CBP/catenin signaling pathway inhibitors and uses thereof
Provided are compounds of formula (Ia), (Ib) and (IIa), and pharmaceutically acceptable salts thereof. Additionally provided are compositions and pharmaceutical compositions comprising the compounds, therapeutic methods using same for modulating (e.g., inhibiting) CREB binding protein (CBP)/β-catenin mediated signaling in treating a condition, disease or disorder (e.g., fibrosis, cancer, neurological conditions, metabolic disorders (e.g., diabetes, etc.), and skin conditions (dermatitis, psoriasis, scarring, alopecia, etc.) mediated by aberrant CBP/β-catenin signaling, and cosmetic methods for treating skin conditions (e.g., aging, etc.). Additionally, provided are methods for enhancing vaccine efficacy using the compounds and compositions. Further provided are methods for efficiently synthesizing a clinical grade drug, comprising use, in a penultimate, or last reaction step under GMP conditions, of an intermediate 2-propynyl-compound to form a clinical grade isoxazole derivative (e.g., via 3+2 cycloaddition).
1. A compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —CH 3 ;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkyl amino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group, or substituted bicyclic aryl, having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, where the substituted bicyclic aryl may have one or more substituents independently selected from amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is hydrogen, phosphate or phosphate salt, or X, wherein X is selected from:
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester, and n is 1 or 2;
L is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —; and
Q is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 0-2 substituents, selected from:
wherein A, B, and D are independently selected from O, S, N, or —CH, wherein Z 1 , Z 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, —OH, —OC 1 -C 6 alkyl, and
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl containing one or more —OH, and wherein Z 3 is selected from hydrogen, halogen, or a direct-bonded, or —NH-linked, —OC 1 -C 3 alkyl linked, or —NHC 1 -C 3 alkyl linked aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl, heterocycloalkyl, or —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 , each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
2. The compound of claim 1 , wherein R is a bicyclic aryl selected from naphthyl, quinolinyl, isoquinolinyl, quinoxaline, phthalazine, quinazoline, cinnoline, naphthyridine, or substituted variants thereof.
3. The compound of claim 2 , wherein the compound is of the formula (Ib):
wherein X 1 and X 2 are independently selected from: N, or —CH.
4. The compound of claim 3 , wherein:
L is —CH 2 —;
Q is
wherein A, B, and D are independently selected from O, S, N, or —CH.
5. The compound of claim 4 , wherein A is —CH, B is N, and D is O (Z 3 -isoxazole-), and wherein W is hydrogen, phosphate or phosphate salt, or X, wherein X is selected from:
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester, and n is 1 or 2.
6. The compound of claim 5 , wherein Z 3 is selected from aryl or heteroaryl, each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
7. The compound of claim 6 , wherein Z 3 is selected from aryl or heteroaryl, substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, or nitrogen-bonded heterocycloalkyl.
8. The compound of claim 7 , wherein the compound is:
9. A compound of formula (IIa):
wherein:
R a is methyl or hydrogen;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is X, wherein X is selected from: an alkyl acid or fatty acid,
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester, and n is 1 or 2.
10. A compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —CH 3 ;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group, or substituted bicyclic aryl, having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, where the substituted bicyclic aryl may have one or more substituents independently selected from amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is an ester of an alkyl acid or of a fatty acid;
L is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —; and
Q is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 0-2 substituents, selected from:
wherein A, B, and D are independently selected from O, S, N, or —CH, wherein Z 1 , Z 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, —OH, —OC 1 -C 6 alkyl, and
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl containing one or more —OH, and wherein Z 3 is selected from hydrogen, halogen, or a direct-bonded, or —NH-linked, —OC 1 -C 3 alkyl linked, or —NHC 1 -C 3 alkyl linked aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl, heterocycloalkyl, or —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 , each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
11. The compound of claim 10 , wherein the ester of the alkyl acid or of the fatty acid is selected from:
wherein m is 1 to 14,
12. The compound of claim 10 , wherein R is a bicyclic aryl selected from naphthyl, quinolinyl, isoquinolinyl, quinoxaline, phthalazine, quinazoline, cinnoline, naphthyridine, or substituted variants thereof.
13. The compound of claim 12 , wherein the compound is of the formula (Ib):
wherein X 1 and X 2 are independently selected from: N, or —CH.
14. The compound of claim 13 , wherein:
L is —CH 2 —;
Q is
wherein A, B, and D are independently selected from O, S, N, or —CH.
15. The compound of claim 14 , wherein A is —CH, B is N, and D is O (Z 3 -isoxazole-).
16. The compound of claim 15 , wherein Z 3 is selected from aryl or heteroaryl, each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
17. The compound of claim 16 , wherein Z 3 is selected from aryl or heteroaryl, substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, or nitrogen-bonded heterocycloalkyl.
18. The compound of claim 17 , wherein the compound is:
19. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a p-toluenesulfonate.
20. A composition or pharmaceutical composition comprising the compound of any one of claim 1 , claims 2 - 8 , or claim 19 and a pharmaceutically acceptable carrier.
