Certain 6, 8-(heteroaryl or aryl) disubstituted imidazo[1,2-a]pyrazines as modulators of Hsp90 complex activity
View Patent ↗This invention pertains to compounds of Formula I: and the pharmaceutically-acceptable forms thereof. The variables R 1 , R 2 , R 3 , Z 1 , Z 2 , W, and X shown in Formula I are defined herein. The invention also provides pharmaceutical compositions containing one or more compound of Formula I, or pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods of treating patients suffering from certain diseases and disorders responsive to Hsp90 complex modulation, which comprise administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These diseases include cancer, including chronic myeloid leukemia, melanoma, breast, ovarian, brain, thyroid, colorectal, prostate, and bladder cancer, heart disease, stroke, autoimmune/inflammatory diseases, and neurodegenerative diseases. Thus methods of treatment include administering a sufficient amount of a compound of Formula I or form thereof to decrease the symptoms or slow the progression of these diseases or disorders. The invention also encompasses methods of treating non-human patients, including livestock and domesticated companion animals, suffering from a disease or disorder responsive to Hsp90 complex modulation. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with one or more other therapeutic agent. The invention also includes a method for determining the presence of certain kinases or Hsp90 complex in a sample, comprising contacting the sample with a compound of Formula I or form thereof, and detecting Hsp9O complex activity in the sample.
1. A compound having Formula 1:
or pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, halogen, C 1 –C 7 alkyl, C 1 –C 6 alkoxy, C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), heterocycloalkyl(C 0 –C 2 alkyl), sulfonamide, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, mono- or di-(C 1 –C 6 alkyl)amino, or mono- or di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl); or
R 1 is phenyl or phenyl fused to a 5 to 7-membered heterocycloalkyl ring containing 1 or 2 heteroatoms chosen from N, O, and S, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, C 1 –C 6 alkylthio, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, and —C(O)R 13 where R 13 is C 1 –C 3 haloalkyl, phenyl, heterocycloalkyl, or heteroaryl;
W is phenyl or a 5- or 6-membered heteroaryl containing from 1 to 4 heteroatoms independently chosen from nitrogen, oxygen, and sulfur; wherein W is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, oxo, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl;
X is N or CH;
R 2 is C 1 –C 7 alkyl, C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), heterocycloalkyl(C 0 –C 2 alkyl), C 1 –C 6 alkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, or (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy; or
R 2 is phenyl(C 0 –C 2 alkyl) or heteroaryl(C 0 –C 2 alkyl), each of which is substituted with 0 to 3 substituents independently chosen from
(i) hydroxy, halogen, nitro, cyano, amino, sulfonamide, —CHO, C 1 –C 6 haloalkyl, and C 1 –C 6 haloalkoxy, and
(ii) C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, heterocycloalkyl(C 0 –C 2 alkyl), and —C(O)R 13 ; each of which (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, nitro, cyano, C 1 –C 4 alkoxy, C 3 –C 7 cycloalkyl, and mono- and di-(C 1 –C 4 alkyl)amino;
Z 2 is
wherein
R 8 and R 9 are independently hydrogen, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, or halogen; and n is 0, 1, or 2;
R 10 and R 11 are independently
(iii) hydrogen or C 1 –C 6 alkyl; or
(iv) phenyl or heteroaryl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, and —C(O)R 13 ;
R 3 is hydrogen or C 1 –C 6 alkyl, or
R 3 is C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), heterocycloalkyl(C 0 –C 2 alkyl), phenyl, or heteroaryl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, and —C(O)R 13 ; or
R 3 is phenoxy phenyl, each of which phenyl rings is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, and —C(O)R 13 .
2. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein
R 1 is hydrogen, halogen, C 1 –C 7 alkyl, C 1 –C 6 alkoxy, C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), heterocycloalkyl(C 0 –C 2 alkyl), sulfonamide, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, mono- or di-(C 1 –C 6 alkyl)amino, or mono- or di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl); or
R 1 is phenyl substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C –7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl;
W is phenyl or a 5- or 6-membered heteroaryl ring; substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, oxo, C 1 –C 6 alkyl; C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl;
X is N or CH;
R 2 is C 1 –C 7 alkyl, C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), heterocycloalkyl(C 0 –C 2 alkyl), C 1 –C 6 alkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, or (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy; or
R 2 is phenyl(C 0 –C 2 alkyl) or 5- or 6-membered heteroaryl(C 0 –C 2 alkyl), each of which is substituted with 0 to 3 substituents independently chosen from
(i) hydroxy, halogen, nitro, cyano, amino, sulfonamide, —CHO, C 1 –C 6 haloalkyl, and C 1 –C 6 haloalkoxy, and
(ii) C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, and heterocycloalkyl(C 0 –C 2 alkyl); each of which (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, nitro, cyano, C 1 –C 4 alkoxy, C 3 –C 7 cycloalkyl, and mono- and di-(C 1 –C 4 alkyl)amino;
Z 2 is
wherein
R 8 and R 9 are independently hydrogen, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, or halogen; and n is 0, 1,or 2;
R 10 and R 11 are independently
(iii) hydrogen or C 1 –C 6 alkyl; or
(iv) phenyl or a 5- or 6 membered heteroaryl ring, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl;
R 3 is hydrogen or C 1 –C 6 alkyl, or
R 3 is C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), heterocycloalkyl(C 0 –C 2 alkyl), phenyl, or a 5- or 6-membered heteroaryl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl; or
R 3 is phenoxy phenyl, each of which phenyl rings is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl.
