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)

Patent metadata

Field	Value
Publication number	US-2023159521-A1
Application number	US-202117916405-A
Country	US
Kind code	A1
Filing date	Apr 2, 2021
Priority date	Apr 3, 2020
Publication date	May 25, 2023
Grant date	—

Abstract

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).

First claim

What is claimed is:

1 . A compound represented by Formula I

or a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Z 1 , Z 2 , and Z 3 are each independently —N, —NH, or —CH; provided that at least one of Z 1 , Z 2 , and Z 3 is N or —NH;
V 1 and V 2 are each selected from C and N;
W 1 and W 2 are each selected from —C═O, —CR 2 , N, and —NR 2 , wherein:
when W 1 is —CR 2 , then W 2 is N;
when W 2 is —CR 2 , then W 1 is N or —NR 2 ;
when W 1 is —C═O, then W 2 is —NR 2 ; and
when W 2 is —C═O, then W 1 is —NR 2 ;

for each of the two occurrences, is a single bond or a double bond; provided that one is a single bond and the other is a double bond;
is a double bond except that when either of one of W 1 and W 2 is —C═O, then is a single bond;
R 0 is halogen or

 wherein:
Ring A is C 3 -C 12 carbocyclyl, 3 to 12-membered heterocyclyl, C 6 or C 10 aryl, or 5 to 10-membered heteroaryl;

R 1 is halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —C(═O)R z , —C(═O)OR z , —C(═O)NR w R x , —NR w R x , —NR w C(═O)R z , —NR w C(═O)OR z , —NR w C(═O)NR x R y , —OR z , —OC(═O)R z , —OC(═O)NR w R x , S(═O) 2 R z , C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein:
the C 1 -C 6 alkyl, the C 3 -C 6 cycloalkyl, or the 3 to 6-membered heterocyclyl of W is optionally substituted with 1 to 3 groups selected from —OR z , C 1 -C 3 haloalkyl, —CN, and halogen; and
R w , R x , R y , and R z are each independently hydrogen or C 1 -C 4 alkyl;

X 1 and X 2 are each independently hydrogen, halogen, —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 6 cycloalkyl, or 5 or 6-membered heteroaryl;
R 2 is hydrogen, halogen,

 wherein:
T is absent or a bond, or is selected from —O—, —OCH 2 —, —NH—, —NS(═O) 2 CH 3 , —S—, and —CH 2 —;
Y is selected from C 1 -C 6 alkyl, —(CR a R a ) p COOH, —(CR a R a ) p NR b S(═O) 2 (CR c R c ) q OH, —(CR a R a ) p C(═O)NR b (CR c R c ) q COOH, and —(CR a R a ) p (O)(CR c R c ) q COOH; wherein:
R a , for each occurrence, is independently hydrogen, halogen, —OH, or C 1 -C 4 alkyl optionally substituted with 1 to 3 groups selected from halogen and —OH;
or alternatively, when R a , for each occurrence, is C 1 -C 4 alkyl, two R a groups together with their intervening carbon atom form cyclopropyl or cyclobutyl;
R b and R c , for each occurrence, are each independently hydrogen or C 1 -C 2 alkyl; and
p and q are each independently an integer selected from 1 and 2;

Ring B is C 3 -C 12 carbocyclyl, 3 to 12-membered heterocyclyl, C 6 or C 10 aryl, or 5 to 10-membered heteroaryl;

R 3 is -C(═O)OR d ; wherein R d is C 1 -C 4 alkyl optionally substituted with —OC(O)R e , —OC(═O)OR e , or —OP(═O)OR f R f ; wherein:
R e , for each occurrence, is independently hydrogen, —CH 3 , or —C 2 H 5 ;
R f , for each occurrence, is independently —OH, —CH 3 , —C 2 H 5 , —OCH 3 , or —OC 2 H 5 ;

