# US 11,440,898 B2 · Isoquinoline compounds, methods for their preparation, and therapeutic uses thereof in conditions associated with the alteration of the activity of beta galactosidase

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- Number: US 11,440,898 B2
- Document ID: US11440898B2
- Status: Granted
- Kind: B2
- Application number: 16/473,966
- Filed: 2017-12-27
- Published: 2020-03-05
- Granted: 2022-09-13
- Earliest claimed: 2016-12-28
- Assignees: Minoryx Therapeutics S.L.
- Applicants: Minoryx Therapeutics S.L.
- Inventors: Ana Maria García Collazo; Marc Martinell Pedemonte; Elena Cubero Jordà; Xavier Barril Alonso; Laura Pilar Rodriguez Pascau
- Web page: https://patentgrep.com/patent/US11440898B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D 401/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- 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

The application is directed to compounds of formula (I):(I), and formula (IA):(IA) and their salts and solvates, wherein R1, R2, R3, R4, R5, n, A1, A2, A3, and Y are as set forth in the specification, as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of conditions associated with the alteration of the activity of β-galactosidase, specially galactosidase beta-1 or GLB 1, including GM 1 gangliosidoses and Morquio syndrome, type B.

## Claims

### Claim 1

A compound of formula (I):
or a salt or solvate thereof,
wherein:
each of A1 is independently selected from the group consisting of nitrogen and CH; and
each of A2 and A3 is independently selected from the group consisting of nitrogen, CH, and C(R6); wherein
each A1 is CH and each of A2 and A3 is independently selected from CH and C(R6), provided that only one of A2 and A3 is C(R6); or
exactly one of A2 and A3 is C(R6) and no less than one and no more than two of A1, A2, and A3 are nitrogen;
R1, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, —CN, —ORb, and —C1-4 alkyl, wherein said —C1-4 alkyl group is optionally substituted by 1, 2 or 3 independently selected halogen atoms, with the proviso that at least one R1, R2, and R3 is other than hydrogen;
R6 is —B—NH—R7;
B is —CO— or —SO2—;
each R4 is independent selected from the group consisting of halogen, —C1-4 alkyl, —C1-4 alkoxy, —CN and hydroxy;
n has a value selected from 0, 1 or 2;
R5 is hydrogen or —C1-4 alkyl;
R7 is selected from the group consisting of —C1-4 alkyl, —C3-10 cycloalkyl, —C1-4 alkyl-C3-10 cycloalkyl, —C6-10 aryl, —C1-4 alkyl-C6-10 aryl, (5- to 10-membered)-C1-9 heteroaryl, —C1-4 alkyl-(5- to 10-membered)-C1-9 heteroaryl, (5- to 10-membered)-C1-9 heterocyclyl, and —C1-4 alkyl-(5- to 10-membered)-C1-9 heterocyclyl; said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups optionally being substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen, hydroxyl, —CN, —ORb, —SRb, —N(Rb)2, —C1-4alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted C6-10 aryl, optionally substituted (5- to 10-membered)-C1-9 heteroaryl, and (5- to 10-membered)-C1-9 heterocyclyl; said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl is optionally fused to a further (second) ring, and
each Rb is independently hydrogen, —C1-4 alkyl, —C3-10 cycloalkyl, or (5- to 10-membered)-C1-9 heterocyclyl; said alkyl, cycloalkyl or heterocyclyl groups optionally being substituted by 1, 2 or 3 fluorine atoms.

### Claim 2 (depends on 1)

The compound of claim 1, having the formula (IA):
or a salt or solvate thereof, wherein:
R1, R2, R3, R4, and R5, are as defined in claim 1, with the proviso that at least one R1, R2, and R3 is other than hydrogen;
n is 0 or 1, and
Y is selected from the group consisting of
wherein R6 is as defined in claim 1.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R3 is selected from the group consisting of halogen, —CN, and —ORb.

### Claim 4 (depends on 2)

The compound of claim 2, wherein Y is selected from the group consisting of Y1 and Y2.

### Claim 5 (depends on 2)

The compound of claim 2, wherein Y is selected from the group consisting of Y3, Y4, Y5, Y6, Y7, and Y8.

### Claim 6 (depends on 2)

The compound of claim 2, wherein Y is selected from the group consisting of Y9, Y10, Y11, Y12, Y13, Y14, Y15, Y16, Y17, Y18, Y19, Y20, Y21, and Y22.