3. A compound or pharmaceutically acceptable salt thereof according to claim 2 wherein
R 1 is halogen, C 1 –C 7 alkyl, C 1 –C 6 alkoxy, C 3 –C 7 cycloalkyl(C 0 –C 2 alkyl), or heterocycloalkyl(C 0 –C 2 alkyl); or
R 1 is phenyl substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl.
4. A compound or pharmaceutically acceptable salt thereof according to claim 3 wherein
R 1 is halogen or C 1 –C 7 alkyl; or
R 1 is phenyl substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, halogen, C 1 –C 6 alkyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 2 haloalkyl, C 1 –C 2 haloalkoxy, and mono- and di-(C 1 –C 4 alkyl)amino.
5. A compound or pharmaceutically acceptable salt thereof according to claim 4 wherein
R 1 is phenyl substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, halogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, C 1 –C 2 haloalkyl, C 1 –C 2 haloalkoxy, and mono- and di-(C 1 –C 4 alkyl)amino.
6. A compound or pharmaceutically acceptable salt thereof according to claim 4 wherein
R 1 is bromo or C 1 –C 4 alkyl; or
R 1 is phenyl substituted with 0 to 2 substituents independently chosen from fluoro, chloro, bromo, C 1 –C 2 alkyl, and C 1 –C 2 alkoxy.
7. A compound or pharmaceutically acceptable salt thereof according to claim 6 wherein
W is phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl, thienyl, oxazolyl, or isoxazolyl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, sulfonamide, —CHO, halogen, oxo, C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 6 haloalkyl, C 1 –C 6 haloalkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and C 2 –C 6 alkanoyl.
8. A compound or pharmaceutically acceptable salt thereof according to claim 7 wherein
W is phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl, thienyl, oxazolyl, or isoxazolyl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, halogen, oxo, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, C 1 –C 2 haloalkyl, C 1 –C 2 haloalkoxy, and mono- and di-(C 1 –C 4 alkyl)amino.
9. A compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein
W is imidazolyl, pyrrolyl, or pyrazolyl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, cyano, halogen, oxo, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, trifluoromethyl, and trifluoromethoxy.
10. A compound or pharmaceutically acceptable salt thereof according to claim 6 of Formula 2
11. A compound or pharmaceutically acceptable salt thereof according to claim 6 of Formula 3
12. A compound or pharmaceutically acceptable salt thereof according to claim 6 of Formula 4:
13. A compound or pharmaceutically acceptable salt thereof according to claim 11 , wherein X is N.
14. A compound or pharmaceutically acceptable salt thereof according to claim 11 , wherein X is CH.
15. A compound or pharmaceutically acceptable salt thereof according to claim 9 wherein
Z 2 is
wherein
R 8 and R 9 are independently hydrogen or C 1 –C 6 alkyl; and n is 0, 1, or 2; and
R 10 and R 11 are independently hydrogen, C 1 –C 6 alkyl, or phenyl.
16. A compound or pharmaceutically acceptable salt thereof according to claim 15 , wherein
Z 2 is
wherein, R 10 and R 11 are independently hydrogen, methyl, or ethyl.
17. A compound or pharmaceutically acceptable salt thereof according to claim 16 wherein R 10 and R 11 are both hydrogen.
