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Abstract
The present invention is directed to compounds of formula (I), (Ia),(Ic) and (Id), compositions, and uses thereof as an inhibitor of the p38 kinase, and
wherein, inter alia
- R1 is C(Z)N(R10′)(CR10R20)vRb, C(Z)O(CR10R20)vRb, N(R10′)C(Z)(CR10R20)vRb; N(R10′)C(Z)N(R10′)(CR10R20)vRb; or N(R10′)OC(Z)(CR10R20)vRb;
- R3 is C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-10 alkyl, aryl, arylC1-10 alkyl, heteroarylC1-10 alkyl, or a heterocyclylC1-10 alkyl moiety, and wherein each of these moieties may be optionally substituted;
- X is R2, OR2′, S(O)mR2′, (CH2)n′N(R10′)S(O)mR2′, (CH2)n′N(R10′)C(O)R2′, (CH2)n′NR4R14, (CH2)n′N(R2 ′)(R2″), or N(R10′)—Rh—NH—C(═N—CN)NRqRq′; and
- R2 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, heterocyclic, or a heterocyclylC1-10 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or a pharmaceutically acceptable salt thereof.
-
Citations
71 Claims
-
1. A compound of the formula:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 69, 70, 71)
-
2. The compound according to claim 1 which is Formula (I), or a pharmaceutically acceptable salt thereof.
-
3. The compound according to claim 1 which is Formula (Ia), or a pharmaceutically acceptable salt thereof.
-
4. The compound according to claim 1 wherein R1 is C(Z)N(R10′
- )(CR10R20)vRb or N(R10′
)C(Z)(CR10R20)vRb.
- )(CR10R20)vRb or N(R10′
-
5. The compound according to claim 4 wherein R1 is C(Z)N(R10′
- )(CR10R20)vRb.
-
6. The compound according to claim 1 wherein Rb is an optionally substituted C1-10 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted aryl C1-10 alkyl, or an optionally substituted C3-7 cycloalkyl C1-10 alkyl.
-
7. The compound according to claim 6 wherein Rb is optionally substituted C1-10 alkyl, optionally substituted heteroaryl, or an optionally substituted aryl.
-
8. The compound according to claim 7 wherein Rb is propyl, isopropyl, thiazolyl, phenyl, or 4-F phenyl.
-
9. The compound according to claim 6 wherein Rb is an optionally substituted aryl or aryl C1-10alkyl moiety, and the aryl ring is substituted independently at each occurrence one or more times by halogen, alkyl, cyano, OR8, SR5, S(O)2R5, C(O)Rj, C(O)ORj, -Z′
- -(CR10R20)s-Z′
, halosubstituted C1-10 alkyl, or an optionally substituted aryl; and
whereinR8 is independently selected at each occurrence from hydrogen, C1-4 alkyl, halo-substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C5-7 cycloalkenyl, C5-7cycloalkenyl C1-4 alkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclyl, or a heterocyclylC1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; Rj is independently selected at each occurrence from hydrogen, C1-4alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; Z′
is independently selected at each occurrence from oxygen, or sulfur; ands is an integer having a value of 1, 2, or 3, independently selected at each occurrence.
- -(CR10R20)s-Z′
-
10. The compound according to claim 1 wherein Rb is phenyl, naphthylene, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-diflurophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl, 2-methyl phenyl, 3-methylphenyl, 4-methylphenyl, 6-methyl phenyl, 2-methyl phenyl, 3-amino phenyl, 3,4-dimethyl phenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl, 4-ethoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-thiomethyiphenyl, 4-acetyiphenyl, 4-dimethylaminophenyl, benzyl, phenethyl, phenyipropyl, 2,3-difluoro-benzyl, 3,5-difluoro-benzyl, biphenyl, 4′
- -fluorobiphenyl, 4-sulfonamindo-2-methylphenyl, 3-phenyloxyphenyl, 4-phenyloxyphenyl, 4-(1-piperidinylsulfonyl)-phenyl, or 3-(aminocarbonyl)phenyl.
-
11. The compound according to claim 6 wherein Rb is a C1-10alkyl, or a C1-10alkyl substituted one or more times, independently by halogen, cyano, alkoxy, thiol, or hydroxy.
