US 10,766,860 B2Granted

Lysyl oxidase-like 2 inhibitors and uses thereof

AssigneePharmakea, Inc.

InventorsMartin W. Rowbottom, John Howard Hutchinson, David Lonergan

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Abstract

Described herein are compounds that are LOXL2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with LOXL2 activity.

Claims11

Dependent claims

A compound of Formula (VI), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
each R1 is independently H, D, or F;
RA is H, D, halogen, —CN, —OR5, —N(R5)2, or substituted or unsubstituted phenyl;
L1 is absent, —O—, —S—, —S(═O)—, —S(═O)2—, or —NR2—;
R2 is H, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl;
each R3 is independently H, D, halogen, —CN, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl;
m is 0, 1, or 2;
each R4 is independently selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted aryl;
each R5 is independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted aryl, —C1-C4alkylene-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted aryl, and —C1-C4alkylene-(substituted or unsubstituted aryl);
Ring A is phenyl;
or Ring A is bicyclic C9-C10carbocycle;
R6 is H, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl;
Q is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, —C1-C4alkylene-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted aryl, —C1-C4alkylene-(substituted or unsubstituted aryl), substituted or unsubstituted heteroaryl, or —C1-C4alkylene-(substituted or unsubstituted heteroaryl);
wherein if Q is substituted then Q is substituted with one or more R8;
or Q and R6 are taken together with the N atom to which they are attached to form a ring B, wherein ring B is a substituted or unsubstituted pyrrolidinyl, wherein if ring B is substituted then ring B is substituted with 1-3 R8;
each R8 is independently D, halogen, CN, —OR5, —SR5, —S(═O)R4, —S(═O)2R4, —S(═O)2N(R5)2, NR5S(═O)2R4, C(═O)R4, OC(═O)R4, CO2R5, OCO2R4, N(R4)2, OC(═O)N(R5)2, —NHC(═O)R4, —NHC(═O)OR4, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or two R8 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted carbocycle;
wherein any substituted group of RA, R3, R4, R5, and R8 is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O)C1-C4alkyl, and —S(═O)2C1-C4alkyl.

15 more elements

A compound that is:

4-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamide;
Racemic-(4-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;
4-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamide;
4-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamide;
3-(4-(Aminomethyl)pyridin-2-yl)-N-(2-methoxyethyl)benzamide;
Racemic-(3-(4-(aminomethyl)pyridin-2-yl)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;
3-(4-(Aminomethyl)pyridin-2-yl)-N-phenylbenzamide;
3-(4-(Aminomethyl)pyridin-2-yl)-N-benzylbenzamide;
3-(4-(Aminomethyl)pyridin-2-yl)-N-(5-chloro-2-methylphenyl)benzamide;
3-(4-(Aminomethyl)pyridin-2-yl)-N-(6-chloro-1H-indol-4-yl)benzamide;
4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamide;
Racemic-4-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;
4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamide;
4-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-methoxyethyl)benzamide;
Racemic-(3-((4-(aminomethyl)pyridin-2-yl)oxy)phenyl)(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)methanone;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenylbenzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-benzylbenzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-methoxyphenyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-methoxyphenyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-fluorophenyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorophenyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromophenyl)benzamide;
Methyl 4-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate;
Ethyl 3-(3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)benzoate;
3-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic acid;
4-(3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)benzoic acid;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2,4-difluorobenzyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(trifluoromethyl)benzyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-bromobenzyl)benzamide;
Methyl 4-((3-((4-(aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoate;
4-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic acid;
3-((3-((4-(Aminomethyl)pyridin-2-yl)oxy)benzamido)methyl)benzoic acid;
(R)-3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(2-hydroxy-1-phenylethyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-fluoro-4-(1H-imidazol-1-yl)benzyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(4-(4-ethylpiperazin-1-yl)benzyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(3-carbamimidoylbenzyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-phenethylbenzamide;
(3-((4-(Aminomethyl)pyridin-2-yl)oxy)phenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(benzo[b]thiophen-2-ylmethyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-(pyrazin-2-ylmethyl)benzamide;
3-((4-(Aminomethyl)pyridin-2-yl)oxy)-N-tridecylbenzamide;
or
3-(((4-(Aminomethyl)pyridin-2-yl)oxy)methyl)-N-phenylbenzamide;
or a pharmaceutically acceptable salt, or solvate thereof.

44 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/555,785Filed 3 Mar 2016 · us provisional application
Priority: 6 Mar 2015
Published: US 2018/0057458 A11 Mar 2018
Granted: 8 Sep 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07D 213/56
Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals: amides
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 35/00
Antineoplastic agents

Family

Application62/129,531Us provisional application · filed 6 Mar 2015
US 2018/0057458 A1Pre-grant publication · published 1 Mar 2018
US 10,766,860 B2This patent

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

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Abstract

A compound of Formula (VI), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
each R1 is independently H, D, or F;
RA is H, D, halogen, —CN, —OR5, —N(R5)2, or substituted or unsubstituted phenyl;
L1 is absent, —O—, —S—, —S(═O)—, —S(═O)2—, or —NR2—;
R2 is H, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl;
each R3 is independently H, D, halogen, —CN, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl;
m is 0, 1, or 2;
each R4 is independently selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, and substituted or unsubstituted aryl;
each R5 is independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted aryl, —C1-C4alkylene-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted aryl, and —C1-C4alkylene-(substituted or unsubstituted aryl);
Ring A is phenyl;
or Ring A is bicyclic C9-C10carbocycle;
R6 is H, C1-C6alkyl, C1-C6fluoroalkyl, or C1-C6deuteroalkyl;
Q is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, —C1-C4alkylene-(substituted or unsubstituted C3-C8cycloalkyl), substituted or unsubstituted aryl, —C1-C4alkylene-(substituted or unsubstituted aryl), substituted or unsubstituted heteroaryl, or —C1-C4alkylene-(substituted or unsubstituted heteroaryl);
wherein if Q is substituted then Q is substituted with one or more R8;
or Q and R6 are taken together with the N atom to which they are attached to form a ring B, wherein ring B is a substituted or unsubstituted pyrrolidinyl, wherein if ring B is substituted then ring B is substituted with 1-3 R8;
each R8 is independently D, halogen, CN, —OR5, —SR5, —S(═O)R4, —S(═O)2R4, —S(═O)2N(R5)2, NR5S(═O)2R4, C(═O)R4, OC(═O)R4, CO2R5, OCO2R4, N(R4)2, OC(═O)N(R5)2, —NHC(═O)R4, —NHC(═O)OR4, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or two R8 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted carbocycle;
wherein any substituted group of RA, R3, R4, R5, and R8 is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2(C1-C4alkyl), —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O)C1-C4alkyl, and —S(═O)2C1-C4alkyl.

15 more elements

Facts

Application

15/555,785Filed 3 Mar 2016 · us provisional application

Priority

6 Mar 2015

Published

US 2018/0057458 A11 Mar 2018

Granted

8 Sep 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07D 213/56
Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals: amides
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 35/00
Antineoplastic agents