Pyrimidine substituted purine derivatives
The present invention relates to purine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to purine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative conditions or disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative conditions or disorders including tumors and cancers as well as other disorders or conditions related to or associated with PI3 and/or mTOR kinases.
1. A method for making a compound of Formula (I), the method comprising
reacting a compound of Formula (II),
with a morpholine of Formula (III),
thereby providing a compound of Formula (I); wherein
R 1 is selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl;
R 2 is selected from the group consisting of H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 hetero aryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 2 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 2 -C 12 heterocycloalkyloxy, optionally substituted C 2 -C 12 heterocycloalkenyloxy, optionally substituted C 6 -C 18 aryloxy, optionally substituted C 1 -C 1 heteroaryloxy, optionally substituted C 1 -C 12 alkylamino, SR 8 , SO 3 H, SO 2 NR 8 R 9 , SO 2 R 8 , SONR 8 R 9 , SOR 8 , COR 8 , COOH, COOR 8 , CONR 8 R 9 , NR 8 COR 9 , NR 8 COOR 9 , NR 8 SO 2 R 9 , NR 8 CONR 8 R 9 , NR 8 R 9 , and acyl;
R 3 , and R 4 are each independently selected from the group consisting of H, F, Cl, Br, OH, optionally substituted C 1 -C 6 alkyl, OR 8 , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 COR 9 , and NR 8 SO 2 R 9 ;
R 6 is selected from the group consisting of H, OH, OR 8 , OP g O , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 P g N , N(P g N ) 2 , NR 8 COR 9 , and NR 8 SO 2 R 9 ; or
R 8 and R 9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety;
each R 8 and R 9 is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl;
P g O is a protecting group for oxygen;
each P g N is independently a protecting group for nitrogen;
each R Z is independently selected from the group consisting of C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, cyanoC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylaminoC 1 -C 6 alkyl, and di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl;
q is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
X is a group of formula (CR 10 2 ) m ;
each R 10 is independently selected from the group consisting of: H and optionally substituted C 1 -C 6 alkyl; and
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4.
2. The method of claim 1 , wherein the addition of the morpholine of Formula (III) is performed at elevated temperature.
3. The method of claim 1 , wherein the reaction of the compound of Formula (II) and the morpholine of Formula (III) is performed in the presence of a solvent.
4. The method of claim 1 , wherein the solvent is dimethyl acetamide, DMF, or THF.
5. The method of claim 1 , wherein the reaction of the compound of Formula (II) and the morpholine of Formula (III) is performed in the presence of microwave irradiation.
6. The method of claim 1 , further comprising making the compound of Formula (II) by reacting a compound of Formula (IV),
with a boronic acid or a boronic ester of Formula (V),
thereby providing a compound of Formula (II).
7. A method for making a compound of Formula (I), the method comprising
1) reacting a compound of Formula (VI),
with a halide, alcohol, aryl boronic acid, or heteroaryl boronic acid,
2) reacting a compound of Formula (IV),
with a boronic acid or a boronic ester of Formula (V),
3) reacting a compound of Formula (II),
with a morpholine of Formula (III),
thereby providing a compound of Formula (I), wherein
R 1 is selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl;
R 2 is selected from the group consisting of H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 hetero aryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 2 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 2 -C 12 heterocycloalkyloxy, optionally substituted C 2 -C 12 heterocycloalkenyloxy, optionally substituted C 6 -C 18 aryloxy, optionally substituted C 1 -C 1 heteroaryloxy, optionally substituted C 1 -C 12 alkylamino, SR 8 , SO 3 H, SO 2 NR 8 R 9 , SO 2 R 8 , SONR 8 R 9 , SOR 8 , COR 8 , COOH, COOR 8 , CONR 8 R 9 , NR 8 COR 9 , NR 8 COOR 9 , NR 8 SO 2 R 9 , NR 8 CONR 8 R 9 , NR 8 R 9 , and acyl;
R 3 , and R 4 are each independently selected from the group consisting of H, F, Cl, Br, OH, optionally substituted C 1 -C 6 alkyl, OR 8 , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 COR 9 , and NR 8 SO 2 R 9 ;
R 6 is selected from the group consisting of H, OH, OR 8 , OP g O , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 P g N , N(P g N ) 2 , NR 8 COR 9 , and NR 8 SO 2 R 9 ; or
R 8 and R 9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety;
each R 8 and R 9 is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl;
P g O is a protecting group for oxygen;
each P g N is independently a protecting group for nitrogen;
each R Z is independently selected from the group consisting of C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, cyanoC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylaminoC 1 -C 6 alkyl, and di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl;
q is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
X is a group of formula (CR 10 2 ) m ;
each R 13 is independently selected from the group consisting of: H and optionally substituted C 1 -C 6 alkyl; and
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4.
