Modulators of the integrated stress pathway

Patent metadata

Field	Value
Publication number	US-10836725-B2
Application number	US-201716098946-A
Country	US
Kind code	B2
Filing date	May 5, 2017
Priority date	May 5, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
D is

L 1 is 2-7-membered heteroalkylene and L 2 is selected from C 1 -C 6 alkylene or 2-7-membered heteroalkylene, wherein each alkylene and heteroalkylene is optionally substituted by 1-5 R X ;
R 1 and R 2 are each hydrogen or C 1 -C 6 alkyl;
A and W are each independently phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 R Y ;
each R X is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, amino-C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, oxo, halo, cyano, —OR A , —NR B R C , —NR B C(O)R D , —C(O)NR B R C , —C(O)R D , —C(O)OH, —C(O)OR D , —S(O)R D , and —S(O) 2 R D ;
each R Y is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, halo-C 1 -C 6 alkoxy, amino-C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, oxo, halo, cyano, —OR A , —NR B R C , —NR B C(O)R D , —C(O)NR B R C , —C(O)R D , —C(O)OH, —C(O)OR D , —S(R F ) m , —S(O)R D , —S(O) 2 R D , and G 1 ; or
2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, optionally substituted with 1-5 R X ;
each G 1 is independently C 3 -C 6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 R Z ;
each R Z is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, halo, cyano, —OR A , —NR B R C , —NR B C(O)R D , —C(O)NR B R C , —C(O)R D , —C(O)OH, —C(O)OR D , and —S(O) 2 R D ;
R A is, at each occurrence, independently hydrogen, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, —C(O)NR B R C , —C(O)R D , —C(O)OH, or —C(O)OR D ;
each of R B and R C is independently hydrogen or C 1 -C 6 alkyl; or
R B and R C together with the atom to which they are attached form a 3-7-membered heterocyclyl optionally substituted with 1-3 R Z ;
each R D is independently C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, or —NR B1 R C1 ;
each R E is independently hydrogen, C 1 -C 6 alkyl, or halo-C 1 -C 6 alkyl;
each R F is independently hydrogen, C 1 -C 6 alkyl, halo, or halo-C 1 -C 6 alkyl;
each of R B1 and R C1 is independently hydrogen or C 1 -C 6 alkyl; and
m is 1, 3, or 5.

2. The compound of claim 1 , wherein D is substituted with 0 R X .

3. The compound of claim 1 , wherein D is

4. The compound of claim 1 , wherein L 2 is selected from —CH 2 —*, —CH 2 CH 2 —*, CH 2 CH 2 CH 2 —*, —CH 2 (CH 3 )—*, —CH 2 (CH 3 )CH 2 —*, CH 2 O—* or CH 2 CH 2 O—*, and “-*” indicates the attachment point to A and W, respectively.

5. The compound of claim 1 , wherein L 1 is independently selected from CH 2 O—* or CH 2 CH 2 O—*, L 2 is independently selected from —CH 2 —*, —CH 2 CH 2 —*, CH 2 CH 2 CH 2 —*, —CH 2 (CH 3 )—*, —CH 2 (CH 3 )CH 2 —*, CH 2 O—* or CH 2 CH 2 O—*, and “-*” indicates the attachment point to A and W, respectively.

6. The compound of claim 1 , wherein A is phenyl and W is independently phenyl or 5-6 membered heteroaryl, wherein A and W are each optionally substituted with 1-5 R Y .

7. The compound of claim 1 , wherein A is

and W is selected from the group consisting of:

8. The compound of claim 1 , wherein each R Y is independently R Y is C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, halo-C 1 -C 6 alkoxy, halo, cyano, —OR A , —NR B R C , —S(O) 2 R D , —S(R F ) m , or G 1 , or 2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, optionally substituted with 1-5 R X .

9. The compound of claim 8 , wherein R Y is chloro, fluoro, —CH 3 , —CH 2 CH 3 , CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CF 3 , —CH 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCHF 2 , —OCF 3 , —OCH 2 CHF 2 , N(CH 3 ) 2 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , or SCF 3 .

10. The compound of claim 1 , wherein G 1 is phenyl optionally substituted with 1-3 R Z .

11. The compound of claim 10 , wherein each R Z is C 1 -C 6 alkyl.

12. A compound represented by Formula (I-b):

or a pharmaceutically acceptable salt thereof, wherein:
L 1 is selected from CH 2 O—* or CH 2 CH 2 O—*, L 2 is selected from —CH 2 —*, —CH 2 CH 2 —*, CH 2 CH 2 CH 2 —*, —CH 2 (CH 3 )—*, —CH 2 (CH 3 )CH 2 —*, CH 2 O—* or CH 2 CH 2 O—*, and “—*” indicates the attachment point to A and W, respectively;
R 1 and R 2 are each hydrogen or C 1 -C 6 alkyl;
A is phenyl substituted with 1-2 R Y ;
W is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-5 R Y ,
each R X is oxo or —OR A ;
each R Y is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, halo-C 1 -C 6 alkoxy, halo, cyano, —OR A , —NR B R C , —S(O) 2 R D , —S(R F ) m , or G 1 ; or
2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, optionally substituted with 1-5 R X ;
G 1 is phenyl optionally substituted with 1-3 R Z ;
each R Z is independently C 1 -C 6 alkyl;
R A is, at each occurrence, independently hydrogen, C 1 -C 6 alkyl, or halo-C 1 -C 6 alkyl;
each of R B and R C is independently hydrogen or C 1 -C 6 alkyl;
each R D is independently C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, or —NR B1 R C1 ;
each R F is independently hydrogen, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, or halo;
each of R B1 and R C1 is independently hydrogen or C 1 -C 6 alkyl; and
m is 1, 3, or 5.

13. A compound selected from the group consisting of:

Assignees

• Calico Life Sciences Llc
• Abbvie Inc

Inventors

• Pliushchev Marina
• Frost Jennifer M
• Black Lawrence A
• Xu Xiangdong
• Sweis Ramzi Farah
• Shi Lei
• Zhang Qingwei I
• Tong Yunsong
• Hutchins Charles W
• Chung Seungwon
• Dart Michael J

Classifications

• C07C2602/38

  the bicyclo ring system containing five carbon atoms · CPC title

• C07C2602/44

  the bicyclo ring system containing eight carbon atoms · CPC title

• C07D213/40

  Acylated substituent nitrogen atom · CPC title

• C07D307/52

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D271/07

  with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical · CPC title