4-amino substituted-6-aryl/heteroaryl substituted-2-methylsulfanyl-pyrimidine-5-carbaldehyde intermediates
Novel substituted 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.
1. A compound of the formula
wherein
R 1 is an optionally substituted aryl ring;
R 3 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety, which moieties, excluding hydrogen, are optionally substituted;
m is 0 or an integer having a value of 1 or 2; and
Rg is a C 1-4 alkyl.
2. The compound according to claim 1 wherein R 1 is a phenyl substituted one or more times independently with halogen, C 1-4 alkyl, or halo-substituted-C 1-4 alkyl.
3. The compound according to claim 2 wherein the phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4- position, or tri-substituted in the 2, 4, 6-position.
4. The compound according to claim 1 wherein R 3 is an optionally substituted C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, or aryl.
5. The compound according to claim 4 wherein the R 3 moiety is optional substituted one or more times, independently by C 1-10 alkyl, halo-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkenyl C 1-10 alkyl, halogen, (CR 10 R 20 ) n OR 6 , (CR 10 R 20 ) n SH, (CR 10 R 20 ) n S(O) m R 7 , (CR 10 R 20 ) n NHS(O) 2 R 7 , (CR 10 R 20 ) n NR 4 R 14 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 4 R 14 , (CR 10 R 20 ) n C(Z)R 6 , (CR 10 R 20 ) n OC(Z)R 6 , (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n C(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)R 6 , (CR 10 R 20 ) n NR 10 C(═NR 10 ) NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z) NR 4 R 14 , or (CR 10 R 20 ) n NR 10 C(Z)OR 7 ; and wherein
R 4 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4 alkyl, or R 4 and R 14 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 NR 9 ;
R 6 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl or heteroarylC 1-10 alkyl, wherein each of these moieties may be optionally substituted;
R 7 is a C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted;
R 9 is hydrogen, C(Z)R 6 or optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl;
R 10 and R 20 are independently selected at each occurrence from hydrogen or C 1-4 alkyl;
n is 0 or an integer having a value of 1 to 10;
m is 0 or an integer having a value of 1 or 2;
Z is oxygen or sulfur.
6. The compound according to claim 5 wherein the R 3 moiety is optionally substituted one or more times, independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
7. The compound according to claim 1 which is:
2-Methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde;
4-(2-Chlorophenyl)-6-(1-ethylpropylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2-Chlorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2-Fluorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde; or
4-(2-Fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
8. The compound according to claim 1 which is
4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-Cyclopropylamino-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(Cyclopropylmethylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2,6-Difluorophenylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2-Fluorophenyl)-6-(2-fluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-sec-Butylamino-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(4-Fluoro-2-methylphenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(Cyclopropylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(Cyclopropylmethylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(4-Fluoro-2-methyl-phenyl)-6-(2-fluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-sec-Butylamino-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(2,6-Difluorophenylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
4-(1-Ethylpropylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde; or
2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylamino-pyrimidine-5-carbaldehyde.
9. The compound which is 4-(2,6-Difluorophenylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
10. The compound according to claim 2 wherein the phenyl is substituted one or more times independently with fluoro or methyl.
11. The compound according to claim 1 wherein R 1 is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 6-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.
12. The compound according to claim 11 wherein R 1 is 2-methyl-4-fluorophenyl.
13. The compound according to claim 1 wherein R 1 is optionally substituted one or more times, independently, by halogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, cyano, nitro, (CR 10 R 20 ) v NR 4 R 14 , (CR 10 R 20 ) v C(Z)NR 4 R 14 , (CR 10 R 20 ) v C(Z)OR 8 , (CR 10 R 20 ) v COR a′ , (CR 10 R 20 ) v C(O)H, SR 5 , S(O)R 5 , S(O) 2 R 5 , (CR 10 R 20 ) v OR 8 , ZC(Z)R 11 , NR 10 C(Z)R 11 , or NR 10 S(O) 2 R 7 ; and wherein
R 4 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4 alkyl, or R 4 and R 14 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 NR 9 ;
R 5 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or NR 4 R 14 , excluding the moieties SR 5 being SNR 4 R 14 , S(O) 2 R 5 being SO 2 H and S(O)R 5 being SOH;
R 6 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl or heteroarylC 1-10 alkyl, wherein each of these moieties may be optionally substituted;
R 7 is a C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted;
R 8 is hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7 , or (CR 10 R 20 ) t NR 4 R 14 ; and wherein the cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted;
R 9 is hydrogen, C(Z)R 6 or optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl;
R 10 and R 20 are independently selected at each occurrence from hydrogen or C 1-4 alkyl;
R 11 is C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 ; and wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may be optionally substituted;
v is 0 or an integer having a value of 1 or 2;
t is an integer having a value of 1 to 3; wherein
R a′ is C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclyl C 1-4 alkyl, (CR 10 R 20 ) v OR 7 , (CR 10 R 20 ) v S(O) m R 7 , (CR 10 R 20 ) v NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 ,
wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted; and
Z is oxygen or sulfur.
14. The compound according to claim 11 wherein R 3 is an optionally substituted C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, or aryl.
15. The compound according to claim 14 wherein R 3 is an optionally substituted C 1-10 alkyl, or aryl.
16. The compound according to claim 15 wherein R 3 is a phenyl ring, substituted one or more times independently by halogen, C 1-4 alkyl, or halo-substituted-C 1-4 alkyl.
