Phenoxy-pyridyl-pyrimidine compounds and methods of use

Patent metadata

Field	Value
Publication number	US-2023057166-A1
Application number	US-201917275606-A
Country	US
Kind code	A1
Filing date	Sep 12, 2019
Priority date	Sep 12, 2018
Publication date	Feb 23, 2023
Grant date	—

Abstract

Described herein are phenoxy-pyridyl-pyrimidine compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I structure or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

First claim

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 0 is hydrogen or fluoro;
R 1 is C 3-12 cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —(C 1-6 alkylene)-(C 3 -C 12 cycloalkyl), or —(C 1-6 alkylene)-(3- to 14-membered heterocyclyl), —(C 1-6 alkylene)-OR 1c , or —(C 1-6 alkylene)-NR 1a R 1b ; wherein the C 3-12 cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C 1-6 alkylene of R 1 are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 1a , R 1b and R 1c is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 1a and R 1b are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
R 2A and R 28 are independently hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), or —O(C 1-6 haloalkyl);
R 3 is hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), or —O(C 1-6 haloalkyl);
R 4 and R 5 are independently hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-20 aryl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —OR 7A , —NR 8A R 8B , —NR 8 C(O)R 7 , —NR 8 C(O)OR 7A , —NR 8 C(O)NR 8A R 8B , —NR 8 SO 2 R 9 , —NR 8 SO 2 NR 8A R 8B , —NR 8 S(O)(═NR 8C )R 9 , —C(O)N(R 8 )SO 2 R 9 , C(O)R 7 , —C(O)OR 7A , —SO 2 R 9 , —NR 8 S(O)(═NR 8C )R 9 , or —SO 2 NR 8A R 8B ; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 6-20 aryl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl of R 4 and R 5 are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
n is 0, 1, 2, or 3;
each R 6 is independently halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SO 2 (C 1-6 alkyl) or —SO 2 (C 1-6 haloalkyl);
each R 7 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 7 and R 7A are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 7A is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R 7 and R 7A are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 8 is independently hydrogen or C 1 -C 6 alkyl;
each R 8A is independently hydrogen or C 1 -C 6 alkyl;
each R 8B is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, and 3- to 12-membered heterocyclyl of R 8B are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 8C is independently hydrogen or C 1 -C 6 alkyl;
each R 9 is independently C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ;
each R 10 is independently oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, —C(O)R a , —C(O)OR b , —C(O)NR c R d , —OR b , —OC(O)R a , —OC(O)NR c R d , —SR b , —S(O)R e , —S(O) 2 R e , —S(O)(═NH)R e , —S(O) 2 NR c R d , —NR c R d , —N(R f )C(O)R a , —N(R f )C(O)OR b , —N(R f )C(O)NR c R d , —N(R f )S(O) 2 R e , —N(R f )S(O) 2 NR c R d , —P(O)R g R h or —SiR i R j R k ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R 10 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R a are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R b is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R b are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R c and R d is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R c and R d are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
or R c and R d are taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

each R e is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R e are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
each R f is independently hydrogen or C 1-6 alkyl;
each R g and R h is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C 1-6 alkyl; wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R g and R h are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;
or R g and R h are taken together with the phosphorus atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

each R i , R j and R k is independently C 1-6 alkyl;
each R 11 is independently oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, —C(O)R a1 , —C(O)OR b1 , —C(O)NR c1 R d1 , —OR b1 , —OC(O)R a1 , —OC(O)NR c1 R d1 , —SR b1 , —S(O)R e1 , —S(O) 2 R e1 , —S(O) 2 NR c1 R d1 , —NR c1 R d1 , —N(R f1 )C(O)R a1 , —N(R f1 )C(O)OR b1 , —N(R f1 )C(O)NR c1 R d1 , —N(R f1 )S(O) 2 R e1 , —N(R f1 )S(O) 2 NR c1 R d1 , —P(O)R g1 R h1 , or —SiR i1 R j1 R k1 ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered het

Assignees

• Genentech Inc

Inventors

• Braun Marie-Gabrielle
• Ly Cuong Q
• Castanedo Georgette
• Gibbons Paul
• Lee Wendy
• Rudolph Joachim
• Blaquiere Nicole Alice
• Schwarz Jacob Bradley
• Beveridge Ramsay
• Leclerc Jean-Philippe
• Lemire Alexandre
• Fu Leo

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title