IRE1 small molecule inhibitors

Patent metadata

Field	Value
Publication number	US-11021466-B2
Application number	US-201916543188-A
Country	US
Kind code	B2
Filing date	Aug 16, 2019
Priority date	Jun 1, 2017
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.

First claim

What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,

is a substituted C 3 -C 10 cycloalkyl that is substituted with 1-3R 1 and 0-3R 2 ;
each R 1 is independently —OR 6 , —SR 6 , —S(═O)R 7 , —S(═O) 2 R 7 , or —N(R 6 ) 2 ;
each R 2 is independently H, halogen, —CN, —OR 8 , —SR 8 , —S(═O)R 9 , —S(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —NR 8 S(═O) 2 R 9 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 8 , —OCO 2 R 9 , —N(R 8 ) 2 , —OC(═O)N(R 8 ) 2 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R 6 is independently H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 fluoroalkyl, —X-optionally substituted C 1 -C 4 alkyl, —X-optionally substituted C 1 -C 4 heteroalkyl, —X-optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R 6 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
X is —(C═O)—;
each R 7 is independently optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R 8 is independently H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R 8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R 9 is independently optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, or optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
A 2 is N or CR A ;
R A , R A1 , R A2 ,and R A3 are each independently H, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted aryl, or —OR 10 ;
R 10 is independently H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R 3 is independently H, halogen, —CN, —OR 11 , —SR 11 , —N(R 11 ) 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R 11 is independently H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
n is 0, 1, 2, 3, or 4;
R 4 and R 5 are each independently H, halogen, —CN, —OR 12 , —SR 12 , —N(R 12 ) 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 12 is independently H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein

is substituted C 4 -C 7 cycloalkyl that is substituted with 1-3R 1 and 0-3R 2 .

3. The compound of claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, wherein

and
q is 0, 1, 2, or 3.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein

and
q is 0, 1, 2, or 3.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein

and
q is 0, 1, 2, or 3.

6. The compound of claim 3 , or a pharmaceutically acceptable salt, or solvate thereof, wherein

R 6 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, optionally substituted C 1 -C 4 fluoroalkyl, —X-optionally substituted C 1 -C 4 alkyl, —X-optionally substituted C 1 -C 4 heteroalkyl, or —X-optionally substituted C 1 -C 4 fluoroalkyl;
q is 0 or 1; and
R 2 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 heteroalkyl, or optionally substituted C 1 -C 4 fluoroalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:

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

9. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (Ia)

10. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (Ib)

11. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (Ic)

Assignees

• Univ Cornell

Inventors

• Vacca Joseph P
• Li Dansu
• Bettigole Sarah

Classifications

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D417/04

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

• C07D239/84

  Nitrogen atoms · CPC title

• C07D401/04

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

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title