Kinase Inhibitors Useful For The Treatment Of Proliferative Diseases

Abstract

The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.

1 - 98 . (canceled) 
     
     
         99 . A method of modulating a kinase activity of a wild-type kinase species, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of the formula Ia′ or IIa′ 
       
         
           
           
               
               
           
         
         wherein X—Y is N—CH2; 
         X2 is a direct bond; 
         E1 is phenyl; 
         Q1 is N and Q2 is CR3; 
         A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; 
         G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; 
         the A ring may be optionally substituted with one or more —X1-A1 moieties; 
         X1 is selected from the group consisting of —(CH 2 ) n —(O) r —(CH 2 ) n —, —(CH 2 ) n —(NR3)-(CH 2 ) n —, —(CH 2 ) n —(S) r —(CH 2 ) n —, —(CH 2 ) n —(C═O) r —(CH 2 ) n —, —(CH 2 ) n —(C(═O)—NR3) r -(CH 2 ) n —, and —(CH 2 ) n —(SO 2 —NR3) r -(CH 2 ) n —, wherein any of the alkylenes may be straight or branched chain; 
         A1 is selected from the group consisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4) 2 , —R5, —C(O)N(R4) 2 , C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkyl group is fully or partially fluorinated; 
         when A and A1 have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 or Z3 substituent; 
         when A and A1 have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent; 
         when A and A1 have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent; 
         each Z1 is independently and individually selected from the group consisting of hydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, —SOR3, (R4) 2 NSO 2 —, —SO 2 R3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, phenoxy, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —S(O) 2 R5, —N═S(O)R6R8, —S(O)(═NR3)R6, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —S(O) 2 NHC(O)R8, —(CH 2 ) n NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2  (CH 2 ) n R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, —(CH 2 ) n S(O) 2 NH(CH 2 ) q R5, —CH(OH)(CH 2 ) p R5, —CH(OH)CH(OH)R4, —(CH 2 ) n N(R4) 2 , —(CH 2 ) n R5, —C(═NH)R5, —C(═NH)N(R4) 2 , —C(═NOR3)R5, —C(═NOR3)N(R4) 2 , and —NHC(═NH)R8; 
         in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, C1-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl-, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n —, (R4) 2 NC2-C6alkylO—(CH 2 ) n —, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —SO 2 R5, —SO 2 R8, —(CH 2 ) n N(R4)C(O)R8, —C(O)R8, ═O═NOH, ═N(OR6), —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —(CH 2 )NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2 R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, and —(CH 2 ) n R5; 
         in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, —N(R4)-C(═O)R8, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —N(R4)SO 2 R5, —N(R4)SO 2 R8, —(CH 2 ) n —N(R3) 2 , —(CH 2 ) n —N(R4) 2 , —O—(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —C(═O)R5, —C(═O)R8, and nitro; 
         in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) q —O—(CH 2 ) n -G1, —(CH 2 ) q —O—(CH 2 ) n -G4, —(CH 2 ) q —NR3-(CH 2 ) n -G1, —(CH 2 ) q —NR3-(CH 2 ) n -G4, —(CH 2 ) q NHC(O)(CH 2 ) n R5, —(CH 2 ) q C(O)NH(CH 2 ) q R5, —(CH 2 ) q C(O)R5, —(CH 2 ) q OC(O)R5, —(CH 2 ) q R5, —(CH 2 ) q NR4(CH 2 ) q R5, and —(CH 2 ) q O(CH 2 ) q R5; 
         in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio, (R3) 2 N—, (R4) 2 N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 N(R4) 2 , halogen, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated, —O—(CH 2 ) q —N(R4) 2 , —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —(NR3) r -(CH 2 ) n —R17, —(O) r —R17, —(S) r —R17, and —(CH 2 ) r —R17; 
         in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, and Z3-substituted phenyl; 
         each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, —(CH 2 )—N(R7) 2 , —(CH 2 )—R5, —(CH 2 )—C(O)N(R7) 2 , —(CH 2 ) n C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R5 is independently and individually selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         and wherein the symbol (##) is the point of attachment of the R5 moiety; 
         each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl, and G1; 
         each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl, —(CH 2 ) q —R5, —(CH 2 ) n —C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , and R5; 
         each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, and —N(R4) 2 ; 
         R16 is independently and individually selected from the group consisting of hydrogen, C1-C6alkyl, and halogen; 
         each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl; 
         wherein R17 can be further substituted with one or more Z2, Z3 or Z4 moieties; 
         R19 is H or C1-C6 alkyl; 
         wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; 
         and k is 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, and salts thereof. 
       
