Smith Synthesizer). The mixture was then filtered through a small pad of celite and purified by preparative TLC (5% MeOH / EtOAc) to give 6-cioro-3- (4-isobutyl-oxazol-2-yl) -4 phenyl-1H-quinolin-2-one (d) (2 mg, 20%). 1 H NMR (acetone-de): d 11.20 (s broad, 1H), 7.60-7.20 (m, 9H), 2.20 (d, 2H), 1.80-1.65 (m, 1H), 0.75 (d, 6H). LCMS: 379. 3 (M + H).

EXAMPLE 50 (General procedure for the preparation of 3- (1,2,3-triazol-4-iD-quinolinones) 3- (1-Benzyl-1 H-f1.2,3] triazol-4-yl) -6-chloro-4-phenyl-1H-quinolin-2-one To a solution of the but-3-inoic (2-benzoyl-4-chloro-phenyl) -amide (from Example 7) (0.056 g, 0.188 mmol) in 50% aqueous ter-butanol (5 mL), Benzyl azide (0.07 mL, 0.56 mmol), sodium ascorbate (0.012 g, 0.0564 mmol) and copper sulphate (II) pentahydrate (0.002 g, 5.64 μmol) were added. After stirring at 70 ° C for 15 hours, the reaction mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The aqueous layer was further extracted with ethyl acetate (2X15 mL) and the combined organic layers were dried (MgSO4) and concentrated. The residual yellow oil was purified by flash chromatography (silica gel) to provide the 3- (1-benzyl-1 H- [1, 2.3] triazol-4-yl) -6-chloro-4-phenyl! -1 H -quinolin-2-one (0.064 g, 82% > yield) as a white solid. 1 H NMR (300 MHz, CDCl 3): d 12.42 (s, 1 H), 7.51 (s, 1H), 7.39-7.32 (m, 7.5H), 7.29 (s, 0.5H), 7.18-7.15 (m, 3H ), 7.09-7.06 (m, 2H), 5.46 (s, 2H). MS: 413 (M + H).

EXAMPLE 51 3-, 3-Methyl-isoxazol-5-yl) -6-nitro-4-phenyl-1H-quinolin-2-one Prepared according to the procedure described in Example 41, 80% yield. 1 H NMR (400 MHz, CDCl 3) d 8.32 (m, 1 H), 8.12 (d, 1 H), 7.46 (m, 4 H), 7.20 (m, 2 H), 6.41 (s, 1 H), 2.20 (s, 3H). Mass spectrum (ESI, m / z) calculated for C-? 9H? 3N304 347.1, found 348.1 (M + H).

EXAMPLE 52 6-Amino-3- (3-rnethyl-isoxazol-5-yl, -4-phenyl-1H-quinolin-2-one A flask loaded with 3- (3-methyl-isoxazol-5-yl) -6-nitro-4-phenyl-1 H -quinolin-2-one (0.2 g, 0.58 mmol) (Example 51), 50 mg of Pd / C at 10% and 10 mL of methanol was stirred on a Parr apparatus under 1054 kgf / cm2 (15 PSI) of H2 for 8 hours. The solution was filtered and concentrated to provide 0.18 g (100% >) of the title compound as a white solid. 1 H NMR (400 MHz, CD 3 OD) d 7.44 (m, 3 H), 7.22 (m, 3 H), 7.04 (m, 1 H), 6.50 (m, 1 H), 6.34 (s, 1 H), 2.20 (s, 3 H) ). Mass spectrum (ESI, m / z) calculated for C19H15N302 317.1, found 318.1 (M + H).

EXAMPLE 53 N-r3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinolin-6-acetamide A flask loaded with 6-amino-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-quinoline! In-2-one (0.027 mg, 0.085 mmol) (Example 52), acetic anhydride (0.01 mL, 0.100 mmol), NEt3 (0.018 mL, 0.13 mmol) and 1 mL of THF was stirred for 6 hours at 25 ° C. The title compound was eluted from 5 g of SPE with 100% EtAc to provide 0.015 g (50%) of a white solid. 1 H NMR (400 MHz, CDCl 3) d 12.30 (s, 1 H), 8.06 (s, 1 H), 7.72 (m, 1H), 7.36 (m, 5H), 7.14 (m, 2H), 6.36 (s, 1 H), 2.22 (s, 3H), 2.02 (s, 3H).

Mass spectrum (ESI, m / z) calculated for C2? H17N303 359.1, found 360. 2 (M + H).

EXAMPLE 54 N-r3- (3-Methyl-isoxazol-5-ip-2-oxo-4-phenyl-1,2-dihydro-quinolin-6-methanesulfonamide) Prepared according to the procedure described in Example 53, substituting methan sulfonyl chloride for acetic anhydride. 1 H NMR (400 MHz, DMSO-d 6) d 12.32 (s, 1 H), 9.66 (s, 1 H), 7.45 (m, 5H), 7.24 (m, 2H), 7.02 (m, 1 H), 6.44 (s, 1H), 2.88 (s, 3H), 2.12 (s, 3H). Mass spectrum (ESI, m / z) calculated for C2oH? N3? 4S 395.1, found 396.1 (M + H).

EXAMPLE 55 N-r3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinolin-6-n-acrylamide Prepared according to the procedure described in Example 53 1 H NMR (400 MHz, CDCl 3) d 7.98 (m, 1 H), 7.40 (m, 5 H), 7.24 (m, 2 H), 6.32 (m, 3 H), 6.78 (m, 1 H), 2.22 (s, 3 H) ). Mass spectrum (ESI, m / z) calculated for C22H17N303 371.1, found 372.1 (M + H).

EXAMPLE 56 3-, 3-MethyI-isoxazol-5-yl) -4-phenyl-6- (pyridin-2-ylamino) -1H-quinolin-2-one a) 2-Chloro-3- (3-methyl-isoxazol-5-yl) -6-nitro-4-phenyl-quinoline A flask loaded with (2-amino-5-nitro-phenyl) -phenyl-methanone (1.3 g, 5.4 mmol), (3-methyl-isoxazol-5-yl) -acetic acid (0.74 g, 5.3 mmol), and 10 mL of phosphorus oxychloride was heated at 60 ° C for 6 hours. The reaction was concentrated and triturated with saturated NaHCO3 to provide 1.9 g of a white solid which was used without further purification. b. 2-Chloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-quinolin-6-ylamine A flask loaded with 2-chloro-3- (3-methyl-isoxazol-5-yl) -6-nitro-4-phenyl-quinoline (1.1 g, 3.0 mmol), NH4CI (1.6 g, 30 mmol), powder of iron (0.87 g, 15 mmol), EtOH (20 mL) and H20 (10 mL) was heated at 80 ° C for 1 hour. The reaction was filtered and concentrated and eluted from 20 g of SPE with 30%) EtAc / hexanes to give 0.8 g (80%) of the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3) d 7.96 (m, 1 H), 7.40 (m, 3 H), 7.22 (m, 3 H), 6.62 (m, 1 H), 5.92 (s, 1 H), 3.98 m (m, 2 H) ), 2.22 (s, 3H). Mass spectrum (ESI, m / z) calculated for C 9H? CIN30 335.1, found 336.1 (M + H). A flask loaded with 2-chloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-quinolin-6-ylamine (35 mg, 0.10 mmol), 2-bromopyridine (22 mg, 0.14 mmol) , Xanthphos (7 mg, 12 mol%), Pd2 (dba) 3 (5 mg, 5 mol%), potassium t-butoxide (13 mg, 0.11 mmol) and dioxane (0.5 mL) was heated to 110 °. C for 3 hours. The product was eluted from 5 g of SPE with 30% EtAc / hexanes and then dissolved in 1.8 mL of acetic acid and 0.2 mL of H20 and heated at 110 ° C for 5 hours. The solution was concentrated, and the residue was dissolved in DCM and washed with aqueous NaHCO 3, dried (Na 2 SO) and concentrated. The title compound was eluted from 5 g of SPE with 30% EtAc / hexanes to provide 10 mg (25%) of a white solid. 1 H NMR (400 MHz, CDCl 3 + CD 3 OD) d 7.98 (m, 1 H), 7.59 (m, 1 H), 7.38 (m, 4 H), 7.14 (m, 4 H), 6.61 (m, 2 H), 6.32 (s, 1 H), 2.14 (s, 3 H). Mass spectrum (ESI, m / z) calculated for C24H? SN 02 394.1, found 394.1 (M + H).

EXAMPLE 57 3- (3H-lm-dazol-4-yl) -2-oxo-4-phene-1,2-dihydro-quinoIin-6-carbonitrile a) (2-Amino-5-bromo-phenyl ') - phenyl-methanone A flask loaded with (2-amino-phenyl) -phenyl-methanone (5 g, 25 mmol) and DCM (80 mL) was cooled to -10 ° C and NBS (4.5 g, 25 mmol) was added for 30 min. minutes via an addition funnel. The reaction was terminated after the addition of NBS and the reaction was diluted with 80 mL of DCM, washed with saturated NaHCO 3 (2x100 mL), dried over Na 2 SO 4 and concentrated to provide 7 g of a crude product, which was used without further purification. b) 4-Amino-3-benzoyl-benzonitrile A flask loaded with (2-amino-5-bromo-phenyl) -phenyl-methanone (93 mg, 0.33 mmol), copper cyanide (50 mg, 0.56 mmol) and 2 mL of DMA was heated at 180 ° C for 30 minutes in a microwave reactor. The title compound was eluted from 5g SPE with 20% EtAc / hexanes to provide 50 mg (71%) of a white solid. 1 H NMR (400 MHz, CDCl 3) d 7.81 (m, 1 H), 7.62 (m, 3 H), 7.50 (m, 3 H), 6.78 (m, 1 H), 6.68 (m, 2 H). The title compound was obtained from 4-amino-3-benzoyl-benzonitrile and (3H-imidazol-4-yl) -acetic acid according to the procedure in Example 41. 1 H NMR (400 MHz, DMSO-d 6) d 4.30 (broad, 1H), 12.90 (broad, 1H), 8.92 (s, 1H), 8.02 (m, 1H), 7.56 (m, 4H), 7.32 (m, 3H), 6.72 (s, 1H). Mass spectrum (ESI, m / z) calculated for C19H? 2N40 312.1, found 313.1 (M + H).

