# US 9,750,748 B2 · Pyridazinones as DAAO enzyme inhibitors

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- Number: US 9,750,748 B2
- Document ID: US9750748B2
- Status: Granted
- Kind: B2
- Application number: 14/652,484
- Filed: 2013-12-17
- Published: 2015-11-19
- Granted: 2017-09-05
- Earliest claimed: 2012-12-17
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: William Farnaby; Charlotte Fieldhouse; Katherine Hazel; Catrina Kerr; Natasha Kinsella; David Livermore; Kevin Merchant; David Miller
- Web page: https://patentgrep.com/patent/US9750748B2

## CPC

- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 237/16: Two oxygen atoms
- C07D 237/20: Nitrogen atoms (nitro radicals C07D237/12)
- C07D 237/22: Nitrogen and oxygen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- 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)

## Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1 and R2 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

## Claims

### Claim 1

A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
R1 is chosen from a hydrogen or fluorine atom or a trifluoromethyl group;
R2 is chosen from a C2-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, or —NR3R4 group,
wherein the alkyl, cycloalkyl and tetrahydropyranyl groups are unsubstituted or substituted by at least one substituent chosen from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, difluoromethyl, trifluoromethyl, C1-C6 alkoxy, difluoromethoxy or trifluoromethoxy;
R3 and R4 are each independently chosen from a hydrogen atom or a C1-C6 alkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 8-membered heterocyclic ring, wherein each alkyl group or the heterocyclic ring is unsubstituted or substituted by at least one substituent chosen from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, difluoromethyl, trifluoromethyl, C1-C6 alkoxy, difluoromethoxy or trifluoromethoxy;
with the proviso that the compound of formula (I) is not:
2,3 -dihydro-4-hydroxy-6-morpholinopyridazin-3 -one, or
6-amino-4-hydroxy-pyridazinone.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 represents a hydrogen atom.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 is chosen from a C2-C6 alkyl or C3-C6 cycloalkyl group.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R2 represents a —NR3R4 group, and wherein R3 and R4 are each independently chosen from a hydrogen atom or a C1-C4 alkyl group.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 represents a —NR3R4 group, and wherein R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 6-membered heterocyclic ring.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein the heterocyclic ring is chosen from an azetidinyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, piperazinyl, pyrazolyl, pyrazinyl, imidazolyl, isoxazolyl, triazolyl, tetrazolyl or pyridinyl moiety.

### Claim 7 (depends on 1)

The compound according claim 1, wherein R2 is chosen from a C2-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, or —NR3R4 group,
wherein the alkyl, cycloalkyl and tetrahydropyranyl groups are unsubstituted or substituted by at least one substituent chosen from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl or methoxy;
R3 and R4 are each independently chosen from a hydrogen atom or a C1-C6 alkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 8-membered heterocyclic ring,
wherein each alkyl group or the heterocyclic ring is unsubstituted or substituted by at least one substituent chosen from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl or methoxy.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein
R1represents a hydrogen atom; and
R2 is chosen from a C2-C5 alkyl, C3-C6 cycloalkyl, tetrahydropyranyl, or —NR3R4 group,
wherein R3 and R4 are each independently chosen from a C1-C3 alkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered heterocyclic ring.

### Claim 9 (depends on 1)

The compound according to claim 1 chosen from:
6-Ethyl-4-hydroxypyridazin-3 (2H)-one,
4-Hydroxy-6-(3 -methylbutyl)pyridazin-3 (2H)-one,
6-Cyclopropyl-4-hydroxypyridazin-3 (2H)-one,
4-Hydroxy-6-(tetrahydro-2H-pyran-4-yl)pyridazin-3 (2H)-one,
4-Hydroxy-6-(2-methylpropyl)pyridazin-3 (2H)-one,
6-Cyclopentyl-4-hydroxypyridazin-3(2H)-one,
6-Cyclohexyl-4-hydroxypyridazin-3 (2H)-one,
4-Hydroxy-6-isopropylpyridazin-3 (2H)-one,
6-(Azetidin-1-yl)-4-hydroxypyridazin-3 (2H)-one,
6-(Dimethylamino)-4-hydroxypyridazin-3 (2H)-one,
4-Hydroxy-6-(methyl(propyl)amino)pyridazin-3 (2H)-one,
6-(Ethyl(methyl)amino)-4-hydroxypyridazin-3 (2H)-one,
4-Hydroxy-6-(piperidin-1-yl)pyridazin-3(2H)-one,
6-tert-Butyl-4-hydroxypyridazin-3(2H)-one,
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 2)

The compound according to claim 2, wherein R2 is chosen from a C2-C6 alkyl or C3-C6 cycloalkyl group.

### Claim 11 (depends on 2)

The compound according to claim 2, wherein R2 represents a —NR3R4 group, and wherein R3 and R4 are each independently chosen from a hydrogen atom or a C1-C4 alkyl group.

### Claim 12 (depends on 2)

The compound according to claim 2, wherein R2 represents a —NR3R4 group, and wherein R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 6-membered heterocyclic ring.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein the heterocyclic ring is chosen from an azetidinyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, piperazinyl, pyrazolyl, pyrazinyl, imidazolyl, isoxazolyl, triazolyl, tetrazolyl or pyridinyl moiety.

### Claim 14 (depends on 2)

The compound according claim 2, wherein R2 is chosen from a C2-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, or —NR3R4 group,
wherein the alkyl, cycloalkyl and tetrahydropyranyl groups are unsubstituted or substituted by at least one substituent chosen from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl or methoxy;
R3 and R4 are each independently chosen from a hydrogen atom or a C1-C6 alkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 8-membered heterocyclic ring,
wherein each alkyl group or the heterocyclic ring is unsubstituted or substituted by at least one substituent chosen from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl or methoxy.

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

A combination of the compound according to claim 1 and at least one agent chosen from carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone or lithium.

### Claim 17 (depends on 1)

A process for the preparation of the compound according to claim 1, comprising:
(i) when R2 represents an unsubstituted or substituted C2-C8 alkyl, C3-C8 cycloalkyl or tetrahydropyranyl group, hydrogenating a compound of formula (II)
wherein R2′ represents a moiety of formula (III)
wherein R10 and R11 are each independently chosen from a hydrogen atom or an alkyl group, and wherein the total number of carbon atoms in R10 and R11 taken together is 0 or an integer in the range from 1 to 6, or R10 and R11 together with the carbon atoms to which they are attached form either a 3- to 8-membered cycloalkenyl ring, or, a ring of formula (IV)
wherein the moiety of formula (III) is unsubstituted or substituted with at least one substituent chosen from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, difluoromethyl, trifluoromethyl, C1-C6 alkoxy, difluoromethoxy or trifluoromethoxy; or
(ii) when R2 represents a group —NR3R4, reacting a compound of formula (V)
wherein Hal represents a halogen atom, with a compound of formula (VI), HNR3R4, wherein R3 and R4 are each independently chosen from a hydrogen atom or a C1-C6 alkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated 4-to 8-membered heterocyclic ring, wherein each alkyl group or the heterocyclic ring is unsubstituted or substituted by at least one substituent chosen from halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, difluoromethyl, trifluoromethyl, C1-C6 alkoxy, difluoromethoxy or trifluoromethoxy;
and optionally thereafter carrying out at least one of the following procedures:
converting the compound according to claim 1 into another compound according to claim 1;
removing any protecting groups; or
forming a pharmaceutically acceptable salt.

### Claim 18 (depends on 1)

A method of treating schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound according to claim 1.