     
     
         100 . The method of  claim 99 , said species being C-Raf kinase, B-Raf kinase and oncogenic forms thereof. 
     
     
         101 . The method of  claim 99  wherein said compound is selected from the group consisting of 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         102 . The method of  claim 99  wherein said compound is selected from the group consisting of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea, 1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         103 . The method of  claim 99  wherein said compound is selected from the group consisting of 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         104 . The method of  claim 99  wherein said compound is selected from the group consisting of 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         105 . The method of  claims 101 - 104 , said species being C-Raf kinase, B-Raf kinase and oncogenic forms thereof. 
     
     
         106 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, secondary cancer growth arising from metastasis, diseases characterized by hyper-vascularization, inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, cardiovascular disease and diseases characterized by angiogenesis, comprising the step of administering to such individual a compound of the formula Ia′ or IIa′ 
       
         
           
           
               
               
           
         
         wherein X—Y is N—CH 2 ; 
         X2 is a direct bond; 
         E1 is phenyl; 
         Q1 is N and Q2 is CR3; 
         A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; 
         G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; 
         the A ring may be optionally substituted with one or more —X1-A1 moieties; 
         X1 is selected from the group consisting of —(CH 2 ) n —(O), —(CH 2 ) n —, —(CH 2 ) n —(NR3) r -(CH 2 ) n —, —(CH 2 ) n —(S) r —(CH 2 ) n —, —(CH 2 ) n —(C═O) r —(CH 2 ) n —, —(CH 2 ) n —(C(═O)—NR3) r -(CH 2 ) n —, and —(CH 2 ) n —(SO 2 —NR3) r -(CH 2 ) n —, wherein any of the alkylenes may be straight or branched chain; 
         A1 is selected from the group consisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4) 2 , —R5, —C(O)N(R4) 2 , C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkyl group is fully or partially fluorinated; 
         when A and A1 have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 or Z3 substituent; 
         when A and A1 have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent; 
         when A and A1 have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent; 
         each Z1 is independently and individually selected from the group consisting of hydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, 
         (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, 
         (R4) 2 N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, —SOR3, (R4) 2 NSO 2 —, —SO 2 R3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, phenoxy, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —S(O) 2 R5, —N═S(O)R6R8, —S(O)(═NR3)R6, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —S(O) 2 NHC(O)R8, —(CH 2 ) n NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2  (CH 2 ) n R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, —(CH 2 ) n S(O) 2 NH(CH 2 ) q R5, —CH(OH)(CH 2 ) p R5, —CH(OH)CH(OH)R4, —(CH 2 ) n N(R4) 2 , —(CH 2 ) n R5, —C(═NH)R5, —C(═NH)N(R4) 2 , —C(═NOR3)R5, —C(═NOR3)N(R4) 2 , and —NHC(═NH)R8; 
         in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, C1-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl-, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n —, (R4) 2 NC2-C6alkylO—(CH 2 ) n —, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —SO 2 R5, —SO 2 R8, —(CH 2 ) n N(R4)C(O)R8, —C(O)R8, ═O, ═NOH, ═N(OR6), —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —(CH 2 )NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2 R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, and —(CH 2 ) n R5; 
         in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, —N(R4)-C(═O)R8, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —N(R4)SO 2 R5, —N(R4)SO 2 R8, —(CH 2 ) n —N(R3) 2 , —(CH 2 ) n —N(R4) 2 , —O—(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —C(═O)R5, —C(═O)R8, and nitro; 
         in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) q —O—(CH 2 ) n -G1, —(CH 2 ) q —O—(CH 2 ) n -G4, —(CH 2 ) q —NR3-(CH 2 ) n -G1, —(CH 2 ) q —NR3-(CH 2 ) n -G4, —(CH 2 ) q NHC(O)(CH 2 ) n R5, —(CH 2 ) q C(O)NH(CH 2 ) q R5, —(CH 2 ) q C(O)R5, —(CH 2 ) q OC(O)R5, —(CH 2 ) q R5, —(CH 2 ) q NR4(CH 2 ) q R5, and —(CH 2 ) q O(CH 2 ) q R5; 
         in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio, (R3) 2 N—, (R4) 2 N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 N(R4) 2 , halogen, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated, —O—(CH 2 ) q —N(R4) 2 , —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —(NR3) r -(CH 2 ) n —R17, —(O) r —R17, —(S) r —R17, and —(CH 2 ) r —R17; 
         in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, and Z3-substituted phenyl; 
         each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, —(CH 2 ) p —N(R7) 2 , —(CH 2 ) p —R5, —(CH 2 ) p —C(O)N(R7) 2 , —(CH 2 ) n C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R5 is independently and individually selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         and wherein the symbol (##) is the point of attachment of the R5 moiety; 
         each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl, and G1; 
         each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl, —(CH 2 ) q —R5, —(CH 2 ) n —C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , and R5; 
         each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, and —N(R4) 2 ; 
         R16 is independently and individually selected from the group consisting of hydrogen, C1-C6alkyl, and halogen; 
         each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl; 
         wherein R17 can be further substituted with one or more Z2, Z3 or Z4 moieties; 
         R19 is H or C1-C6 alkyl; 
         wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; 
         and k is 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, and salts thereof. 
       
