US 12,227,508 B2
TGF-β inhibitors
Marina Gelman, San Francisco, CA (US); Todd Kinsella, Redwood City, CA (US); Somasekhar Bhamidipati, Foster City, CA (US); Ihab Darwish, San Carlos, CA (US); Rajinder Singh, Belmont, CA (US); and Jiaxin Yu, San Carlos, CA (US)
Assigned to Rigel Pharmaceuticals, Inc., South San Francisco, CA (US)
Filed by Rigel Pharmaceuticals, Inc., South San Francisco, CA (US)
Filed on Oct. 7, 2022, as Appl. No. 17/962,305.
Application 17/962,305 is a continuation of application No. 17/087,459, filed on Nov. 2, 2020, granted, now 11,466,018.
Application 17/087,459 is a continuation of application No. 15/563,075, granted, now 10,822,337, issued on Nov. 3, 2020, previously published as PCT/US2016/024840, filed on Mar. 30, 2016.
Claims priority of provisional application 62/141,511, filed on Apr. 1, 2015.
Prior Publication US 2023/0123591 A1, Apr. 20, 2023
Int. Cl. C07D 487/04 (2006.01); C07D 401/04 (2006.01); C07D 403/04 (2006.01); C07D 417/04 (2006.01); C07D 471/04 (2006.01); C07D 519/00 (2006.01)
CPC C07D 487/04 (2013.01) [C07D 401/04 (2013.01); C07D 403/04 (2013.01); C07D 417/04 (2013.01); C07D 471/04 (2013.01); C07D 519/00 (2013.01)] 22 Claims
 
1. A compound having the structure of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof,
wherein
m is 1 or 2;
p is 0 or 1;
X is —CH2— or —O—;
A is

OG Complex Work Unit Chemistry
n is 0, 1, 2, 3, 4, or 5;
wherein each R1 is independently halogen, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6alkoxy, —C1-C6haloalkoxy, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—(C0-C6alkyl)-Ar, —O—(C0-C6alkyl)-Het, —O—(C0-C6alkyl)-Cak, —O—(C0-C6alkyl)-Hca, —NO2, or —CN, wherein the Ar, Het, Cak, Hca, and alkyl are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —ORa, —SRa, —NRa2, —C(O)ORa, —C(O)NRa2, —C(O)Ra, —S(O)Ra, —S(O)2Ra, —S(O)ORa, —S(O)2ORa, —S(O)NRa2, —S(O)2NRa2, —OC(O)Ra, —OC(O)ORa, —OC(O)NRa2, —N(R)C(O)Ra, —N(R)C(O)ORa, —N(R)C(O)NRa2, —N(R)S(O)Ra, —N(Ra)S(O)2Ra, C1-C6alkyl, or C1-C6haloalkyl;
each Ra is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano; or

OG Complex Work Unit Chemistry
wherein the Y ring is a 5- to 9-membered Hca optionally substituted by halo or C1-C6alkyl;
each R2 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, —ORc, —SRc, —NRc2, C3-8Cak, —NO2 or —CN, wherein each Rc is independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl; and
Z is a fused bicyclic ring of the formula

OG Complex Work Unit Chemistry
wherein
ring A is Ar or 5- or 6-membered Het,
wherein
Z is optionally substituted by one or two —RZ groups that are each independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)S(O)2R, —O—C1-6alkyl-OR, —O—C1-6alkyl-SR, —O—C1-6alkyl-NR2, or C3-8Cak wherein each Cak and alkyl group is optionally substituted by one or two —RZ2 groups;
wherein each —RZ2 is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —ORb, —NRb2, —C(O)Rb, —C(O)ORb, —C(O)NRb2, —S(O)2NRb2, or —S(O)2Rb;
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, and alkyl are optionally substituted with C1-C6alkyl, halogen, or C1-C6haloalkyl; and
each Rb is independently hydrogen or C1-C6alkyl.