IP Library › Granted Patent US 12,391,669
Granted Patent B2
US 12,391,669 · App. 17/271,363 · Granted Aug 19, 2025

Substituted pyrimidines as IRE1 kinase inhibitors

Inventors: Bradley Backes (San Francisco, CA); Feroz R. Papa (San Francisco, CA); Scott Andre Oakes (San Francisco, CA); Dustin J. Maly (Seattle, WA)
Assignee: The Regents of the University of California et al.
C07D401/14C07D417/14
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Quick Facts
Patent No.
US 12,391,669
App. No.
17/271,363
Granted
Aug 19, 2025
Kind
B2
Abstract

Disclosed herein are, inter alia, compounds modulating Inositol-Requiring Enzyme 1α (IRE1α) and IRE1β activity and methods of use thereof for treating IRE1α-mediated and IRE1β-mediated disorders.

Claims (85)

1. A compound of formula (Ia) or formula (Ib):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

wherein:

R 11 is NR 14 R 14 or a nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl is substituted with n independently selected R 5 substituents;

each R 14 is independently hydrogen, alkyl, heteroalkyl, CH 2 X 14 , CH(X 14 ) 2 , C(X 14 ) 3 , C(O)R 14A , C(O)NR 14A R 14B , C(O)NHNR 14A R 14B , C(O)OR 14A , NR 14A R 14B , NR 14A C(O)R 14B , NHC(O)NR 14A R 14B , NR 14A C(O)OR 14B , NHNR 14A R 14B , NR 14A OR 14B , NR 14A S(O) 2 R 14B , OR 14A , OCH 2 X 14 , OCH(X 14 ) 2 , OC(X 14 ) 3 , SR 14A , S(O)R 14A , S(O) 2 R 14A , S(O) 2 NR 14A R 14B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R 14A is independently hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R 14B is independently hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

any R 14A and R 14B , together with the nitrogen atom to which they are bonded, independently forms a heterocycloalkyl or heteroaryl;

each X 14 is independently halogen;

each R 5 is independently halogen, CN, NO 2 , alkyl, heteroalkyl, CH 2 X 5 , CH(X 5 ) 2 , C(X 5 ) 3 , C(O)R 5A , C(O)NR 5A R 5B , C(O)NHNR 5A R 5B , C(O)OR 5A , NR 5A R 5B , NR 5A C(O)R 5B , NHC(O)NR 5A R 5B , NR 5A C(O)OR 5B , NHNR 5A R 5B , N 3 , NR 5A OR 5B , NR 5A S(O) 2 R 5B , OR 5A , OCH 2 X 5 , OCH(X 5 ) 2 , OC(X 5 ) 3 , SR 5A , S(O)R 5A , S(O) 2 R 5A , S(O) 2 NR 5A R 5B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R 5A is independently hydrogen, alkyl, heteroalkyl, CH 2 X 5 , CH(X 5 ) 2 , C(X 5 ) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X 5 , OCH(X 5 ) 2 , OC(X 5 ) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R 5B is independently hydrogen, alkyl, heteroalkyl, CH 2 X 5 , CH(X 5 ) 2 , C(X 5 ) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X 5 , OCH(X 5 ) 2 , OC(X 5 ) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

any R 5A and R 5B , together with the nitrogen atom to which they are bonded, independently forms a heterocycloalkyl or heteroaryl;

each X 5 is independently halogen;

L 2 is a bond;

R 10 is alkyl, heteroalkyl, CH 2 X 10 , CH(X 10 ) 2 , C(X 10 ) 3 , C(O)R 10A , C(O)NR 10A R 10B , C(O)NHNR 10A R 10B C(O)OR 10A , NR 10A R 10B , NR 10A C(O)R 10B , NHC(O)NR 10A R 10B , NR 10A C(O)OR 10B , NHNR 10A R 10B , NR 10A OR 10B , NR 10A S(O) 2 R 10B , OR 10A , OCH 2 X 10 , OCH(X 10 ) 2 , OC(X 10 ) 3 , SR 10A , S(O)R 10A , S(O) 2 R 10A , S(O) 2 NR 10A R 10B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 10A is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 10B is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