18. A compound or pharmaceutically acceptable salt thereof according to claim 9 of Formula 6
19. A compound or pharmaceutically acceptable salt thereof according to claim 9 of Formula 7
20. A compound or pharmaceutically acceptable salt thereof according to claim 9 of Formula 8
21. A compound or pharmaceutically acceptable salt thereof according to claim 19 wherein
R 2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrrolyl, furanyl, thienyl, oxazolyl, or isoxazolyl, each of which may be either directly attached or bound via a C 1 –C 2 alkyl linker, and each of which is substituted with 0 to 3 substituents independently chosen from:
(i) hydroxy, halogen, nitro, cyano, amino, sulfonamide, —CHO, C 1 –C 6 haloalkyl, and C 1 –C 6 haloalkoxy, and
(ii) C 1 –C 6 alkyl, C 2 –C 6 alkenyl, C 2 –C 6 alkynyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, (C 1 –C 6 alkoxy)C 1 –C 6 alkyl, (C 1 –C 6 alkoxy)C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, mono- and di-(C 1 –C 6 alkyl)amino, amino(C 1 –C 6 alkyl), mono- and di-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), C 2 –C 6 alkanoyl, and heterocycloalkyl(C 0 –C 2 alkyl); each of which (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, nitro, cyano, C 1 –C 4 alkoxy, C 3 –C 7 cycloalkyl, and mono- and di-(C 1 –C 4 alkyl)amino.
22. A compound or pharmaceutically acceptable salt thereof according to claim 21 , wherein
R 2 is phenyl(C 0 –C 2 alkyl), pyridyl(C 0 –C 2 alkyl), or pyrimidinyl(C 0 –C 2 alkyl), each of which is substituted with 0 to 3 substituents independently chosen from:
(i) hydroxy, halogen, nitro, cyano, amino, C 1 –C 2 haloalkyl, and C 1 –C 2 haloalkoxy, and
(ii) C 1 –C 6 alkyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, (C 1 –C 6 alkoxy)C 1 C 6 alkyl, C 1 –C 4 alkylthio, mono- and di-(C 1 –C 4 alkyl)amino, mono- and di-(C 1 –C 4 alkyl)amino(C 1 –C 4 alkyl), and heterocycloalkyl(C 0 –C 2 alkyl); each of which (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, nitro, cyano, C 1 –C 4 alkoxy, C 3 –C 7 cycloalkyl, and mono- and di-(C 1 –C 4 alkyl)amino.
23. A compound or a pharmaceutically acceptable salt thereof according to claim 22 , wherein
R 2 is phenyl or benzyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, C 1 –C 4 alkylthio, C 1 –C 2 haloalkyl, and C 1 –C 2 haloalkoxy.
24. A compound or pharmaceutically acceptable salt thereof according to claim 23 , wherein
R 3 is hydrogen or C 1 –C 6 alkyl, or
R 3 is C 3 –C 7 cycloalkyl, (C 3 –C 7 cycloalkyl)methyl, heterocycloalkyl, (heterocycloalkyl)C 1 –C 2 alkyl, phenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrrolyl, furanyl, thienyl, oxazolyl, or isoxazolyl, each of which is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, halogen, C 1 –C 6 alkyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 2 haloalkyl, C 1 –C 2 haloalkoxy, and mono- and di-(C 1 –C 4 alkyl)amino; or
R 3 is phenoxyphenyl, each of which phenyl rings is substituted with 0 to 3 substituents independently chosen from hydroxy, nitro, cyano, amino, halogen, C 1 –C 6 alkyl, C 3 –C 7 cycloalkyl, C 1 –C 6 alkoxy, C 1 –C 2 haloalkyl, C 1 –C 2 haloalkoxy, and mono- and di-(C 1 –C 4 alkyl)amino.
25. A compound or pharmaceutically acceptable salt thereof according to claim 24 , wherein
R 3 is hydrogen, C 1 –C 6 alkyl, C 3 –C 7 cycloalkyl(C 0 –C 1 alkyl), phenyl, or phenoxyphenyl.
26. A compound or pharmaceutically acceptable salt thereof according to claim 25 , wherein R 3 is hydrogen or C 1 –C 4 alkyl.
27. A compound or pharmaceutically acceptable salt thereof according to claim 1 of Formula 9
28. A compound or pharmaceutically acceptable salt thereof according to claim 1 of Formula 10
29. A compound or pharmaceutically acceptable salt thereof according to claim 1 of Formula 11
30. A compound or pharmaceutically acceptable salt thereof according to claim 1 of Formula 12
31. A compound or pharmaceutically acceptable salt thereof according to claim 1 of Formula 13
32. A compound or pharmaceutically acceptable salt thereof according to claim 1 of Formula 14
33. A compound or pharmaceutically acceptable salt thereof according to claim 30 , wherein
R 1 is bromo or C 1 –C 4 alkyl; or
R 1 is phenyl substituted with 0 to 2 substituents independently chosen from fluoro, chloro, bromo, C 1 –C 2 alkyl, and C 1 –C 2 alkoxy;
R 2 is phenyl or benzyl, each of which is substituted with 0 to 3 substituents independently chosen from:
(i) hydroxy, halogen, amino, C 1 –C 2 haloalkyl, and C 1 –C 2 haloalkoxy, and
(ii) C 1 –C 6 alkyl, C 1 –C 6 alkoxy, mono- and di-(C 1 –C 4 alkyl)amino, mono- and di-(C 1 –C 4 alkyl)amino(C 1 –C 4 alkyl), piperazinyl(C 0 –C 1 alkyl), piperidinyl(C 0 –C 1 alkyl), and morpholinyl(C 0 –C 1 alkyl); each of which (ii) is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C 1 –C 2 alkoxy, and mono- and di-(C 1 –C 4 alkyl)amino; and
R 3 is hydrogen or C 1 –C 4 alkyl.
34. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound exhibits an IC 50 of 25 micromolar or less in an in vitro assay of tumor cell proliferation.
35. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound exhibits an IC 50 of 10 micromolar or less in an in vitro assay of tumor cell proliferation.
36. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is:
1-{3-[8-(4-Phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-o-tolyl-urea;
1-(4-Chloro-phenyl)-3-{3-[8-(4-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(2-Methylsulfanyl-phenyl)-3-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-{3-[8-(2-Phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-o-tolyl-urea;
1-(4-Chloro-phenyl)-3-(3-{8-[4-4chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea;
1-(3-{8-[4-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-o-tolyl-urea;
1-(4-Chloro-phenyl)-3-{3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-o-Tolyl-3-{3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(4-Chloro-phenyl)-3-{3-[8-(4-methyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[4-(4-chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(4-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(3-{8-[4-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-urea;
1-(3-{8-[4-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl) -urea;
1-(3-{8-[4-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-{4-[(3-ethoxy-propylamino)-methyl]-phenyl}-urea;
1-(4-Chloro-phenyl)-3-{3-[8-(3-phenyl-pyrazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(3-phenyl-pyrazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
4-Chloro-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
3-Morpholin-4-ylmethyl-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
4-Morpholin-4-ylmethyl-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-{3-[8-(2-p-Tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea;
1-(4-Morpholin-4-ylmethyl-phenyl)-3-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
6-(4-Morpholin-4-ylmethyl-phenyl)-8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazine;
1-(4-Chloro-phenyl)-3-{3-[8-(2-o-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-o-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(4-Chloro-phenyl)-3-(3-{8-[2-(2-methoxy-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea;
1-(4-Chloro-phenyl)-3-(3-{8-[2-(2-fluoro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-(3-{8-[2-(2-fluoro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea;
1-(3-{8-[2-(2-Fluoro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea;
1-(3-{8-[2-(2Methoxy-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea;
1-(4-Chloro-phenyl)-3-{3-[8-(2-isopropyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-isopropyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;
1-{3-[8-(4-Bromo-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea;
4-Fluoro-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
3-Methoxy-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide
3-Methoxy-4-methyl-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
N-{3-[8-(2-Phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
2,6-Dimethyl-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
4-Fluoro-N-{3-[8-(2-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
3-Methoxy-N-{3-[8-(2-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
3-Methoxy-4-methyl-N-{3-[8-(2-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide;
2-(4-Chloro-phenyl)-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-acetamide;
2-(4-Chloro-phenyl)-N-(3-{8-[2-(4-chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-acetamide;
N-(3-{8-[2-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-2-(3-trifluoromethyl-phenyl)-acetamide;
1-(3-{8-[2-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-urea;
1-(4-Chloro-benzyl)-3-(3-{8-[2-(4chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-urea; or
1-(3-{8-[2-(4-Chloro-phenyl)-imidazol-1-yl]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-3-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-urea.
37. A pharmaceutical composition, comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 , together with at least one pharmaceutically acceptable carrier or excipient.
38. A pharmaceutical composition according to claim 37 , wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a capsule, a syrup, ophthalmic solution, or a transdermal patch.
39. A method for modulating binding of ATP to Hsp90 complex in vitro, the method comprising contacting cells expressing Hsp90 complex with a compound according to claim 1 or pharmaceutically acceptable salt thereof in an amount sufficient to detectably decrease the level of an Hsp90 substrate protein in vitro.
40. A method for modulating the activity of Hsp90 complex, the method comprising contacting cells expressing Hsp90 complex with a compound according to claim 1 or pharmaceutically acceptable salt thereof in an amount sufficient to detectably decrease the level of an Hsp90 substrate protein in vitro.
41. The method of claim 40 wherein the substrate protein is ErbB2, Akt, or Raf.