21. A composition or pharmaceutical composition comprising the compound of any one of claims 10 to 18 , and a pharmaceutically acceptable carrier.
22. A method of treating a disease or disorder, comprising administering to a patient or a warm-blooded mammal, having a disease or disorder mediated by CREB binding protein (CBP)/β-catenin signaling, a therapeutically effective amount of a compound, or of a composition or pharmaceutical composition comprising same wherein the disease or disorder is one or more of fibrosis, metabolic disease, and skin conditions, and wherein the compound is of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —CH 3 ;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group, or substituted bicyclic aryl, having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, where the substituted bicyclic aryl may have one or more substituents independently selected from amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is hydrogen, phosphate or phosphate salt, or X, wherein X is selected from:
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester, and n is 1 or 2;
L is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —; and
Q is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 0-2 substituents, selected from:
wherein A, B, and D are independently selected from O, S, N, or —CH, wherein Z 1 , Z 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, —OH, —OC 1 -C 6 alkyl, and
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl containing one or more —OH, and wherein Z 3 is selected from hydrogen, halogen, or a direct-bonded, or —NH-linked, —OC 1 -C 3 alkyl linked, or —NHC 1 -C 3 alkyl linked aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl, heterocycloalkyl, or —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 , each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
23. The method of claim 22 , wherein, in the compound, W is X, wherein X is selected from:
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester and n is 1 or 2.
24. The method of claim 22 , wherein, in the compound, X is
wherein Z is OR 4 where R 4 is a hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester and n is 1 or 2.
25. The method of claim 22 , wherein the metabolic disorder comprises one or more of diabetes and/or fatty liver disease.
26. The method of claim 25 , wherein the fatty liver disease comprises one or more of alcoholic hepatic steatosis (ALD), non-alcoholic hepatic steatosis (NAFLD), and/or non-alcoholic steatohepatitis (NASH).
27. The method of claim 22 , wherein the fibrosis is fibrosis of the lung, liver, kidney, heart, endometrium, skin or systemic fibrosis.
28. The method of claim 27 , wherein the fibrosis comprises fibrosis in a SARS-CoV-2 (COVID-19) patient tissue.
29. The method of claim 22 , wherein the skin condition comprises one or more of atopic dermatitis, psoriasis, acne, fibrosis, wounding, scarring, burns, sun or U.V. damage, diabetic ulceration, chronic ulceration, and/or alopecia.
30. The method of claim 29 , wherein administration comprises topical or transdermal administration.
31. A cosmetic method for treating a skin condition, comprising topically administering to a patient or a warm-blooded mammal, having a skin condition, a cosmeceutically effective amount of a compound, or of a composition or pharmaceutical composition comprising same, and wherein the compound is of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —CH 3 ;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group, or substituted bicyclic aryl, having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, where the substituted bicyclic aryl may have one or more substituents independently selected from amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is hydrogen, phosphate or phosphate salt, or X, wherein X is selected from:
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester, and n is 1 or 2;
L is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —; and
Q is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 0-2 substituents, selected from:
wherein A, B, and D are independently selected from O, S, N, or —CH, wherein Z 1 , Z 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, —OH, —OC 1 -C 6 alkyl, and
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl containing one or more —OH, and wherein Z 3 is selected from hydrogen, halogen, or a direct-bonded, or —NH-linked, —OC 1 -C 3 alkyl linked, or —NHC 1 -C 3 alkyl linked aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl, heterocycloalkyl, or —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 , each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
32. The method of claim 31 , wherein the skin condition comprises one or more aging skin conditions selected from wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of vibrance, loss of elasticity, thinning, loss of vibrance, scarring, acne, sun damage, hair loss, loss of hair coloration, reduced cuticle growth, reduced nail growth.
33. A method of treating a disease or disorder, comprising administering to a patient or a warm-blooded mammal, having a disease or disorder mediated by CREB binding protein (CBP)/β-catenin signaling, a therapeutically effective amount of a compound, or of a composition or pharmaceutical composition comprising same, wherein the disease or disorder is one or more skin conditions selected from atopic dermatitis, psoriasis, acne, fibrosis, wounding, scarring, burns, sun or U.V. damage, diabetic ulceration, chronic ulcerations and alopecia, and wherein the compound is of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —CH 3 ;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group, or substituted bicyclic aryl, having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, where the substituted bicyclic aryl may have one or more substituents independently selected from amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is an ester of an alkyl acid or of a fatty acid;
L is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —; and
Q is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 0-2 substituents, selected from:
wherein A, B, and D are independently selected from O, S, N, or —CH, wherein Z 1 , Z 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, —OH, —OC 1 -C 6 alkyl, and
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl containing one or more —OH, and wherein Z 3 is selected from hydrogen, halogen, or a direct-bonded, or —NH-linked, —OC 1 -C 3 alkyl linked, or —NHC 1 -C 3 alkyl linked aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl, heterocycloalkyl, or —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 , each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
