NZ620239B2 - Pyridazinone compounds and their use as daao inhibitors - Google Patents

Pyridazinone compounds and their use as daao inhibitors Download PDF

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NZ620239B2
NZ620239B2 NZ620239A NZ62023912A NZ620239B2 NZ 620239 B2 NZ620239 B2 NZ 620239B2 NZ 620239 A NZ620239 A NZ 620239A NZ 62023912 A NZ62023912 A NZ 62023912A NZ 620239 B2 NZ620239 B2 NZ 620239B2
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New Zealand
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formula
ethyl
hydroxypyridazin
compound
hydroxy
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NZ620239A
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NZ620239A (en
Inventor
William Farnaby
Charlotte Fieldhouse
Katherine Hazel
Catrina Kerr
Natasha Kinsella
David Livermore
Kevin Merchant
David Miller
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Takeda Pharmaceutical Company Limited
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Priority claimed from GBGB1114399.7A external-priority patent/GB201114399D0/en
Priority claimed from GB201118658A external-priority patent/GB201118658D0/en
Priority claimed from GBGB1203533.3A external-priority patent/GB201203533D0/en
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Priority claimed from PCT/GB2012/000672 external-priority patent/WO2013027000A1/en
Publication of NZ620239A publication Critical patent/NZ620239A/en
Publication of NZ620239B2 publication Critical patent/NZ620239B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Abstract

Provided are pyridazinone derivative compounds, of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 4-Hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one and 6-{2-[3-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one. The compounds are inhibitors of D-amino acid oxidase enzyme (DAAO). The compounds may be useful in the treatment of schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain. -one. The compounds are inhibitors of D-amino acid oxidase enzyme (DAAO). The compounds may be useful in the treatment of schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain.

Description

PYRIDAZINONE COMPOUNDS AND THEIR USE AS DAAO INHIBITORS The t invention relates generally to pyridazinone derivatives, processes for their preparation, and pharmaceutical compositions containing them. Also described herein is the use of such compounds in therapy, particularly in the treatment or prevention of conditions having an association with the D-amino acid oxidase enzyme (DAAO).
The hyper-dopaminergic theory has driven phrenia drug ery for decades and has produced notable drugs such as clozapine and pine. Although these medicaments can be highly efficacious against the positive symptoms of phrenia and have significantly benefited many patients they are not the complete answer, with fewer or no effects against the ve and cognitive aspects of the disease and with undesired side effect es in some cases. Amongst alternative hypotheses the hyperglutamatergic theory has much merit with the first real evidence coming from the use of PCP (phencyclidine), MK801 or ketamine, direct N-methyl-D-aspartate (NMDA)- receptor antagonists that are able to produce schizophrenia-like symptomatology in healthy human eers or exacerbate the clinical signs in schizophrenia patients.
However, direct modulation of the NMDA receptor using agonists has not proved successful with excitotoxicity (excessive stimulation by the neurotransmitter) leading to undesirable side effects. An alternative approach is to target the co-agonists required for NMDA receptor activation. These are glycine and serine (D-SER). Attempts to enhance NMDA receptor activity through the use of glycine transporter inhibitors have produced clinical nds (but no marketed drugs to-date). D-SER is a co-agonist with even greater potency than glycine and so tion of D-SER may represent an alternative strategy. One way to increase levels of D-SER is to reduce the activity of DAAO, the enzyme which removes it from the synaptic cleft.
DAAO enzyme inhibitors are known in the art. For e, Adage et al., European Neuropsychopharmacology 2008 , 18 , 4 have described AS-057278, a small molecule DAAO enzyme inhibitor. Likewise, Sparey et al., Bioorganic & Medicinal Chemistry Letters, 2008 , 18 , 3386–3391 have demonstrated that molecules containing small heterocyclic rings hed with a carboxylic acid group can inhibit the DAAO enzyme. DAAO inhibitors which avoid the carboxylic acid group have been described by Ferraris et al., J. Med. Chem. 2008, 51, 3357–3359 and by Duplantier et al., J. Med.
Chem. 2009, 52, 3576–3585. A further series of carboxylic acid-containing DAAO enzyme inhibitors from Sepracore are described in .
We have now ered a new class of compounds that are DAAO enzyme inhibitors which have ble activity profiles. The compounds of this invention have beneficial potency, selectivity and/or pharmacokinetic properties and/or at least provide the public with a useful choice.
In one aspect, the present invention relates to a compound of formula (I) wherein R represents a hydrogen or fluorine atom or a trifluoromethyl group; 2 3 R represents a group –X-Y-R ; X and Y each independently represent a bond, an oxygen atom or a group -C(O), 4 4, -S(O)n, -C(O)NR , NR -NR4, , or 4 5 -CR R -, provided that X and Y cannot both simultaneously ent a bond and provided that if X and Y are both other than a bond, then at least one of X and Y 4 5 represents -CR R -; n is 0, 1 or 2; each R independently represents a hydrogen atom or a C1-C6 alkyl or C1-C6 haloalkyl group; each R independently ents a hydrogen atom, a C1-C6 alkyl or C1-C6 haloalkyl group or =CH-; R represents a 3- to 10-membered saturated or rated carbocyclic or heterocyclic ring system, the ring system itself being optionally substituted by at least one substituent selected from halogen, hydroxyl, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylsulphinyl, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxycarbonyl, amino (-NH2), -CON(R )2, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, C3-C6 lkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylmethyl, -[O]p-(CH 2)q-O-R and a 4- to ered saturated or unsaturated heterocyclic ring (optionally substituted with at least one substituent selected from C1-C4 alkyl and C1-C4 alkoxy); each R independently represents a hydrogen atom or a C1-C6 alkyl group; p is 0 or 1; q is 1, 2, 3 or 4; and R represents a C1-C6 alkyl group; or a pharmaceutically acceptable salt thereof.
In r aspect the present invention relates to a pharmaceutical composition comprising a nd of the invention a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
In another aspect the present invention relates to a compound of the invention or a pharmaceutically acceptable salt thereof for use in treating a condition whose development or symptoms are linked to D-amino acid oxidase (DAAO) enzyme In another aspect the present ion s to a compound of the invention or a pharmaceutically acceptable salt f for use in treating schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain.
In another aspect the present invention relates to a combination of a compound of the invention or a ceutically able salt thereof and one or more agents selected from carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone and lithium.
In another aspect the present invention relates nd of formula (XXX) (XXX) n P1 and P2 each independently represent a benzyl protecting group, R20 represents a hydrogen atom or a trimethylsilane leaving group and R1 is as defined in formula (I) of the invention.
In another aspect the present invention relates to the use of a compound of the invention or a pharmaceutically acceptable salt f in the manufacture of a medicament for treating a condition whose development or symptoms are linked to D-amino acid oxidase (DAAO) enzyme activity.
In another aspect the present invention relates to the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating schizophrenia, schizophreniform disorder, affective disorder, cognitive disorders or pain.
Certain statements that appear below are r than what appears in the statements of the invention above. These statements are provided in the interests of ing the reader with a better tanding of the invention and its practice. The reader is directed to the accompanying claim set which defines the scope of the invention.
In the context of the present specification, unless otherwise stated, an alkyl, alkenyl or alkynyl substituent group or an alkyl, alkenyl or alkynyl moiety in a tuent group may be linear or branched. Examples of C1-C6 alkyl groups/moieties include methyl, ethyl, propyl, 2-methylpropyl, 2-methylpropyl, 2-methylbutyl, 3-methyl butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2--methyl-pentyl, 3-methylpentyl, 4-methylpentyl, ylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, n-butyl, isobutyl, utyl, n-pentyl, isopentyl, neopentyl and n-hexyl. Examples of C2-C6 l groups/moieties include ethenyl, propenyl, 1-butenyl, nyl, 1-pentenyl, 1-hexenyl, 1,3- butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl. Examples of C2-C6 alkynyl /moieties include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl and 1-hexynyl.
Similarly, an alkylene group/moiety may be linear or ed. Examples of C1-C6 alkylene groups/moieties include methylene, ne, n-propylene, n-butylene, n-pentylene, n-hexylene, ylethylene, 2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2- or 3- ethylpropylene.
A C1-C6 haloalkyl or C1-C6 haloalkoxy substituent group/moiety will se at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or pentafluoroethyl.
A C1-C6 hydroxyalkyl substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two, three or four hydroxyl groups, examples of which include – CH 2OH, -CH2CH 2OH, -CH2CH 2CH 2OH, -CH(OH)CH2OH, -CH(CH3)OH and - CH(CH 2OH) 2.
The alkyl groups in a di-C1-C6 alkylamino group/moiety may be the same as, or different from, one another.
In the definition of R , the saturated or unsaturated 3- to 10-membered carbocyclic or heterocyclic ring system may have alicyclic or aromatic properties as too will the 4- to 6-membered saturated or unsaturated heterocyclic ring substituent. An unsaturated ring system will be partially or fully unsaturated.
For the avoidance of doubt, when R represents an ally tuted 3- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system, then it should be understood that the invention does not ass any unstable ring structures or any O-O, O-S or S-S bonds and that a substituent, if present, may be attached to any suitable ring atom. The R moiety may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. r comments apply with respect to the optional 4- to 6-membered saturated or unsaturated cyclic ring substituent on the R ring system.
When any chemical moiety or group in formula (I) is described as being optionally substituted, it will be appreciated that the moiety or group may be either unsubstituted or substituted by one or more of the specified substituents. It will be appreciated that the number and nature of substituents will be selected so as to avoid ally undesirable combinations.
In an ment, R represents a hydrogen atom.
X and Y each independently represent a bond, an oxygen atom or a group -C(O), 4 4, -S(O)n, -C(O)NR , -S(O)2NR -NR4, , or 4 5 -CR R -, provided that X and Y cannot both simultaneously represent a bond and provided that if X and Y are both other than a bond, then at least one of X and Y 4 5 represents -CR R -.
Each R independently represents a hydrogen atom or a C1-C6, or C1-C4, or C1- C2 alkyl, preferably methyl, group or a C1-C6, or C1-C4, or C1-C2 haloalkyl, preferably trifluoromethyl, group.
Each R independently represents a hydrogen atom, a C1-C6, or C1-C4, or C1-C2 alkyl, preferably methyl, group, a C1-C6, or C1-C4, or C1-C2 haloalkyl, ably 4 5 trifluoromethyl, group or a group =CH- such that -CR R - ents an alkenylene 4 4 moiety, -CR =CH- or –CH=CR -.
In one embodiment, X represents a bond, an oxygen atom or a group -C(O), , - 4 4, , -S(O)2NR -NR4, 4 5 C(O)NR , or -CR R - (e.g. 4 5 CH2 or CH(CH3)), and Y represents a bond or –CR R - (e.g. CH2 or CH(CH3)), subject to the above provisos.
In another ment, X represents a bond, an oxygen atom or a group -C(O), -S(O)n, 4 4, 4 5 -C(O)NR , -S(O)2NR , or -CR R - (e.g. CH2 or 4 5 CH(CH3)), and Y represents a bond or –CR R - (e.g. CH2 or CH(CH3)), subject to the above provisos. 4 5 In still another embodiment, X represents –CR R - (e.g. CH2 or CH(CH3)) and Y 4 4, represents a bond, an oxygen atom or a group –C(O), -S(O)n, -C(O)NR , -S(O)2NR -NR4, 4 5 , or -CR R - (e.g. CH2 or CH(CH3)), subject to the above provisos.
In a further embodiment, X represents a group –S(O) n (e.g. -S-), -CHR (e.g. CH2 or CH(CH3)) or and Y represents a bond or a group -CHR (e.g. CH2), subject to the above provisos.
In a still further embodiment, X represents a group –S(O)n (e.g. -S-), -NR (e.g. 4 4 N(CH3)), -CHR (e.g. CH2 or CH(CH3)) or , especially -CHR , and Y represents a bond or a group -CHR (e.g. CH2), t to the above provisos.
Specific examples of combinations of X and Y e any one or more of the following: X Y S CH2 CH2 S CH2 CH2 S CH(CH3) SO2 CH2 CH2 SO2 O CH2 O CH(CH3) C(O) CH2 C(O)NH CH2 S(O)2NH CH2 CH2 CH(CH3) CH(CH3) CH2 CH2 C(CH3)2 C(CH3)2 CH2 - bond bond -CH=CHCH2 bond bond CH2 cyclopropyl bond bond cyclopropyl CH(CH3) bond bond CH(CH3) N(CH3) CH2 In one embodiment, preferred combinations of X and Y include any one or more of the following: X Y S CH2 CH2 CH2 CH2 bond bond CH2 Cyclopropyl (e.g. bond bond Cyclopropyl (e.g.
CH(CH3) bond bond CH(CH3) N(CH3) CH2 In still another ment, it is preferred that X and Y both represent CH2.
Each R independently represents a hydrogen atom or C1-C6, or C1-C4, or C1-C2 alkyl group. Examples of alkyl groups are described above and include methyl, ethyl, isopropyl , n-propyl and n- butyl.
