IP Library › Granted Patent US 11,242,361

Granted Patent B2

US 11,242,361 · App. 16/902,019 · Granted Feb 8, 2022

Proteasome activity enhancing compounds

Inventors: Matthew Cullen (Braintree, MA); Sheila Hauck (Lincoln, MA); Bolin Geng (Andover, MA); Megan Foley (Cambridge, MA); Cecilia M. Bastos (S. Grafton, MA); Benito Munoz (Newtonville, MA); Markus Haeberlein (Wellesley, MA); Bradley Tait (North Andover, MA)

Assignee: Proteostasis Therapeutics, Inc.

C07F7/1804 C07B59/002 C07D209/12 C07D209/14 C07D401/06 C07D401/14 C07D403/06 C07D417/14 C07D471/04 C07D519/00 C07B2200/05

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,242,361
App. No.: 16/902,019
Granted: Feb 8, 2022
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention is directed to compounds having the Formula (I), (II), (III), (IV), and (V), compositions thereof, and methods for the treatment of a condition associated with a dysfunction in proteostasis.

Claims (75)

1. A compound having a structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof:

wherein

R 1 and R 2 are hydrogen;

R g is selected from the group consisting of hydrogen, halo, and R c ;

R j is C 1-4 alkyl;

R 3b and R 3c are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein each C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, aryl, heterocyclic, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, C(O)OR′, C(O)NR″R″, S(O) 2 , S(O) 2 NR″R″, NR″S(O) 2 R c , NR″C(O)R c , NR″C(O)OR′, NR″C(O)NR″R″, CN, OR′, OC(O)R c , NR″R″, optionally substituted heterocyclic, and optionally substituted heteroaryl;

each R′ is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

each R″ is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or two geminal R″ groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;

R 3f is selected from the group consisting of hydrogen, halo, NO 2 , and CN; and

Z is

wherein:

G is absent, C(R n ) 2 , O, or S; and

each R m and R n are independently selected from the group consisting of hydrogen, deuterium, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein

each n is independently 0, 1 or 2,

each R c is independently selected from the group consisting of hydrogen and C 1 -C 10 alkyl, and

each R d is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R j is methyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b and R 3c are each hydrogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen and R 3c is halo.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen and R 3c is optionally substituted methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3c is C 1-10 alkyl substituted with a substituent selected from the group consisting of halo, oxo, C(O)OR′, C(O)NR″R″, S(O) 2 NR″R″, NR″S(O) 2 R c , NR″C(O)R c , NR″C(O)OR′, OR′, OC(O)R c , NR″R″, optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein

each R′ is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl, and

each R″ is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, and optionally substituted C 3 -C 12 cycloalkyl; or two geminal R″ groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3c is C 1-10 alkyl substituted with C(O)NR″R″, wherein each R″ is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, and optionally substituted C 3 -C 12 cycloalkyl; or two geminal R″ groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3f is halo or CN.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein each R m and R n are independently selected from the group consisting of hydrogen, deuterium, optionally substituted C 1 -C 10 alkyl, halo, OR c , NR d R d , C(O)R c , and N(R d )(COOR c ), and wherein each R c is selected from the group consisting of hydrogen and C 1 -C 10 alkyl and each R d is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein Z is selected from the group consisting of optionally substituted 1-piperidinyl, and optionally substituted 4-morpholinyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein Z is optionally substituted 1-pyrrolidinyl or optionally substituted 1-piperidinyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein Z is optionally substituted 1-piperidinyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, selected from the group consisting of:

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

16. A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

17. A method of alleviating the symptoms of a cancer selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, multiple myeloma, basal cell carcinoma, neuroblastoma, hematologic cancer, rhabdomyosarcoma, liver cancer, skin cancer, leukemia, basal cell carcinoma, bladder cancer, endometrial cancer, glioma, lymphoma, and gastrointestinal cancer in a subject in need thereof comprising administering to said subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

18. A compound having a structure of Formula (III), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof:

wherein

Q 6 and Q 7 are CH;

R 1 and R 2 are hydrogen;

R g is selected from the group consisting of hydrogen, halo, and OR c ;

R i is C 1-4 alkyl;

