Pyrano[4,3-b]indole derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD)

A compound represented by one of the following structural formulae:

• a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
• W1 is absent or a bond, —O—, or —CRDRD—;
• W2 is —O—, —(CRDRD)p—, or —C═O;
• provided that W1 and W2 are not both —O—;
• RA and RB are each independently hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy;
• or alternatively RA and RB are each independently C1-C3 alkyl or C1-C3 alkoxy, and/or RA and RB together with their intervening C atom form a C3-C6 cycloalkyl or a 3 to 6-membered heterocyclyl containing at least one oxygen atom;
• RC is independently hydrogen, —OH, C1-C3 alkyl, or C1-C3 haloalkyl;
• RD, for each occurrence, is independently hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy;
• or alternatively RD, for each occurrence, is independently C1-C3 alkyl or C1-C3 alkoxy, and two RD groups together with their intervening C atom form a C3-C6 cycloalkyl or a 3 to 6-membered heterocyclyl containing at least one oxygen atom;
• U1 and U2 are each independently hydrogen, halogen, —NH2, —CH3, or —OH;
• provided that one of U1 and U2 is —OH or —NH2 but U1 and U2 are not both —OH or —NH2 and U1 and U2 are not both hydrogen;
• Ring A is C3-C12 carbocyclyl or 3 to 12-membered heterocyclyl;
• X is absent, —(CRERE)q—, or —CH2OCH2—;
• wherein:
• RE, for each occurrence, is independently hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy;
• Y is —COOH or
• Ring B is C3-C12 cycloalkyl, a 3 to 12-membered heterocyclyl, a phenyl, or a 5 or 6-membered heteroaryl;
• R1 and R2, for each occurrence, are each independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or O—(C3-C6 cycloalkyl);
• and
• R3, for each occurrence, is independently halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —OH, —O(CRfRf)rCOOH, ═O, —COOH, —C(═O)NRfRf, —(CRfRf)rCOOH, phenyl, or 5 or 6-membered heteroaryl;
• wherein:
• Rf for each occurrence, is independently hydrogen, halogen, or —CH3;
• and
• the phenyl, or the 5 or 6-membered heteroaryl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C2 alkyl, C1-C2haloalkyl, C1-C2 alkoxy, —OH, and —COOH;
• R4, for each occurrence, is independently halogen, cyano, C1-C2 alkyl, C1-C2haloalkyl, C1-C2 alkoxy, —COOH, —CH2COOH, or —OCH2COOH;
• k and n are each independently an integer selected from 0, 1, 2, and 3;
• j and m are each independently an integer selected from 0, 1, and 2;
• p and r are each independently an integer selected from 1 and 2;
• and
• q is an integer selected from 1, 2, and 3.