     
     
         107 . The method of  claim 106  wherein said compound is selected from the group consisting of 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         108 . The method of  claim 106  wherein said compound is selected from the group consisting of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea, 1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         109 . The method of  claim 106  wherein said compound is selected from the group consisting of 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         110 . The method of  claim 106  wherein said compound is selected from the group consisting of 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         111 . A method of treating an individual suffering from chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, hypereosinophillic syndrome, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis, melanomas, colon cancer, thyroid cancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonary disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof, comprising the step of administering to such individual a compound of the formula Ia′ or IIa′ 
       
         
           
           
               
               
           
         
         wherein X—Y is N—CH2; 
         X2 is a direct bond; 
         E1 is phenyl; 
         Q1 is N and Q2 is CR3; 
         A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; 
         G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; 
         the A ring may be optionally substituted with one or more —X1-A1 moieties; 
         X1 is selected from the group consisting of —(CH 2 ) n —(O) r —(CH 2 ) n —, —(CH 2 ) n —(NR3) r -(CH 2 ) n —, —(CH 2 ) n —(S) r —(CH 2 ) n —, —(CH 2 ) n —(C═O) r —(CH 2 ) n —, —(CH 2 ) n —(C(═O)—NR3) r -(CH 2 ) n —, and —(CH 2 ) n —(SO 2 —NR3) r -(CH 2 ) n —, wherein any of the alkylenes may be straight or branched chain; 
         A1 is selected from the group consisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4) 2 , —R5, —C(O)N(R4) 2 , C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkyl group is fully or partially fluorinated; 
         when A and A1 have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 or Z3 substituent; 
         when A and A1 have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent; when A and A1 have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent; 
         each Z1 is independently and individually selected from the group consisting of hydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, —SOR3, (R4) 2 NSO 2 —, —SO 2 R3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, phenoxy, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —S(O) 2 R5, —N═S(O)R6R8, —S(O)(═NR3)R6, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —S(O) 2 NHC(O)R8, —(CH 2 ) n NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2  (CH 2 ) n R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, —(CH 2 ) n S(O) 2 NH(CH 2 ) q R5, —CH(OH)(CH 2 ) p R5, —CH(OH)CH(OH)R4, —(CH 2 ) n N(R4) 2 , —(CH 2 ) n R5, —C(═NH)R5, —C(═NH)N(R4) 2 , —C(═NOR3)R5, —C(═NOR3)N(R4) 2 , and —NHC(═NH)R8; 
         in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, C1-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl-, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n —, (R4) 2 NC2-C6alkylO—(CH 2 ) n —, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —SO 2 R5, —SO 2 R8, —(CH 2 ) n N(R4)C(O)R8, —C(O)R8, ═O═NOH, ═N(OR6), —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —(CH 2 )NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2 R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, and —(CH 2 ) n R5; 
         in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, —N(R4)-C(═O)R8, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —N(R4)SO 2 R5, —N(R4)SO 2 R8, —(CH 2 ) n —N(R3) 2 , —(CH 2 ) n —N(R4) 2 , —O—(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —C(═O)R5, —C(═O)R8, and nitro; 
         in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) q —O—(CH 2 ) n -G1, —(CH 2 ) q —O—(CH 2 ) n -G4, —(CH 2 ) q —NR3-(CH 2 ) n -G1, —(CH 2 ) q —NR3-(CH 2 ) n -G4, —(CH 2 ) q NHC(O)(CH 2 ) n R5, —(CH 2 ) q C(O)NH(CH 2 ) q R5, —(CH 2 ) q C(O)R5, —(CH 2 ) q OC(O)R5, —(CH 2 ) q R5, —(CH 2 ) q NR4(CH 2 ) q R5, and —(CH 2 ) q —O(CH 2 ) q R5; 
         in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio, (R3) 2 N—, (R4) 2 N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 N(R4) 2 , halogen, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated, —O—(CH 2 ) q —N(R4) 2 , —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —(NR3) r -(CH 2 ) n —R17, —(O) r —R17, —(S) r —R17, and —(CH 2 ) r —R17; 
         in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, and Z3-substituted phenyl; 
         each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, —(CH 2 )—N(R7) 2 , —(CH 2 )—R5, —(CH 2 )—C(O)N(R7) 2 , —(CH 2 ) n C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R5 is independently and individually selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         and wherein the symbol (##) is the point of attachment of the R5 moiety; 
         each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl, and G1; 
         each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl, —(CH 2 ) q —R5, —(CH 2 ) n —C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , and R5; 
         each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, and —N(R4) 2 ; 
         R16 is independently and individually selected from the group consisting of hydrogen, C1-C6alkyl, and halogen; 
         each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl; 
         wherein R17 can be further substituted with one or more Z2, Z3 or Z4 moieties; 
         R19 is H or C1-C6 alkyl; 
         wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; 
         and k is 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, and salts thereof. 
       
