Capsaicinoid prodrug compounds and their use in treating medical conditions

1. A compound of Formula I or Formula II, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof; wherein:

R 1 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 1 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;

R 2 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 2 attached to the same carbon atom are taken together to represent an oxo group; or two occurrences of R 2 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;

R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-8 membered heterocycloalkyl, or —C(═NH)—NH 2 ; wherein C 1-6 alkyl, C 3-7 cycloalkyl, and 4-8 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl; provided that if R 3 is hydrogen, methyl, or ethyl, then at least one of R 1 and R 2 is not hydrogen; and

R 4 is hydrogen, or two occurrences of R 4 are taken together with the carbon atoms to which they are attached to form a cis or trans double bond;

m is 0, 1, 2, or 3; and

n is 0, 1, or 2; and

Formula II is represented by:

or a pharmaceutically acceptable salt thereof; wherein:

R 1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 4-8 membered heterocycloalkyl;

R 2 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 2 are taken together to represent an oxo group; or two occurrences of R 2 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring;

R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-8 membered heterocycloalkyl, or —C(═NH)—NH 2 ; wherein C 1-6 alkyl, C 3-7 cycloalkyl, and 4-8 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, and C 1-4 alkoxyl;

R 4 is hydrogen, or two occurrences of R 4 are taken together with the carbon atoms to which they are attached to form a cis or trans double bond;

Ring A is one of the following:

a 3-8 membered heterocyclic ring or a C 3-8 saturated or partially unsaturated carbocyclic ring, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, oxo, and C 1-4 haloalkoxyl; or

a 6-membered carbocyclic aromatic ring substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl; and

n is 0 or 1.

2. The compound of claim 1 , wherein the compound is a compound of Formula I or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein at least one R 1 represents C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 1 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.

4. The compound of claim 2 , wherein R 1 represents independently for each occurrence C 1-6 alkyl or C 3-7 cycloalkyl.

5. The compound of claim 2 , wherein two occurrences of R 1 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.

6. The compound of claim 2 , wherein at least one R 2 represents C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 6 aryl, or 3-8 membered heterocycloalkyl; or two occurrences of R 2 attached to the same carbon atom are taken together to represent an oxo group; or two occurrences of R 2 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.

7. The compound of claim 2 , wherein R 2 is C 1-6 alkyl.

8. The compound of claim 2 , wherein two occurrences of R 2 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.

9. The compound of claim 1 , wherein the compound is a compound of Formula II or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein R 1 is hydrogen or C 1-6 alkyl.

11. The compound of claim 9 , wherein R 2 represents independently for each occurrence C 1-6 alkyl or C 3-7 cycloalkyl; or two occurrences of R 2 are taken together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic or heterocyclic ring.

12. The compound of claim 9 , wherein Ring A is a 3-8 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, oxo, and C 1-4 haloalkoxyl.

13. The compound of claim 9 , wherein Ring A is a 5-6 membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl.

14. The compound of claim 9 , wherein Ring A is a 3-8 membered saturated heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, oxo, and C 1-4 haloalkoxyl.

15. The compound of claim 9 , wherein Ring A is a C 3-8 saturated or partially unsaturated carbocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, oxo, and C 1-4 haloalkoxyl.

16. The compound of claim 9 , wherein Ring A is a 6-membered carbocyclic aromatic ring substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl.

17. A method of treating or preventing pain in a subject, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to treat or prevent the pain.

18. A method of agonizing the activity of TRPV1, comprising exposing a TRPV1 to an effective amount of a compound of claim 1 to agonize the activity of said TRPV1.

19. A compound in Table 1, Table 1A, or a pharmaceutically acceptable salt thereof:

TABLE 1

No.

R*

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

TABLE 1A

No.

R*

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

1-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

20. The compound of claim 9 , wherein R 3 is 4-8 membered heterocycloalkyl or —C(═NH)—NH 2 .