R k is halogen, —CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy, or O—(C 3 -C 6 cycloalkyl);
R m , for each occurrence, is independently halogen, —CN, ═O, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(═O)R r , —C(═O)OR r , —C(═O)NR p R q , —C(═O)NR p OR r , —NR p R q , —NR p C(═O)R r , —NR p S(═O) 2 R r , —OR r , S(═O) 2 R r , —S(═O)2NR p R q , —P(═O)R s R t , C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl,
wherein the C 1 -C 6 alkyl, the phenyl, or the 5 or 6-membered heteroaryl of R m is optionally substituted with 1 to 3 groups selected from halogen, CN, —C(═O)OR r , —NR p R q , and —OR r ; and
wherein the C 3 -C 6 cycloalkyl or the 3 to 6-membered heterocyclyl of R m is optionally substituted with 1 to 3 groups selected from halogen, CN, ═O, —C(═O)OR r , —NR p R q , and —OR r ;
wherein R p and R q , for each occurrence, are each independently hydrogen or C 1 -C 4 alkyl optionally substituted with 1 to 3 groups selected from —OH, —OCH 3 , —OC 2 H 5 , and —COOH;
wherein R r , for each occurrence, is each independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein the C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl of R r is optionally substituted with 1 to 3 groups selected from —OH, —OCH 3 , —OC 2 H 5 , —CH 2 OH, —C(═O)OH, —(O)C(═O)OH, and —(O)P(═O)(OH) 2 ; and
wherein R s and R t , for each occurrence, are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 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 0, 1, and 2.

2 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein two of Z 1 , Z 2 , and Z 3 are N or —NH; n is an integer selected from 0 and 1; and wherein all other variables not specifically defined herein are as defined in the preceding claim.

3 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or claim 2 , represented by Formula II

wherein:
R 3 is —C(═O)OR d ; wherein R d is C 1 -C 4 alkyl optionally substituted with —OC(O)R e , —OC(═O)OR e , or —OC(═O)OR f R f ; wherein:
R e , for each occurrence, is independently hydrogen or —CH 3 ;
R f , for each occurrence, is independently —OH, —CH 3 , or —OCH 3 ;

n is an integer selected from 0 and 1;

and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

4 . The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 3 , represented Formulae IIIa, Mb, IIIc, or IIId

wherein:
Ring A is optionally substituted with R k and Ring A is 5 or 6-membered carbocyclyl, phenyl, or 5 or 6-membered heteroaryl;
R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C(═O)OR z , —C(═O)NR w R x , —NR w R x , —OR z , —S(═O) 2 R z , C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein:
the C 1 -C 6 alkyl, the C 3 -C 6 cycloalkyl, or the 3 to 6-membered heterocyclyl of R 1 is optionally substituted with 1 to 3 groups selected from —OR z and halogen; and

R w , R x , R y , and R z are each independently hydrogen or C 1 -C 4 alkyl;
X 1 and X 2 are each independently hydrogen, halogen, —CN, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkoxy or C 3 -C 4 cycloalkyl;
R 2 is as defined in claim 1 , except when R 2 is

 Ring B is optionally substituted with R m and Ring B is C 4 -C 9 carbocyclyl, phenyl, 4 to 9-membered heterocyclyl, or 5 to 6-membered heteroaryl;
R 3 is absent or is —C(═O)O(CH 2 ) 2 (O)P(═O)(OH) 2 ;
R k is halogen, —CN, —CH 3 , C 1 haloalkyl, or —OCH 3 ;
n is an integer selected from 0 and 1;

and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

Assignees

• Vertex Pharma

Inventors

• Giroux Simon
• Nuhant Philippe Marcel
• Bandarage Upul Keerthi
• Garcia Barrantes Pedro Manuel
• Liao Yusheng
• Gale-Day Zachary
• Gu Wenxin
• Karns Alexander S
• Zhang Hu
• Allen Emily Elizabeth
• Xu Jinwang
• Deninno Michael Paul
• Tang Qing
• 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

• A61P11/08

  Bronchodilators · CPC title

• A61P1/14

  Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title