IP Library › Granted Patent US 7,838,544

Granted Patent B2

US 7,838,544 · App. 11/803,808 · Granted Nov 23, 2010

Heterocyclic inhibitors of 11-β hydroxyl steroid dehydrogenase type 1 and methods of using the same

Assignee: Incyte Corporation

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Quick Facts

Patent No.: US 7,838,544
App. No.: 11/803,808
Granted: Nov 23, 2010
Kind: B2

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Abstract

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1 and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1.

Claims (130)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is CH;

E is O or C(OR E1 )R E2 ;

R E1 and R E2 are each H;

Q is N or NR 1 ;

T is C;

U is N or NR 1c ;

V is N or NR 1e ;

is a single or double bond;

R 1 , R 1c and R 1e are independently selected from H, (C 1-6 )alkyl and (C 3-6 )cycloalkyl; wherein R 1c or R 1e that is (C 1-6 )alkyl or (C 3-6 )cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, CF 3 , OH, (C 1-6 )alkoxy, (C 3-6 )cycloalkyl and heterocycloalkyl;

L is (CR 2 R 3 ) m or (CR 2 R 3 ) n -J-(CR 2 R 3 ) p ;

R 2 and R 3 are independently selected from H and (C 1-6 )alkyl; wherein R 2 and R 3 that are (C 1-6 )alkyl are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, CN and OR 4 ;

or R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl ring or a 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl ring, each optionally substituted by 1, 2 or 3 substituents independently selected from halogen, CN and OR 4 ;

n, m and p are independently selected from 0, 1, 2, 3 and 4;

J is selected from O, SO v , C(═O), NR 4 , NR 4 C(═O), NR 4 SO 2 , NR 4 C(═O)NR 4 , C(═O) and OC(═O);

v is 1 or 2;

R 4 is independently selected from H, (C 1-6 )alkyl, (C 3-6 )cycloalkyl and (C 3-6 )cycloalkyl(C 1-4 )alkyl;

Cy is arylene, heteroarylene, heterocycloalkylene, or cycloalkylene, each optionally substituted by 1, 2 or 3 substituents independently selected from halogen, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 2-4 )alkynyl, (C 1-4 )haloalkyl, CN, NO 2 , OR a , SR a , C(═O)OR a , (O) u C(═O)R b , (O) u C(═O)NR c R d , NR c R d , NR c C(═O)R b , NR c C(═O)OR a , SO v R b , and SO v NR c R d ;

u is 0 or 1;

R a is independently selected from H, (C 1-10 )hydrocarbyl, C(═O)(C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, and heterocycloalkyl(C 1-3 )alkyl; wherein R a that is (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocycloalkyl(C 1-3 )alkyl is optionally substituted with OH, NH 2 , halogen, CN, (C 1-7 )hydrocarbyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocyclo-alkyl (C 1-3 )alkyl;

R b is independently selected from H, (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, and heterocycloalkyl(C 1-3 )alkyl; wherein R b that is (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl or heterocycloalkyl(C 1-3 )alkyl is optionally substituted with OH, NH 2 , halogen, CN, (C 1-7 )hydrocarbyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocycloalkyl(C 1-3 )alkyl;

R c and R d are independently selected from H, (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, and heterocycloalkyl(C 1-3 )alkyl;

wherein R c and R d that are (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocycloalkyl(C 1-3 )alkyl are optionally substituted with OH, NH 2 , halogen, CN, (C 1-7 )hydrocarbyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocycloalkyl(C 1-3 )alkyl;

or R c and R d , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl ring;

W is selected from (C 1-6 )hydrocarbylene, O, SO v , NR e , C(═O), C(═O)O, C(═O)NR e , SO v NR e and NR e C(═O)NR e ; wherein W that is (C 1-6 )hydrocarbylene is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, OR f and NR f 2 ;

R e is independently selected from H, (C 1-10 )hydrocarbyl, C(═O)(C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, and heterocycloalkyl (C 1-3 )alkyl; wherein R e that is (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocycloalkyl(C 1-3 )alkyl is optionally substituted with OH, NH 2 , halogen, (C 1-7 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, or heterocycloalkyl(C 1-3 )alkyl;

