Inhibitors of TNF superfamily costimulatory interactions and methods for uses of the same

Patent metadata

Field	Value
Publication number	US-10562848-B2
Application number	US-201616062501-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Dec 15, 2015
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

Disclosed herein are inhibitors of TNF superfamily costimulatory interactions, and methods for their use in modulating TNF superfamily costimulatory interactions and treating immune system related disorders. In particular, disclosed herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof:

wherein the substituents are described herein.

First claim

What is claimed:

1. A compound of formula (I):

wherein
L has a structure:

and X 1 and X 2 are each independently CR or N;
each R 1 independently is SO 3 H, —CO 2 R, or NO 2 ;
each R 2 independently is —NO 2 , —CO 2 R, —NH 2 , —Cl, —F, —CF 3 , phenyl, or phenyl substituted with one or more of —NO 2 , —CO 2 R, —NH 2 , —Cl, —F, or —CF 3 , and/or two adjacent R 2 together form —(N═N—NH)—;
each R independently is H, C 1-5 alkyl, or —O—C 1-5 alkyl;
n is 1, 2, 3, or 4; and
m is 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein at least one of X 1 and X 2 is CR.

3. The compound of claim 2 , wherein R is H.

4. The compound of claim 1 wherein at least one of X 1 and X 2 is N.

5. The compound of claim 1 , wherein at least one R 1 is SO 3 H or CO 2 R.

6. The compound of claim 5 , wherein R is selected from C 1-5 alkyl and H.

7. The compound of claim 1 , wherein the compound-is substituted with R 1 at position 1, 4, 5, or a combination thereof.

8. The compound of claim 1 , wherein R 1 is 1-SO 3 H, 5-SO 3 H, 4-CO 2 Me, 5-CO 2 H, or a combination thereof.

9. The compound of claim 1 , wherein at least one R 2 is —NO 2 , NH 2 , or —CO 2 R.

10. The compound of claim 9 , wherein R is selected from C 1-5 alkyl and H.

11. The compound of claim 1 , wherein two adjacent R 2 together form —(N═N—NH)—.

12. The compound of claim 1 , wherein the compound is substituted with R 2 at the 4′ position or the 3′ position.

13. The compound of claim 1 , wherein R 2 is 4′-NO 2 , 4′-CO 2 Me, 4′—NH 2 , 3′,4′-(N═N—NH)—, 4′-C 6 H 4 -(4″-NO 2 ), or 4′-C 6 H 4 -(4″—CO 2 R).

14. The compound of claim 1 selected from the group consisting of:

15. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

16. A method of modulating TNF superfamily costimulatory interactions in a subject, comprising administering to the subject a compound according to claim 1 .

17. The method of claim 16 , wherein the compound or composition modulates one or more interactions selected from the group consisting of CD40-CD40L, TNF-R 1 -TNF-α, CD80(137)-CD28, CD80(137)-CD152(CTLA4), CD86(67-2)-CD28, CD86-CD152, CD27-CD70, CD137(4-1BB)-4-1BBL, HVEM-LIGHT(CD258), CD30-CD30L, GITR-GITRL, BAFF-R(CD268)-BAFF(CD257), RANK(CD265)-RANKL(CD254), OX40(CD134)-OX40L(CD252), and combinations thereof.

18. A method of treating an inflammatory or immune system disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

19. The method of claim 18 , wherein the subject is a nonautologous organ or cell transplant recipient and suffers from rejection of the nonautologous organ or cell transplant.

20. The method of claim 18 , wherein the inflammatory or immune system disorder comprises rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), type I (juvenile) diabetes, mixed connective tissue disease MCTD, Celiac disease, Crohn's disease, ulcerative colitis, Grave's disease, Sjögren's syndrome, dermatomyositis, psoriasis, scleroderma, polymyositis, vasculitis, Wegener's granulomatosis, alopecia areata, chronic inflammatory disease, autoimmune disease, neurodegenerative disorder, graft-versus-host disease, cancer, atherosclerosis, a rejection of a nonautologous organ transplant, or a rejection of nonautologous cell transplant.

Assignees

• Univ Miami

Inventors

• Buchwald Peter

Classifications

• C07C237/42

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated · CPC title

• C07C2603/18

  Fluorenes; Hydrogenated fluorenes · CPC title

• C07C309/51 Primary

  at least one of the nitrogen atoms being part of any of the groups [IMAGE cpc-sch-C07C-0976.gif], X being a hetero atom, Y being any atom · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07D249/18

  Benzotriazoles · CPC title