-
12. The compound according to claim 11 wherein Rb is methyl, ethyl, propyl, isopropyl, t-butyl, butyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, heptyl, 2-methylpropyl, 2,2,2-trifluroethyl, 2-fluoroethyl, cyanomethyl, cyanoethyl, 2-methoxy-ethyl, 2-hydroxy propyl, serinol, or ethylthioethyl.
-
13. The compound according to claim 6 wherein Rb is an optionally substituted heteroaryl, heteroaryl C1-10alkyl, heterocyclic or heterocyclic C1-10alkyl.
-
14. The compound according to claim 13 wherein Rb is a 1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl, isoquinoline, 3-thiophene, indol-5yl, pyridin-3-yl, pyridine-4-yl, indazolyl, benzothiazolyl, 2-methyl-1,3-benzothiazol-5-yl, pyrazol-3-yl, 4-morpholino, 2-furanyl, 2-furanylmethyl, 2-thienyl, 2-thienylmethyl, tetrahydro-2H-pyran-4yl, tetrahydro-2H-pyran-4yl methyl, tetrahydro-2-furanyl, tetrahydro-2-furanylmethyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1H-imidazol-4-yl or 1H-imidazol-4-yl-ethyl.
-
15. The compound according to claim 1 wherein Rb is an optionally substituted C3-7 cycloalkyl or optionally substituted C3-7 cycloalkyl C1-10alkyl.
-
16. The compound according to claim 15 wherein Rb is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, or cyclopentylmethyl.
-
17. The compound according to claim 6 wherein Rb is selected from the group consisting of methyl-1,3-benzothiazol-5-yl, 4′
- -fluoro-3-biphenyl, 4-fluoro-phenyl, 2-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-fluorophenethyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 4-acetylphenyl, 4-trifluorophenyl, 4-methyl-3-fluoro-phenyl, 4-thiomethylphenyl, 4-ethyloxyphenyl, 4-methoxyphenyl, 3-phenyloxyphenyl, 3-methylphenyl, 2-methylphenyl, 5-methyl-1,3-thiazol-2-yl, 3-pyridinyl, 4-pyridinyl, 4-cyanophenyl, 3-cyanophenyl, 4-(phenylcarbonyl)phenyl, 1H-indazol-6-yl, and 3-(aminosulfonyl)phenyl.
-
18. The compound according to claim 1 wherein R1′
- is independently selected from halogen, C1-4 alkyl, or halo-substituted-C1-4 alkyl.
-
19. The compound according to claim 18 wherein R1′
- substituents are independently selected from fluorine, methyl, or CF3.
-
20. The compound according to claim 18 wherein g is 1.
-
21. The compound according to claim 1 wherein X is S(O)mR2.
-
22. The compound according to claim 1 wherein X is (CH2)nNR4R14, or (CH2)n′
- N(R2′
)(R2″
).
- N(R2′
-
23. The compound according to claim 22 wherein X is (CH2)nNR4R14, and R4 and R14 are independently selected from hydrogen, optionally substituted C1-10 alkyl, optionally substituted aryl, optionally substituted aryl-C1-4 alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic C1-4 alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C1-4 alkyl.
-
24. The compound according to claim 23 wherein the C1-10 alkyl may be substituted one or more times, independently at each occurrence with NR4′
- R14′
;
halogen, hydroxy, alkoxy, C(O)NR4′
R14′
;
or NR4′
C(O)C1-10alkyl.
- R14′
-
25. The compound according to claim 24 wherein R4′
- and R14′
;
are independently selected from hydrogen or a C1-4 alkyl.
- and R14′
-
26. The compound according to claim 25 wherein X is 3-(diethylamino)-propylamino.
-
27. The compound according to claim 22 wherein X is (CH2)nNR4R14 and one of R4 and R14 is an optionally substituted heteroaryl C1-4 alkyl, and the heteroaryl moiety is selected from the group consisting of thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.
-
28. The compound according to claim 27 wherein the heteroaryl moiety is selected from the group consisting of pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.
-
29. The compound according to claim 22 wherein X is (CH2)nNR4R14 and one of R4 and R14 is a heterocyclic C1-4 alkyl and the heterocyclic moiety is selected from the group consisting of tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, diazepinyl, piperazinyl, and morpholino.
-
30. The compound according to claim 29 wherein the heterocyclic moiety is selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino.
-
31. The compound according to claim 22 wherein X is (CH2)nNR4R14 and R4 and R14 together with the nitrogen cyclize to form an optionally substituted ring selected from the group consisting of pyrrolidine, piperidine, piperazine, and morpholine.
-
32. The compound according to claim 22 wherein the R4 and R14 cyclized ring is optionally substituted one or more times independently by an optionally substituted C1-10 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic, (CR10R20)nN(R10′
- )C(Z)OR7, or NR4′
R14′
.
- )C(Z)OR7, or NR4′
-
33. The compound according to claim 32 wherein the optional substituents on the cyclized ring are selected from the group consisting of phenyl, pyrrolidinyl, morpholino, piperazinyl, 4-methyl-1-piperazinyl, piperidinyl, 2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, 5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, diphenylmethyl, methyl, ethyl, propyl, butyl, amino, methylamino, and dimethylamino.
-
34. The compound according to claim 1 wherein X is R2 and R2 is an optionally substituted heterocyclic or heterocyclic C1-10 alkyl ring substituted one or more times independently at each occurrence by an optionally substituted heterocyclic, heterocyclic C1-10 alkyl, aryl, aryl C1-10 alkyl, C1-10 alkyl, (CR10R20)nNReRe′
- , or (CR10R20)nN(R10′
)C(Z)OR7; and
whereinn is independently selected at each occurrence from 0 or an integer having a value of 1 to 10; R7 is independently selected at each occurrence from C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; Re are Re′
are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4alkyl, aryl, aryl-C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, heteroaryl or a heteroaryl C1-4 alkyl moiety;
or Re and Re′
together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; andwherein each of these moieties, excluding hydrogen, may be substituted 1to 4 times, independently at each occurrence by halogen;
hydroxy;
hydroxy substituted C1-10alkyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
amino, mono &
di-substituted C1-4 alkyl amino;
S(O)mRf;
C(O)Rj;
C(O)ORj;
(CR10R20)nN(R10′
)C(Z)OR7;
(CR10R20)nN(R10′
)C(Z)NRdRd′
;
C(O)NR4′
R14′
;
NR4′
C(O)C1-10alkyl;
NR4′
C(O)aryl;
cyano;
nitro;
C1-10 alkyl;
C3-7cycloalkyl;
C3-7 cycloalkyl C1-10 alkyl;
halosubstituted C1-10 alkyl;
aryl, aryl C1-4 alkyl, heterocyclic, heterocyclicC1-4 alkyl, heteroaryl, or heteroC1-4alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C1-4 alkyl, hydroxy, hydroxy substituted C1-4 alkyl, C1-10 alkoxy, S(O)malkyl, amino, mono &
di-substituted C1-4 alkyl amino, C1-4 alkyl, or CF3;Rf is independently selected at each occurrence from C1-10alkyl, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10alkyl, heterocyclic, or a heterocyclic C1-10alkyl moiety, and wherein these moieties may all be optionally substituted; and Rj is independently selected at each occurrence from hydrogen, C1-4alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted.
- , or (CR10R20)nN(R10′
-
35. The compound according to claim 32 wherein R2 is selected from the group consisting of 1,4′
- -bipiperin-1-yl, 4-methyl-1,4′
-bipiperin-1-yl, 4-piperidinylamino, 4-amino-1-piperidinyl, 2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-methyl-1-piperazinyl, (4-morpholinyl)-1-piperidinyl,(4-methyl-1-piperazinyl)-1-piperidinyl, 4-ethyl-1-piperazinyl, (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 5-chloro-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 4-(1-pyrrolidinyl)-1-piperidinyl, 4-(diphenylmethyl)-1-piperazinyl, 4-methyihexahydro-1H-1,4-diazepin-1-yl, 4-propyl-1-piperazinyl, and 4-butyl-1-piperazinyl.
- -bipiperin-1-yl, 4-methyl-1,4′
-
36. The compound according to claim 35 wherein R2 is 1,4′
- -bipiperin-1-yl, 4-(1-pyrrolidinyl)-1-piperidinyl, and 4-methyl-1-piperazinyl.