EXAMPLE 58 3- (1-methyl-1 H-imidazol-4-yl, -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile The title compound was prepared according to the procedure in Example 41. 1 H NMR (400 MHz, CD 3 OD) d 8.82 (s, 1 H), 7.92 (m, 1 H), 7.62 (m, 4 H), 7.49 (s, 1H), 7.38 (m, 2H), 6.62 (s, 1H), 3.78 (s, 3H). Mass spectrum (ESI, m / z) calculated for C20H14N4O 326.1, found 327.2 (M + H).

EXAMPLE 59 3- (3-Amino-isoxazol-5-yl) -6-chloro-4-phenyl-1H-quinolin-2-one a) 6-Chloro-4-phenyl-3- [3-H-quinolin-2-one The title compound was prepared from [3- (trityl-amino) -isoxazol-5-yl] -acetic acid (US Patent, 4,394,504) according to Example 3. 1 H NMR (400 MHz, DMSO-d6 ) d 12.36 (s, 1H), 7.64 (dd, 1 H), 7.42 (m, 4H), 7.20 (m, 18H), 6.90 (d, 1H), 6.02 (s, 1H). Mass spectrum (ESI, m / z) calculated for C37H26CIN302 579.1, found 580.0 (M + H). A flask loaded with 6-chloro-4-phenyl-3- [3- (trityl-amino) -isoxazol-5-yl] -1 H -quinolin-2-one (0.43 g, 0.74 mmol), DCM (9 mL), MeOH (1 mL) and (TFA 1 mL) was stirred at 25 ° C for 1 hour and then concentrated. The residue was triturated with EtOAc and the title compound was collected by filtration to give 0.17 g (75%) of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d 12.45 (s, 1 H), 7.64 (dd, 1 H), 7.46 (m, 4 H), 7.28 (m, 2 H), 6.90 (d, 1 H), 5.98 ( s, 1H), 5.42 (broad s, 2H). Mass spectrum (ESI, m / z) calculated for C? SH? 2CIN302 337.1, found 338.0 (M + H).

EXAMPLE 60 N-r5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-incetamide A flask loaded with 3- (3-amino-isoxazole) -5-yl) -6-cioro-4-phenyl-1H-quinolin-2-one (example 59) (22 mg, 0.063 mmol), acetic anhydride (9 mg, 0.082 mmol), 2,6-lutidine (11 mg, 0.10 mmol), DMAP (10 mg, 0.082 mmol) and DMF (0.5 mL) was heated at 50 ° C for 2 hours. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-100% CH3CN in 0.1% TFA / H2O for 30 minutes to provide 15 mg (60%) of the title compound. 1 H NMR (400 MHz, DMSO-d 6) d 12.54 (s, 1 H), 10.80 (s, 1 H), 7.68 (m, 1 H), 7.46 (m, 4 H), 7.30 (m, 2 H), 6.96 (m, 2H), 2.04 (s, 3H). Mass spectrum (ESI, m / z) calculated for C2oH1 CIN303 379.1, found 380.0 (M + H).

EXAMPLE 61 N'-r5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-ip-isoxazol-3-yl) -N, N-dimethyl-formamidine A flask loaded with 3- (3-amino-isoxazol-5-yl) -6-chloro-4-phenyl-1 H -quinolin-2-one (example 59) (15 mg, 0.045 mmol), methanesulfonyl chloride ( 7.4 mg, 0.065 mmol), 2,6-lutidine (7.4 mg, 0.068 mmol) and DMF (0.1 mL) was stirred at 25 ° C for 2 hours. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-70% CH3CN in 0.1% TFA / H2O for 20 minutes to provide 15 mg (68%) of the title compound as a salt of TFA. 1 H NMR (400 MHz, DMSO-d 6) d 12.62 (s, 1 H), 8. 52 (s, 1 H), 7.68 (d, 1 H), 7.48 (m, 4 H), 7.32 (m, 2 H), 6.96 ( d, 1 H), 6.80 (s, 1 H), 3.25 (s, 3 H), 3.12 (s, 3 H). Mass spectrum (ESI, m / z) calculated for C2? H-CIN402 392.1, found 393.1 (M + H).

EXAMPLE 62 N'-r5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-ip-N, N-dimethyl-acetamidine This was prepared according to Example 61, substituting dimethylacetamide for dimethylformamide and heating at 50 ° C for 8 hours. H NMR (400 MHz, CD3OD) d 7.68 (dd, 1 H), 7.52 (m, 4 H), 7.32 (m, 2 H), 7.18 (d, 1 H), 6.60 (s, 1 H), 3.42 (s, 3H), 3.32 (s, 3H), 2.36 (s, 3H). Mass spectrum (ESI, m / z) calculated for C22H? 9CIN402 406.1, found 407.1 (M + H).

EXAMPLE 63 N'-r5- (6-Chloro-2-oxo-4-pheny1,2-dihydro-quinolin-3-yl) -soxazol-3-p-N, N-dimethyl-propionamidine This was prepared according to example 62, substituting the N, N-dimethylpropionamide by N, N-dimethylacetamide. 1 H NMR (400 MHz, CD 3 OD) d 7.68 (dd, 1 H), 7.52 (m, 4 H), 7.32 (m, 2 H), 7.18 (d, 1 H), 6.60 (s, 1 H), 3.44 (s, 3H), 3.32 (s, 3H), 2.72 (c, 2H), 1.14 (t, 3H). Mass spectrum (ESI, m / z) calculated for C23H2- | CIN402 420.1, found 421.1 (M + H).

EXAMPLE 64 N-r5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-methanesulfonamide A flask loaded with 3- (3-amino-isoxazol-5-yl) -6-chloro-4-phenyl-1 H -quinolin-2-one (Example 59) (17 mg, 0.050 mmol), methanesulfonyl chloride (7.5 mg, 0.066 mmol) and pyridine (0.2 mL) was stirred at 25 ° C for 3 hours. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-70% CH3CN in 0.1% TFA / H2O for 10 minutes to provide 10 mg (50%). 1 H NMR (400 MHz, CD 3 OD) d 7.52 (dd, 1 H), 7.46 (m, 3 H), 7.36 (d, 1 H), 7.22 (m, 2 H), 7.12 (d, 1 H), 6.54 (s, 1 H) , 3.00 (s, 3H). Mass spectrum (ESI, m / z) calculated for C19H? 4CIN304S 415.0, found 416.0 (M + H).

EXAMPLE 65 5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazo [-3-ill-carbamic acid] 2-methanesulfonyl ethyl ester This was prepared according to Example 64 from 3- (3-amino-isoxazol-5-yl) -6-chloro-4-phenyl-1H-quinolin-2-one and the 2,5-dioxo ester. -l-1-lyric acid of carbonic acid, 2-methanesulfonyl-ethyl ester. 1 H NMR (400 MHz, DMSO-d 6) d 12.62 (s, 1 H), 10.78 (s, 1 H), 7.66 (dd, 1 H), 7.48 (m, 4 H), 7.32 (m, 2 H), 6.96 (d , 1 H), 6. 89 (s, 1H), 4.42 (t, 2H), 3.56 (t, 2H), 3.12 (s, 3H). Mass spectrum (ESI, m / z) calculated for C22H18CIN306S 487.0, found 488.0 (M + H).

EXAMPLE 66 1-f5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-in-3- (2-morpholin-4-yl-ethyl) .-urea A flask loaded with 3- (3-amino-isoxazol-5-yl) -6-chloro-4-phenyl-1H-quinolin-2-one (example 59) (15 mg, 0.045 mmol), 2.6- lutidine (5.5 mg, 0.052 mmol), 4-nitrophenyl chloroformate (10 mg, 0.05 mmol) and DMA (0.3 mL) was stirred at 25 ° C for 10 minutes and then 2-morpholin-4-yl-ethylamine was added. (12 mg, 0.092 mmol) and stirring continued for 30 minutes. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 20-50% CH3CN in 0.1% TFA / H2O for 10 minutes to provide 6 mg (22%) of the title compound as a TFA 1 H NMR (400 MHz, CD 3 OD) d 7.62 (dd, 1 H), 7.52 (, 3 H), 7.44 (m, 2 H), 7.30 (m, 2 H), 7.12 (d, 1 H), 6.60 (s, 1 H) , 3.72 (m, 4H), 3.40 (m, 2H), 2.52 (m, 6H). Mass spectrum (ESI, m / z) calculated for C25H24CIN5? 4 493.1, found 494.0 (M + H).

EXAMPLE 67 3- (3-Methyl-isoxazol-5-yl) -4,6-diphenyl-1H-quinolin-2-one A flask was charged with 6-bromo-3- (3-methyl-isoxazo! -5-yl) -4-phenyl-1H-quinolin-2-one (25 mg, 0.066 mmol) (Example 39), phenyl acid boronic (12 mg, 0.098 mmol), Pd (PPh3) 4 (7 mg, 10% in mol), Na2C03 2M (0.25 mL), EtOH (0.25 mL) and toluene (0.5 mL) and heated for 2 hours at 80 ° C. The reaction was diluted with EtAc (10 mL) and washed with brine (2x10 mL). The organic layer was concentrated and the title product (12 mg, 50%) was eluted with 5 g of SPE with 50% EtAc / hex. 1 H NMR (400 MHz, CDCl 3) d 11.42 (s, 1 H), 7. 82 (dd, 1 H), 7.20 (m, 12H), 6.52 (s, 1H), 2.24 (s, 3H). Mass spectrum (ESl / m / z) calculated for C25H-.8N202 378.1, found 379.1 (M + H).

