7- or 8-hydroxy-isoquinoline and 7- or 8-hydroxy-quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD)

1 . A compound of Formula I:

a deuterated derivative of the compound of Formula I, and/or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is —OH;

R 1′ is hydrogen or halogen;

W 1 and W 2 are —CH;

X is selected from —C═O, —CR 2 , N, and —NR 3 ;

Y is selected from —C═O, —CR 2 , N, and —NR 3 , wherein

if X is —C═O, then Y is —NR 3 ,

if X is —CR 2 , then Y is N,

if X is N, then Y is —CR 2 , and

if X is —NR 3 , then Y is —C═O;

(z) is a double bond unless X or Y is C═O, and when X or Y is C═O, then (z) is a single bond;

R 2 is selected from —CN, —C(═O)OH, —C(═O)NH 2 , —C(═O)NHR 7 , —C(═O)NHCH 2 R 7 , —OCH 2 R 7 , —OR 7 , —NHR 7 , —NHCH 2 R 7 , C 6 or C 10 aryl, 5 to 10-membered heteroaryl, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 heteroalkyl, and 3 to 10-membered heterocyclyl,

wherein the alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl of R 2 is optionally substituted with 1-3 groups independently selected from halogen, —C(═O)OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 or C 10 aryl, 3 to 10-membered heterocyclyl, 5 to 10-membered heteroaryl (optionally further substituted with halogen, —OH, —OCH 3 , —C(═O)OH) and C 3 -C 6 cycloalkyl (optionally further substituted with halogen, —OH, —OCH 3 , and/or —C(═O)OH), and

wherein the heteroalkyl of R 2 contains 1-3 heteroatoms independently selected from N, O, and S;

R 3 is selected from hydrogen, C 6 or C 10 aryl, C 1 -C 8 alkyl, and C 3 -C 8 cycloalkyl;

wherein R 3 is optionally substituted with 1-3 groups independently selected from ═O, —OH, —CH 2 OH, —C(═O)OH, NH 2 , C 3 -C 6 cycloalkyl (optionally substituted with ═O, —CH 2 OH, and/or —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally substituted with ═O, —CH 2 OH, and/or —C(═O)OH), and

wherein the heterocyclyl of R 3 contains 1-3 nitrogen atoms; and

wherein R 3 is optionally fused to a C 3 -C 6 cycloalkyl;

R 4 is selected from

R 5 is selected from C 6 or C 10 aryl, —O(phenyl), 5 or 6-membered heteroaryl, C 3 -C 6 carbocyclyl, and 3 to 6-membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1-3 nitrogens and wherein R 5 is optionally substituted with (R 6 ) n , wherein n is 1, 2, or 3;

provided that R 5 is not imidazolyl;

R 6 , for each occurrence, is independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkoxy;

R 7 is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 or C 10 aryl, C 2 -C 8 heteroalkyl, 3 to 8-membered heterocyclyl, and 5 to 8-membered heteroaryl,

wherein R 7 is optionally substituted with 1-3 groups independently selected from halogen, ═O, —OH, —OCH 3 , —CH 3 , —C(═O)OH, —C(═O)NR 8 , —CN, —NH 2 , C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —C(═O)OH, and —NH 2 ), C 3 -C 6 cycloalkyl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —C(═O)OH, and —NH 2 ), C 6 or C 10 aryl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —C(═O)OH, and —NH 2 ), C 2 -C 6 heteroalkyl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —C(═O)OH, and —NH 2 ), and 3 to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, ═O, OH, CN, COOH, and NH 2 ), 5 or 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —COOH, and —NH 2 ), and

wherein the heteroalkyl, heterocyclyl, or heteroaryl of R 7 contains 1-3 atoms independently selected from N, O, and S; and

R 8 is selected from C 1 -C 6 alkyl and C 6 or C 10 aryl, wherein R 8 is optionally substituted with halogen and/or —OH.

2 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from phenyl and C 3 -C 8 cycloalkyl,

wherein R 3 is optionally substituted with 1-2 groups independently selected from ═O, —OH, —CH 2 OH, —C(═O)OH, —NH 2 , C 3 -C 6 cycloalkyl (optionally further substituted with 1-2 groups independently selected from ═O, —CH 2 OH, and —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from ═O, —CH 2 OH, and —C(═O)OH);

wherein the 3 to 6-membered heterocyclyl contains 1-2 nitrogen atoms; and

wherein R 3 is optionally fused to a C 3 -C 6 cycloalkyl.