-
37. The compound according to claim 1 wherein R2 is optionally substituted one or more times, independently at each occurrence, with C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10alkyl, C5-7cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, halogen, —
- C(O), cyano, nitro, aryl, aryl C1-10 alkyl, heterocyclic, heterocyclic C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
)S(O)2R7, (CR10R20)nNR4R14, (CR10R20)nCN, (CR10R20)nS(O)2NR4R14, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR4R14, (CR10R20)nN(R10′
)C(Z)R6, (CR10R20)nN(R10′
)C(═
N(R10′
))NR4R14, (CR10R20)nC(═
NOR6)NR4R14, (CR10R20)nOC(Z)NR4R14, (CR10R20)nN(R10′
)C(Z)NR4R14, or (CR10R20)nN(R10′
)C(Z)OR7; and
whereinn is independently selected at each occurrence from 0 or an integer having a value of 1to 10; R6 is independently selected at each occurrence from hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted; and R7 is independently selected at each occurrence from C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl moiety, and wherein each of these moieties may be optionally substituted.
- C(O), cyano, nitro, aryl, aryl C1-10 alkyl, heterocyclic, heterocyclic C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
-
38. The compound according to claim 36 wherein R2 is an optionally substituted C1-10 alkyl.
-
39. The compound according to claim 38 wherein the C1-10alkyl is optionally substituted by (CR10R20)nC(Z)OR6, (CR10R20)nOR6, or (CR10R20)nNR4R14.
-
40. The compound according to claim 1 wherein R2 is (CR10R20)q′
- X1(CR10R20)qC(A1)(A2)(A3), or (CR10R20)q′
C(A 1)(A2)(A3).
- X1(CR10R20)qC(A1)(A2)(A3), or (CR10R20)q′
-
41. The compound according to claim 40 wherein X1 is oxygen or N(R10′
- ).
-
42. The compound according to claim 41 wherein at least one of A1, A2 or A3 is substituted by (CR10R20)nOR6.
-
43. The compound according to claim 42 wherein q is 0 or 1, and q′
- is 0.
-
44. The compound according to claim 22 wherein X is (CH2)n′
- N(R2′
)(R2″
), and R2′
is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, heterocyclic, heterocyclyl C1-10 alkyl, or heteroarylC1-10 alkyl.
- N(R2′
-
45. The compound according to claim 44 wherein the R2′
- moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, at each occurrence, by C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-10alkyl, C5-7cycloalkenyl, C5-7 cycloalkenylC1-10 alkyl, halogen, —
C(O), cyano, nitro, aryl, aryl C1-10 alkyl, aryl, aryl C1-10 alkyl, heterocyclic, heterocyclic C1-10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
)S(O)2R7, (CR10R20)nNReRe′
, (CR10R20)nNReRe′
C1-4alkylNReRe′
, (CR10R20)nCN, (CR10R20)nS(O)2NReRe′
, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NReRe′
, (CR10R20)nN(R10′
)C(Z)R6, (CR10R20)nN(R10′
)C(═
N(R10′
))NReRe′
, (CR10R20)nC(═
NOR6) NReRe′
, (CR10R20)nOC(Z)NReRe′
, (CR10R20)nN(R10′
)C(Z) NReRe′
, or (CR10R20)nN(R10′
)C(Z)OR7; and
whereinR6 is independently selected at each occurrence from hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted; R7 is independently selected at each occurrence from C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; Re are Re′
are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4alkyl, aryl, aryl-C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, heteroaryl or a heteroaryl C1-4 alkyl moiety;
or Re and Re′
together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; andwherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen;
hydroxy;
hydroxy substituted C1-10alkyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
amino, mono &
di-substituted C1-4 alkyl amino;
S(O)mRf;
C(O)Rj;
C(O)ORj;
(CR10R20)nN(R10′
)C(Z)OR7;
(CR10 R20)nN(R10′
)C(Z)NRdRd′
;
C(O)NR4′
R14′
;
NR4′
C(O)C1-10alkyl;
NR4′
C(O)aryl;
cyano;
nitro;
C1-10 alkyl;
C3-7cycloalkyl;
C3-7cycloalkyl C1-10 alkyl;
halosubstituted C1-10 alkyl;
aryl;
aryl C1-4 alkyl;
heterocyclic;
heterocyclicC1-4 alkyl;
heteroaryl, or heteroC1-4alkyl; and
wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C1-4 alkyl, hydroxy, hydroxy substituted C1-4 alkyl, C1-10 alkoxy, S(O)malkyl, amino, mono &
di-substituted C1-4 alkyl amino, C1-4 alkyl, or CF3;Rf is independently selected at each occurrence from C1-10alkyl, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10alkyl, heterocyclic, or a heterocyclic C1-10alkyl moiety, and wherein these moieties may all be optionally substituted; Rj is independently selected at each occurrence from hydrogen, C1-4alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; and
n is 0 or an integer having a value of 1 to 10, and is independently selected at each occurrence.
- moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, at each occurrence, by C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-10alkyl, C5-7cycloalkenyl, C5-7 cycloalkenylC1-10 alkyl, halogen, —
-
46. The compound according to claim 45 wherein R2′
- is a heterocyclic ring or heterocyclic C1-10 alkyl substituted one or more times, independently by C1-10 alkyl, aryl, arylC1-10 alkyl, (CR10R20)nNReRe′
, or (CR10R20)nN(R 10′
)C(Z)OR7.
- is a heterocyclic ring or heterocyclic C1-10 alkyl substituted one or more times, independently by C1-10 alkyl, aryl, arylC1-10 alkyl, (CR10R20)nNReRe′
-
47. The compound according to claim 22 wherein the (CH2)n′
- N(R2′
)(R2″
) moiety is 1-(phenylmethyl)-4-piperidinamine, 2-[4-(phenylmethyl)-1-piperazinyl]ethylamine, 2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine, 1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine, 3-[(hexahydro-1H-azepin-1-yl)propyl]amine, (1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine, 3-[(2-oxo-1-pyrrolidinyl)propyl]amine, 2-[(4-morpholinyl)ethyl]amine, 2-[(1-pyrrolidinyl)ethyl]amine, or [(1-ethyl-2-pyrrolidinyl)methyl]amine.
- N(R2′
-
48. The compound according to claim 45 wherein R2′
- is a C1-10 alkyl substituted by (CR10R20)nNReRe′
or (CR10R20)nNReRe′
C1-4alkylNReRe′
.
- is a C1-10 alkyl substituted by (CR10R20)nNReRe′
-
49. The compound according to claim 48 wherein Re and Re′
- are independently selected from methyl, ethyl, isopropyl, n-butyl, or t-butyl, and n=0.
-
50. The compound according to claim 22 wherein (CH2)n′
- N(R2′
)(R2″
) is 3-(dimethylamino)propyl(methyl)amine, 3-(diethylamino)propylamine, propylamine, (2,2-dimethylpropyl)amine, (2-hydroxypropyl)amino, 2-(dimethylamino)ethylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(dimethylamino)propylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(diethylamino)propylamine, 2-(methylamino)ethylamine, [(1-methylethyl)amino]ethylamine, 3-(diethylamino)propylamine, 3-(dibutylamino)propylamine, 3-[(1-methylethyl)amino]propylamine, 3-(1,1-dimethylethyl)aminopropylamine, 3-(dimethylamino)-2,2-dimethylpropylamine, 4-(diethylamino)-1-methylbutylamine, or 3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine.
- N(R2′
-
51. The compound according to claim 1 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
-
52. The compound according to claim 51 wherein R3 is optionally substituted one or more times, independently at each occurrence, with halogen, nitro, C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-10 alkyl, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
- )S(O)2R7, (CR10R20)nNR16R26, (CR10R20)nCN, (CR10R20)nS(O)2NR16R26, (CR10 R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR16R26, (CR10R20)nN(R10′
)C(Z)R6, (CR10R20)nN(R10′
)C(═
N(R10′
))NR16R26, (CR10R20)nOC(Z)NR16R26, (CR10R20)nN(R10′
)C(Z)NR16R26, or (CR10R20)nN(R10′
)C(Z)OR7; and
whereinR16 and R26 are each independently selected at each occurrence from hydrogen, or C1-4 alkyl;
or the R16 and R26 together with the nitrogen which they are attached form an unsubstituted or substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9′
;R6 is independently selected at each occurrence from hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted; R7 is independently selected at each occurrence from C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and n is 0 or an integer having a value of 1 to 10, and is independently selected at each occurrence.