R f is independently selected from H, (C 1-4 )alkyl, and (C 1-4 )haloalkyl;

X is selected from (C 1-6 )hydrocarbylene, arylene, heteroarylene, and heterocycloalkylene; wherein X that is (C 1-6 )hydrocarbylene, arylene, heteroarylene, or heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-4 )haloalkyl, CN, NO 2 , OR f and NR f 2 ;

Y is selected from (C 1-6 )hydrocarbylene, O, SO v , NR e , C(═O), C(═O)O, C(═O)NR e , SO v NR e , or NR e C(═O)NR e ; wherein Y that is (C 1-6 )hydrocarbylene is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, OR f , and NR f 2 ;

Z is selected from H, halogen, CN, NO 2 , OR f , NR f 2 ,(C 1-14 )hydrocarbyl, heteroaryl, and heterocycloalkyl; wherein Z that is (C 1-14 )hydrocarbyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, (C 1-6 )hydrocarbyl, (C 1-4 )haloalkyl, aryl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , (O) u C(═O)R b , (O) u C(═O)NR c R d , (O) u C(═O)(O) u R a , NR c R d , NR c C(═O)R b , NR c C(═O)OR a , NR c SO 2 R b , SO v R b and SO v NR c R d ; and

a, b, c and d are independently selected from 0 and 1;

provided that the compound of Formula I is other than 1-(4-methyl-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-yl)piperidin-4-ol; 4-(4-methyl-5-(1-phenylcyclopropyl)-4H-1,2,4-triazol-3-yl)morpholine; and 3-(1-adarnantyl)-4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazole.

2. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein U and V are both N; T is C; and Q is N—R 1 .

3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein E is O.

4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein E is C(OR E1 )R E2 and R E1 and R E2 are H.

5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy is arylene or cycloalkylene, each optionally substituted by 1, 2, or 3 substituents selected from halogen, (C 1-4 )alkyl, (C 1-4 )haloalkyl, CN and OR a .

6. The compound of claim 5 , or pharmaceutically acceptable salt thereof, wherein Cy is phenyl, optionally substituted with halogen.

7. The compound of claim 5 , or pharmaceutically acceptable salt thereof, wherein Cy is bicycle[2.2.23]octanyl, optionally substituted by 1, 2 or 3 substituents selected from halogen, (C 1-4 )alkyl, (C 1-4 )haloalkyl, CN and OR a .

8. A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein:

A is CH;

E is O or C(OR E1 )R E2 ;

R E1 and R E2 are each H;

Q is N or NR 1 ;

T is C;

U is N or NR 1c ;

V is N or NR 1e ;

is a single or double bond;

R 1 , R 1c and R 1e are independently selected from H, (C 1-6 )alkyl and (C 3-6 )cycloalkyl; wherein R 1 , R 1c , or R 1e that is (C 1-6 )alkyl or (C 3-6 )cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, CF 3 , OH, (C 1-6 )alkoxy, (C 3-6 )cycloalkyl and heterocycloalkyl;

L is (CR 2 R 3 ;

n, m and p are independently selected from 0, 1, 2, 3 and 4;

J is selected from O, SO v , C(═O), NR 4 , NR 4 C(═O), NR 4 SO 2 , NR 4 C(═O)NR 4 , C(═O)O and OC(═O);

v is 1 or 2;

R 4 is independently selected from H, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, and (C 3-6 )cycloalkyl(C 1-4 )alkyl;

u is 0 or 1;

R c and R d are independently selected from H, (C 1-10 )hydrocarbyl, (C 1-6 )haloalkyl, heteroaryl, heteroaryl(C 1-3 )alkyl, heterocycloalkyl, and heterocycloalkyl(C 1-3 )alkyl;

or R c and R d , together with the N atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl ring;

R f is independently selected from H, (C 1-4 )alkyl, and (C 1-4 )haloalkyl;

a, b, c and d are independently selected from 0 and 1;

9. The compound of claim 8 , or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7- membered cycloalkyl ring optionally substituted by 1, 2, or 3 substituents independently selected from halogen and OR 4 .

