IRE1 small molecule inhibitors

Patent metadata

Field	Value
Publication number	US-11945784-B2
Application number	US-201917296771-A
Country	US
Kind code	B2
Filing date	Dec 2, 2019
Priority date	Dec 3, 2018
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

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 C 3 -C 10 cycloalkyl;
each R1 is independently —OR 6a , —SR 6a , —S(═O)R 7 , —S(═O) 2 R 7 , or —N(R 6b ) 2 ;
each R 2 is independently halogen, —CN, —OR 8a , —SR 8a , —S(═O)R 9 , —S(═O) 2 R 9 , —S(═O) 2 N(R 8b ) 2 , —NR 8a S(═O) 2 R 9 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 8a , —OCO 2 R 9 , —N(R 8b ) 2 , —OC(═O)N(R 8b ) 2 , —NR 8a C(═O)R 9 , —NR 8a 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;
Y 5 is CR 4 ;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from N and CR 5 with the proviso that no more than two of Y 1 , Y 2 , Y 3 , and Y 4 are N;
each R 6a 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 3 -C 4 cycloalkylC 1 -C 3 alkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R 6b 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 3 -C 4 cycloalkylC 1 -C 3 alkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R 6b 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 8a 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;
each R 8b 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 8b 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 1 -C 4 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
A 2 is N or CR A ;
R A is H, halogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted aryl, or —OR 10 ;
R A1 , R A2 , R A3 and R A4 are each independently H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, or optionally substituted aryl;
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;

is phenylene or a 6-membered heteroarylene ring comprising 1 or 2 nitrogen atoms in the ring;
B is

each R 3 is independently 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;
p is 1, 2, or 3;
q is 0, 1, 2, or 3;
R 4 and each 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 R A1 is H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein R A2 is Ff.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein each R 1 is —N(R 6b ) 2 .

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein each R 6b is independently H or optionally substituted —C 1 -C 3 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein two R 6b are taken together with the N atom to which they are attached to form an optionally substituted heterocycle.

8. The compound of <s> any one of </s> claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein q is 0.

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

10. The compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein A 2 is CR A , and R A is H.

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

Assignees

• Univ Cornell

Inventors

• Vacca Joseph P
• Bettigole Sarah Elizabeth

Classifications

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D213/76

  to which a second hetero atom is attached (nitro radicals C07D213/61) · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D239/69

  Benzenesulfonamido-pyrimidines · CPC title