# US 2014/0155439 A1 · Enzyme inhibitors

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- Number: US 2014/0155439 A1
- Document ID: US20140155439A1
- Status: Published application
- Kind: A1
- Application number: 14/175,072
- Filed: 2014-02-07
- Published: 2014-06-05
- Earliest claimed: 2009-02-27
- Assignees: Chroma Therapeutics Ltd.
- Inventors: Alastair David Graham Donald; David Festus Charles Moffat; Andrew James Belfield; Carl Leslie North; Stewart Andrew Wayne Jones
- Web page: https://patentgrep.com/patent/US20140155439A1

## CPC

- C07C 237/20: the carbon skeleton containing six-membered aromatic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/10: of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- 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 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- 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
- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 213/56: Amides
- C07D 213/58: Amidines
- C07C 2601/08: the ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of formula (I), inhibit HDAC activity: wherein A, B and D independently represent ═CH— or ═N—; W is —CH═CH— Or —CH2CH2—; R1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R2 and R3 are selected from the side chains of a natural or non-natural alpha amino acid, provided that neither R2 nor R3 is hydrogen, or R2 and R3, taken together with the carbon to which they are attached, form a 3-6 membered saturated cycloalkyl or heterocyclyl ring; Y is a bond, —C(C═O)—, —S(═O)2—, —C(C═O)O—, —C(C═O)NR′—, —C(═S)—NR′, —C(═NH)NR′ or —S(═O)2NR— wherein R′ is hydrogen or optionally substituted C1-C6 alkyl; L1 is a divalent radical of formula -(Alk1)m(Q)(Alk2)p— wherein in, n, p, Q, AIk1 and AIk2 are as defined in the claims; X1 represents a bond; —C(═O); or —S(═O)2—; —NR4C(═O)—, —C(C═O)NR4—, —NR4C(═O)NR5—, —NR4S(═O)2—, or —S(═O)2NR4— wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; and z is 0 or 1.

## Claims

### Claim 1

A compound of formula (I):
wherein
A, B and D independently represent ═CH— or ═N—;
W is —CH═CH— or CH2CH2—;
R1 is a carboxylic acid group (—COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group;
R2 and R3 are selected from the side chains of a natural or non-natural alpha amino acid, provided that neither R2 nor R3 is hydrogen, or R2 and R3, taken together with the carbon to which they are attached, form a 3-6 membered saturated cycloalkyl or heterocyclyl ring;
Y is a bond, —C(═O)—, —S(═O)2—, —C(C═O)O—, —C(C═O)NR′—, —C(═S)—NR′, —C(═NH)NR′ or —S(═O)2NR′— wherein R′ is hydrogen or optionally substituted C1-C6 alkyl;
L1 is a divalent radical of formula -(Alk1)m-(Q)n(Alk2)p- wherein
m, n and p are independently 0 or 1,
Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X2-Q1- or -Q1-X2— wherein X2 is —O—, —S— or NRA— wherein RA is hydrogen or optionally substituted C1-C3 alkyl, and Q1 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members,
Alk1 and Alk2 independently represent optionally substituted divalent C3-C7 cycloalkyl radicals, or optionally substituted straight or branched, —C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals which may optionally contain or terminate in an ether (—O—), thioether (—S—) or amino (NRA-) link wherein RA is hydrogen or optionally substituted C1-C3 alkyl;
X1 represents a bond; —C(C═O); or —S(═O)2—; NR4C(═O)—, —C(C═O)NR4—, —NR4C(═O)NR5—, —NR4S(═O)2—, or —S(═O)2NR4— wherein R4 and R5 are independently hydrogen or optionally substituted C1-C6 alkyl; and
z is 0 or 1.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein A, B and D are each ═CH—.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein one of A, B and D is ═N— and the others are each ═CH—.

### Claim 4

A compound as claimed in any of the preceding claims wherein the radical HONHC(═O)—W— is attached to the ring containing A, B and C in a position meta- or para- to the radical R1R2R3C-NHYL1X1[CH2]z—.

### Claim 5

A compound as claimed in any of the preceding claims wherein, in the radical R1R2R3C-NHYL1X1[CH2]—, z is 0.

