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Abstract
Novel substituted 2,4,8-trisubstituted 8H-pyrido[2,3-d]pyrimidin-7-one containing compounds and compositions, and their use use in therapy as CSBP/RK/p38 kinase inhibitors.
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Citations
76 Claims
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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)
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2. The compound according to claim 1 which is Formula (I), or a pharmaceutically acceptable salt thereof.
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3. The compound according to claim 1 which is Formula (Ia), or a pharmaceutically acceptable salt thereof.
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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 5 wherein Rb is selected from an optionally substituted C1-10 alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted aryl C1-10 alkyl, optionally substituted C3-7cycloalkyl 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, optionally substituted C3-7cycloalkyl or an optionally substituted aryl.
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8. The compound according to claim 7 wherein Rb is propyl, cyclopropyl, isopropyl, thiazolyl, phenyl, or 4-fluoro-phenyl.
-
9. The compound according to claim 8 wherein v is 0;
- Rb is thiazolyl;
Z is oxygen, and R10′
is hydrogen.
- Rb is thiazolyl;
-
10. The compound according to claim 1 wherein R1′
- is independently selected at each occurrence from halogen, C1-4 alkyl, or halo-substituted-C1-4 alkyl.
-
11. The compound according to claim 10 wherein R1′
- is independently selected at each occurrence from fluorine, methyl, or CF3.
-
12. The compound according to claim 1 wherein X is S(O)mR2.
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13. The compound according to claim 1 wherein X is (CH2)n′
- NR4R14, or (CH2)nN(R2′
)(R2″
).
- NR4R14, or (CH2)nN(R2′
-
14. The compound according to claim 13 wherein the R4 and R14 moieties, are optionally substituted, 1 to 4 times, independently at each occurrence, by halogen;
- hydroxy;
hydroxy substituted C1-10alkyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
C1-10 alkyl;
halosubstituted C1-4 alkyl;
SR5;
S(O)R5;
S(O)2R5;
C(O)Rj;
C(O)ORj;
C(O)NR4′
R14′
;
NR4′
C(O)C1-10alkyl;
NR4′
C(O)aryl;
NR4′
R14′
;
cyano;
nitro;
C1-10 alkyl;
C3-7cycloalkyl;
C3-7cycloalkyl C1-10 alkyl;
halosubstituted C1-10 alkyl;
an unsubstituted or substituted aryl, or arylC1-4 alkyl;
an unsubstituted or substituted heteroaryl or hetero C1-4 alkyl;
an unsubstituted or substituted heterocyclic or heterocyclic C1-4 alkyl, and wherein these aryl, heteroaryl or heterocyclic containing moieties are substituted one to two times independently at each occurrence by halogen;
C1-4 alkyl, hydroxy;
hydroxy substituted C1-4 alkyl;
C1-4 alkoxy;
S(O)malkyl;
amino, mono &
di-substituted C1-4 alkyl amino, or CF3; and
whereinRj 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.
- hydroxy;
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15. The compound according to claim 14 wherein 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.
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16. The compound according to claim 15 wherein the C1-10 alkyl is substituted one or more times, independently at each occurrence with NR4′
- R14, halogen, hydroxy, alkoxy, C(O)NR4′
R14′
or NR4C(O)C1-10alkyl.
- R14, halogen, hydroxy, alkoxy, C(O)NR4′
-
17. The compound according to claim 14 wherein X is (CH2)n′
- NR4R14;
one of R4 and R14 is an optionally substituted heteroaryl C1-4 alkyl, and the heteroaryl moiety is selected from thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.
- NR4R14;
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18. The compound according to claim 17 wherein the heteroaryl C1-4 alkyl moiety is imidazolyl methyl;
- the other of R4 and R14 is hydrogen; and
n′
is 0.