10. The compound of claim 9 , or pharmaceutically acceptable salt thereof, wherein the cycloalkyl ring is optionally substituted by halogen.

11. The compound of claim 8 , or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- or 4-membered cycloalkyl ring optionally substituted by 1, 2, or 3 substituents independently selected from halogen and OR 4 .

12. The compound of claim 11 , or pharmaceutically acceptable salt thereof, wherein the cycloalkyl ring is optionally substituted by halogen.

13. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein b, c and d are all 0; and

Z is selected from H, halogen, CN, OR f , (C 1-14 )hydrocarbyl, heteroaryl and heterocycloalkyl; and

wherein Z that is (C 1-14 )hydrocarbyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halogen, (C 1-6 )hydrocarbyl, (C 1-4 )haloalkyl, aryl, heteroaryl, heterocycloalkyl, CN, OR a , and C(O)(NR c R d ).

14. The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein Z is H, halogen, CN or (C 1-14 )hydrocarbyl.

15. The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein Z is heteroaryl or heterocycloalkyl, each optionally substituted by 1 or 2 substituents selected from halogen, (C 1-4 )haloalkyl, CN, OR a and C(O) u(NR c R d ).

16. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein W is O; c and d are 0; Z is selected from (C 1-14 )hydrocarbyl, heteroaryl and heterocycloalkyl; wherein each (C 1-14 )hydrocarbyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halogen, CN, OR a and C(O) u (NR c R d ).

17. The compound of claim 16 , or pharmaceutically acceptable salt thereof;

wherein a is 0.

18. The compound of claim 1 , or pharmaceutically acceptable salt thereof; wherein W is selected from (C 1-6 )hydrocarbylene, O, SO v , C(═O), C(═O)NR e , SO v NR e , or NR e C(═O)NR e ; wherein, W that is (C 1-6 )hydrocarbylene is optionally substituted by 1, 2 or 3 substituents that are OR f .

19. The compound of claim 1 , or pharmaceutically acceptable salt thereof; wherein X is (C 1-6 )hydrocarbylene, optionally substituted by 1, 2 or 3 substituents independently selected from halogen, (C 1-6 )alkyl, (C 1-4 )haloalkyl, CN and OR f .

20. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein X is selected from arylene, heteroarylene and heterocycloalkylene, each optionally substituted by 1, 2, or 3 substituents independently selected from halogen, (C 1-6 )alkyl, (C 1-4 )haloalkyl, CN and OR f .

21. The compound of claim 20 , or pharmaceutically acceptable salt thereof; wherein X is heteroarylene.

22. The compound of claim 21 , or pharmaceutically acceptable salt thereof, wherein X is 1,2,4-oxadizolenyl.

23. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Y is selected from (C 1-6 )hydrocarbylene, O, SO v , C(═O), C(═O)NR e and SO v NR e ; wherein Y that is (C 1-6 )hydrocarbylene is optionally substituted by 1, 2 or 3 substituents independently selected from halogen and OR f .

24. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Z is selected from H, halogen, CN, OR f and (C 1-14 )hydrocarbyl.

25. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Z is selected from (C 1-14 )hydrocarbyl, heteroaryl and heterocycloalkyl; each optionally substituted by 1, 2 or 3 substituents independently selected from halogen, (C 1-6 )hydrocarbyl, (C 1-4 )haloalkyl, CN and OR a .

26. The compound of claim 25 , or pharmaceutically acceptable salt thereof, wherein Z is aryl.

27. The compound of claim 26 , or pharmaceutically acceptable salt thereof, wherein Z is phenyl.

28. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein b is 0.

29. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein d is 0.

30. The compound of claim 1 , wherein R 2 and R 3 , together with the carbon to which they are attached, form a cyclopropane ring;

Cy is phenyl optionally substituted with halogen;

b, c and d are 0; and

Z is selected from H, halogen, CN, OR f and (C 1-6 )hydrocarbyl.

