# US 12,213,969 B2 · 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors

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

- Number: US 12,213,969 B2
- Document ID: US12213969B2
- Status: Granted
- Kind: B2
- Application number: 18/215,887
- Filed: 2023-06-29
- Published: 2023-12-28
- Granted: 2025-02-04
- Earliest claimed: 2016-06-17
- Assignees: Valo Health, Inc.
- Applicants: Valo Health, Inc.
- Inventors: Xiaozhang Zheng; Pui Yee Ng; Mary-Margaret Zablocki
- Web page: https://patentgrep.com/patent/US12213969B2

## CPC

- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 209/54: Spiro-condensed
- C07D 221/20: Spiro-condensed ring systems
- 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
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention is directed to inhibitors of histone deacetylases (HDACs) such as HDAC6, and their use in the treatment of diseases such as cell proliferative diseases (e.g., cancer), neurological (e.g., neurodegenerative disease or neurodevelopmental disease), inflammatory or autoimmune disease, infection, metabolic disease, hematologic disease, or cardiovascular disease.

## Claims

### Claim 1

A compound of the Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X1, X2, X3, X4, X5, and X6 are each independently, at each occurrence, —CR1R2—, —NR3—, —O—, —C(O)—, —S(O)2—, —S(O)—, or —S—;
Y1, Y2, Y3 and Y4 are each independently, at each occurrence, N or CR1, wherein —C(O)NHOH is attached at Y2 or Y3, and Y2 or Y3 is a carbon atom when attached to —C(O)NHOH;
L is a bond, —(CR1R2)p—, —C(O)NR3—, —S(O)2—, —S(O)2NR3—, —S(O)—, —S(O)NR3—, —C(O)(CR1R2)pO—, or —C(O)(CR1R2)p—;
R is —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —C5-C12spirocycloalkyl, 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, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO2, —CN, —R1, —R2, —SR3, —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, heterocyclyl, aryl, or heteroaryl;
R1 and R2 are independently, 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 and O, —OH, halogen, —NO2, —CN, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —S(O)2N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)2R5, —S(O)2(C1-C6alkyl), —(C1-C6alkyl)S(O)2R5, —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2(C1-C6alkyl), or —(CHR5)pNR3R4, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —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;
or R1 and R2, when on the same atom, can combine with the carbon atom to which they are both attached to form a cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, or spirocycloalkenyl;
or R1 and R2, when on adjacent or non-adjacent atoms, can combine to form a heterocyclyl, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or cycloalkenyl;
R3 and R4 are independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P, and 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)pN(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-C6alkyl)2, —S(O)2N(C1-C6alkyl)2, —S(O)2NH(C1-C6alkyl), —C(O)C1-C6alkyl, —CO2C1-C6alkyl, —N(C1-C6alkyl)S(O)2(C1-C6alkyl), —S(O)R5, —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)R5, heterocyclyl, aryl, or heteroaryl;
R5 is independently, at each occurrence, —H, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH, halogen, —NO2, —CN, —NHC1-C6(alkyl), —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)S(O)2(C1-C6alkyl), —S(O)(C1-C6alkyl), —S(O)N(C1-C6alkyl)2, —N(C1-C6alkyl)S(O)(C1-C6alkyl) or —(CH2)pN(C1-C6alkyl)2;
p is 0, 1, 2, 3, 4, 5, or 6;
n is 0, 1, 2, 3, or 4;
m is 0, 1, or 2; and
wherein the sum m+n is 4.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is 2.

### Claim 3 (depends on 1)

The compound of claim 1, wherein m is 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein m is 0.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X1 is —CH2— and X2 is —CH2—.

### Claim 6 (depends on 1)

The compound of claim 1, wherein X5 is C(O).

### Claim 7 (depends on 5)

The compound of claim 5, wherein Y1 and Y4 are each CR1, wherein —C(O)NHOH is attached at Y2 or Y3, and Y2 or Y3 is a carbon atom when attached to —C(O)NHOH.

### Claim 8 (depends on 7)

The compound of claim 7, wherein L is a bond, —(CR1R2)p—, or —C(O)(CR1R2)p—.

### Claim 9 (depends on 8)

The compound of claim 8, wherein p is 0 or 1.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R is —H or an optionally substituted group selected from —C1-C6alkyl, aryl, and heteroaryl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R is an optionally substituted group selected from aryl or heteroaryl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula IA:
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 7)

The compound of claim 7, wherein n is 2.

### Claim 14 (depends on 7)

The compound of claim 7, wherein m is 1.

### Claim 15 (depends on 7)

The compound of claim 7, wherein m is 0.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula IB:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The compound of claim 16, wherein n is 2.

### Claim 18 (depends on 16)

The compound of claim 16, wherein m is 1.

### Claim 19 (depends on 16)

The compound of claim 16, wherein m is 0.

### Claim 20 (depends on 1)

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