3 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is C 1 -C 6 alkyl optionally substituted with 1-2 groups independently selected from ═O, —OH, —CH 2 OH, —C(═O)OH, —NH 2 , C 3 -C 6 cycloalkyl (optionally further substituted with 1-2 groups independently selected from ═O, —CH 2 OH, and —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from ═O, —CH 2 OH, and —C(═O)OH),

wherein the 3 to 6-membered heterocyclyl contains 1-2 nitrogen atoms; and

wherein R 3 is optionally fused to a C 3 -C 6 cycloalkyl.

4 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from C 4 cyclic and C 8 spirocyclic alkyls optionally substituted with 1-2 groups independently selected from ═O, —OH, —CH 2 OH, —C(═O)OH, and —NH 2 .

5 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is selected from:

6 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 is hydrogen.

7 . The compound, deuterated derivative, or pharmaceutically acceptable salt according claim 1 , wherein R 5 is selected from phenyl, 5 or 6-membered heteroaryl, C 3 -C 6 carbocyclyl, and 3 to 6-membered heterocyclyl,

wherein R 5 is optionally substituted with 1 or 2 groups independently selected from halogen and —CH 3 .

8 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is selected from

9 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from —OR 7 , —NHR 7 , —C(═O)NHR 7 , and —NHCH 2 R 7 .

10 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from —CN, —C(═O)OH, —C(═O)NH 2 , —C(═O)NHCH 2 R 7 , and —OCH 2 R 7 .

11 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 7 is selected from C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl, each of which is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH 3 , —C(═O)OH, ═O, —OCH 3 , and —OH.

12 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 7 is selected from C 2 -C 8 heteroalkyl and 3 to 8-membered heterocyclyl,

wherein the heteroalkyl or heterocyclyl contains 1-3 heteroatoms independently selected from N, O, and S; and

wherein the heteroalkyl or heterocyclyl is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH 3 , —C(═O)OH, ═O, —OCH 3 , and —OH.

13 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 7 is selected from aryl and 5 to 8-membered heteroaryl,

wherein the aryl or heteroaryl contain 1-3 heteroatoms independently selected from N, O, and S; and

wherein the aryl or heteroaryl is optionally substituted with 1-3 groups independently selected from Br, Cl, F, —CH 3 , —C(═O)OH, ═O, —OCH 3 , and —OH.

14 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 7 is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heteroalkyl, 3 to 8-membered heterocyclyl, phenyl, and 5 to 8-membered heteroaryl,

wherein R 7 is optionally substituted with 1-3 groups independently selected from halogen, ═O, —C(═O)OH, phenyl, 5 to 8-membered heteroaryl, C 1 -C 6 alkyl (optionally further substituted with 1-3 groups independently selected from ═O, OH, CN, COOH, and NH 2 ), C 3 -C 6 cycloalkyl (optionally further substituted with 1-3 groups independently selected from ═O, —OH, —CN, —COOH, and —NH 2 ), C 2 -C 6 heteroalkyl (optionally further substituted with 1-3 groups independently selected from halogen, ═O, —OH, —CN, —COOH, and —NH 2 ), and 3 to 6-membered heterocyclyl (optionally further substituted with 1-3 groups independently selected from ═O, —OH, —CN, —COOH, and —NH 2 ); and

wherein the heteroalkyl, heterocyclyl, or heteroaryl of R 7 contains 1-3 atoms independently selected from N, O, and S.

15 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from

16 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from

17 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from

18 . The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is selected from

19 . A compound selected from:

deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

20 . A pharmaceutical composition comprising the compound according to claim 1 , a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

21 . A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof at least one compound chosen from the compounds, deuterated derivatives, and pharmaceutically acceptable salts according to claim 1 .

22 . A method of increasing alpha-1 antitrypsin activity comprising contacting said alpha-1 antitrypsin with at least one compound chosen from the compounds, deuterated derivatives, and pharmaceutically acceptable salts according to claim 1 .