Substituted aminopyrimidine compounds and methods of use
The invention relates to the preparation and use of new aminopyrimidine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form and formulations thereof for the modulation of a disorder or disease which is mediated by the activity of the PI3K enzymes. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of disorders or diseases, such as disorders of immunity and inflammation in which PI3K enzymes play a role in leukocyte function, and hyperproliferative disorders associated with PI3K activity, including but not restricted to leukemias and solid tumors, in mammals, especially humans.
1. A compound having Formula (I):
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein:
X is (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl, or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein X is optionally substituted by 1, 2, 3, 4, or 5 R 1 groups;
Y is
wherein Y is optionally substituted by 1, 2, 3, or 4 R 2 groups;
each R 1 and R 2 is independently H, F, Cl, Br, CN, NO 2 , oxo (═O), —C(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —OC(═O)NR a R b , —OC(═O)OR a , —N(R c )C(═O)NR a R b , —N(R c )C(═O)OR a , —N(R c )C(═O)R a , —S(═O) 2 NR a R b , —S(═O) 2 R a , —N(R c )S(═O) 2 R a , —N(R c )—(C 1 -C 4 )alkylene-S(═O) 2 R a , —(C 1 -C 4 )alkylene-C(═O)NR a R b , —(C 1 -C 4 )alkylene-N(R c )C(═O)NR a R b , —(C 1 -C 4 )alkylene-N(R c )C(═O)OR a , —(C 1 -C 4 )alkylene-OC(═O)NR a R b , —(C 1 -C 4 )alkylene-S(═O) 2 NR a R b , —(C 1 -C 4 )alkylene-N(R c )S(═O) 2 R a , OR a , NR a R b , —(C 1 -C 4 )alkylene-OR a , —(C 1 -C 4 )alkylene-NR a R b , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl, or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, OR a , NR a R b , (C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ;
each R 3 and R 4 is independently H, F, CN, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —(C 1 -C 4 )alkylene-C(═O)NR a R b , —(C 1 -C 4 )alkylene-N(R c )C(═O)NR a R b , —(C 1 -C 4 )alkylene-N(R c )C(═O)OR a , —(C 1 -C 4 )alkylene-OC(═O)NR a R b , —(C 1 -C 4 )alkylene-S(═O) 2 NR a R b , —(C 1 -C 4 )alkylene-N(R c )S(═O) 2 R b , —(C 1 -C 4 )alkylene-OR a , —(C 1 -C 4 )alkylene-NR a R b , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl, or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, OR a , NR a R b , (C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ; or R 3 and R 4 , together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring; and
each R a , R b and R c is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl, or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, CN, N 3 , OH, NH 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylamino; or R a and R b , together with the nitrogen atom they are attached to, form an optionally substituted 3-8 membered heterocyclic ring.
2. The compound according to claim 1 , wherein X is (C 3 -C 7 )heterocyclyl or 5-10 membered heteroaryl, wherein X is optionally substituted by 1, 2, 3, or 4 R 1 groups.
3. The compound according to claim 1 , wherein each R 1 and R 2 is independently H, F, Cl, CN, oxo (═O), —C(═O)OR a , —C(═O)NR a R b , —N(R c )C(═O)NR a R b , —N(R c )C(═O)OR a , —N(R c )C(═O)R a , —S(═O) 2 NR a R b , —N(R c )S(═O) 2 R a , —N(R c )—(C 1 -C 4 )alkylene-S(═O) 2 R a , —(C 1 -C 4 )alkylene-C(═O)NR a R b , —(C 1 -C 4 )alkylene-N(R c )C(═O)NR a R b , —(C 1 -C 4 )alkylene-S(═O) 2 NR a R b , —(C 1 -C 4 )alkylene-N(R c )S(═O) 2 R a , OR a , NR a R b , —(C 1 -C 4 )alkylene-OR a , —(C 1 -C 4 )alkylene-NR a R b , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, phenyl, —(C 1 -C 4 )alkylene-phenyl, or 5-6 membered heteroaryl, wherein each of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, phenyl, —(C 1 -C 4 )alkylene-phenyl and 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, OR a , NR a R b , (C 1 -C 3 )alkyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b .
4. The compound according to claim 1 , wherein each R 3 and R 4 is independently H, F, CN, —C(═O)NR a R b , —(C 1 -C 2 )alkylene-C(═O)NR a R b , —(C 1 -C 2 )alkylene-N(R c )C(═O)NR a R b , —(C 1 -C 2 )alkylene-N(R c )C(═O)OR a , —(C 1 -C 2 )alkylene-OC(═O)NR a R b , —(C 1 -C 2 )alkylene-S(═O) 2 NR a R b , —(C 1 -C 2 )alkylene-N(R c )S(═O) 2 R b , —(C 1 -C 2 )alkylene-OR a , —(C 1 -C 2 )alkylene-NR a R b , (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 5 ) heterocyclyl, phenyl, —(C 1 -C 2 )alkylene-phenyl, 5-membered heteroaryl, or —(C 1 -C 2 )alkylene-(5-membered heteroaryl), wherein each of the (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 5 )heterocyclyl, phenyl, —(C 1 -C 2 )alkylene-phenyl, 5-membered heteroaryl and —(C 1 -C 2 )alkylene-(5-membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, OR a , NR a R b , (C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ; or R 3 and R 4 , together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring.
5. The compound according to claim 1 , wherein each R a , R b and R c is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, or 5-10 membered heteroaryl, wherein each of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, N 3 , OH, NH 2 , (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )alkylamino.
6. The compound according to claim 1 , wherein X is a monovalent heterocyclyl or heteroaryl group derived from one of the following structures:
and wherein X is optionally substituted by 1, 2, or 3 R 1 groups.
7. The compound according to claim 1 , wherein Y is
and wherein Y is optionally substituted by 1 or 2 R 2 groups.
8. The compound according to claim 1 , wherein each R 1 and R 2 is independently H, F, Cl, CN, oxo (═O), —C(═O)OR a , —C(═O)NR a R b , —N(R c )C(═O)NR a R b , —N(R c )C(═O)OR a , —N(R c )C(═O)R a , —S(═O) 2 NR a R b , —N(R c )S(═O) 2 R a , OR a , NR a R b , (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 5 )heterocyclyl, phenyl, or —(C 1 -C 2 )alkylene-phenyl, wherein each of the (C 1 -C 3 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 5 )heterocyclyl, phenyl and —(C 1 -C 2 )alkylene-phenyl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, OR a NR a R b and (C 1 -C 3 )alkyl.
9. The compound according to claim 1 , wherein each R 3 and R 4 is independently H, F, CN, (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl, or —(C 1 -C 2 )alkylene-(C 3 -C 5 )heterocyclyl, wherein each of the (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl and —(C 1 -C 2 )alkylene-(C 3 -C 5 )heterocyclyl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, Br, CN, OR a , NR a R b , (C 1 -C 6 )alkyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ; or R 3 and R 4 , together with the carbon atom they are attached to, form an optionally substituted 3-8 membered carbocyclic or heterocyclic ring.
10. The compound according to claim 1 , wherein each R a , R b and R c is independently H, (C 1 -C 3 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl, or 5-6 membered heteroaryl, wherein each of the (C 1 -C 3 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 5 )heterocyclyl and 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, CN, OH, NH 2 , (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy and (C 1 -C 3 )alkylamino.
11. The compound of claim 1 having one of the following structures:
12. A pharmaceutical composition comprising the compound according to claim 1 , and one or more pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or a combination thereof.
13. The pharmaceutical composition according to claim 12 further comprising one or more therapeutic agents.
14. A method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering a therapeutically effective amount of the compound according to claim 1 , to a patient in need thereof, wherein the disorder is rheumatoid arthritis.
15. A method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering the pharmaceutical composition according to claim 12 , to a patient in need thereof, wherein the disorder is rheumatoid arthritis.