US2021269399A1PendingUtilityA1
Modulators of the integrated stress pathway
Est. expiryMay 5, 2036(~9.8 yrs left)· nominal 20-yr term from priority
Inventors:Carmela SidrauskiMarina PliushchevJennifer M. FrostLawrence A. BlackXiangdong XuRamzi F. SweisLei ShiQingwei ZhangYunsong TongCharles W. HutchinsSeungwon ChungMichael J. Dart
A61K 31/4965A61P 37/08C07D 231/12A61P 3/10A61P 13/02A61P 25/04A61K 31/505C07D 271/10C07D 307/52A61P 7/00A61P 37/02A61P 21/04A61K 31/417A61P 13/12A61K 31/421A61P 15/00A61K 31/44C07C 2603/90A61K 31/197A61P 19/02A61P 9/00C07D 235/00C07D 471/04A61K 31/4439A61K 31/42C07C 2602/44A61K 31/341C07D 239/34C07D 333/20A61P 25/28C07D 261/08A61P 17/02C07C 2602/38C07D 241/12A61K 31/426A61P 1/16A61P 27/02A61K 31/415C07D 213/89A61K 31/50C07D 213/42C07D 213/40C07D 263/32A61P 5/40C07D 307/36C07D 209/14A61K 31/4245C07C 2602/42A61K 31/18A61P 25/14C07C 235/22C07C 2602/40A61P 1/18A61P 17/00A61P 5/14A61P 11/06C07D 277/28C07D 271/07A61P 17/08C07C 311/16C07D 213/64A61P 9/14A61K 31/4045A61P 19/00A61P 21/00A61P 29/00A61P 37/06A61P 3/00A61P 9/10A61P 17/06A61P 3/04A61P 1/04A61P 25/00C07C 323/09A61K 31/381A61P 35/00C07D 237/08A61P 31/18A61P 43/00A61P 21/02A61P 25/16
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Claims
Abstract
Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.
Claims
exact text as granted — not AI-modified1 .- 40 . (canceled)
41 . A method of making a compound of Formula (1-6):
or a pharmaceutically acceptable salt thereof, comprising:
(i) contacting a compound of formula (1-1):
with compound of Formula (1-2):
to make a compound of Formula (1-3):
followed by a hydrolysis step to make a compound of formula (1-4):
(ii) contacting the compound of formula (1-4) with a compound of Formula (1-5):
thereby making the compound of Formula (1-6); wherein:
D is
L 1 is 2-7-membered heteroalkylene and L 2 is selected from C1-C6 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 C1-C6 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 C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 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 , —SR E , —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.
42 . The method of claim 41 , wherein D is substituted with 0 R X .
43 . The method of claim 41 , wherein D is
44 . The method of claim 41 , wherein L 1 is independently selected from —CH 2 O—* or —CH 2 CH 2 O—*, and “—*” indicates the attachment point to A.
45 . The method of claim 41 , wherein L 2 is independently selected from —CH 2 —*, —CH 2 CH 2 —*, —CH 2 CH 2 CH 2 —*, —CH(CH 3 )—*, —CH(CH 3 )CH 2 —*, —CH 2 O—*, or —CH 2 CH 2 O—*, and “—*” indicates the attachment point to W.
46 . The method of claim 41 , 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 .
47 . The method of claim 41 , wherein A is
48 . The method of claim 41 , wherein W is selected from the group consisting of:
49 . The method of claim 41 , wherein each R Y is independently 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 .
50 . The method of claim 41 , wherein each R Y is independently 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 .
51 . The method of claim 41 , wherein G 1 is phenyl optionally substituted with 1-3 R Z .
52 . The method of claim 51 , wherein R Z is C 1 -C 6 alkyl.
53 . The method of claim 41 , 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.
54 . The method of claim 41 , wherein the compound of Formula (1-6) is selected from the group consisting of:
and a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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