Substituted pyrazolo[1,5-α]pyrimidines as CRF receptor antagonists
Compounds are provided herein that antagonize corticotropin-releasing factor (CRF) receptors, in particular CRF receptor 1 (CRF 1 ), as well as related preparations, compositions and methods for treating diseases and/or disorders that would benefit from the same such as congenital adrenal hyperplasia (CAH).
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is H or C 1-6 alkyl;
R 2 is C 3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C 3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-Cy, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(N e )NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , S(O) 2 NR c R d , and Cy; and
wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 haloalkyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(R e )NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a ,
OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;
each Cy is independently C 3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C 3-10 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e1 )NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(NR e1 )NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , SR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
each R a is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R b is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R d is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; or
any R c and R d , taken together with the nitrogen atom to which they are attached, independently forms a 4- to 7-membered heterocycloalkyl, wherein each 4- to 7-membered heterocycloalkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R a1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R b1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R c1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a 2, NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R d1 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR e2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; or
any R c1 and R d1 , taken together with the nitrogen atom to which they are attached, independently forms a 4- to 7-membered heterocycloalkyl, wherein each 4- to 7-membered heterocycloalkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C(NR e2 )NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(NR c2 )NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , SR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R a2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl;
each R b2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl;
each R c2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl;
each R d2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-C 3-7 cycloalkyl, C 1-4 alkylene-4- to 10-membered heterocycloalkyl, C 1-4 alkylene-C 6-10 aryl, C 1-4 alkylene-5- to 10-membered heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl;
each R e is independently H, CN, or C 1-4 alkyl;
each R e1 is independently H, CN, or C 1-4 alkyl; and
each R e2 is independently H, CN, or C 1-4 alkyl;
with the provisos that:
(1) any ring-forming carbon atom or any ring-forming nitrogen atom of any aforementioned heterocycloalkyl is optionally and independently substituted with one ═O substituent; and
(2) any ring-forming sulfur atom of any aforementioned heterocycloalkyl is optionally and independently substituted with one or two ═O substituents.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is C 1-6 alkyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is CH 2 CH 2 CH 3 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is C 6-10 aryl or 5- to 10-membered heteroaryl;
wherein the C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-Cy, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(NR e )NR c R d , C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , S(O) 2 NR c R d , and Cy; and
wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 haloalkyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(NR e )NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
5 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl or 5- or 6-membered heteroaryl;
wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-Cy, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(NR e )NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , S(O) 2 NR c R d , and Cy; and
wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 haloalkyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(R e )NR c R d , NR c C(O)R b , NR c C(O)NR c R d , C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
6 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl, pyrazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl;
wherein the phenyl, pyrazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylene-Cy, C 2-6 alkenyl, C 2-6 alkynyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , R c C(NR e )NR c R d , NR c C(O)R b , NR c C(O)NR d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , S(O) 2 NR c R d , and Cy; and
wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl substituent is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 haloalkyl, C(NR e )NR c R d , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(NR e )NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , OC(O)NR c R d , SR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .
7 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl, pyrazol-1-yl, isoxazol-4-yl, 2-(dimethylamino)thiazol-4-yl, 1,2,4-triazol-1-yl, 1,2,3-thiadiazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, or pyrimidin-5-yl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 1 is C 1-6 alkyl;
R 2 is C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , OR a , OC(O)R b , S(O) 2 R b , and S(O) 2 NR c R d ;
each R a is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1 or 2 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , SR a2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R b is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1 or 2 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , SR a2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R c is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1 or 2 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , SR a2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R d is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1 or 2 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , SR a2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; or
any R c and R d , taken together with the nitrogen atom to which they are attached, independently forms a 4- to 7-membered heterocycloalkyl, wherein each 4- to 7-membered heterocycloalkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-4 alkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , OR a2 , OC(O)R b2 , SR a2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R a2 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl;
each R b2 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl;
each R c2 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl; and
each R d2 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, wherein each C 1-6 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , OH, OC 1-6 alkyl, and OC 1-6 haloalkyl.
9 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
11 . A method for reducing the level of at least one biomarker in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein reducing the level of at least one biomarker in the subject is effective to reduce the level of the at least one biomarker in the subject compared to the level of the at least one biomarker in the subject prior to administration of the therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof; and
wherein the at least one biomarker in the subject is selected from the group consisting of (a) androstenedione, (b) 17-hydroxyprogesterone (17-OHP), and (c) testosterone.
12 . A method for reducing the severity of at least one symptom of congenital adrenal hyperplasia (CAH) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein the at least one symptom of congenital adrenal hyperplasia (CAH) in the subject is selected from the group consisting of acne, a fertility problem, growth impairment, hirsutism, and precocious puberty.
13 . A method for reducing the dosage of corticosteroid needed by a subject to treat congenital adrenal hyperplasia (CAH) in the subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
14 . A method for reducing the severity of at least one side effect of glucocorticoid treatment in a subject having congenital adrenal hyperplasia (CAH), wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof;
wherein the at least one side effect of glucocorticoid treatment in the subject is selected from the group consisting of acne, adrenal suppression, akathisia, anxiety, avascular necrosis of the bone, cataract, central serous chorioretinopathy, cognitive impairment, coronary heart disease, a Cushingoid feature, Cushing's syndrome, delayed wound healing, delirium, dementia, depression, dermatoprosis, diabetes mellitus, dyslipidemia, easy bruising, ecchymosis, an erosion, euphoria, gastritis, gastrointestinal bleeding, glaucoma, growth suppression, hair loss, heart failure, hepatic steatosis, hirsutism, hyperglycemia, hypertension, irritability, ischemic heart disease, a mood change, mood lability, mydriasis, myopathy, an opportunistic ocular infection, osteoporosis, pancreatitis, peptic ulcer, a predisposition to an infection, ptosis, purpura, psychosis, a reactivation of a latent infection, skin atrophy, striae, suppression of cell-mediated immunity, visceral perforation, and weight gain.
