# US 10,501,424 B2 · 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

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- Number: US 10,501,424 B2
- Document ID: US10501424B2
- Status: Granted
- Kind: B2
- Application number: 16/222,871
- Filed: 2018-12-17
- Published: 2019-04-25
- Granted: 2019-12-10
- Earliest claimed: 2015-02-02
- Assignees: FORMA Therapeutics, Inc.
- Applicants: FORMA Therapeutics, Inc.
- Inventors: Xiaozhang Zheng; Pui Yee Ng; Bingsong Han; Jennifer R. Thomason; Mary-Margaret Zablocki; Cuixian Liu; Aleksandra Rudnitskaya; David R. Lancia, Jr.; David S. Millan; Matthew W. Martin
- Web page: https://patentgrep.com/patent/US10501424B2

## CPC

- C07D 267/14: condensed with one six-membered ring
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 243/14: 1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D 267/12: condensed with carbocyclic rings or ring systems
- C07D 291/08: condensed with carbocyclic rings or ring systems
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/08: linked by a carbon chain containing alicyclic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 493/08: Bridged systems
- C07D 495/10: Spiro-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 498/08: Bridged systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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 Formula I: where R, L, X1, X2, X3, X4, Y1, Y2, Y3, and Y4 are described herein.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X1 is NR3;
X2 and X4 are each CR1R2;
X3 is CR1′R2′;
Y1 and Y4 are not bonded to —C(O)NHOH and are each CR1;
Y2 and Y3 are each CR1 when not bonded to —C(O)NHOH and Y2 and Y3 are C when bonded to —C(O)NHOH;
L is selected from the group consisting of a bond, —(CR1R2)n—, —C(O)O—, —C(O)NR3—, —S(O)2—, —S(O)2NR3—, —S(O)—, and —S(O)NR3—, wherein L is bound to the ring nitrogen through the carbonyl or sulfonyl group;
R is independently selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C4-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, —C5-C12 spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —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, heterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;
each R1 and R2 are independently, and at each occurrence, selected from the group consisting of —H, —R3, —R4, —C1-C6 alkyl, —C2-C6 alkenyl, —C4-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, —OH, halogen, —NO2, —CN, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)2R5, —S(O)2(C1-C6 alkyl), —(C1-C6 alkyl)S(O)2R5, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), and —(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, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;
R1′ and R2′ are independently, and at each occurrence, selected from the group consisting of H, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO2, oxo, —CN, —R3, —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, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein at least one of R1′ or R2′ is not H;
R3 and R4 are independently, and at each occurrence, selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C4-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, —S(O)2N(C1-C6 alkyl)2, —S(O)2(C1-C6 alkyl), —(C1-C6 alkyl)S(O)2R5, —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, and —(CHR5)nN(C1-C6 alkyl)2, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of —OH, halogen, —NO2, oxo, —CN, —R5, —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —S(O)2NH(C1-C6 alkyl), —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), —S(O)R5, —S(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)R5, heterocyclyl, aryl, and heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O;
or R3 and R can combine with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each heterocycle or heteroaryl is optionally substituted with —R4, —OR4, or —NR4R5;
R5 is independently, and at each occurrence, selected from the group consisting of —H, —C1-C6 alkyl, —C2-C6 alkenyl, —C4-C8 cycloalkenyl, —C2-C6 alkynyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, —OH, halogen, —NO2, —CN, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —S(O)2NH(C1-C6 alkyl), —S(O)2N(C1-C6 alkyl)2, —S(O)2(C1-C6 alkyl), —C(O)C1-C6 alkyl, —CO2C1-C6 alkyl, —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —S(O)(C1-C6 alkyl), —S(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)(C1-C6 alkyl) and —(CH2)nN(C1-C6 alkyl)2; and
each n is independently and at each occurrence an integer from 0 to 6.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

The compound of claim 2, wherein the compound is of the Formula IA-11:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 4)

The compound of claim 4, wherein the compound is of the Formula IB-5:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The compound of claim 1, wherein one of R1′ and R2′ is H and the other of R1′ and R2′ is optionally substituted aryl or optionally substituted heteroaryl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein the R3 and R combine with the nitrogen atom to which they are attached to form an optionally substituted heterocycle.

### Claim 9 (depends on 8)

The compound of claim 8, wherein one of R1′ and R2′is H and the other of R1′ and R2′ is optionally substituted aryl.

### Claim 10 (depends on 8)

The compound of claim 8, wherein one of R1′ and R2′ is H and the other of R1′ and R2′ is optionally substituted heteroaryl.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 11)

The compound of claim 11, wherein one of R′ and R2′ is H and the other of R1′ and R2′ is optionally substituted aryl or optionally substituted heteroaryl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R is an optionally substituted group selected from the group consisting of —C1-C6 alkyl, —C3-C8 cycloalkyl, heterocyclyl, aryl, and heteroaryl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R is —C1-C6 alkyl substituted with an optionally substituted group selected from the group consisting of aryl, heteroaryl, and —C3-C8 cycloalkyl.

### Claim 15 (depends on 14)

The compound of claim 14, wherein one of R′ and R2′ is H and the other of R1′ and R2′ is optionally substituted aryl.

### Claim 16 (depends on 14)

The compound of claim 14, wherein one of R1′ and R2′ is H and the other of R1′ and R2′ is optionally substituted heteroaryl.

### Claim 17 (depends on 1)

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