### Claim 6

A compound as claimed in any of the preceding claims wherein, in the radical R1R2R3C-NHYL1X1[CH2]z—, Y is a bond.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

A compound as claimed in any of claims 1 to 6 wherein, in the radical R1R2R3C-NHYL1X1[CH2]z—, X1 is a bond.

### Claim 8 (depends on 1, 2, 3, 4)

A compound as claimed in any of claims 1 to 4 wherein, in the radical R1R2R3C-NHYL1X1[CH2]z—, z is 0, Y and X1 are each a bond, and Cis a divalent radical of formula -(Alk1)m(Q)n(Alk2)p- wherein one of m and p is 0 and the other is 1, and n is 0

### Claim 9 (depends on 1, 2, 3, 4)

A compound as claimed in any of claims 1 to 4 wherein the radical -YL1X1[CH2]z— is —CH2—.

### Claim 10

A compound as claimed in any of the preceding claims wherein R1 is an ester group of formula R12OC(═O)— wherein R12 is R7R8CR9— wherein
(i) R7 is hydrogen or optionally substituted (C1-C3)alkyl-(Z1)a-[(C1-C3)alkyl]b- or (C2-C3)alkenyl-(Z1)a—[(C1-C3)alkyl]b- wherein a and b are independently 0 or 1 and Z1 is —O—, —S—, or —NR13— wherein R13 is hydrogen or (C1-C3)alkyl; and R8 and R9 are independently hydrogen or (C1-C3)alkyl-; or
(ii) R7 is hydrogen or optionally substituted R14R15N—(C1-C3)alkyl- wherein R14 is hydrogen or (C1-C3)alkyl and R15 is hydrogen or (C1-C3)alkyl; or R14 and R15 together with the nitrogen to which they are attached form an optionally substituted monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R8 and R9 are independently hydrogen or (C1-C3)alkyl-; or
(iii) R7 and R8 taken together with the carbon to which they are attached form an optionally substituted monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, or bridged monocyclic carbocyclic ring system of 7 to 10 ring atoms, and R9 is hydrogen,
and wherein in cases (i), (ii) and (iii), “alkyl” includes fluoroalkyl.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

A compound as claimed in any of claims 1 to 10 wherein R1 is an ester group of formula R12OC(═O)— wherein R12 is methyl, trifluoromethyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclopentyl, methyl-substituted cyclopentyl, cyclohexyl, allyl, bicyclo[2.2.1]hept-2-yl, 2,3-dihydro-1H-inden-2-yl, phenyl, benzyl, 2-, 3- or 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl or methoxyethyl.

### Claim 12

A compound as claimed in any of the preceding claims wherein R1 is an ester group of formula R12OC(═O)— wherein R12 is cyclopentyl.

### Claim 13

A compound as claimed in any of the preceding claims wherein one of the substitutents R2 and R3 is a C1-C6 alkyl substituent, and the other is selected from the group consisting of methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, phenyl, benzyl, thienyl, cyclohexyl, and cyclohexylmethyl; or R2 and R3 taken together with the carbon to which they are attached form a 3-6 membered saturated spiro cycloalkyl ring.

### Claim 14

A compound as claimed in any of the preceding claims wherein one of R2 and R3 is methyl or ethyl, and the other is benzyl or C1-C6 alkyl; or R2 and R3 taken together with the carbon to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

### Claim 15

A compound as claimed in any of the preceding claims wherein one of R2 and R3 is methyl and the other is methyl, ethyl, n- or iso-propyl, benzyl or n, sec or tert butyl; or R2 and R3 taken together with the carbon to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

### Claim 16 (depends on 1)

A compound as claimed in claim 1 having formula (IE):
wherein R1, W and B are as defined in claim 1, one of R2 and R3 is methyl, and the other is methyl, ethyl, n- or iso-propyl, benzyl or n, sec or tert butyl; or R2 and R3 taken together with the carbon to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

### Claim 17 (depends on 16)

A compound as claimed in claim 16 wherein R1 is an ester group of formula R12OC(═O)— wherein R12 is cyclopentyl.

### Claim 18 (depends on 16, 17)

A compound as claimed in claim 16 or claim 17 wherein W is CH═CH—.

### Claim 19

A compound as claimed in any of the preceding claims which is in pharmaceutically acceptable salt form.

### Claim 20 (depends on 1)

A compound as claimed in claim 1 selected from the group consisting of:
Cyclopentyl 1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclobutanecarboxylate,
Cyclopentyl 1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclohexanecarboxylate,
Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclobutanecarboxylate,
Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclopentanecarboxylate,
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-2-methyl-D-alaninate,
Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclopropanecarboxylate,
Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclohexanecarboxylate,
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-α-methyl-L-phenylalaninate,
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-2-methyl-D-leucinate,
Cyclopentyl N-{4-[((1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-2-methyl-L-leucinate,
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-L-isovalinate,
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-3-methyl-L-isovalinate,
Cyclopentyl 1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclopentanecarboxylate,
Cyclopentyl 1-({4-[3-(hydroxyamino)-3-oxopropyl]benzyl}amino)cyclopentanecarboxylate,
Cyclopentyl N-{4-[3-(hydroxyamino)-3-oxopropyl]benzyl}-2-methyl-D-alaninate,
Cyclopentyl N-{4-[3-(hydroxyamino)-3-oxopropyl]benzyl}-2-methyl-D,L-leucinate,
Cyclopentyl N-{4-[3-(hydroxyamino)-3-oxopropyl]benzyl}-3-methyl-L-isovalinate,
1-({4-[3-(Hydroxyamino)-3-oxopropyl]benzyl}amino)cyclo pentanecarboxylic acid,
N-{4-[3-(Hydroxyamino)-3-oxopropyl]benzyl}-2-methyl-D,L-leucine,
1-({4-[(1E)-3-(Hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclopentanecarboxylic acid,
1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclopentanecarboxylic acid,
1-[({6-[(1E)-3-(Hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclobutanecarboxylic acid,
t-Butyl 1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]-2-methyl-D-alaninate,
3-Methylcyclopentyl N-({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)-2-methyl-L-alaninate,
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

A compound as claimed in claim 1 selected from the group consisting of:
Cyclopentyl 1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclobutanecarboxylate,
Cyclopentyl 1-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]pyridin-3-yl}methyl)amino]cyclohexanecarboxylate,
Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclobutanecarboxylate,
Cyclopentyl 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}amino)cyclopentanecarboxylate,
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-2-methyl-D-alaninate and
Cyclopentyl N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl]benzyl}-α-methyl-L-phenylalaninate;
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound as claimed in any of the preceding claims wherein R1 is an ester group as defined in claim 1, together with a pharmaceutically acceptable carrier.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)

The use of a compound as claimed in any of claims 1 to 21 wherein R1 is an ester group as defined in claim 1 for, or in the preparation of a medicament for, inhibition of HDAC activity.

### Claim 24 (depends on 23)

The use as claimed in claim 23 wherein the disease is, cell-proliferation disease, polyglutamine disease, neurodegenerative disease, autoimmune disease, inflammatory disease, organ transplant rejection, diabetes, haematological disorders or inflammatory sequelia of infection.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)

A method for the treatment of a disease which responds to inhibition of HDAC activity, which comprises administering to a subject suffering such disease an effective amount of a compound as claimed in any of claims 1 to 21 wherein R1 is an ester group as defined in claim 1.

### Claim 26 (depends on 25)

A method as claimed in claim 25 wherein the disease is transplant rejection, rheumatoid arthritis, psoriatic arthritis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, and inflammation accompanying infectious conditions (e.g., sepsis), psoriasis, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, multiple sclerosis, atopic dermatitis, and graft versus host disease.

### Claim 27 (depends on 23, 24, 25)

The use as claimed in claim 23 or claim 24, or a method as claimed in claim 24 or claim 25 wherein the treatment is of cancer cell proliferation.

### Claim 28 (depends on 23, 24, 25)

The use as claimed in claim 23 or claim 24, or a method as claimed in claim 24 or claim 25 wherein the treatment is of rheumatoid arthritis.