- )S(O)2R7, (CR10R20)nNR16R26, (CR10R20)nCN, (CR10R20)nS(O)2NR16R26, (CR10 R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR16R26, (CR10R20)nN(R10′
-
53. The compound according to claim 52 wherein the R3 is an optionally substituted aryl.
-
54. The compound according to claim 53 wherein the R3 aryl is a phenyl substituted one or more times independently at each occurrence by halogen, (CR10R20)nOR6, C1-10 alkyl, (CR10R20)nNR16R26, or halosubstituted C1-10 alkyl.
-
55. The compound according claim 54 wherein the phenyl is substituted one or more times independently by halogen, hydroxy, alkoxy, amino, C1-10alkyl, or CF3.
-
56. The compound according to claim 55 wherein the phenyl is disubstituted independently at each occurrence by halogen or methyl.
-
57. The compound according to claim 56 wherein R3 is 2,6-difluorophenyl.
-
58. The compound according to claim 1 wherein R3 is a 2,6-difluoro phenyl, R1′
- is independently selected at each occurrence from hydrogen, fluorine, or methyl;
g is 1 or 2;
R1 is C(Z)N(R10′
)(CR10R20)vRb, Rb is C1-10 alkyl or an optionally substituted aryl;
X is CH2)n′
N(R2′
)(R2″
), n is 0, and R2′
is a C1-10 alkyl substituted by (CR10R20)nNReRe′
; and
wherein Re are Re′
are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4alkyl, aryl, aryl-C1-4 alkyl, heterocyclic, heterocyclic C1-4 alkyl, heteroaryl or a heteroaryl C1-4 alkyl moiety;
or Re and Re′
together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; andwherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen;
hydroxy;
hydroxy substituted C1-10alkyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
amino, mono &
di-substituted C1-4 alkyl amino;
S(O)mRf;
C(O)Rj;
C(O)ORj;
(CR10R20)nN(R10′
)C(Z)OR7;
(CR10R20)nN(R10′
)C(Z)NRdRd′
;
C(O)NR4′
R14′
;
NR4′
C(O)C1-10alkyl;
NR4′
C(O)aryl;
cyano;
nitro;
C1-10 alkyl;
C3-7cycloalkyl;
C3-7cycloalkyl C1-10 alkyl;
halosubstituted C1-10 alkyl;
aryl;
aryl C1-4 alkyl;
heterocyclic;
heterocyclieC1-4 alkyl;
heteroaryl or heteroC1-4alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C1-4 alkyl, hydroxy, hydroxy substituted C1-4 alkyl, C1-10 alkoxy, S(O)malkyl, amino, mono &
di-substituted C1-4 alkyl amino, C1-4 alkyl, or CF3;Rf is independently selected at each occurrence from C1-10alkyl, aryl, aryl C1-10alkyl, heteroaryl, heteroaryl C1-10alkyl, heterocyclic, or a heterocyclic C1-10alkyl moiety, and wherein these moieties may all be optionally substituted; Rj is independently selected at each occurrence from hydrogen, C1-4alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; R7 is independently selected at each occurrence from C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10.
- is independently selected at each occurrence from hydrogen, fluorine, or methyl;
-
59. The compound according to claim 58 wherein R1 is C(Z)N(R10′
- )(CR10R20)vRb, Re and Re′
are independently selected from methyl, ethyl, isopropyl, n-butyl, or t-butyl, Rb is C1-10 alkyl, g is 1;
Z is oxygen, R10′
is hydrogen, and v=0.