17. The compound according to claim 16 wherein the phenyl ring is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position.
18. The compound according to claim 17 wherein R 3 is a 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.
19. The compound according to claim 16 wherein R 3 is a 2,6-difluorophenyl.
20. The compound according to claim 1 wherein Rg is methyl.
21. The compound according to claim 19 wherein Rg is methyl.
22. The compound according to claim 1 wherein m is 0.
23. The compound according to claim 21 wherein m is 0.
24. A compound of the formula
wherein
R 1 is an optionally substituted heteroaryl ring;
R 3 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety, which moieties, excluding hydrogen, are optionally substituted;
m is 0 or an integer having a value of 1 or 2; and
Rg is a C 1-4 alkyl.
25. The compound according to claim 24 wherein R 3 is an optionally substituted C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylalkyl, or aryl.
26. The compound according to claim 25 wherein the R 3 moiety is optionally substituted one or more times, independently by C 1-10 alkyl, halo-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkenyl C 1-10 alkyl, halogen, (CR 10 R 20 ) n OR 6 , (CR 10 R 20 ) n SH, (CR 10 R 20 ) n S(O) m R 7 , (CR 10 R 20 ) n NHS(O) 2 R 7 , (CR 10 R 20 ) n NR 4 R 14 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 4 R 14 , (CR 10 R 20 ) n C(Z)R 6 , (CR 10 R 20 ) n OC(Z)R 6 , (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n C(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)R 6 , (CR 10 R 20 ) n NR 10 C(═NR 10 ) NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z) NR 4 R 14 , or (CR 10 R 20 ) n NR 10 C(Z)OR 7 ; and wherein
R 4 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4 alkyl, or R 4 and R 14 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 NR 9 ;
R 6 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl or heteroarylC 1-10 alkyl, wherein each of these moieties may be optionally substituted;
R 7 is a C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted;
R 9 is hydrogen, C(Z)R 6 or optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl;
R 10 and R 20 are independently selected at each occurrence from hydrogen or C 1-4 alkyl;
n is 0 or an integer having a value of 1 to 10;
m is 0 or an integer having a value of 1 or 2;
Z is oxygen or sulfur.
27. The compound according to claim 26 wherein the R 3 moiety is optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
28. The compound according to claim 24 wherein R 3 is a phenyl ring, substituted one or more times independently by halogen, C 1-4 alkyl ,or halo-substituted-C 1-4 alkyl.
29. The compound according to claim 28 wherein the phenyl ring is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position.
30. The compound according to claim 24 wherein R 3 is a 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.
31. The compound according to claim 28 wherein R 3 is a 2,6-difluorophenyl.
32. The compound according to claim 24 wherein Rg is methyl.
33. The compound according to claim 31 wherein Rg is methyl.
34. The compound according to claim 24 wherein m is 0.
35. The compound according to claim 33 wherein mis 0.
36. The compound according to claim 24 wherein R 1 is substituted one or more times, independently, by halogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, cyano, nitro, (CR 10 R 20 ) v NR 4 R 14 , (CR 10 R 20 ) v C(Z)NR 4 R 14 , (CR 10 R 20 ) v C(Z)OR 8 , (CR 10 R 20 ) v COR a′ , (CR 10 R 20 ) v C(O)H, SR 5 , S(O)R 5 , S(O) 2 R 5 , (CR 10 R 20 ) v OR 8 , ZC(Z)R 11 , NR 10 OC(Z)R 11 , or NR 10 S(O) 2 R 7 ; and wherein
R 4 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alyl, optionally substituted aryl, or optionally substituted aryl-C 1-4 alkyl, or R 4 and R 14 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 NR 9 ;
R 5 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or NR 4 R 14 , excluding the moieties SR 5 being SNR 4 R 14 , S(O) 2 R 5 being SO 2 H and S(O)R 5 being SOH;
R 6 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl or heteroarylC 1-10 alkyl, wherein each of these moieties may be optionally substituted;
R 7 is a C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted;
R 8 is hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7 , or (CR 10 R 20 ) t NR 4 R 14 ; and wherein the cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted;
R 9 is hydrogen, C(Z)R 6 or optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl;
R 10 and R 20 are independently selected at each occurrence from hydrogen or C 1-4 alkyl;
R 11 is C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 ; and wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may be optionally substituted;
v is 0 or an integer having a value of 1 or 2;
t is an integer having a value of 1 to 3; wherein
R a′ is C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, heterocyclyl C 1-4 alkyl, (CR 10 R 20 ) v OR 7 , (CR 10 R 20 ) v S(O) m R 7 , (CR 10 R 20 ) v NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 ,
wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted; and
Z is oxygen or sulfur.
37. The compound according to claim 13 wherein R 1 is an optionally substituted phenyl.
38. The compound according to claim 13 wherein R 1 is a phenyl ring, optionally substituted one or more times independently by halogen, C 1-4 alkyl, or halo-substituted-C 1-4 alkyl.
39. The compound according to claim 13 wherein R 1 is a phenyl ring substituted in the 2, 4, or 6-position, or di-substituted in the 2,4-position.
40. The compound according to claim 24 wherein Rg is methyl, m is 0.
41. The compound according to claim 40 wherein R 3 is an optionally substituted aryl.