Amino-pyrrolopyrimidinone compounds and methods of use thereof
The application relates to a compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of BTK, a pharmaceutical composition comprising a compound of Formula (I), and a method of treating or preventing a disease in which BTK plays a role.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
A is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 4 ;
R 1 is (C 3 -C 7 ) cycloalkyl or 4- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more R 5 ;
R 2 is H or (C 1 -C 4 ) alkyl; or
when q is 0, R 1 and R 2 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclyl ring comprising 0 to 1 additional heteroatoms selected from N, O, and S and optionally substituted with one or more NR 6 R 7 ;
R 3 is H or N(R 8 ) 2 ;
each R 4 is independently (i) (C 1 -C 4 ) alkyl, (ii) (C 1 -C 4 ) alkoxy optionally substituted with one or more (C 1 -C 4 ) alkoxy, (iii) halogen, (iv) (CH 2 ) n C(═O)NHR 25 , (v) (CH 2 ),NHC(═O)R 25 , (vi) (CH 2 ) n NHC(═O)NHR 25 , or (vii) C(═O)R 25 ;
each R 5 is independently (i) (C 1 -C 6 ) alkyl optionally substituted with one or more (C 1 -C 4 ) alkoxy or phenyl, (ii) (C 2 -C 4 ) alkenyl optionally substituted with one or more C(═O)(C 1 -C 4 ) alkyl, (iii) (C(R 12 ) 2 ) r OH, (iv) (C(R 12 ) 2 ) r NR 13 R 14 , (v) C(═O)OH, (vi) C(═O)O(C 1 -C 4 ) alkyl, (vii) C(═O)NR 13 R 15 , (viii) C(═O)R 16 , (ix) S(O) p R 16 , or (x) 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more (C 1 -C 4 ) alkyl, or (xi) two R 5 together with the carbon atom to which they are attached form (═O), or (xii) two R 5 together with the atoms to which they are attached form a bridged 3- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
R 6 is H or (C 1 -C 4 ) alkyl;
R 7 is H, (C 1 -C 4 ) alkyl, or C(═O)R 24 ;
each R 8 is independently (i) H, (ii) (C 1 -C 4 ) alkyl, or (iii) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more (C 1 -C 4 ) alkyl, or (iv) two R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl ring comprising 0 to 1 additional heteroatoms selected from N, O, and S and optionally substituted with one or more (C 1 -C 4 ) alkyl;
each R 12 is independently H or (C 1 -C 6 ) alkyl;
R 13 is H or (C 1 -C 4 ) alkyl;
R 14 is (i) H, (ii) (C 1 -C 4 ) alkyl, (iii) (C(R 18 ) 2 ) r C(═O)NR 19 R 20 , (iv) (CH 2 ) n (C 6 -C 10 ) aryl optionally substituted with one or more (C 1 -C 4 ) alkyl or halogen, (v) C(═O)R 2 i , (vi) C(═O)O(C 1 -C 4 ) alkyl, (vii) S(O) 2 (C 1 -C 8 ) alkyl, (viii) S(O) 2 NH(C 1 -C 8 ) alkyl, (ix) S(O) 2 N((C 1 -C 8 ) alkyl) 2 , or (x) C(═O)(C 1 -C 8 ) alkyl optionally substituted with one or more R 22 ; or
R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, OH, NH 2 , and (═O);
R 15 is (i) H, (ii) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or (iii) (C 1 -C 4 ) alkyl optionally substituted with one or more substituents selected from OH, 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; or
R 13 and R 15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, and OH, or form a 5- to 8-membered bicyclic heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, and OH;
R 16 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, or 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkoxy, O-phenyl, halogen, CN, NH 2 , (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, and OS(O) 2 (C 1 -C 4 ) alkyl, and wherein the heterocyclyl is optionally substituted with one or more R 23 ;
each R 18 is independently H or (C 1 -C 4 ) alkyl;
R 19 is H or (C 1 -C 4 ) alkyl;
R 20 is H or (CH 2 ) n (C 6 -C 10 ) aryl optionally substituted with one or more (C 1 -C 4 ) alkyl;
R 21 is (C 3 -C 7 ) cycloalkyl, 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, OH, and halogen;
each R 22 is independently (i) (C 1 -C 4 ) alkoxy, (ii) OH, (iii) NH 2 , (iv) (C 1 -C 4 ) alkylamino, (v) di-(C 1 -C 4 ) alkylamino, or (vi) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (a) (C 1 -C 4 ) alkyl, (b) (CH 2 ) x (C 6 -C 10 ) aryl, and (c) C(═O)(C 6 -C 10 )aryl optionally substituted with one or more (C 1 -C 4 ) alkyl;
each R 23 is independently (C 1 -C 4 ) alkyl or C(═O)(C 1 -C 4 ) alkyl, or two R 23 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
R 24 is (C 1 -C 4 ) alkyl optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkoxy and 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S;
R 25 is (C 1 -C 4 ) alkyl optionally substituted with one or more (C 1 -C 4 ) alkoxy, (C(R 26 ) 2 ) x (C 6 -C 10 ) aryl, (C(R 26 ) 2 ) x -heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, or (C(R 26 ) 2 ) x -heterocyclyl, wherein the heterocyclyl comprises one or two 4- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, alkoxy, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, cyano, halogen, OH, NH 2 , (C 6 -C 10 ) aryl, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S;
each R 26 is independently H or (C 1 -C 4 ) alkyl, or two R 26 together with the atom to which they are attached form a (C 3 -C 6 ) cycloalkyl ring or 3- or 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
each n and each p is independently 0, 1, or 2;
each r is independently 0, 1, 2, or 3; and
each q and each x is independently 0, 1, 2, or 3.
