Substituted tricyclic pyrazolo-pyrimidine compounds
The present invention relates to substituted tricyclic pyrazolo-pyrimidine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted tricyclic pyrazolo-pyrimidine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.
1. A compound of formula A or A′:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
W, when linked to the ring structure with a double bond, is O, and when linked to the ring structure with a single bond, is hydrogen, unsubstituted C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more groups, each of which is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl]CO[(C 1 -C 6 )alkyl], NHCO(C 1 -C 6 )alkyl, CON[(C 1 -C 6 )alkyl] 2 , CONH(C 1 -C 6 )alkyl, and CN;
X, when linked to the ring structure with a double bond, is O, and when linked to the ring structure with a single bond, is hydrogen, unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, OR X1 , or NR X2 R X3 , wherein said alkyl is optionally substituted with one or more groups, each of which is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, and OCF 3 ;
R X1 , R X2 , and R X3 are each independently selected from hydrogen, unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, unsubstituted C 6 -C 10 aryl, and substituted C 6 -C 10 aryl, wherein said alkyl or aryl is optionally substituted with one or more R X4 ;
each R X4 is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, OCF 3 , C 1 -C 6 alkoxy, and unsubstituted C 1 -C 6 alkyl;
Y and Z are each independently selected from N and NR N2 ;
R N2 is selected from hydrogen and unsubstituted C 1 -C 6 alkyl;
R 1 and R 2 are each independently selected from hydrogen, unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, and (CH 2 ) 0-3 -T 1 , wherein said alkyl or alkenyl is optionally substituted with one or more R 4 ;
or R 1 and R 2 , taken together with the nitrogen atom to which they are attached form an unsubstituted heterocycle comprising one, two, or three 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, or substituted heterocycle comprising one, two, or three 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said heterocycle is optionally substituted with one or more R 6 ;
T 1 is selected from unsubstituted C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted C 6 -C 10 aryl, substituted C 6 -C 10 aryl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, and substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more R 4 ;
R 3 is selected from unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, unsubstituted C 6 -C 15 aryl, substituted C 6 -C 15 aryl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, and substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with one or more R 9 ;
each R 4 is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, OCF 3 , CF 3 , CH 2 F, CHF 2 , COOH, SO 2 NH 2 , C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, unsubstituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, unsubstituted C 6 -C 10 aryl, substituted C 6 -C 10 aryl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, and substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with one or more R 5 ;
each R 5 is independently selected from halogen, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, and unsubstituted C 6 -C 10 aryl;
each R 6 is independently selected from unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, unsubstituted C 6 -C 10 aryl, substituted C 6 -C 10 aryl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, and substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl, aryl, and heteroaryl is optionally substituted with one or more R 7 ;
each R 7 is independently selected from unsubstituted C 6 -C 10 aryl and substituted C 6 -C 10 aryl, wherein said aryl is optionally substituted with one or more R 8 ;
each R 8 is independently selected from halogen, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, CF 3 , CH 2 F, CHF 2 , COOH, SO 2 NH 2 , C 1 -C 6 alkoxy, unsubstituted C 1 -C 6 alkyl, and unsubstituted C 2 -C 6 alkenyl;
each R 9 is independently selected from unsubstituted C 6 -C 10 aryl, substituted C 6 -C 10 aryl, halogen, OH, NO 2 , COOH, NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, OCF 3 , CF 3 , CH 2 F, CHF 2 , CN, unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, unsubstituted C 3 -C 10 cycloalkyl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, and S(C 1 -C 6 ) alkyl, wherein said alkyl or aryl is optionally substituted with one or more R 10 ;
each R 10 is independently selected from halogen, OH, NO 2 , COOH, CF 3 , OCF 3 , CH 2 F, CHF 2 , C 1 -C 6 alkoxy, unsubstituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, S(C 1 -C 6 alkyl), unsubstituted C 6 -C 10 aryl, CN, NH 2 , NH(C 1 -C 6 alkyl), N[(C 1 -C 6 alkyl*, NHC(O)O-Q-T, and NHC(O)-Q-T;
Q is (CH 2 ) 0-6 ;
T is selected from halogen, OH, NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, NHC(O)(C 1 -C 6 )alkyl, unsubstituted C 6 -C 10 aryl, substituted C 6 -C 10 aryl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, unsubstituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, and substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein said aryl, cycloalkyl, heteroaryl, or heterocycle is optionally substituted with one or more R 12 ;
each R 12 is independently selected from halogen, OH, NO 2 , unsubstituted C 1 -C 6 alkyl, CF 3 , unsubstituted C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, CN, NH 2 , NH(C 1 -C 6 alkyl), and N[(C 1 -C 6 alkyl)] 2 ; and
R S is hydrogen or unsubstituted or substituted C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein the compound is of formula A, or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof.
3. The compound of claim 2 , wherein the compound is of formula A1a or A1b:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
R N1 is selected from hydrogen and unsubstituted C 1 -C 6 alkyl; and
X′ is selected from hydrogen, unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, OR X1 , or NR X2 R X3 , wherein said alkyl is optionally substituted with one or more groups, each of which is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, and OCF 3 .
4. The compound of claim 3 , wherein X′ is hydrogen, unsubstituted C 1 -C 6 alkyl, or NR X2 R X3 .
5. The compound of claim 4 , wherein R X2 and R X3 are each independently selected from hydrogen and unsubstituted C 1 -C 6 alkyl.
6. The compound of claim 3 , wherein R 3 is unsubstituted or substituted C 6 -C 15 aryl.
7. A compound of formula Xa or Xat:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
na is selected from 0, 1, 2, 3, 4, and 5;
R a is selected from halogen, OH, nitro, NH 2 , NH[(C 1 -C 6 )alkyl], N[(C 1 -C 6 )alkyl] 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 6 -C 10 aryloxy, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, NHC(O)R t , NHC(O)OR t , and NHC(O)NHR t ;
R t is selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 6 -C 10 aryloxy, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;
R 98 and R 99 are each independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, and (CH 2 ) 0-3 -T 1 , or R 98 and R 99 , together with the nitrogen atom to which they are attached, form an unsubstituted or substituted heterocycle comprising one, two, or three 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S; and
T 1 is selected from unsubstituted or substituted C 6 -C 15 aryl comprising one, two or three 5- or 6-membered rings, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S.
8. The compound of claim 3 , wherein the compound is of formula La or Lb:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
R r1 and R r2 are each independently selected from O and NR 13 ;
q 1 is 0, 1, 2, 3, or 4;
each R p1 is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, OCF 3 , C 1 -C 6 alkoxy, and unsubstituted C 1 -C 6 alkyl; and
R 13 is selected from hydrogen and unsubstituted C 1 -C 6 alkyl.
9. The compound of claim 8 , wherein X′ is hydrogen, unsubstituted C 1 -C 6 alkyl, or NR X2 R X3 .
10. The compound of claim 9 , wherein R X2 and R X3 are each independently selected from hydrogen and unsubstituted C 1 -C 6 alkyl.
11. The compound of claim 8 , wherein R 3 is unsubstituted or substituted C 6 -C 15 aryl.
12. A compound of formula Xb:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
R a is selected from halogen, OH, nitro, NH 2 , NH[(C 1 -C 6 )alkyl], N[(C 1 -C 6 )alkyl] 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 6 -C 10 aryloxy, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, NHC(O)R t , NHC(O)OR t , and NHC(O)NHR t ;
R t is selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 6 -C 10 aryloxy, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;
R b and R c are each independently selected from NR Xb , CHR Xb , O, and S;
R Xb is selected from hydrogen and unsubstituted or substituted C 1 -C 6 alkyl;
R d is selected from halogen, OH, nitro, NH 2 , NH[(C 1 -C 6 )alkyl], N[(C 1 -C 6 )alkyl] 2 , 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-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, NHC(O)R t , NHC(O)OR t , and C(O)NHR t ;
R 96 is selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, OH, NH 2 , NH[(C 1 -C 6 )alkyl], and N[(C 1 -C 6 )alkyl] 2 ;
na is selected from 0, 1, 2, 3, 4, and 5; and
nd is selected from 0, 1, 2, 3, and 4.
13. The compound of claim 2 , wherein the compound is of formula A1:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
R N2 is selected from hydrogen and unsubstituted C 1 -C 6 alkyl; and
W′ is selected from hydrogen, unsubstituted C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one or more groups, each of which is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, and CN.
14. The compound of claim 13 , wherein the compound is of formula B:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
M is independently selected from single bond, unsubstituted C 1 -C 6 alkyl and substituted C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with R 10 ;
each R 10 is independently selected from halogen, unsubstituted C 1 -C 3 alkyl, and OH;
R 4a , R 5a , R 6a , R 7a , and R 8a are each independently selected from hydrogen, halogen, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, unsubstituted C 6 -C 10 aryl, substituted C 6 -C 10 aryl, unsubstituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, OH, NO 2 , COOH, NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CF 3 , CH 2 F, CF 2 H, CN, unsubstituted C 1 -C 6 alkyl, unsubstituted C 2 -C 6 alkenyl, unsubstituted C 3 -C 8 cycloalkyl, and S(C 1 -C 6 alkyl), wherein said aryl is optionally substituted with R 11 ; and
each R 11 is selected from CN, OCF 3 , CF 3 , CH 2 F, CF 2 H, halogen, C 1 -C 6 alkoxy, unsubstituted C 1 -C 6 alkyl, S(C 1 -C 6 )alkyl, unsubstituted C 6 -C 10 aryl, NH 2 , N[(C 1 -C 6 )alkyl] 2 , and NH(C 1 -C 6 )alkyl.
15. The compound of claim 13 , wherein the compound is of formula N:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
R N2 is selected from hydrogen and unsubstituted C 1 -C 6 alkyl;
R r6 and R r7 are each independently selected from O and NR 13 ;
q 3 is 0, 1, 2, 3, or 4;
each R p3 is independently selected from halogen, SH, OH, NO 2 , NH 2 , N[(C 1 -C 6 )alkyl] 2 , NH(C 1 -C 6 )alkyl, CN, OCF 3 , C 1 -C 6 alkoxy, and unsubstituted C 1 -C 6 alkyl; and
R 13 is selected from hydrogen and unsubstituted C 1 -C 6 alkyl.
16. A compound of formula Ya:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, wherein:
na is selected from 0, 1, 2, 3, 4, and 5;
R a is selected from halogen, OH, nitro, NH 2 , NH[(C 1 -C 6 )alkyl], N[(C 1 -C 6 )alkyl] 2 , unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 6 -C 10 aryloxy, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, NHC(O)R t , NHC(O)OR t , and NHC(O)NHR t ;
R t is selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, unsubstituted or substituted C 6 -C 10 aryloxy, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, and unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S;
R b and R c are each independently selected from NR Xb , CHR Xb , O, and S;
R Xb is selected from hydrogen and unsubstituted or substituted C 1 -C 6 alkyl;
R d is selected from halogen, OH, nitro, NH 2 , NH[(C 1 -C 6 )alkyl], N[(C 1 -C 6 )alkyl] 2 , 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-membered rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 cycloalkyl, unsubstituted or substituted heterocycle comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, NHC(O)R t , NHC(O)OR t , and C(O)NHR t ;
R 95 is selected from hydrogen, halogen, OH, nitro, NH 2 , NH[(C 1 -C 6 )alkyl], N[(C 1 -C 6 )alkyl] 2 , and unsubstituted or substituted C 1 -C 6 alkyl; and
nd is selected from 0, 1, 2, 3, and 4.
17. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof.
18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable excipient or carrier.
19. A compound having the following structure
or a pharmaceutically acceptable salt, tautomer, metabolite, polymorph, analog or derivative thereof.