8. A method for making a compound of Formula (I), the method comprising
reacting a compound of Formula (VII),
with an organometallic reagent,
thereby providing a compound of Formula (I), wherein
R 1 is selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl;
R 2 is selected from the group consisting of H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 hetero aryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 2 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 2 -C 12 heterocycloalkyloxy, optionally substituted C 2 -C 12 heterocycloalkenyloxy, optionally substituted C 6 -C 18 aryloxy, optionally substituted C 1 -C 1 heteroaryloxy, optionally substituted C 1 -C 12 alkylamino, SR 8 , SO 3 H, SO 2 NR 8 R 9 , SO 2 R 8 , SONR 8 R 9 , SOW, COR 8 , COOH, COOR 8 , CONR 8 R 9 , NR 8 COR 9 , NR 8 COOR 9 , NR 8 SO 2 R 9 , NR 8 CONR 8 R 9 , NR 8 R 9 , and acyl;
R 3 , and R 4 are each independently selected from the group consisting of H, F, Cl, Br, OH, optionally substituted C 1 -C 6 alkyl, OR 8 , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 COR 9 , and NR 8 SO 2 R 9 ;
R 6 is selected from the group consisting of H, OH, OR 8 , OP g O , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 P g N , N(P g N ) 2 , NR 8 COR 9 , and NR 8 SO 2 R 9 ; or
R 8 and R 9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety;
each R 8 and R 9 is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl;
P g O is a protecting group for oxygen;
each P g N is independently a protecting group for nitrogen;
each R Z is independently selected from the group consisting of C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, cyanoC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylaminoC 1 -C 6 alkyl, and di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl;
q is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
X is a group of formula (CR 10 2 ) m ;
each R 13 is independently selected from the group consisting of: H and optionally substituted C 1 -C 6 alkyl; and
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4.
9. The method of claim 8 , wherein the organometallic reagent is organozinc.
10. The method of claim 8 , further comprising making a compound of Formula (VII) by reacting a compound of Formula (VIII),
with N-bromosuccinimide,
thereby providing a compound of Formula (VII).
11. The method of claim 10 , further comprising making a compound of Formula (VIII) by reacting a compound of Formula (IX),
with a morpholine of Formula (III),
thereby providing a compound of Formula (VIII).
12. The method of claim 11 , wherein the addition of the morpholine is performed at elevated temperature.
13. The method of claim 11 , wherein the reaction of the compound of Formula (IX) and the morpholine of Formula (III) is performed in the presence of a solvent.
14. The method of claim 13 , wherein solvent is dimethyl acetamide, DMF, or THF.
15. The method of claim 11 , wherein the reaction of the compound of Formula (IX) and the morpholine of Formula (III) is performed in the presence of microwave irradiation.
16. The method of claim 11 , further comprising making a compound of Formula (IX)
by reacting a compound of Formula (X),
with a boronic acid or a boronic ester of Formula (V),
thereby providing a compound of Formula (IX).
17. The method of claim 16 , wherein the reaction of the compound of Formula (X) and the boronic acid or boronic ester of Formula (V) is performed in the presence of a palladium catalyst.