R 10A and R 10B , together with the nitrogen atom to which they are bonded, form a heterocycloalkyl or heteroaryl;

each X 10 is independently halogen;

R 1 is hydrogen, halogen, CN, NO 2 , alkyl, heteroalkyl, CH 2 X 1 , CH(X 1 ) 2 , C(X 1 ) 3 , C(O)R 1A , C(O)NR 1A R 1B , C(O)NHNR 1A R 1B C(O)OR 1A , NR 1A R 1B , NR 1A C(O)R 1B , NHC(O)NR 1A R 1B , NR 1A C(O)OR 1B , NHNR 1A R 1B , N 3 , NR 1A OR 1B , NR 1A S(O) 2 R 1B , OR 1A , OCH 2 X 1 , OCH(X 1 ) 2 , OC(X 1 ) 3 , SR 1A , S(O)R 1A , S(O) 2 R 1A , S(O) 2 NR 1A R 1B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 1A is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 1B is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

R 1A and R 1B , together with the nitrogen atom to which they are bonded, form a heterocycloalkyl or heteroaryl;

each X 1 is independently halogen;

R 2 is hydrogen, halogen, CN, NO 2 , alkyl, heteroalkyl, CH 2 X 2 , CH(X 2 ) 2 , C(X 2 ) 3 , C(O)R 2A , C(O)NR 2A R 2B , C(O)NHNR 2A R 2B , C(O)OR 2A , NR 2A R 2B , NR 2A C(O)R 2B , NHC(O)NR 2A R 2B , NR 2A C(O)OR 2B , NHNR 2A R 2B , N 3 , NR 2A OR 2B , NR 2A S(O) 2 R 2B , OR 2A , OCH 2 X 2 , OCH(X 2 ) 2 , OC(X 2 ) 3 , SR 2A , S(O)R 2A , S(O) 2 R 2A , S(O) 2 NR 2A R 2B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 2A is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 2B is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

R 2A and R 2B , together with the nitrogen atom to which they are bonded, form a heterocycloalkyl or heteroaryl;

each X 2 is independently halogen;

R 3 is hydrogen, halogen, CN, NO 2 , alkyl, heteroalkyl, CH 2 X 3 , CH(X 3 ) 2 , C(X 3 ) 3 , C(O)R 3A , C(O)NR 3A R 3B C(O)NHNR 3A R 3B , C(O)OR 3A , NR 3A R 3B , NR 3A C(O)R 3B , NHC(O)NR 3A R 3B , NR 3A C(O)OR 3B , NHNR 3A R 3B N 3 , NR 3A OR 3B , NR 3A S(O) 2 R 3B , OR 3A , OCH 2 X 3 , OCH(X 3 ) 2 , OC(X 3 ) 3 , SR 3A , S(O)R 3A , S(O) 2 R 3A , S(O) 2 NR 3A R 3B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 3A is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 3B is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

R 3A and R 3B , together with the nitrogen atom to which they are bonded, form a heterocycloalkyl or heteroaryl;

each X 3 is independently halogen;

ring A is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with n independently selected R 8 substituents;

each R 8 is independently halogen, CN, NO 2 , alkyl, heteroalkyl, CH 2 X 8 , CH(X 8 ) 2 , C(X 8 ) 3 , C(O)R 8A , C(O)NR 8A R 8B , C(O)NHNR 8A R 8B , C(O)OR 8A , NR 8A R 8B , NR 8A C(O)R 8B , NHC(O)NR 8A R 8B , NR 8A C(O)OR 8B , NHNR 8A R 8B , N 3 , NR 8A OR 8B , NR 8A S(O) 2 R 8B , OR 8A , OCH 2 X 8 , OCH(X 8 ) 2 , OC(X 8 ) 3 , SR 8A , S(O)R 8A 'S(O) 2 R 8A , S(O) 2 NR 8A R 8B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of halogen, NO 2 , alkyl, heteroalkyl, CF 3 , CCl 3 , CBr 3 , CI 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , N 3 , NHOH, NHS(O) 2 H, OH, OCH 2 F, OCH 2 Cl, OCH 2 Br, OCH 2 I, OCHF 2 , OCHCl 2 , OCHBr 2 , OCHI 2 , OCF 3 , OCCl 3 , OCBr 3 , OCI 3 , ONH 2 , OS(O) 2 OH, SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

