Alpha-carbolines for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9428500-B2
Application number	US-201314399925-A
Country	US
Kind code	B2
Filing date	May 10, 2013
Priority date	May 11, 2012
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

The present invention relates to inhibitors of the oncogenic protein kinase ALK of formula (I) as herein described and pharmaceutical compositions thereof, as well as to key intermediates towards their synthesis. The compounds of formula (I) are useful in the preparation of a medicament, in particular for the treatment of cancer.

First claim

The invention claimed is:

1. Compounds of formula (I)

wherein:
R1 is H or C1-C3 alkyl
R2 is either halogen or

X is either CH or N
R3 is either C 1 -C 3 alkyl or (1-methylpiperidin-4-yl)
Rx and Ry are either H or nitro
Rz and Rz′ are H, OH, or oxo
Rt and R′t can be the same or different and are H or C 1 -C 3 alkoxy
Ra is H or F
Rb is H, C1-C3 alkoxy, trifluoromethyl, or halogen
Re is H or halogen
Rf is H, C1-C3 alkyl or trifluoromethyl
Rg is H or F
Rk is H, halogen, trifluoromethyl, C1-C3 alkoxy, C1-C3 alkylsulfonamino
Rl is H or F
Rm is H, C1-C3 alkoxy, F or trifluoromethyl
Rn is H, C1-C3 alkyl or a 5- to 6 -membered aromatic or heteroaromatic ring
Rp is either C1-C3 alkyl or 5- to 6 -membered aromatic or heteroaromatic ring
Rq is either H or tri(C 1 -C 4 )alkylsilyl
Rs is tri(C 1 -C 4 )alkylsilyl
Rh is either H , C1-C3 alkoxy or C1-C3 alkylcarbonylamino
Ru is either H or F
Rv is a C1-C3 alkyl
Rw and Rw′ can be the same or different and are hydroxyl or C1-C3 alkoxy
L and L′ are O, S, SO or SO 2 ;
Z is either C or N
and pharmaceutically acceptable salts thereof.

2. The compounds of claim 1 wherein
R1 is H or methyl
R2 is as defined in claim 1
X is either CH or N
R3 is either methyl or 1-methylpiperidin-4-yl
Rx and Ry are either H or nitro
Rz is H, OH or oxo
Rz′ is H
Rt and R′t can be the same or different and can be H or methoxy
Ra is H or F
Rb is H, methoxy, trifluoromethyl, F or Cl
Re is H or Cl
Rf is H, methyl or trifluoromethyl
Rg is H or F
Rk is H, Cl, F, trifluoromethyl, methoxy, methylsulfonamino
Rl is H or F
Rm is H, methoxy, F or trifluoromethyl
Rn is H, methyl, ethyl or phenyl
Rp is ethyl or phenyl
Rq is either H or triisopropylsilyl
Rs is triisopropylsilyl
Ru is F
Rv is methyl
Rw and Rw′ are either hydroxyl and methoxy, respectively or both are methoxy
Z is either C or N
L is O and Rh is H
L′ is S and Rh is methoxy.

3. The compounds of claim 1 wherein:
R1 is H
R2 is

X is CH
and wherein R3, Ra, Rb, Re, Rf, Rg, Rk, Rl, Rm, Rn, Rz, Rt, R′t ,Rp, Z, Rw and Rw′ are as defined in claim 1 .

4. The compounds of claim 1 wherein R1, R2, R3, X, L, L′ , Z, Rx, Ry, Ra, Rb, Re, Rf, Rg, Rh, Rk, Rl, Rm, Rp, Rq, Rs, Rz, Rz′, Rt, R′t, Ru, Rv, Rw and Rw′ are as defined in any one of claims 1 - 3 and wherein when R2 is

then two of Rk, Rl and Rm are H while the third is as defined in claim 1 .

5. The compounds of claim 3 wherein R2 is selected from the list of

and Rk, Rl, Rm, Rn and Rp are defined in claim 3 .

6. The compounds of claim 1 wherein R3 is methyl and wherein R1, R2, X, L, L′, Z, Rx, Ry, Ra, Rb, Re, Rf, Rg, Rh, Rk, Rl, Rm, Rn, Rp, Rq, Rs, Rz, Rz′ Rt, R′t , Ru, Rv, Rw and Rw′ are as defined in claim 1 .

7. The compounds of claim 1 wherein R3 is (1-methylpiperidin-4-yl), R1, R2, X, L, L′, Z, Rx, Ry, Ra, Rb, Re, Rf, Rg, Rh, Rk, Rl, Rm, Rn, Rp, Rq, Rs, Rz, Rz′ Rt, R′t , Ru, Rv, Rw and Rw′ are as defined in claim 1 .

8. The compounds of claim 1 , selected from the list of:
(E)-6-[4-(4-Methylpiperazin-1-yl)phenyl]-4-(2-phenylvinyl)-9H-pyrido[2,3-b]indole;
(E)-6-[6-(4-Methylpiperazin-1-yl)-pyridin-3-yl]-4-(2-phenylvinyl)-9H-pyrido[2,3-b]indole;
4-Biphenyl-4-yl-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-4-[2-(3-Fluorophenyl)vinyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-4-[2-(4-Methoxyphenyl)vinyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-(4-Benzyloxyphenyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
6-[4-(4-Methylpiperazin-1-yl)phenyl]-4-[4-(3-(trifluoromethyl)phenoxymethyl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-4-(2-(2-Methoxyphenyl)vinyl))-6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole;
(E)-6-(4-(4-Methylpiperazin-1-yl)phenyl)-4-(2-(2-(trifluoromethyl)phenyl)vinyl)-9H-pyrido[2,3-b]indole;
4-[4-(4-Chloro-3-methyl-phenoxymethyl)phenyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
6-[4-(4-Methylpiperazin-1-yl)phenyl]-4-phenylethynyl-9H-pyrido[2,3-b]indole;
(E)-4-(2-(4-Fluorophenyl)vinyl))-6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole;
(E)-6-(4-(4-Methylpiperazin-1-yl)phenyl)-4-(2-(4-(trifluoromethyl)phenyl)vinyl))-9H-pyrido[2,3-b]indole;
4-(3-Fluorobiphenyl-4-yl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-(4-Benzylphenyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-Biphenyl-3-yl-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-((2-Methoxyphenyl)ethynyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
6-[4-(4-Methylpiperazin-1-yl)phenyl]-4-((2-(trifluoromethyl)phenyl)ethynyl)-9H-pyrido[2,3-b]indole;
4-((4-Fluorophenyl)ethynyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-(2-Fluorophenyl)ethynyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-4-(2-(2-Fluorophenyl)vinyl))-6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole;
(E)-4-(2-(2-Chlorophenyl)vinyl))-6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole;
6-(4-(4-Methylpiperazin-1-yl)phenyl)-N-(3-nitrophenyl)-9H-pyrido[2,3-b]indol-4-amine;
6-(4-(4-Methylpiperazin-1-yl)phenyl)]-N-(2-nitrophenyl)-9H-pyrido[2,3-b]indol-4-amine;
4-((2-Chlorophenypethynyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-((2-Methoxyphenypethynyl)-9-methyl-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4,6-Bis-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
4-(4-Benzylphenyl)-6-(4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole;
(E)-6-(4-(4-(1-Methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(2-(2-(trifluoromethyl)phenyl)vinyl))-9H-pyrido[2,3-b]indole;
6-(4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-N-(2-nitrophenyl)-9H-pyrido[2,3-b]indol-4-amine;
(E)-6-(4-(4-Methylpiperazin-1-yl)phenyl)-4-(1-phenylprop-1-en-2-yl)-9H-pyrido[2,3-b]indole;
(4-{6-[4-(4-Methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indol-4-yl}-phenyl)phenyl-methanol;
(4-{6-[4-(4-Methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indol-4-yl }-phenyl)phenyl-methanone;
4-Chloro-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-N-[2-(2-{6-[4-(4-Methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indol-4-yl}-vinyl)phenyl]-methanesulfonamide;
6-[4-(4-Methylpiperazin-1-yl)phenyl]-4-(4-naphthalen-1-yl-phenyl)-9H-pyrido[2,3-b]indole;
(E)-4-(1,2-Diphenylvinyl)-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-6-[4-(4-Methylpiperazin-1-yl)phenyl]-4-(1-phenyl-but-1-enyl)-9H-pyrido[2,3-b]indole;
(E)-6-(4-(4-Methylpiperazin-1-yl)phenyl)-4-(1-phenylbut-1-en-2-yl)-9H-pyrido[2,3-b]indole;
4-[4-(2,4-Dimethoxybenzyl)phenyl]-6[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-4-[1-(2-Methoxyphenyl)-prop-1-en-2-yl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-9H-pyrido[2,3-b]indole;
(E)-6-[4-(4-Methylpiperazin-1-yl)-phenyl]-4-[1-(2-(trifluoromethy

Assignees

• Universita' Degli Studi Di Milano—Bicocca
• Univ Geneve
• Université Claude Bernard—Lyon 1
• Univ Degli Studi Di Milano—Bicocca
• Univ Geneve
• Univ Claude Bernard—Lyon

Inventors

• Gambacorti-Passerini Carlo
• Mologni Luca
• Scapozza Leonardo
• Bisson William
• Ahmed Shaheen
• Goekjian Peter
• Tardy Sébastien
• Orsato Alexandre
• Gueyrard David
• Benoit Joseph

Classifications

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07F7/0812

  comprising a heterocyclic ring · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title