1H-pyrazolo[4,3-G]isoquinoline and 1H-pyrazolo[4,3-g]quinoline derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD)

A compound represented by Formula II

• a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
• W1 and W2 are each independently selected from —C═O, —CR2, N, and —NR2, wherein:
• when W1 is —CR2, then W2 is N;
• when W2 is —CR2, then W1 is N;
• when W1 is —C═O, then W2 is —NR2;
• and
• when W2 is —C═O, then W1 is —NR2
• (h) is a double bond except that when one of W1 and W2 is —C═O, then (h) is a single bond;
• Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, C6 or C10 aryl, or 5 to 10-membered heteroaryl;
• R1 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, —C(═O)Rz, —C(═O)ORz, —C(═O)NRwRx, —NRwRx, —NRwC(═O)Rz, —NRwC(═O)ORz, —NRwC(═O)NRxRy, —ORz, —OC(═O)Rz, —OC(═O)NRwRx, S(═O)2Rz, C3-C6 cycloalkyl, or 3 to 6-membered heterocyclyl;
• wherein:
• the C1-C6 alkyl, the C3-C6 cycloalkyl, or the 3 to 6-membered heterocyclyl of R1 is optionally substituted with 1 to 3 groups independently selected from —ORz, C1-C3 haloalkyl, —CN, and halogen;
• and
• Rw, Rx, Ry, and Rz are each independently hydrogen or C1-C4 alkyl;
• X1 and X2 are each independently hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, or 5 or 6-membered heteroaryl;
• R2 is hydrogen, halogen,
• wherein:
• T is absent, or is selected from —O—, —OCH2—, —NH—, —NS(═O)2CH3, —S—, and —CH2—;
• Y is selected from C1-C6 alkyl, —(CRaRa)pCOOH, —(CRaRa)pNRbS(═O)2(CRcRc)qOH, —(CRaRa)pC(═O)NRb(CRcRc)gCOOH, and —(CRaRa)p(O)(CRcRc)qCOOH;
• wherein:
• Ra, for each occurrence, is independently hydrogen, halogen, —OH, or C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from halogen and —OH;
• or alternatively, when Ra, for each occurrence, is independently C1-C4 alkyl, two Ra groups together with their intervening carbon atom form cyclopropyl or cyclobutyl;
• Rb and Rc, for each occurrence, are each independently hydrogen or C1-C2 alkyl;
• and
• p and q are each independently an integer selected from 1 and 2;
• Ring B is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, C6 or C10 aryl, or 5 to 10-membered heteroaryl;
• R3 is —C(═O)ORd;
• wherein Rd is C1-C4 alkyl optionally substituted with —OC(O)Re, —OC(═O)ORe, or —OP(═O)RfRf;
• wherein:
• Re, for each occurrence, is independently hydrogen or —CH3;
• Rf, for each occurrence, is independently —OH, —CH3, or —OCH3;
• Rk is halogen, —CN, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, or O—(C3-C6 cycloalkyl);
• Rm, for each occurrence, is independently halogen, —CN, ═O, C1-C6 alkyl, C1-C6 alkoxy, —C(═O)Rr, —C(═O)ORr, —C(═O)NRpRq, —C(═O)NRpORr, —NRpRq, —NRpC(═O)Rr, —NRpS(═O)2Rr, —ORr, S(═O)2Rr, —S(═O)2NRpRq, —P(═O)RsRt, C3-C6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl,
• wherein the C1-C6 alkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, CN, —C(═O)ORr, —NRpRq, and —ORr;
• and
• wherein the C3-C6 cycloalkyl or the 3 to 6-membered heterocyclyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, CN, ═O, —C(═O)ORr, —NRpRq, and —ORr;
• wherein Rp and Rq, for each occurrence, are each independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 groups independently selected from —OH, —OCH3, —OC2H5, and —COOH;
• wherein Rr, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3 to 6-membered heterocyclyl;
• wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 3 to 6-membered heterocyclyl of Rr is optionally substituted with 1 to 3 groups independently selected from —OH, —OCH3, —OC2H5, —CH2OH, —C(═O)OH, —(O)C(═O)OH, and —(O)P(═O)(OH)2;
• and
• wherein Rs and Rt, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or —OH;
• k and m are each independently an integer selected from 0, 1, 2, 3, 4, and 5;
• and
• n is an integer selected from 0and 1.