Multicyclic compounds and methods of using same
View Patent ↗The invention generally relates to compounds represented by Structural Formula I: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in treatment of cancer (e.g., mantle cell lymphoma), and other diseases and disorders (e.g., PAK-mediated, for example, PAK4-mediated, diseases and disorders).
1. A compound represented by Structural Formula (XI) or (XII):
or a pharmaceutically acceptable salt thereof, wherein:
Y is —C(R 8 )═C(R 6 )—R 5 —N(R 7 )-*, wherein “*” represents a portion of Y directly adjacent to —[C(R 3a )(R 3b )] m —;
R 1a is selected from hydroxyl, halogen, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and halo(C 1 -C 4 )alkoxy; and
R 9a is a 6-15-member aryl or a 5-15-member heteroaryl, optionally substituted with one or more substituents independently selected from halogen, (C 1 -C 4 )alkyl optionally substituted with hydroxyl, (C 2 -C 4 )alkenyl, (C 1 -C 4 )haloalkyl, —C(O)(C 1 -C 4 )alkyl and —C(O)NR 11 R 12 , wherein:
R 11 and R 12 are each independently hydrogen, C 1 -C 4 alkyl, 3-15-member carbocyclyl, or a 3-15-member heterocyclyl; or
R 11 and R 12 are taken together with the nitrogen atom to which they are commonly attached to form a 3-7-member heterocyclyl, optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl;
each of R 3a and R 3b is independently selected from hydrogen, deuterium, halo, and (C 1 -C 4 )alkyl;
R 5 is —C(O)—;
R 6 and R 8 is each independently selected from hydrogen, halo, CN, and (C 1 -C 4 )alkyl;
R 7 is selected from hydrogen and (C 1 -C 4 )alkyl;
each R 13 is independently selected from amino, halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl;
m is 1, 2, or 3; and
q is 0, 1, 2, or 3.
2. The compound of claim 1 , wherein R 9a is selected from phenyl, thiophenyl, pyridinyl and pyrimidinyl.
3. The compound of claim 1 or 2 , wherein q is 0, 1 or 2.
4. The compound of claim 1 or 2 , wherein q is 1.
5. The compound of claim 1 or 2 , wherein q is 0.
6. The compound of claim 1 or claim 2 , wherein R 1a is selected from halogen and halo(C 1 -C 4 )alkyl.
7. The compound of claim 1 or claim 2 , wherein R 1a is selected from fluoro, chloro, —CF 3 and —CHF 2 .
8. The compound of claim 1 or 2 , wherein R 9a is phenyl or a 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.
9. The compound of claim 1 or claim 2 , wherein R 9a is substituted with 1 or 2 substituents.
10. The compound of claim 1 or 2 , wherein R 9a is substituted with one substituent selected from:
halogen; (C 1 -C 4 )alkyl optionally substituted with hydroxyl; (C 2 -C 4 )alkenyl; (C 1 -C 4 )haloalkyl; —C(O)(C 1 -C 4 )alkyl; and —C(O)NR 11 R 12 , wherein R 11 and R 12 are taken together with the nitrogen atom to which they are commonly attached to form a 3-7-member heterocyclyl, optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl;
and is further optionally substituted with one substituent selected from halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl.
11. The compound of claim 1 or 2 , wherein R 9a is substituted with at least one substituent independently selected from —C(O)(C 1 -C 4 )alkyl, —C(O)—N(R 11 )(R 12 ), hydroxy-substituted (C 1 -C 4 )alkyl, and (C 2 -C 4 )alkenyl, wherein R 11 and R 12 are each independently selected from (C 1 -C 4 )alkyl; or R 11 and R 12 are taken together with the nitrogen to which they are bound to form a saturated 3-7-member heterocyclyl comprising 0 or 1 additional heteroatoms selected from N, O and S, and wherein the saturated 3-7-member heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl.
12. The compound of claim 11 , wherein R 9a is selected from phenyl, thiophen-2-yl, pyridin-3-yl and pyrimidin-3-yl.
13. The compound of claim 12 , wherein R 9a is selected from 4-dimethylaminocarbonylphenyl, 5-acetylthiophen-2-yl, 5-(1-hydroxyethyl)thiophen-2-yl, 5-(2-hydroxypropan-2-yl)thiophen-2-yl, 5-(prop-1-en-2-yl)thiophen-2-yl, 4-(4-methylpiperazin-1-ylcarbonyl)phenyl, 4-(morpholin-4-ylcarbonyl)phenyl, difluoroazetidin-1-ylcarbonyl)phenyl, 4-(piperazin-1-ylcarbonyl)phenyl, 4-(piperidin-1-ylcarbonyl)phenyl, 4-(3,3-dimethylmorpholin-4-ylcarbonyl)phenyl, 2-(morpholin-1-ylcarbonyl)pyrimidin-5-yl or (4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl.
14. The compound of claim 1 represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
X 6 is —N— or —C(H)—;
R 20 is halogen, (C 1 -C 4 )alkyl optionally substituted with hydroxyl, (C 2 -C 4 )alkenyl, (C 1 -C 4 )haloalkyl, —C(O)(C 1 -C 4 )alkyl and —C(O)NR 11a R 12a , wherein:
R 11a and R 12a are each independently hydrogen, C 1 -C 4 alkyl, 3-15-member carbocyclyl, or a 3-15-member heterocyclyl; or
R 11a and R 12a are taken together with the nitrogen atom to which they are commonly attached to form a 3-7-member heterocyclyl, optionally substituted with 1 or 2 substituents independently selected from halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl;
each R 21 , if present, is independently fluoro, chloro, bromo or iodo; and
q 1 is 0, 1, 2, 3 or 4.
16. The compound of claim 1 , represented by any one of the following structural formulas, or a pharmaceutically acceptable salt thereof:
Cpd.
No.
Compound Structure
300
301
304
305
306
308
311
313
314
315
316
317
318
319
320
321
323
325
326
327
328
329
332
333
334
335
336
338
339
342
344
345
347
348
349
350
351
352
355
17. A pharmaceutical composition comprising:
(a) a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier.