# US 10,870,645 B2 · Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors

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- Number: US 10,870,645 B2
- Document ID: US10870645B2
- Status: Granted
- Kind: B2
- Application number: 16/522,082
- Filed: 2019-07-25
- Published: 2019-11-14
- Granted: 2020-12-22
- Earliest claimed: 2015-02-02
- Assignees: Valo Early Discovery, Inc.
- Applicants: Valo Early Discovery, Inc.
- Inventors: Xiaozhang Zheng; Pui Yee Ng; Aleksandra Rudnitskaya; David R. Lancia, Jr.
- Web page: https://patentgrep.com/patent/US10870645B2

## CPC

- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 267/22: Eight-membered rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with HDAC6, having a Formulae I or Formula II: where R, L, X1, X2, X3, X4, X5, Y1, Y2, Y3, and Y4 are described herein.

## Claims

### Claim 1

A compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
X1 is O;
X2, X3, X4 and X5 are each CR1R2;
Y1 and Y4 are each independently N or CR1;
one of Y2 and Y3 is C bonded to C(O)NHOH and the other of Y2 and Y3 is N or CR1;
L is a bond, —(CR1R2)n—, —C(O)—, —C(O)O—, —C(O)NR3—, —S(O)2—, —S(O)2NR3—, —S(O)—, —S(O)NR3—, —C(O)(CR1R2)nO—, or —C(O)(CR1R2)n—;
R is independently, and at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —C5-C12spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO2, —CN, —R1, —R2, —OR3, —NHR3, —NR3R4, —S(O)2NR3R4, —S(O)2R1, —C(O)R1, —CO2R1, —NR3S(O)2R1, —S(O)R1, —S(O)NR3R4, —NR3S(O)R1, heterocycle, aryl, or heteroaryl, with the proviso that when L is —C(O)— the spiroheterocyclyl is not bound to L via a nitrogen atom;
R1 and R2 are independently, and at each occurrence, —H, R3, R4, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, —OH, halogen, —NO2, —CN, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —S(O)2N(C1-C6alkyl)2, —N(C1C6alkyl)S(O)2R5, —S(O)2(C1-C6alkyl), —(C1-C6alkyl)S(O)2R5, —C(O)C1-C6alkyl, —N(C1-C6alkyl)S(O)2(C1-C6alkyl), or —(CHR5)nNR3R4, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO2, oxo, —CN, —R5, —OR3, —NHR3, —NR3R4, —S(O)2N(R3)2, —S(O)2R5, —C(O)R5, —CO2R5, —NR3S(O)2R5, —S(O)R5, —S(O)NR3R4, —NR3S(O)R5, heterocyclyl, aryl, or heteroaryl;
R3 and R4 are independently, and at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, —S(O)2N(C1-C6alkyl)2, —S(O)2(C1-C6alkyl), —(C1-C6alkyl)S(O)2R5, —C(O)C1-C6alkyl, —CO2C1-C6alkyl, or —(CHR5)nN(C1-C6alkyl)2, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO2, oxo, —CN, —R5, —O(C1-C6)alkyl, —NH(C1-C6alkyl), N(C1-C6alkly)2, —S(O)2N(C1-C6alkyl)2, —S(O)2NH(C1-C6alkyl), —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2C1-C6alkyl, —S(O)R5, —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)R5, heterocycle, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O;
R5 is independently, and at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C3-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, —OH, halogen, —NO2, —CN, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —S(O)2NH(C1-C6alkyl), —S(O)2N(C1-C6alkyl)2, —S(O)2(C1-C6alkyl), —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)SO2(C1-C6alkyl), —S(O)(C1-C6alkyl), —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)(C1-C6alkyl) or (CH2)nN(C1-C6alkyl)2; and
n is independently and at each occurrence an integer from 0 to 6.

### Claim 2 (depends on 1)

The compound of claim 1, wherein L is CH2.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R is —C3-C8cycloalkyl, heterocyclyl, or aryl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L is —C(O)—.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R is —C3-C8cycloalkyl, heterocyclyl, or aryl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein L is a bond.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R is —C3-C8cycloalkyl, heterocyclyl, or aryl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein L is —S(O)2—.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R is —C3-C8cycloalkyl, heterocyclyl, or aryl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein L is —C(O)NR3—.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R3 is —H.

### Claim 12 (depends on 10)

The compound of claim 10, wherein R is —C3-C8cycloalkyl, heterocyclyl, or aryl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein each R1 and R2 is —H.

### Claim 14 (depends on 1)

The compound of claim 1 wherein the compound is of Formula IIA:

### Claim 15 (depends on 1)

The compound of claim 1 wherein the compound is of Formula II-B:

### Claim 16 (depends on 1)

The compound of claim 1 selected from:
N-hydroxy-4-phenyl-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;
4-benzyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;
4-benzoyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;
4-(cyclohexanecarbonyl)-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;
N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;
N-hydroxy-4-(phenylsulfonyl)-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-9-carboxamide;
N9-hydroxy-N4-phenyl-2,3,5,6-tetrahydro-4H-benzo[g][1,4]oxazocine-4,9-dicarboxamide;
N-hydroxy-4-phenyl-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;
4-benzyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;
4-benzoyl-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;
4-(cyclohexanecarbonyl)-N-hydroxy-3,4,5,6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide;
N-hydroxy-4-(tetrahydro-2H-pyran-4-carbonyl)-3 ,4, 5 ,6-tetrahydro-2H-benzo [g][1,4]oxazocine-8-carboxamide;
N-hydroxy-4-(phenyl sulfonyl)-3 ,4, 5, 6-tetrahydro-2H-benzo[g][1,4]oxazocine-8-carboxamide; and
N8-hydroxy-N4-phenyl-2,3,5,6-tetrahydro-4H-benzo[g][1,4]oxazocine-4,8-dicarboxamide.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.