IP Library › Granted Patent US 9,850,262

Granted Patent B2

US 9,850,262 · App. 15/153,379 · Granted Dec 26, 2017

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)

Assignee: Proteostasis Therapeutics, Inc.

C07F7/1856 C07B59/002 C07D209/12 C07D209/14 C07D401/06 C07D401/14 C07D403/06 C07D417/14 C07D471/04 C07D519/00 C07B2200/05

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Quick Facts

Patent No.: US 9,850,262
App. No.: 15/153,379
Granted: Dec 26, 2017
Kind: B2

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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 (303)

1. A compound having the Formula (IV):

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein

Z is an optionally substituted N-heterocyclic;

R 1 and R 2 are each independently selected from hydrogen and optionally substituted C 1 -C 10 alkyl;

R 3f 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 , 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 )C(O)OR 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;

each of R 3b and R 3c 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 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 )C(O)OR 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; and

R g 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 , 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 )C(O)OR 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;

R j is optionally substituted C 1 -C 4 alkyl;

each R c 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 d 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 d groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl; and

each n is independently, 1or 2.

2. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.

3. The compound of claim 1 , wherein each of R 3b and R 3c is independently selected from the group consisting of hydrogen, halo, NR d R d , NO 2 , CN, optionally substituted C 1 -C 10 alkyl, C(O)OR c , C(O)R c , NR d C(O)R c , OC(O)R c , and OR c .

4. The compound of claim 1 , wherein R g and R 3b are both hydrogen and R 3c is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, CN, and OR c .

5. The compound of claim 1 , wherein R g and R 3c are both hydrogen and R 3b is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, CN, and OR c .

6. The compound of claim 1 , wherein R 3f is selected from the group consisting of hydrogen, halo, N 3 , C(O)OR c , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NO 2 , and NR d R d .

7. The compound of claim 6 , wherein R 3f is selected from the group consisting of halo and CN.

8. The compound of claim 1 , wherein Z is selected from the group consisting of optionally substituted 1-pyrrolidinyl and optionally substituted 1-piperidinyl.

9. The compound of claim 8 , wherein Z is optionally substituted 1-piperidinyl.

10. The compound of claim 1 , wherein R j is methyl, and R 3f is selected from the group consisting of halo, N 3 , C(O)OR c , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NO 2 and NR d R d .

11. The compound of claim 1 , wherein Z is:

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

each R m and R n 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 , NRR 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.

12. The compound of claim 11 wherein each R m and R n are each independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

13. The compound of claim 11 wherein G is O.

14. The compound of claim 11 , wherein G is S.

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 compound having the Formula (V):

or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein

R i is an optionally substituted C 1 -C 4 alkyl;

R 3f is selected from the group consisting of halo, N 3 , C(O)OR c , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NO 2 and NR d R d ;

R 1 and R 2 are each independently selected from hydrogen and optionally substituted C 1 -C 10 alkyl;

one of R 3b and R 3c is hydrogen and the other of R 3b and 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 )C(O)OR 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;

Z 2 is selected from the group consisting of optionally substituted 1-pyrrolidinyl and 1-piperdinyl;

each R d 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 terminal R d groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl; and

each n is independently 0, 1 or 2.

17. The compound of claim 16 , wherein Z 2 is an optionally substituted 1-piperidinyl.

18. The compound of claim 16 , wherein R 3b is hydrogen, and R 3c is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, CN, and OR c .

19. The compound of claim 16 , wherein R 3c is hydrogen, and R 3b is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, CN, and OR c .

20. The compound of claim 16 , wherein R i is methyl or ethyl.

21. The compound of claim 20 , wherein R i is methyl.

22. The compound of claim 16 , wherein R i is methyl, R 3f is selected from the group consisting of halo and CN, and Z 2 is an optionally substituted 1-piperidinyl.

23. The compound of claim 16 , wherein Z 2 is an optionally substituted 1-pyrrolidinyl.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 16 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

25. A compound selected from the group consisting of those shown in the Table below, or a pharmaceutically acceptable salt thereof:

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Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2016

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

To: PROTEOSTASIS THERAPEUTICS, INC.

Reel/Frame 039698/0171 →

Continuity (3)

Continuation PCTUS2014065204 · Nov 12, 2014

Provisional Application 61903330 · Nov 12, 2013

Related Publication 20160333031A1 · Nov 17, 2016