Amino acid compounds with unbranched linkers and methods of use
The invention relates to compounds of formula (A): or a salt thereof, wherein R 1 , R 2 , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a , R 11b , R 21 , n, and G are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are α V β 6 integrin inhibitors that are useful for treating fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP).
1. A compound of formula (A):
or a salt thereof, wherein:
R 1 is hydrogen;
R 2 is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl optionally substituted by R 12 ;
G is —C(O)R 3 ;
R 3 is tetrahydropyranyl optionally substituted by R 3f ;
R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , and R 10b are each independently hydrogen, deuterium, or halogen;
each R 11a and R 11b are independently hydrogen, deuterium, or halogen;
n is 0, 1, or 2;
each R 3f is independently oxo or R 12 ;
each R 12 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, halogen, deuterium, —CN, —OR 13 , —SR 13 , —NR 14 R 15 , —NO 2 , —C═NH(OR 13 ), —C(O)R 13 , —OC(O)R 13 , —C(O)OR 13 , —C(O)NR 14 R 15 , —NR 13 C(O)R 14 , —NR 13 C(O)OR 14 , —NR 13 C(O)NR 14 R 15 , —S(O)R 13 , —S(O) 2 R 13 , —NR 13 S(O)R 14 , —NR 13 S(O) 2 R 14 , —S(O)NR 14 R 15 , —S(O) 2 NR 14 R 15 , or —P(O)(OR 13 )(OR 14 ), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and C 6 -C 14 aryl of R 12 are independently optionally substituted by R 12a ;
each R 12a is independently deuterium, halogen, oxo, —OR 16 , —NR 16 R 17 , —C(O)R 16 , —C(O)OR 16 , —NR 16 C(O)OR 18 , —CN, —S(O)R 16 , —S(O) 2 R 16 , —P(O)(OR 16 )(OR 17 ), C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, or C 1 -C 6 alkyl, wherein the C 6 -C 14 aryl, and C 1 -C 6 alkyl of R 12a are independently optionally substituted by R 12b ;
each R 12b is independently deuterium, oxo, —OH, halogen, or C 1 -C 6 alkyl;
each R 13 is independently hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 6 -C 14 aryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 6 -C 14 aryl of R 13 are each independently optionally substituted by R 13a ;
each R 13a is independently halogen, deuterium, oxo, —CN, —NR 19 R 20 , —P(O)(OR 19 )(OR 20 ), or C 1 -C 6 alkyl optionally substituted by deuterium, halogen, —OH, or oxo;
each R 14 is independently hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 6 -C 14 aryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 6 -C 14 aryl of R 14 are independently optionally substituted by deuterium, halogen, oxo, —CN, OR 18 , —NR 19 R 20 , or C 1 -C 6 alkyl optionally substituted by deuterium, halogen, —OH, or oxo;
each R 15 is independently hydrogen, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 6 -C 14 aryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 6 -C 14 aryl of R 15 are independently optionally substituted by deuterium, halogen, oxo, —CN, OR 18 , —NR 19 R 20 , or C 1 -C 6 alkyl optionally substituted by deuterium, halogen, —OH, or oxo;
each R 16 is independently hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6 alkynyl optionally substituted by deuterium, halogen, or oxo;
each R 17 is independently hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6 alkynyl optionally substituted by deuterium, halogen, or oxo;
each R 18 is independently hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6 alkynyl optionally substituted by deuterium, halogen, or oxo;
each R 19 is independently hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6 alkynyl optionally substituted by deuterium, halogen, or oxo;
each R 20 is independently hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C 2 -C 6 alkynyl optionally substituted by deuterium, halogen, or oxo; and
R 21 is hydrogen, deuterium, C 1 -C 6 alkyl optionally substituted by deuterium, halogen, or oxo, C 2 -C 6 alkenyl optionally substituted by deuterium, halogen, or oxo, or C 3 -C 6 cycloalkyl optionally substituted by deuterium, halogen, or oxo.
2. The compound of claim 1 , or a salt thereof, wherein R 21 is methyl, ethyl, 1-propyl, or 2-propyl, and the carbon to which R 21 is bonded is in the R configuration or the S configuration.