- the other of R4 and R14 is hydrogen; and
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19. The compound according to claim 14 wherein X is (CH2)n′
- NR4R14 and one of R4 and R14 is an optionally substituted heterocyclic or heterocyclic C1-4 alkyl moiety selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholino, tetrahydropyrrole C1-4 alkyl, tetrahydropyran C1-4 alkyl, tetrahydrofuran C1-4 alkyl, pyrrolinyl C1-4 alkyl, pyrrolidinyl C1-4 alkyl, imidazolinyl C1-4 alkyl, imidazolidinyl C1-4 alkyl, indolinyl C1-4 alkyl, pyrazolinyl C1-4 alkyl, pyrazolidinyl C1-4 alkyl, piperidinyl C1-4 alkyl, piperazinyl C1-4 alkyl, and morpholino C1-4 alkyl.
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20. The compound according to claim 19 wherein the optionally substituted heterocyclic or heterocyclic C1-4 alkyl moiety is selected from pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolinyl C1-4 alkyl, pyrrolidinyl C1-4 alkyl, piperidinyl C1-4 alkyl, piperazinyl C1-4 alkyl, and morpholino C1-4 alkyl.
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21. The compound according to claim 14 wherein X is (CH2)n′
- NR4R14 and R4 and R14 together with the nitrogen cyclize to form an optionally substituted ring selected from pyrrolidine, piperidine, piperazine, and morpholine.
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22. The compound according to claim 14 wherein X is 1,4′
- -bipiperin-1′
yl or 4-methyl-1,4′
-bipiperin-1′
yl.
- -bipiperin-1′
-
23. The compound according to claim 1 wherein the R2′
- moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, by 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, (CR10R20)nR6, (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; andwherein 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, heteroaryl or a heteroaryl C1-4 alkyl moiety, which moieties, excluding hydrogen may be optionally substituted;
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 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 independently selected at each occurrence from 0 or an integer having a value of 1 to 10.
- moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, by 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, —
-
24. The compound according to claim 23 wherein X is (CH2)n′
- N(R2′
)(R2″
);
R2 is an optionally substituted C1-10 alkyl moiety, and the alkyl is substituted by (CR10R20)nNReRe′
or (CR10R20)nNReRe′
C1-4alkyl NReRe′
.
- N(R2′
-
25. The compound according to claim 24 wherein Re are Re′
- are independently selected at each occurrence from hydrogen, or C1-4 alkyl.
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26. The compound according to claim 13 wherein X moiety is 3-(diethylamino)propylamino, 3-(dimethylamino)propyl(methyl)amino, 3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino, 1-methylethyl)aminopropylamino, (1,1-dimethylethyl)aminopropylamino, (1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino, 2-aminoethyl(methyl)amino, or a 2-(dimethylamino)ethyl(methyl)amino.
-
27. 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, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
)S(O)2R7, (CR10R20)nNReRe′
, (CR10R20)nNReRe′
C1-4alkyl NReRe′
, (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
whereinRe 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, heteroaryl or a heteroaryl C1-4 alkyl moiety, which moieties, excluding hydrogen may be optionally substituted;
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 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 independently selected at each occurrence from 0 or an integer having a value of 1 to 10.
- C(O), cyano, nitro, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
-
28. The compound according to claim 27 wherein R2 is a C1-10 alkyl optionally substituted by (CR10R20)nC(Z)OR6, (CR10R20)nOR6, or (CR10R20)nNR4R14.
-
29. The compound according to claim 1 wherein R2 is the (CR10R20)q′
- X1(CR10R20)qC(A1)(A2)(A3), or (CR10R20)q′
C(A1)(A2)(A3).
- X1(CR10R20)qC(A1)(A2)(A3), or (CR10R20)q′
-
30. The compound according to claim 29 wherein X1 is oxygen or N(R10).
-
31. The compound according to claim 29 wherein R2 is (CR10R20)q′
- X1(CR10R20)qC(A1)(A2)(A3), at least one of A1, A2 or A3 is substituted by (CR10R20)nOR6, q is 1 or 2, and q′
is 0.
- X1(CR10R20)qC(A1)(A2)(A3), at least one of A1, A2 or A3 is substituted by (CR10R20)nOR6, q is 1 or 2, and q′
-
32. The compound according to claim 1 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
-
33. The compound according to claim 32 wherein R3 is optionally substituted one or more times, independently at each occurrence, with wherein these moieties are all optionally substituted one or more times, independently at each occurrence, by hydrogen, halogen, nitro, C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-10alkyl, 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, (CR10R20)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′
,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.