34. The method of claim 33 , wherein the fibrosis is fibrosis of the skin.
35. The method of claim 33 , wherein administration comprises topical or transdermal administration.
36. A cosmetic method for treating a skin condition, comprising topically administering to a patient or a warm-blooded mammal, having a skin condition, a cosmeceutically effective amount of a compound, or of a composition or pharmaceutical composition comprising same, and wherein the compound is of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R a is hydrogen or —CH 3 ;
R b is a monocyclic aryl group having 5 to 7 ring members, which may have 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, and which may have one or more substituents selected from a group consisting of halide, cyano, and lower alkyl;
R is a phenyl group; a substituted phenyl group having one or more substituents wherein the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl groups; a benzyl group; a substituted benzyl group with one or more substituents where the one or more substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group; or a bicyclic aryl group, or substituted bicyclic aryl, having 8 to 11 ring members, which may have 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, where the substituted bicyclic aryl may have one or more substituents independently selected from amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl, and hydroxyl group;
R 2 is hydrogen, or —CH 3 ;
Y is selected from: hydrogen, deuterium, or halogen;
W is an ester of an alkyl acid or of a fatty acid;
L is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —; and
Q is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 0-2 substituents, selected from:
wherein A, B, and D are independently selected from O, S, N, or —CH, wherein Z 1 , Z 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, —OH, —OC 1 -C 6 alkyl, and
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl containing one or more —OH, and wherein Z 3 is selected from hydrogen, halogen, or a direct-bonded, or —NH-linked, —OC 1 -C 3 alkyl linked, or —NHC 1 -C 3 alkyl linked aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl, heterocycloalkyl, or —NHC 1 -C 4 alkyl, —N(C 1 -C 4 alkyl) 2 , each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
37. The method of claim 36 , wherein the skin condition comprises one or more aging skin conditions selected from wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of vibrance, loss of elasticity, thinning, loss of vibrance, scarring, acne, sun damage, hair loss, loss of hair coloration, reduced cuticle growth, reduced nail growth.
38. The method of claim 22 or claim 31 , wherein R is a bicyclic aryl selected from naphthyl, quinolinyl, isoquinolinyl, quinoxaline, phthalazine, quinazoline, cinnoline, naphthyridine, or substituted variants thereof.
39. The method of claim 38 , wherein the compound is of the formula (Ib):
wherein X 1 and X 2 are independently selected from: N, or —CH.
40. The method of claim 39 , wherein:
L is —CH 2 —;
Q is
wherein A, B, and D are independently selected from O, S, N, or —CH.
41. The method of claim 40 , wherein A is —CH, B is N, and D is O (Z 3 -isoxazole-), and wherein W is hydrogen, phosphate or phosphate salt, or X, wherein X is selected from:
wherein Z is OR 4 where R 4 is hydrogen or C 1 -C 6 alkyl, or Z is an amino acid or amino acid ester, and n is 1 or 2.
42. The method of claim 41 , wherein Z 3 is selected from aryl or heteroaryl, each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
43. The method of claim 42 , wherein Z 3 is selected from aryl or heteroaryl, substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, or nitrogen-bonded heterocycloalkyl.
44. The method of claim 43 , wherein the compound is:
45. The method of claim 22 , wherein the pharmaceutically acceptable salt is a p-toluenesulfonate.
46. The method of claim 31 , wherein the pharmaceutically acceptable salt is a p-toluenesulfonate.
47. The method of claim 33 or claim 36 , wherein the ester of the alkyl acid or of the fatty acid is selected from:
wherein m is 1 to 14,
48. The method of claim 33 or claim 36 , wherein R is a bicyclic aryl selected from naphthyl, quinolinyl, isoquinolinyl, quinoxaline, phthalazine, quinazoline, cinnoline, naphthyridine, or substituted variants thereof.
49. The method of claim 48 , wherein the compound is of the formula (Ib):
wherein X 1 and X 2 are independently selected from: N, or —CH.
50. The method of claim 49 , wherein:
L is —CH 2 —;
Q is
wherein A, B, and D are independently selected from O, S, N, or —CH.
51. The method of claim 50 , wherein A is —CH, B is N, and D is O (Z 3 -isoxazole-).
52. The method of claim 51 , wherein Z 3 is selected from aryl or heteroaryl, each of which is substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 alkyl-C(O)NH—OH, —NH 2 , —C(O)NH—C 1 -C 6 alkyl-heteroaryl, —NHC(O)C 1 -C 6 alkyl-C(O)NH—OH, heteroaryl, cycloalkyl, heterocycloalkyl, or a nitrogen-bonded cycloalkyl or heterocycloalkyl, —NHC 1 -C 4 alkyl, or —N(C 1 -C 4 alkyl) 2 .
53. The method of claim 52 , wherein Z 3 is selected from aryl or heteroaryl, substituted by 0-4 substituents independently selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, —OH, —OC 1 -C 6 alkyl, or nitrogen-bonded heterocycloalkyl.
54. The method of claim 53 , wherein the compound is: