Diarylalkylamine REV-ERB antagonists and their use as medicaments

Patent metadata

Field	Value
Publication number	US-9949968-B2
Application number	US-201615359135-A
Country	US
Kind code	B2
Filing date	Nov 22, 2016
Priority date	Oct 9, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

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 as anti-proliferative and proapoptotic agents for cancer therapy.

First claim

The invention claimed is:

1. A method of modulating REV-ERBs activity in a cell, wherein the method comprises contacting the cell with a modulating amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein Ar and Ar′ are independently selected from the group consisting of a 5- to 10-membered aromatic and heteroaromatic single or fused rings comprising up to 3 heteroatoms selected from N, O and S;
R is selected from the group consisting of hydrogen, a linear or branched unsubstituted or substituted C 1-6 alkyl and an unsubstituted or substituted aryl C 1-6 alkyl;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, linear or branched, unsubstituted or substituted C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, OH, CN, fluoro C 1-6 alkyl and fluoro C 1-6 alkoxy; R 1 , R 2 , R 3 and R 4 can be attached to any position of Ar and Ar′ group, respectively;
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of CH and N;
R 5 and R 6 are independently selected from the group consisting of H, halogen, unsubstituted or substituted linear or branched C 1-6 alkyl, ═O, unsubstituted or substituted aryl, unsubstituted or substituted aryl C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkylCO, unsubstituted or substituted arylCO, unsubstituted or substituted aryl C 1-6 alkylCO, COOR 7 , CONR 8 R 9 and SO 2 R 10 wherein R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen and linear or branched C 1-6 alkyl; R 5 and R 6 can be attached to any carbon atom of the ring to which they are connected and they may be connected to the same carbon atom or to different carbon atoms of the ring; and
R 11 is selected from the group consisting of H, linear or branched C 1-6 alkyl, C 1-6 alkylCO, aryl and aryl C 1-6 alkyl;
or R 5 and R 6 , or R 5 and R 11 or R 6 and R 11 are linked together to form an unsubstituted or substituted 4- to 10-membered ring, saturated or unsaturated, and containing up to two nitrogen atoms;
q and p are, independently, 0 or an integer from 1 to 2 with the proviso that when both Y and X are N, neither q and p are 0;
R 12 and R 13 are independently selected from the group consisting of H, F, C 1-6 alkyl, C 1-6 alkyl-OH, ═O, OH, COOH, CO 2 Me, CONH 2 , CONHMe and CONMe 2 and can be attached to any position of the ring to which they are connected and they may be connected to the same carbon atom or to different carbon atoms of the ring;
W is selected from the group consisting of a bond and a heteroatom selected from the group consisting of O, S and NR 14 , wherein R 14 is selected from the group consisting of H, linear or branched C 1-6 alkyl, C 1-6 alkylCO, unsubstituted or substituted aryl, unsubstituted or substituted aryl C 1-6 alkyl, unsubstituted or substituted arylCO, SO 2 R 15 , CONR 16 R 17 and COOR 18 , wherein R 15 , R 16 , R 17 and R 18 are independently selected from the group consisting of H and linear or branched C 1-6 alkyl;
m is an integer from 1 to 3, n is 0 or an integer from 1 to 3 with the proviso that when W is bond, n is not 0.

2. A method of treating cancer associated with REV-ERBs activity in a mammal, wherein the cancer does not comprise breast cancer and wherein the method comprises administering to the mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein Ar and Ar′ are independently selected from the group consisting of a 5- to 10-membered aromatic and heteroaromatic single or fused rings comprising up to 3 heteroatoms selected from N, O and S;
R is selected from the group consisting of hydrogen, a linear or branched unsubstituted or substituted C 1-6 alkyl and an unsubstituted or substituted aryl C 1-6 alkyl;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, linear or branched, unsubstituted or substituted C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, OH, CN, fluoro C 1-6 alkyl and fluoro C 1-6 alkoxy; R 1 , R 2 , R 3 and R 4 can be attached to any position of Ar and Ar′ group, respectively;
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of CH and N;
R 5 and R 6 are independently selected from the group consisting of H, halogen, unsubstituted or substituted linear or branched C 1-6 alkyl, ═O, unsubstituted or substituted aryl, unsubstituted or substituted aryl C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkylCO, unsubstituted or substituted arylCO, unsubstituted or substituted aryl C 1-6 alkylCO, COOR 7 , CONR 8 R 9 and SO 2 R 10 wherein R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen and linear or branched C 1-6 alkyl; R 5 and R 6 can be attached to any carbon atom of the ring to which they are connected and they may be connected to the same carbon atom or to different carbon atoms of the ring; and
R 11 is selected from the group consisting of H, linear or branched C 1-6 alkyl, C 1-6 alkylCO, aryl and aryl C 1-6 alkyl;
or R 5 and R 6 , or R 5 and R 11 or R 6 and R 11 are linked together to form an unsubstituted or substituted 4- to 10-membered ring, saturated or unsaturated, and containing up to two nitrogen atoms;
q and p are, independently, 0 or an integer from 1 to 2 with the proviso that when both Y and X are N, neither q and p are 0;
R 12 and R 13 are independently selected from the group consisting of H, F, C 1-6 alkyl, C 1-6 alkyl-OH, ═O, OH, COOH, CO 2 Me, CONH 2 , CONHMe and CONMe 2 and can be attached to any position of the ring to which they are connected and they may be connected to the same carbon atom or to different carbon atoms of the ring;
W is selected from the group consisting of a bond and a heteroatom selected from the group consisting of O,S and NR 14 , wherein R 14 is selected from the group consisting of H, linear or branched C 1-6 alkyl, C 1-6 alkylCO, unsubstituted or substituted aryl, unsubstituted or substituted aryl C 1-6 alkyl, unsubstituted or substituted arylCO, SO 2 R 15 , CONR 16 R 17 and COOR 18 , wherein R 15 , R 16 , R 17 and R 18 are independently selected from the group consisting of H and linear or branched C 1-6 alkyl;
m is an integer from 1 to 3, n is 0 or an integer from 1 to 3 with the proviso that when W is bond, n is not 0;
or a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable carrier, stabilizer, diluent or excipient thereof.

3. The method according to claim 2 wherein the cancer is Erb-B2 positive cancer.

4. The method according to claim 2 wherein the cancer is selected from the group consisting of ovary cancer, colon cancer, liver cancer, central nervous system cancer, kidney cancer pancreas cancer and prostate cancer.

5. The method according to claim 2 wherein the cancer is selected from a cancer with deletion or mutation of the tumor suppressor p53 gene.

Assignees

• Fondazione St Italiano Tecnologia

Inventors

• Grimaldi Benedetto
• Torrente Esther
• Scarpelli Rita
• Bottegoni Giovanni
• Bandiera Tiziano
• Veronesi Marina

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D333/20

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• C07D295/04

  with substituted hydrocarbon radicals attached to ring nitrogen atoms · CPC title