### Claim 7 (depends on 1)

The compound of claim 1, wherein B is —CO—.

### Claim 8 (depends on 1)

The compound of claim 1, wherein B is —SO2—.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R7 is selected from the group consisting of —C1-4 alkyl, —C3-10 cycloalkyl, —C1-4 alkyl-C3-10 cycloalkyl, —C6-10 aryl, —C1-4 alkyl-C6-10 aryl, (5- to 10-membered)-C1-9 heteroaryl, —C1-4 alkyl-(5- to 10-membered)-C1-9 heteroaryl, (5- to 10-membered)-C1-9 heterocyclyl, and —C1-4 alkyl-(5- to 10-membered)-C1-9 heterocyclyl,
wherein said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups being substituted with 1, 2, or 3 groups independently selected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)2, —C1-4alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted —C6-10 aryl, optionally substituted (5- to 10-membered)-C1-9 heteroaryl, and (5- to 10-membered)-C1-9 heterocyclyl; said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl is fused to a further (second) ring.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R7 is —C1-4 alkyl,
wherein said alkyl is substituted with 1, 2, or 3 groups each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb, —SRb, —N(Rb)2, —C1-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted —C6-10 aryl, optionally substituted (5- to 10-membered)-C1-9 heteroaryl, and (5- to 10-membered)-C1-9 heterocyclyl; said aryl, heteroaryl, and heterocyclyl optionally fused to a further (second) ring.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R7 is selected from the group consisting of —C3-10 cycloalkyl, —C1-4 alkyl-C3-10 cycloalkyl, —C6-10 aryl, —C1-4 alkyl-C6-10 aryl, (5- to 10-membered)-C1-9 heteroaryl, —C1-4 alkyl-(5- to 10-membered)-C1-9 heteroaryl, (5- to 10-membered)-C1-9 heterocyclyl, and —C1-4 alkyl-(5- to 10-membered)-C1-9 heterocyclyl, wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl is fused to a further (second) ring.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R7 is selected from the group consisting of —C1-4 alkyl, —C3-10 cycloalkyl, —C1-4 alkyl-C3-10 cycloalkyl, —C6-10 aryl, —C1-4 alkyl-C6-10 aryl, (5- to 10-membered)-C1-9 heteroaryl, —C1-4 alkyl-(5- to 10-membered)-C1-9 heteroaryl, (5- to 10-membered)-C1-9 heterocyclyl, and —C1-4 alkyl-(5- to 10-membered)-C1-9 heterocyclyl.