- )S(O)2R7, (CR10R20)nNR16R26, (CR10R20)nCN, (CR10R20)nS(O)2NR16R26, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR16R26, (CR10R20)nN(R10′
-
34. The compound according to claim 33 wherein the R3 optional substituent is independently selected at each occurrence from halogen, C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nNR16R26, or halo-substituted C1-10 alkyl.
-
35. The compound according to claim 33 wherein R3 is a phenyl substituted one or more times independently at each occurrence by fluorine, chlorine, hydroxy, methoxy, amino, methyl, or trifluoromethyl.
-
36. The compound according to claim 1 wherein R3 is a 2,6-difluorophenyl.
-
37. The compound according to claim 1 wherein R3 is an aryl ring substituted 1 to 4 times, independently at each occurrence by halogen, C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nNR16R26, or halo-substituted C1-10 alkyl;
- R1′
is independently selected at each occurrence from halogen, C1-4 alkyl, or halo-substituted-C1-4 alkyl;
g is 0, or 1;
R1 is C(Z)N(R10′
)(CR10R20)vRb ;
v is 0;
Rb is thiazolyl;
Z is oxygen, R10′
is hydrogen;
X is (CH2)n′
NR4R14;
one of R4 and R14 is an optionally substituted heteroaryl C1-4 alkyl, and the other of R4 and R14 is hydrogen.
- R1′
-
38. The compound according to claim 1 which is:
-
N-(cyclopropylmethyl)-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino }-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; N-(cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide; N-(cyclopropylmethyl)-3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylbenzamide; N-(cyclopropylmethyl)-3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylbenzamide; N-(cyclopropylmethyl)-3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylbenzamide; 3-[2-[(2-aminoethyl)(methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide; N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide; N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylphenyl)-2-thiophenecarboxamide; N-(3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylphenyl)-2-thiophenecarboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-2-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide; N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide; 6-chloro-N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide; N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-6-chloro-3-pyridinecarboxamide; 6-chloro-N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylphenyl)-3-pyridinecarboxamide; 6-chloro-N-(3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylphenyl)-3-pyridinecarboxamide; N-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(2-phenylethyl)benzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(1-methylpropyl)benzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-cyclopropyl-4-methylbenzamide; N-cyclopropyl-3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylbenzamide; N-cyclopropyl-3-(8-(2,6-difluorophenyl)-7-oxo-2-{[2-(propylamino)ethyl]amino}-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(1-methylpropyl)benzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-4-methylbenzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(2-phenylethyl)benzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(2-phenylethyl)benzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(2-phenylethyl)benzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylphenyl)-3-thiophenecarboxamide; N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide; 3-[2-[(2-aminoethyl)(methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3-thiophenecarboxamide; N-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3-isoquinolinecarboxamide; 6-chloro-N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3-pyridinecarboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-2-hydroxy-1-naphthalenecarboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-4-fluoro-1-naphthalenecarboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-5-methyl-2-pyrazinecarboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-1H-indole-5-carboxamide; 3-amino-N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]benzamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-1H-indole-7-carboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-2-(3-methylphenyl)acetamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3,4-dimethylbenzamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3-fluoro-4-methylbenzamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3,5-dihydroxy-4-methylbenzamide; 2-(2,3-difluorophenyl)-N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]acetamide; 2-(3,5-difluorophenyl)-N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]acetamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-1-methyl-1H-imidazole-4-carboxamide; 4-[(3-{[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]amino}-3-oxopropyl)amino]-4-oxobutanoic acid; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-1H-pyrazole-3-carboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-2-thiophenecarboxamide; N-[3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-2-[(2,2,2-trifluoroethyl)oxy]acetamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide; N-cyclopentyl-3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-propylbenzamide; N-cyclopentyl-3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-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]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-cyclopentyl-4-methylbenzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-propylbenzamide; N-cyclopentyl-3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino-]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide; 3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide; N-cyclobutyl-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; N-cyclopentyl-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide; N-cyclopropyl-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; N-(cyclopropylmethyl)-3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylbenzamide; 8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-4-[2-methyl-5-(4-morpholinylcarbonyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-N-heptyl-4-methylbenzamide; N-(cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(3-pyridinylmethyl)benzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(3-phenylpropyl)benzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(2-phenylethyl)benzamide; 3-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide;
ora pharmaceutically acceptable salt thereof.
