Substituted tetrahydrofurans as modulators of sodium channels

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

X 2a C—R 2a ;

X 4a C—R 4a ;

X 5a C—R 5a ;

X 6a C—R 6a ;

each R is independently H or C 1 -C 6 alkyl;

R 2a , R 4a , R 5a , and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;

R 5b1 and R 5b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;

X 3c is N or C—R 3c ;

X 4c is N or C—R 4c ;

X 5c is N or C—R 5c ;

X 6c is N or C—R 6c ;

R 2c is H, OH, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein said cycloalkyl of R 2c is optionally substituted with 1-2 halo;

L 1 is a bond or O;

L 2 is a bond or C 1 -C 6 alkylene;

R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 5c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

R 6c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

provided that no more than one of X 3c , X 4c , X 5c , and X 6c are N.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 5b1 and R 5b2 are each independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

X 3c is C—R 3c ;

X 4c is C—R 4c ;

X 5c is C—R 5c ;

X 6c is C—R 6c ; and

R 2c is H, OH, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.

3. The compound of claim 1 , wherein the compound has formula (I-A)

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound has formula (I-B)

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3R,4S,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3S,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

and

(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

(2S,3R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluorophenyl)tetrahydrofuran-2-carboxamide

(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,

(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-(difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide.

7. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

8. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the voltage-gated sodium channel is Na v 1.8.

10. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , where the method comprises treating or lessening the severity in the subject of neuropathic pain.

12. The method of claim 11 , wherein the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, idiopathic small-fiber neuropathy, or diabetic neuropathy.

13. The method of claim 10 , wherein the method comprises treating or lessening the severity in the subject of musculoskeletal pain.

14. The method of claim 13 , wherein the musculoskeletal pain comprises osteoarthritis pain.

15. The method of claim 10 , wherein the method comprises treating or lessening the severity in the subject of acute pain.

16. The method of claim 15 , wherein the acute pain comprises acute post-operative pain.

17. The method of claim 10 , wherein the method comprises treating or lessening the severity in the subject of postsurgical pain.

18. The method of claim 17 , wherein the postsurgical pain comprises bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain.

19. The method of claim 10 , wherein the method comprises treating or lessening the severity in the subject of visceral pain.

20. A method of treating or lessening the severity in a subject of pain comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. The method of claim 10 , wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound.