Pyran dervatives as CYP11A1 (cytochrome P450 monooxygenase 11A1) inhibitors

Patent metadata

Field	Value
Publication number	US-10717726-B2
Application number	US-201716472377-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Dec 22, 2016
Publication date	Jul 21, 2020
Grant date	Jul 21, 2020

Abstract

Compounds of formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 23 , R 24 , L, A and B are as defined in claim 1 , or pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as cytochrome P450 monooxygenase 11A1 (CYP11A1) inhibitors. The compounds are useful as medicaments in the treatment of steroid receptor, particularly androgen receptor, dependent diseases and conditions, such as prostate cancer.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
ring B is a 4-10 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S;
ring A is selected from:

L is absent, —CH 2 —, —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —, or when ring A is (1), L is —C(O)—CH 2 —;
R 1 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, halo C 1-7 alkyl, halo C 1-7 alkoxy, or C 1-7 alkylthio;
R 2 is hydrogen, C 1-7 alkyl, halogen, hydroxy, halo C 1-7 alkyl, nitro, halo C 1-7 alkoxy, or thiol;
or R 1 and R 2 together with the carbon atoms to which they are attached form a fused 1,3 dioxole ring;
R 3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl, C 1-7 alkoxy, hydroxy C 1-7 alkyl, halo C 1-7 alkyl, cyano C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkylthio, aminocarbonyl C 2-7 alkenyl, halo C 1-7 alkylthio, C 1-7 alkoxycarbonyl C 1-7 alkyl, C 1-7 alkoxycarbonyl C 2-7 alkenyl, ═NSO 2 R 29 , —S(O)—C 1-7 alkyl, —S(O)(NR 14 )(R 22 ), —S(NR 15 )(C 1-7 alkyl), —C(S)NR 18 R 19 , -D-C(O)—NR 6 R 7 , —C(O)R 8 , -D-NR 9 R 10 , —SO 2 R 11 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered carbocyclyl C 1-7 alkyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclyl C 1-7 alkyl;
R 4 is hydrogen, halogen, hydroxy, C 1-7 alkyl, halo C 1-7 alkyl, or oxo;
R 5 is hydrogen, halogen, or C 1-7 alkyl;
R 6 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxy C 1-7 alkyl, cyano C 1-7 alkyl, —C 1-7 alkyl-O—C(O)C 1-7 alkyl, or optionally substituted 4-10 membered heterocyclyl;
R 8 is hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 alkoxy, halo C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkylcarbonyl, C 1-7 alkoxycarbonyl, —C 1-7 alkyl-O—C(O)—C 1-7 alkyl, —C 1-7 alkyl-SO 2 (C 1-7 alkyl), —N═S(O)(C 1-7 alkyl)(C 1-7 alkyl), or optionally substituted 4-10 membered heterocyclyl;
R 9 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, —SO 2 (C 1-7 alkyl), or —SO 2 (C 3-7 cycloalkyl);
R 11 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, halo C 1-7 alkyl, cyano C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, —NR 12 R 13 , optionally substituted 3-10 membered carbocyclyl, or optionally substituted 4-10 membered heterocyclyl;
R 12 is hydrogen, C 1-7 alkyl, hydroxy C 1-7 alkyl, cyano C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, or C 1-7 alkylcarbonyl;
R 7 , R 10 , R 13 , R 18 , and R 19 are independently hydrogen, C 1-7 alkyl, or C 3-7 cycloalkyl;
R 14 is hydrogen, C 1-7 alkyl, C 1-7 alkylcarbonyl, or —SO 2 R 21 ;
R 15 is hydrogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkylcarbonyl, or —SO 2 R 17 , R 17 is C 1-7 alkyl or an optionally substituted 3-10 membered carbocyclyl;
R 20 and R 21 are independently C 1-7 alkyl, C 3-7 cycloalkyl, or optionally substituted 3-10 membered carbocyclyl;
R 22 is C 1-7 alkyl or C 3-7 cycloalkyl;
R 23 is hydrogen or oxo;
R 24 is hydrogen or C 1-7 alkyl;
D is absent, C 1-7 alkyl, or C 2-7 alkenyl;
wherein the optional substitution in each occurrence is selected from 1-3 substituents independently selected from C 1-7 alkyl, halogen, hydroxy, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkoxycarbonyl, or oxo; and
wherein the heterocyclyl group in each occurrence has 1-4 heteroatoms independently selected from N, O, and S;
or a tautomer, or a pharmaceutically acceptable salt thereof;
with the proviso that the compound is not
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2,5-dimethylphenyl)methoxy]-4H-pyran-4-one;
5-[(2,4-Dichlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
5-[(3-Chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-methylphenyl)methoxy]-4H-pyran-4-one;
5-[(3,4-Dichlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-fluorophenyl)methoxy]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-(1-naphthalenylmethoxy)-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[[3-(trifluoromethyl)phenyl]methoxy]-4H-pyran-4-one;
5-[(2-Chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
5-[(2-Chloro-6-fluorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
5-[(4-Chlorophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
5-[(4-Bromophenyl)methoxy]-2-[(3,4-dihydro-2(1H)-isoquinolinyl)methyl]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2-fluorophenyl)methoxy]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(2-methylphenyl)methoxy]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-(phenylmethoxy)-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[[4-(trifluoromethyl)phenyl]methoxy]-4H-pyran-4-one;
Methyl 4-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)benzoate;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-fluorophenyl)methoxy]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3,5-dimethoxyphenyl)methoxy]-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-nitrophenyl)methoxy]-4H-pyran-4-one;
Methyl 5-(((6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)fu ran-2-carboxylate;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-(2-phenylethoxy)-4H-pyran-4-one;
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(3-methylphenyl)methoxy]-4H-pyran-4-one; or
2-[(3,4-Dihydro-2(1H)-isoquinolinyl)methyl]-5-[(4-nitrophenyl)methoxy]-4H-pyran-4-one.