-
-
39. The compound according to claim 1 which is:
-
N-(cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide; N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide; 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide; 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide; 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide; N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide; N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide; 3-[8-(2,6-Difluoro-phenyl)-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propyl-benzamide; 3-[8-(2,6-Difluoro-phenyl)-2-methanesulfonyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propyl-benzamide; 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide;
ora pharmaceutically acceptable salt thereof.
-
-
40. A compound according to claim 1 as defined in any one of the Examples according to Formula (I) or (Ia).
-
41. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof according to claim 1, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
-
2. The compound according to claim 1 which is Formula (I), or a pharmaceutically acceptable salt thereof.
-
42. A compound of the formula:
- View Dependent Claims (43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)
-
43. The compound according to claim 42 which is Formula (I), or a pharmaceutically acceptable salt thereof.
-
44. The compound according to claim 42 which is Formula (Ia), or a pharmaceutically acceptable salt thereof.
-
45. The compound according to claim 42 wherein Rb is an optionally substituted heteroaryl, or an optionally substituted heteroaryl C1-10 alkyl.
-
46. The compound according to claim 45 wherein the Rb is an optionally substituted pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, pyrrolyl C1-4alkyl, oxazolylC1-4alkyl, thiazolylC1-4alkyl, isoxazolyl C1-4alkyl, isothiazolyl C1-4alkyl, imidazolyl C1-4alkyl, pyrazolyl C1-4alkyl, triazolyl C1-4alkyl, pyridazinyl C1-4alkyl, pyrimidinyl C1-4alkyl, pyrazinyl C1-4alkyl, benzoxazolyl C1-4alkyl, benzimidazolyl C1-4alkyl, or benzothiazolyl C1-4alkyl.
-
47. The compound according to claim 42 wherein Rb is an optionally substituted thiazolyl, v is zero, Z is oxygen, and R10′
- is hydrogen.
-
48. The compound according to claim 42 wherein R1′
- is independently selected, at each occurrence from halogen, C1-4 alkyl, or halo-substituted-C1-4 alkyl.
-
49. The compound according to claim 48 wherein R1′
- is independently selected at each occurrence from fluorine, methyl, or CF3.
-
50. The compound according to claim 42 wherein X is S(O)mR2.
-
51. The compound according to claim 42 wherein X is (CH2)nNR4R14, or (CH2)nN(R2′
- )(R2″
).
- )(R2″
-
52. The compound according to claim 51 wherein the R4 and R14 moieties, are optionally substituted, 1 to 4 times, independently at each occurrence, by halogen;
- hydroxy;
hydroxy substituted C1-10alkyl;
C1-10 alkoxy;
halosubstituted C1-10 alkoxy;
C1-10 alkyl;
halosubstituted C1-4 alkyl;
SR5;
S(O)R5;
S(O)2R5;
C(O)Rj;
C(O)ORj;
C(O)NR4′
R14′
;
NR4′
C(O)C1-10alkyl;
NR4′
C(O)aryl;
NR4′
R14′
;
cyano;
nitro;
C1-10 alkyl;
C3-7cycloalkyl;
C3-7cycloalkyl C1-10 alkyl;
halosubstituted C1-10 alkyl;
an unsubstituted or substituted aryl, or arylC1-4 alkyl;
an unsubstituted or substituted heteroaryl or hetero C1-4 alkyl;
an unsubstituted or substituted heterocyclic or heterocyclic C1-4 alkyl, and wherein these aryl, heteroaryl or heterocyclic containing moieties are substituted one to two times independently at each occurrence by halogen;
C1-4 alkyl, hydroxy;
hydroxy substituted C1-4 alkyl;
C1-4 alkoxy;
S(O)malkyl;
amino, mono &
di-substituted C1-4 alkyl amino, or CF3; and
whereinRj 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.