R represents a C1-C6, or C1-C4, or C1-C2 alkyl group, examples of which have been previously described. ing to one embodiment, R may represent a 3- to 10-membered (e.g. 3-, 4-, 5- or 6- to 7-, 8-, 9- or 10-membered) saturated or unsaturated carbocyclic or heterocyclic ring system which is optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. ne, chlorine or bromine), yl, cyano, oxo, C1-C6, or C1-C4, or C1-C2 alkyl, C2-C6 or C2-C4 alkenyl, C1-C6, or C1-C4, or C1-C2 haloalkyl, C1-C6, or C1-C4, or C1-C2 hydroxyalkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or C1-C4, or C1-C2 haloalkoxy, C1-C6, or C1-C4, or C1-C2 alkylthio, C1-C6, or C1-C4, or C1-C2 alkylsulphinyl, C1-C6, or C1-C4, or C1-C2 alkylsulphonyl, C1-C6, or C1-C4, or C1-C2 alkylcarbonyl, C1-C6, or C1-C4, or C1- C2 alkylcarbonyloxy, C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl, amino, -CON(R )2, C1-C6, or C1-C4, or C1-C2 alkylamino, di-(C1-C6, or C1-C4, or C1-C2 alkyl)amino, C3-C6 or C3-C5 cycloalkyl, C3-C6 or C3-C5 cycloalkyloxy, C3-C6 or C3-C5 cycloalkylmethyl, -[O]p-(CH 2)q-O-R and a 4- to 6-membered saturated or unsaturated heterocyclic ring (optionally substituted with at least one substituent, e.g. one, two or three substituents independently, ed from C1-C4 alkyl such as methyl or ethyl and C1-C4 alkoxy such as methoxy or ethoxy).
The heterocyclic ring system will comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, sulphur and oxygen. es of saturated or unsaturated 3- to 10-membered carbocyclic or heterocyclic ring systems that may be used, which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused, include one or more (in any combination) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, zinyl, morpholinyl, thiomorpholinyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl), tetrahydrofuranyl, icyclo[2.2.1]heptyl, naphthyl, benzofuranyl, hienyl, benzodioxolyl, inyl, oxazolyl, thiadiazolyl (e.g. 1,2,3- thiadiazolyl), 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, imidazo[1,2- a]pyridinyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, pyrrolyl, l, thiazolyl, indolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.
Preferred ring systems e , pyridinyl, oxazolyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, 2,3-dihydrobenzofuranyl, pyrimidinyl, imidazo[1,2-a]pyridinyl, pyrazolyl, lyl and piperidinyl.
Advantageously, the ring system is phenyl, pyridinyl, cyclopropyl, cyclopentyl, exyl or tetrahydropyranyl.
In a red ment, the ring system is phenyl or pyridinyl, ularly phenyl.
The 4- to 6-membered saturated or unsaturated heterocyclic ring substituent will comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from en, sulphur and oxygen. Preferably the ring heteroatoms are selected from en and oxygen. Examples of such ring substituents e azetidinyl, pyrrolidinyl and oxadiazolyl such as 1,2,4-oxadiazolyl.
In one embodiment, R represents a 3-, 4- or 5- to 6-, 7-, 8- or 9-membered, e.g. 3- to 6- or 5- to 9-membered, saturated or unsaturated carbocyclic or cyclic ring system optionally substituted by at least one substituent (e.g. one, two, three or four substituents independently) selected from halogen (e.g. fluorine, chlorine or bromine), hydroxyl, cyano, oxo, C1-C4 alkyl (e.g. methyl or ethyl), C2-C4 alkenyl (e.g. ethenyl), C1-C2 haloalkyl (e.g. difluoromethyl or trifluoromethyl), C1-C2 hydroxyalkyl (e.g. hydroxymethyl), C1-C4 alkoxy (e.g. methoxy or ethoxy), C1-C2 haloalkoxy (e.g. difluoromethoxy or trifluoromethoxy), C1-C4 alkylthio (e.g. methylthio or ethylthio), C1-C4 alkylsulphinyl (e.g. methylsulphinyl or ethylsulphinyl), C1-C4 alkylsulphonyl (e.g. methylsulphonyl or ethylsulphonyl), C1-C4 alkylcarbonyl (e.g. methylcarbonyl or ethylcarbonyl), C1-C4 alkylcarbonyloxy (e.g. methylcarbonyloxy), C1-C4 alkoxycarbonyl (e.g. methoxycarbonyl), amino, -CON(R )2, C1-C4 alkylamino (e.g. methylamino or ethylamino), di-(C1-C4 alkyl)amino (e.g. dimethylamino), C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylmethyl, -[O]p-(CH 2)q-O-R and a 4- to 6-membered saturated or unsaturated heterocyclic ring optionally tuted by methyl or methoxy.
In another embodiment, R represents a 5- or ered unsaturated carbocyclic or heterocyclic ring system, the heterocyclic ring system comprising one or two ring atoms independently ed from nitrogen and , wherein the carbocyclic or heterocyclic ring system is optionally substituted by one, two, three or four substituents independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, oxo, C1-C4 alkyl (e.g. methyl or ethyl), C2-C4 alkenyl (e.g. ethenyl), C1-C2 haloalkyl (e.g. difluoromethyl or trifluoromethyl), C1-C2 yalkyl (e.g. hydroxymethyl), C1-C4 alkoxy (e.g. methoxy or ethoxy), C1-C2 haloalkoxy (e.g. romethoxy or trifluoromethoxy), C1-C4 alkylthio (e.g. methylthio or ethylthio), C1-C4 alkylsulphinyl (e.g. methylsulphinyl or ulphinyl), C1-C4 alkylsulphonyl (e.g. methylsulphonyl or ethylsulphonyl), C1-C4 alkylcarbonyl (e.g. carbonyl or ethylcarbonyl), C1-C4 alkylcarbonyloxy (e.g. methylcarbonyloxy), C1-C4 carbonyl (e.g. methoxycarbonyl), amino, carboxamido (-CONH2), C1-C4 alkylamino (e.g. methylamino or ethylamino), di-(C1-C4 alkyl)amino (e.g. dimethylamino), C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylmethyl, -[O]p-(CH 2)q-O-R and a 4- to 6-membered saturated or unsaturated heterocyclic ring, preferably containing at least one ring nitrogen atom, optionally substituted by methyl or methoxy.
In still another embodiment, R represents a 3- to 6-membered, preferably 5- to 6- membered, saturated or unsaturated carbocyclic or heterocyclic ring system such as cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, phenyl or pyridinyl, which ring system is optionally substituted by at least one substituent (e.g. one, two, three or four, preferably one or two, substituents independently) selected from cyano, fluorine, chlorine, methyl, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy and methoxy.
Specific es of R include one or more of the following substituents in any combination: The ring substituents R* are independently selected from cyano, halogen (e.g. fluorine or chlorine), methyl, methoxy, difluoromethyl, difluoromethoxy, oromethyl or trifluoromethoxy.
In a preferred embodiment, R represents a hydrogen atom; 2 3 R represents a group –X-Y-R ; 4 4 X represents a group -S(O)n or -CHR and Y represents a group -CHR ; n is 0, 1 or 2; each R independently represents a hydrogen atom or a methyl group; and R represents a 5- or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring system, which ring system is optionally substituted by at least one substituent selected from ne, chlorine, trifluoromethyl and methoxy.
In another preferred ment, R represents a hydrogen atom; 2 3 R represents a group –X-Y-R ; X represents a group -S(O)n , -CHR or and Y represents a bond or a group -CHR ; n is 0, 1 or 2, preferably 0; each R ndently represents a en atom or a methyl group, preferably a hydrogen atom; and R represents a 3- to 6-membered saturated or unsaturated yclic or heterocyclic ring system (preferably phenyl), which ring system is optionally substituted by at least one substituent (preferably one or two substituents independently) selected from fluorine, chlorine, difluoromethyl, trifluoromethyl, trifluoromethoxy and methoxy.
In still another preferred embodiment, R represents a en atom; 2 3 R represents a group –X-Y-R ; 4 4 X represents a group -S(O)n , -NR , -CHR or and Y represents a bond or a group -CHR ; n is 0, 1 or 2, preferably 0; each R independently represents a en atom or a methyl group, preferably a hydrogen atom; and R represents a 3- to 6-membered saturated or unsaturated carbocyclic or cyclic ring system (preferably phenyl), which ring system is optionally substituted by at least one substituent (preferably one or two substituents independently) selected from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, methyl and methoxy.
Examples of compounds of the invention include: 4-Hydroxy(2-phenylethyl)pyridazin-3(2H)-one, 6-[2-(4-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 6-[(4-Chlorobenzyl)sulfanyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[6-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 6-[2-(3-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(2-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(3,5-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(3,4-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 6-(2-Cyclohexylethyl)hydroxypyridazin-3(2H)-one, 6-(2-Cyclopropylethyl)hydroxypyridazin-3(2H)-one, 6-(2-Cyclopentylethyl)hydroxypyridazin-3(2H)-one, 4-Hydroxy[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one, 2,4-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-{2-[3-(Difluoromethyl)phenyl]ethyl}hydroxypyridazin-3(2H)-one, 6-Benzylhydroxypyridazin-3(2H)-one, 6-[2-(3-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one, oxy(1-phenylcyclopropyl)pyridazin-3(2H)-one, 4-[2-(5-Hydroxyoxo-1,6-dihydropyridazinyl)ethyl]benzonitrile, 6-[2-(3-Fluoromethylphenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(4-Fluoromethylphenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(3,4-Dimethoxyphenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one, 6-[2-(4-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(2-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 6-(4-(Difluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one, 6-(4-(Trifluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one, 6-(3-(Difluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one, 4-Fluorophenyl)cyclopropyl]hydroxypyridazin-3(2H)-one, 6-[1-(4-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 6-((Cyclopropylmethyl)(methyl)amino)hydroxypyridazin-3(2H)-one, 6-((Cyclohexylmethyl)(methyl)amino)hydroxypyridazin-3(2H)-one, 6-(3-Chlorobenzyl)hydroxypyridazin-3(2H)-one, hlorobenzyl)hydroxypyridazin-3(2H)-one, 6-(Cyclohexylmethyl)hydroxypyridazin-3(2H)-one, 6-(4-Fluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(2-Chlorofluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(2-Chlorobenzyl)hydroxypyridazin-3(2H)-one, 6-(3-Fluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(2-Fluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(4-Methylbenzyl)hydroxypyridazin-3(2H)-one, 6-(3-Methylbenzyl)hydroxypyridazin-3(2H)-one, 4-Hydroxy(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one, 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy[2-(oxanyl)ethyl]pyridazin-3(2H)-one, 6-{[(4-Fluorophenyl)methyl](methyl)amino}hydroxy-pyridazin-3(2H)-one, 2,6-Difluorophenyl)ethyl]hydroxy-pyridazin-3(2H)-one, 6-[2-(2-Chlorofluorophenyl)ethyl]hydroxy-pyridazin-3(2H)-one, 6-{[3,5-bis(Trifluoromethyl)phenyl]methyl}hydroxypyridazin-3(2H)-one, 6-(1-Phenylethyl)hydroxypyridazin-3(2H)-one, 6-(Cyclopropylmethyl)hydroxy-2,3-dihydropyridazinone , 4-Hydroxy{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-2,3-dihydropyridazin- 3-one, 2-Chloro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, 6-{2-[2-Fluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, 6-{2-[3,5-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazin one, 6-{2-[2,4-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydro-pyridazin- 3-one, 6-{2-[3,4-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazin one, oxy(3-methyl(trifluoromethyl)phenethyl)pyridazin-3(2H)-one, 3,4-bis(Benzyloxy)((3-chloro(trifluoromethyl)phenyl)ethyl)-pyridazine, 4-Hydroxy{2-[2-methyl(trifluoromethyl)phenyl]ethyl}-2,3- dihydropyridazinone, 6-{2-[3,5-Difluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, 6-{2-[3-Fluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, and pharmaceutically acceptable salts of any one thereof.
It should be noted that each of the chemical compounds listed above ents a particular and independent aspect of the invention.