2. The compound of claim 1 , wherein A is phenyl, thiophenyl, or pyridinyl optionally substituted with one or more R 4 .
3. The compound of claim 1 , wherein A is phenyl, thiophenyl, or pyridinyl substituted with one to two R 4 .
4. The compound of claim 1 , wherein A is phenyl substituted with one to two R 4 .
5. The compound of claim 1 , wherein R 2 is H.
6. The compound of claim 1 , wherein R 3 is H, NH 2 , NHCH 3 , or 4-methylpiperazine.
7. The compound of claim 1 , wherein R 3 is H.
8. The compound of claim 1 , wherein at least one R 4 is C(═O)NHR 25 , NHC(═O)R 25 , (CH 2 )C(═O)NHR 25 , or (CH 2 )NHC(═O)R 25 .
9. The compound of claim 1 , wherein R 1 is 4- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with one to three R 5 .
10. The compound of claim 1 , wherein R 1 is piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyl optionally substituted with one to three R 5 .
11. The compound of claim 1 , wherein R 1 is tetrahydropyranyl optionally substituted with one to three R 5 .
12. The compound of claim 1 , wherein q is 0 or 1.
13. The compound of claim 1 , wherein the compound is of Formula (Ia′), (Ib′), or (Ic′):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein w is 1 or 2.
14. The compound of claim 1 , wherein the compound is of Formula (Id′), (Ie′), or (If′):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 5 ′ is H or R 5 .
15. The compound of claim 1 , wherein the compound is of any of Formulae (Ig1)-(Ig12), (Ih1)-(Ih12), and (Ii1)-(Ii12):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein w is 1 or 2.
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
17. The compound of claim 1 , wherein at least one R 4 is NHC(═O)R 25 .
18. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
19. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
20. A pharmaceutical composition comprising a compound of claim 18 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
21. A pharmaceutical composition comprising the compound of claim 19 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
22. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
23. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
24. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
25. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
26. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.
27. A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
A is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 4 ;
R 1 is (C 3 -C 7 ) cycloalkyl or 4- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more R 5 ;
R 2 is H or (C 1 -C 4 ) alkyl; or
when q is 0, R 1 and R 2 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclyl ring comprising 0 to 1 additional heteroatoms selected from N, O, and S and optionally substituted with one or more NR 6 R 7 ;
R 3 is H or N(R 8 ) 2 ;
each R 4 is independently NR 9 S(O) p R 10 or NH(CH 2 ) n R 11 ;
each R 5 is independently (i) (C 1 -C 6 ) alkyl optionally substituted with one or more (C 1 -C 4 ) alkoxy or phenyl, (ii) (C 2 -C 4 ) alkenyl optionally substituted with one or more C(═O)(C 1 -C 4 ) alkyl, (iii) (C(R 12 ) 2 ) r OH, (iv) (C(R 12 ) 2 ) r NR 13 R 14 , (v) C(═O)OH, (vi) C(═O)O(C 1 -C 4 ) alkyl, (vii) C(═O)NR 13 R 15 , (viii) C(═O)R 16 , (ix) S(O) p R 16 , or (x) 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more (C 1 -C 4 ) alkyl, or (xi) two R 5 together with the carbon atom to which they are attached form (═O), or (xii) two R 5 together with the atoms to which they are attached form a bridged 3- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
R 6 is H or (C 1 -C 4 ) alkyl;
R 7 is H, (C 1 -C 4 ) alkyl, or C(═O)R 24 ;
each R 8 is independently (i) H, (ii) (C 1 -C 4 ) alkyl, or (iii) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more (C 1 -C 4 ) alkyl, or (iv) two R 8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl ring comprising 0 to 1 additional heteroatoms selected from N, O, and S and optionally substituted with one or more (C 1 -C 4 ) alkyl;