3. The compound of claim 1 , or a salt thereof, wherein R 7a and R 7b are both: hydrogen, deuterium, or fluorine.
4. The compound of claim 1 , or a salt thereof, wherein R 21 is hydrogen and the compound is represented by formula (I):
wherein each R 12b is independently deuterium, oxo, —OH, or halogen.
5. The compound of claim 1 , or a salt thereof, wherein n is 0 or 2.
6. The compound of claim 1 , or a salt thereof, wherein n is 1.
7. The compound of claim 1 , or a salt thereof, wherein R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a , and R 11b are each hydrogen.
8. The compound of claim 1 , or a salt thereof, wherein R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 11a , and R 11b are each deuterium.
9. The compound of claim 1 , or a salt thereof, wherein at least one of R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b R 11a , R 11b , R 12 , R 12a , R 12b , R 13 , R 13a , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , or R 20 is deuterium.
10. The compound of claim 7 , wherein R 2 is 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl and is represented by the compound of formula (II):
or a salt thereof.
11. The compound of claim 1 , or a salt thereof, wherein G is —C(O)R 3 and R 3 is tetrahydropyran-4-yl optionally substituted by R 3f .
12. The compound of claim 1 , or a salt thereof, wherein R 3 is tetrahydropyranyl substituted by 0-5 R 3f .
13. The compound of claim 12 , or a salt thereof, wherein R 3 is tetrahydropyran-4-yl substituted by 0-5 R 3f .
14. The compound of claim 12 , or a salt thereof, wherein R 3 is substituted by 1-5 R 3f , wherein at least one R 3f is C 1 -C 6 alkyl substituted by 0-5 moieties selected from the group consisting of halogen, —NR 16 R 17 , —NR 16 C(O)OR 18 , and C 6 -C 14 aryl, wherein the C 6 -C 14 aryl of R 3f is independently substituted by 0-5 R 12b .
15. The compound of claim 14 , or a salt thereof, wherein the at least one R 3f is C 1 -C 2 alkyl substituted by 0-5 fluoro, —NH 2 , —NHC(O)O-t-butyl, or phenyl.
16. The compound of claim 12 , or a salt thereof, wherein R 3 is substituted by:
A) 1-5 R 3f , wherein at least one R 3f is:
I) unsubstituted C 6 -C 14 aryl,
II) C 6 -C 14 aryl, which is independently substituted by 1-5 R 12a ,
III) phenyl which is independently substituted by 1-5 R 12a ,
IV) unsubstituted phenyl, or
V) —C(O)R 13 , —C(O)OR 13 , or —S(O) 2 R 13 , wherein each R 13 is independently C 1 -C 6 alkyl substituted by 0-5 —OR 18 , wherein R 18 is C 1 -C 6 alkyl substituted by 0-5 deuterium, halogen, or oxo; or
B) two or more R 3f , wherein each R 3f is independently selected from the group consisting of C 1 -C 6 alkyl, —C(O)R 13 , and —C(O)OR 13 .
17. The compound of claim 1 , or a salt thereof, wherein R 3 is selected from the group consisting of:
18. The compound of claim 1 , or a salt thereof, wherein at least one of R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b R 11a , R 11b , R 12 , R 12a , R 12b , R 13 , R 13a , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 or R 21 is deuterium.
19. The compound of claim 1 , wherein the compound is represented by formula (I-B):
or a salt thereof.
20. The compound of claim 1 , wherein the compound is represented by (II-A-6f):
or a salt thereof.
21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
22. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
23. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)nonanoic acid; 9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-carboxamido)nonanoic acid; 2 (3 methyltetrahydro-2H-pyran-3-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 2-(4-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 2-(4-Phenyltetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 2-(4-(aminomethyl)tetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 2-(4-fluorotetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 2-(2,6-dimethyltetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 2-(2,2-dimethyltetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-2-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carboxamido)nonanoic acid; 2-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; 5,5-difluoro-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid; and 2-(4-cyanotetrahydro-2H-pyran-4-carboxamido)-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid.
24. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
31. The compound of claim 22 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising any one or more of the compounds of claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
33. The compound of claim 10 , or a salt thereof, wherein the carbon to which the —CO 2 H group is bonded is in the S configuration.