EXAMPLE 68 3- (3-Methyl-isoxazol-5-ip-4-phenyl-6- (3-trifluoromethyl-phenyl) -MH-quinolin-2-one This was prepared according to Example 67. 1 H NMR (400 MHz, CDCl 3) d 12.68 (s, 1 H), 7.84 (dd, 1 H), 7.68 (m, 1 H), 7.50 (m, 8 H), 7.32 (m , 2H), 6.50 (s, 1H), 2.30 (s, 3H). Mass spectrum (ESI, m / z) calculated for C26H? 7F3N202 446.1, found 447.1 (M + H).

EXAMPLE 69 6- (3-Methoxy »-phenyl] -3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one This was prepared according to Example 67. 1 H NMR (400 MHz, CDCl 3) d 12.78 (s, 1 H), 7.82 (dd, 1 H), 7.44 (m, 5 H), 7.26 (m, 3 H), 7.08 (m , 1H), 6.98 (m, 1H), 6. 84 (m, 1H), 6.46 (s, 1H), 3.86 (s, 3H), 2.28 (s, 3H). Mass spectrum (ESI, m / z) calculated for C 26 H 20 N 2 O 3 408.1, found 409.1 (M + H).

EXAMPLE 70 3- (3-Methyl-isoxazoi-5-ip-2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile A flask loaded with 6-bromo-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one (30 mg, 0.077 mmol) (example 39), Pd (PPh3 ) 4 (5 mg, 5% mol), NaCN (8 mg, 0.16 mmol), Cul (1.5 mg, 10 mol%) and 0.7 mL of CH3CN and heated in a sealed tube in a microwave reactor to 100 ° C for 1 hour. The title compound was obtained by elution from 10 g of SPE with 50% EtAc / hexanes to provide 13 mg (50% >) of a white solid. 1 H NMR (400 MHz, CD 3 OD) d 7.78 (dd, 1 H), 7.50 (m, 5 H), 7.28 (m, 2 H), 6.42 (s, 1 H), 2.20 (s, 3 H). Mass spectrum (ESI, m / z) calculated for C20H? 3N3O2 327.1, found 328.1 (M + H).

EXAMPLE 71 3- (3-Methyl-isoxazol-5-yl) -6-methylsulfanyl-4-phenyl-1H-quinolin-2-one One flask was charged with 6-bromo-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one (30 mg, 0.079 mmol) (example 39), 1 mL of THF and cooled to 0 ° C. A 2M solution of i-PrMgCI in THF (0.39 mL, 0.077 mmol) was added and the reaction was stirred for 5 minutes at 0 ° C and then cooled to -78 ° C and a 2M solution of n-BuLi was added to it. hexanes (0.06 mL, 0.12 mmol). After stirring for 15 minutes, dimethyl disulfide (15 mg, 0.16 mmol) was added and the reaction was allowed to reach room temperature and stirred for 30 minutes. The reaction was diluted with EtAc (10 mL) and washed with brine (2x10 mL). The organic layer was concentrated and the title product (14 mg, 50%) was eluted from 5 g of SPE with 50%) of EtOAc / hexanes. 1 H NMR (400 MHz, CD 3 OD) d 7.54 (dd, 1 H), 7.48 (m, 3 H), 7.48 (d, 1 H), 7.24 (m, 2 H), 7.06 (d, 1 H), 6.36 (s, 1H), 2. 34 (s, 3H), 2.24 (s, 3H). Mass spectrum (ESI, m / z) calculated for C2oHi6N202S 348.1, found 349.1 (M + H).

EXAMPLE 72 6-Methanesulfonyl-3- (3-methyl-isoxasol-5-yl) -4-phenyl-1H-quinolin-2-one A flask loaded with 3- (3-methyl-isoxazol-5-yl) -6-methylsulfanyl-4-phenyl-1 H-quinolin-2-one (example 71) (50 mg, 0.14 mmol), MCPBA (77 %, 64 mg, 0.29 mmol) and 2 mL of DCM were stirred for 30 minutes at 25 ° C. The reaction was diluted with 10 mL of DCM, washed with saturated NaHCO3 (2x10 mL) and brine (10 mL). The organic layer was concentrated and the title compound was eluted from 10 g of SPE with 50% EtAc / hexanes to provide 43 mg (80%) of a white solid. 1 H NMR (400 MHz, DMSO-d 6) d 12.80 (s, 1 H), 8.12 (dd, 1 H), 7. 62 (d, 1H), 7.59 (d, 1H), 7.50 (m, 3H), 7.32 (m, 2H), 6.52 (s, 1H), 3.18 (s, 3H), 2.18 (s, 3H). Mass spectrum (ESI, m / z) calculated for C2oH? 6N2? 4S 380.1, found 381.0 (M + H).

EXAMPLE 73 6-Fluoro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one a) (2-Amino-5-fluoro-phenyl-phenyl-methanone) A flask loaded with (2-amino-phenyl) -phenyl-methanone (0.23 g, 1.2 mmol), N-fluorobenzenesulfonimide (0.37 g, 1.2 mmol) and 4 mL of CH 3 CN, was stirred for 4 days at room temperature. The reaction was diluted with 20 mL of EtOAc, washed with saturated NaHCO 3 (2x20 mL) and brine (20 mL). The organic layer was concentrated and the title compound was eluted from 20 g of SPE with 5% EtAc / hexanes to provide 40 mg (15% o) of a white solid. 1 H NMR (400 MHz, CDCl 3) d 7.60 (m, 5H), 7.10 (m, 2H), 6.72 (m, 1H), 5.1 (broad s, 2H).

The title compound was obtained according to the procedure for Example 41 from (2-amino-5-fluoro-phenyl) -phenyl-methanone. 1 H NMR (400 MHz, CDCl 3) d 12.20 (s, 1 H), 7.48 (m, 4 H), 7.35 (m, 1 H), 7.26 (m, 2 H), 6.96 (dd, 1 H), 6.48 (s, 1 H) ), 2.30 (s, 3H). Mass spectrum (ESI, m / z) calculated for C? 9H? 3FN202 320.1, found 321.1 (M + H).

EXAMPLE 74 3- (3-Metii-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one The title compound was prepared according to example 41 from (2-amino-phenyl) -phenyl-methanone. 1 H NMR (400 MHz, DMSO-d 6) d 12.38 (s, 1 H), 7.60 (t, 1 H), 7.42 (m, 4 H), 7.28 (m, 2 H), 7.18 (t, 1 H), 7.04 (d , 1H), 6.42 (s, 1H), 2.16 (s, 3H). Mass spectrum (ESI, m / z) calculated for C? 9H? N202 302.1, found 303.1 (M + H).

EXAMPLE 75 6-Fluoro-7-methoxy-3- (3-methyl-isoxasol-5-yl) -4-phenyl-1H-quinolin-2-one a) (2-Amino-5-fluoro-4-methoxy-phenyl) -phenyl-methanone A solution of 6,7-difluoro-2-phenyl-benzo [d] [1,3] oxazin-4-one (WO 0050427A1) (0.3 g, 1.2 mmol) in 4 mL of THF at 0 ° C was added. he added a 1M solution in THF of phenyl magnesium bromide (1.2 mL, 1.2 mmol) and the solution was allowed to stir for 30 minutes at 0 ° C. The reaction was diluted with 20 mL of EtAc, washed with saturated NaHCO3 (2x20 mL) and brine (20 mL) and the organic layer was concentrated. The residue was dissolved in MeOH (10 mL) and 6N NaOH (0.6 mL, 3.5 mmol) was added and the reaction was heated at 90 ° C for 1 hour. The reaction was concentrated and then diluted with EtOAc (20 mL) and washed with brine (2x20 mL). The title compound was eluted from 10 g of SPE with 30% or EtOAc / hexanes to provide 34 mg (12%) of a white solid. Mass spectrum (ESI, m / z) calculated for C? 4H12FN02 245.1, found 246.1 (M + H). The title compound was obtained according to example 41. 1 H NMR (400 MHz, CDCl 3) d 12.90 (s, 1 H), 7.46 (m, 3 H), 7.22 (m, 2H), 7.04 (d, 1H), 6.94 (d, 1 H), 6.30 (s, 1 H), 4.02 (s, 3H), 2.26 (s, 3H). Mass spectrum (ESI, m / z) calculated for C2oHidFN203 350.1, found 351.1 (M + H).

EXAMPLE 76 5.β-Dichloro-3- (3-methyl-ε-soxazol-5-γ-4-phenyl-1H-quinolin-2-one This was prepared according to Example 5 from (6-amino-2,3-dichloro-phenyl) -phenyl-methanone (J. Chem. Soc. Sec. O, 1968, (19), 2452-4 ). 1 H NMR (400 MHz, CDCl 3 + CD 3 OD) d 7.58 (d, 1 H), 7.24 (m, 4H), 7.04 (m, 1H), 5.84 (s, 1H), 2.22 (s, 3H). Mass spectrum (ESI, m / z) calculated for C19Hi2Ci2N2? 2 370.1, found 371.1 (M + H).

EXAMPLE 77 6-Chloro-4- (4-etl-phenyl-3- (3H-imidazol-4-i)) - 1 H -quinolin-2-one a) (2-Amino-5-chloro-phenyl) - (4-ethyl-phenyl) -metanone The title compound was prepared from 6-chloro-2-phenyl-benzo [d] [1, 3] oxazin-4-one and 4-ethylphenyl magnesium bromide, according to the procedure in Example 75a in a 60% yield. 1 H NMR (400 MHz, CDCl 3) d 7.61 (d, 2 H), 7.42 (d, 1 H), 7.30 (m, 4 H), 6.72 (d, 1 H), 6.01 (broad s, 2 H), 2.78 (c, 2 H) ), 1.30 (t, 3H). Mass spectrum (ESI, m / z) calculated for C15H14CINO 259.1, found 260.1 (M + H). This was prepared according to Example 5. 1 H NMR (400 MHz, CD 3 OD) d 8.68 (s, 1 H), 7.62 (d, 1 H), 7.48 (m, 3 H), 7.22 (d, 2 H), 7.12 (d , 1H), 6.42 (s, 1H), 2.82 (c, 2H), 1.36 (t, 3H).