R 9 is H or (C 1 -C 4 ) alkyl;
R 10 is unsubstituted (C 1 -C 4 ) alkyl or unsubstituted (C 6 -C 10 ) aryl;
R 11 is unsubstituted (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 17 ;
each R 12 is independently H or (C 1 -C 6 ) alkyl;
R 13 is H or (C 1 -C 4 ) alkyl;
R 14 is (i) H, (ii) (C 1 -C 4 ) alkyl, (iii) (C(R 18 ) 2 ) r C(═O)NR 19 R 20 , (iv) (CH 2 ) n (C 6 -C 10 ) aryl optionally substituted with one or more (C 1 -C 4 ) alkyl or halogen, (v) C(═O)R 21 , (vi) C(═O)O(C 1 -C 4 ) alkyl, (vii) S(O) 2 (C 1 -C 8 ) alkyl, (viii) S(O) 2 NH(C 1 -C 8 ) alkyl, (ix) S(O) 2 N((C 1 -C 8 ) alkyl) 2 , or (x) C(═O)(C 1 -C 8 ) alkyl optionally substituted with one or more R 22 ; or
R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, OH, NH 2 , and (═O);
R 15 is (i) H, (ii) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or (iii) (C 1 -C 4 ) alkyl optionally substituted with one or more substituents selected from OH, 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; or
R 13 and R 15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, and OH, or form a 5- to 8-membered bicyclic heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, and OH;
R 16 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, or 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkoxy, O-phenyl, halogen, CN, NH 2 , (C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino, and OS(O) 2 (C 1 -C 4 ) alkyl, and wherein the heterocyclyl is optionally substituted with one or more R 23 ;
each R 17 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, C(═O)NH 2 , C(═O)NH(C 1 -C 4 ) alkyl, or C(═O)N((C 1 -C 4 ) alkyl) 2 ;
each R 18 is independently H or (C 1 -C 4 ) alkyl;
R 19 is H or (C 1 -C 4 ) alkyl;
R 20 is H or (CH 2 ) n (C 6 -C 10 ) aryl optionally substituted with one or more (C 1 -C 4 ) alkyl;
R 21 is (C 3 -C 7 ) cycloalkyl, 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, OH, and halogen;
each R 22 is independently (i) (C 1 -C 4 ) alkoxy, (ii) OH, (iii) NH 2 , (iv) (C 1 -C 4 ) alkylamino, (v) di-(C 1 -C 4 ) alkylamino, or (vi) 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S and optionally substituted with one or more substituents selected from (a) (C 1 -C 4 ) alkyl, (b) (CH 2 ) x (C 6 -C 10 ) aryl, and (c) C(═O)(C 6 -C 10 )aryl optionally substituted with one or more (C 1 -C 4 ) alkyl;
each R 23 is independently (C 1 -C 4 ) alkyl or C(═O)(C 1 -C 4 ) alkyl, or two R 23 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
R 24 is (C 1 -C 4 ) alkyl optionally substituted with one or more substituents selected from (C 1 -C 4 ) alkoxy and 5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S;
each n and each p is independently 0, 1, or 2;
each r is independently 0, 1, 2, or 3;
each q and each x is independently 0, 1, 2, or 3; and
provided that when R 4 is NR 9 S(O) p R 10 , A is optionally substituted with one additional R 4 .
28. The compound of claim 27 , wherein A is phenyl, thiophenyl, or pyridinyl optionally substituted with one or more R 4 .
29. The compound of claim 27 , wherein A is phenyl, thiophenyl, or pyridinyl substituted with one to two R 4 .
30. The compound of claim 27 , wherein A is phenyl substituted with one to two R 4 .
31. The compound of claim 27 , wherein R 2 is H.
32. The compound of claim 27 , wherein R 3 is H, NH 2 , NHCH 3 , or 4-methylpiperazine.
33. The compound of claim 27 , wherein R 3 is H.
34. The compound of claim 27 , wherein R 1 is 4- to 7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with one to three R 5 .
35. The compound of claim 27 , wherein R 1 is piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyl optionally substituted with one to three R 5 .
36. The compound of claim 27 , wherein R 1 is tetrahydropyranyl optionally substituted with one to three R 5 .
37. The compound of claim 27 , wherein q is 0 or 1.
38. The compound of claim 27 , selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.