# US 10,307,410 B2 · Mcl-1 modulating compounds for cancer treatment

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- Number: US 10,307,410 B2
- Document ID: US10307410B2
- Status: Granted
- Kind: B2
- Application number: 15/122,890
- Filed: 2015-03-03
- Published: 2017-03-16
- Granted: 2019-06-04
- Earliest claimed: 2014-03-04
- Assignees: Centre Regional De Lutte Contre Le Cancer Francois Baclesse; Universite de Caen Basse Normandie; Institut De Cancerologie De L'ouest Rene Gauducheau
- Applicants: Centre Regional De Lutte Contre Le Cancer Francois Baclesse; Universite De Caen Basse-Normandie; Institut De Cancerologie De L'ouest Rene Gauducheau
- Inventors: Laurent Poulain; Anne-Sophie Voisin-Chiret; Jana Sopkova-de Oliveira Santos; Ronan Bureau; Grégory Burzicki; Marcella De Giorgi; Serge Perato; Jade Fogha; Sylvain Rault; Philippe Juin; Fabien Gautier
- Web page: https://patentgrep.com/patent/US10307410B2

## CPC

- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/22: containing two or more pyridine rings directly linked together, e.g. bipyridyl
- C07D 213/30: Oxygen atoms
- C07D 213/55: Acids; Esters
- C07D 213/57: Nitriles
- C07D 213/58: Amidines
- C07D 401/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention relates to compounds of formula (I), and to their therapeutic use in the treatment of cancer: Wherein Y1, Y2, Ar1, Ar2, R1, R2, i, j, k, l are as defined in claim 1.

## Claims

### Claim 1

A pharmaceutical composition comprising a compound of formula (I):
wherein:
Y1, Y2 are —N═C—;
Ar1, Ar2 are each independently selected from C6-C10 aryl or a 5 to 7membered heteroaryl, said aryl and heteroaryl groups being optionally substituted by one to three R3 groups provided that:
Ar1, Ar2 cannot both identically represent either a 4-pyridyl, an unsubstituted 2or 3-thiophenyl, or a 3,4-dimethoxyphenyl or a 3,4,5-trimethoxyphenyl,
R1 is selected from, C1-C6 alkyl, C6-C10 aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, (C6-C10)arylcarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, C(═O)H, COOH, OH said alkyl groups being optionally substituted by OH;
R2 is selected from (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C2-C6)alkenyl;
k is 0 or 1;
l is 1;
R3 is, at each occurrence, independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, C(═O)H, (CH2)nCO2H, (CH2)pCN, (CH2)qC(═N(OH))NH2, I, Cl, Br, F, C6-C10 aryl, and a 5 to 7 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, said alkyl groups being optionally substituted by OH;
n is 0, 1, 2, 3;
p is 0, 1, 2, 3;
q is 0, 1, 2, 3;
with the exclusion of the following compound:
2-(pyridin-3-yl)-5-(5-(pyridin-3-yl)-3-styrylpyridin-2-yl)pyridine;
and the pharmaceutically acceptable salts thereof, in admixture with at least one pharmaceutically acceptable excipient or carrier.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein Ar1 and/or Ar2 are selected from phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, thiophenyl, or triazolyl.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein at least one of Ar1, Ar2 is a 5 to 7 membered heteroaryl containing a nitrogen atom.

### Claim 4 (depends on 2)

The pharmaceutical composition of claim 2, wherein Ar1 is 3-pyridyl or phenyl.

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, wherein Ar2 is 3-pyridyl or phenyl.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein R1 is selected from C1-C6 alkyl, and R2 is selected from (C6-C10)aryl(C2-C6)alkenyl.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein R1 is 5-methyl.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein R2 is 5-styryl.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, comprising a structure compound of formula (Ia):
wherein:
X1, X2, are at each occurrence, independently selected from C or N.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the compound of formula (I) is selected from:
5,6′-di(pyridin-3-yl)-5′-methyl-3-((E)-styryl)-2,3′-bipyridine;
5,6″-di(pyridin-3-yl)-3,5″-bis-((E)-styryl)-[2,3′;6′,3″]terpyridine;
2-(5-methyl-6-(pyridin-3-yl)pyridin-3-yl)-5-phenyl-3-styrylpyridine; or
2-(5-methyl-6-phenylpyridin-3-yl)-5-(pyridin-3-yl)-3-styrylpyridine.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, comprising a Bcl−XL inhibitor.

### Claim 12 (depends on 1)

A combination comprising a compound of formula (I) according to claim 1, in combination with a Bcl−XL inhibitor.

### Claim 13

A method for treating cancer, comprising administration of a therapeutically effective amount of a compound of formula (I) to a patient in need thereof, wherein formula (I) is:
wherein:
Y1, Y2 are —N═C—;
Ar1, Ar2 are each independently selected from C6-C10 aryl or a 5 to 7 membered heteroaryl, said aryl and heteroaryl groups being optionally substituted by one to three R3 groups provided that:
Ar1, Ar2 cannot both identically represent either a 4-pyridyl, an unsubstituted 2 or 3-thiophenyl, or a 3,4-dimethoxyphenyl or a 3,4,5-trimethoxyphenyl;
R1 is selected from, C1-C6 alkyl, C6-C10 aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, (C6-C10)arylcarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, C(═O)H, COOH, OH said alkyl groups being optionally substituted by OH;
R2 is selected from (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C2-C6)alkenyl;
k is 0 or 1;
l is 1;
R3 is, at each occurrence, independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, C(═O)H, (CH2)nCO2H, (CH2)pCN, (CH2)qC(═N(OH))NH2, I, Cl, Br, F, C6-C10 aryl, and a 5 to 7 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, said alkyl groups being optionally substituted by OH;
n is 0, 1, 2, 3;
p is 0, 1, 2, 3;
q is 0, 1, 2, 3;
with the exclusion of the following compound:
2-(pyridin-3-yl)-5-(5-(pyridin-3-yl)-3-styrylpyridin-2-yl)pyridine;
and a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable excipient or carrier.

### Claim 14 (depends on 13)

The method of claim 13, wherein the compound of formula (I) is administered together with a Bcl−XL inhibitor.

### Claim 15 (depends on 13)

The method according to claim 13, wherein the method induces apoptose mediated by Mcl−1 protein.

### Claim 16

A compound of formula (I):
wherein:
Y1, Y2 are —N═C—;
Ar1, Ar2 are each independently selected from C6-C10 aryl or a 5 to 7 membered heteroaryl, said aryl and heteroaryl groups being optionally substituted by one to three R3 groups provided that:
Ar1, Ar2 cannot both identically represent either a 4-pyridyl, an unsubstituted 2 or 3-thiophenyl, or a 3,4-dimethoxyphenyl or a 3,4,5-trimethoxyphenyl;
R1 is selected from, C1-C6 alkyl, C6-C10 aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, (C6-C10)arylcarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, C(═O)H, COOH, OH said alkyl groups being optionally substituted by OH;
R2 is selected from (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C2-C6)alkenyl;
k is 0 or 1;
l is 1;
R3 is, at each occurrence, independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, C(═O)H, (CH2)nCO2H, (CH2)pCN, (CH2)qC(═N(OH))NH2, I, Cl, Br, F, C6-C10 aryl, and a 5 to 7 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, said alkyl groups being optionally substituted by OH;
n is 0, 1, 2, 3;
p is 0, 1, 2, 3;
q is 0, 1, 2, 3;
with the exclusion of the following compound:
2-(pyridin-3-yl)-5-(5-(pyridin-3-yl)-3-styrylpyridin-2-yl)pyridine and the pharmaceutically acceptable salts thereof.

### Claim 17 (depends on 16)

The compound of formula (I) of claim 16, wherein R1 is methyl and R2 is styryl.

### Claim 18 (depends on 17)

The compound of formula (I) of claim 17, wherein R1 is 5-methyl and R2 is 5-styryl.