Mass spectrum (ESI, m / z) calculated for C20H16CIN3O 349.1, found 350.1 (M + H).

EXAMPLE 78 6-Bromo-4- (4-ethyl-phenyl) -3- (3H-imidazol-4-yl) -1H-quinolin-2-one This was prepared according to example 41. 1 H NMR (400 MHz, CD3OD) d 8.82 (s, 1H), 7.78 (dd, 1H), 7.48 (d, 2H), 7.42 (d, 1H), 7.30 (d, 1H), 7.22 (d, 2H), 6.48 (s, 1 H), 2.82 (c, 2H), 1.36 (t, 3H). Mass spectrum (ESI, m / z) calculated for C2oHi6BrN3? 393.1, found 394.1 (M + H).

EXAMPLE 79 4- (4-Ethyl-pheny1) -3- (3H-imidazoI-4-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile a) 4-Amino-3- (4-ethyl-benzoyl) -benzonitrile A flask loaded with (2-amino-5-bromo-phenyl) - (4-ethyl-phenyl) -methanone (0.10 g, 0.32 mmol), copper cyanide (0.0347 g, 0.41 mmol), and 1 mL of DMF was heated at 180 ° C for 1 hour in a microwave reactor.

The title compound was eluted from 5 g of SPE with 100% > DCM torque to provide 0.07 g (81%) of a white solid. 1 H NMR (400 MHz, CDCl 3) d 7.84 (d, 1 H), 7.58 (d, 2 H), 7.50 (dd, 1 H), 7.36 (d, 2 H), 6.78 (d, 1 H), 6.60 (broad s, 2H), 2.78 (c, 2H), 1.30 (t, 3H). This was prepared according to example 41. 1 H NMR (400 MHz, CD 3 OD) d 8.60 (s, 1 H), 7.90 (dd, 1 H), 7.50 (m, 4 H), 7.22 (d, 2 H), 6.48 (s, 1 H), 2.82 (c, 2H), 1.36 (t, 3H). Mass spectrum (ESI, m / z) calculated for C2-.Hi6N40 340.1, found 341.1 (M + H).

EXAMPLE 80 6-Cioro-4- (4-ethyl-phenyl-3- (3-methyl-isoxazol-5-yl, -1H-quininoin-2-one) 2-benzylamino-5-chloro-benzoic acid benzyl ester To a mixture of 5-chloroisatoic anhydride (5.00 g, 25.3 mmol) and benzyl bromide (78.83 g, 50.6 mmol) in 50 mL of CH3CN, 7.57 mL of DBU (50.6 mmol) was added at room temperature under Ar. The resulting mixture was stirred at room temperature for 16 hours. It was treated with 100 ml of EtOAc, the mixture was washed with H20, brine and dried (Na2SO). Removal of the solvent in vacuo was followed by flash chromatography of the residue on silica gel (10% DCM / 5% hexanes or EtOAc / hexanes), providing 6.50 g (73%) of the product as a brown oil: 1H -RMN (CDCI3; 400 MHz) d 8.17 (t, 1H, J = 5.2 Hz), 7.92 (d, 1H, J = 2.8 Hz), 7.19-7.48 (m, 11H), 6.56 (d, 1 H, J = 9.2 Hz), 5.31 (s, 2H), 4.43 (d, 2H, J = 5.2 Hz). Mass spectrum (ESI, m / z): Calculated for C2? H18CIN02, 352.1 (M + H), found 352.0. b. Acid benzyl ester 2-. { benzyl-f2- (3-methyl-isoxazol-5-yl) -acetyl] -amino) -5-chloro-benzoic acid A solution of the benzyl ester of 2-benzylamino-5-chloro-benzoic acid (3.30 g, 9.38 mmol) and (3-methyl-isoxazol-5-yl) -acetic acid (1.39 g, 9.85 mmol) in 15 ml of POCI3l it was heated at 80 ° C for 3 hours and then cooled to room temperature. It was treated with 50 ml of EtOAc, the mixture was washed with H20 (5 x 20 ml), brine (20 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10-40%) EtOAc / hexanes) gave 3.60 g (81%) of the product as a brown oil: 1 H-NMR (CDCl 3; MHz) d 7.92 (d, 1H, J = 2.5 Hz), 7.34-7.43 (m, 6H), 7.22-7.26 (m, 3H), 7.08-7.14 (m, 2H), 6.84 (d, 2H, J = 8.6 Hz), 6.01 (s, 1 H), 5.10-5.20 (m, 3H), 4.32 (d, 1H, J = 14.2 Hz), 3.44 (d, 2H, J = 1.9 Hz), 2.25 (s, 3H) ). Mass spectrum (ESI, m / z): Calculated for C27H23CIN2Δ4, 475.1 (M + H), found 475.1. c. 1-Benzyl-6-chloro-4-hydroxy-3- (3-methyl-isoxazol-5-yl-1 H-quinolin-2-one To a mixture of benzyl ester of 2- acid. { benzyl- [2- (3-methyl-isoxazol-5-yl) -acetyl] -amino} -5-Chloro-benzoic acid (3.30 g, 7.58 mmol) in 25 ml of DMF at 0 ° C, NaH (340 mg) was added. The mixture was stirred at room temperature for 1 hour under Ar. It was treated with 200 ml of EtOAc, the mixture was extracted with H20 (4 x 50 ml). The combined aqueous layers were neutralized to pH = 6 with 1 N HCl and extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with H20 (2 x 50 ml), brine (50 ml) and dried (Na2SO). Removal of the solvent under reduced pressure gave 2.35 g (92%) of the product as a white solid: 1 H-NMR (CD 3 OD, 400 MHz) d 9.49 (s, 1 H), 8.21 (d, 1 H, J = 2.6 Hz), 7.48 (dd, 1H, J = 9.0, 2.6 Hz), 7.17-7.36 (m, 7H), 5.60 (s, 2H), 2.43 (s, 3H), 2.54 (s, 3H). Mass spectrum (ESI, m / z): Calculated for C20H? 5CIN2O3, 367.1 (M + H), found 367.0. d. 1-Benzyl-6-chloro-3- (3-methyl-x-oxazol-5-yD-2-oxo-1,2-dihydro-quinoline-4-yl ester of trifluoro-methanesulfonic acid To a solution of 1-benzyl-6-chloro-4-hydroxy-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one (1.00 g, 2.73 mmol) and Et3N (0.57) ml, 4.10 mmol) in 20 ml of low DCM at -78 ° C, Tf20 (0.50 ml, 3.0 mmol) was added slowly under Ar. The mixture was heated to room temperature. It was treated with 150 mL of EtOAc, the mixture was washed with H20 (4 x 50 mL), brine (40 mL), and dried (Na2SO4). Removal of the solvent under reduced pressure gave 1.35 g (99% >) of the product as a light yellow solid: 1 H-NMR (CDCl 3, 400 MHz) d 7.95 (d, 1 H, J = 2.3 Hz), 7.55 (dd) , 1H, J = 9.0, 2.3 Hz), 7.27-7.37 (m, 4H), 7.21 (d, 2H, J = 8.3 Hz), 7.17 (s, 1H), 5.60 (s, 2H), 2.42 (s, 3H). Mass spectrum (ESI, m / z): Calculated for C2? Hi4CIF3N205S, 499.0 (M + H), found 499.0. and. 1-Benzyl-6-chloro-4- (4-ethyl-phenyl, -3- (3-methyl-isoxazol-5-yl) .- 1 H-quinolin-2-one A mixture of 1-benzyl-6-chloro-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinolin-4-yl ester of trifluoromethanesulfonic acid (40 mg, 0.080 mmol), 4-ethylbenzeneboronic acid (14.4 mg, 0.096 mmol), Pd (PPh3) 4 (9.2 mg, 0.0080 mmol) and Na2C03 (80 μL, 0.16 mmol, 2.0 M) in 1 mL of 1,4-dioxane, it was stirred at 100 ° C for 1 hour, then cooled to room temperature. It was treated with 40 ml of EtOAc, the mixture was washed with H20 (2 x 10 ml), brine (10 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (25% EtOAc / hexane) gave 29.5 mg (81% >) of the product as a white solid: 1 H-NMR (CDCl 3; MHz) d 7.41 (dd, 1H, J = 9.0, 2.2 Hz), 7.24-7.38 (m, 8H), 7.15 (d, 2H, J = 8.0 Hz), 6.48 (s, 1H), 5.64 (s, 2H ), 3.71 (s, 1H), 2. 74 (c, 2H, J = 7.6 Hz), 2.23 (s, 3H), 1.31 (t, 2H, J = 7.6 Hz). Mass spectrum (ESI, m / z): Calculated for C23H23CIN202, 455.1 (M + H), found 455. 1. 6-Chloro-4- (4-ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one A solution of 1-benzyl-6-chloro-4- (4-ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one (29 mg, 0.064 mmol) in 1 mL of CH3SO3H, stirred at 100 ° C for 16 hours, then cooled to room temperature. It was treated with 20 mL of H20, the mixture was neutralized to pH = 7 with 2N NaOH and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with H20 (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (40% EtOAc / DCM), gave 14 mg (60%) of the product as a yellow solid: 1 H-NMR (CDCl 3, 400 MHz) d 12.0 (s, 1 H), 7.51 (dd, 1 H, J = 8.7, 2. 4 Hz), 7.36 (d, 1H, J = 8.7 Hz), 7.25-7.30 (m, 3H), 7.13 (d, 2H, J = 8.2 Hz), 6. 40 (s, 1H), 2.74 (c, 2H, J = 7.6 Hz), 2.27 (s, 3H), 1.31 (t, 2H, J = 7.6 Hz). Mass spectrum (ESI, m / z): Calculated for C21H17C1N202, 365.1 (M + H), found 365.1.

EXAMPLE 81 6-Chloro-3- (3-methyl-isoxazol-5-ip-4-piperidin-1-yl-1H-quinolin-2-one) to. 1-Benzyl-6-chloro-3- (3-methyl-isoxazol-5-yl) -4-piperidin-1-yl-1 H-quinolin-2-one To a solution of the trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3- (3-methy-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-4-yl ester ( 25 mg, 0.050 mmol) in 1 ml of THF, piperidine (17 mg, 0.20 mmol) was added. The mixture was stirred at room temperature for 16 hours. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc / hexanes) gave 21.0 mg (97%) of the product as a yellow-green oil: 1 H-NMR (CDCl 3, 400 MHz ) d 7.93 (d, 1H, J = 2.6 Hz), 7.37 (dd, 1H, J = 9.0, 2.3 Hz), 7.18-7.33 (m, 6H), 6.56 (s, 1H), 5.50 (s, 2H) , 2.99 (m, 4H), 2.40 (s, 3H), 1.64-1.76 (m, 6H). Mass spectrum (ESI, m / z): Calculated for C25H24CIN302, 434.2 (M + H), found 434.1. b. 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-piperidin-1-yl-1 H-quinolin-2-one A solution of 1-benzyl-6-chloro-3- (3-methyl-isoxazol-5-yl) -4-piperidin-1-yl-1H-quinolin-2-one (21 mg, 0.488 mmol) in 1 mL of CH3SO3H, stirred at 110 ° C for 8 hours, then cooled to room temperature. It was treated with 20 mL of H20, the mixture neutralized to pH = 7 with a 2N NaOH solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with H20 (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-40% EtOAc / DCM) gave 4.5 mg (27%) of the product as a yellow solid: 1 H-NMR (CDCl 3; MHz) d 10.9 (s, 1H), 7.83 (d, 1H, J = 2.2 Hz), 7.45 (dd, 1H, J = 8.6, 2.2 Hz), 7.18 (d, 1H, J = 8.6 Hz), 6.50 (s, 1H), 3.00 (s broad, 4H), 2.42 (s, 3H) , 1.62-1.78 (m, 6H). Mass spectrum (ESI, m / z): Calculated for C? 8H? 8CIN30-, 344.1 (M + H), found 344.1.

EXAMPLE 82 6-Chloro-4-cyclohexyl-3- (3-methyl-isoxazole-5-i0-1H-quinolin-2-one) to. 1-Benzyl-6-chloro-4-cyclohexyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one A solution of cyclohexylmagnesium chloride (250 ul, 0.50 mmol, 2M in THF) was added to a suspension of copper (I) bromide-dimethyl sulphide (51 mg, 0.25 mmol) in 2 ml of THF at -78 °. C under N2. The mixture was allowed to warm to room temperature until a homogeneous dark-colored solution was observed (ca. 15 minutes), then cooled again to -78 ° C. A solution of 1-benzyl-6-chloro-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinolin-4-yl ester of trifluoro-methanesulfonic acid (80 mg, 0.16 mmoles) in 2 ml of THF was added to the mixture. The resulting mixture was stirred at -78 ° C for 2 hours and warmed to room temperature. It was treated with 2 ml of saturated NH 4 Cl, followed by 20 ml of H 2 O, the mixture was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with H20 (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-30% EtOAc / hexanes) gave 61 mg (88%) of the product as a white solid: 1 H-NMR (CDCl 3; 400 MHz) d 8.08 (broad s, 1H), 7.40 (dd, 1H, J = 9.2, 2.2 Hz), 7.20-7.34 (m, 6H), 6.42 (s, 1H), 5.53 (s, 2H), 2.98 (s broad, 1H), 2.41 (s, 3H), 1.67-1.93 (m, 7H), 1.22-1.40 (m, 3H). Mass spectrum (ESI, m / z): Calculated for C26H25CIN202, 433.2 (M + H), found 433.1. b. 6-Chloro-4-cyclohexyl-3- (3-methyl-isoxazol-5-yl) -1 H-quinolin-2-one A solution of 1-benzyl-6-chloro-4-cyclohexyl-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one in 1 mL of CH3SO3H was stirred at 110 ° C for 4 hours, then cooled to room temperature. It was treated with 20 ml of H20, the mixture was neutralized to pH = 7 with a 2N NaOH solution and extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with H20 (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-40%) EtOAc / DCM) gave 25 mg (61%) of the product as a white solid: 1 H-NMR (CDCl 3, 400 MHz) d 12.5 (s, 1H), 8.04 (broad s, 1 H), 7.47 (dd, 1 H, J = 8.8, 1.9 Hz), 7.28 (d, 1H, J = 8.8 Hz), 6.38 (s) , 1 H), 2.94 (broad s, 1 H), 2.45 (s, 3H), 1.71-1.97 (m, 7H), 1.11-1.40 (m, 3H). Mass spectrum (ESI, m / z): Calculated for d9H19CIN202, 343.1 (M + H), found 343. 1.

EXAMPLE 83 4-Cycloheptyl-1-enyl-3-methyl-isoxazol-5-yl-2-oxo-1,2-dihydro-quinoline-6-carbonitrile 2-amino-5-cyano-benzoic acid methyl ester A mixture of the 2-amino-5-bromo-benzoic acid methyl ester (5.00 g, 21.7 mmol) and CuCN (2.34 g, 26.1 mmol, 2.0 M) in 25 mL of NMP was stirred under reflux for 5 hours, then it was cooled to room temperature. The mixture was poured into a hydrated FeCl3 solution (15 g FeCl3.6H20) and concentrated HCl (2.2 ml) in 15 ml H20. The resulting mixture was stirred at 60 ° C for 1 hour, cooled to room temperature. It was treated with 200 ml of EtOAc, the mixture was washed with H20 (40 ml), 1N NaOH (3X30 ml), brine (30 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave a slightly light solid. Recrystallization of the solid from hexanes / DCM / EtOAc gave 3.25 g (85% >) of the product as a yellow solid: H-NMR (CDCl 3, 400 MHz) d 8.20 (d, 1H, J = 1.9 Hz), 7.45 (dd, 1 H, J = 8.9, 1.9 Hz), 6.67 (d, 1H, J = 8.9 Hz), 6.29 (broad s, 2H), 3.90 (s, 3H). Mass spectrum (ESI, m / z): Calculated for C9H8N202, 177.1 (M + H), found 177.2. b. 5-Cyano-2-f2- (3-methy1-isoxazol-5-yl) -acetylamino-benzoic acid methyl ester A solution of 2-amino-5-cyano-benzoic acid methyl ester (1.50 g, 8.51 mmol) and (3-methyl-isoxazol-5-yl) -acetic acid (1.32 g, 9. 36 mmole) in 40 ml of POCI3, heated at 80 ° C for 2 hours and then cooled to room temperature. It was treated with 50 mL of EtOAc, the mixture was washed with H20 (3 x 40 mL), saturated NaHCO3 (40 mL), brine (40 mL) and dried (Na2S4). Removal of the solvent under reduced pressure afforded 2.31 g (91%) of the product as a light yellow solid: 1 H-NMR (CDCl 3, 400 MHz) d 11.49 (s, 1 H), 8.85 (d, 1 H, J = 8.8 Hz ), 8.35 (d, 1H, J = 2.0 Hz), 7.79 (dd, 1H, J - 8.8, 2.0 Hz), 6.20 (s, 1H), 3.97 (s, 3H), 3.95 (s, 2H), 2.33 (s, 3H). Mass spectrum (ESI, m / z): Calculated for C15H13N3? 4, 300.1 (M + H), found 299.9. c. 6-Cyano-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-4-yl ester of trifluoro-methanesulfonic acid To a mixture of 5-cyano-2- [2- (3-methyl-isoxazol-5-yl) -acetylamino] -benzoic acid methyl ester (1.00 g, 3.34 mmol) in 30 ml of DMSO at room temperature, KOtBu (809 mg, 6.85 mmol) was added. The mixture was stirred at room temperature for 15 minutes under Ar, N-phenyltrifluoromethanesulfonimide (2.53 g, 7.02 mmol) was added. The mixture was stirred at room temperature for 1 hour. It was treated with 150 ml of EtOAc, the mixture was washed with H20 (2 x 50 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with H20 (2 x 50 ml), brine (50 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10-25% EtOAc / DCM) gave 670 mg (50%) of the product as a white solid: 1H-NMR (CD3OD, 400 MHz) d 8.20 (d, 1H, J = 1.7 Hz), 7.99 (dd, 1 H, J = 8.6, 1.7 Hz), 7.56 (d, 1 H, J = 8.6 Hz), 7.17 (s, 1 H) 2.40 (s, 3H). Mass spectrum (ESI, m / z): Calculated for Ci5H8F3N3? 5S, 400.0 (M + H), found 399.9. d. 4-Cyclohept-1-enyl-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile A mixture of the 6-cyano-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-4-yl ester of trifluoromethanesulfonic acid (30 mg, 0.075 mmol), cyclohepten-1-ylboronic acid (12.6 mg, 0.090 mmol), Pd (PPh3) (8.7 mg, 0.0075 mmol) and Na2C03 (375 ul, 0.75 mmol, 2.0 M) in 1 ml of 1,4-dioxane, was stirred at 80 ° C for 1 hour, then cooled to room temperature. It was treated with 20 ml of H20, the mixture was acidified to pH = 7 with 1N HCl and then extracted with EtOAc (3 x 15 ml). The combined organic layers were washed with H20 (20 ml), brine (15 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10-20% EtOAc / DCM) yielded 15.1 mg (58%) of the product as a white solid: 1 H-NMR (CDCl 3; MHz) d 12.3 (s, 1 H), 8.08 (d, 1 H, J = 1.7 Hz), 7.77 (d, 1 H, J = 8.6, 1.7 Hz), 7.43 (d, 1 H, J = 8.6 Hz) , 6.70 (s, 1H), 5.79 (t, 1 H, J = 6.1 Hz), 2.44 (s, 3H), 2.26-2.52 (m, 4H), 1.62-1.94 (m, 6H). Mass spectrum (ESI, m / z): Calculated for C2? H19N302, 346.2 (M + H), found 346.1.

