# US 10,766,860 B2 · Lysyl oxidase-like 2 inhibitors and uses thereof

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- Number: US 10,766,860 B2
- Document ID: US10766860B2
- Status: Granted
- Kind: B2
- Application number: 15/555,785
- Filed: 2016-03-03
- Published: 2018-03-01
- Granted: 2020-09-08
- Earliest claimed: 2015-03-06
- Assignees: Pharmakea, Inc.
- Applicants: PharmAkea, Inc.
- Inventors: Martin W. Rowbottom; John Howard Hutchinson; David Lonergan
- Web page: https://patentgrep.com/patent/US10766860B2

## CPC

- C07D 213/56: Amides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 35/00: Antineoplastic agents
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/53: Nitrogen atoms
- C07D 213/55: Acids; Esters
- C07D 213/643: 2-Phenoxypyridines; Derivatives thereof
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 213/81: Amides; Imides
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
each R1 is H.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Ring A is phenyl;
or Ring A is bicyclic C9-C10carbocycle that is naphthyl, indanyl, indenyl, or tetrahyodronaphthyl.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Ring A is

### Claim 5 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Q is substituted or unsubstituted C3-C6cycloalkyl, —C1-C2alkylene-(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted phenyl, —C1-C2alkylene-(substituted or unsubstituted phenyl), substituted or unsubstituted heteroaryl, or —C1-C2alkylene-(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.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
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.

### Claim 7 (depends on 5)

The compound of claim 5, wherein the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
ring B is a substituted or unsubstituted pyrrolidinyl, wherein if ring B is substituted then ring B is substituted with 1-3 R8; and
n is 0, 1, 2, or 3.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound has the structure of Formula (XII), or a pharmaceutically acceptable salt, or solvate thereof:

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound has the structure of Formula (XIII), or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
L1 is —O—.

### Claim 10

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.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, or solvate thereof, of claim 1, and at least one pharmaceutically acceptable excipient.