each R 8A is independently hydrogen, alkyl, heteroalkyl, CH 2 X 8 , CH(X 8 ) 2 , C(X 8 ) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X 8 , OCH(X 8 ) 2 , OC(X 8 ) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R 8B is independently hydrogen, alkyl, heteroalkyl, CH 2 X 8 , CH(X 8 ) 2 , C(X 8 ) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X 8 , OCH(X 8 ) 2 , OC(X 8 ) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

any R 8A and R 8B , together with the nitrogen atom to which they are bonded, independently forms a heterocycloalkyl or heteroaryl;

each X 8 is independently halogen;

L 1 is alkylene, —CH 2 NR 12 S(O) 2 —, —CH 2 S(O) 2 NR 12 —, —C(O)—, —C(O)NR 12 —, —C(O)NR 12 CH 2 —, —C(O)O—, —NR 12 —, —NR 12 C(O)—, —NR 12 C(O)O—, —NR 12 S(O) 2 —, —NR 12 S(O) 2 CH 2 —, —O—, —OC(O)—, —OC(O)NR 12 —, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 NR 12 —, or —S(O) 2 NR 12 CH 2 —;

R 12 is hydrogen, alkyl, heteroalkyl, CH 2 X 12 , CH(X 1 2 ) 2 , C(X 1 2 ) 3 , C(O)R 12A , C(O)NR 12A R 12B C(O)NHNR 12A R 12B , C(O)OR 12A , NR 12A R 12B , NR 12A C(O)R 12B , NHC(O)NR 12A R 12B , NR 12A C(O)OR 12B , NHNR 12A R 12B , NR 12A OR 12B , NR 12A S(O) 2 R 12B , OR 12A , OCH 2 X 12 , OCH(X 12 ) 2 , OC(X 12 ) 3 , SR 12A , S(O)R 12A S(O) 2 R 12A , S(O) 2 NR 12A R 12B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 12A is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 12B is hydrogen, alkyl, heteroalkyl, CH 2 X, CH(X) 2 , C(X) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X, OCH(X) 2 , OC(X) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

R 12A and R 12B , together with the nitrogen atom to which they are bonded, form a heterocycloalkyl or heteroaryl;

each X 12 is independently halogen;

each X is independently halogen;

ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with n independently selected R 6 substituents;

each R 6 is independently halogen, CN, NO 2 , alkyl, heteroalkyl, CH 2 X 6 , CH(X 6 ) 2 , C(X 6 ) 3 , C(O)R 6A , C(O)NR 6A R 6B , C(O)NHNR 6A R 6B , C(O)OR 6A , NR 6A R 6B , NR 6A C(O)R 6B , NHC(O)NR 6A R 6B , NR 6A C(O)OR 6B , NHNR 6A R 6B , N 3 , NR 6A OR 6B , NR 6A S(O) 2 R 6B , OR 6A , OCH 2 X 6 , OCH(X 6 ) 2 , OC(X 6 ) 3 , SR 6A , S(O)R 6A , S(O) 2 R 6A , S(O) 2 NR 6A R 6B , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of halogen, NO 2 , alkyl, heteroalkyl, CF 3 , CCl 3 , CBr 3 , CI 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , N 3 , NHOH, NHS(O) 2 H, OH, OCH 2 F, OCH 2 Cl, OCH 2 Br, OCH 2 I, OCHF 2 , OCHCl 2 , OCHBr 2 , OCHI 2 , OCF 3 , OCCl 3 , OCBr 3 , OCI 3 , ONH 2 , OS(O) 2 OH, SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

each R 6A is independently hydrogen, alkyl, heteroalkyl, CH 2 X 6 , CH(X 6 ) 2 , C(X 6 ) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X 6 , OCH(X 6 ) 2 , OC(X 6 ) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R 6B is independently hydrogen, alkyl, heteroalkyl, CH 2 X 6 , CH(X 6 ) 2 , C(X 6 ) 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NH 2 , NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OS(O) 2 OH, OCH 2 X 6 , OCH(X 6 ) 2 , OC(X 6 ) 3 , ONH 2 , SH, S(O) 2 NH 2 , S(O) 2 OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

any R 6A and R 6B , together with the nitrogen atom to which they are bonded, independently forms a heterocycloalkyl or heteroaryl;

each X 6 is independently halogen;

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; and

z is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 11 is a 3- to 7-membered nitrogen-containing heterocycloalkyl, wherein the 3- to 7-membered nitrogen-containing heterocycloalkyl is optionally substituted with n independently selected R 5 substituents.

3. The compound of claim 2 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 11 is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2-oxazepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl, or 1,2,3,6-tetrahydropyridinyl, wherein the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2-oxazepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl, or 1,2,3,6-tetrahydropyridinyl is optionally substituted with n independently selected R 5 substituents.

4. The compound of claim 2 , wherein the compound is of formula (IIa) or formula (IIb):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5. The compound of claim 4 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 0, 1, or 2.

6. The compound of claim 4 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

R 5 is halogen; and

n is 1.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 is hydrogen or C 1 -C 3 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

R 2 is hydrogen; and

R 3 is hydrogen.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

ring A is a C 6 -C 10 aryl, wherein the C 6 -C 10 aryl is substituted with n independently selected R 8 substituents; and

each R 8 is independently halogen, NO 2 , C 1 -C 6 alkyl, 2- to 6-membered heteroalkyl, CF 3 , CCl 3 , CBr 3 , CI 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , N 3 , NHOH, NHS(O) 2 H, OH, OCH 2 F, OCH 2 Cl, OCH 2 Br, OCH 2 I, OCHF 2 , OCHCl 2 , OCHBr 2 , OCHI 2 , OCF 3 , OCCl 3 , OCBr 3 , OCI 3 , ONH 2 , OS(O) 2 OH, SH, S(O) 2 NH 2 , S(O) 2 OH, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- or 6-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- or 6-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of halogen, NO 2 , C 1 -C 6 alkyl, 2- to 6-membered heteroalkyl, CF 3 , CCl 3 , CBr 3 , CI 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OCH 2 F, OCH 2 Cl, OCH 2 Br, OCH 2 I, OCHF 2 , OCHCl 2 , OCHBr 2 , OCHI 2 , OCF 3 , OCCl 3 , OCBr 3 , OCI 3 , ONH 2 , OS(O) 2 OH, SH, S(O) 2 NH 2 , S(O) 2 OH, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- or 6-membered heteroaryl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

ring A is phenyl, wherein the phenyl is substituted with n independently selected R 8 substituents; and

each R 8 is independently halogen or C 1 -C 6 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein L 1 is alkylene.

12. The compound of claim 11 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein L 1 is —CH 2 —, —CH(CH 3 )—, or —CH 2 CH 2 —.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein L 1 is —C(O)—, —C(O)NR 12 —, —C(O)O—, —NR 12 —, —NR 12 C(O)—, —NR 12 C(O)O—, —NR 12 S(O) 2 —, —O—, —OC(O)—, —OC(O)NR 12 —, —S—, —S(O)—, —S(O) 2 —, or —S(O) 2 NR 12 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein L 1 is —CH 2 NHS(O) 2 —, —C(O)NH—, —C(O)NHCH 2 —, —C(O)N(CH 3 )CH 2 —, —NHS(O) 2 —, or —NHS(O) 2 CH 2 —.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

ring B is a 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- or 6-membered heteroaryl, wherein the 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- or 6-membered heteroaryl is substituted with n independently selected R 6 substituents; and