31. The compound of claim 30 , or pharmaceutically acceptable salt thereof, wherein Z is halogen.

32. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon to which they are attached, form a cyclopropane ring;

Cy is phenyl optionally substituted with halogen;

b, c and d are 0; and

Z is heteroaryl or heterocyloalkyl optionally substituted by C(═O)NR c R d .

33. The compound of claim 32 , or pharmaceutically acceptable salt thereof; wherein Z is pyridinyl optionally substituted by C(═O)NR c R d .

34. The compound of claim 32 , or pharmaceutically acceptable salt thereof, wherein Z is pyrazolyl optionally substituted by C(═O)NR c R d .

35. The compound of claim 32 , or pharmaceutically acceptable salt thereof, wherein Z is piperazinyl optionally substituted by C(═O)OR a .

36. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon to which they are attached, form a cyclopropane ring;

Cy is phenyl optionally substituted with halogen;

W is O;

c and d are 0; and

Z is heteroaryl optionally substituted by halogen, CN, OR a , SR a , (C 1-6 )hydrocarbyl or (C 1-4 )haloalkyl.

37. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein

a is 0;

Cy is bicyclo[2.2.2] octanyl;

b is 0;

X is heteroaryl;

d is 0; and

Z is aryl optionally substituted by halogen, CN, OR a , SR a , (C 1-6 )hydrocarbyl or (C 1-4 )haloalkyl.

38. The compound of claim 37 , or pharmaceutically acceptable salt thereof, wherein X is 1,2,4-oxadiazolyl and Z is phenyl optionally substituted by halogen, CN, OR a , SR a , (C 1-6 )hydrocarbyl, or (C 1-4 )haloalkyl.

39. A compound selected from:

4-{5-[1-(4-chlorophenyl)cyclopropyl]-4-methyl-4H-1,2,4-triazol-3-yl} cyclohexanol; and

3-[1-(4-chlorophenyl)cyclopropyl]-4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H -1,2,4-triazole; and pharmaceutically acceptable salts thereof.

40. A composition comprising at least one compound of claim 1 , or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

41. A method of modulating activity of 11βHSD1 comprising contacting said 11βHSD1 with a compound of claim 1 , or pharmaceutically acceptable salt thereof.

42. The method of claim 41 , wherein said modulating is inhibiting.

43. A method of treating a disease in a patient, wherein said disease is associated with expression or activity of 11βHSD1 and is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, depression, glaucoma, cardiovascular disorders, osteoporosis, inflammation, metabolic syndrome, atherosclerosis, type 2 diabetes, androgen excess, or polycystic ovary syndrome (PCOS), comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.

44. A method of treating obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, depression, glaucoma, cardiovascular disorders, osteoporosis, inflammation, metabolic syndrome, atherosclerosis, type 2 diabetes, androgen excess, or polycystic ovary syndrome (PCOS) in a patient, comprising administering to said patient a therapeutically acceptable amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.

45. The compound of claim 8 , or pharmaceutically acceptable salt thereof, wherein U and V are both N; T is C; and Q is N—R 1 .

Assignments (3)

CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY INFORMATION PREVIOUSLY RECORDED ON REEL 035920 FRAME 0576. ASSIGNOR(S) HEREBY CONFIRMS THE RECEIVING PARTY NAME SHOULD BE RECORDED AS TWO PARTIES. Recorded Jul 2, 2015

From: INCYTE CORPORATION

To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION

Reel/Frame 036054/0740 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2015

From: INCYTE CORPORATION

To: INCYTE HOLDINGS CORPORATION AND INCYTE CORPORATION

Reel/Frame 035920/0576 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 12, 2007

From: LI, YUN-LONG; ZHUO, JINCONG; YAO, WENQING

To: INCYTE CORPORATION

Reel/Frame 019555/0538 →

Continuity (3)

Provisional Application 6080132600 · May 17, 2006

Provisional Application 6080870300 · May 26, 2006

Related Publication 20070270424A1 · Nov 22, 2007