18. A method for making a compound of Formula (I), the method comprising
1) reacting a compound of Formula (XI),
with a halide, alcohol, aryl boronic acid, or heteroaryl boronic acid,
2) reacting a compound of Formula (X),
with a boronic acid or a boronic ester of Formula (V),
3) reacting a compound of Formula (IX),
with a morpholine of Formula (III),
4) reacting a compound of Formula (VIII),
with N-bromosuccinimide,
5) reacting a compound of Formula (VII),
with an organometallic reagent,
thereby providing a compound of Formula (I), wherein
R 1 is selected from the group consisting of: H, halogen and optionally substituted C 1 -C 6 alkyl;
R 2 is selected from the group consisting of H, halogen, OH, NO 2 , CN, NH 2 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 hetero aryl, optionally substituted C 1 -C 12 alkyloxy, optionally substituted C 2 -C 12 alkenyloxy, optionally substituted C 2 -C 12 alkynyloxy, optionally substituted C 2 -C 10 heteroalkyloxy, optionally substituted C 3 -C 12 cycloalkyloxy, optionally substituted C 3 -C 12 cycloalkenyloxy, optionally substituted C 2 -C 12 heterocycloalkyloxy, optionally substituted C 2 -C 12 heterocycloalkenyloxy, optionally substituted C 6 -C 18 aryloxy, optionally substituted C 1 -C 1 heteroaryloxy, optionally substituted C 1 -C 12 alkylamino, SR 8 , SO 3 H, SO 2 NR 8 R 9 , SO 2 R 8 , SONR 8 R 9 , SOR 8 , COR 8 , COOH, COOR 8 , CONR 8 R 9 , NR 8 COR 9 , NR 8 COOR 9 , NR 8 SO 2 R 9 , NR 8 CONR 8 R 9 , NR 8 R 9 , and acyl;
R 3 , and R 4 are each independently selected from the group consisting of H, F, Cl, Br, OH, optionally substituted C 1 -C 6 alkyl, OR 8 , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 COR 9 , and NR 8 SO 2 R 9 ;
R 6 is selected from the group consisting of H, OH, OR 8 , OP g O , OCOR 8 , CH 2 OH, NH 2 , NR 8 R 9 , NR 8 P g N , N(P g N ) 2 , NR 8 COR 9 , and NR 8 SO 2 R 9 ; or
R 8 and R 9 when taken together with the atoms to which they are attached form an optionally substituted cyclic moiety;
each R 8 and R 9 is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 10 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl;
P g O is a protecting group for oxygen;
each P g N is independently a protecting group for nitrogen;
each R Z is independently selected from the group consisting of C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, cyanoC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylaminoC 1 -C 6 alkyl, and di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl;
q is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
X is a group of formula (CR 10 2 ) m ;
each R 10 is independently selected from the group consisting of: H and optionally substituted C 1 -C 6 alkyl; and
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4.
19. The method of claim 7 , wherein the halide is an alkyl halide, arylalkyl halide, or heteroaryl alkyl halide.
20. The method of claim 19 , wherein the alkyl halide is an alkyl bromide.
21. The method of claim 19 , wherein the arylalkyl halide is a benzyl halide.
22. The method of claim 7 , wherein the reaction of the compound of Formula (VI) and a halide, alcohol, aryl boronic acid, or heteroaryl boronic acid is performed in the presence of a base.
23. The method of claim 22 , wherein the base is potassium carbonate.
24. The method of claim 22 , wherein the reaction of the compound of Formula (VI) and alcohol is performed in the presence of a phosphine.
25. The method of claim 22 , wherein the reaction of the compound of Formula (VI) and the halide, alcohol, aryl boronic acid, or heteroaryl boronic acid is performed in the presence of an activating agent.
26. The method of claim 25 , wherein the activating agent is diethylazodicarboxylate.
27. The method of claim 22 , wherein the reaction of the compound of Formula (VI) and the aryl boronic acid or heteroaryl boronic acid is performed in the presence of a catalytic amount of copper.