The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises (i) when X represents a sulphur atom or when X is a bond and Y represents a sulphur atom, reacting a compound of a (II) in which Hal represents a halogen atom such as chlorine and R is as defined in formula 3 3 (I), with a nd of formula (III), HS-[Y]t-R , where t is 0 or 1 and Y and R are as defined in formula (I); or (ii) when X represents SO or when X is a bond and Y represents SO, oxidising a compound of formula (IV) (IV) 1 1 in which P represents a protecting group (e.g. methyl propionate) and R is as d in formula (I) with a le oxidising agent, followed by reaction with a compound of 1 3 1 formula (V), L -[Y]w-R , where w is 0 or 1, L represents a leaving group (e.g. n) and Y and R are as defined in formula (I); or (iii) when X represents SO2 or when X is a bond and Y represents SO2, oxidising a compound of a (IV) as defined in (ii) above with a le oxidising agent, followed by reaction with a compound of formula (V) as defined in (ii) above; or (iv) when X represents an oxygen atom or when X is a bond and Y represents an oxygen atom, ng a compound of formula (II) as defined in (i) above, with a 3 3 compound of formula (VI), HO-[Y]z-R , where z is 0 or 1 and Y and R are as defined in formula (I); or (v) when X represents C(O) or when X is a bond and Y represents C(O), reacting a compound of formula (II) as defined in (i) above with carbon dioxide, followed by addition of an activating agent and reaction with a compound of formula (Va), M-[Y]w- 3 20 20 3 R , where M is Li or MgR , R represents a halogen atom and w, Y and R are as defined in formula (V) in (ii) above; or 4 4 (vi) when X represents -C(O)NR or when X is a bond and Y represents -C(O)NR , reacting a nd of formula (VII) (VII) in which R is as defined in formula (I), with a compound of formula (VIII), 4 3 3 4 R HN-[Y]g-R , where g is 0 or 1 and Y, R and R are as defined in formula (I); or (vii) when X represents -S(O)2NR or when X is a bond and Y represents -S(O)2NR , reacting a compound of formula (II) as defined in (i) above with sulphur dioxide, followed by addition of an oxidising-chlorinating agent and then reaction with a compound of formula (VIII) as defined in (vi) above; or 4 4 (viii) when X represents -NR or when X is a bond and Y ents -NR , reacting a compound of formula (II) as defined in (i) above, with a compound of formula (VIII) as defined in (vi) above; or 4 5 4 5 4 (ix) when X represents -CR R - or when X is a bond and Y represents -CR R - and R and R each ndently represent a C1-C6 alkyl group, reacting a compound of formula (II) as defined in (i) above with a compound of formula (IX), L - 4’ 5’ 3 2 4’ CR R -[Y]h-R , where h is 0 or 1, L represents a leaving group (e.g. halogen), R ’ 3 and R each independently ent a C1-C6 alkyl group and Y and R are as defined in formula (I); or 4 5 4 5 (x) when X ents -CR R - or when X is a bond and Y represents -CR R - and 4 5 R and R each independently represent a hydrogen atom or a C 1-C6 alkyl group but do not both simultaneously represent a C1-C6 alkyl group, reacting a compound of formula 4 3 (II) as d in (i) above with a compound of formula (IXa), R C(O)-[Y]h-R , 3 4 wherein h, Y, and R are as defined in a (IX) in (ix) above and R is as defined in formula (I) above, followed by a hydrogenation reaction; or (xi) when X and Y each represent -CHR , hydrogenating a compound of formula 1 3 4 wherein R , R and R are as defined in formula (I); or 4 5 4 5 (xii) when X represents -CR R - or when X is a bond and Y represents -CR R - and R is =CH, ng a compound of formula (XI) (XI) 22 1 wherein R represents a hydrogen atom or a C1-C6 alkyl group and R is as defined in 24 26 3 24 formula (I), with a compound of formula (IXb), R -CH(R )-[Y]h-R , wherein R represents a phosphonate moiety (e.g. (OR)2 where R is an alkyl group such as 26 3 ethyl), R represents a hydrogen atom or a C1-C6 alkyl group and h, Y and R are as defined in formula (IX) in (ix) above; or (xiii) when X represents a group or when X is a bond and Y represents a group , reacting a compound of formula (XII) (XII) 1 3 where k is 0 or 1 and Y, R and R are as defined in formula (I), with diiodomethane and zinc-copper couple; or (xiv) when X represents a group or when X is a bond and Y represents a group , ng a compound of formula (XIII) (XIII) 1 3 where l is 0 or 1 and Y, R and R are as defined in formula (I), with diiodomethane and zinc-copper couple; and optionally thereafter carrying out one or more of the ing procedures: ● converting a compound of formula (I) into another compound of formula (I) ● removing any protecting groups ● forming a pharmaceutically acceptable salt.
Process (i) may conveniently be carried out in an organic solvent, such as e, in the presence of a palladium catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0) (Pd 2(DBA) 3) and an organophosphorous compound such as 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). ses (ii) and (iii) may conveniently be d out in an c solvent, such as dichloromethane, using a suitable amount of an oxidising agent such as meta - chloroperoxybenzoic acid.
Process (iv) may conveniently be carried out in an organic solvent, such as toluene, in the presence of a copper (I) iodide catalyst at elevated temperature (e.g. 30ºC to 150ºC).
The first step of process (v) may conveniently be d out in an organic solvent, such as diethyl ether, at low temperature (e.g. -78ºC) in the presence of a reagent such as butyllithium. A suitable activating agent to use in the second step would be a compound such as N,O-dimethylhydroxylamine hydrochloride which is commercially available, e.g. from the Sigma-Aldrich Corporation, to form a ‘Weinreb amide’ which is then reacted with the compound of formula (Va) to form the appropriate compound of formula (I).
Process (vi) may conveniently be carried out in an organic solvent using a le amide ng reagent. Various amide coupling reagents are known in the art such as dicyclohexylcarbodiimide (DCC), ropylcarbodiimide (DIC), O-(benzotriazol yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) and O-(benzotriazol- 1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU).
The first step of process (vii) may conveniently be carried out in an organic t, such as diethyl ether, at low temperature (e.g. -78ºC) in the presence of a reagent such as isopropylmagnesium chloride. A suitable oxidising-chlorinating agent to use in the second step would be sulphuryl chloride and the uent reaction with a compound of formula (VIII) may be carried out in accordance with known sulphonamide coupling procedures in the art.
The ion reaction in process (viii) may conveniently be carried out in an organic solvent, such as toluene, in the presence of (1) a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(DBA) 3), (2) a base such as sodium t-butoxide and (3) an organophosphorous compound such as 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos).
Processes (ix) and (x) may iently be carried out in an organic solvent, such as diethyl ether, at low temperature (e.g. -78ºC) in the presence of a reagent such as butyllithium.
The hydrogenation reaction in process (x) and process (xi) may be carried out ing to techniques known in the art, e.g. in the ce of an organic solvent, such as ethanol, using hydrogen gas and a palladium on carbon catalyst, under acid sed conditions as required.
Process (xii) is ous to a Horner-Wadsworth-Emmons reaction as known, for example, from Wadsworth, W. Org. React. 1977, 25 , 73. Suitable reaction conditions for carrying out this type of reaction are known in the art.
Processes (xiii) and (xiv) are analogous to the Simmons-Smith cyclopropanation reaction of alkenes, for example, as described by Howard H. Simmons, Ronald D.
Smith (1959) "A New Synthesis of Cyclopropanes" J. Am. Chem. Soc. 81 (16): 4256– 4264.
Compounds of formula (IV) in which P represents a protecting group such as -CH2CH2C(O)OCH3 may be prepared by reacting a compound of formula (II) as d above with methyl 3-sulfanylpropanoate.
Compounds of formula (VII) may be prepared by reacting a compound of formula (II) as d above with carbon dioxide in an organic solvent such as diethyl ether at low temperature (e.g. -78ºC) in the presence of a t such as butyllithium.
Compounds of formula (X) in which the CR groups are linked by a carbon-carbon double bond may be prepared by processes analogous to process (xii) above.
Compounds of formula (X) in which the CR groups are linked by a carbon-carbon 4 3 triple bond, each R represents a hydrogen atom and R represents an optionally substituted heterocyclic ring system may be prepared according to the ing reaction scheme: (X) Step 1 is carried out by reacting the pyridazine compound (in which R is as hereinbefore d) with ethynyltrimethylsilane in an organic solvent such as ydrofuran.
Step 2 is carried out using potassium carbonate in a polar solvent such as methanol. 3 3 Step 3 is carried out using a compound of formula R -Br where R represents an optionally tuted heterocyclic ring system as hereinbefore defined, in the presence of copper(I) iodide and a suitable palladium catalyst.
Compounds of formula (X) in which the CR groups are linked by a carbon-carbon 4 3 triple bond, each R represents a hydrogen atom and R represents an optionally substituted carbocyclic ring system may be prepared according to the following reaction scheme: (II) (X) Step 4 is carried out by ng the compound of formula (II) as hereinbefore defined 3 3 with a compound of formula, HC ≡C-R , where R represents an optionally tuted carbocyclic ring system as before defined, in the presence of copper(I) iodide and a suitable palladium st.
Compounds of formula (XI) may be prepared by reacting a compound of formula (II) as defined above with dimethylformamide in an organic solvent, such as diethyl ether, at low temperature (e.g. -78ºC) in the ce of a reagent such as butyllithium, optionally followed by an alkylation reaction.
Compounds of formula (XII) may be prepared by processes analogous to those used for the preparation of compounds of formula (X).
Compounds of formula (XIII) may be prepared according to the following reaction scheme: (XIII) Step a is d out using, for example, copper cyanide. The compound of formula (II) is as hereinbefore defined.
Step b is carried out using a Grignard reagent of formula R -[Y]l-MgBr where l, Y and R are as defined in formula (XIII).
Step c is carried out using Tebbe reagent solution yclopentadienyl)-µ-chloro- (dimethylaluminum)-µ-methylenetitanium).
Compounds of formulae (II), (III), (V), (Va), (VI), (VIII), (IX), (IXa) and (IXb) are either commercially available, are well known in the ture or may be prepared using known techniques.
Also described herein are intermediates, e.g. intermediates of formula (XXX), (XXX) 1 2 20 wherein P and P each independently represent a protecting group (e.g. benzyl), R represents a hydrogen atom or a leaving group (e.g. trimethylsilane, Si(CH3)3) and R is as defined in formula (I) above.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as phenol, hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of a (I) may involve, at an appropriate stage, the removal of one or more protecting .
The protection and deprotection of functional groups is bed in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley- Interscience (1999).
The compounds of formula (I) above may be converted to a ceutically acceptable salt thereof, ably an acid on salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, te, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, e, 1- hydroxynapthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt.
In one embodiment, compounds of a (I) may bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of a (I), or may be uced by ng the compounds of formula (I) to chelating moieties capable of binding to a ctive metal atom. Such radiolabeled versions of the nds may be used, for example, in diagnostic imaging studies. nds of formula (I) and their salts may be in the form of hydrates or solvates which are also contemplated herein. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
Compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all ric and optical isomers (including atropisomers) of the compounds of a (I) and mixtures thereof ing racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.
The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as D-amino acid oxidase enzyme (DAAO) inhibitors, and thus may be used in the ent of schizophrenia and other psychotic disorders (e.g. , psychotic disorder, psychosis), ia and other cognitive disorders, anxiety disorders (e.g. , generalized anxiety disorder), mood disorders (e.g. , depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, r depression), sleep disorders, disorders usually first diagnosed in infancy, childhood, or adolescence (e.g. , attention-deficit disorder and disruptive behaviour disorders), pain (e.g. neuropathic pain) and neurodegenerative disorders ( e.g.
Parkinson’s or Alzheimer’s disease).
Thus, described herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions whose development or ms are linked to DAAO enzyme activity.
Also described herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt f as hereinbefore defined for the preparation of a medicament for the treatment of conditions whose development or symptoms are linked to DAAO enzyme activity.
In the context of the present ication, the term "therapy" also includes "prophylaxis" unless there are specific tions to the ry. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is ed to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at risk of developing a particular disorder or ion generally e those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
In particular, the compounds of the invention ding pharmaceutically acceptable salts) may be used in the treatment of the positive symptoms of schizophrenia, schizophreniform disorder or schizoaffective disorder (e.g. voices or hallucinations), cognitive disorders (such as dementia and impaired learning) and also pain (such as neuropathic pain).
Also bed herein is a method of treating at least one symptom or condition associated with schizophrenia, schizophreniform disorder, schizoaffective disorder and other psychotic disorders (e.g., tic disorder, sis), dementia and other cognitive disorders, anxiety disorders (e.g., generalized anxiety disorder), mood disorders (e.g., depressive disorders, major depressive disorders, bipolar disorders ing bipolar I and II, bipolar mania, bipolar depression), sleep disorders, disorders usually first diagnosed in infancy, childhood, or cence (e.g., attention-deficit disorder, autistic spectrum disorders and disruptive behaviour disorders), pain (e.g. neuropathic pain) and neurodegenerative disorders (e.g. Parkinson’s or Alzheimer’s disease) which comprises administering to a t in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
Such symptoms and conditions include, but are not limited to, anxiety, agitation, hostility, panic, an eating disorder, an affective m, a mood symptom, a negative and positive psychotic symptom commonly ated with psychosis and neurodegenerative disorder.
For the mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (µg/kg) to 100 micrograms per am body weight (µg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the nd of the invention may be in the range from 0.01 micrograms per kilogram body weight (µg/kg) to 100 milligrams per kilogram body weight (mg/kg).
The compounds of formula (I) and pharmaceutically acceptable salts f may be used on their own but will generally be stered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, t or carrier.
Therefore also described herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
Also described herein is a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a nd of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a ceutically acceptable adjuvant, diluent or carrier.
Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceutics - The Science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 1988.
Pharmaceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum n, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, l glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium de, zinc salts, colloidal , magnesium icate, polyvinyl pyrrolidone, ose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, ly, nasally, buccally, vaginally or via an implanted reservoir. Oral stration is preferred. The pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, ynovial, ternal, intrathecal, esional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a e injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated ing to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable on or suspension in a non- toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the able diluents and solvents that may be employed are mannitol, water, Ringer's on and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including tic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride tives are useful in the preparation of injectables, as are natural pharmaceutically able oils, such as olive oil or castor oil, especially in their polyoxyethylated ns. These oil solutions or sions may also contain a long-chain alcohol diluent or dispersant such as that described in Ph. Helv. or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to ques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used e lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a e form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or ring and/or colouring agents may be added.
The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, x and polyethylene glycols.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques wellknown in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable vatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by ), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
The compounds of the invention (that is, compounds of a (I) and ceutically acceptable salts thereof) may also be administered in conjunction with other compounds used for the treatment of the above conditions and/or with serine.
Also described herein are combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another eutic agent or agents and/or with serine, for the treatment of one or more of the conditions previously indicated. Such therapeutic agents may be selected from the ing: (i) pressants such as, for example, amitriptyline, amoxapine, bupropion, citalopram, ramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, mine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, otan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (ii) atypical antipsychotics including, for e, quetiapine and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (iii) antipsychotics including, for example, pride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, romazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone, and lents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (iv) anxiolytics ing, for example, irone, azapirones, iazepines, barbiturates, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof. Example anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, epate, chlordiazepoxide, epam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, epam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazepam; and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (v) anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, and gabapentin, and equivalents and pharmaceutically active isomer(s) and/or lite(s) thereof; (vi) Alzheimer's therapies including, for example, donepezil, memantine, tacrine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (vii) son's therapies including, for example, deprenyl, , Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, and Dopamine agonists and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (viii) migraine therapies including, for example, almotriptan, amantadine, riptine, butalbital, cabergoline, dichloralphenazone, eletriptan, riptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, and zomitriptan, and equivalents and pharmaceutically active isomer(s) and/or lite(s) f; (ix) stroke therapies including, for example, abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase, repinotan, traxoprodil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) f; (x) urinary incontinence therapies including, for example, darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (xi) neuropathic pain therapies including, for example, gabapentin, lidoderm, and pregablin, and equivalents and ceutically active isomer(s) and/or metabolite(s) (xii) nociceptive pain therapies such as, for example, celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and lents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (xiii) insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, yzine, mecloqualone, nin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, roletamide, fos, secobarbital, zaleplon, and Zolpidem, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (xiv) mood stabilizers including, for example, carbamazepine, divalproex, ntin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (xv) 5HT1B ligands such as, for example, compounds disclosed in WO 99/05134 and WO 02/08212; (xvi) mGluR2 agonists; (xvii) alpha 7 nicotinic agonists such as, for example, nds disclosed in WO 96/006098, WO 97/030998, WO 99/003859, WO 00/042044, WO 01/029034, WO 01/60821, WO 01/36417, WO 02/096912, WO 03/087102, WO 03/087103, WO 03/087104, WO 16617, , and ; (xviii) chemokine receptor CCRl inhibitors; and (xix) delta opioid agonists such as, for example, compounds sed in WO 66 and WO 02/094794.
Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges and/or the dosage such as bed in the publication reference.
Also described herein is a combination (for example for the treatment of phrenia, cognitive disorders or pain) of a compound of formula (I) or a ceutically acceptable salt thereof as hereinbefore d and one or more agents selected from carbamazepine, olanzapine, quetiapine, mil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone and m.
Also described herein is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, idone or lithium, for simultaneous, sequential or separate use in therapy.
Also described herein is a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone or lithium, and instructions for the simultaneous, sequential or separate stration of the preparations to a patient in need thereof.
The present invention will now be further explained by reference to the following illustrative examples.
The methods used for synthesis of the compounds of the invention are illustrated by the general schemes below and the preparative examples that follow. The ng materials and reagents used in preparing these compounds are available from commercial suppliers. These general schemes are merely illustrative of methods by which the compounds of this invention can be synthesised, and various modifications to these schemes can be made and will be ted to one skilled in the art having referred to this disclosure.
Nuclear magnetic resonance (NMR) spectra were recorded at 400MHz; the chemical shifts (δ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance ment fitted with a 5mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 software, unless stated ise.
Purity was assessed using UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450nm, using a Waters Acquity UPLC system equipped with Acquity UPLC BEH or HSS C18 columns (2.1mm id x 50mm long) operated at 50 or 60°C. Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.05% formic acid or 0.025% a.
Mass spectra were recorded with a Waters SQD single quadrupole mass ometer using heric pressure ionisation, unless stated otherwise.
Compounds were purified using normal phase chromatography on silica or alumina, or by reverse phase chromatographic methods, using Biotage or Isolute KPNH Cartridge, SCX cartridge and SCX-2 solid phase extraction cartridges.
Preparative High Performance Liquid Chromatography (HPLC) was performed using an Agilent Technologies 1100 Series system typically using Waters 19mm id x 100mm long C18 s such as XBridge or SunFire 5µm materials at 20 mL/min. Mobile phases lly consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.1% a, unless stated otherwise.
In the following descriptions “room temperature” s a temperature in the range from 20oC to 25oC.
The abbreviations used in the specific examples have the following meanings: DMSO Dimethyl ide DMSO-d6 Deuterated dimethyl sulfoxide MeOH-d Deuterated methanol MeOH Methanol MS Mass spectrum NMR r magnetic resonance Pd2(DBA)3 Tris(dibenzylideneacetone)dipalladium(0) MgSO4 Magnesium sulphate XANTPHOS 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene DBU 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine CHCl3 Trichloromethane CDCl3 Deuterated oromethane CD2Cl2 Deuterated dichloromethane MTBE Methyl tert-butyl ether THF Tetrahydrofuran CO2 Carbon dioxide 1. Intermediates Scheme 1: Intermediate 1: 3,4-bis(Benzyloxy)chloropyridazine Phenylmethanol (6.72 g, 62.2 mmol) was added dropwise to a sion of sodium hydride (60 % suspension in mineral oil; 2.486 g, 62.2 mmol) in tetrahydrofuran (total volume: 100 ml) at room ature. The resulting mixture was stirred for 1 hour and then cooled to 0 °C before 3,4,6-trichloropyridazine (5.7 g, 31.1 mmol) was added portionwise over 10 minutes. The on was then allowed to warm to room temperature and stirred for 16 hours before being poured into water and extracted with ethyl acetate (twice). The organic layer was washed with brine, dried (magnesium sulphate) and evaporated. The residue was purified by silica chromatography (eluting with 5-20 % ethyl acetate in petrol containing 5 % tetrahydrofuran) to yield 3,4- bis(benzyloxy)chloropyridazine (4.0 g, 12.24 mmol, 39.4 % yield) as the major product. 1H NMR (400 MHz, DMSO-d 6): δ ppm 7.31 – 7.52 (m, 11 H) 5.51 (s, 2 H) and 5.31 (s, 2 H).
Intermediate 2: 3,4-bis(Benzyloxy)(phenylethynyl)pyridazine Ph O Ph O N A 20 ml microwave vial was charged with 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1; 440 mg, 1.35 mmol), DBU (1230 mg, 8.08 mmol) and ethynylbenzene (413 mgs, 4.04 mmol) in tetrahydrofuran (5 ml) to produce an orange solution. The mixture was purged with en and dichlorobis(triphenylphosphine)palladium(II) (47.3 mg, 0.067 mmol) and (I) iodide (25.6 mg, 0.135 mmol) were added before the whole was subjected to microwave radiation for 1 hour at 80 °C. Upon cooling, the resulting mixture was diluted with ethyl acetate and washed with brine and the organic layer was purified by silica chromatography (eluting with 0-30 % ethyl e-petrol) to yield 3,4-bis(benzyloxy)- 6-(phenylethynyl)pyridazine (320 mg, 0.815 mmol, 61 % yield). 1H NMR (400 MHz, DMSO-d 6): δ 7.34 – 7.58 (m, 15 H), 7.06 (s, 1 H), 5.56 (s, 2 H) and 5.34 (s, 2 H).
MS ES+: 393.
Intermediate 3: 3,4-bis(Benzyloxy)[(4-fluorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynylfluorobenzene in 72 % yield. 1H NMR (400 MHz, DMSO-d 6): δ 7.67 - 7.76 (m, 2 H), 7.57 (s, 1 H), 7.29 - 7.53 (m, 12 H), 5.58 (s, 2 H) and 5.31 (s, 2 H).
MS ES+: 410.
Scheme 2: Intermediate 4: 3,4-bis(Benzyloxy)[(trimethylsilyl)ethynyl]pyridazine A 20 ml microwave vial was charged with 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1, 3.06 mmol) and ethynyltrimethylsilane (902 mg, 9.18 mmol) in tetrahydrofuran (5 ml) to afford an orange on. The reaction was purged with nitrogen before DBU (2.77 ml, 18.36 mmol), dichlorobis(triphenylphosphine)palladium(II) (107 mg, 0.153 mmol) and (I) iodide (58.3 mg, 0.306 mmol) were added and the whole was subjected to microwave radiation for 1 hour at 80 °C. Upon cooling, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was ed by silica chromatography ng with 0-30 % ethyl acetate in ) to yield 3,4- bis(benzyloxy)((trimethylsilyl)ethynyl)pyridazine (838 mg, 2.16 mmol, 70 % yield) 1H NMR (400 MHz, DMSO-d 6): δ 7.08 – 7.28 (m, 11 H), 5.32 (s, 2 H), 5.06 (s, 2 H) and 0.08 (s, 9 H) MS ES+: 389.
Intermediate 5: 3,4-bis(Benzyloxy)ethynylpyridazine Potassium carbonate (295 mg, 2.136 mmol), 3,4-bis(benzyloxy) ((trimethylsilyl)ethynyl) pyridazine (Intermediate 4; 830 mg, 2.14 mmol) and methanol (10 ml) were added to tetrahydrofuran (5 ml) to produce an orange suspension. The mixture was stirred for 1 hour and then partitioned between brine and ethyl acetate. The organic layer was washed with brine and evaporated before the residue was purified by silica chromatography (eluting with 10-50 % ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)ethynylpyridazine (530 mg, 1.68 mmol, 78 % yield). 1H NMR (400 MHz, DMSO-d 6): δ 7.31 – 7.53 (m, 11 H), 5.59 (s, 2 H), 5.30 (s, 2 H) and 4.53 (s, 1 H).
MS ES+: 317.
Scheme 3: Intermediate 6: 3,4-bis(Benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine 3,4-bis(Benzyloxy)ethynylpyridazine (Intermediate 5; 530 mg, 1.68 mmol) and 2- bromo(trifluoromethyl)pyridine (379 mg, 1.68 mmol) were dissolved in tetrahydrofuran (5 ml) to e an orange solution. The reaction mixture was purged with nitrogen and then triethylamine (1.40 ml, 10.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (58.8 mg, 0.08 mmol) and copper(I) iodide (31.9 mg, 0.17 mmol) were added before it was subjected to microwave irradiation for 1 hour at 80 °C. Upon cooling, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo and the crude residue was then purified by silica chromatography (eluting with 0-50 % ethyl e in petrol) to yield 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (460 mg, 0.10 mmol, 60 % yield). 1H NMR (400 MHz, DMSO-d 6): δ 9.08 (s, 1 H), 8.34 - 8.38 (m, 1 H), 7.96 - 8.01 (m, 1 H), 7.70 (s 1 H), 7.33 – 7.53 (m, 10 H), 5.61 (s, 2 H) and 5.33 (s, 2 H).
MS ES+: 462.
Scheme 4: Intermediate 7: 6-Chloro-3,4-bis[(4-methoxybenzyl)oxy]pyridazine To a solution of (4-methoxyphenyl)methanol (1.88 g, 13.63 mmol) in tetrahydrofuran (7.89 ml) was added a on of potassium tert-butoxide in tetrahydrofuran (13.63 ml, 13.63 mmol). After stirring at room temperature for 1.5 hours, the mixture was cooled to 0 °C and trichloropyridazine (1.0 g, 5.45 mmol) was added portion-wise over a period of approximately 5-10 minutes. The resulting mixture was left to stir and warm to room temperature for 16 hours and then poured into water, extracted into ethyl acetate and the combined organics were dried (magnesium sulphate). The solution was then evaporated in vacuo and purified by silica chromatography (eluting with 0-40 % ethyl e in petrol) to yield 6-chloro-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (550 mg, 1.420 mmol, 26 % yield). 1H NMR (400 MHz, ): δ 7.51 (s, 1 H), 7.38 - 7.45 (m, 4 H), 6.91 – 6.99 (m, 4 H), 5.39 (s, 2 H), 5.19 (s, 2 H) and 3.76 (s, 6 H).
