Substituted pyrrolo-aminopyrimidine compounds
The present invention relates to substituted pyrrolo-aminopyrimidine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted pyrrolo-aminopyrimidine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof. The substituted pyrrolo-aminopyrimidine compounds have the following general formula:
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is CH or N;
R 1 is H or unsubstituted or substituted C 1 -C 6 alkyl;
R a1 and R a2 are each independently H, —NHR 2 , —(CH 2 ) m YR 2 , —C(O)YR 2 , —NHC(O)R 2 , halogen, —NHC(O)NHR 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or
when adjacent, R a1 and R a2 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8 carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S;
R 2 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 1 -C 6 alkoxycarbonyl, unsubstituted or substituted aminocarbonyl, unsubstituted or substituted C 1 -C 6 alkylcarbonylamino, unsubstituted or substituted di-C 1 -C 6 -alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 2 and Z, together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted;
Y is NH, NZ or O, provided that when Y is NZ, then Z and R 2 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted;
m is 0, 1, 2 or 3;
R b1 , R b2 , R b3 , R b4 and R b5 are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or
any two adjacent of R b1 , R b2 , R b3 , R b4 and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8 carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S;
R 3 is H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; and
p is 0, 1, 2, 3 or 4.
2. The compound of claim 1 , wherein X is CH and R 1 is H.
3. The compound of claim 2 , wherein R a1 is —NHC(O)R 2 .
4. The compound of claim 2 , wherein R a1 is —C(O)YR 2 .
5. A compound of Formula II, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is H or unsubstituted or substituted C 1 -C 6 alkyl;
T is unsubstituted or substituted C 1 -C 6 alkyl linker or a bond;
Q is H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 5 , NR 5 R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 5 , NHC(O)NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6 or NHS(O) 2 R 5 ;
R b1 , R b2 , R b3 , R b4 and R b5 are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or
any two adjacent of R b1 , R b2 , R b3 , R b4 and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8 carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S;
R 3 , R 5 and R 6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; and
p is 0, 1, 2, 3 or 4.
6. The compound of claim 5 , wherein R 1 is H.
7. The compound of claim 6 , wherein Q is unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.
8. The compound of claim 6 , wherein Q is unsubstituted or substituted C 1 -C 6 alkyl.
9. A compound of Formula III, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is H or unsubstituted or substituted C 1 -C 6 alkyl;
T is unsubstituted or substituted C 1 -C 6 alkyl linker or a bond;
Q is H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 5 , NR 5 R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 5 , NHC(O)NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6 or NHS(O) 2 R 5 ;
R b1 , R b2 , R b3 , R b4 and R b5 are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or
any two adjacent of R b1 , R b2 , R b3 , R b4 and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8 carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S;
R 3 , R 5 and R 6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; and
p is 0, 1, 2, 3 or 4.
10. The compound of claim 9 , wherein R 1 is H.
11. The compound of claim 10 , wherein Q is unsubstituted or substituted phenyl.
12. The compound of claim 10 , wherein Q is unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.
13. A compound of Formula IV, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is H or unsubstituted or substituted C 1 -C 6 alkyl;
T is unsubstituted or substituted C 1 -C 6 alkyl linker or a bond;
Q is H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, OR 5 , NR 5 R 6 , NR 6 C(O)R 5 , NR 6 C(O)OR 5 , NHC(O)NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6 or NHS(O) 2 R 5 ;
R b1 , R b2 , R b3 , R b4 and R b5 are each independently H, halogen, cyano, nitro, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, —(CH 2 ) p OR 3 , or
any two adjacent of R b1 , R b2 , R b3 , R b4 and R b5 , together with the carbon atoms to which they are attached, form an unsubstituted or substituted aryl comprising one or two 5- or 6-member rings, an unsubstituted or substituted C 3 -C 8 carbocycle, an unsubstituted or substituted heteroaryl comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S, or an unsubstituted or substituted heterocycle comprising one or two 5- to 6-member rings which comprises 1-4 heteroatoms selected from N, O and S;
R 3 , R 5 and R 6 are each independently H, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, or R 5 and R 6 , together with the nitrogen atom to which they are attached, form a 5- or 6-member ring which optionally comprises 1-3 additional heteroatoms selected from N, O and S and is optionally substituted; and
p is 0, 1, 2, 3 or 4.
14. The compound of claim 13 , wherein R 1 is H.
15. The compound of claim 14 , wherein Q is unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.
16. The compound of claim 14 , wherein Q is unsubstituted or substituted di-C 1 -C 6 -alkylamino.
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.
21. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of claim 21 and a pharmaceutically acceptable carrier.
23. A compound:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable carrier.