Kinase inhibitors useful for the treatment of proliferative diseases
View Patent ↗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. Compounds of the formula Ia’
wherein X—Y in order is N—CH2;
X2 is a direct bond;
E1 is phenyl;
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 , (R 3 ) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C 6alkoxycarbonylC1-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-C 6alkoxycarbonyl, 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-C 6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C 1-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 -G 4, —(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), —R17, and —(CH 2 ), —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.
2. Compounds of claim 1 having the formula Ic
3. Compounds of claim 2 having the formula Id
wherein A1 is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
4. Compounds of claim 3 having the formula Ie
5. Compounds of claim 3 having the formula lf
wherein R16 is C1-C6alkyl, fluorine or chlorine.
6. Compounds of claim 2 having the formula Ig
wherein A1 is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
7. Compounds of claim 6 having the formula Ih
8. Compounds of claim 6 having the formula Ii
wherein R16 is C1-C6alkyl, fluorine or chlorine.
9. Compounds of claim 1 having formula Ij
wherein A1 is selected from the group consisting of Z2-substituted branched C3-C 8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
10. Compounds of claim 9 having formula Ik
11. Compounds of claim 9 having formula Il
wherein R16 is C1-C6alkyl, fluorine or chlorine.
12. Compounds of claim 1 having formula Im
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
13. Compounds of claim 12 having formula In
14. Compounds of claim 12 having formula Io
wherein R16 is C1-C6alkyl, fluorine or chlorine.
15. Compounds of claim 1 having formula Ip
wherein A1 is selected from the group consisting of Z2-substituted branched C3-C 8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
16. Compounds of claim 15 having formula Iq
17. Compounds of claim 15 having formula Ir
and wherein R16 is C1-C6alkyl, fluorine or chlorine.
18. Compounds of claim 1 having formula Is
wherein the hashed bond is a saturated or unsaturated bond;
and wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, halogen, cyano, C1-C6alkoxy, fluoroC1-C6alkoxy, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
19. Compounds of claim 18 having formula It
20. Compounds of claim 18 having formula Iu
and wherein R16 is C1-C6alkyl, fluorine or chlorine.
21. Compounds of claim 1 having formula Iv
wherein the hashed bond is a saturated or unsaturated bond;
and wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, halogen, cyano, C1-C6alkoxy, fluoroC1-C6alkoxy, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
22. Compounds of claim 21 having formula Iw
23. Compounds of claim 21 having formula Ix
and wherein R16 is C1-C6alkyl, fluorine or chlorine.
24. Compounds of claim 1 having formula Iy
wherein A1 is selected from the group consisting of Z2-substituted branched C3-C 8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
25. Compounds of claim 24 having formula Iz
26. Compounds of claim 24 having formula Iaa
wherein R16 is C1-C6alkyl, fluorine or chlorine.
27. Compounds of claim 1 having formula Ibb
wherein R16 is C1-C6alkyl, or halogen.
28. Compounds of claim 27 having formula Icc
29. Compounds of claim 27 having formula Idd
wherein R16 is C1-C6alkyl, fluorine or chlorine.
30. Compounds of claim 1 having formula Iee
wherein Q1 and Q2 are individually and independently taken from the group consisting of N and CH;
and wherein R16 is C1-C6alkyl, or halogen.
31. Compounds of claim 30 having formula Iff
32. Compounds of claim 30 having formula Igg
wherein R16 is C1-C6alkyl, fluorine or chlorine.
33. Compounds of claim 1 having formula Ihh
and wherein R16 is C1-C6alkyl, or halogen.
34. Compounds of claim 33 having formula Iii
35. Compounds of claim 33 having formula Ijj
wherein R16 is C1-C6alkyl, fluorine or chlorine.
36. Compounds of claim 1 having formula Ikk
wherein Q6 is N or C-A1;
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C 6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
37. Compounds of claim 36 having formula Ill
38. Compounds of claim 36 having formula Imm
wherein R16 is C1-C6alkyl, fluorine or chlorine.
39. Compounds of claim 1 having formula Inn
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C 6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
40. Compounds of claim 39 having formula Ioo
41. Compounds of claim 39 having formula Ipp
wherein R16 is C1-C6alkyl, fluorine or chlorine.
42. Compounds of claim 1 having formula Iqq
wherein Q3, Q4 and Q5 are selected from the group consisting of N—A1 and C-A1, and only one of Q3, Q4, or Q5 is N—A1;
and wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl R19 substituted C3-C8carboyclyl, Z2 substituted C1-C6alkyl, flouroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
43. Compounds of claim 42 having formula Irr
44. Compounds of claim 42 having formula Iss
wherein R16 is C1-C6alkyl, fluorine or chlorine.
45. Compounds of the formula IIa’
wherein X—Y is N—CH2;
Q1 is N and Q2 is CR3;
X2 is a direct bond;
E1 is phenyl;
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 , (R 3 ) 2 N—C(═O)—, (R4) 2 N—C(═O)—, (R4) 2 N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C 6alkoxycarbonylC1-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-C6alky1-, (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-C 6alkoxycarbonyl, 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, ═ 0 , ═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-C 6alkylN(R4)-C2-C6alkyl, (R4) 2 N—C2-C6alkyl-O—C2-C6alkyl, (R4) 2 N—CO—C 1-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 -G 4, —(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.
46. Compounds of claim 45 having the formula IIc
47. Compounds of claim 46 having the formula IId
wherein A1 is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
48. Compounds of claim 47 having the formula IIe
49. Compounds of claim 47 having the formula lf
wherein R16 is methyl, fluorine or chlorine.