### Claim 13 (depends on 1)

The compound of claim 1 selected from the group consisting of:
3-((7-chloroisoquinolin-1-yl)amino)-N-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzamide;
3-((7-chloroisoquinolin-1-yl)amino)-N-(2-morpholino-2-(pyridin-2-yl)ethyl)benzamide;
3-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)benzamide;
N-benzyl-3-((7-chloroisoquinolin-1-yl)amino)benzamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)benzamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(2-(pyridin-3-yl)-2-(pyrrolidin-1-yl)ethyl)benzamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(2-(pyridin-3-yl)-2-(pyrrolidin-1-yl)ethyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)picolinamide;
N-benzyl-4-((7-chloroisoquinolin-1-yl)amino)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(4-methoxybenzyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(3-methoxybenzyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(3,4-dimethoxybenzyl)picolinamide;
N-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-4-((7-chloroisoquinolin-1-yl)amino)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzofuran-5-yl)methyl)picolinamide;
N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-((7-chloroisoquinolin-1-yl)amino)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(chroman-6-ylmethyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(pyridin-3-ylmethyl)picolinamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(pyridin-4-ylmethyl)picolinamide;
4-((7-methoxyisoquinolin-1-yl)amino)-N-(2-(pyridin-3-yl)-2-(pyrrolidin-1-yl)ethyl)picolinamide;
N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-((7-methoxyisoquinolin-1-yl)amino)picolinamide;
N-benzyl-4-((7-methoxyisoquinolin-1-yl)amino)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(2-(pyridin-3-yl)-2-(pyrrolidin-1-yl)ethyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)picolinamide;
N-benzyl-5-((7-chloroisoquinolin-1-yl)amino)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(4-methoxybenzyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(3-methoxybenzyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(3,4-dimethoxybenzyl)picolinamide;
N-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-5-((7-chloroisoquinolin-1-yl)amino)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzofuran-5-yl)methyl)picolinamide;
N-(benzo[d][1,3]dioxol-5-ylmethyl)-5-((7-chloroisoquinolin-1-yl)amino)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(chroman-6-ylmethyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(pyridin-3-ylmethyl)picolinamide;
5-((7-chloroisoquinolin-1-yl)amino)-N-(pyridin-4-ylmethyl)picolinamide;
5-((7-methoxyisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide;
N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-((7-methoxyisoquinolin-1-yl)amino)picolinamide;
5-((7-methoxyisoquinolin-1-yl)amino)-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)picolinamide;
5-((7-cyanoisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide;
5-((7-cyanoisoquinolin-1-yl)amino)-N-(pyridin-3-ylmethyl)picolinamide;
N-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-5-((7-cyanoisoquinolin-1-yl)amino)picolinamide;
5-((5-chloroisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide;
5-((5-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzofuran-5-yl)methyl)picolinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-(2-(pyridin-3-yl)-2-(pyrrolidin-1-yl)ethyl)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)nicotinamide;
N-benzyl-6-((7-chloroisoquinolin-1-yl)amino)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-(4-methoxybenzyl)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-(3-methoxybenzyl)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-(3,4-dimethoxybenzyl)nicotinamide;
N-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-6-((7-chloroisoquinolin-1-yl)amino)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)nicotinamide;
N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-((7-chloroisoquinolin-1-yl)amino)nicotinamide;
6-((7-chloroisoquinolin-1-yl)amino)-N-(chroman-6-ylmethyl)nicotinamide;
5-((7-methoxyisoquinolin-1-yl)amino)-N-(pyridin-3-ylmethyl)picolinamide;
3-((7-chloroisoquinolin-1-yl)amino)-N-(2-(pyridin-3-yl)-2-(pyrrolidin-1-yl)ethyl)benzenesulfonamide;
3-((7-chloroisoquinolin-1-yl)amino)-N-(2-morpholino-2-(pyridin-2-yl)ethyl)benzenesulfonamide;
3-(7-chloroisoquinolin-1-yl)amino)-N-(1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)benzenesulfonamide;
N-benzyl-3-((7-chloroisoquinolin-1-yl)amino)benzenesulfonamide;
3-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)benzenesulfonamide;
3-((7-chloroisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide;
3-(7-chloroisoquinolin-1-yl)amino)-N-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)benzenesulfonamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(2-morpholino-2-(pyridin-2-yl)ethyl)benzenesulfonamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(1-methyl-1H-benzo[d][1,2,3]triazol-4-yl)benzenesulfonamide;
N-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-3-((7-chloroisoquinolin-1-yl)amino)benzenesulfonamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)benzenesulfonamide;
N-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-4-((7-chloroisoquinolin-1-yl)amino)benzenesulfonamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)benzenesulfonamide;
4-((7-chloroisoquinolin-1-yl)amino)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)benzenesulfonamide; and
N-benzyl-4-((7-chloroisoquinolin-1-yl)amino)benzenesulfonamide;
or a salt or solvate thereof.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

A method of treating or preventing a condition associated with the alteration of the activity of GLB1 in a patient, comprising administering to the patient in need thereof an effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 16 (depends on 1)

A method of treating GM1 gangliosidosis or Morquio B syndrome in a patient, comprising administering to the patient in need thereof an effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 17 (depends on 1)

A method of increasing β-galactosidase activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 18 (depends on 16)

The method of claim 16, further comprising administering to the patient an effective amount of an enzyme for enzyme replacement therapy.

### Claim 19 (depends on 18)

The method of claim 18, wherein the enzyme is β-galactosidase or an analog thereof.

### Claim 20 (depends on 16)

The method of claim 16, further comprising administering to the patient a small molecule chaperone.

### Claim 21 (depends on 20)

The method of claim 20, wherein the small molecule chaperone binds competitively to an enzyme.

### Claim 22 (depends on 20, 21)

The method of claim 20 or 21, wherein the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, aminosugars, thiophenylglycosides, glycosidase, sulfatase, glycosyl transferase, phosphatase, and peptidase inhibitors.

### Claim 23 (depends on 22)

The method of claim 22, wherein the small molecule chaperone is selected from the group consisting of 1-deoxygalactonojirimycin (DGJ), N-nonyldeoxynojirimycin (NN-DNJ), N-butyldeoxygalactonojirimycin (NB-DGJ), galactose, fluorous iminoalditol, and epi-isofagomine.