# US 12,180,205 B2 · O-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors

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- Number: US 12,180,205 B2
- Document ID: US12180205B2
- Status: Granted
- Kind: B2
- Application number: 17/276,502
- Filed: 2019-09-18
- Published: 2022-02-10
- Granted: 2024-12-31
- Earliest claimed: 2018-09-19
- Assignees: Biogen MA Inc.
- Applicants: Biogen Ma Inc.
- Inventors: Nathan Genung; Kevin M. Guckian; Jeffrey Vessels; Lei Zhang; Ryan Gianatassio; Edward Yin Shiang Lin; Zhili Xin
- Web page: https://patentgrep.com/patent/US12180205B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 35/00: Antineoplastic agents
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Described herein are compounds represented by formulas (IA) or (IB) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same and methods of preparing and using the same. The variables R1, R3, R4, Y1, Y2, Ar, Z and n are as defined herein.

## Claims

### Claim 1

A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl;
n is 0, 1, or 2; and
when n is other than 0, R1, for each occurrence, is independently halo or C1-C4 alkyl.

### Claim 2

A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl;
n is 0, 1, or 2; and
when n is other than 0, R1, for each occurrence, is independently halo or C1-C4 alkyl.

### Claim 3 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ar is an optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.

### Claim 4 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ar is optionally substituted with one or more groups selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, —CN, —NO2, —ORz, —NRxRy, —S(O)iRx, —NRxS(O)iRy, —S(O)iNRxRy, —C(═O)ORx, —OC(═O)ORx, —C(═S)ORx, —O(C═S)Rx, —C(═O)NRxRy, —NRxC(═O)Ry, —C(═S)NRxRy, —NRxC(═S)Ry, —NRx(C═O)ORy, —O(C═O)NRxRy, —NRx(C═S)ORy, —O(C═S)NRxRy, —NRx(C═O)NRxRy, —NRx(C═S)NRxRy, —C(═S)Rx, —C(═O)Rx, phenyl and monocyclic heteroaryl;
wherein
the C1-C4 alkyl group substituent on Ar is optionally substituted with —CN, —NO2, —ORz, —NRxRy, —S(O)iRx, —NRxS(O)iRy, —S(O)iNRxRy, —C(═O)ORx, —OC(═O)ORx, —C(═S)ORx, —O(C═S)Rx, —C(═O)NRxRy, —NRxC(═O)Ry, —C(═S)NRxRy—NRxC(═S)Ry, —NRx(C═O)ORy, —O(C═O)NRxRy, —NRx(C═S)ORy, —O(C═S)NRxRy, —NRx(C═O)NRxRy, —NRx(C═S)NRxRy, —C(═S)Rx, —C(═O)Ry, C3-C6 cycloalkyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy) or phenyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy);
the C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl and monocyclic heteroaryl group substituent on Ar are optionally and independently substituted with C1-C4 alkyl, C1-C4 haloalkyl, halo, —CN, —NO2, —ORz, —NRxRy, —S(O)iRx, —NRxS(O)iRy, —S(O)iNRxRy, —C(═O)ORx, —OC(═O)ORx, —C(═S)ORx, —O(C═S)Ry, —C(═O)NRxRy, —NRxC(═O)Ry, —C(═S)NRxRy, —NRxC(═S)Ry, —NRx(C═O)ORy, —O(C═O)NRxRy, —NRx(C═S)ORy, —O(C═S)NRxRy, —NRx(C═O)NRxRy, —NRx(C═S)NRxRy, —C(═S)Rx, or —C(═O)Rx;
each Rx and each Ry is independently —H, C1-C4 alkyl, or C3-C8 cycloalkyl; wherein the C1-C4 alkyl or C3-C8 cycloalkyl represented by Rx or Ry is optionally substituted with one or more substituents selected from halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy);
Rz is —H, C1-C4 alkyl, C3-C8 cycloalkyl, or C3-C8 heterocyclyl; wherein the C1-C4 alkyl, C3-C8 cycloalkyl, or C3-C8 heterocyclyl group represented by Rz is optionally substituted with one or more substituents selected from —CN, halo, hydroxyl, C1-C4alkyl, C1-C4alkoxy, C3-C6 cycloalkyl and phenyl (optionally substituted with one or more groups selected from —CH3, halomethyl, halo, methoxy and halomethoxy); and
i is 0, 1, or 2.

### Claim 5 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ar is optionally substituted with one or more groups selected from optionally substituted C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, halo, —CN, —ORz, —NRxRy, —C(═O)NRxRy, —C(═S)NRxRy, —O(C═O)NRxRy, —O(C═S)NRxRy, —C(═O)Rx, —C(═O)ORx, —NRxC(═O)Ry, phenyl and optionally substituted monocyclic heteroaryl.

