	US 12,391,669 B2
	Substituted pyrimidines as IRE1 kinase inhibitors
Bradley Backes, San Francisco, CA (US); Feroz R. Papa, San Francisco, CA (US); Scott Andre Oakes, San Francisco, CA (US); and Dustin J. Maly, Seattle, WA (US)
Assigned to The Regents of the University of California et al., Oakland, CA (US)
Appl. No. 17/271,363
Filed by THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, Oakland, CA (US); and UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION, Seattle, WA (US)
PCT Filed Aug. 30, 2019, PCT No. PCT/US2019/049238 § 371(c)(1), (2) Date Feb. 25, 2021, PCT Pub. No. WO2020/047518, PCT Pub. Date Mar. 5, 2020.
Claims priority of provisional application 62/725,177, filed on Aug. 30, 2018.
Prior Publication US 2021/0198238 A1, Jul. 1, 2021
Int. Cl. A61K 31/506 (2006.01); C07D 239/12 (2006.01); C07D 401/14 (2006.01); C07D 417/14 (2006.01)

CPC C07D 401/14 (2013.01) [C07D 417/14 (2013.01)]

18 Claims

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

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

wherein:

R¹¹is NR¹⁴R¹⁴or a nitrogen-containing heterocycloalkyl, wherein the nitrogen-containing heterocycloalkyl is substituted with n independently selected R⁵substituents;

each R¹⁴is independently hydrogen, alkyl, heteroalkyl, CH₂X¹⁴, CH(X¹⁴)₂, C(X¹⁴)₃, C(O)R^14A, C(O)NR^14AR^14B, C(O)NHNR^14AR^14B, C(O)OR^14A, NR^14AR^14B, NR^14AC(O)R^14B, NHC(O)NR^14AR^14B, NR^14AC(O)OR^14B, NHNR^14AR^14B, NR^14AOR^14B, NR^14AS(O)₂R^14B, OR^14A, OCH₂X¹⁴, OCH(X¹⁴)₂, OC(X¹⁴)₃, SR^14A, S(O)R^14A, S(O)₂R^14A, S(O)₂NR^14AR^14B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R^14Ais independently hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R^14Bis independently hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X¹⁴is independently halogen;

each R⁵is independently halogen, CN, NO₂, alkyl, heteroalkyl, CH₂X⁵, CH(X⁵)₂, C(X⁵)₃, C(O)R^5A, C(O)NR^5AR^5B, C(O)NHNR^5AR^5B, C(O)OR^5A, NR^5AR^5B, NR^5AC(O)R^5B, NHC(O)NR^5AR^5B, NR^5AC(O)OR^5B, NHNR^5AR^5B, N₃, NR^5AOR^5B, NR^5AS(O)₂R^5B, OR^5A, OCH₂X⁵, OCH(X⁵)₂, OC(X⁵)₃, SR^5A, S(O)R^5A, S(O)₂R^5A, S(O)₂NR^5AR^5B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R^5Ais independently hydrogen, alkyl, heteroalkyl, CH₂X⁵, CH(X⁵)₂, C(X⁵)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X⁵, OCH(X⁵)₂, OC(X⁵)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R^5Bis independently hydrogen, alkyl, heteroalkyl, CH₂X⁵, CH(X⁵)₂, C(X⁵)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X⁵, OCH(X⁵)₂, OC(X⁵)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X⁵is independently halogen;

L²is a bond;

R¹⁰is alkyl, heteroalkyl, CH₂X¹⁰, CH(X¹⁰)₂, C(X¹⁰)₃, C(O)R^10A, C(O)NR^10AR^10B, C(O)NHNR^10AR^10BC(O)OR^10A, NR^10AR^10B, NR^10AC(O)R^10B, NHC(O)NR^10AR^10B, NR^10AC(O)OR^10B, NHNR^10AR^10B, NR^10AOR^10B, NR^10AS(O)₂R^10B, OR^10A, OCH₂X¹⁰, OCH(X¹⁰)₂, OC(X¹⁰)₃, SR^10A, S(O)R^10A, S(O)₂R^10A, S(O)₂NR^10AR^10B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^10Ais hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^10Bis hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X¹⁰is independently halogen;

R¹is hydrogen, halogen, CN, NO₂, alkyl, heteroalkyl, CH₂X¹, CH(X¹)₂, C(X¹)₃, C(O)R^1A, C(O)NR^1AR^1B, C(O)NHNR^1AR^1BC(O)OR^1A, NR^1AR^1B, NR^1AC(O)R^1B, NHC(O)NR^1AR^1B, NR^1AC(O)OR^1B, NHNR^1AR^1B, N₃, NR^1AOR^1B, NR^1AS(O)₂R^1B, OR^1A, OCH₂X¹, OCH(X¹)₂, OC(X¹)₃, SR^1A, S(O)R^1A, S(O)₂R^1A, S(O)₂NR^1AR^1B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^1Ais hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^1Bis hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X¹is independently halogen;

R²is hydrogen, halogen, CN, NO₂, alkyl, heteroalkyl, CH₂X², CH(X²)₂, C(X²)₃, C(O)R^2A, C(O)NR^2AR^2B, C(O)NHNR^2AR^2B, C(O)OR^2A, NR^2AR^2B, NR^2AC(O)R^2B, NHC(O)NR^2AR^2B, NR^2AC(O)OR^2B, NHNR^2AR^2B, N₃, NR^2AOR^2B, NR^2AS(O)₂R^2B, OR^2A, OCH₂X², OCH(X²)₂, OC(X²)₃, SR^2A, S(O)R^2A, S(O)₂R^2A, S(O)₂NR^2AR^2B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^2Ais hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^2Bis hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X²is independently halogen;