Intermediate 8: 6-[(4-Chlorobenzyl)sulfanyl]-3,4-bis[(4- methoxybenzyl)oxy]pyridazine A mixture of 6-chloro-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 7; 550 mg, 1.42 mmol), (4-chlorophenyl)methanethiol (248 mg, 1.56 mmol), Pd2(DBA)3 (52.1 mg, 0.057 mmol), OS (65.8 mg, 0.114 mmol) and Hunig’s base (ethyl diisopropylamine; 404 mg, 3.13 mmol) was subjected to microwave irradiation at 120 °C for 1 hour. The resulting mixture was poured into water and extracted into ethyl acetate before the combined organics were washed with brine and then dried (magnesium sulphate). The resulting solution was evaporated in vacuo and purified by silica chromatography (eluting with 0-40 % dichlormethane in petrol) to yield 6-[(4- chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (201 mg, 1.42 mmol, 28 % yield). 1H NMR (400 MHz, MeOH-d): δ 7.25 - 7.48 (m, 8 H), 6.88 – 6.95 (m, 4 H), 5.42 (s, 2 H), 5.08 (s, 2 H), 4.41 (s, 2 H) and 3.83 (s, 6 H).
MS ES+: 509.
Intermediate 9: 3,4-bis(Benzyloxy){[6-(trifluoromethyl)pyridin yl]ethynyl}pyridazine A microwave vial was charged with 5-iodo(trifluoromethyl)pyridine (617 mg, 2.260 mmol), (I) iodide (39.1 mg, 0.205 mmol), bis(triphenylphosphine)palladium(II) chloride (72.1 mg, 0.103 mmol), 1,8-diazabicycloundecene (DBU; 1858 µl, 12.33 mmol) and tetrahydrofuran (6849 µl). The reaction e was then purged and evacuated with nitrogen and to this was then added 3,4-bis(benzyloxy) ethynylpyridazine (Intermediate 5: 650 mg, 2.1 mmol). The reaction was heated to 80 °C whilst being subjected to microwave radiation for 1 hour. Upon cooling the reaction mixture was partitioned n ethyl acetate and water, at which point a solid formed which was filtered and discarded. The organics were then washed with water and brine, dried ), filtered and concentrated to afford a brown oil. This was purified by silica chromatography (eluting with 0-100 % ethyl acetate in petrol) to yield 3,4- bis(benzyloxy){[6-(trifluoromethyl)pyridinyl]ethynyl}pyridazine as a yellow amorphous solid (yield = 10 %) MS ES : 462.
Intermediate 10: 3,4-bis(Benzyloxy)[(3-fluorophenyl)ethynyl]pyridazine O N Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from s(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynylfluorobenzene.
H NMR (400 MHz, DMSO-d6): δ 7.32 – 7.64 (m, 15 H), 5.56 (s, 2 H) and 5.30 (s, 2 MS ES : 411.
Intermediate 11: 3,4-bis(Benzyloxy)[(2-fluorophenyl)ethynyl]pyridazine ed as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynylfluorobenzene.
H NMR (400 MHz, DMSO-d6): δ 7.63 – 7.76 (m, 1 H), 7.58 (s, 2 H), 7.30-7.50 (m, 12 H), 5.59 (s, 2 H) and 5.32 (s, 2 H).
MS ES : 411.
Intermediate 12: 3,4-bis(Benzyloxy)[(3,5-difluorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynyl-3,5-difluorobenzene.
H NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1 H), 7.32 – 7.52 (s, 13 H), 5.59 (s, 2 H) and .30 (s, 2 H).
MS ES : 429. ediate 13: 3,4-bis(Benzyloxy)[2-(3,4-difluorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynyl-3,4-difluorobenzene.
H NMR (400 MHz, DMSO-d6): δ 7.52 – 7.67 (s, 1 H), 7.36 – 7.59 (s, 13 H), 5.58 (s, 2 H) and 5.31 (s, 2 H).
MS ES : 429.
Intermediate 14: s(Benzyloxy){2-[3-(trifluoromethoxy)phenyl]- ethynyl}pyridazine ed as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine mediate 1) and 1- ethynyltrifluoromethoxybenzene (prepared as described in Published International Patent Application No. , see ation 28).
H NMR (400 MHz, DMSO-d6): δ 7.60 – 7.75 (m, 3 H), 7.31 – 7.57 (s, 12 H), 5.58 (s, 2 H) and 5.28 (s, 2 H).
MS ES : 477.
Intermediate 15: 3,4-bis(Benzyloxy){2-[3-(trifluoromethyl)phenyl]- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy){[6-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-iodo(trifluoromethyl)benzene.
H NMR (400 MHz, DMSO-d6): δ 8.01 (s, br, 1 H), 7.96 (d, J=7.83 Hz, 1 H), 7.87 (d, J=7.83 Hz, 1 H), 7.70 - 7.77 (m, 1 H), 7.64 (s, 1 H), 7.29 - 7.52 (m, 10 H), 5.59 (s, 2 H), .31 (s, 2 H).
MS ES : 461.
Intermediate 16: 3,4-bis(Benzyloxy){2-[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy){[6-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 3-bromotrifluoromethylpyridine.
MS ES : 462.
Intermediate 17: s(Benzyloxy)(cyclohexylethynyl)pyridazine Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and ethynylcyclohexane.
H NMR (400 MHz, CD2Cl2) δ .56 (m, 2 H), 7.33 - 7.48 (m, 8 H), 6.92 (s, 1 H), .63 (s, 2 H), 5.17 (s, 2 H), 2.61 - 2.73 (m, 1H), 1.90 - 2.00 (m, 2 H), 1.75 - 1.84 (m, 2 H), 1.52 - 1.67 (m, 4 H), 1.35 - 1.46 (m, 2 H).
MS ES : 399.
Intermediate 18: 3,4-bis(Benzyloxy)(cyclopropylethynyl)pyridazine Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and ethynylcyclopropane.
H NMR (400 MHz, DMSO-d6) δ 7.14 - 7.55 (m, 11 H), 5.53 (s, 2 H), 5.25 (s, 2 H), 1.57 - 1.67 (m, 1 H), 0.92 - 0.99 (m, 2 H), 0.77 - 0.84 (m, 2 H).
MS ES : 357.
Intermediate 19: 3,4-bis(Benzyloxy)(cyclopentylethynyl)pyridazine Prepared as bed for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine mediate 1) and ethynylcyclopentane.
H NMR (400 MHz, CD2Cl2) δ 7.28 - 7.55 (m, 10 H), 6.82 - 6.90 (m, 1 H), 5.57 (s, 2 H), 5.14 (s, 2 H), 2.79 - 2.94 (m, 1 H), 1.97 - 2.13 (m, 2 H), 1.49 - 1.86 (m, 6 H) MS ES : 385.
Intermediate 20: 3,4-bis(Benzyloxy)[(4-methoxycyclohexen ynyl]pyridazine A microwave reaction vial was charged with 4-methoxycyclohexenyl trifluoromethanesulfonate (1069 mg, 4.11 mmol), copper(I) iodide (16.83 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium(0) (54.6 mg, 0.05 mmol), triethylamine (1432 µl, 10.27 mmol) and dry N,N-dimethylformamide (6849 µl). The reaction was evacuated and purged with nitrogen and a solution of 3,4-bis(benzyloxy) ethynylpyridazine (Intermediate 5; 650 mg, 2.06 mmol) in dry tetrahydrofuran (3 ml) was added before the whole was then stirred in the microwave at 70 °C for 1 hour.
Upon cooling, the resulting mixture was partitioned between ethyl acetate and water and the organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to afford a brown oil. This was purified by chromatography on silica eluting with 0-75 % ethyl acetate in petrol to give 3,4-bis(benzyloxy)[(4- methoxycyclohexenyl)ethynyl]pyridazine mediate 20) as a brown oil (860 mg, 85 %).
H NMR (400 MHz, CD2Cl2) δ 7.28 - 7.57 (m, 10 H), 6.90 (s, 1 H), 6.22 (br s, 1 H), .60 (s, 2 H), 5.14 (s, 2 H), 3.45 - 3.55 (m, 1 H), 3.31 - 3.38 (m, 3 H), 2.10 - 2.56 (m, 4 H), 1.88 - 1.97 (m, 1 H), 1.64 - 1.78 (m, 1 H) MS ES : 427.
Intermediate 21: 3,4-bis(Benzyloxy)[(2,4-difluorophenyl)ethynyl]pyridazine Prepared as described for s(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynyl-2,4-difluorobenzene.
H NMR (400 MHz, CD2Cl2) δ 7.49 - 7.67 (m, 3 H), 7.31 - 7.51 (m, 8 H), 6.85 - 7.07 (m, 3 H), 5.70 (s, 2 H), 5.23 (s, 2 H).
MS ES : 429.
Intermediate 22: 3,4-bis(Benzyloxy){[3-(difluoromethyl)phenyl]- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy){[6-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 9) from 3,4-bis(benzyloxy)ethynylpyridazine mediate 5) and 3-bromodifluoromethylpyridine.
H NMR (400 MHz, CDCl3) δ 7.65 - 7.85 (m, 2 H), 7.21 - 7.65 (m, 12 H), 6.99 (s, 1 H), 6.40 - 6.90 (m, 1 H, CHF2), 5.70 (s, 2 H), 5.24 (s, 2 H).
MS ES : 443.
Intermediate 23: 6-Benzyl-3,4-bis(benzyloxy)pyridazine To a solution of 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1: 0.22 g, 0.67 mmol) in tetrahydrofuran (6 ml) and water (0.6 ml) was added cesium ate (0.66 g, 2.01 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.049 g, 0.067 mmol). The reaction was then purged and evacuated with nitrogen several times before 9-benzylborabicyclo[3.3.1]nonane (9-BBN; 4.02 ml, 2.01 mmol) was added. The reaction vessel was then sealed and heated to 60 °C for 1 hour. Upon cooling, the resulting mixture was diluted with ethyl acetate and washed 5 times with a 1:1 mixture of water and saturated aqueous brine. The organics portion was dried (MgSO4), filtered and concentrated to give an orange oil. The crude oil was purified by silica tography (eluting with 0-80 % ethyl e in petrol) to yield 6-benzyl- 3,4-bis(benzyloxy)pyridazine as a colourless oil (yield = 64 %).
H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.33 Hz, 2 H), 7.12 - 7.48 (m, 13 H), 6.55 (s, 1 H), 5.64 (s, 2 H), 5.08 (s, 2 H), 4.17 (s, 2 H).
MS ES : 383.
Intermediate 24: 3,4-bis(Benzyloxy)((3-chlorophenyl)ethynyl)pyridazine O N To a solution of 1-chloroiodobenzene (0.862 g, 3.62 mmol) in dry tetrahydrofuran (11 ml) was added copper(I) iodide (0.063 g, 0.33 mmol), bis(triphenylphosphine)- palladium(II) chloride (0.115 g, 0.16 mmol) and 1,8-diazabicycloundecene and (DBU; 2.97 ml, 19.72 mmol). The reaction was then purged and evacuated with nitrogen several times before 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5; 1.04 g, 3.29 mmol) was added. The reaction vessel was sealed and heated to 80 °C for 1 hour. Upon cooling, the resultant mixture was partitioned between ethyl acetate and water. The combined organic portions were washed with water (x 2) and brine, dried (MgSO4), filtered and trated to give a brown oil. The crude oil was ed by silica tography (eluting with 0-20 % ethyl acetate in petrol) to yield 3,4- bis(benzyloxy)((3-chlorophenyl)ethynyl)pyridazine as a yellow solid (yield = 30 %).
H NMR (400 MHz, CDCl3) δ 7.21 - 7.65 (m, 14 H), 6.97 (s, 1 H), 5.70 (s, 2 H), 5.23 (s, 2 H).
MS ES : 427/429.
Intermediate 25: 3,4-bis(Benzyloxy)(1-phenylethenyl)pyridazine A mixture of 3,4-bis(benzyloxy)chloropyridazine ( Intermediate 1: 3 g, 9.18 mmol), dioxane (32.1 ml) and water (9.64 ml) was degassed and to this was added mono(bis(ditert-butyl (4-(dimethylamino)phenyl)phosphonio)palladium(IV)) dichloride (0.195 g, 0.275 mmol), cesium carbonate (10.14 g, 31.1 mmol) and 4,4,5,5-tetramethyl(1- phenylethenyl)-1,3,2-dioxaborolane (3 g, 13.04 mmol). The mixture was heated to 80 °C for 6 hours and upon cooling was partitioned n dichloromethane and water.
The organic n was dried (MgSO4), filtered and concentrated to give an orange oil.
The crude oil was purified by silica chromatography eluting with 0-60 % ethyl acetate in petrol to afford 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine as a brown oil (yield = 91 %).
H NMR (400 MHz, CHCl3-d) δ 7.54 - 7.66 (m, 2 H), 7.24 - 7.44 (m, 13 H), 6.72 (s, 1H), 6.02 (s, 1H), 5.70 (s, 2H), 5.63 (s, 1H), 5.11 (s, 2H).
MS ES : 395.
