Modulators of the integrated stress pathway

Patent metadata

Field	Value
Publication number	US-10913727-B2
Application number	US-201716098679-A
Country	US
Kind code	B2
Filing date	May 5, 2017
Priority date	May 5, 2016
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

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

We claim:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
D is selected from the group consisting of

L 1 is CH 2 O—*, wherein “—*” indicates the attachment point to A;
R 1 and R 2 are each independently hydrogen or C 1 -C 6 alkyl;
Q is C(O) or S(O) 2 ;
A is phenyl and W is 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 , —SR E , —S(O)R B , —S(O) 2 R D , and G 2 ;
each R Y is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, hydroxy-C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkenyl, halo-C 1 -C 6 alkyl, halo-C 1 -C 6 alkoxy, amino-C 1 -C 6 alkyl, amido-C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, siloxy-C 1 -C 6 alkoxy, hydroxyl-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkenyl, C 1 -C 6 alkoxy-C 1 -C 6 alkoxy, 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 , —S(O)NR B R C , —NR B S(O) 2 R D , —OS(O)R D , —OS(O) 2 R D , R F S—C 1 -C 6 alkyl, R D C(O)NR B —C 1 -C 6 alkyl, (R B )(R C )N—C 1 -C 6 alkoxy, R D OC(O)NR B —C 1 -C 6 alkyl, G 1 , G 1 -C 1 -C 6 alkyl, G 1 -N(R B ), G 1 -C 1 -C 6 alkenyl, G 1 -O—, G 1 C(O)NR B —C 1 -C 6 alkyl, and G 1 -NR B C(O); or
2 R Y groups on adjacent atoms, together with the atoms to which they are attached form a fused phenyl, a 3-7-membered fused cycloalkyl ring, a 3-7-membered fused heterocyclyl ring, or a 5-6-membered fused heteroaryl ring, each optionally substituted with 1-5 R X ;
each G 1 or G 2 is independently 3-7 membered cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7 membered cycloalkyl, 4-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-6 R Z ;
each R Z is independently selected from the group consisting of OR A , C(O)R D , halo, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, C(O)R D , and C(O)OR D ;
R A is, at each occurrence, independently hydrogen, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, —ORA 1 , —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, C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, G 1 -C 1 -C 6 alkyl, 3-7 membered cycloalkyl, or 4-7-membered heterocyclyl, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-6 R Z ; or
R B and R C together with the atom to which they are attached form a 3-7-membered cycloalkyl or heterocyclyl ring optionally substituted with 1-6 R Z ;
R D is, at each occurrence, independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, or halo-C 1 -C 6 alkyl;
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, or halo;
each RA 1 is hydrogen, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, 3-7 membered cycloalkyl, or 4-7-membered heterocyclyl;
m is 1, 3, or 5; and
t is 0 or 1.

2. The compound of claim 1 , wherein D is substituted with one R X , and R X is OH.

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

4. The compound of claim 1 , wherein D is

5. The compound of claim 1 , wherein t is 1.

6. The compound of claim 1 , wherein t is 0.

7. The compound of claim 1 , wherein each of R 1 and R 2 is independently hydrogen.

8. The compound of claim 1 , wherein one of R 1 and R 2 is independently hydrogen and the other of R 1 and R 2 is independently CH 3 .

9. The compound of claim 1 , wherein Q is C(O).

10. The compound of claim 1 , wherein A is

11. The compound of claim 1 , wherein W is selected from the group consisting of:

12. The compound of claim 1 , wherein each R Y is independently selected from the group consisting of chloro, fluoro, oxo, CN, OH, CF 3 , CHF 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH═CHCH 2 OH, CH 2 CH 2 OH, CH 2 NH 2 , NHCH 3 , CH 2 NHC(O)CH 3 , N(CH 2 CH 3 ) 2 , CH 2 N(CH 3 ) 2 , C(CH 3 ) 2 OH, CH(CH 3 ) 2 , CH 2 CH 2 CH 3 , C(CH 3 ) 3 , CH 2 CH(CH 3 ) 2 , CH 2 CH 2 OH, CH(OH)CH 3 , CH 2 CH 2 CH 2 OCH 3 , CH 2 CF 3 , CH 2 C(CH 3 ) 2 OH, CH 2 SCH 3 , CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 C(CH 3 ) 2 OH, CH 2 NHC(O)CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 OCH 3 , OCH(CH 3 ) 2 , OCF 3 , OCH 2 CF 3 , OCH 2 CH 2 N(CH 3 ) 2 , CH 2 OH, CH 2 OCH 3 , OCH 2 CH 2 OH, OCHF 2 , OCF 3 , OCH 3 , CH 2 OH, C(O)OH, C(O)CH 3 , C(O)OCH 3 , C(O)NH 2 , C(O)NHCH 2 CH 2 CH 2 OH, CH 2 CN, C(O)OCH 2 CH 3 , C(O)NHCH 2 CH 3 , OCH 2 CH 2 OSi(CH 3 ) 2 C(CH 3 ) 3 , CH 2 N(CH 3 ) 2 , CH 2 NHC(O)CH 3 , CH 2 NHC(O)OC(CH 3 ) 3 , CH═CHCH 2 OCH 3 , CH═CHC(CH 3 ) 2 OH, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , NHCH 2 CH 3 , NHC(O)CH 3 , NHC(O)CH 2 OCH 3 , NHS(O) 2 CH 3 , SCH 3 , SCH 2 CH 3 , SO 2 NH 2 , S(O)CH 3 , S(O) 2 CH 3 , C(O)NHG 1 , N(CH 3 )CH 2 G 1 , NHG 1 , OG 1 , CH 2 G 1 , CH 2 CH 2 G 1 , CH 2 NHC(O)G 1 , and CH═CHG 1 , or
2 R Y groups on adjacent atoms, together with the atoms to which they are attached, form a 5-7-membered fused heterocyclyl ring, 5-6-membered fused heteroaryl, a 5-6-membered fused cycloalkyl, or a fused phenyl, each optionally substituted with 1-5 Rx.

13. The compound of claim 11 , wherein the 2 R Y together with the atoms to which they are attached form a dioxolanyl, hexahydropyrimidinyl, pyridyl, or pyrimidinyl ring, each of which is optionally substituted with 1-5 R X .

14. The compound of claim 13 , wherein each R X is independently C 1 -C 6 alkyl, fluoro, chloro, oxo, OCH 3 , C(O)OCH 3 , or G 2 .

15. The compound of claim 1 , wherein G 1 is pyrrolidinyl, azetidinyl, cyclopropyl, cyclohexyl, cyclohexenyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, piperidinyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, morphilino, furanyl, triazolyl, oxetanyl, or pyrazinyl, each of which is optionally substituted with 1-5 R Z .

16. The compound of claim 15 , wherein each R Z is independently fluoro, chloro, OH, OCH 3 , oxo, CH 3 , CHF 2 , CF 3 , C(O)CH 3 or C(O)OC(CH 3 ) 3 .

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

or a pharmaceutically acceptable salt thereof, wherein:
D is bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, or bicyclo[2.1.1]hexane, each of which is optionally substituted with 1-4 R X ;
L 1 CH 2 O—*, wherein “—*” indicates the attachment po

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

• C07D213/54

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C235/14

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C233/74

  with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C233/79

  with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C255/41

  the carbon skeleton being further substituted by carboxyl groups, other than cyano groups · CPC title