R³is hydrogen, halogen, CN, NO₂, alkyl, heteroalkyl, CH₂X³, CH(X³)₂, C(X³)₃, C(O)R^3A, C(O)NR^3AR^3BC(O)NHNR^3AR^3B, C(O)OR^3A, NR^3AR^3B, NR^3AC(O)R^3B, NHC(O)NR^3AR^3B, NR^3AC(O)OR^3B, NHNR^3AR^3BN₃, NR^3AOR^3B, NR^3AS(O)₂R^3B, OR^3A, OCH₂X³, OCH(X³)₂, OC(X³)₃, SR^3A, S(O)R^3A, S(O)₂R^3A, S(O)₂NR^3AR^3B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^3Ais hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^3Bis hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X³is independently halogen;

ring A is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with n independently selected R⁸substituents;

each R⁸is independently halogen, CN, NO₂, alkyl, heteroalkyl, CH₂X⁸, CH(X⁸)₂, C(X⁸)₃, C(O)R^8A, C(O)NR^8AR^8B, C(O)NHNR^8AR^8B, C(O)OR^8A, NR^8AR^8B, NR^8AC(O)R^8B, NHC(O)NR^8AR^8B, NR^8AC(O)OR^8B, NHNR^8AR^8B, N₃, NR^8AOR^8B, NR^8AS(O)₂R^8B, OR^8A, OCH₂X⁸, OCH(X⁸)₂, OC(X⁸)₃, SR^8A, S(O)R^8A'S(O)₂R^8A, S(O)₂NR^8AR^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, NO₂, alkyl, heteroalkyl, CF₃, CCl₃, CBr₃, CI₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, N₃, NHOH, NHS(O)₂H, OH, OCH₂F, OCH₂Cl, OCH₂Br, OCH₂I, OCHF₂, OCHCl₂, OCHBr₂, OCHI₂, OCF₃, OCCl₃, OCBr₃, OCI₃, ONH₂, OS(O)₂OH, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

each R^8Ais independently hydrogen, alkyl, heteroalkyl, CH₂X⁸, CH(X⁸)₂, C(X⁸)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X⁸, OCH(X⁸)₂, OC(X⁸)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R^8Bis independently hydrogen, alkyl, heteroalkyl, CH₂X⁸, CH(X⁸)₂, C(X⁸)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X⁸, OCH(X⁸)₂, OC(X⁸)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X⁸is independently halogen;

L¹is alkylene, —CH₂NR¹²S(O)₂—, —CH₂S(O)₂NR¹²—, —C(O)—, —C(O)NR¹²—, —C(O)NR¹²CH₂—, —C(O)O—, —NR¹²—, —NR¹²C(O)—, —NR¹²C(O)O—, —NR¹²S(O)₂—, —NR¹²S(O)₂CH₂—, —O—, —OC(O)—, —OC(O)NR¹²—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR¹²—, or —S(O)₂NR¹²CH₂—;

R¹²is hydrogen, alkyl, heteroalkyl, CH₂X¹², CH(X¹₂)₂, C(X¹₂)₃, C(O)R^12A, C(O)NR^12AR^12BC(O)NHNR^12AR^12B, C(O)OR^12A, NR^12AR^12B, NR^12AC(O)R^12B, NHC(O)NR^12AR^12B, NR^12AC(O)OR^12B, NHNR^12AR^12B, NR^12AOR^12B, NR^12AS(O)₂R^12B, OR^12A, OCH₂X¹², OCH(X¹²)₂, OC(X¹²)₃, SR^12A, S(O)R^12AS(O)₂R^12A, S(O)₂NR^12AR^12B, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^12Ais hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R^12Bis hydrogen, alkyl, heteroalkyl, CH₂X, CH(X)₂, C(X)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X, OCH(X)₂, OC(X)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X¹²is 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 R⁶substituents;

each R⁶is independently halogen, CN, NO₂, alkyl, heteroalkyl, CH₂X⁶, CH(X⁶)₂, C(X⁶)₃, C(O)R^6A, C(O)NR^6AR^6B, C(O)NHNR^6AR^6B, C(O)OR^6A, NR^6AR^6B, NR^6AC(O)R^6B, NHC(O)NR^6AR^6B, NR^6AC(O)OR^6B, NHNR^6AR^6B, N₃, NR^6AOR^6B, NR^6AS(O)₂R^6B, OR^6A, OCH₂X⁶, OCH(X⁶)₂, OC(X⁶)₃, SR^6A, S(O)R^6A, S(O)₂R^6A, S(O)₂NR^6AR^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, NO₂, alkyl, heteroalkyl, CF₃, CCl₃, CBr₃, CI₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, N₃, NHOH, NHS(O)₂H, OH, OCH₂F, OCH₂Cl, OCH₂Br, OCH₂I, OCHF₂, OCHCl₂, OCHBr₂, OCHI₂, OCF₃, OCCl₃, OCBr₃, OCI₃, ONH₂, OS(O)₂OH, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

each R^6Ais independently hydrogen, alkyl, heteroalkyl, CH₂X⁶, CH(X⁶)₂, C(X⁶)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X⁶, OCH(X⁶)₂, OC(X⁶)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R^6Bis independently hydrogen, alkyl, heteroalkyl, CH₂X⁶, CH(X⁶)₂, C(X⁶)₃, C(O)NH₂, C(O)OH, NH₂, NHC(O)H, NHC(O)NH₂, NHC(O)NHNH₂, NHC(O)OH, NHNH₂, NHOH, NHS(O)₂H, OH, OS(O)₂OH, OCH₂X⁶, OCH(X⁶)₂, OC(X⁶)₃, ONH₂, SH, S(O)₂NH₂, S(O)₂OH, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or

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

each X⁶is independently halogen;

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

z is 0, 1, or 2.

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