     
     
         112 . The method of  claim 111  wherein said compound is selected from the group consisting of 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         113 . The method of  claim 111  wherein said compound is selected from the group consisting of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea, 1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         114 . The method of  claim 111  wherein said compound is selected from the group consisting of 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         115 . The method of  claim 111  wherein said compound is selected from the group consisting of 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         116 . A method of administering to a mammal a compound of the formula Ia′ or IIa′ 
       
         
           
           
               
               
           
         
         wherein X—Y is N—CH2; 
         X2 is a direct bond; 
         E1 is phenyl; 
         Q1 is N and Q2 is CR3; 
         A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; 
         G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; 
         the A ring may be optionally substituted with one or more —X1-A1 moieties; 
         X1 is selected from the group consisting of —(CH 2 ) n —(O) r —(CH 2 ) n —, —(CH 2 ) n —(NR3)-(CH 2 ) n —, —(CH 2 ) n —(S) r —(CH 2 ) n —, —(CH 2 ) n —(C═O) r —(CH 2 ) n —, —(CH 2 ) n —(C(═O)—NR3) r -(CH 2 ) n —, and —(CH 2 ) n —(SO 2 —NR3) r -(CH 2 ) n —, wherein any of the alkylenes may be straight or branched chain; 
         A1 is selected from the group consisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4) 2 , —R5, —C(O)N(R4) 2 , C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkyl group is fully or partially fluorinated; 
         when A and A1 have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 or Z3 substituent; 
         when A and A1 have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent; 
         when A and A1 have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent; 
         each Z1 is independently and individually selected from the group consisting of hydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl, (R4) 2 NC1-C6alkyl, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n , (R4) 2 NC2-C6alkylO—(CH 2 ) n , (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, —SOR3, (R4) 2 NSO 2 —, —SO 2 R3, —SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH 2 ) n N(R4)C(O)R8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, phenoxy, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —S(O) 2 R5, —N═S(O)R6R8, —S(O)(═NR3)R6, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —S(O) 2 NHC(O)R8, —(CH 2 ) n NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2  (CH 2 ) n R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, —(CH 2 ) n S(O) 2 NH(CH 2 ) q R5, —CH(OH)(CH 2 ) p R5, —CH(OH)CH(OH)R4, —(CH 2 ) n N(R4) 2 , —(CH 2 ) n R5, —C(═NH)R5, —C(═NH)N(R4) 2 , —C(═NOR3)R5, —C(═NOR3)N(R4) 2 , and —NHC(═NH)R8; 
         in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, C1-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3) 2 N—, (R4) 2 N—, (R4) 2 NC1-C6alkyl-, (R4) 2 NC2-C6alkylN(R4)-(CH 2 ) n —, (R4) 2 NC2-C6alkylO—(CH 2 ) n —, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —SO 2 R5, —SO 2 R8, —(CH 2 ) n N(R4)C(O)R8, —C(O)R8, ═O═NOH, ═N(OR6), —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) n —O—(CH 2 ) n -G1, —(CH 2 ) n —O—(CH 2 ) n -G4, —(CH 2 ) n —NR3-(CH 2 ) n -aryl, —(CH 2 ) n —NR3-(CH 2 ) n -G1, —(CH 2 ) n —NR3-(CH 2 ) n -G4, —(CH 2 ) n NHC(O)NHS(O) 2 R8, —(CH 2 ) n NHS(O) 2 NHC(O)R8, —C(O)NHS(O) 2 R8, —(CH 2 )NHC(O)(CH 2 ) n R5, —(CH 2 ) n NHS(O) 2 R5, —(CH 2 ) n C(O)NH(CH 2 ) q R5, —(CH 2 ) n C(O)R5, —(CH 2 ) n OC(O)R5, and —(CH 2 ) n R5; 
         in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3) 2 N—C(═O)—, (R4) 2 N—C(═O)—, —N(R4)-C(═O)R8, (R3) 2 NSO 2 —, (R4) 2 NSO 2 —, —N(R4)SO 2 R5, —N(R4)SO 2 R8, —(CH 2 ) n —N(R3) 2 , —(CH 2 ) n —N(R4) 2 , —O—(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —C(═O)R5, —C(═O)R8, and nitro; 
         in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4) 2 N—C2-C6alkyl, (R4) 2 N—C2-C6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO 2 R8, —COR8, —(CH 2 ) n -G1, —(CH 2 ) n -G4, —(CH 2 ) q —O—(CH 2 ) n -G1, —(CH 2 ) q —O—(CH 2 ) n -G4, —(CH 2 ) q —NR3-(CH 2 ) n -G1, —(CH 2 ) q —NR3-(CH 2 ) n -G4, —(CH 2 ) q NHC(O)(CH 2 ) n R5, —(CH 2 ) q C(O)NH(CH 2 ) q R5, —(CH 2 ) q C(O)R5, —(CH 2 ) q OC(O)R5, —(CH 2 ) q R5, —(CH 2 ) q NR4(CH 2 ) q R5, and —(CH 2 ) q —O(CH 2 ) q R5; 
         in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         each Z6 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio, (R3) 2 N—, (R4) 2 N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO 2 R6-, —CON(R3) 2 , —CON(R4) 2 , —COR5, —SO 2 N(R4) 2 , halogen, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partially fluorinated, —O—(CH 2 ) q —N(R4) 2 , —N(R3)-(CH 2 ) q —N(R4) 2 , —O—(CH 2 ) q —O-alkyl, —N(R3)-(CH 2 ) q —O-alkyl, —O—(CH 2 ) q —R5, —N(R3)-(CH 2 ) q —R5, —(NR3) r -(CH 2 ) n —R17, —(O) r —R17, —(S) r —R17, and —(CH 2 ) r —R17; 
         in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls; 
         wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, and Z3-substituted phenyl; 
         each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl, —(CH 2 ) p —N(R7) 2 , —(CH 2 ) p —R5, —(CH 2 ) p —C(O)N(R7) 2 , —(CH 2 ) n C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R5 is independently and individually selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         and wherein the symbol (##) is the point of attachment of the R5 moiety; 
         each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl, and G1; 
         each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl, —(CH 2 ) q —R5, —(CH 2 ) n —C(O)R5, —(CH 2 ) n —C(O)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and —(CH 2 ) n —R17; 
         each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substituted G1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3) 2 , N(R4) 2 , and R5; 
         each R10 is independently and individually selected from the group consisting of CO 2 H, CO 2 C1-C6alkyl, CO—N(R4) 2 , OH, C1-C6alkoxy, and —N(R4) 2 ; 
         R16 is independently and individually selected from the group consisting of hydrogen, C1-C6alkyl, and halogen; 
         each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl; 
         wherein R17 can be further substituted with one or more Z2, Z3 or Z4 moieties; 
         R19 is H or C1-C6 alkyl; 
         wherein two R3 or R4 moieties are independently and individually taken from the group consisting of C1-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; 
         and k is 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, and salts thereof, 
         said method of administration selected from the group consisting of oral, parenteral, inhalation, and subcutaneous. 
       
     
     
         117 . The method of  claim 116  wherein said compound is selected from the group consisting of 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         118 . The method of  claim 116  wherein said compound is selected from the group consisting of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea, 1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea, 1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof. 
     
     
         119 . The method of  claim 116  wherein said compound is selected from the group consisting of 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, and salts thereof. 
     
     
         120 . The method of  claim 116  wherein said compound is selected from the group consisting of 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea, and salts thereof.