R 3a is selected from the group consisting of hydrogen, halo, and OR c ;

R 3b is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein each C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, aryl, heterocyclic, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, C(O)OR′, C(O)NR″R″, S(O) 2 , S(O) 2 NR″R″, NR″S(O) 2 R c , NR″C(O)R c , NR″C(O)OR′, NR″C(O)NR″R″, CN, OR′, OC(O)R c , NR″R″, optionally substituted heterocyclic, and optionally substituted heteroaryl;

R 3c is selected from the group consisting of optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein each C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, aryl, heterocyclic, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, C(O)OR′, C(O)NR″R″, S(O) 2 , S(O) 2 NR″R″, NR″S(O) 2 R c , NR″C(O)R c , NR″C(O)OR′, NR″C(O)NR″R″, CN, OR′, OC(O)R c , NR″R″, optionally substituted heterocyclic, and optionally substituted heteroaryl;

R 3e and R 3g are hydrogen;

R 3f is selected from the group consisting of hydrogen, halo, NO 2 , and CN; and

Z 1 is

wherein:

G is absent, C(R n ) 2 , O, or S; and

each n is independently 0, 1 or 2,

each R c is independently selected from the group consisting of hydrogen and C 1-10 alkyl, and

each R d is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

19. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R i is methyl.

20. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen; and

R 3c is C 1-10 alkyl substituted with a substituent selected from the group consisting of halo, oxo, C(O)OR′, C(O)NR″R″, S(O) 2 NR″R″, NR″S(O) 2 R c , NR″C(O)R c , NR″C(O)OR′, OR′, OC(O)R c , NR″R″, optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein

each R′ is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl, and

21. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen.

22. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen and R 3c is halo.

23. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3b is hydrogen and R 3c is optionally substituted methyl.

24. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3c is C 1-10 alkyl substituted with a substituent selected from the group consisting of halo, oxo, C(O)OR′, C(O)NR″R″, S(O) 2 NR″R″, NR″S(O) 2 R c , NR″C(O)R c , NR″C(O)OR′, OR′, OC(O)R c , NR″R″, optionally substituted heterocyclic, and optionally substituted heteroaryl, wherein

each R′ is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl, and

25. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3c is C 1-10 alkyl substituted with C(O)NR″R″, wherein each R″ is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, and optionally substituted C 3 -C 12 cycloalkyl; or two geminal R″ groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.

26. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein R 3f is halo or CN.

27. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein each R m and R n are independently selected from the group consisting of hydrogen, deuterium, optionally substituted C 1 -C 10 alkyl, halo, OR c , NR d R d , C(O)R c , and N(R d )(COOR c ), and wherein each R c is selected from the group consisting of hydrogen and C 1-10 alkyl and each R d is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

28. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein Z is selected from the group consisting of optionally substituted 1-piperidinyl, and optionally substituted 4-morpholinyl.

29. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein Z 1 is optionally substituted 1-pyrrolidinyl or optionally substituted 1-piperidinyl.

30. The compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein Z 1 is optionally substituted 1-piperidinyl.

31. A compound, or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, selected from the group consisting of:

32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

33. A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

34. A method of alleviating or ameliorating the symptoms of a cancer selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, multiple myeloma, basal cell carcinoma, neuroblastoma, hematologic cancer, rhabdomyosarcoma, liver cancer, skin cancer, leukemia, basal cell carcinoma, bladder cancer, endometrial cancer, glioma, lymphoma, and gastrointestinal cancer in a subject in need thereof comprising administering to said subject an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 1, 2020

From: CULLEN, MATTHEW; HAUCK, SHEILA; GENG, BOLIN; FOLEY, MEGAN; BASTOS, CECILIA M.; MUNOZ, BENITO; HAEBERLEIN, MARKUS; TAIT, BRADLEY

To: PROTEOSTASIS THERAPEUTICS, INC.

Reel/Frame 053102/0245 →

Continuity (5)

Continuation 15830261 · Dec 4, 2017

Continuation 15153379 · May 12, 2016

Continuation PCTUS2014065204 · Nov 12, 2014

Provisional Application 61903330 · Nov 12, 2013

Related Publication 20200308198A1 · Oct 1, 2020