EXAMPLE 84 6-Chloro-3- (3-methyl-α-oxazol-5-yl, -4-m-tolyl-1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 85 6-Chloro-3- (3-methyl-isoxazol-5-yl, -4-p-tolyl-1H-quinolin-2-one) Prepared according to the procedure described for Example 80.

EXAMPLE 86 6-Chloro-3- (3-meth yl-isoxazol-5-yl) -4-o-tolyl-1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 87 6-Chloro-4-, 2-chloro-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 88 6-Chloro-4- (4-chloro-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 89 4- (4-Acetyl-3-hydroxy-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 90 4- (3-Acetyl-4-hydroxy-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-ip-1H-quinolin-2-one) Prepared according to the procedure described for Example 80.

EXAMPLE 91 6-Chloro-4- (4-idroxy-phenyi) -3-y3-methyl-isoxazoI-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 92 4- (5-Acetyl-2-methoxy-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80 EXAMPLE 93 4- (5-Acetyl-2-hydroxy-phenin-6-chloro-3- (3-methy1-isoxazol-5-yl) -1H-quinolin-2-na Prepared according to the procedure described for Example 80.

EXAMPLE 94 6-Chloro-4- (2-methoxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 95 6-Chloro-4- (4-methoxy-phenyl) -3- (3-methyl-isoxazol-5-y-1H-quinolin-2-one) Prepared according to the procedure described for Example 80.

EXAMPLE 96 6-Chloro-4- (2-hydroxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinol-p-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 97 6-Chloro-4- (3-methoxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 98 6-Chloro-3- (3-meth yl-isoxazol-5-yl) -4-naphthalen-1-yl-1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 99 6-Chloro-3- (3-methyl-x-oxazol-5-yl) -4-naphthalen-2-yl-1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 100 6-Chloro-4- (4-fluoro-phenyl) -3- (3-methy1-isoxazol-5-yl) -1H-quinol-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 101 4-Biphenyl-4-yl-6-chloro-3-, 3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 102 6-Chloro-4-cyclohex-1-en-l-3- (3-methy1-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 103 6-Chloro-4-furan-2-yl-3- (3-methy1-isoxazol-5-yl) -1H-quinolip-2-opa Prepared according to the procedure described for Example 80.

EXAMPLE 104 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-thiophen-2-yl-1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 105 4-Benzofuran-2-yl-6-chloro-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 106 3-R6-Chloro-3- (3-methyl-5-oxa-2-yl) -2-oxo-1,2-dihydro-quinoline-4-benzoic acid Prepared according to the procedure described for Example 80.

EXAMPLE 107 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-morpholin-1-yl-quinolin-2-one Prepared according to the procedure described for Example 81, EXAMPLE 108 6-Chloro-3- (3-methyl-isoxazol-5-ip-4- (4-methyl-piperazin-1-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 109 6-Chloro-3- (3-methy1-isoxazol-5-yl) -4- (4-methyl-piperazin-1-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 110 6-Chloro-4-imidazol-1-yl-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 111 4-Benzorbthiophene-2-yl-6-chloro-3- (3-methyl-5-oxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 112 6-Chloro-4-cyclohept-1-enyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 113 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (4-propyl-piperidin-1-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 114 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (3-methyl-piperidin-1-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 115 6-Chloro-4-cycloheptyl-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81.

EXAMPLE 116 6-Chloro-4- (4,4-dimethyl-piperidin-1-yl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 81, EXAMPLE 117 4- (4 ° ter-Butyl-phenyl-6-chloro-3> (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 118 6-Chloro-3- (3-methyl-α-oxazol-5-yl) -4- (4-propyl-phenyl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 119 6-Chloro-4- (4-isopropyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 80.

EXAMPLE 120 6-Bromo-4- (4-ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one Prepared according to the procedure described for Example 41.

EXAMPLE 121 4- (4-Ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile Prepared according to the procedures described for examples 83 and 79.

EXAMPLE 122 4- (4-tert-Buty) -phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 123 3- (3-Methyl-5-oxazol-5-yl-2-oxo-4- (4-propyl-phenyl-1,2-dihydro-quinoline-6-carbonitrile) Prepared according to the procedure described for Example 83.

EXAMPLE 124 4- (4-lsopropyl-pheyp-3- (3-methyl-isoxazole-5-H.-2-oxo-1,2-dihydro-quinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 125 3- (3-Methyl-isoxazole-5-in-2-oxo-4- (4-trifluoromethyl-phenin-1,2-dihydroquinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 126 4- (4-Acetyl-pheyp-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-di-dichloroquinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 127 3- (3-Methyl-isoxazol-5-yl) -4- (4-methylsulfanyl-phenyl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 128 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-vinyl-phenyl) -1,2-dihydro-quinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 129 4- (4-Ethyl-phenyl) -3- (2-methyl-thiazol-4-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 130 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-trifluoromethoxy-phenyl) -1,2-dihydroquinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 131 4- (4-Cyano-phenyl) -3- (3-methy1-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinolin-6- carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 132 4- (4-Methanesulfonyl-phenyl-3- (3-methyl-isoxazol-5-ip-2-oxo-1,2-dihydroquinoline-6-carbonitrile Prepared according to the procedure described for Example 83.

EXAMPLE 133 6-Bromo-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-thione A flask loaded with (2-amino-5-bromo-phenyl) -phenyl-methanone (0.69 g, 2.5 mmol), (3-methyl-isoxazol-5-yl) -acetic acid (0.35 g, 2.5 mmol), and 5 mL of phosphorus oxychloride was heated at 80 ° C for 6 hours. The reaction was concentrated and triturated with saturated NaHCO 3 to provide 0.6 g of a 6-bromo-2-chloro-3- (5-methyl-isoxazol-3-yl) -4-phenyl-quinoline. The solution of the preceding compound in 20 mL of ethanol was followed by treatment with thiourea (0.12 g, 1.6 mmol), and the solution was heated at 8 TJ ° C for 3 hours. The solution was concentrated and the title compound was purified by flash chromatography to provide 0.06 g (50%) of a white solid. 1 H NMR (400 MHz, CDCl 3) d 12.92 (s, 1H); 7.72 (dd, 1 H), 7.56 (d, 1 H), 7.42 (m, 4H), 7.20 (m, 2H), 6.00 (s, 1H), 2.24 (s, 3H). Mass spectrum (ESI, m / z) calculated for C-.9H13BrN2OS 396.0, found 397.0 (M + H).

EXAMPLE 134 6-Bromo-3- (3H-imidazol-4-yl) -4-phenyl-1H-quinolin-2-one Prepared according to the procedure described for Example 41. H NMR (400 MHz, CD3OD) d 7.60 (m, 5H), 7.38 (d, 1 H), 7.28 (m, 2H), 7.18 (m, 1H), 5.90 (broad s, 1H). Mass spectrum (ESI, m / z) calculated for C18H? 2BrN30 365.1, found 366.2 (M + H).

EXAMPLE 135 6-Bromo-3- (3H-imidazol-4-yl, -1-methyl-4-phenyl-1 H-quinolin-2-one) A flask containing 6-bromo-3- (3H-imidazol-4-yl) -4-phenyl-1H-quinolin-2-one (23 mg, 0.063 mmol) (Example 134), K2CO3 (30 mg, 0.22 mmoles), methyl iodide (4 μL, 0.063 mmol) and 0.1 mL of DMF, was stirred at ° C for 3 hours. The compound was purified by RP-HPLC, eluting with 30-70% CH3CN in 0.1% TFA / H20 for 20 minutes, to provide 13 mg (42%) of the title compound as a TFA salt. 1 H NMR (400 MHz, CD 3 OD) d 8.82 (s, 1 H), 7.90 (dd, 1 H), 7.70 (d, 1 H), 7.62 (m, 3 H), 7.34 (m, 3 H), 6.60 (s, 1 H) 3.92 (s, 3H). Diff Noe, radiation at 3.92 ppm (N-CH3), improved 7.70 ppm (d, 1H, H-8). Mass spectrum (ESI, m / z) calculated for C19H- | BrN302 379.0, found 380.0 (M + H). Table 1 lists the LC data and the mass spectrum of the selected compounds of the present invention: TABLE 1 fifteen twenty IV. Results An autophosphorylation assay of fluorescence polarization competition was used to determine the potency for the inhibition of c-fms exhibited by the compounds selected from Formulas I and II. The assay was performed in 96-well black microplates (LJL BioSystems). The buffer of the assay was 100 mM HEPES, pH 7.5, 1 mM DTT, 0.01% Tween-20 or (volume / volume). The compounds were diluted in an assay buffer containing 4% DMSO just before the assay. To each well was added 5 μL of the compound, followed by the addition of 3 μL of a mixture containing 33 nM c-fms (3DP) and 16.7 mM MgCl 2 (Sigma) in a test buffer. The kinase reaction was initiated by adding 2 μL of 5 mM ATP (Sigma) in a test buffer. The final concentrations in the assay were 10 nM c-fms, 1 mM ATP, 5 mM MgCl 2, or 2% DMSO. The control reactions were run on each plate: in negative and positive control wells, the assay buffer (made at 4% in DMSO), was replaced by the compound; in addition, the positive control wells received 1. 2 μL of 50 mM EDTA. Plates were incubated at room temperature for 45 minutes. 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). After a 5-minute incubation, each well received 10 μL of a 1: 1: 3 mixture of anti-phosphotyrosine, 10X, green PTK marker, 10X (vortexed), FP dilution buffer, respectively (all from PanVera , cat. # P2837). The plate was covered, incubated for 30 minutes at room temperature and the polarization of the fluorescence was read in the Analyst. The parameters of the instrument were: excitation filter of 485 nm; 530 nm emission filter; height Z: average of the well; G factor: 0.93. Under these conditions, the fluorescence polarization values for the positive and negative controls were approximately 300 and 150, respectively, and were used to define 100%) and 0% > of inhibition of the reaction of c-fms. The Cl50 values reported are the averages of three independent measurements. Table 2 lists the representative compounds of Formulas I and II of the invention.

