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

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:
• R1 is —OH;
• R1′ is hydrogen or halogen;
• W1 and W2 are —CH;
• X is selected from —C═O, —CR2, N, and —NR3;
• Y is selected from —C═O, —CR2, N, and —NR3, wherein
• if X is —C═O, then Y is —NR3,
• if X is —CR2, then Y is N,
• if X is N, then Y is —CR2, and
• if X is —NR3, 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;
• R2 is selected from —CN, —C(═O)OH, —C(═O)NH2, —C(═O)NHR7, —C(═O)NHCH2R7, —OCH2R7, —OR7, —NHR7, —NHCH2R7, C6 or C10 aryl, 5 to 10-membered heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 heteroalkyl, and 3 to 10-membered heterocyclyl,
• wherein the alkyl, heteroalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl of R2 is optionally substituted with 1-3 groups independently selected from halogen, —C(═O)OH, C1-C6 alkyl, C3-C8 cycloalkyl, C6 or C10 aryl, 3 to 10-membered heterocyclyl, 5 to 10-membered heteroaryl (optionally further substituted with halogen, —OH, —OCH3, —C(═O)OH) and C3-C6 cycloalkyl (optionally further substituted with halogen, —OH, —OCH3, and/or —C(═O)OH), and
• wherein the heteroalkyl of R2 contains 1-3 heteroatoms independently selected from N, O, and S;
• R3 is selected from hydrogen, C6 or C10 aryl, C1-C8 alkyl, and C3-C8 cycloalkyl;
• wherein R3 is optionally substituted with 1-3 groups independently selected from ═O, —OH, —CH2OH, —C(═O)OH, NH2, C3-C6 cycloalkyl (optionally substituted with ═O, —CH2OH, and/or —C(═O)OH), and 3 to 6-membered heterocyclyl (optionally substituted with ═O, —CH2OH, and/or —C(═O)OH), and
• wherein the heterocyclyl of R3 contains 1-3 nitrogen atoms;
• and
• wherein R3 is optionally fused to a C3-C6 cycloalkyl;
• R4 is selected from
• R5 is selected from C6 or C10 aryl, —O(phenyl), 5 or 6-membered heteroaryl, C3-C6 carbocyclyl, and 3 to 6-membered heterocyclyl, wherein the heterocyclyl or heteroaryl contains 1-3 nitrogens and wherein R5 is optionally substituted with (R6)n, wherein n is 1, 2, or 3;
• provided that R5 is not imidazolyl;
• R6, for each occurrence, is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy;
• R7 is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C6 or C10 aryl, C2-C8 heteroalkyl, 3 to 8-membered heterocyclyl, and 5 to 8-membered heteroaryl,
• wherein R7 is optionally substituted with 1-3 groups independently selected from halogen, ═O, —OH, —OCH3, —CH3, —C(═O)OH, —C(═O)NR8, —CN, —NH2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —C(═O)OH, and —NH2), C3-C6 cycloalkyl (optionally substituted with 1-3 groups selected from ═O, —OH, —CN, —C(═O)OH, and —NH2), C6 or C10 aryl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —C(═O)OH, and —NH2), C2-C6 heteroalkyl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —C(═O)OH, and —NH2), and 3 to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from halogen, ═O, OH, CN, COOH, and NH2), 5 or 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from ═O, —OH, —CN, —COOH, and —NH2), and
• wherein the heteroalkyl, heterocyclyl, or heteroaryl of R7 contains 1-3 atoms independently selected from N, O, and S;
• and
• R8 is selected from C1-C6 alkyl and C6 or C10 aryl, wherein R8 is optionally substituted with halogen and/or —OH.