US 10,947,226 B2Granted

Bicyclic pyridone lactams and methods of use thereof

AssigneeGenentech, Inc.

InventorSnahel Patel

Life of this patent

Estimating the term…

Abstract

The invention provides novel compounds having the general formula I: wherein R1, X, Z1 to Z5, L, n, the A ring, and the B ring, are as described herein, pharmaceutical compositions including the compounds and methods of using the compounds.

Claims23

Dependent claims

The compound of formula (Ia), (Ib), (Ic) or (Id):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of H, C1-C4 alkyl, and C1-C4 haloalkyl;
the A ring is tetrazolyl or a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
wherein the A ring is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano;
and wherein if a nitrogen atom in the A ring is substituted, the substituent is not halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;
the B ring is selected from the group consisting of phenyl, 5 or 6 membered heteroaryl, 3 to 7 membered cycloalkyl, and 4 to 7 membered heterocyclyl;
wherein the B ring is optionally substituted with:
(a) 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2—(C3-C6 cycloalkyl), and CH2CH2—(C3-C6 cycloalkyl);
wherein if a nitrogen atom in the C ring is substituted, the substituent is not halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;
(b) 1 to 2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), and unsubstituted 5 or 6 membered heteroaryl;
or
(c) two adjacent substituents which together form phenyl, 5 or 6 membered heteroaryl, 4 to 6 membered heterocyclyl or C4-C6 cycloalkyl;
L is selected from the group consisting of a bond, O, S, NH, NCH3, (CH2)m, CH(CH3), C(CH3)2, CF2, CH2O, CH2S, CH(OH), CH2NH, and CH2N(CH3), or L is absent such that the A ring and the B ring are fused;
m is 1 or 2;
R3 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, —C(R4)2—C3-C6 cycloalkyl, 4 to 6 membered heterocyclyl, and —C(R4)2-(4 to 6 membered heterocyclyl);
and
each R4 is independently selected from the group consisting of H, F, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

14 more elements

A compound selected from the group consisting of:

1-benzyl-N-[(7S)-1,5-dimethyl-2,6-dioxo-8,9-dihydro-7H-pyrido[3,2-b]azepin-7-yl]-1,2,4-triazole-3-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(7S)-1,5-dimethyl-2,6-dioxo-8,9-dihydro-7H-pyrido[3,2-b]azepin-7-yl]-1,2,4-triazole-3-carboxamide;
1-benzyl-N-[(3S)-1-methyl-2,7-dioxo-4,5-dihydro-3H-pyrido[1,2-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-benzyl-N-[(3R)-1-methyl-2,7-dioxo-4,5-dihydro-3H-pyrido[1,2-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3S)-1-methyl-2,7-dioxo-4,5-dihydro-3H-pyrido[1,2-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3R)-1-methyl-2,7-dioxo-4,5-dihydro-3H-pyrido[1,2-a][1,3]diazepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-benzyl-N-[(3S)-1,7-dimethyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3S)-1,7-dimethyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-benzyl-N-[(3S)-1,8-dimethyl-2,7-dioxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-benzyl-N-[(3R)-1,8-dimethyl-2,7-dioxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
(S)—N-(1,8-dimethyl-2,7-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrido[3,4-b]azepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;
(R)—N-(1,8-dimethyl-2,7-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrido[3,4-b]azepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3S)-1,8-dimethyl-2,7-dioxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3R)-1,8-dimethyl-2,7-dioxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3S)-1,7-dimethyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3S)-7-(cyclopropylmethyl)-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3S)-7-(cyclopropylmethyl)-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3R)-7-(cyclopropylmethyl)-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3R)-7-(cyclopropylmethyl)-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3S)-7-ethyl-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3S)-7-ethyl-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
(5S)-5-(2-fluorophenyl)-N-[(3R)-7-ethyl-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(3R)-7-ethyl-1-methyl-2,8-dioxo-4,5-dihydro-3H-pyrido[4,3-b]azepin-3-yl]-1,2,4-triazole-3-carboxamide;
1-[(2-fluorophenyl)methyl]-N-[(7R)-1,5-dimethyl-2,6-dioxo-8,9-dihydro-7H-pyrido[3,2-b]azepin-7-yl]-1,2,4-triazole-3-carboxamide;
and
1-benzyl-N-[(7R)-1,5-dimethyl-2,6-dioxo-8,9-dihydro-7H-pyrido[3,2-b]azepin-7-yl]-1,2,4-triazole-3-carboxamide;
or a pharmaceutically acceptable salt thereof.

24 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/385,353Filed 16 Apr 2019 · continuation
Priority: 17 Oct 2016
Published: US 2019/0241565 A18 Aug 2019
Granted: 16 Mar 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…

Family

Application62/409,214Us provisional application · filed 17 Oct 2016
PCT/EP2017/076385Parent of this continuation · filed 16 Oct 2017
US 2019/0241565 A1Pre-grant publication · published 8 Aug 2019
US 10,947,226 B2This patent

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

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Abstract

The compound of formula (Ia), (Ib), (Ic) or (Id):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of H, C1-C4 alkyl, and C1-C4 haloalkyl;
the A ring is tetrazolyl or a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
wherein the A ring is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano;
and wherein if a nitrogen atom in the A ring is substituted, the substituent is not halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;
the B ring is selected from the group consisting of phenyl, 5 or 6 membered heteroaryl, 3 to 7 membered cycloalkyl, and 4 to 7 membered heterocyclyl;
wherein the B ring is optionally substituted with:
(a) 1 to 4 substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2—(C3-C6 cycloalkyl), and CH2CH2—(C3-C6 cycloalkyl);
wherein if a nitrogen atom in the C ring is substituted, the substituent is not halogen, cyano, or a C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 thioalkyl having an oxygen or sulfur atom directly bonded to the nitrogen atom;
(b) 1 to 2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CH2-(4 to 6 membered heterocyclyl), CH2CH2-(4 to 6 membered heterocyclyl), and unsubstituted 5 or 6 membered heteroaryl;
or
(c) two adjacent substituents which together form phenyl, 5 or 6 membered heteroaryl, 4 to 6 membered heterocyclyl or C4-C6 cycloalkyl;
L is selected from the group consisting of a bond, O, S, NH, NCH3, (CH2)m, CH(CH3), C(CH3)2, CF2, CH2O, CH2S, CH(OH), CH2NH, and CH2N(CH3), or L is absent such that the A ring and the B ring are fused;
m is 1 or 2;
R3 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, —C(R4)2—C3-C6 cycloalkyl, 4 to 6 membered heterocyclyl, and —C(R4)2-(4 to 6 membered heterocyclyl);
and
each R4 is independently selected from the group consisting of H, F, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

14 more elements

Facts

Application

16/385,353Filed 16 Apr 2019 · continuation

Priority

17 Oct 2016

Published

US 2019/0241565 A18 Aug 2019

Granted

16 Mar 2021

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…