50. Compounds of claim 46 having the formula IIg
wherein A1 is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
51. Compounds of claim 50 having the formula IIh
52. Compounds of claim 50 having the formula IIi
wherein R16 is methyl, fluorine or chlorine.
53. Compounds of claim 45 having formula IIj
wherein A1 is selected from the group consisting of Z2-substitued branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
54. Compounds of claim 53 having formula IIk
55. Compounds of claim 53 having formula IIl
wherein R16 is methyl, fluorine or chlorine.
56. Compounds of claim 45 having formula IIm
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
57. Compounds of claim 56 having formula IIn
58. Compounds of claim 56 having formula llo
wherein R16 is C1-C6alkyl, fluorine or chlorine.
59. Compounds of claim 45 having formula IIp
wherein A1 is selected from the group consisting of Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
60. Compounds of claim 50 having formula IIq
61. Compounds of claim 50 having formula IIr
and wherein R16 is methyl, fluorine or chlorine.
62. Compounds of claim 45 having formula IIs
wherein the hashed bond is a saturated or unsaturated bond;
and wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, halogen, cyano, C1 -C6alkoxy, fluoroC1 -C6alkoxy, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
63. Compounds of claim 62 having formula IIt
64. Compounds of claim 62 having formula IIu
and wherein R16 is C1-C6alkyl, fluorine or chlorine.
65. Compounds of claim 45 having formula IIv
wherein the hashed bond is a saturated or unsaturated bond;
and wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, halogen, cyano, C1 -C6alkoxy, fluoroC1 -C6alkoxy, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
66. Compounds of claim 65 having formula IIw
67. Compounds of claim 65 having formula IIx
and wherein R16 is C1-C6alkyl, fluorine or chlorine.
68. Compounds of claim 45 having formula IIy
wherein A1 is selected from the group consisting of Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
69. Compounds of claim 68 having formula IIz
70. Compounds of claim 68 having formula IIaa
wherein R16 is methyl, fluorine or chlorine.
71. Compounds of claim 45 having formula IIbb
wherein R16 is C1-C6alkyl, or halogen.
72. Compounds of claim 71 having formula IIcc
73. Compounds of claim 71 having formula IIdd
wherein R16 is C1-C6alkyl, fluorine or chlorine.
74. Compounds of claim 45 having formula IIee
wherein Q1 and Q2 individually and independently taken from the group consisting of N and CH;
and wherein R16 is C1-C6alkyl, or halogen.
75. Compounds of claim 74 having formula IIff
76. Compounds of claim 74 having formula IIgg
wherein R16 is C1-C6alkyl, fluorine or chlorine.
77. Compounds of claim 45 having formula IIhh
and wherein R16 is C1-C6alkyl, or halogen.
78. Compounds of claim 77 having formula IIii
79. Compounds of claim 77 having formula IIjj
and wherein R16 is methyl, fluorine or chlorine.
80. Compounds of claim 45 having formula IIkk
wherein Q6 is N or C-A1;
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
81. Compounds of claim 80 having formula IIll
82. Compounds of claim 80 having formula IImm
wherein R16 is C1-C6alkyl, fluorine or chlorine.
83. Compounds of claim 45 having formula IInn
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
84. Compounds of claim 83 having formula IIoo
85. Compounds of claim 83 having formula IIpp
wherein R16 is C1-C6alkyl, fluorine or chlorine.
86. Compounds of claim 45 having formula IIqq
wherein Q3, Q4 and Q5 are selected from the group consisting of N—A1 and C-A1, and only one of Q3, Q4, or Q5 is N—A1;
wherein A1 is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is C1-C6alkyl, or halogen.
87. Compounds of claim 86 having formula IIrr
88. Compounds of claim 86 having formula IIss
wherein R16 is C1-C6alkyl, fluorine or chlorine.
89. A compound 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-tert-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-tert-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-l-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-tert-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-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-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-(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-(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-(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-(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-(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-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)urea, 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-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea, 1-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropteridin-6-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-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-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-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-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-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-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-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-dihydropyrimido[4,5-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-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-(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-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-(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-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-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethy)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-(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-(5-(7-amino-l-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-l-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-(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-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-l-phenyl-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-(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-(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-(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, and 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.
90. A compound selected from the group consisting of 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-butylisoxazol1-3-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-dihydropyrido[4,3-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-(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-(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-(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-l-yl)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-(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-(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, 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-l-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-l-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-(5-(7-amino-l-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-(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-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-(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-(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-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-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-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-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-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-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-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-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-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, (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-(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 9 pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, (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-(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-(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-butylisoxazol1-5-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-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)-2,4-difluorophenyl)urea, 1-(3-tert-butylisoxazol1-5-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-(2,4-difluoro-5-(7-(methylamino)-2-oxo-l-phenyl-1,2-dihydropyrido[4,3-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-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-fluoro-4-methylphenyl)-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-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-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-isopropylurea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-(pyridin-3-yl)ethyl)urea, (R)-1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenylethyl)urea, and (S)-1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenylethyl)urea, and salts thereof.
91. A pharmaceutical composition comprising a compound of claims 1 , 45 , 89 or 90 and salts thereof, together with a pharmaceutically acceptable carrier, said carrier including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
92. 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, or a salt thereof.
93. A pharmaceutical composition comprising a compound of claim 92 , together with a pharmaceutically acceptable carrier, said carrier including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.