Sulfamoyl benzamides and methods of their use

• US 7,544,676 B2
• Filed: 11/09/2006
• Issued: 06/09/2009
• Est. Priority Date: 11/10/2005
• Status: Expired due to Fees

• Current Assignee: Adolor Corporation (Merck & Co., Inc.)
• Original Assignee: Adolor Corporation (Merck & Co., Inc.)
• Inventors: Dolle, Roland E., Worm, Karin
• Primary Examiner(s): Shiao; Rei-Tsang
• Assistant Examiner(s): CHU, YONG LIANG
• Application Number:
  US11/558,332
• Publication Number:
  US 20080058302A1
• Time in Patent Office: 943 Days
• Field of Search: 514/231.2, 514/608, 514/210.01, 514/237.8, 514/323, 514/424, 514/470, 514/563, 544/158, 544/144, 564/86, 564/88, 546/201, 548/484, 548/542, 548/950
• US Class Current: 514/210.01
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 311/38 having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
• CPC Class Codes: C07C 311/40 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 311/42 to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 295/26 Sulfur atoms

Abstract

Novel sulfamoyl benzamide compounds, pharmaceutical compositions containing the sulfamoyl benzamide compounds, and methods of their pharmaceutical use are disclosed. In certain embodiments, the sulfamoyl benzamide compounds are agonists and/or ligands of cannabinoid receptors and may be useful, inter alia, for treating and/or preventing pain, gastrointestinal disorders, inflammation, auto-immune diseases, ischemic conditions, immune-related disorders, hypertension, neurological disorders, and neurodegenerative diseases, for providing cardioprotection against ischemic and reperfusion effects, for inducing apoptosis in malignant cells, for inhibiting mechanical hyperalgesia associated with nerve injury, and as an appetite stimulant.

Claims

1. A compound of formula I:

2. A compound of claim 1, wherein R⁶ and R⁸ are each H.

3. A compound according to claim 2, wherein R^y and R^z are each independently H or alkyl, or R^y and R^z, when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —

O—

, —

S—

, —

N(R⁹)—

, —

N(R¹⁰)—

C(═

O)—

, or —

C(═

O)—

N(R¹⁰)—

.

4. A compound according to claim 3, wherein R^y and R^z are each independently H or C₁-C₃alkyl.

5. A compound according to claim 2, wherein R^y is H.

6. A compound according to claim 5, wherein R^z is alkyl or aralkyl.

7. A compound according to claim 6, wherein R^z is C₁-C₃alkyl.

8. A compound according to claim 7, wherein R^z is C₂-C₃alkyl substituted with (C₁-C₃alkyl)(C₁-C₃alkyl)amino or C₁-C₃alkoxy.

9. A compound according to claim 3, wherein R^y and R^z, when taken together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl ring.

10. A compound according to claim 2, wherein R⁴ is H or alkyl.

11. A compound according to claim 10, wherein R⁴ is H.

12. A compound according to claim 2, wherein R⁶ and R⁸ are each H.

13. A compound according to claim 2, wherein R⁵ is

14. A compound according to claim 13, wherein R⁵ is

15. A compound according to claim 14, wherein R^a is H.

16. A compound according to claim 15, wherein the aryl of said R⁵ is phenyl.

17. A compound according to claim 2, wherein R⁵ is

18. A compound according to claim 17, wherein r is 0, 1, or 2.

19. A compound according to claim 18, wherein r is 0.

20. A compound according to claim 17, wherein Z is

21. A compound according to claim 20, wherein R^c is H or C₁-C₃alkyl.

22. A compound according to claim 20, wherein R^c is phenyl.

23. A compound according to claim 20, wherein R^d and R^e are each independently H or C₁-C₆alkyl.

24. A compound according to claim 20, wherein R^d and R^e, taken together with the carbon atom to which they are attached, form a monocyclic carbocyclic, bicyclic carbocyclic, monocyclic heterocyclic, or bicyclic heterocyclic ring.

25. A compound according to claim 24, wherein R^c is C₁-C₃alkyl or phenyl.

26. A compound according to claim 20, wherein R^d and R^e, taken together with the carbon atom to which they are attached, form a bicycloalkyl, tricycloalkyl, heterobicyclic, or heterotricyclic ring.

27. A compound according to claim 26, wherein R^d and R^e, taken together with the carbon atom to which they are attached, form a bicycloalkyl or tricycloalkyl ring.

28. A compound according to claim 27, wherein the bicycloalkyl ring is substituted with 1-3 alkyl groups.

29. A compound according to claim 20, wherein R^e, R^d, and R^e, taken together with the carbon atom to which they are attached, form a bicycloalkyl, tricycloalkyl, heterobicyclic, or heterotricyclic ring.