Intermediate 26: 3,4-bis(Benzyloxy)(1-phenylcyclopropyl)pyridazine To a sion of sodium hydride (0.487 g, 12.17 mmol, 60% in mineral oil) in DMSO (33.8 ml) stirring under nitrogen was added trimethyl sulfoxonium iodide (2.68 g, 12.17 mmol) in 4 portions over 20 minutes. A solution of 3,4-bis(benzyloxy)(1- phenylethenyl)pyridazine (Intermediate 25; 3.2 g, 8.11 mmol) in tetrahydrofuran (50.7 ml) was added via a ng funnel over 90 minutes before the reaction was left to stir at room temperature for 18 hours. The resulting mixture was concentrated, poured into ice water and extracted with ethyl acetate (x3). The cs portion was dried (MgSO4), filtered and concentrated to give a brown oil. The crude oil was purified by silica chromatography (eluting with 0-50 % ethyl acetate in petrol) to yield 3,4- bis(benzyloxy)(1-phenylcyclopropyl)pyridazine as a yellow oil (yield = 23 %).
H NMR (400 MHz, CHCl3-d) δ 7.47 - 7.63 (m, 2 H), 7.22 - 7.46 (m, 11 H), 7.10 - 7.25 (m, 2 H), 6.40 (s, 1 H), 5.62 (s, 2 H), 4.97 (s, 2 H), 1.71 - 1.85 (m, 2 H), 1.25 - 1.38 (m, 2 H).
MS ES : 409.
Scheme 5a: 'Hal' denotes halogen Intermediate 27: 4-{2-[5,6-bis(Benzyloxy)pyridazinyl]ethynyl}benzonitrile Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 4-iodobenzonitrile in 73 % yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.67 - 7.81 (m, 4 H), 7.32 - 7.65 (m, 10 H), 7.08 (s, 1 H), 5.68 (s, 2 H) and 5.23 (s, 2 H).
MS ES+: 418.
Intermediate 28: s(Benzyloxy)[2-(3-fluoromethylphenyl)- ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 2-fluoroiodomethylbenzene in 67 % yield.
Intermediate 29: 3,4-bis(Benzyloxy)[2-(4-fluoromethylphenyl)- ethynyl]pyridazine ed as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-fluoroiodomethylbenzene in 67 % yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.29 - 7.58 (m, 12 H), 6.99 - 7.08 (m, 2 H), 5.62 (s, 2 H), 5.17 (s, 2 H) and 2.29 (s, 3 H).
MS ES+: 425.
Intermediate 30: s(Benzyloxy)[2-(3,4-dimethoxyphenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 4-iodo-1,2-dimethoxybenzene in 17 % yield. 1H NMR (400 MHz, CDCl 3) δ 7.52 - 7.61 (m, 2 H), 7.33 - 7.47 (m, 8 H), 7.18 - 7.26 (m, 1 H), 7.09 - 7.15 (m, 1 H), 6.97 (s, 1 H), 6.87 (m, 1 H), 5.69 (s, 2 H), 5.22 (s, 2 H) and 3.89 - 3.96 (m, 6 H).
MS ES+: 453.
Intermediate 31: 3,4-bis(Benzyloxy){2-[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from s(benzyloxy)ethynylpyridazine (Intermediate 5) and 3-bromo(trifluoromethyl)pyridine in 31% yield.
MS ES+: 462.
Intermediate 32: 3,4-bis(Benzyloxy)[2-(2-chloro fluorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin ynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-chlorofluoroiodobenzene.
MS ES+: 445.
Intermediate 33: 3,4-bis(Benzyloxy)[2-(2,6-difluorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 2-bromo-1,3-difluorobenzene.
MS ES+: 429.
Intermediate 34: 3,4-bis(Benzyloxy)[2-(4-chlorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin ynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-chloroiodobenzene in 70% yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.22 - 7.75 (m, 15 H), 5.45 - 5.68 (m, 2 H) and 5.30 (s, 2 H).
MS ES+: 427.
Intermediate 35: 3,4-bis(Benzyloxy)[2-(2-chlorophenyl)ethynyl]pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-chloroiodobenzene in 59% yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.72 - 7.81 (m, 1 H), 7.61 - 7.68 (m, 1 H), 7.29 - 7.58 (m, 13 H), 5.58 (s, 2 H) and 5.32 (s, 2H).
MS ES+: 427 and 429.
Intermediate 36: 3,4-bis(Benzyloxy){2-[4-(difluoromethoxy)phenyl]- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from s(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-(difluoromethoxy)iodobenzene in 58 % yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.60 - 7.69 (m, 2 H), 7.49 - 7.55 (m, 2 H), 7.32 - 7.48 (m, 8 H), 7.12 - 7.20 (m, 2 H), 7.03 (s, 1 H), 6.39 - 6.81 (m, 1 H), 5.63 (s, 2 H) and 5.14 - 5.22 (m, 2 H).
MS ES+: 459.
Intermediate 37: 3,4-bis(Benzyloxy){2-[4-(trifluoromethoxy)phenyl]- ethynyl}pyridazine O F O N Prepared as bed for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and (trifluoromethoxy)benzene.
MS ES+: 477.
Intermediate 38: 3,4-bis(Benzyloxy){2-[3-(difluoromethoxy)phenyl]- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and 1-(difluoromethoxy)iodobenzene in 87% yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.29 - 7.56 (m, 13 H), 7.14 - 7.23 (m, 1 H), 6.39 - 6.79 (m, 1 H), 5.63 (s, 2 H) and 5.19 (s, 2H).
MS ES+: 459.
Scheme 5b: 'Hal' denotes halogen Intermediate 39: 3,4-bis(Benzyloxy){2-(3-(trifluoromethoxy)phenyl)- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynyl(trifluoromethoxy)benzene in 37 % yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.25 - 7.79 (m, 15 H), 5.59 (s, 2 H) and 5.25 - 5.34 (m, 2 H).
MS ES+: 477.
Intermediate 40: 3,4-bis(Benzyloxy){2-[2-(trifluoromethyl)phenyl]- ethynyl}pyridazine Prepared as bed for 3,4-bis(benzyloxy)(phenylethynyl)pyridazine mediate 2) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1- ethynyl(trifluoromethyl)benzene in quantitative yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.86 - 7.94 (m, 2 H), 7.76 - 7.83 (m, 1 H), 7.67 - 7.74 (m, 1 H), 7.28 - 7.54 (m, 11 H), 5.59 (s, 2 H) and 5.30 - 5.37 (m, 2 H).
MS ES+: 461.
Scheme 6: Intermediate 41: 3,4-bis(Benzyloxy)[1-(4-fluorophenyl)ethenyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 2- (1-(4-fluorophenyl)ethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 92 % yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.54 - 7.64 (m, 2 H), 7.18 - 7.46 (m, 10 H), 6.94 - 7.07 (m, 2 H), 6.71 (s, 1 H), 5.95 (s, 1 H), 5.70 (s, 2 H), 5.59 (s, 1 H) and 5.14 (s, 2 H) MS ES : 413. ediate 42: 3,4-bis(Benzyloxy)[1-(4-fluorophenyl)cyclopropyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)(1-phenylcyclopropyl)pyridazine (Intermediate 26) from 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine (Intermediate 41) in 16 % yield. 1H NMR (400 MHz, CDCl 3) δ 7.48 - 7.60 (m, 2 H), 7.14 - 7.45 (m, 10 H), 6.95 - 7.07 (m, 2 H), 6.33 (s, 1 H), 5.62 (s, 2 H), 5.01 (s, 2 H), 1.73 - 1.82 (m, 2 H) and 1.22 - 1.34 (m, 2 H).
MS ES : 427.
Intermediate 43: 3,4-bis(Benzyloxy){1-[3-(trifluoromethyl)phenyl]- ethenyl}pyridazine Prepared as described for s(benzyloxy)(1-phenylethenyl)pyridazine mediate 25) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 4,4,5,5-tetramethyl(1-(3-(trifluoromethyl)phenyl)ethenyl)-1,3,2-dioxaborolane in 45 % yield.
MS ES : 463. 4,4,5,5-Tetramethyl(1-(3-(trifluoromethyl)phenyl)ethenyl)-1,3,2-dioxaborolane was ed as follows: A flask was charged with (1,3-bis(2,6-diisopropylphenyl)-2,3-dihydro-1H-imidazol yl)copper(II) chloride (0.675 g, 1.38 mmol), sodium tert-butoxide (0.133 g, 1.38 mmol) and THF ( 100 ml) and stirred under nitrogen for 10 minutes. Bis(pinacolato)diborane (7.72 g, 30.4 mmol) was added to the on and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -78°C and a solution of 1- ethynyl(trifluoromethyl)benzene (4.7 g, 27.6 mmol) in THF (20 ml) and MeOH (1.23 ml, 30.4 mmol) were added via syringe. The flask was then stirred at -40°C (Acetonitrile/CO2 bath) overnight. Reaction was at room temperature in the morning.
The reaction was cooled to -78°C and then filtered through a pad of silica and diatomaceous earth (sold under the trade mark “Celite”) to give a brown solution which was concentrated and the residue was purified by silica chromatography eluting with 0- % Et2O/Petrol to yield 4,4,5,5-tetramethyl(1-(3-(trifluoromethyl)phenyl)ethenyl)- dioxaborolane (2.15g, 26%) 1H NMR (400 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.63 - 7.70 (m, 1H), 7.48 - 7.53 (m, 1H), 7.40 - 7.47 (m, 1H), 6.09 - 6.20 (m, 2H), 1.34 (s, 12H) Intermediate 44: 3,4-bis(Benzyloxy)[(E)[4-(trifluoromethyl)phenyl]- ethenyl]pyridazine A microwave vial was charged with s(benzyloxy)chloropyridazine (Intermediate 1) (5g, 15.30 mmol), (E)(trifluoromethyl)styrylboronic acid (4.96 g, 22.95 mmol), potassium carbonate (7.40 g, 53.6 mmol) and tetrakis(triphenyl phosphine)palladium(0) (0.530 g, 0.459 mmol). The reaction was evacuated and purged with nitrogen before dioxane (3.40 ml) was added and the whole was heated under vacuum. Water (1.7 ml) was then added and the on mixture heated at 120 °C under microwave irradiation for 1 hour. The reaction e was diluted with ethyl acetate and washed with water and then brine and the combined organics were dried (MgSO4) and concentrated in vacuo to give the desired compound as an orange solid (5.6g, 79%). 1H NMR (400 MHz, DMSO-d 6) δ 7.85 - 7.94 (m, 2 H), 7.65 - 7.82 (m, 4 H), 7.28 - 7.55 (m, 11 H), 5.57 (s, 2 H) and 5.33 (s, 2 H).
MS ES+: 463.
Scheme 7: Intermediate 45: 5,6-bis(Benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazinamine 3,4-Bis(benzyloxy)chloropyridazine (Intermediate 1) (1 g, 3.1 mmol), [1,1'-bis(ditert-butylphosphino )ferrocene]palladium(II) dichloride (0.100 g, 0.15 mmol) and sodium tert-butoxide (0.59 g, 6.1 mmol) were added to e (10.2 ml). The resulting mixture was purged with en before 4-fluorobenzylamine (78 mg, 6.1 mmol) was added. The mixture was heated at 120 °C for 1 hour under microwave irradiation. Upon cooling the crude mixture was quenched with water and extracted with ethyl acetate before the organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100 % ethyl acetate / petrol to yield the title compound.
MS ES+: 416.
Intermediate 46: 5,6-bis(Benzyloxy)-N-(cyclopropylmethyl)-N-methylpyridazin amine Prepared as described for s(benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin amine (Intermediate 45) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1-cyclopropyl-N-methylmethanamine in 17% yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.25 - 7.53 (m, 10 H), 6.29 (s, 1 H), 5.45 (s, 2 H), 5.15 (s, 2 H), 3.28 - 3.37 (m, 2 H), 3.07 (s, 3 H), 0.91 - 1.03 (m, 1 H), 0.41 - 0.53 (m, 2 H) and 0.14 - 0.27 (m, 2 H).
MS ES+: 376.
Intermediate 47: s(Benzyloxy)-N-(cyclohexylmethyl)-N-methylpyridazin amine Prepared as described for 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin amine (Intermediate 45) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 1-cyclohexyl-N-methylmethanamine in 26% yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.27 - 7.50 (m, 10 H), 6.17 (s, 1 H), 5.43 (s, 2 H), 5.15 (s, 2 H), 3.14 - 3.20 (m, 2 H), 3.01 (s, 3 H) and 1.07 - 1.76 (m, 11 H).
MS ES+: 418.
Scheme 8: ‘Hal’ denotes halogen; Ar denotes an aromatic moiety Intermediate 48: 3,4-bis(Benzyloxy)[(3-chlorophenyl)methyl]pyridazine To a stirred solution of 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) (1 g, 3.1 mmol) in dry tetrahydrofuran (12.2 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.153 mmol) and (3- chlorobenzyl)zinc(II) chloride (9.2 ml of a 0.5 M solution in tetrahydrofuran, 4.6 mmol). The reaction was stirred at 60 °C for 17 hours and then partitioned between ethyl e and water. The c extracts were washed with water and brine and then dried, filtered and concentrated to give a yellow oil. The oil was purified using 0- 70% ethyl acetate in petrol to afford the title compound (310 mg, 23 %). 1H NMR (400 MHz, CD2Cl2) δ 7.47 - 7.55 (m, 2 H), 7.29 - 7.44 (m, 8 H), 7.19 - 7.28 (m, 3 H), 7.09 - 7.17 (m, 1 H), 6.57 - 6.63 (m, 1 H), 5.57 (s, 2 H), 5.04 - 5.12 (m, 2 H) and 4.09 - 4.15 (m, 2 H).
MS ES+: 417.
Intermediate 49: 3,4-bis(Benzyloxy)[(4-chlorophenyl)methyl]pyridazine ed as described for 3,4-bis(benzyloxy)[(3-chlorophenyl)methyl]pyridazine (Intermediate 48) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and (4- chlorobenzyl)zinc(II) chloride in 95 % yield. 1H NMR (400 MHz, CD 2Cl2) δ 7.47 - 7.55 (m, 2 H), 7.23 - 7.43 (m, 10 H), 7.12 - 7.19 (m, 2 H), 6.56 (s, 1 H), 5.56 (s, 2 H), 5.04 - 5.10 (m, 2 H) and 4.02 - 4.16 (m, 2 H).
MS ES+: 417.
Intermediate 50: 3,4-bis(Benzyloxy)(cyclohexylmethyl)pyridazine To a solution of s(benzyloxy)chloropyridazine (Intermediate 1) (1 g, 3.06 mmol) and bis(tri-tert-butylphosphine)palladium (0.063 g, 0.122 mmol) in N- methylpyrrolidine (30.0 ml) under nitrogen was added (cyclohexylmethyl)zinc(II) bromide (0.5 M in tetrahydrofuran) (12.24 ml, 6.12 mmol) and the resulting brown mixture was stirred at room ature overnight and then heated at 100 °C for 2 hours. The reaction mixture was then allowed to cool, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and brine. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. The oil was purified by silica chromatography ng with 0-30 % ethyl acetate in petrol) to yield the title nd (540 mg, 1.39 mmol, 45 % yield). 1H NMR (400 MHz, CDCl 3) δ 7.50 - 7.61 (m, 2 H), 7.30 - 7.45 (m, 8 H), 6.56 (s, 1 H), .62 (s, 2 H), 5.20 (s, 2 H), 2.61 - 2.69 (m, 2 H), 1.53 - 1.76 (m, 7 H), 1.10 - 1.23 (m, 2 H) and 0.84 - 1.04 (m, 2H).
MS ES+: 389.
Intermediate 51: 3,4-bis(Benzyloxy)[(4-fluorophenyl)methyl]pyridazine To a solution of 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) (1 g, 3.06 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (0.117 g, 0.245 mmol) and ium (II) acetate (0.027 g, 0.122 mmol) in tetrahydrofuran (6.12 ml) under nitrogen was added (4-fluorobenzyl)zinc(II) bromide (9.18 ml, 4.59 mmol) and the resulting red/brown mixture was heated at 65 °C for 24 hours. The reaction mixture was cooled, diluted with ethyl e and washed with saturated aqueous sodium bicarbonate solution, saturated ammonium chloride solution and brine. The organics were dried (MgSO4), filtered and solvent d in vacuo to give a brown oil. The oil was purified by silica chromatography ng with 0-100 % ethyl e in petrol) to yield the title compound (663 mg, 1.61 mmol, 97 % yield). 1H NMR (400 MHz, CDCl 3) δ 7.49 - 7.60 (m, 2 H), 7.23 - 7.44 (m, 8 H), 7.11 - 7.20 (m, 2 H), 6.92 - 7.02 (m, 2 H), 6.48 (s, 1 H), 5.62 (s, 2 H), 5.08 (s, 2 H) and 4.07 - 4.20 (m, 2 H).
MS ES+: 401.
Intermediate 52: 3,4-bis(Benzyloxy)[(2-chloro fluorophenyl)methyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and (2-chlorofluorobenzyl)zinc(II) chloride in 23 % yield. 1H NMR (400 MHz, CDCl 3) δ 7.45 - 7.58 (m, 2 H), 7.12 - 7.43 (m, 10 H), 6.96 - 7.08 (m, 1 H), 6.60 (s, 1 H), 5.61 (s, 2 H), 5.12 (s, 2 H) and 4.34 (s, 2 H).
MS ES+: 435.
Intermediate 53: 3,4-bis(Benzyloxy)[(2-chlorophenyl)methyl]pyridazine ed as described for 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and (2-chlorobenzyl)zinc(II) chloride in 38 % yield. 1H NMR (400 MHz, CDCl 3) δ 7.48 - 7.62 (m, 2 H), 7.15 - 7.45 (m, 12 H), 6.62 (s, 1 H), .62 (s, 2 H), 5.11 (s, 2 H) and 4.29 (s, 2 H).
MS ES+: 417.
Intermediate 54: 3,4-bis(Benzyloxy)[(3-fluorophenyl)methyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and orobenzyl)zinc(II) chloride in 32 % yield. 1H NMR (400 MHz, DMSO-d 6) δ 6.99 - 7.55 (m, 15 H), 5.43 - 5.58 (m, 2 H), 5.18 - .31 (m, 2 H) and 4.08 - 4.17 (m, 2H) MS ES+: 401.
Intermediate 55: 3,4-bis(Benzyloxy)[(2-fluorophenyl)methyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and (2-fluorobenzyl)zinc(II) chloride in 77 % yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.23 - 7.51 (m, 12 H), 7.09 - 7.23 (m, 3 H), 5.48 (s, 2 H), 5.14 - 5.29 (m, 2 H) and 4.13 (s, 2H).
MS ES+: 401. ediate 56: 3,4-bis(Benzyloxy)[(4-methylphenyl)methyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and (4-methylbenzyl)zinc(II) chloride in 45 % yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.05 - 7.50 (m, 15 H), 5.48 (s, 2 H), 5.18 (s, 2 H), 3.99 - 4.07 (m, 2 H) and 2.23 - 2.28 (m, 3 H).
MS ES+: 397.
Intermediate 57: 3,4-bis(Benzyloxy)[(3-methylphenyl)methyl]pyridazine Prepared as described for s(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine mediate 1) and (3-methylbenzyl)zinc(II) chloride in 66 % yield. 1H NMR (400 MHz, DMSO-d 6) δ 7.00 - 7.50 (m, 15 H), 5.31 - 5.62 (m, 2 H), 5.11 - 5.25 (m, 2 H), 3.97 - 4.14 (m, 2 H) and 2.21 - 2.29 (m, 3H).
MS ES+: 397.
Intermediate 58: 3,4-bis(Benzyloxy){[3- (trifluoromethyl)phenyl]methyl}pyridazine Prepared as described for 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and (3-(trifluoromethyl)benzyl)zinc(II) chloride in 33 % yield. 1H NMR (400 MHz, CD 2Cl2) δ ppm 7.47 - 7.54 (m, 4 H), 7.42 - 7.46 (m, 2 H), 7.29 - 7.42 (m, 8 H), 6.61 (s, 1 H), 5.56 (s, 2 H), 5.09 (s, 2 H) and 4.24 (br s, 2 H).
MS ES+: 451. ediate 58a: 3,4-bis(Benzyloxy){[3,5-bis(trifluoromethyl)phenyl]- methyl}pyridazine To a solution of 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) (1 g, 3.06 icyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (0.143 g, 0.3 mmol) and palladium (II) acetate (0.034 g, 0.15 mmol) in tetrahydrofuran (10 ml) under nitrogen was added the supernatant zinc reagent [generated from the addition of 1- (chloromethyl)-3,5-bis(trifluoromethyl)benzene (3 g, 11.43 mmol) to a suspension of magnesium (0.694 g, 28.6 mmol) in lithium chloride (28.6 ml, 14.28 mmol) in tetrahydrofuran (1M) and zinc(II) de (12.57 ml, 12.57 mmol) in tetrahydrofuran, warmed to 30 °C to initiate and stirred for one hour to complete] and the resulting red/brown mixture was heated at 65 °C for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and brine. The organics were dried (MgSO4), filtered and t removed in vacuo to give a brown oil. The oil was ed by silica chromatography eluting with 0-40 % ethyl acetate in petrol to yield the title compound (520mg 33 %). 1H NMR (400 MHz, DMSO-d 6) δ 7.93 - 8.10 (m, 3 H), 7.23 - 7.53 (m, 11), 5.49 (s, 2 H), 5.23 (s, 2 H) and 4.34 (s, 2 H).
MS ES+: 519.
Scheme 9: Intermediate 59: 4-{2-[5,6-bis(Benzyloxy)pyridazinyl]ethynyl}oxanol 3,4-bis(Benzyloxy)ethynylpyridazine (Intermediate 5; 3.0 g, 9.49 mmol) was dissolved in tetrahydrofuran (24 ml) under nitrogen atmosphere and the ing solution was cooled to -78 0C. n-Butyl lithium (23 % solution in hexane; 7.92 ml, 28.48 mmol, 3.0 eq) was added slowly at -78 0C and the resulting mixture was allowed to stir for 30 minutes. Dihydro-2H-pyran-4(3H)-one (1.0 g, 10.44 mmol, 1.1 equiv.) was added slowly to reaction mass and the whole was allowed to warm to room temperature.
The crude mixture was then poured into a ted solution of aqueous ammonium chloride (300 ml) and product was extracted into ethyl acetate (100 ml × 2). The organic layer was separated, washed with brine, dried (Na2SO4) and trated in vacuo. The crude product was purified by column chromatography on silica gel (eluting with 0-30 % ethyl acetate in hexane) to yield the desired material (2.0 g, 501 % yield).
Scheme 10: ediate 60: 3,4-bis(Benzyloxy)[2-(3,6-dihydro-2H-pyran yl)ethynyl]pyridazine ,6-bis(Benzyloxy)pyridazinyl]ethynyl}oxanol mediate 59; 2.0 g, 4.8 mmol) was dissolved in romethane (20 ml). Triethylamine (2.94 g, 28.82 mmol, 6.0 equiv.) was added to the clear solution followed by the addition of methanesulfonyl chloride (1.64 g, 14.42 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred for an hour at room temperature before the reaction mass was poured into water (200 ml) and product was extracted into ethyl acetate (100 ml × 2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to get the crude title compound (1.0 g, 52 % yield) which was used as such for the next step without further cation.
Scheme 11: Intermediate 61: 5,6-bis(Benzyloxy)-N-[(4-fluorophenyl)methyl]-N- methylpyridazinamine ,6-bis(Benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazinamine (Intermediate 45; 0.7 g, 1.68 mmol) was dissolved in methylformamide (8 ml) and the solution was cooled to 0 0C before sodium hydride (60% by weight in paraffin; 0.101 g, 2.53 mmol, 1.5 equiv.) was added under nitrogen atmosphere. The reaction mixture was allowed to warm at room temperature for approximately 30 minutes and iodomethane (1.189 g, 8.43 mmol, 5 equiv.) was added. The on was allowed to stir at room temperature for one hour before being poured into water (100 ml) and the organic materials were extracted into ethyl acetate (50 ml × 2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel, eluting with 0-50 % ethyl e in hexane) to yield ,6-bis(benzyloxy)-N-(4-fluorobenzyl)-N-methylpyridazinamine (0.51 g, 64 % yield).
Scheme 12: Intermediate 62: Ethyl 5,6-bis(benzyloxy)pyridazinecarboxylate 3,4-Bis(benzyloxy)chloropyridazine (Intermediate 1; 5.0 g, 15.33 mmol) was dissolved in ethanol (75 ml) at room temperature. Sodium e (2.52 g, 30.67 mmol) was added and the resulting suspension was purged with nitrogen for 10 minutes. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.877 g, 1.073 mmol) was added and reaction was flushed with carbon monoxide gas.
Further carbon monoxide was bubbled into the reaction for 15 minutes at room temperature and then the whole was stirred at 90 °C with carbon monoxide bubbling for 2 hours. Upon completion, the reaction mass was poured into water (50 ml) followed by brine (100 ml) and product was extracted into ethyl acetate (3 x 100 ml). The combined organic layers were ted, dried (Na2SO4) and concentrated in vacuo. The crude product was purified on column tography (silica, 0-20 % ethyl acetate in hexane) to afford 5,6-bis(benzyloxy)pyridazinecarboxylate (3.8 g, 68 % yield). 1H NMR (DMSO-d 6) δ 7.28 – 7.58 (m, 11 H), 5.73 (s, 2 H), 5.26 (s, 2 H), 4.46 – 4.52 (q, 2 H) and .48 (t, 3 H).
Intermediate 63: 5,6-bis(Benzyloxy)pyridazinecarbaldehyde Ethyl 5,6-bis(benzyloxy)pyridazinecarboxylate (Intermediate 62; 3.8 g, 10.43 mmol) was dissolved in THF (95 ml) and cooled to 0-5 °C under en atmosphere.
