CDP protein secretion inhibitors

Patent metadata

Field	Value
Publication number	US-11339193-B2
Application number	US-201917042009-A
Country	US
Kind code	B2
Filing date	Mar 29, 2019
Priority date	Mar 29, 2018
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

Provided herein are compounds that inhibit protein secretion, e.g., via inhibition of Sec61. Also provided are compositions of the inhibitor compounds, and methods of using these inhibitors. The compounds disclosed herein can be used, e.g., for the treatment of cancer, arthritis, and/or inflammation.

First claim

What is claimed:

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

wherein
R 1 is H, C 0-3 alkylene-CN, or C 2-6 alkynyl;
R 2 is isobutyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 0-3 alkylene-C 3-8 cycloalkyl, C 0-3 alkylene-C 3-8 cycloalkenyl, C 0-3 alkylene-C 3-6 heterocycloalkyl, or C 0-3 alkylene-C 3-6 heterocycloalkenyl;
R 3 is C 1-6 alkyl, C 2-8 alkenyl, C 1-6 haloalkyl, C 1-8 hydroxyalkyl, C 0-3 alkylene-C 3-8 cycloalkyl, or C 0-3 alkylene-C 3-8 cycloalkenyl;
R 4 is C 1-8 alkyl, C 2-8 alkenyl, C 1-8 hydroxyalkyl, C 0-3 alkylene-C 3-8 cycloalkyl, C 0-3 alkylene-C 3-8 cycloalkenyl, or C 0-3 alkylene-C 3-6 heterocycloalkyl;
R 5 is C 3-8 cycloalkyl, C 3-8 cycloalkenyl, halo-substituted aryl, benzothiophenyl, tetrahydrobenzothiophenyl, triazolyl, quinolinyl, quinolinonyl, quinolonyl, tetrahydroquinolinyl, tetrahydroquinolinonyl, tetrahydroquinolonyl or indolyl,
wherein the indolyl is N-substituted, and the quinolonyl or tetraquinolonyl is optionally N-substituted, and the N-substituent comprises C 3-8 alkynyl, C 0-2 alkylene- C 3-8 cycloalkyl, C 0-2 alkylene- C 3-8 cycloalkenyl, C 0-2 alkylene-substituted aryl, or C 0-2 alkylene-heteroaryl, and the substituted aryl is substituted with one or more groups selected from halo, alkyl, haloalkyl, OH, and alkoxy; and
the benzothiophenyl is substituted with one or more groups selected from halo, haloalkyl, alkyl, OH, and alkoxy;

R 6 is CH 3 , CH 2 CH(CH 3 ) 2 , CH 2 CH(CH 3 )(CH 2 ) 3 CH 3 , C 1-8 haloalkyl, or C 0-3 alkylene-C 3-8 cycloalkenyl;
R 7 is C 1-8 alkyl; and
each of R N2 , R N3 , R N4 , R N5 , R N6 , and R N7 is independently H or C 1-3 alkyl.

2. The compound or salt of claim 1 , wherein R 1 is:
(i) CH 2 CN; or
(ii) (CH 2 ) 0-2 C≡CH; or
(iii) H.

3. The compound or salt of claim 1 , wherein R 2 is isobutyl, C 1-8 haloalkyl, C 0-3 alkylene-C 3-8 cycloalkenyl or C 0-3 alkylene-C 3-8 cycloalkyl.

4. The compound or salt of claim 1 , wherein R 2 is CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 -1-cyclohexenyl, CH 2 -1-cyclopentenyl, CH 2 -cyclopropyl, CH 2 -cyclopentyl, CH 2 -cyclohexyl, or CH 2 -4-tetrahydropyranyl.

5. The compound or salt of claim 1 , wherein R 3 is:
(i) CH(CH 3 ) 2; or
(ii) C 1-8 haloalkyl, C 0-3 alkylene-C 3-8 cycloalkyl, or C 0-3 alkylene-C 3-8 cycloalkenyl.

6. The compound or salt of claim 1 , wherein R 4 is CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , tetrahydropyranyl, or cyclopentyl.

7. The compound or salt of claim 1 , wherein R 4 is C 1-8 haloalkyl, C 0-3 alkylene-C 3-8 cycloalkyl or C 0-3 alkylene-C 3-8 cycloalkenyl.

8. The compound or salt of claim 1 , wherein R 5 comprises:
(i) cyclohexyl, cyclopentyl, or cyclopentenyl; or
(ii) quinolinyl, quinolinonyl, quinolonyl, tetrahydroquinolinyl, tetrahydroquinolinonyl, or tetrahydroquinolonyl, and R 5 is substituted with one or more of C 3-8 alkynyl, C 0-2 alkylene-C 3-8 cycloalkyl, C 0-2 alkylene- C 3-8 cycloalkenyl, C 0-2 alkylene- aryl, or C 0-2 alkylene-heteroaryl.

9. The compound or salt of claim 1 , wherein R 5 is

and R′ is C 4 alkynyl, CH 2 -fluoropyridyl, CH 2 -methylpyridyl, CH 2 -methoxyphenyl, CH 2 -methylphenyl, CH 2 -fluorophenyl, CH 2 -chlorophenyl, CH 2 -bromophenyl, CH2-difluorophenyl, CH 2 -fluoromethoxyphenyl, or CH 2 -methylisooxazolyl, optionally wherein R′ is para-fluorobenzyl, para-chlorobenzyl, para-methylbenzyl, or para-bromobenzyl.

10. The compound or salt of claim 1 , wherein R 5 comprises benzothiophenyl, and the benzothiophenyl is substituted with one or more of chloro, fluoro, bromo, methyl, and methoxy.

11. The compound or salt of claim 1 , wherein R 6 is CH 3 , CH 2 CH(CH 3 ) 2 , CH 2 CH(CH 3 )(CH 2 ) 3 CH 3 , CH 2 CF 3 , or CH 2 CH 2 CF 3 .

12. The compound or salt of claim 1 , wherein R 6 is C 1-8 haloalkyl or C 0-3 alkylene-C 3-8 cycloalkenyl.

13. The compound or salt of claim 1 , wherein:
(i) R 3 is 1-cyclopentenyl or 1-cyclohexenyl; or
(ii) R 4 is 1-cyclopentenyl or 1-cyclohexenyl; or
(iii) R 6 is CH 2 -1-cyclopentenyl or CH 2 -1-cyclohexenyl; or
(iv) a combination of the foregoing.

14. The compound or salt of claim 1 , wherein R 7 is CH 3 .

15. The compound or salt of claim 1 , wherein:
(i) at least one of R N2 , R N3 , R N4 , R N5 , RN 6 , and R N7 is H; or
(ii) at least one of R N2 , R N3 , R N4 , R N5 , R N6 , and R N7 is CH 3 ; or
(iii) both (i) and (ii).

16. The compound or salt of claim 1 , wherein R N2 is H, R N3 is CH 3 , R N4 is H, R N5 is CH 3 , R N6 is H, and R 7 is CH 3 .

17. The compound of claim 1 , as listed in Table A, or a pharmaceutically acceptable salt thereof;

TABLE A

C-03

C-04

C-05

C-06

C-07

C-08

C-09

C-10

C-11

Assignees

• Kezar Life Sciences
• Univ California

Inventors

• Mcminn Dustin
• Taunton John William
• Sharp Phillip Patrick

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K11/02 Primary

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title