Heterocyclic derivatives for the treatment of cystic fibrosis

Patent metadata

Field	Value
Publication number	US-10745407-B2
Application number	US-201816493532-A
Country	US
Kind code	B2
Filing date	Mar 14, 2018
Priority date	Mar 14, 2017
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof: It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses, in particular to modulate CFTR protein or ABC protein activities.

First claim

The invention claimed is:

1. A compound of formula I:

or pharmaceutically acceptable salts or solvates thereof wherein:
R 1 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl and hydroxyl-C 1-6 alkyl;
Z is C═O or SO 2 ;
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of CR vii and N, with the proviso that the number of nitrogen atoms in the ring is comprised from 0 to 2;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, COR viii , COOR viii , heterocycloalkyl, CONHR viii , CONR viii R ix , 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, CN, NO 2 , NR x R xi , N(R ix )COR x , N(R ix )COOR xi , N(R ix )CONR xi R x , N(R ix )SO 2 R x , SO 2 R x , SO 2 NR ix R x , halogen, and hydroxy-C 1-6 alkyl;
A 1 , A 2 , A 3 , and A 4 , are independently selected from the group consisting of CR xii R xiii , O, NR xiv , CO and SO 2 , wherein
R xii and R xiii 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 viii R ix , OH, O—C 1-6 alkyl, O-aryl, O—C 1-6 alkylaryl, O-heteroaryl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, C 1-6 alkylaryl, C 3-6 cycloalkylaryl, C 3-6 cycloalkylheteroaryl, C 3-6 cycloheteroalkylaryl, C 3-6 cycloheteroalkylheteroaryl, C 1-6 alkylheteroaryl, S-aryl, S-heteroaryl, SO-aryl, SO-heteroaryl, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 alkyl-O—C 1-6 alkyl, CN, halogen, NR x R xi , N(R ix )COR x ;
R xiv is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylaryl, C 1-6 alkyl-C 3-6 cycloalkyl, C 1-6 alkyl-heterocycloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, hydroxyl-C 1-6 alkyl, COR viii , CONHR viii , CONR viii , CONR viii R ix , SO 2 R viii , C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkyl-O-aryl, C 1-6 alkyl-O-heteroaryl, C 1-6 alkyl-O-heterocycloalkyl, C 1-6 alkylCOOR viii ;
or
when each of A 1 and A 3 , or A 2 and A 4 , or A 1 and A 4 represents CR xii R xiii , the two groups R xii can be linked together to form a ring and thus the moiety

has a meaning selected from the group consisting of:

n and m are each independently selected from the group consisting of 0, 1, 2;
B represents an unsubstituted or a substituted aromatic or heteroaromatic ring selected from the group consisting of:

wherein
R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, O—C 1-6 alkyl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, O-haloC 1-6 alkyl, COR viii , COOR viii , CONHR viii , CONR viii R ix , OH, CN, NR x R xi , N(R ix )COR x , N(R ix )CONR x R xi and hydroxy-C 1-6 alkyl
or
when R 6 and R 7 are present on a 6-membered heteroaromatic ring, taken together with the carbon atoms to whom they are bound, they can form a saturated or unsaturated 5-membered or 6-membered carbocyclic ring or a 5-membered or 6-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N, and S or a 5-membered or 6-membered heteroaryl ring containing from 1 to 3 heteroatoms selected from O, N, and S;
Y and W are independently selected from the group consisting of O, S, SO 2 , CR iv R v , CR v , N, and NR vi ;
R i , R ii , R iii and R iv are independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, OH, O—C 1-6 alkyl and O-haloC 1-6 alkyl
or
when R i and R ii , or R iii and R iv are taken together with the carbon atoms to whom they are bound, they can represent C═O;
R v is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, O—C 1-6 alkyl, halogen, C 3-6 cycloalkyl, OH and O-haloC 1-6 alkyl;
R vi is selected from the group consisting of hydrogen and C 1-6 alkyl;
R vii is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, haloC 1-6 alkyl, O-haloC 1-6 alkyl, COR viii , COOR viii , CONHR viii , CONR viii R ix , OH, O—C 1-6 alkyl, halogen, CN, NO 2 , NR x R xi , N(R ix )COR x , N(R ix )COOR xi , N(R ix )CONR x R xi , and N(R ix )SO 2 R x ;
R viii is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy-C 1-6 alkyl and C 1-6 alkyl-O—C 1-6 alkyl;
R ix is selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy-C 1-6 alkyl, and C 1-6 alkyl-O—C 1-6 alkyl;
R x is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy-C 1-6 alkyl, and C 1-6 alkyl-O—C 1-6 alkyl;
R xi is selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, aryl-C 1-6 alkyl, heteroaryl-C 1-6 alkyl, and heterocycloalkyl-C 1-6 alkyl.

2. The compound of formula I according to claim 1 , wherein
R 1 is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl;
Z is C═O or SO 2 ;
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of CR vii and N, with the proviso that the number of nitrogen atoms in the ring is comprised from 0 to 2;
R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, COR viii , COOR viii , CONHR viii , CONR viii R ix , O—C 1-6 alkyl, O—C 1-6 alkylaryl, O-heterocycloalkyl, O-aryl, O-haloC 1-6 alkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkyl-O-aryl, CN, NR x R xi , halogen, and hydroxy-C 1-6 alkyl;
A 1 , A 2 , A 3 , and A 4 , are independently selected from the group consisting of CR xii R xiii , O, NR xiv , and CO wherein
R xii and R xiii are independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, COR viii , COOR viii , CONHR viii , CONR viii R ix , OH, O—C 1-6 alkyl, O-aryl, O—C 1-6 alkylaryl, O-heteroaryl, O—C 3-6 cycloalkyl, O-heterocycloalkyl, C 1-6 alkylaryl, C 1-6 alkylheteroaryl, NR x R xi , N(R ix )COR x , C 1-6 alkyl-O—C 1-6 alkyl, CN and halogen;
R xiv is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylaryl, C 1-6 alkyl-C 3-6 cycloalkyl, C 1-6 alkyl-heterocycloalkyl, C 3-6 cycloalkyl, hydroxy-C 1-6 alkyl, heterocycloalkyl, COR viii , COOR viii , CONHR viii and SO 2 R viii , C 1-6 alkylCOOR viii ;
or
when each of A 1 and A 3 , or A 2 and A 4 , or A 1 and A 4 represents CR xii R xiii , the two groups R xii can be linked together to form a ring and thus the moiety

has a meaning selected from the group consisting of:

n and m are each independently selected from the group consisting of 0, 1, 2;
B represents an unsubstituted or a substituted aromatic or heteroaromatic ring selected from the group consisting of:

Assignees

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

Inventors

• Bandiera Tiziano
• Bertozzi Fabio
• Di Fruscia Paolo
• Sorana Federico
• Berti Francesco
• Rodriguez Gimeno Alejandra
• Caci Emanuela
• Ferrera Loretta
• Pedemonte Nicoletta
• Vicente Galietta Luis Juan

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title