each R 6 is independently halogen, NO 2 , C 1 -C 6 alkyl, 2- to 6-membered heteroalkyl, CF 3 , CCl 3 , CBr 3 , CI 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , N 3 , NHOH, NHS(O) 2 H, OH, OCH 2 F, OCH 2 Cl, OCH 2 Br, OCH 2 I, OCHF 2 , OCHCl 2 , OCHBr 2 , OCHI 2 , OCF 3 , OCCl 3 , OCBr 3 , OCI 3 , ONH 2 , OS(O) 2 OH, SH, S(O) 2 NH 2 , S(O) 2 OH, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- or 6-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- or 6-membered heteroaryl is optionally and independently substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents independently selected from the group consisting of halogen, NO 2 , C 1 -C 6 alkyl, 2- to 6-membered heteroalkyl, CF 3 , CCl 3 , CBr 3 , CI 3 , C(O)NH 2 , C(O)OH, NH 2 , NHC(O)H, NHC(O)NHNH 2 , NHC(O)OH, NHNH 2 , NHOH, NHS(O) 2 H, OH, OCH 2 F, OCH 2 Cl, OCH 2 Br, OCH 2 I, OCHF 2 , OCHCl 2 , OCHBr 2 , OCHI 2 , OCF 3 , OCCl 3 , OCBr 3 , OCI 3 , ONH 2 , OS(O) 2 OH, SH, S(O) 2 NH 2 , S(O) 2 OH, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- or 6-membered heteroaryl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein z is 0.

17. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or tautomer thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 23, 2024
From: PAPA, FEROZ R.; BACKES, BRADLEY J.; OAKES, SCOTT A.
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 068666/0517 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 23, 2024
From: MALY, DUSTIN J.
To: UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION
Reel/Frame 068666/0635 →
CONFIRMATORY LICENSE Recorded Nov 22, 2023
From: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065664/0854 →
Continuity (2)
Provisional Application 62725177 · Aug 30, 2018
Related Publication 20210198238A1 · Jul 1, 2021
References Cited (18)
US 6046208A · Adams et al. · 2000 [cited by applicant]
US 20060009453A1 · Geuns-Meyer et al. · 2006 [cited by applicant]
US 20070213325A1 · Cee et al. · 2007 [cited by examiner]
CA 2974788A1 · 2016 [cited by examiner]
WO WO2005113494A2 · 2005 [cited by applicant]
WO WO2005113494A3 · 2005 [cited by applicant]
WO WO2018166528A1 · 2018 [cited by applicant]
WO WO2020047518A1 · 2020 [cited by examiner]
PubChemCID 57507169 , US National Library of Medicine, Aug. 8, 2012, p. 1-15; p. 2, https://pubchem.ncbi.nim.nih.gov/compound/57507169) (Year: 2012). [cited by examiner]
Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205. [cited by examiner]
Dörwald, F. Zaragoza. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design, Weinheim: WILEY-VCH Verlag Gmbh & Co. KGaA, 2005, Preface. [cited by examiner]
Harrington, P.E. et al. (Sep. 24, 2014). “Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability,” [cited by applicant]
International Search Report mailed on Nov. 26, 2019, for PCT Application No. PCT/US2019/049238, filed Aug. 30, 2019, 2 pages. [cited by applicant]
Partial Supplementary European Search Report mailed on Jun. 3, 2022, for EP Application No. 19854296.1, 11 pages. [cited by applicant]
PubChem CID 57507169, “4-(4-Methoxy-2-Methyl-1,3-Thiazol-5-y1)-N-Phenylpyrimidin-2-Amine,” Aug. 8, 2012, 15 pages. [cited by applicant]
Ramirez-Montagut, et al. (May 19, 2003). Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity, [cited by applicant]
Sawaya, G.F. et al. (Oct. 16, 2003). “Risk of cervical cancer associated with extending the interval between cervical-cancer screenings,” [cited by applicant]
Written Opinion mailed on Nov. 26, 2019, for PCT Application No. PCT/US2019/049238, filed Aug. 30, 2019, 3 pages. [cited by applicant]