- hydroxy;
-
53. The compound according to claim 52 wherein 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.
-
54. The compound according to claim 53 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′
-
55. The compound according to claim 51 wherein X is (CH2)n′
- NR4R14;
one of R4 and R14 is an optionally substituted heteroaryl C1-4 alkyl, and the heteroaryl moiety is selected from thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.
- NR4R14;
-
56. The compound according to claim 55 wherein the heteroaryl C1-4 alkyl moiety is imidazolyl methyl;
- the other of R4 and R14 is hydrogen; and
n is 0.
- the other of R4 and R14 is hydrogen; and
-
57. The compound according to claim 51 wherein X is (CH2)nNR4R14 and one of R4 and R14 is an optionally substituted heterocyclic or heterocyclic C1-4 alkyl moiety selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholino, tetrahydropyrrole C1-4 alkyl, tetrahydropyran C1-4 alkyl, tetrahydrofuran C1-4 alkyl, pyrrolinyl C1-4 alkyl, pyrrolidinyl C1-4 alkyl, imidazolinyl C1-4 alkyl, imidazolidinyl C1-4 alkyl, indolinyl C1-4 alkyl, pyrazolinyl C1-4 alkyl, pyrazolidinyl C1-4 alkyl, piperidinyl C1-4 alkyl, piperazinyl C1-4 alkyl, and morpholino C1-4 alkyl.
-
58. The compound according to claim 57 wherein the optionally substituted heterocyclic or heterocyclic C1-4 alkyl moiety is selected from pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolinyl C1-4 alkyl, pyrrolidinyl C1-4 alkyl, piperidinyl C1-4 alkyl, piperazinyl C1-4 alkyl, and morpholino C1-4 alkyl.
-
59. The compound according to claim 51 wherein X is (CH2)n′
- NR4R14 and R4 and R14 together with the nitrogen cyclize to form an optionally substituted ring selected from pyrrolidine, piperidine, piperazine, and morpholine.
-
60. The compound according to claim 42 wherein X is 1,4′
- -bipiperin-1′
yl or 4-methyl-1,4′
-bipiperin-1′
yl.
- -bipiperin-1′
-
61. The compound according to claim 51 wherein X is (CH2)nN(R2′
- )(R2″
);
R2′
is an optionally substituted C1-10 alkyl moiety, and the alkyl is substituted by (CR10R20)nNReRe′
or (CR10R20)nNReRe′
C1-4alkyl NReRe′
.
- )(R2″
-
62. The compound according to claim 61 wherein Re and Re′
- are independently selected at each occurrence from hydrogen, or an optionally substituted C1-4 alkyl.
-
63. The compound according to claim 42 wherein X is 3-(diethylamino)propylamino, 3-(dimethylamino)propyl(methyl)amino, 3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino, 1-methylethyl)aminopropylamino, (1,1-dimethylethyl)aminopropylamino, (1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino, 2-aminoethyl(methyl)amino, or a 2-(dimethylamino)ethyl(methyl)amino.
-
64. The compound according to claim 42 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, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
)S(O)2R7, (CR10R20)nNReRe′
, (CR10R20)nNReRe′
C1-4alkyl NReRe′
, (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
whereinRe are Re′
are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4alkyl, aryl, arylC1-4 alkyl, heteroaryl or a heteroaryl C1-4 alkyl moiety, which moieties, excluding hydrogen may be optionally substituted;
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 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 independently selected at each occurrence from 0 or an integer having a value of 1 to 10.
- C(O), cyano, nitro, (CR10R20)nOR6, (CR10R20)nSH, (CR10R20)nS(O)mR7, (CR10R20)nN(R10′
-
65. The compound according to claim 64 wherein R2 is a C1-10 alkyl optionally substituted by (CR10R20)nC(Z)OR6, (CR10R20)nOR6, or (CR10R20)nNR4R14.
-
66. The compound according to claim 42 wherein R3 is an optionally substituted C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylalkyl, or aryl.
-
67. The compound according to claim 66 wherein R3 is optionally substituted one or more times, independently at each occurrence, with wherein these moieties are all optionally substituted one or more times, independently at each occurrence, by hydrogen, halogen, nitro, C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-7cycloalkyl, 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, (CR10R20)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 independently selected at each occurrence from 0 or an integer having a value of 1 to 10.
- )S(O)2R7, (CR10R20)nNR16R26, (CR10R20)nCN, (CR10R20)nS(O)2NR16R26, (CR10R20)nC(Z)R6, (CR10R20)nOC(Z)R6, (CR10R20)nC(Z)OR6, (CR10R20)nC(Z)NR16R26, (CR10R20)nN(R10′
-
68. The compound according to claim 67 wherein the optional substituent is independently selected from halogen, C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nNR16R26, or halo-substituted C1-10 alkyl.
-
69. The compound according to claim 42 wherein R3 is a phenyl ring substituted one or more times by independently at each occurrence by fluorine, chlorine, hydroxy, methoxy, amino, methyl, or trifluoromethyl.
-
70. The compound according to claim 69 wherein R3 is a phenyl ring substituted one or more times by fluorine or methyl.
-
71. The compound according to claim 70 wherein R3 is a 2,6-difluorophenyl.
-
72. The compound according to claim 42 wherein R3 is an aryl ring substituted 1 to 4 times, independently at each occurrence by halogen, C1-10 alkyl, (CR10R20)nOR6, (CR10R20)nNR16R26, or halo-substituted C1-10 alkyl;
- R1′
is independently selected at each occurrence from halogen, C1-4 alkyl, or halo-substituted-C1-4 alkyl;
g is 0, 1 or 2;
v is 0;
Rb is thiazolyl;
Z is oxygen, and R10′
is hydrogen.
- R1′
-
73. The compound according to claim 42 which is:
-
3-(8-(2,6-Difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-{8-(2,6-Difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[8-(2,6-Difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]-pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-(8-(2,6-Difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[8-(2,6-Difluorophenyl)-2-({3[-(1-methylethyl)amino]propyl}amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[8-(2,6-Difluorophenyl)-2-({3[-(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[8-(2,6-Difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-{8-(2,6-Difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-(8-(2,6-Difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-[(5-methyl-2-furanyl)methyl]benzamide; 3-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(2-thienyl-methyl)benzamide 3-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-[2-(1H-imidazol-4-yl)ethyl]-4-methylbenzamide; 3-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methyl-N-1,3-thiazol-2-ylbenzamide; 3-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methyl-N-1,3-thiazol-2-ylbenzamide; 4-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-1,3-thiazol-2-ylbenzamide; 3-[2-{[3-(Diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-1,3-thiazol-2-ylbenzamide;
ora pharmaceutically acceptable salt thereof.
-
-
74. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof according to claim 42, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
-
43. The compound according to claim 42 which is Formula (I), or a pharmaceutically acceptable salt thereof.
-
75. A compound of the formula:
- View Dependent Claims (76)
-
76. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof according to claim 75, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
-
76. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof according to claim 75, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
Specification
- Resources
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-
Current AssigneeGlaxo Group Limited (GSK plc)
-
Original AssigneeGlaxo Group Limited (GSK plc)
-
InventorsNorton, Beth A., Nevins, Neysa, Livia, Stefano, Boehm, Jeffrey C., Wan, Zehong, Lin, Xichen, Cooper, Anthony William James, Bamborough, Paul, Callahan, James F.
-
Primary Examiner(s)Berch; Mark L.
-
Assistant Examiner(s)Jaisle; Cecilia M
-
Application NumberUS11/388,968Publication NumberTime in Patent Office1,453 DaysField of Search514/324.2, 514/264.1, 514/264.11, 514/234.2, 544/117, 544/279US Class Current514/264.1CPC 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 11/02 Nasal agents, e.g. deconges...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 17/16 Emollients or protectives, ...A61P 19/00 Drugs for skeletal disordersA61P 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 27/00 Drugs for disorders of the ...A61P 27/02 Ophthalmic agentsA61P 27/16 OtologicalsA61P 29/00 : Non-central analgesic, anti...A61P 3/00 : Drugs for disorders of the ...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/00 : Antiinfectives, i.e. antibi...A61P 31/04 : Antibacterial agentsA61P 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