Chromenone analogs as sirtuin modulators
The present invention relates to novel chromenone analog sirtuin modulator compounds of Formula (I): or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions and treatment methods and combination therapies thereof for use in increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity.
1. A compound of the formula (II):
or a salt thereof:
wherein:
each R 20 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 )alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from:
or
R 11 is selected from:
or
R 11 is selected from
wherein:
R 11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), and when R 11 is phenyl, R 11 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, O-(saturated heterocycle), fluoro-substituted-O-(saturated heterocycle), or
C 1 -C 4 alkyl-substituted 0-(saturated heterocycle);
wherein:
each R 13 is independently selected from hydrogen and —C 1 -C 4 alkyl; or
two R 13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatomic unit selected from NH, S, S(═O), S(═O) 2 , and O;
wherein:
when R 13 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 and
when two R 13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at any carbon atom with —OH, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a 5-7 membered aryl or heteroaryl other than optionally substituted tetrazolyl;
wherein:
R 12 is optionally substituted with one or more substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and
when R 12 is phenyl, R 12 may also be optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle), wherein any phenyl, second heterocycle or saturated heterocycle portion of a substituent of R 12 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 is —NH—C(═O)-†; wherein:
† represents where X 1 is bound to R 11 ; and
each of R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3
wherein:
when R 14 is C 1 -C 4 alkyl, R 12 is other than optionally substituted phenyl.
2. A compound which is selected from:
Compd No
[M + H]+
Structure
227
417
231
428
234
428
250
414
251
411
252
412
253
412
256
414
257
414
261
412
268
415
273
358
280
378
281
383
282
394
283
399
286
386
296
396
307
418
315
510
316
497
318
501
319
463
320
494
322
496
323
480
324
462
325
446
327
460
329
445
331
476
334
467
335
378
337
380
338
483
339
492
3. The compound of claim 2 which is selected from:
Compd No
[M + H]+
Structure
227
417
231
428
234
428
251
411
252
412
253
412
261
412
280
378
296
396
315
510
323
480
337
380
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent; and a compound according to claim 1 or a pharmaceutical salt thereof.