IP Library › Granted Patent US 8,552,184
Granted Patent B2
US 8,552,184 · App. 12/495,857 · Granted Oct 8, 2013

Compounds and methods for treating disorders related to glucose metabolism

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Patent No.
US 8,552,184
App. No.
12/495,857
Granted
Oct 8, 2013
Kind
B2
Abstract

The present invention relates to compounds and pharmaceutically acceptable salts thereof, and compositions comprising the same, that are useful in modulating lyn kinase activity, treating obesity, type II diabetes, metabolic syndrome, and in reducing blood glucose level, weight gain, or fat depot level, or treating a disease or condition associated with the same.

Claims (55)

1. A compound of Formula I

wherein:

R 1 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, and heteroaryl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R 2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R 2 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, and heteroaryl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R 3 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, and heteroaryl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R 2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R 4 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, and heteroaryl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a2 , SRz a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R 5 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, and heteroaryl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

or two adjacent groups of R 1 , R 2 , R 3 , R 4 , and R 5 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R 6 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O) b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, aryl, and heteroaryl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R 7 is H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 ;

R 8 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 ;

R a1 , R b1 , R c1 , and R d1 are each, independently, selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, NO 2 , CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

R a2 , R b2 , R c2 , and R d2 are each, independently, selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

or R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

Z 1 is O, S, or NR 9 ;

R 9 is H, OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, aryloxy, heteroaryloxy, CN, or NO 2 ;

Z 2 is O, S, or NR 10 ;

R 10 is H, OH, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, aryloxy, heteroaryloxy, CN, or NO 2 ;

L 1 is O, S, or NR 11 ; and

R 11 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 ;

or a pharmaceutically acceptable salt thereof;

provided that the compound is not 5-m-methylphenoxyuracil or a pharmaceutically acceptable salt thereof.

2. The compound, or pharmaceutically effective salt thereof, of claim 1 , wherein the compound of Formula I has Formula Ia:

wherein:

R 2 , R 3 , and R 4 are each, independently, H, halo, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl;

R 7 is H, C 1-6 alkyl, C(O)R b1 , C(O)NR c1 R d1 , or C(O)OR a1 ;

R 8 is H, C 1-6 alkyl, C(O)R b1 , C(O)NR c1 R d1 , or C(O)OR a1 ;

R a1 , R b1 , R c1 , and R d1 are each, independently, selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, NO 2 , CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO 2 , CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1-6 haloalkoxy;

Z 1 is O or S;

Z 2 is O or S; and

L 1 is O or S.

3. A compound of Formula Ib

wherein:

R 2 , R 3 , R 4 , and R 5 are each, independently, H, F, Cl, CH 3 , SCH 3 , OCH 3 , C(CH 3 ) 3 , CH(CH 3 ) 2 , or C 2 H 5 ;

or a pharmaceutically acceptable salt thereof;

provided that the compound is not 5-m-methylphenoxyuracil or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 1 and R 5 are each, independently, H, halo, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl.

5. The compound of claim 1 wherein R 1 and R 5 are each, independently, H or C 1-3 alkyl.

6. The compound of claim 1 wherein R 2 , R 3 , and R 4 are each, independently, H, halo, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl.

7. The compound of claim 1 wherein R 2 , R 3 , and R 4 are each, independently, H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl.

8. The compound of claim 1 wherein R 2 , R 3 , and R 4 are each, independently, H or C 1-6 alkyl.

9. The compound of claim 1 wherein R 2 , R 3 , and R 4 are each, independently, H or C 1-3 alkyl.

10. The compound of claim 1 wherein R 6 is H, halo, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl.

11. The compound of claim 1 wherein R 6 is H or C 1-3 alkyl.

12. The compound of claim 1 wherein R 7 is H, C 1-6 alkyl, C(O)R b1 , C(O)NR c1 R d1 , or C(O)OR a1 .

13. The compound of claim 1 wherein R 7 is H.

14. The compound of claim 1 wherein R 8 is H, C 1-6 alkyl, C(O)R b1 , C(O)NR c1 R d1 , or C(O)OR a1 .

15. The compound of claim 1 wherein R 8 is H.

16. The compound of claim 1 wherein Z 1 is O or S.

17. The compound of claim 1 wherein Z 1 is O.

18. The compound of claim 1 wherein Z 1 is NH, N(OH), N—O—C 1-6 alkyl, N—O-phenyl, CN, or NO 2 .

19. The compound of claim 1 wherein Z 2 is O or S.

20. The compound of claim 1 wherein L 1 is O or S.

Assignments (3)
SECURITY INTEREST Recorded Nov 23, 2021
From: ADHERA THERAPEUTICS, INC.
To: CAVALRY FUND I LP
Reel/Frame 058312/0195 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 16, 2009
From: MELIOR DISCOVERY, INC.
To: MELIOR PHARMACEUTICALS I, INC.
Reel/Frame 023659/0389 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 18, 2009
From: REAUME, ANDREW G.; SAPORITO, MICHAEL S.; OCHMAN, ALEXANDER R.; LIPINSKI, CHRISTOPHER A.
To: MELIOR DISCOVERY, INC.
Reel/Frame 023110/0400 →