15 . A method for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
16 . The method of claim 15 , wherein the congenital adrenal hyperplasia (CAH) is classic congenital adrenal hyperplasia.
17 . The method of claim 16 , wherein the classic congenital adrenal hyperplasia is due to 21-hydroxylase deficiency.
18 . The method of claim 16 , wherein the subject has a mutation in the CYP21A2 gene located on chromosome 6p21.
19 . The method of claim 16 , wherein the subject does not have a mutation of the 11β-hydroxylase gene CYP11B1 (11β-OH CAH).
20 . The method of claim 16 , wherein the method further comprises administering to the subject a therapeutically effective amount of a glucocorticoid.
21 . The method of claim 20 , wherein the glucocorticoid is selected from the group consisting of dexamethasone, hydrocortisone, prednisolone, and prednisone.
22 . A method for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, wherein the method comprises:
(i) measuring the level of at least one biomarker in a biological sample obtained from the subject, wherein the at least one biomarker obtained from the subject is selected from the group consisting of (a) androstenedione, (b) 17-hydroxyprogesterone (17-OHP), and (c) testosterone;
(ii) analyzing the level of the at least one biomarker in the biological sample obtained from the subject to determine if the level of the at least one biomarker in the biological sample obtained from the subject is elevated compared to a healthy subject not having congenital adrenal hyperplasia (CAH); and
(iii) administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, if the subject is determined to have an elevated level of at least one biomarker selected from the group consisting of (a) androstenedione, (b) 17-hydroxyprogesterone (17-OHP), and (c) testosterone.
23 . A compound having the structure:
24 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and the compound of claim 23 .
25 . A method for reducing the level of at least one biomarker in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 23 ;
wherein reducing the level of at least one biomarker in the subject is effective to reduce the level of the at least one biomarker in the subject compared to the level of the at least one biomarker in the subject prior to administration of the therapeutically effective amount of the compound of claim 23 ; and
wherein the at least one biomarker in the subject is selected from the group consisting of (a) androstenedione, (b) 17-hydroxyprogesterone (17-OHP), and (c) testosterone.
26 . A method for reducing the severity of at least one symptom of congenital adrenal hyperplasia (CAH) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 23 ;
wherein the at least one symptom of congenital adrenal hyperplasia (CAH) in the subject is selected from the group consisting of acne, a fertility problem, growth impairment, hirsutism, and precocious puberty.
27 . A method for reducing the dosage of corticosteroid needed by a subject to treat congenital adrenal hyperplasia (CAH) in the subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 23 .
28 . A method for reducing the severity of at least one side effect of glucocorticoid treatment in a subject having congenital adrenal hyperplasia (CAH), wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 23 ;
wherein the at least one side effect of glucocorticoid treatment in the subject is selected from the group consisting of acne, adrenal suppression, akathisia, anxiety, avascular necrosis of the bone, cataract, central serous chorioretinopathy, cognitive impairment, coronary heart disease, a Cushingoid feature, Cushing's syndrome, delayed wound healing, delirium, dementia, depression, dermatoprosis, diabetes mellitus, dyslipidemia, easy bruising, ecchymosis, an erosion, euphoria, gastritis, gastrointestinal bleeding, glaucoma, growth suppression, hair loss, heart failure, hepatic steatosis, hirsutism, hyperglycemia, hypertension, irritability, ischemic heart disease, a mood change, mood lability, mydriasis, myopathy, an opportunistic ocular infection, osteoporosis, pancreatitis, peptic ulcer, a predisposition to an infection, ptosis, purpura, psychosis, a reactivation of a latent infection, skin atrophy, striae, suppression of cell-mediated immunity, visceral perforation, and weight gain.
29 . A method for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 23 .
30 . The method of claim 29 , wherein the congenital adrenal hyperplasia (CAH) is classic congenital adrenal hyperplasia.
31 . The method of claim 30 , wherein the classic congenital adrenal hyperplasia is due to 21-hydroxylase deficiency.
32 . The method of claim 30 , wherein the subject has a mutation in the CYP21A2 gene located on chromosome 6p21.
33 . The method of claim 30 , wherein the subject does not have a mutation of the 11b-hydroxylase gene CYP11B1 (11b-OH CAH).
34 . The method of claim 30 , wherein the method further comprises administering to the subject a therapeutically effective amount of a glucocorticoid.
35 . The method of claim 34 , wherein the glucocorticoid is selected from the group consisting of dexamethasone, hydrocortisone, prednisolone, and prednisone.
36 . A method for treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, wherein the method comprises:
(i) measuring the level of at least one biomarker in a biological sample obtained from the subject, wherein the at least one biomarker obtained from the subject is selected from the group consisting of (a) androstenedione, (b) 17-hydroxyprogesterone (17-OHP), and (c) testosterone;
(ii) analyzing the level of the at least one biomarker in the biological sample obtained from the subject to determine if the level of the at least one biomarker in the biological sample obtained from the subject is elevated compared to a healthy subject not having congenital adrenal hyperplasia (CAH); and
(iii) administering to the subject a therapeutically effective amount of the compound of claim 23 , if the subject is determined to have an elevated level of at least one biomarker selected from the group consisting of (a) androstenedione, (b) 17-hydroxyprogesterone (17-OHP), and (c) testosterone.