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

Patent metadata

Field	Value
Publication number	US-12502376-B2
Application number	US-202117916448-A
Country	US
Kind code	B2
Filing date	Apr 2, 2021
Priority date	Apr 3, 2020
Publication date	Dec 23, 2025
Grant date	Dec 23, 2025

Abstract

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

First claim

What is claimed is:

1 . 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:
W 1 is absent or a bond, —O—, or —CR D R D —;
W 2 is —O—, —(CR D R D ) p —, or —C═O;
provided that W 1 and W 2 are not both —O—;
R A and R B are each independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
or alternatively R A and R B are each independently C 1 -C 3 alkyl or C 1 -C 3 alkoxy, and/or R A and R B together with their intervening C atom form a C 3 -C 6 cycloalkyl or a 3 to 6-membered heterocyclyl containing at least one oxygen atom;
R C is independently hydrogen, —OH, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
R D , for each occurrence, is independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
or alternatively R D , for each occurrence, is independently C 1 -C 3 alkyl or C 1 -C 3 alkoxy, and two R D groups together with their intervening C atom form a C 3 -C 6 cycloalkyl or a 3 to 6-membered heterocyclyl containing at least one oxygen atom;
U 1 and U 2 are each independently hydrogen, halogen, —NH 2 , —CH 3 , or —OH;
provided that one of U 1 and U 2 is —OH or —NH 2 but U 1 and U 2 are not both —OH or —NH 2 and U 1 and U 2 are not both hydrogen;
Ring A is C 3 -C 12 carbocyclyl or 3 to 12-membered heterocyclyl;
X is absent, —(CR E R E ) q —, or —CH 2 OCH 2 —; wherein:
R E , for each occurrence, is independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
Y is —COOH or

Ring B is C 3 -C 12 cycloalkyl, a 3 to 12-membered heterocyclyl, a phenyl, or a 5 or 6-membered heteroaryl;
R 1 and R 2 , for each occurrence, are each independently halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, or O—(C 3 -C 6 cycloalkyl); and
R 3 , for each occurrence, is independently halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, —OH, —O(CR f R f ) r COOH, ═O, —COOH, —C(═O)NR f R f , —(CR f R f ) r COOH, phenyl, or 5 or 6-membered heteroaryl; wherein:
R f for each occurrence, is independently hydrogen, halogen, or —CH 3 ; and
the phenyl, or the 5 or 6-membered heteroaryl of R 3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, —OH, and —COOH;

R 4 , for each occurrence, is independently halogen, cyano, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, —COOH, —CH 2 COOH, or —OCH 2 COOH;
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.

2 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
R A and R B are each independently hydrogen, halogen, —OH, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or C 1 -C 2 alkoxy; or alternatively R A and R B are each independently C 1 -C 3 alkyl, and or R A and R B together with their intervening C atom form a cyclopropyl or a cyclobutyl; and R D , for each occurrence, is independently hydrogen, halogen, —OH, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or C 1 -C 2 alkoxy; or alternatively R D , for each occurrence, is independently C 1 -C 3 alkyl, and or two R D groups together with their intervening C atom form a cyclopropyl or a cyclobutyl.

3 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by one of the following structural formulae:

and wherein R A and R B are each independently hydrogen or C 1 -C 2 alkyl.

4 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
U 1 is —NH 2 or —OH; and U 2 is hydrogen, halogen, or —CH 3 —.

5 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by the following structural formula:

and wherein U 2 is hydrogen, F, or Cl.

6 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is optionally substituted with R 3 and Ring A is 4 to 9-membered carbocyclyl or 5 or 6-membered heterocyclyl.

7 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is optionally substituted with R 3 and Ring A is cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, tetrahydro-2H-pyranyl, piperidinyl, spiro[2.3]hexanyl, 1-iminohexahydro-1λ 6 -thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide, or 2,3-dihydro-1H-indenyl.

8 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is optionally substituted with R 3 and Ring A is

9 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3 , for each occurrence, is independently halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, —OH, —O(CR f R f ) r COOH, ═O, —COOH, —C(═O)NR f R f , —(CR f R f ) r COOH, phenyl, or a 5-membered heteroaryl; wherein:
R f for each occurrence, is independently hydrogen or —CH 3 ; and
the phenyl or the 5-membered heteroaryl of R 3 is optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, —OH, and —COOH.

10 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein:
R 3 , for each occurrence, is independently F, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OH, —OCH 3 , —COOH, —CH 2 COOH, —CF 2 COOH, —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , ═O, —OCH 2 COOH, —OCHCH 3 COOH, phenyl, pyrazolyl, or oxazolyl; wherein: the phenyl of R 3 is substituted with —COOH; the pyrazolyl of R 3 is substituted with —COOH and —CH 3 ; and the oxazolyl of R 3 is substituted with —COOH.

11 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by one of the following structural formulae:

and wherein n is an integer selected from 0, 1, and 2.

12 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is represented by one of the following structural formulae:

and wherein R 3 is F, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OH, or —OCH 3 .

13 . The compound, tautomer, deuterated derivative, or

Assignees

• Vertex Pharma

Inventors

• Clark Michael Philip
• Giroux Simon
• Collier Philip Noel
• Tang Qing
• Waal Nathan D
• Kesavan Sarathy
• Jones Peter
• Brodney Michael Aaron
• Gu Wenxin
• Boucher Diane Marie
• Fanning Lev T D
• Hall Amy B
• Hurley Dennis James
• Johnson Jr Mac Arthur
• Maxwell John Patrick
• Swett Rebecca Jane
• Tapley Timothy Lewis
• Thomson Stephen A
• Damagnez Veronique
• Cottrell Kevin Michael

Classifications

• C07D495/20

  Spiro-condensed systems · CPC title

• C07D491/20

  Spiro-condensed systems · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title

• A61K38/57

  from animals; from humans {(A61K38/553, A61K38/556 take precedence)} · CPC title

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title