TABLE 2 H A: < 0.5 μM B: > 0.5 μM and < 1 μM C: > 1 μMy < 10μM D: > 10μM

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of Formula (I): (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is -H, C? .6 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -CORa, -COORa, -CONRaRb or -S02Ra, R2 is phenyl, naphthyl or biaryl, each of which may be optionally substituted with one or more of C-? -6 alkyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3l -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORbl -N02, -S02Ra, -S03R, -S02NRaRb, -N = C ( Ra) -NRbRc, -CH2NRaRb, -CH2NRaRbNRcRd, -NRaS02Rb, -NRaCONRbRc, or -CH2N (CH2CH2) 2NRa; or a bicyclic mono- or 8- to 10-membered heteroaromatic or heteroaromatic ring or heterocyclic ring, having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of Ci- β, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF 3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF 3, -OCO-alkyl, -CORa, -CN, -COORa > -CONRaRb, -N (Ra) CORb, -N02, -S02Ra, -S03Ra, -S02NRaRb, -N = C (Ra) -NRbRc, -CH2NRaR, -CH2NRaRbNRcRd, -NRaS02Rb, -NRaCONRbRc, -N (Ra) CON (Rb) -alkyl-Rc or -CH2N (CH2CH2) 2NRa; R3 is phenyl, naphthyl, biaryl or cycloalkyl, each of which may be optionally substituted with one or more of Ct-6 alkyl, C2.6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy , aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3. -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -SRa, -S02Ra, -NRaS02Rb, -S03Ra or -S02NRaRb; or a 5- to 7-membered heterocyclic ring having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C 1-6 alkyl, C 2-6 alkenyl, amino, aminoalkyl , heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, - N02, -SRa, -S02Ra, -NRaS02Rb, -S03Ra or -S02NRaR; or a bicyclic mono or 8 to 10 membered heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of Ct-6 alkyl, alkenyl of C2-6, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaR, -N (Ra) CORb, -N02, -SRa, -S02Ra, -NRaS02Rb, -S03Ra or -S02NRaRb; X is O, S, N (Ra) N (Ra) (Rb), N (Ra) N (Rb) CORc; and Y1, Y2, Y3 and Y4 are, independently -C (R4) - or -N-, wherein each R4 is independently -H, Ci-β alkyl, C2_6 alkenyl, amino, aminoalkyl, halogen , hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -S02Ra, -S03Ra or -S02NRaRb, -N (Ra) S02Rb or wherein two independent R4 substituents, taken together with Y1 = Y2, Y2 = Y3 or Y3 = Y4, form a heterocyclic cyclic 5- to 7-membered aryl or heteroaryl ring containing 0-3 heteroatoms selected from N, O or S, which may be optionally substituted with -H, C? _6 alkyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02 > -S02Ra, -N (Ra) S02R, -S03Ra or -S02NRaRb, wherein Ra, R, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, may be substituted with one or more of the following: -S02NH2, S02-alkyl or -C02-alkyl.

2. The compound according to claim 1, further characterized in that R1 is -H; R2 is a bicyclic mono- or 8- to 10-membered heteroaromatic or heterocyclic ring having from one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C? Alkyl? 6, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -S02Ra, -S03Ra, -S02NRaRb, -N = C (Ra) -NRbRc, -CH2NRaR, -CH2NRaRbNRcRd, -NRaS02Rb, -NRaCONRbRc, -N (Ra) CON (Rb) -alkyl-Rc or -CH2N (CH2CH2) 2NRa; R3 is phenyl, naphthyl or cycloalkyl, each of which may be optionally substituted with one or more of C6_6 alkyl, C2.6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl , aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -SRa, -S02Ra, -S03Ra or -S02NRaRb; or a bicyclic mono- or 8- to 10-membered 5- to 7-membered heteroaromatic ring having one to four heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C-? -6 alkyl , C2.6 alkenyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, - CONRaRb, -N (Ra) CORb, -N02, -SRa, -S02Ra, -S03Ra or -S02NRaRb; X is O; and Y1, Y2, Y3 and Y4 are -C (R4) -, wherein each R4 is independently -H, Ci-β alkyl, C2.6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, - CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb , -N02, -S02Ra, -S03Ra or -S02NRaR, -N (Ra) S02Rb, or wherein Ra, R > Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, may be substituted with one or more of the following: -S02NH2, S02-alkyl or -C02-alkyl.

3. A compound of Formula (II): -0 or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein R1 is -H, C -.-6 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -CORa, -COORa, -CONRaRb or -S02Ra, R2 is a 5- or 7-membered heterocyclic or heteroaromatic ring, having one to three heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C? -6 alkyl, amino , aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb , -N02, -S02Ra, -NRaS02Rb, -S03Ra or -S02NRaRb; R5, R6 and R7 are independently alkyl of C6-6) C2.6 alkenyl) amino, aminoalkyl, heteroaryl, halogen, meta-hydroxy, para-hydroxy, meta-methoxy, para-methoxy, C2-alkoxy. 5, -CF3, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02, -SRa, -S02Ra , -NRaS02Rb, -S03Ra or -S02NRaRb; X is O, S, N (Ra) N (Ra) (Rb), N (Ra) N (Rb) CORc; and Y1, Y2, Y3 and Y4 are independently -C (R4) - or -N-, wherein each R4 is independently -H, C6-6 alkyl, C2.6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaraicyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORbl -N02, -S02Ra, -S03Ra or -S02NRaRb, -N (Ra) S02Rb or wherein two independent R4 substituents, taken together with Y1 = Y2, Y2 = Y3 or Y3 = Y4, form a heterocyclic cyclic 5- to 7-membered aryl or heteroaryl ring containing 0-3 heteroatoms selected from N, O or S, which may be optionally substituted with -H, Cus, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, -CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) COR, -N02, -S02Ra, -NRaS02Rb, -S03Ra or -S02NRaRb , wherein Ra, Rb, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, each of which, except hydrogen, may be substituted with one or more of the following: -S02NH2, S02-alkyl or -C02-alkyl, with the proviso that R2 is not an isoxazoline ring, pyrazoiin or benzimidazole and with the proviso that if Y2 is -C (R4), then R4 does not It is a heteroaromatic of Ci.

4. The compound according to claim 3, further characterized in that R1 is -H; R2 is a 5- to 7-membered heterocyclic or heteroaromatic ring, having one to three heteroatoms selected from N, O or S, and which may be optionally substituted with one or more of C?-6 alkyl, amino, aminoalkyl, heteroaryl, halogen, hydroxy, -CF3, alkoxy, aryl, aralkyl, heteroaralkyl, aryloxy, arylalkoxy, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) CORb, -N02 , -S02Ra, -S03Ra or -S02NRaRb; R3 is X is O; and Y1, Y2, Y3 and Y4 are -C (R4) -, wherein each R4 is independently -H, C6_6 alkyl, C2.6 alkenyl, amino, aminoalkyl, halogen, hydroxy, hydroxyalkyl, - CF3, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, heteroaryloxy, arylalkoxy, SRa, NRaRb, PhCF3, -OCF3, -OCO-alkyl, -CORa, -CN, -COORa, -CONRaRb, -N (Ra) Corbl -N02, -S02Ra, -S03Ra or -S02NRaRb, -N (Ra) S02Rb or wherein Ra, Rb, Rc and Rd are independently hydrogen, alkoxy, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl , each of which, except hydrogen, may be substituted with one or more of the following: -S02NH2, S02-alkyl or -C02-alkyl.

5. The compound according to claim 1, further characterized in that it is one of 6-chloro-3- (3-methyl-isoxazoi-5-yl) -4- (pyridin-4-yl) -1H-qui nolin-2-one; 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (pyridin-3-yl) -1 H -quinolin-2-one; 6-chloro-3- (3-methyl-isoxazol-5-yl) -4- (pyridin-2-yl) -1 H -quinolin-2-one; 6-Chloro-3,4-diphenyl-1 H-quinolin-2-one; 6-Chloro-3- [3- (4-methyl-piperazin-1-ylmethyl) -isoxazol-5-yl] -4-phenyl-1H-quinolin-2-one; 6-Chloro-4-phenyl-3-. { 3 - [(2-piperidin-1-yl-ethylamino) -methyl] -isoxazol-5-yl} -1 H-quinolin-2-one; 6-Chloro-4-phenyl-3-. { 3 - [(2-pyrrolidin-1-yl-ethylamino) -methyl] -isoxazol-5-yl} -1 H-quinolin-2-one; 6-Chloro-3-. { 3 - [(2-morpholin-4-yl-ethylamino) -methyl] -isoxazol-5-yl} -4-phenyl-1H-quinolin-2-one; 6-Chloro-4-phenyl-3- [3- (4-pyridin-2-yl-piperazin-1-ymethyl) -isoxazol-5-yl] -1H-quinolin-2-one; 6-Chloro-4-cyclohex-1-enyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4-furan-2-yl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-thiophen-2-yl-1 H -quinolin-2-one; 4-Benzofuran-2-yl-6-chloro-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazole-5-ii) -4-morpholin-4-yl-1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (4-methyl-piperazin-1-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (4-methyl-piperidin-1-yl) -1 H -quinolin-2-one; 6-Chloro-4-imidazol-1 -yl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 4-Benzo [b] thiophen-2-yl-6-cioro-3- (3-methyI -soxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4-cyclohep-1-enyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (4-propyl-piperidin-1-yl) -1H-quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (3-methyl-piperidin-1-yl) -1 H -quinolin-2-one; 6-Chloro-4-cycloheptyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4- (4,4-dimethyl-piperidin-1-yl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 4- (4-tert-Butyl-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-yl) -1 H -quinone-2-one; N '- [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -N, N-d-methyl-formamidine; N '- [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -N, N-dimethyl-acetamidine; N '- [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -N, N-dimethyl-propionamidine; N- [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -methanesulfonamide; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-piperidin-1-yl-1 H -quinolin-2-one; 6-Chloro-4-cyclohexyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 4-Cyclohept-1-enyl-3- (3-methyl-5-oxazol-5-yl) -2-oxo-1, 2-dihydro-quinoline-6-carbonitrile; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-naphthalen-1-yl-1 H -quinolin-2-one; and 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-naphthalen-2-yl-1 H -quinolin-2-one.

