Compounds and compositions for the treatment of cystic fibrosis

Patent metadata

Field	Value
Publication number	US-11999734-B2
Application number	US-201917259221-A
Country	US
Kind code	B2
Filing date	Jul 12, 2019
Priority date	Jul 13, 2018
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising the compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular to modulate CFTR protein or ABC protein activities.

First claim

The invention claimed is:

1. A compound of Formula (Ia):

or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, or stereoisomers thereof wherein:
Z is selected from the group consisting of C═O, SO 2 or CONR i ;
R i is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and heterocycloalkyl;
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of CR ii and N, with the proviso that the number of nitrogen atoms in the ring is comprised from 0 to 2;
each R ii is independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-aryl, O-heteroaryl, COR viii , COOR viii , CONHR c , CONR d R e , OH, O—C 1-6 alkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, O-haloC 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkyl-O—C 3-6 cycloalkyl, C 1-6 alkyl-O-heterocycloalkyl, CN, NO 2 , NHR c , NR d R e , N(R e )COR c , N(R e )COOR c , N(R x )CONR ix R x , N(R x )SO 2 R xi , SO 2 R xi , SO 2 NHR c , SO 2 NR d R e , halogen, and hydroxy-C 1-6 alkyl;
A 1 and A 4 are CR iii R iv ,
A 2 and A 3 are selected from a bond and CR iii R iv ;
R iii and R iv are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, haloC 1-6 alkyl, COR viii , COOR viii , CONHR viii , CONR ix R x , OH, and O—C 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, CN, halogen, NR ix R x , and N(R ix )COR viii , or R iii and R iv form a C 3 -C 6 cycloalkyl with the C to which they are linked;
or, when A 3 is a bond, two groups R iv on A 1 and A 2 , or on A 1 and A 4 are linked together to form a ring and thus the moiety

represents one of the structures selected from the group consisting of:

wherein R a and R b are independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, OH, O—C 1-6 alkyl, and C 1-6 alkyl-O—C 1-6 alkyl,
B is selected from the group consisting of:

wherein
Y and W are independently selected from the group consisting of O, S, CR v , CR v R vi , N, and NR vii , wherein
R v and R vi are selected form the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O—C 1-6 alkyl, O—C 1-6 alkylaryl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, O-haloC 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkyl-O—C 3-6 cycloalkyl, C 1-6 alkyl-O-heterocycloalkyl, C 1-6 alkyl-O-aryl, C 1-6 alkyl-O-heteroaryl, hydroxy-C 1-6 alkyl, COR vii , COOR viii , CONHR viii , and CONR ix R x ;
R vii is selected form the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 2-6 alkyl-O—C 1-6 alkyl, C 2-6 alkyl-O—C 3-6 cycloalkyl, C 2-6 alkyl-O-heterocycloalkyl, C 2-6 alkyl-O-aryl, and C 2-6 alkyl-O-heteroaryl;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, COR viii , COOR viii , CONHR viii , CONR ix R x , OH, O—C 1-6 alkyl, O—C 1-6 alkylaryl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, O-heteroaryl, O-aryl, O-haloC 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkyl-O—C 3-6 cycloalkyl, C 1-6 alkyl-O-heterocycloalkyl, C 1-6 alkyl-O-aryl, C 1-6 alkyl-O-heteroaryl, hydroxy-C 1-6 alkyl, CN, NO 2 , NR ix R x , N(R x )COR viii , N(R x )COOR viii , N(R x )CONR ix R x , N(R x )SO 2 R xi , SO 2 R xi , SO 2 NR ix R x , and halogen;
R viii is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-O—C 1-6 alkyl, and C 1-6 alkyl-O-heterocycloalkyl;
R ix is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R x is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-O—C 2-6 alkyl, and hydroxy-C 2-6 alkyl;
R xi is selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R c is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkyl-O—C 1-6 alkyl, and C 2-6 alkyl-O-heterocycloalkyl;
R d is selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, aryl, and heteroaryl;
R e is selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, aryl, heteroaryl, C 1-6 alkyl-O—C 2-6 alkyl, and hydroxy-C 2-6 alkyl;
provided that at least one of R iii or R iv of at least one of A 1 , A 2 , A 3 or A 4 is not H and that, when Z is C═O, A 1 is not CH(C 1-6 alkyl) when A 4 is CH 2 or A 1 is not CH 2 when A 4 is CH(C 1-6 alkyl).

2. The compound of Formula (Ia) according to claim 1 wherein Z is C═O;
X 1 , X 2 , X 3 and X 4 are CR ii ;
each R ii is independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, COR viii , COOR viii , CONHR c , CONR d R e , OH, O—C 1-6 alkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, O-haloC 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkyl-O—C 3-6 cycloalkyl, C 1-6 alkyl-O-heterocycloalkyl, CN, NO 2 , NHR c , NR d R e , SO 2 R xi , SO 2 NHR c , SO 2 NR d R e , halogen, and hydroxy-C 1-6 alkyl;
R iii and R iv are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, haloC 1-6 alkyl, COR viii , COOR viii , CONHR viii , CONR ix R x , OH, O—C 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, CN, and halogen.

3. The compound of Formula (Ia) according to claim 1 wherein R iii and R iv are independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, OH, O—C 1-6 alkyl, and halogen or, when A 3 is a bond, two groups R iv on A 1 and A 2 , are linked together to form a ring and thus the moiety

represents:

4. The compound of Formula (Ia) according to claim 1 wherein R iii and R iv are independently selected from the group consisting of hydrogen and methyl.

5. The compound of Formula (Ia) according to claim 1 , selected from the group consisting of:

040
(2-methyl-5,6,7,8,9,10-hexahydro-7,10-

epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-

pyrazol-3-yl)methanone

041
(1H-indol-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10-

epiminocyclohepta[b]indol-11-yl)methanone

042
(5-bromofuran-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10-

epiminocyclohepta[b]indol-11-yl)methanone

047

Assignees

• Fondazione St Italiano Tecnologia
• St Giannina Gaslini
• Fond Per La Ricerca Sulla Fibrosi Cistica Onlus
• Fond Per La Ricerca Sulla Fibrosi Cistica—Onlus

Inventors

• Bandiera Tiziano
• Bertozzi Fabio
• Giacomina Francesca
• Giovani Simone
• Sorana Federico
• Caci Emanuela
• Ferrera Loretta
• Pedemonte Nicoletta
• Galietta Luis Juan Vicente

Classifications

• C07D471/18 Primary

  Bridged systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D451/00 Primary

  Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title