### Claim 6 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ar is optionally substituted with one or more groups selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, —CN, and —ORz; wherein Rz is C1-C4 alkyl optionally substituted with one or more halo groups.

### Claim 7 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ar is
each of which is optionally substituted with one substituent RAr selected from selected from C1-C4 alkyl, C1-C4 haloalkyl, halo, —CN, and —ORz; Rz is H, C1-C4 alkyl, C3-C8 cycloalkyl or C3-C6 heterocyclyl, wherein the C1-C4 alkyl, C3-C8 cycloalkyl and C3-C6 heterocyclyl represented by Rz are each optionally and independently substituted with one or more substituents independently selected from halo, —CN, C1-C4 alkyl and C1-C4 alkoxy.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein the compound is selected from
N-(4-fluoro-5-(((2S,4R)-4-((6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((6-(azetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-(3-fluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((2,6-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((6-acetylpyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((5-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((4-methoxypyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-2-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((3-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((5-chloropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((4-fluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((2-fluoropyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((2-methoxypyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((4-chloropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((4,5-difluoropyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-morpholinopyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-methoxypyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((3,5-dimethylpyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((2,5-dimethylpyridin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-hydroxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((2-methylpyridin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-fluoropyridazin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-fluoropyrimidin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((5-(difluoromethyl)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((6-methoxypyridin-3-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methylpyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-fluoro-4-methoxypyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-(pyrimidin-5-yloxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-(((2S,4R)-4-((6-chloropyrimidin-4-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)-4-fluorothiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((6-((1-methylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyrazin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyrazin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((4-((2-methoxyethyl(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-morpholinopyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((4-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-(4-fluorophenoxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-(2-methoxyethoxy)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-4-((5-((2-methoxyethyl(methyl)amino)pyridin-2-yl)oxy)-2-methylpyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(4-fluoro-5-(((2S,4R)-2-methyl-4-((4-(4-methylpiperazin-1-yl)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)thiazol-2-yl)acetamide;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

### Claim 11 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted
optionally substituted
optionally substituted
optionally substituted N
optionally substituted
or optionally substituted

### Claim 12 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted
optionally substituted,
optionally substituted
optionally substituted
optionally substituted
or optionally substituted

### Claim 13 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted
optionally substituted
or optionally substituted

### Claim 14 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted
optionally substituted
or optionally substituted

### Claim 15 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from optionally substituted C1-C4 alkyl, C1-C4 haloalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, halo, —CN, —ORz, —NRxRy, —C(═O)NRxRy, —C(═S)NRxRy, —O(C═O)NRxRy, —O(C═S)NRxRy, —C(═O)Rx, —C(═O)ORx, —NRxC(═O)Ry, phenyl and optionally substituted monocyclic heteroaryl.

### Claim 16 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from —CH3, —CF3, —CHF2, —F, —Cl, —CN, —OCH3, —OCHF2, —OC2H5, —OCH2CF3, —O(CH2)2(O)CH3, —OCH(CH3)2, —O-(3-methoxycyclobutyl), —O-cyclobutyl, —O-cyclopentyl,
—COCH3, —N(H)CH3, —N(CH3)C2H5, —N(H)cyclobutyl, —NHCH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH3)(CH2CH2(O)CH3), —OH, azetidinyl,
oxetanyl, pyrrolidinyl, morpholinyl, 4-methylpiperazinyl, and piperazinyl.

### Claim 17 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from —CH3, —CF3, —CHF2, —F, —Cl, —CN, —OCH3, —OCHF2, —OC2H5, —OCH2CF3, —O(CH2)2(O)CH3, —OCH(CH3)2, —O-(3-methoxycyclobutyl), —O-cyclobutyl, —O-cyclopentyl,
—COCH3, —N(H)CH3, —N(CH3)C2H5, —N(H)cyclobutyl, —NHCH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH3)(CH2CH2(O)CH3), —OH, azetidinyl,
oxetanyl, pyrrolidinyl, morpholinyl, 4-methylpiperazinyl, and piperazinyl.

### Claim 18 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from —CH3, —CF3, —CHF2, —F, —Cl, —CN, —OCH3, —O(CH2)2(O)CH3, and —OCHF2.

### Claim 19 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from —CH3, —CF3, —CHF2, —F, —Cl, —CN, —OCH3, —O(CH2)2(O)CH3, and —OCHF2.

### Claim 20 (depends on 8)

The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein Ar is represented by the following formula: