IP Library › Granted Patent US 9,540,322

Granted Patent B2

US 9,540,322 · App. 13/100,922 · Granted Jan 10, 2017

MIF modulators

Inventors: William L. Jorgensen (Deep River, CT); Richard J. Bucala (Cos Cob, CT)

Assignee: Yale University

C07D209/18 C07D235/12 C07D235/24 C07D249/06 C07D263/58 C07D275/04 C07D307/80 C07D307/83 C07D401/04 C07D401/06 C07D403/04 C07D405/06 C07D413/04 C07D417/04

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Quick Facts

Patent No.: US 9,540,322
App. No.: 13/100,922
Granted: Jan 10, 2017
Kind: B2

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Abstract

The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression.

Claims (77)

1. A compound according to formula III H:

wherein

each X 1 is selected from —H, R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each X 2 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each X 3 is —OH or —O(C 1 -C 6 alkyl);

each X 4 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each X 5 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each Y 1 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each Y 2 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each Y 3 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each Y 4 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ; and

each Y 5 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

provided that X 3 is OH or Y 3 is —O(C 1 -C 6 )alkyl or —OH;

each R a is independently unsubstituted (C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl substituted with up to five halogen atoms and up to two substituents selected from the group consisting of —C≡N; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR 4 2 ; —OR b ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)NR c 2 ; —S(C 1 -C 6 )alkyl; —S(O)(C 1 -C 6 )alkyl; and —SO 2 (C 1 -C 6 )alkyl;

each R b is independently hydrogen or (C 1 -C 6 )alkyl;

each R c is independently hydrogen;

(C 1 -C 6 )alkyl; —(C 2 -C 6 )alkylene-OR b ; —(C 1 -C 6 )alkylene-C(═O)OR b ; —(C 1 -C 6 )alkylene-OC(═O)R b ; —(C 2 -C 6 )alkylene-NR b 2 ; —(C 1 -C 6 )alkylene-C(═O)NR b 2 ; —(C 1 -C 6 )alkylene-NR b C(═O)R b ; —(C 1 -C 6 )alkylene-NR b C(═O)NR b 2 ; or, optionally, within any occurrence of NR c 2 , independently of any other occurrence of NR c 2 , the two R c groups in combination are —(CH 2 ) α — or —(CH 2 ) β Q(CH 2 ) 2 —;

each α is independently selected from the group consisting of 4, 5, and 6;

each β is independently selected from the group consisting of 2 and 3;

each Q is independently selected from the group consisting of O, S, NR b ; NC(═O)R b ; NSO 2 R b ; N(C 2 -C 6 )alkylene-OR b ; N(C 1 -C 6 )alkylene-C(═O)OR b ; N(C 1 -C 6 )alkylene-OC(═O)R b ; N(C 2 -C 6 )alkylene-NR b 2 ; N(C 1 -C 6 )alkylene-C(═O)NR b 2 ; N(C 1 -C 6 )alkylene-NR b C(═O)R b ; and N(C 1 -C 6 )alkylene-NR b C(═O)NR b 2 ,

or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.

2. A compound according to formula III-B:

wherein

B is selected from the group consisting of —Ar 2 and —CH 2 Ar 2 ;

Ar 2 is an unsubstituted or substituted aromatic ring which is a 5, 6, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl group containing 0, 1, 2, 3 or 4 nitrogen atoms, 0, 1 or 2 oxygen atoms, and 0, 1 or 2 sulfur atoms as heteroatoms;

wherein the optional substituents of Ar 2 are each independently selected from —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl;

and —SO 2 NR c 2 ;

each X 1 is selected from —H, —R a ; —OH; —OR a ; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 ;

each X 3 is —OH or —O(C 1 -C 6 alkyl);

each R b is independently hydrogen or (C 1 -C 6 )alkyl;

each R c is independently hydrogen;

each α is independently selected from the group consisting of 4, 5, and 6;

each β is independently selected from the group consisting of 2 and 3; and

each Q is independently selected from the group consisting of O, S, NR b ;

NC(═O)R b ; NSO 2 R b ; N(C 2 -C 6 )alkylene-OR b ; N(C 1 -C 6 )alkylene-C(═O)OR b ; N(C 1 -C 6 )alkylene-OC(═O)R b ; N(C 2 -C 6 )alkylene-NR b 2 ; N(C 1 -C 6 )alkylene-C(═O)NR b 2 ; N(C 1 -C 6 )alkylene-NR b C(═O)R b ; and N(C 1 -C 6 )alkylene-NR b C(═O)NR b 2 ,

or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.

3. A compound according to claim 2 , wherein B is —CH 2 Ar 2 .

4. A compound according to claim 2 , wherein the optional substituents of Ar 2 are independently selected from the group consisting of —(C 1 -C 6 )alkyl; —OH; —O(C 1 -C 6 )alkyl; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 .

5. A compound according to claim 2 , wherein the optional substituents of Ar 2 are independently selected from the group consisting of —(C 1 -C 6 )alkyl; —OH; —O(C 1 -C 6 )alkyl; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl;

halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ;

—C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 .