- )(CR10R20)vRb, Re and Re′
-
60. The compound according to claim 1, which is:
-
1,1-Dimethylethyl{1-[4-{5-[(cyclobutylamino)carbonyl]-2-methylphenyl}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}carbamate; 3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-cyclobutyl-4-methylbenzamide; 1,1-Dimethylethyl{1-[4-(5-{[(cyclopropylmethyl)amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}carbamate; 3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide; 3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-[2-(4-fluorophenyl)ethyl]-4-methylbenzamide; 1,1-Dimethylethyl (1-{8-(2,6-difluorophenyl)-4-[5-({[2-(4-fluorophenyl)ethyl]amino}carbonyl)-2-methylphenyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl}-4-piperidinyl)carbamate; 3-[2-[(2-Aminoethyl)(methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide; N-(Cyclopropylmethyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide; N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide; 1,1-Dimethylethyl 4-{[4-(5-{[(cyclopropylmethyl)amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate; N-(3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-thiophenecarboxamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)-propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; 3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide; 3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide; 3-{8-(2,6-Difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide; 3-(8-(2,6-Difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide; 3-(8-(2,6-Difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide; 1,1-Dimethylethyl (2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate; 3-[8-(2,6-Difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide; 3-[8-(2,6-Difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide; 1,1-Dimethylethyl 4-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate; 3-{8-(2,6-Difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide; N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide; N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido [4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; N-(3-{8-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; 1,1-dimethylethyl 4-{[8-(2,6-difluorophenyl)-4-(5-{[(3-fluoro-4-methylphenyl)carbonyl]amino}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate; N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;
ora pharmaceutically acceptable salt thereof.
-
-
61. The compound according to claim 1 which is:
-
N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide; N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide; N-{3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; 3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-dipyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide; 3-[8-(2,6-Difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-dlpyrimidin-4-yl]-4-methyl-N-propylbenzamide; 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide;
or a pharmaceutically acceptable salt thereof.
-
-
62. A compound according to claim 1 which is
N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; -
N-(3-{8-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide; 3-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide;
3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide;
3-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide;3-{8-(2,6-difluorophenyl)-2-[4-(methylamino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide;
3-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide;3-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide;
3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide;3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide; 3-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide; 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide; 3-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide; 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide; 3-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide; 3-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide; 3-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide;
or a pharmaceutically acceptable salt thereof.
-
-
63. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier or diluent.
-
64. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to Claim 1, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.
-
69. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to claim 60 and a pharmaceutically acceptable carrier or diluent.
-
70. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to claim 61 and a pharmaceutically acceptable carrier or diluent.
-
71. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to claim 62 and a pharmaceutically acceptable carrier or diluent.
-
2. The compound according to claim 1 which is Formula (I), or a pharmaceutically acceptable salt thereof.
-
65. A compound of the formula:
- View Dependent Claims (66, 67, 68)
-
66. A compound according to claim 65 wherein:
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4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1 ,3-thiazol-2-ylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(1-methylethyl)benzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-propylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-phenylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)benzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-dimethylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-methylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-(1-methylethyl)benzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoic acids; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-propylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-phenylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-3-methylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N,3-trimethylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,3-dimethylbenzamide; 4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzamide;
ora pharmaceutically acceptable salt thereof.
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67. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof according to claim 65, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
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68. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof according to claim 65 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.
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66. A compound according to claim 65 wherein:
Specification
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Current AssigneeGlaxo Group Limited (GSK plc)
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Original AssigneeGlaxo Group Limited (GSK plc)
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InventorsCallahan, James F., Yan, Hongxing, Wan, Zehong, Lin, Xichen
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Primary Examiner(s)Berch; Mark L
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Assistant Examiner(s)Jaisle; Cecilia M
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Application NumberUS11/389,112Publication NumberTime in Patent Office1,446 DaysField of Search514/234.2, 514/264.1, 514/264.11, 514/218, 544/117, 544/279, 544/118, 540/553US Class Current514/234.2CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 19/06 Antigout agents, e.g. antih...A61P 19/08 for bone diseases, e.g. rac...A61P 19/10 for osteoporosisA61P 21/00 Drugs for disorders of the ...A61P 25/00 Drugs for disorders of the ...A61P 25/28 for treating neurodegenerat...A61P 27/02 Ophthalmic agentsA61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 31/04 Antibacterial agentsA61P 33/06 AntimalarialsA61P 35/00 Antineoplastic agentsA61P 35/04 : specific for metastasisA61P 37/00 : Drugs for immunological or ...A61P 37/06 : Immunosuppressants, e.g. dr...A61P 43/00 : Drugs for specific purposes...A61P 7/02 : Antithrombotic agents; Anti...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...C07D 487/04 : Ortho-condensed systems