30. A compound according to claim 29, wherein R^c, R^d, and R^e, taken together with the carbon atom to which they are attached, form a bicycloalkyl or tricycloalkyl ring.

31. A compound according to claim 30, wherein the bicycloalkyl ring is substituted with 1-3 alkyl groups.

32. A compound according to claim 17, wherein R⁵ is:

33. A compound according to claim 17, wherein R⁵ is:

34. A compound according to claim 17, wherein Z is a 1 or 2 heteroatom containing C₅-C₆heteroaryl, or a 1 or 2 heteroatom containing C₅-C₆heterocycloalkyl, wherein each heteroatom is independently —

N(R¹¹), O, or S.

35. A compound according to claim 2, wherein each R^a is H.

36. A compound according to claim 2, wherein each R^b is independently H or C₁-C₃alkyl.

37. A compound according to claim 2, wherein R² and R³ are each independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl.

38. A compound according to claim 37, wherein R² and R³ are each independently alkyl or aralkyl.

39. A compound according to claim 38, wherein R² and R³ are each independently C₁-C₃alkyl or C₆arylC₁alkyl.

40. A compound according to claim 39, wherein R² and R³ are each methyl.

41. A compound according to claim 39, wherein R² is methyl and R³ is benzyl.

42. A compound according to claim 36, wherein R² and R³, when taken together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocycloalkyl ring.

43. A compound according to claim 42, wherein R² and R³, when taken together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycloalkyl ring.

44. A compound according to claim 43, wherein R² and R³ taken together with the nitrogen atom to which they are attached, form a piperidine, pyrrolidine, or morpholine ring, each optionally substituted.

45. A compound according to claim 44, wherein R² and R³ taken together with the nitrogen atom to which they are attached, form a piperidine or pyrrolidine ring, each substituted with hydroxy.

46. A compound according to claim 44, wherein R² and R³ taken together with the nitrogen atom to which they are attached, form a morpholine ring.

47. A compound according to claim 2, selected from the group consisting of:

4-(methylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethyl-bicyclo[2.2.1]-heptan-2-yl)benzamide;

N-(bicyclo-[2.2.1]heptan-2-yl)-4-(methylamino)-3-(morpholinosulfonyl)benzamide

N-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(methylamino)-3-(morpholinosulfonyl)benzamide;

N-(5-methyl-3-phenylisoxazol-4-yl)-4-(methylamino)-3-(morpholinosulfonyl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-yl)benzamide;

N-(bicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

N-(7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

3-(1,3-dihydroisoindole-2-sulfonyl)-N-[1-(3-hydroxyadamantan-1-yl)-ethyl]-4-methylaminobenzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-neopentylbenzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1-phenylethyl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-((1-phenylcyclopentyl)methyl)benzamide;

N-(1-ethylpiperidin-3-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1-morpholinobutan-2-yl)benzamide;

3-(N-(2-methoxyethyl)-N-methylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

methyl 2-(N-methyl-2-(methylamino)-5-(1,3,3-trimethylbicyclo[2.2.1 ]heptan-2-yl-carbamoyl)phenylsulfonamido)acetate;

methyl 2-(5-(bicyclo[2.2.1]heptan-2-ylcarbamoyl)-N-methyl-2-(methylamino)phenylsulfonamido)acetate;

methyl 2-(5-(7,7-dimethylbicyclo-[2.2.1]heptan-2-ylcarbamoyl)-N-methyl-2-(methylamino)phenylsulfonamido)acetate;

({5-[1-(3-hydroxyadamantan-1-yl)-ethylcarbamoyl]-2-methylaminobenzenesulfonyl}methylamino)acetic acid methyl ester;

methyl 2-(N-methyl-2-(methylamino)-5-(neopentylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(N-methyl-2-(methylamino)-5-(1-phenylethylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(N-methyl-2-(methylamino)-5-((1-phenylcyclopentyl)methylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(N-methyl-5-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylcarbamoyl)-2-(methylamino)phenylsulfonamido)acetate;

3-(azetidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(2-(dimethylamino)ethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(2-aminoethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

4-morpholino-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-benzamide;

4-(2-methoxyethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

4-(dimethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(ethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(isopropylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide; and

4-amino-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-benzamide;

or a pharmaceutically acceptable salt thereof.

48. A compound according to claim 2, selected from the group consisting of:

4-(methylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethyl-bicyclo-[2.2.1]heptan-2-yl)benzamide;

N-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-4-(methylamino)-3-(morpholinosulfonyl)benzamide;

N-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(methylamino)-3-(morpholinosulfonyl)benzamide;

N-(5-methyl-3-phenylisoxazol-4-yl)-4-(methylamino)-3-(morpholinosulfonyl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethyl-bicyclo-[2.2.1]heptan-2-yl)benzamide;

N-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

N-((1R,2S,4R)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

3-(1,3-dihydroisoindole-2-sulfonyl)-N-[1-(3-hydroxyadamantan-1-yl)-ethyl]-4-methylaminobenzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-neopentylbenzamide

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1-phenylethyl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-((1-phenylcyclopentyl)methyl)benzamide;

N-(1-ethylpiperidin-3-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1-morpholinobutan-2-yl)benzamide;

3-(N-(2-methoxyethyl)-N-methylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

methyl 2-(N-methyl-2-(methylamino)-5-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-ylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(5-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-ylcarbamoyl)-N-methyl-2-(methylamino)phenylsulfonamido)acetate;

methyl 2-(5-((1R,2S,4R)-7,7-dimethylbicyclOl[2.2.1]heptan-2-ylcarbamoyl)-N-methyl-2-(methylamino)phenylsulfonamido)acetate;

({5-[1-(3-hydroxyadamantan-1-yl)-ethylcarbamoyl]-2-methylaminobenzenesulfonyl}methylamino)acetic acid methyl ester;

methyl 2-(N-methyl-2-(methylamino)-5-(neopentylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(N-methyl-2-(methylamino)-5-(1-phenylethylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(N-methyl-2-(methylamino)-5-((1-phenylcyclopentyl)methylcarbamoyl)phenylsulfonamido)acetate;

methyl 2-(N-methyl-5-(8-methyl-8-azabicyclo-[3.2.1]octan-3-ylcarbamoyl)-2-(methylamino)-phenylsulfonamido)acetate;

3-(azetidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(2-(dimethylamino)ethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(2-aminoethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-morpholino-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

4-(2-methoxyethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(dimethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethyl-bicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(ethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

4-(isopropylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide; and

4-amino-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

49. A compound according to claim 47, selected from the group consisting of:

4-(methylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

4-(2-methoxyethylamino)-3-(morpholinosulfonyl)-N-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-(bicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

N-(7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

3-(1,3-dihydroisoindole-2-sulfonyl)-N-[1-(3-hydroxyadamantan-1-yl)-ethyl]-4-methylaminobenzamide;

3(N-(2-methoxyethyl)-N-methylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(2-(dimethylamino)ethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide; and

4-(dimethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

50. A compound according to claim 48, selected from the group consisting of:

4-(methylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethyl-bicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(2-methoxyethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-yl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

N-((1R,2S,4R)-7,7-dimethylbicyclo[2.2.1]heptan-2-yl)-3-(isoindolin-2-ylsulfonyl)-4-(methylamino)benzamide;

3-(1,3-dihydroisoindole-2-sulfonyl)-N-[1-(3-hydroxyadamantan-1-yl)ethyl]-4-methylaminobenzamide;

3-(N-(2-methoxyethyl)-N-methylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(2-(dimethylamino)ethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide; and

4-(dimethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethyl-bicyclo-[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

51. A compound according to claim 49, selected from the group consisting of:

4-(methylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(2-methoxyethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethyl-bicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-yl)benzamide; and

4-(dimethylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

52. A compound according to claim 50, selected from the group consisting of:

4-(methylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(2-methoxyethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

3-(isoindolin-2-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide; and

4-(dimethylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

53. A compound according to claim 2, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-(bicyclo[2.2.1]heptan-2-yl)-3-(N,N-dimethylsulfamoyl)-4-(methylamino)benzamide;

3-(4-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

3-(3-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-(bicyclo[2.2.1]heptan-2-yl)-4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)benzamide;

N-(3,3-dimethylbutan-2-yl)-4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)benzamide;

4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(3,3,5-trimethylcyclohexyl)benzamide;

3-(3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)benzamide;

3-(N-tert-butylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(N-ethyl-N-methyl-sulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

methyl 3-(2-(morpholinosulfonyl)-4-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-ylcarbamoyl)phenyl)amino)propanoate;

4-(2-methoxyethylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(benzylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(2-methoxyethylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

3-(N-(2-hydroxyethyl)-N-methylsulfamoyl)-4-(2-methoxyethylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-amino-3-(N-tert-butylsulfamoyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-benzamide; and

3-(N-benzyl-N-methylsulfamoyl)-4-(2-(dimethylamino)ethylamino)-N(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

54. A compound according to claim 2, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-3-(N,N-dimethylsulfamoyl)-4-(methylamino)benzamide;

3-(4-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(3-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)benzamide;

N-(3,3-dimethylbutan-2-yl)-4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)benzamide;

4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(3,3,5-trimethylcyclohexyl)benzamide;

3-((R)-3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-((S)-3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)benzamide;

3-(N-tert-butylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide;

