# US 2018/0022697 A1 · Glucosylceramide synthase inhibitors and therapeutic methods using the same

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2018/0022697 A1
- Document ID: US20180022697A1
- Status: Published application
- Kind: A1
- Application number: 15/546,320
- Filed: 2016-02-01
- Published: 2018-01-25
- Earliest claimed: 2015-02-02
- Assignees: The Regents of the University of Michigan
- Applicants: The Regents of the University of Michigan
- Inventors: Scott D. Larsen; Akira Abe; Liming Shu; Michael William Wilson; Richard F. Keep; Duxin Sun; James A. Shayman
- Web page: https://patentgrep.com/patent/US20180022697A1

## CPC

- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 207/10: 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 ring carbon atoms
- C07D 263/20: attached in position 2
- C07D 263/24: with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
- C07D 295/125: with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D 295/13: to an acyclic saturated chain
- 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

Glucosylceramide synthase inhibitors and compositions containing the same are disclosed. Methods of using the glucosylceramide synthase inhibitors in the treatment of diseases and conditions wherein inhibition of glucosylceramide synthase provides a benefit, like Gaucher disease and Fabry disease, also are disclosed.

## Claims

### Claim 1

A compound having a structure
wherein R1, independently, is selected from the group consisting of halo, C1-3alkyl, C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl, OC1-3alkyl substituted with one to five fluoro atoms, cyclopropyl, CH2cyclopropyl, Ocyclopropyl, and OCH2cyclopropyl;
NR2R2′ is selected from the group consisting of 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and 1-pyrrolidinyl-3-one;
R3 is H, F, or Cl;
G is (CH2)n;
m is 1 or 2; and
n is 1 or 2,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R1, independently is —OCH3, —OCF3, —OCHF2, —OCH2CF3, —F, —CF3

### Claim 3 (depends on 1)

The compound of claim 1, wherein m is 2, and R1 is —F and —OCH3.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R3 is H.

### Claim 5 (depends on 1)

The compound of claim 1 wherein —NR2R2′ is

### Claim 6 (depends on 1)

The compound of claim 1 wherein G is CH2 or CH2CH2.

### Claim 7 (depends on 1)

The compound of claim 1 wherein
is

### Claim 8

A compound selected from the group consisting of 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(3-fluoro-4-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(3-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluoro-3-methoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-yl)-2-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethoxy)phenyl)propan-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)phenyl)propan-2-yl)acetamide; N-((1R,2R)-1-(4-(difluoromethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide; 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(4-fluorophenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; N-((1R,2R)-1-(4-(cyclopropylmethoxy)phenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2,3-dihydro-1H-inden-2-yl)acetamide; and 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-hydroxy-3-(pyrrolidin-1-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)propan-2-yl)acetamide, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.

### Claim at position 10

-11. (canceled)

### Claim 12 (depends on 1)

A method of treating a disease or condition wherein inhibition of GCS provides a benefit comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof, wherein the disease or condition is a Gaucher disease, Fabry disease, Sandhoff disease, Tay-Sachs disease, Parkinson's disease, type 2 diabetes, hypertrophy or hyperplasia associated with diabetic neuropathy, an elevated plasma TNF-α level, an elevated blood glucose level, an elevated glycated hemoglobin level, a glomerular disease, lupus, a disorder involving cell growth, a disorder involving cell division, a collagen vascular disease, atherosclerosis, renal hypertrophy in a diabetic individual, a growth of arterial epithelial cells, an infection, a tumor, and an autosomal dominant or recessive form of a polycystic kidney disease.

### Claim at position 12

-14. (canceled)

### Claim 15 (depends on 12)

The method of claim 12 wherein the Gaucher disease is type I, type II, or type III Gaucher disease, and the glomerular disease is selected from the group consisting of mesangial proliferative glomerulonephritis, collapsing glomerulopathy, proliferative lupus nephritis, crescentic glomerulonephritis, and membranous nephropathy.

### Claim at position 14

-25. (canceled)

### Claim 26 (depends on 1)

A method of inhibiting glucosylceramide synthase or lowering a glycosphinolipid concentration in an individual in need thereof comprising administering a therapeutically effective amount of a compound of claim 1 to the individual.

### Claim 27

(canceled)

### Claim 28

A compound having a structure
wherein R1 is C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl substituted with one to five fluoroatoms, cyclopropyl, CH2cyclopropyl, or OCH2cyclopropyl.

### Claim 29

(canceled)

### Claim 30

A compound having a structure
wherein R1 is C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl substituted with one to five fluoroatoms, cyclopropyl, CH2cyclopropyl, or OCH2cyclopropyl; and L is a perfluoroalkylsulfonate or arylsulfonate leaving group.

### Claim 31

A compound having a structure
wherein R1 is C1-3alkyl substituted with one to five fluoro atoms, OC1-3alkyl substituted with one to five fluoroatoms, cyclopropyl, CH2cyclopropyl, or OCH2cyclopropyl; and NR2R2′ is selected from the group consisting of 1-pyrrolidinyl, 3-fluoro-1-pyrrolidinyl, 1-morpholinyl, 1-azetidinyl, and 1-pyrrolidinyl-3-one.

### Claim at position 21

-33. (canceled)

### Claim 34 (depends on 32)

A method of treating a disease or condition wherein inhibition of GCS provides a benefit comprising administering a therapeutically effective amount of a compound of claim 32 to an individual in need thereof, wherein the disease or condition is a Gaucher disease, Fabry disease, Sandhoff disease, Tay-Sachs disease, Parkinson's disease, type 2 diabetes, hypertrophy or hyperplasia associated with diabetic neuropathy, an elevated plasma TNF-α level, an elevated blood glucose level, an elevated glycated hemoglobin level, a glomerular disease, or lupus.

### Claim 35

(canceled)

### Claim 36 (depends on 32)

A method of inhibiting glucosylceramide synthase or lowering a glycosphinolipid concentration in an individual in need thereof comprising administering a therapeutically effective amount of a compound of claim 32 to the individual.