6. A compound according to claim 2 , wherein the optional substituents of Ar 2 are independently selected from the group consisting of —(C 1 -C 6 )alkyl; —OH and —O(C 1 -C 6 )alkyl, —C(O)O(C 1 -C 6 )alkyl and —C(O)OH.

7. A compound according to claim 2 , wherein the optional substituents of Ar 2 are independently selected from the group consisting of CH 3 , CH 2 CH 3 , CHCH 2 , C≡CH, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , SH, SCH 3 , F, Cl, Br and I.

8. A compound according to claim 1 , wherein each one of X 1 , X 2 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently selected from the group consisting of —H, —(C 1 -C 6 )alkyl; —OH; —O(C 1 -C 6 )alkyl; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; halogen; —C≡N; —NO 2 ; —C(═O)R b ; —C(═O)OR b ; —C(═O)NR c 2 ; —C(═NR b )NR c 2 ; —OC(═O)(C 1 -C 6 )alkyl; —OC(═O)O(C 1 -C 6 )alkyl; —OC(═O)NR c 2 ; —NR c 2 ; —NR b C(═O)R b ; —NR b C(═O)O(C 1 -C 6 )alkyl; —NR b C(═O)NR c 2 ; —NR b SO 2 R b ; —SR b ; —S(O)R b ; —SO 2 R b ; —OSO 2 (C 1 -C 6 )alkyl; and —SO 2 NR c 2 .

9. A compound according to claim 1 , wherein each one of X 1 , X 2 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently selected from the group consisting of —H, —(C 1 -C 6 )alkyl; —OH and —O(C 1 -C 6 )alkyl, —C(O)O(C 1 -C 6 )alkyl and —C(O)OH.

10. A compound according to claim 1 , wherein each one of X 1 , X 2 , X 4 , X 5 , Y 1 , Y 2 , Y 3 , Y 4 and Y 5 is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CHCH 2 , C≡CH, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , SH, SCH 3 , F, Cl, Br and I.

11. A compound according to claim 1 , wherein X 3 is —OH.

12. A compound according to claim 1 , wherein X % X 2 , X 4 and X 5 are H.

13. A compound according to claim 1 , wherein Y 3 is —O(C 1 -C 6 )alkyl or —OH.

14. A compound according to claim 1 , wherein Y 3 is —OH.

15. A compound according to claim 1 , wherein Y 2 , Y 4 and Y 5 are H.

16. A compound according to claim 2 , wherein B is —Ar 2 .

17. A compound according to claim 11 , wherein X 1 , X 2 , X 4 and X 5 are H.

18. A compound according to claim 13 , wherein Y 1 , Y 2 , Y 4 and Y 5 are H.

19. A compound according to claim 14 , wherein Y 1 , Y 2 , Y 4 and Y 5 are H.

20. A pharmaceutical composition in dosage form comprising an effective amount of at least one compound or pharmaceutically acceptable salt thereof according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

21. A pharmaceutical composition in dosage form comprising an effective amount of at least one compound or pharmaceutically acceptable salt thereof according to claim 2 in combination with a pharmaceutically acceptable carrier, additive or excipient.

22. A compound according to claim 16 , wherein Ar 2 is an unsubstituted or substituted aromatic ring which is a 5- or 6-membered monocyclic heteroaryl group.

23. A compound according to claim 16 , wherein Ar 2 is an unsubstituted or substituted aromatic ring which is an 8, 9, or 10-membered bicyclic heteroaryl group.

24. A compound according to claim 2 , wherein:

the optional substituents of Ar 2 are independently selected from the group consisting of —(C 1 -C 6 )alkyl; —OH and —O(C 1 -C 6 )alkyl, —C(O)O(C 1 -C 6 )alkyl and —C(O)OH; and

each one of X 1 , X 2 , X 4 , and X 5 and is independently selected from the group consisting of —H, —(C 1 -C 6 )alkyl; —OH and —O(C 1 -C 6 )alkyl, —C(O)O(C 1 -C 6 )alkyl and —C(O)OH.

25. A compound according to claim 24 , wherein:

X 1 , X 2 , X 4 and X 5 are H.

26. A compound according to claim 2 , wherein:

the optional substituents of Ar 2 are independently selected from the group consisting of CH 3 , CH 2 CH 3 , CHCH 2 , C≡CH, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , SH, SCH 3 , F, Cl, Br and I; and

each one of X 1 , X 2 , X 4 , X 5 is independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , CHCH 2 , C≡CH, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , SH, SCH 3 , F, Cl, Br and I.

27. A compound according to claim 2 , wherein:

X 1 , X 2 , X 4 and X 5 are H.

28. A compound according to claim 1 , wherein the compound is of the following formula:

29. A compound of the following formula:

or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.

Assignments (2)

CONFIRMATORY LICENSE Recorded Nov 15, 2011

From: YALE UNIVERSITY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 027232/0535 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2011

From: JORGENSEN, WILLIAM L.; BUCALA, RICHARD J.

To: YALE UNIVERSITY

Reel/Frame 026570/0285 →

Continuity (4)

Continuation In Part 12773430 · May 4, 2010

Continuation In Part PCTUS2009004704 · Aug 18, 2009

Provisional Application 61189327 · Aug 18, 2008

Related Publication 20120004261A1 · Jan 5, 2012