3-(N-ethyl-N-methylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

methyl 3-(2-(morpholinosulfonyl)-4-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ylcarbamoyl)phenyl)amino)propanoate;

4-(2-methoxyethylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(benzylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(2-methoxyethylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(N-(2-hydroxyethyl)-N-methylsulfamoyl)-4-(2-methoxyethylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-amino-3-(N-tert-butylsulfamoyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide; and

3-(N-benzyl-N-methylsulfamoyl)-4-(2-(dimethylamino)ethylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

55. A compound according to claim 53, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)benzamide

({5-[1-(3-hydroxyadamantan-1-yl)-ethyl-carbamoyl]-2-methylaminobenzene-sulfonyl}-methylamino)acetic acid methyl ester;

3-(3-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

3-(3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

4-(benzylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(2-methoxyethylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-(3,3-dimethylbutan-2-yl)-4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)benzamide;

3-(N-ethyl-N-methylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]-heptan-2-yl)benzamide; and

4-(2-methoxyethylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

56. A compound according to claim 54, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)-benzamide;

({5-[1-(3-hydroxyadamantan-1-yl)ethylcarbamoyl]-2-methylaminobenzene-sulfonyl}methylamino)acetic acid methyl ester;

3-(3-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-yl)benzamide;

3-((S)-3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

4-(benzylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

3-(N,N-dimethylsulfamoyl)-4-(2-methoxyethylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-(3,3-dimethylbutan-2-yl)-4-(methylamino)-3-(pyrrolidin-1-ylsulfonyl)benzamide;

3-(N-ethyl-N-methylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide; and

4-(2-methoxyethylamino)-3-(pyrrolidin-1-ylsulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

57. A compound according to claim 55, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)-benzamide;

({5-[1-(3-hydroxyadamantan-1-yl)ethylcarbamoyl]-2-methylaminobenzenesulfonyl}-methylamino)acetic acid methyl ester;

3-(3-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide; and

3-(3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

58. A compound according to claim 56, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide;

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)benzamide;

({5-[1-(3-hydroxyadamantan-1-yl)ethylcarbamoyl]-2-methylaminobenzenesulfonyl}-methylamino)acetic acid methyl ester;

3-(3-hydroxypiperidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide; and

3-((S)-3-hydroxypyrrolidin-1-ylsulfonyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide;

or a pharmaceutically acceptable salt thereof.

59. A compound according to claim 57, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide; and

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)benzamide;

or a pharmaceutically acceptable salt thereof.

60. A compound according to claim 58, selected from the group consisting of:

3-(N,N-dimethylsulfamoyl)-4-(methylamino)-N-((1S,4R)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)benzamide; and

N-adamantan-1-yl-4-methylamino-3-(morpholine-4-sulfonyl)benzamide

or a pharmaceutically acceptable salt thereof.

61. A compound according to claim 51 which is 4-(methylamino)-3-(morpholinosulfonyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide. or a pharmaceutically acceptable salt thereof.

62. A compound according to claim 61 which is 4-(methylamino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

72. A compound according to claim 2, which is 3-(morpholinosulfonyl)-4-(1H-pyrazol-1-yl)-N-((1S,4R)-1,3,3-trimethyl-bicyclo[2.2.1]heptan-2-yl)benzamide.

73. A compound according to claim 2, which is 4-((2-methoxyethyl)(methyl)amino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide.

74. A compound according to claim 2, which is 4-((3-methoxypropyl)amino)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide.

63. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and

a compound of formula I;

64. A pharmaceutical composition according to claim 63, wherein R⁶ and R⁸ are each H.

65. A pharmaceutical composition according to claim 64, further comprising at least one cannabinoid.

66. A pharmaceutical composition according to claim 65, wherein the cannabinoid is Δ

⁹-tetrahydrocannabinol or cannabidiol.

67. A pharmaceutical composition according to claim 64, further comprising at least one opioid.

68. A pharmaceutical composition according to claim 67, wherein said opioid is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene;

sufentanil and tramadol, and mixtures thereof.

69. A pharmaceutical composition according to claim 64, further comprising at least one analgesic.

70. A pharmaceutical composition according to claim 69,

wherein the analgesic is aspirin, acetaminophen, ibuprophen, naproxen, or a mixture thereof.

71. A pharmaceutical composition according to claim 64, further comprising at least one agent selected from the group consisting of an anti-seizure agent, an anti-depressant, an anti-Parkinson'"'"'s agent, and mixtures thereof;

wherein;

said anti-seizure agent is selected from the group consisting of carbamazepine, gabapentin, lamotrigine, phenytoin, and a mixture thereof;

said anti-depressant is amitryptiline; and

said anti-Parkinson'"'"'s agent is selected from the group consisting of deprenyl, amantadine, levodopa, carbidopa, and a mixture thereof.