Tetrasubstituted pyrimidine compounds as chemical intermediates
Novel substituted pyrimido[4,5-d]pyrimidin-2-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.
1. A compound of the formula:
wherein
X 1 is a C 1-10 alkyl, aryl or heteroaryl moiety;
R 1 is an optionally substituted aryl or -an optionally substituted heteroaryl ring;
R 3 is a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic, or a heterocyclylC 1-10 alkyl moiety; and wherein each of these moieties are optionally substituted; and
Y is a bond.
2. The compound according to claim 1 wherein X 1 is methyl.
3. The compound according to claim 1 wherein R 1 and R 3 are each an optionally substituted aryl ring.
4. The compound according to claim 3 wherein R 1 and R 3 are each an optionally substituted phenyl ring.
5. The compound according to any claim 1 wherein the R 3 moiety is optionally substituted one or more times independently with 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 , wherein
R 7 is C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or a heteroarylC 1-6 alkyl moiety; and wherein each of these moieties may be optionally substituted;
R 4 and R 14 are each independently selected from hydrogen, optionally substituted C 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 a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 , and which ring is optionally substituted;
Z is oxygen or sulfur;
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; and wherein each of these moieties, excluding hydrogen, may be optionally substituted;
R 9 is hydrogen, C(Z)R 6 , optionally substituted C 1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl;
n is 0 or an integer having a value of 1 to 10; and
R 10 and R 20 are each independently selected from hydrogen or C 1-4 alkyl.
6. The compound according to claim 5 wherein R 3 is an optionally substituted phenyl ring.
7. The compound according to claim 6 wherein R 3 is substituted one or more times, independently with halogen.
8. The compound according to claim 1 wherein R 3 is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.
9. The compound according to claim 1 wherein R 1 is an aryl optionally substituted one to four times, independently, 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 CORa, (CR 10 R 20 ) v C(O)H, S(O)mR 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
Ra 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, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclyl, heterocyclylC 1-4 alkyl, (CR 10 R 20 ) v OR 7 , (CR 10 R 20 ) v S(O)mR 7 , (CR 10 R 20 ) v NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 , and wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl moieties are optionally substituted;
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 (wherein m is 0) being SNR 4 R 14 , S(O) 2 R 5 being SO 2 H (wherein m is 2) and S(O)R 5 being SOH, (wherein m is 1);
R 7 is C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6 alkyl, heteroaryl, or a heteroarylC 1-6 alkyl moiety; 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 alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, and heteroaryl alkyl moieties, may be optionally substituted;
R 10 and R 20 are each independently selected 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 alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted;
t is an integer having a value of 1 to 3; and
v is 0 or an integer having a value of 1 or 2.
10. The compound according to claim 9 wherein R 1 is an optionally substituted phenyl ring.
11. The compound according to claim 10 wherein X 1 is methyl.
12. The compound according to claim 11 wherein R 3 is an optionally substituted phenyl ring.
13. The compound according to claim 4 wherein X 1 is methyl.
14. The compound according to claim 1 wherein R 1 is a phenyl ring substituted by halogen or alkyl.
15. The compound according to claim 1 wherein R 3 is 2,6-difluorophenyl.
16. The compound according to claim 1 which is:
(5-Aminomethyl-2-methylsulfanyl-6-phenyl-pyrimidin-4-yl)-phenylamine; or
5-Aminomethyl-6-(4-fluoro-2-methylphenyl)-2-methylsulfanylpyrimidin-4-yl-(2,6-difluorophenyl)amine.