Substituted imidazo[1,2-a]pyrazines and pyrazino[1,2-a]pyrimidines as topical agents for dermatological applications

1. A compound of formula (I):

or a cosmeceutically acceptable or pharmaceutically acceptable salt thereof,

wherein:

L is —C(O)— or —S(O) 2 —;

X is —C(O)— or —CH 2 C(O)—;

Y is H or C(O)R;

R is C 1-30 alkyl or C 2-30 alkenyl;

R 1 is H or CH 3 ;

R 2 is H or CH 3 ;

R 3 is H or D;

Q is benzyl, phenyl, or an 8- to 11-membered aryl;

wherein the 8- to 11-membered aryl is bicyclic;

wherein the 8- to 11-membered aryl optionally contains 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

wherein the benzyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-4 perfluoroalkyl, C(NH)NH 2 , C(O)OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , NHC(NH)NH 2 , OH, and OC 1-4 alkyl; and

wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 perfluoroalkyl, C(NH)NH 2 , C(O)OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , NHC(NH)NH 2 , OH, and OC 1-4 alkyl; and

n is 1 or 2.

2. The compound of claim 1 , wherein the compound is of formula (Ia):

or a cosmeceutically acceptable or pharmaceutically acceptable salt thereof,

wherein:

Q is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, or naphthyridinyl.

3. The compound of claim 2 , wherein the compound is of formula (Ib):

or a cosmeceutically acceptable or pharmaceutically acceptable salt thereof,

wherein:

X 1 is CH or N;

Y is H or C(O)R;

R is:

 m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The compound of claim 2 , wherein the compound is of formula (Ic):

or a cosmeceutically acceptable or pharmaceutically acceptable salt thereof,

wherein:

X 1 is CH or N;

Y is H or C(O)R;

R is:

and

 m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a cosmeceutically acceptable or pharmaceutically acceptable salt thereof.

6. A cosmeceutical composition comprising a cosmeceutically acceptable excipient and a compound of claim 1 , or a cosmeceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

8. A method for cosmetically treating a skin condition in a mammalian subject, wherein the method comprises topically administering to the mammalian subject in need thereof a cosmeceutically effective amount of a compound of formula (I):

or a cosmeceutically acceptable salt thereof,

wherein:

L is —C(O)— or —S(O) 2 —;

X is —C(O)— or —CH 2 C(O)—;

Y is H or C(O)R;

R is C 1-30 alkyl or C 2-30 alkenyl;

R 1 is H or CH 3 ;

R 2 is H or CH 3 ;

R 3 is H or D;

Q is benzyl, phenyl, or an 8- to 11-membered aryl;

wherein the 8- to 11-membered aryl is bicyclic;

wherein the 8- to 11-membered aryl optionally contains 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

wherein the benzyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-4 perfluoroalkyl, C(NH)NH 2 , C(O)OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , NHC(NH)NH 2 , OH, and OC 1-4 alkyl; and

wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 perfluoroalkyl, C(NH)NH 2 , C(O)OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , NHC(NH)NH 2 , OH, and OC 1-4 alkyl; and

n is 1 or 2.

9. The method of claim 8 , wherein the skin condition is mediated by cyclic adenosine monophosphate response element binding-binding protein (CBP)/β-catenin signaling.

10. The method of claim 8 , wherein the skin condition is an aging skin conditions selected from the group consisting of acne, cracking, dryness, hair loss, hyperpigmentation, loss of elasticity, loss of hair coloration, loss of vibrance, redness, reduced cuticle growth, reduced eyebrow growth, reduced eyelash growth, reduced nail growth, scarring, sun damage, thinning, ultraviolet damage, and wrinkles, or a combination thereof.

11. The method of claim 8 , wherein Y is C(O)R.

12. The method of claim 11 , wherein:

R is:

and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

13. The method of claim 8 , wherein the compound is of formula (Ia):

or a cosmeceutically acceptable salt thereof,

wherein:

Q is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, or naphthyridinyl.

14. The method of claim 13 , wherein the compound is of formula (Ib):

or a cosmeceutically acceptable salt thereof,

wherein:

X 1 is CH or N;

Y is H or C(O)R;

R is:

and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

15. The method of claim 13 , wherein the compound is of formula (Ic):

or a cosmeceutically acceptable salt thereof,

wherein:

X 1 is CH or N;

Y is H or C(O)R;

R is:

and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

16. The method of claim 8 , wherein the compound is selected from the group consisting of:

or a cosmeceutically acceptable salt thereof.

17. A method for cosmetically treating a skin condition in a mammalian subject, wherein the method comprises topically administering to the mammalian subject in need thereof a cosmeceutically effective amount of a cosmeceutical composition comprising a cosmeceutically acceptable excipient and a compound of formula (I):

or a cosmeceutically acceptable salt thereof,

wherein:

L is —C(O)— or —S(O) 2 —;

X is —C(O)— or —CH 2 C(O)—;

Y is H or C(O)R;

R is C 1-30 alkyl or C 2-30 alkenyl;

R 1 is H or CH 3 ;

R 2 is H or CH 3 ;

R 3 is H or D;

Q is benzyl, phenyl, or an 8- to 11-membered aryl;

wherein the 8- to 11-membered aryl is bicyclic;

wherein the 8- to 11-membered aryl optionally contains 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

wherein the benzyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-4 perfluoroalkyl, C(NH)NH 2 , C(O)OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , NHC(NH)NH 2 , OH, and OC 1-4 alkyl; and

wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 perfluoroalkyl, C(NH)NH 2 , C(O)OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , NHC(NH)NH 2 , OH, and OC 1-4 alkyl; and

n is 1 or 2.

18. The method of claim 17 , wherein the skin condition is mediated by cyclic adenosine monophosphate response element binding-binding protein (CBP)/β-catenin signaling.

19. The method of claim 17 , wherein the skin condition is an aging skin condition selected from the group consisting of acne, cracking, dryness, hair loss, hyperpigmentation, loss of elasticity, loss of hair coloration, loss of vibrance, redness, reduced cuticle growth, reduced eyebrow growth, reduced eyelash growth, reduced nail growth, scarring, sun damage, thinning, ultraviolet damage, and wrinkles, or a combination thereof.

20. The method of claim 17 , wherein Y is C(O)R.

21. The method of claim 20 , wherein:

R is:

and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

22. The method of claim 17 , wherein the compound is of formula (Ia):

or a cosmeceutically acceptable salt thereof,

wherein:

Q is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, or naphthyridinyl.

23. The method of claim 22 , wherein the compound is of formula (Ib):

or a cosmeceutically acceptable salt thereof,

wherein:

X 1 is CH or N;

Y is H or C(O)R;

R is:

and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

24. The method of claim 22 , wherein the compound is of formula (Ic):

or a cosmeceutically acceptable salt thereof,

wherein:

X 1 is CH or N;

Y is H or C(O)R;

R is:

and

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

25. The method of claim 17 , wherein the compound is selected from the group consisting of:

or a cosmeceutically acceptable salt thereof.