2. The compound according to claim 1 , wherein the compound is a compound of formula (IA):

wherein
ring B is a 4-10 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from N, O, or S;
L is absent, —CH 2 —, —CH 2 —CH 2 —, or —CH 2 —CH 2 —CH 2 —, or when ring A is (1), L is —C(O)—CH 2 —;
R 1 is hydrogen, C 1-7 alkyl, C 1-7 alkoxy, halogen, cyano, nitro, halo C 1-7 alkyl, halo C 1-7 alkoxy, or C 1-7 alkylthio;
R 2 is hydrogen, C 1-7 alkyl, halogen, hydroxy, halo C 1-7 alkyl, nitro, halo C 1-7 alkoxy, or thiol;
or R 1 and R 2 together with the carbon atoms to which they are attached form a fused 1,3 dioxole ring;
R 3 is hydrogen, halogen, nitro, cyano, oxo, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, hydroxy C 3-7 cycloalkyl, C 1-7 alkoxy, hydroxy C 1-7 alkyl, halo C 1-7 alkyl, cyano C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkylthio, aminocarbonyl C 2-7 alkenyl, halo C 1-7 alkylthio, C 1-7 alkoxycarbonyl C 1-7 alkyl, C 1-7 alkoxycarbonyl C 2-7 alkenyl, ═NSO 2 R 20 , —S(O)—C 1-7 alkyl, —S(O)(NR 14 )(R 22 ), —S(NR 15 )(C 1-7 alkyl), —C(S)NR 18 R 19 , -D-C(O)—NR 6 R 7 , —C(O)R 8 , -D-NR 9 R 10 , —SO 2 R 11 , optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered ca

Assignees

• Orion Corp

Inventors

• Din Belle David
• Mäkelä Mikko
• Passiniemi Mikko
• Pietikäinen Pekka
• Rummakko Petteri
• Tiainen Eija
• Vaismaa Matti
• Wohlfahrt Gerd

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title