US 12,715,880 B2Granted

Macrocyclic diamine derivatives as ENT inhibitors for the treatment of cancers, and combination thereof with adenosine receptor antagonists

AssigneeiTeos Belgium SA

InventorsMichael Deligny, Stefano Crosignani, Erica Joke Katelijne Heleen Houthuys, Michael Rowley

Life of this patent

Estimating the term…

Abstract

The present invention relates to macrocyclic diamine derivatives of formula I, including pharmaceutically acceptable salts and solvates thereof. Compounds of the invention are inhibitors of ENT family transporter, especially of ENT1, and are useful as therapeutic compounds for the treatment of cancers. The invention also relates to the combined use of the macrocyclic diamine derivatives with an adenosine receptor antagonist, for the treatment of cancers.

Claims6

Dependent claims

A compound of formula IIa1:

or a pharmaceutically acceptable salt or solvate thereof.

A compound selected from the group consisting of:

(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl)-3,4,5-trimethoxybenzamide;
74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12S)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-74,75-dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(11R)-74,75-dimethoxy-6-oxo-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotridecaphane-11-yl 3,4,5-trimethoxybenzoate;
(10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-O-yl 3,4,5-trimethoxybenzoate;
(10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphane-O-yl 3,4,5-trimethoxybenzoate;
(12S)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate;
(12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate;
74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12S)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-74,75-dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
75-carbamoyl-74-chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(11Z,16E,10S)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate;
(11Z,16E,10R)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)-diazepanacyclotridecaphane-10-yl 3,4,5-trimethoxybenzoate;
(12S)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-74-carbamoyl-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
74-bromo-75-chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
75-chloro-74-cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-trimethoxybenzoate;
(12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate;
(12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate;
(Z)-benzaldehyde O-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl) oxime;
12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-hydroxybenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-isopropoxybenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(trifluoromethyl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(methylsulfonyl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-phenoxybenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-bromo-3-cyanobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methyl-5-(trifluoromethyl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-fluoro-4-methoxybenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxy-2-(trifluoromethoxy)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl picolinate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl nicotinate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl pyrazine-2-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 6-hydroxynicotinate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl quinoline-5-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl oxazole-4-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1H-1,2,3-triazole-4-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl acetate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclopropanecarboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methylbutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4,4-trifluorobutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl cyclohexanecarboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methylpiperidine-4-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,3-dimethylcyclobutane-1-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-(oxetan-3-yl)acetate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 5-oxopyrrolidine-3-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-benzyl-5-oxopyrrolidine-3-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-methoxycyclohexane-1-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,6-difluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethoxy)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(difluoromethoxy)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-dichlorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-dichlorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2,3-dichlorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 2-chloro-6-fluoro-3-methylbenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-fluoro-5-(trifluoromethyl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-fluoro-3-(trifluoromethyl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyano-3-fluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,5-difluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4-difluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyano-4-fluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-chloro-4-fluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 1-methyl-1H-benzo[d]imidazole-5-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(oxazol-5-yl)benzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,5-dichloro-2-fluorobenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3,4,5-triethoxybenzoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxypropanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-pyrazol-1-yl)propanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-cyanopropanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-cyanobutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-acetamidobutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-tetrazol-1-yl)propanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(dimethylamino)-4-oxobutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-acetamidopropanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(methylamino)-4-oxobutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(1H-1,2,4-triazol-1-yl)propanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-morpholino-4-oxobutanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(4-fluorophenoxy)propanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4,4-difluorocyclohexane-1-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-(2,5-dioxopyrrolidin-1-yl)propanoate;
74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl 3-methoxycyclohexane-1-carboxylate;
74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl benzoate;
(E)-benzaldehyde O-(74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl) oxime;
(E)-benzaldehyde O—((12R) 74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl) oxime;
(E)-benzaldehyde O—((12S)-74,75-dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-12-yl) oxime;
12-hydroxy-74,75-dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
(12R)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
(12S)-12-hydroxy-74,75-dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
74,75-dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
74,75-dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
74,75-dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one;
and pharmaceutically acceptable salts or solvates thereof.

109 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/917,462Filed 7 Apr 2021 · us provisional application
Priority: 7 Apr 2020
Published: US 2023/0203058 A129 Jun 2023
Granted: 25 Aug 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 491/08
In which the condensed system contains two hetero rings: bridged systems
C07D 498/08
In which the condensed system contains two hetero rings: bridged systems
A61K 31/395
Heterocyclic compounds: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K 31/551
Having seven-membered rings, e.g. azelastine, pentylenetetrazole: having two nitrogen atoms, e.g. dilazep

Family

Application63/006,629Us provisional application · filed 7 Apr 2020
US 2023/0203058 A1Pre-grant publication · published 29 Jun 2023
US 12,715,880 B2This patent

From the US filing history. Foreign family members aren’t listed.

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