6. The compound according to claim 3, further characterized in that it is one of 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1H- [1, 5] naphthyridin-2-one; 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1H- [1, 6] naphthyridin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H- [1,8] naphthyridin-2-one; 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1 H- [1,8] naphthyridin-2-one; 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1 H- [1,7] naphthyridin-2-one; 3- [6-Chloro-3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinolin-4-yl] -benzoic acid; 6-Bromo-3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1 H- [1,8] naphthyridin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H- [1,7] naphthyridin-2-one; 6-Chloro-3- (3-methyl-benzo [b] thiophen-2-yl) -4-phenyl-1 H -quinolin-2-one; 6-Chloro-4-phenyl-3-thiophen-2-yl-1 H-quinolin-2-one; 6-Chloro-4-phenyl-3- (1 H -pyrrole) -2-yl-1 H-quinolin-2-one; 6-Chloro-4-phenyl-3-pyrazol-1-yl-1 H-quinolin-2-one; 6-Chloro-3- (5-methyl-2H-pyrazol-3-yl) -4-phenyl-1 H -quinolin-2-one; 3- (1-Benzyl-1 H-imidazol-2-yl) -6-Chloro-4-phenyl-1 H -quinolin-2-one; 6-Chloro-3- (5-methyl-isoxazol-3-yl) -4-phenyl-1 H-quinoIin-2-one; 6-Chloro-4-phenyl-3-pyridin-2-yl-1 H-quinolin-2-one; 3- (2-Methyl-thiazol-4-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile; 6-Chloro-3- (3-hydroxymethyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 5- (6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazole-3-carboxylic acid; 6-Chloro-3 - [(5-morpholin-4-carbonyl) -1 H -pyrrol-2-yl] -4-phenyl-1 H -quinolin-2-one; 6-Chloro-3 - [(3-morpholin-4-carbonyl) isoxazol-5-yl] -4-phenyl-1H-quinolin-2-one; 2-dimethyl ester. { [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-ylmethyl] -amino} malonic 4- ( { [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-ylmethyl] -amino} -methyl) - benzenesulfonamide; 5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-ii) -isoxazole-3-carbonitrile; 6-Chloro-3- (1 H -imidazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 3- (5-bromo-pyridin-3-yl) -6-chloro-4-phenyl-1 H-quinolin-2-one; 6-Chloro-4- (2-fluorophenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 6-Chloro-4-phenyl-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-pyridin-3-yl-1 H -quinolin-2-one; 6-Bromo-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 6-Chloro-4- (3-hydroxyphenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-pyridin-4-yl-1 H -quinolin-2-one; 6- (1, 2-dihydroxy-ethyl) -3- (3-methyl-isoxazoI-5-yl) -4-phenyl-1 H-quinoIin-2-one; 3- (3-methylisoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydroquinoline-6-carboxylic acid; 6- Hydroxymethyl-3- (3-methylisoxazole-5-ii) -4-phenyl-1H-quinolin-2-one; 3- (3-tert-Butyl-isoxazol-5-yl) -6-chloro-4-phenyl-1H-quinolin-2-one; 6-Chloro-3- (3-isopropyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 6-Chloro-3- (4-isobutyl-oxazol-2-yl) -4-phenyl-1 H -quinolin-2-one; 3- (1-Benzyl-1 H- [1,2,3] triazol-4-yl) -6-chloro-4-phenyl-1 H -quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -6-nitro-4-phenyl-1 H -quinolin-2-one; 6-Amino-3- (3-methyl-isoxazol-5-ii) -4-phenyl-1 H -quinolin-2-one; N- [3- (3-Methyl-isoxazoi-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinolin-6-yl] -acetamide; N- [3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinolin-6-yl] -methanesulfonamide; N- [3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinolin-6-yl] -acrylamide; 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-6- (pyridin-2-ylamino) -1 H -quinolin-2-one; 3- (3H-lmidazol-4-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile; 3- (1-Methyl-1 H-imidazol-4-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile; 3- (3-Amino-isoxazol-5-yl) -6-chloro-4-phenyl-1 H-quinolin-2-one; N- [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -acetamide; [5- (6-Chloro-2-oxo-4-phenyl-1,2,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -carbamic acid 2-methanesulfonyl-ethyl ester; 1 - [5- (6-Chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl) -isoxazol-3-yl] -3- (2-morpholin-4-yl-ethyl) )-urea; 3- (3-Methyl-isoxazol-5-yl) -4,6-diphenyl-1 H -quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-6- (3-trifluoromethyl-phenyl) -1H-quinolin-2-one; 6- (3-Methoxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carbonitrile; 3- (3-Methyl-isoxazol-5-yl) -6-methylsufanyl-4-phenyl-1 H -quinolin-2-one; 6-Methanesulfonyl-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H-quinolin-2-one; 6-Fluoro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 3- (3-Methyl-isoxazol-5-yl) -4-phenyl-1H-quinolin-2-one; 6-Fluoro-7-methoxy-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 5,6-Dichloro-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H -quinolin-2-one; 6-Cloro-4- (4-ethyl-phenyl) -3- (3H-imidazol-4-yl) -1 H -quinolin-2-one; 6-Bromo-4- (4-ethyl-phenyl) -3- (3H-imidazol-4-yl) -1 H -quinolin-2-one; 4- (4-Ethyl-phenyl) -3- (3H-imidazol-4-yl) -2-oxo-1,2-dihydro-quinolin-6-carbonitrile; 6-Chloro-4- (4-ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-m-tolyl-1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-p-tolyl-1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4-o-tolyl-1 H -quinolin-2-one; 6-Chloro-4- (2-chloro-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4- (4-chloro-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 4- (4-Acetyl-3-hydroxy-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 4- (3-Acetyl-4-hydroxy-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 6-Chloro-4- (4-hydroxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 4- (5-Acetyl-2-methoxy-phenyl) -6-chloro-3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 4- (5-Acetyl-2-hydroxy-phenyl) -6-chloro-3- (3-methyl-isoxazoi-5-yl) -1 H -quinolin-2-one; 6-Chloro-4- (2-methoxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one, 6-Chloro-4- (4-methoxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 6-Chloro-4- (2-hydroxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4- (3-methoxy-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-4- (4-fluoro-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 4-Biphenyl-4-yl-6-chloro-3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 6-Chloro-3- (3-methyl-isoxazol-5-yl) -4- (4-propyl-phenyl) -1 H -quinolin-2-one; 6-Chloro-4- (4-isopropyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1H-quinolin-2-one; 6-Bromo-4- (4-ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -1 H -quinolin-2-one; 4- (4-Ethyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile; 4- (4-tert-Butyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinolin-6-carbonitrile; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-propyl-phenyl) -1,2-dihydro-quinoline-6-carbonitrile; 4- (4-lsopropyl-phenyl) -3- (3-methyl-isoxazoI-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-trifluoromethyl-phenyl) -1,2-dihydro-quinoline-6-carbonitrile; 4- (4-Acetyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile; 3- (3-Methyl-isoxazol-5-yl) -4- (4-methylsulfanyl-phenyl) -2-oxo-1,2-dihydro-quinolin-6-carbonitrile; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-vinyl-phenyl) -1,2-dihydro-quinoline-6-carbonitrile; 4- (4-Ethyl-phenyl) -3- (2-methyl-thiazol-4-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile; 3- (3-Methyl-isoxazol-5-yl) -2-oxo-4- (4-trifluoromethoxy-phenyl) -1,2-dihydro-quinoline-6-carbonitrile; 4- (4-Cyano-phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile; 4- (4-Methanesulfonyl-phenyl) -3- (3-methyl-isoxazol-5-yl) -2-oxo-1,2-dihydro-quinoline-6-carbonitrile; 6- Bromo-3- (3-methyl-isoxazol-5-yl) -4-phenyl-1 H-quinolin-2-thione; 6-Bromo-3- (3H-imidazol-4-yl) -4-phenyl-1 H -quinolin-2-one; 6-Bromo-3- (3H-imidazol-4-yl) -1-methyl-4-phenyl-1 H -quinolin-2-one and 6-chloro-4-phenyl-3-pyridin-2-yl-1 H-quinolin-2-one.

7. A pharmaceutical composition comprising a compound as defined in any of claims 1-6 and a pharmaceutically acceptable carrier.

8. A method for inhibiting the activity of a tyrosine kinase protein, comprising contacting the kinase with an effective inhibitory amount of at least one compound as defined in any of claims 1-6.

9. The method according to claim 8, further characterized in that the protein tyrosine kinase is c-fms.

10. The use of at least one compound as defined in any of claims 1-6, for preparing a medicament for treating inflammation in a mammal.

11. The use of at least one compound as defined in any of claims 1-6, to prepare a medicament for treating cancer in a mammal.

12. The use of at least one compound as defined in any of claims 1-6, for preparing a medicament for treating cardiovascular disease in a mammal.

13. The use of at least one compound as defined in any of claims 1-6, for preparing a medicament for treating glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, angiogenesis related to the tumor, restenosis, schizophrenia or Alzheimer's dementia in a mammal.

14. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound as defined in any of claims 1-6.

15. The dosage form according to claim 14, further characterized in that it is adapted for parenteral or oral administration.