A solution of di-isobutyl-aluminium e in THF (1 M, 21 ml, 20.8 mmol) was added at 0-5 °C and reaction mixture was stirred at room ature for 2 hours. Upon completion the reaction was quenched by the addition of ethyl acetate and then saturated aqueous ammonium chloride solution. The resulting mass was filtered and extracted into ethyl acetate (3 x 50 ml) and the combined cs were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, eluting with dichloromethane) to afford 5,6- bis(benzyloxy)pyridazinecarbaldehyde (2.9 g, 87 % yield).
Intermediate 64: (5,6-bis(Benzyloxy)pyridazinyl)(cyclopropyl)methanol BnO N ,6-bis(Benzyloxy)pyridazinecarbaldehyde (Intermediate 63; 0.5 g, 1.562 mmol) was dissolved into THF (10 ml) and cooled to 0-5 °C under a nitrogen atmosphere. A solution of cyclopropyl ium bromide in THF (0.5 M, 4.7 ml, 2.34 mmol) was added at 0-5 °C and reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction was quenched by addition of ethyl acetate and saturated aqueous ammonium chloride solution and extracted into ethyl acetate (2 x 50 ml). The combined organics were separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 0-2 % methanol in dichloromethane) to afford (5,6-bis(benzyloxy)pyridazin yl)(cyclopropyl)methanol (0.35 g, 61.9 % yield).
MS ES+: 363.
Intermediate 65: 3,4-bis(Benzyloxy)(cyclopropylidenemethyl)pyridazine (5,6-bis(Benzyloxy)pyridazinyl)(cyclopropyl)methanol mediate 64, 0.34 g, 0.94 mmol) was dissolved in dichloromethane (10.2 ml) and cooled at 0-5 °C under nitrogen atmosphere. ylamine (0.474 g, 4.70 mmol) and methanesulfonylchloride (0.162 g, 1.401 mmol) were added to the reaction and it was allowed to stir at room temperature for 3 hours. Upon completion the reaction was quenched by pouring into saturated aqueous sodium bicarbonate solution (25 ml) and the product was extracted into ethyl e (2 x 50 ml). The combined organics were separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 0-10 % ethyl acetate in n-hexane) to afford 3,4- bis(benzyloxy)(cyclopropylidenemethyl)pyridazine (0.18 g, 56 % yield). 1H NMR (CD 2Cl2) δ 7.28 - 7.57 (m, 10 H), 6.67 (s, 1 H), 6.23 (s, 1 H), 5.59 (s, 2 H), .14 - 5.19 (m, 2 H) and 1.90 - 2.05 (m, 4 H).
MS ES+: 345.
Intermediate 66: 4,4,5,5-Tetramethyl{1-[4-(trifluoromethyl)phenyl]ethenyl}- 1,3,2-dioxaborolane A e of (1,3-bis(2,6-diisopropylphenyl)-2,3-dihydro-1H-imidazolyl)copper(II) chloride (0.718 g, 1.469 mmol), sodium utoxide (0.141 g, 1.469 mmol) and THF (106 ml) was d to stir under en for 10 s. 4,4,4',4',5,5,5',5'- Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.21 g, 32.3 mmol) was added and the mixture stirred for 30 minutes at room temperature. The mixture was cooled to -78 °C and a solution of 1-ethynyl(trifluoromethyl)benzene (5 g, 29.4 mmol) in THF (21.30 ml) and methanol (1.308 ml, 32.3 mmol) was added via syringe. The whole mixture was then stirred at -40 °C with slow warming to 20 °C overnight. The resulting mixture was filtered through a pad of diatomaceous earth to give a brown solution which was concentrated in vacuo. The e was purified by column chromatography (silica, eluting with 0-6 % diethyl ether in petrol). The combined fractions were subjected to further purification by column chromatography (silica, eluting with 0-50 % dichloromethane in petrol) to afford 4,4,5,5-tetramethyl{1-[4- (trifluoromethyl)phenyl]ethenyl}-1,3,2-dioxaborolane as a yellow solid (2.82 g, 32 %). 1H NMR (DMSO-d 6) δ 7.67 - 7.72 (m, 2 H) 7.61 - 7.66 (m, 2 H) 6.21 (m, 1 H) 6.11 (m, 1 H) and 1.28 (s, 12 H).
Intermediate 67: 3,4-bis(Benzyloxy){1-[4-(trifluoromethyl)phenyl]ethenyl}- pyridazine Prepared according to the method for 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 4,4,5,5-tetramethyl{1-[4-(trifluoromethyl)-phenyl]ethenyl}-1,3,2-dioxaborolane (Intermediate 66) in 48 % yield. 1H NMR (DMSO-d 6) δ 7.72 (m, 2 H), 7.30 - 7.50 (m, 13 H), 6.02 (s, 1 H), 5.87 (s, 1 H), .55 (s, 2 H) and 5.31 (s, 2 H).
MS: ES+: 463.
Intermediate 68: 3,4-bis(Benzyloxy){1-[4-(trifluoromethyl)phenyl]- cyclopropyl}pyridazine Prepared ing to the method for 3,4-bis(benzyloxy)(1- phenylcyclopropyl)pyridazine (Intermediate 26) from 3,4-bis(benzyloxy){1-[4- (trifluoromethyl)phenyl]ethenyl}-pyridazine (Intermediate 67) in 38 % yield. 1H NMR (DMSO-d 6) δ 7.65 (m, 2 H) 7.29 - 7.48 (m, 12 H) 6.90 (s, 1 H) 5.50 (s, 2 H) .19 (s, 2 H) 1.54 - 1.59 (m, 2 H) and 1.34 - 1.38 (m, 2 H).
MS: ES+: 477. ediate 69: 3,4-bis(Benzyloxy){2-[2-chloro(trifluoromethyl)phenyl]- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy)((3-methyl(trifluoromethyl)phenyl)- ethynyl)pyridazine (Intermediate 74) from 3,4-bis(benzyloxy)ethynylpyridazine (Intermediate 5) and ochloro(trifluoromethyl)benzene in 75 % yield. 1H NMR (DMSO-d 6) δ 8.11 (s, 1 H), 8.00 (m, 1 H), 7.84 (m, 1 H), 7.62 (s, 1 H), 7.32 - 7.52 (m, 10 H), 5.60 (s, 2 H) and 5.33 (s, 2 H).
MS: ES+: 495.
Intermediate 70: 3,4-bis(Benzyloxy){2-[2-fluoro(trifluoromethyl)phenyl]- ethynyl}pyridazine Prepared as described for 3,4-bis(benzyloxy)((3-methyl(trifluoromethyl)phenyl)- ethynyl)pyridazine (Intermediate 74) from 3,4-bis(benzyloxy)ethynylpyridazine mediate 5) and 1-bromofluoro(trifluoromethyl)benzene in 16 % yield. 1H NMR (DMSO-d6) δ 7.90 - 8.00 (m, 2 H), 7.72 (m, 1 H), 7.64 (s, 1 H) 7.30 - 7.53 (m, H), 5.60 (s, 2 H) and 5.33 (s, 2 H).
MS: ES+: 479.
Intermediate 71: 3,4-bis(Benzyloxy)[(E)[3,5-bis(trifluoromethyl)phenyl]- ethenyl]pyridazine Prepared as described for 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)chloropyridazine (Intermediate 1) and 2- [(E)[3,5-bis(trifluoromethyl)phenyl]ethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 77 % yield. 1H NMR d 6) δ 8.38 (s, 2 H), 8.04 (s, 1 H), 7.82 - 7.89 (m, 1 H), 7.67 - 7.76 (m, 2 H), 7.31 - 7.54 (m, 10 H), 5.58 (s, 2 H) and 5.32 (s, 2 H).
MS: ES+: 531.
Intermediate 72: 3,4-bis(Benzyloxy)[(E)[2,4-bis(trifluoromethyl)phenyl]- l]pyridazine Prepared from 3,4-bis(benzyloxy)ethenylpyridazine (Intermediate 78) according to the procedure used to synthesise 3,4-bis(benzyloxy)[(E)[2-methyl (trifluoromethyl)phenyl]ethenyl]pyridazine mediate 76) in 36 % yield. 1H NMR (DMSO-d 6) δ 8.27 (m, 1 H), 8.14 (m, 1 H), 8.08 (s, 1 H), 7.87 (m, 1 H), 7.59 (s, 1 H), 7.47 - 7.55 (m, 5 H), 7.32 - 7.46 (m, 6 H), 5.59 (s, 2 H) and 5.35 (s, 2 H).
Intermediate 73: 3,4-bis(Benzyloxy)[(E)[3,4-bis(trifluoromethyl)phenyl]- ethenyl]pyridazine 3,4-bis(Benzyloxy)ethenylpyridazine (Intermediate 78: 0.578 g, 1.816 mmol), cesium carbonate (0.887 g, 2.72 mmol), dichloropalladiumtricyclohexylphosphane (1:2) (0.067 g, 0.091 mmol) and 4-chloro-1,2-bis(trifluoromethyl)benzene (0.542 g, 2.179 mmol) were combined. The reaction vessel was evacuated and purged with nitrogen before toluene (6.05 ml) was added under vacuum and the whole was stirred under nitrogen and heated to 140 0C for 11 hours. Upon quenching with saturated aqueous ammonium chloride, the ing mixture was diluted with dichloromethane, passed through a phase separator and concentrated in vacuo. The residue was purified by column chromatography eluting (silica, 0-50 % ethyl acetate in petrol) to yield crude 3,4-bis(benzyloxy)[(E)[3,4-bis(trifluoromethyl)phenyl]-ethenyl]-pyridazine which was used directly in the next step without further purification.
MS: ES+: 531.
Intermediate 74: 3,4-bis(Benzyloxy)((3-methyl(trifluoromethyl)phenyl)- ethynyl)pyridazine O N 3,4-bis(Benzyloxy)ethynylpyridazine (Intermediate 5; 3.0 g, 9.48 mmol), (I) iodide (0.181 g, 0.948 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (0.333 g, 0.474 mmol) were combined. The reaction vessel was purged with nitrogen, followed by the on of 4-bromomethyl(trifluoromethyl)benzene (2.493 g, 10.43 mmol), 1,8-diazabicycloundecene (8.66 g, 56.9 mmol) and tetrahydrofuran (32 ml) before the resulting mixture was allowed to stir at room temperature overnight. The on was quenched with brine and extracted into ethyl acetate (x 2) and the combined organic ts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a dark brown gum. The gum was ed by column chromatography (silica, 0-50 % ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)((3-methyl (trifluoromethyl)phenyl)-ethynyl)pyridazine as a dark brown oil (1.22 g, 27 %). 1H NMR (CD 2Cl2) δ 7.49 - 7.67 (m, 3 H), 7.33 - 7.46 (m, 10 H), 7.06 (s, 1 H), 5.64 (s, 2 H), 5.20 (s, 2 H) and 2.50 (s, 3 H).
MS ES+: 475.
Intermediate 75: 3,4-bis(Benzyloxy){2-[3-chloro(trifluoromethyl)phenyl]- ethynyl}pyridazine BnO N Prepared as described for 3,4-bis(benzyloxy)((3-methyl(trifluoromethyl)- phenyl)ethynyl)pyridazine mediate 74) using 4-bromochloro(trifluoromethyl )benzene in 98 % yield. 1H NMR (CD 2Cl2) δ 7.80 (s, 1 H), 7.71 - 7.76 (m, 1 H), 7.62 - 7.69 (m, 1 H), 7.52 (d, 1 H), 7.32 - 7.46 (m, 9 H), 7.08 (s, 1 H), 5.64 (s, 2 H) and 5.22 (s, 2 H).
MS ES+: 495.
Intermediate 76: 3,4-bis(Benzyloxy)[(E)[2-methyl (trifluoromethyl)phenyl]ethenyl]pyridazine 1-Bromomethyl(trifluoromethyl)benzene (1.144 g, 4.79 mmol), 3,4- nzyloxy)ethenylpyridazine (Intermediate 78; 1.27 g, 3.99 mmol), palladium(II) acetate (0.045 g, 0.199 mmol), triethylamine (10.56 ml, 76 mmol), tri-o- tolylphosphine (0.243 g, 0.798 mmol) and acetonitrile (8 ml) were combined. The reaction mixture was subjected to microwave irradiation at 120 °C for 30 minutes before being quenched with water and extracted into ethyl acetate. The ed organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford an orange gum. This was purified by column chromatography (silica, eluting with 0-30 % ethyl e in petrol) to afford 3,4-bis(benzyloxy)[(E)[2-methyl (trifluoromethyl)phenyl]ethenyl]pyridazine as a white solid (1.04 g, 55 %). 1H NMR (CD 2Cl2) δ 7.78 (d, 1 H), 7.71 (d, 1 H), 7.26 - 7.57 (m, 13 H), 7.09 (br. s., 1 H), 5.62 (s, 2 H), 5.28 (s, 2 H) and 2.52 (s, 3 H).
MS ES+: 477.
Intermediate 77: 3,4-bis(Benzyloxy)[(E)[3,5-difluoro (trifluoromethyl)phenyl]ethenyl]pyridazine A e of 3,4-bis(benzyloxy)ethenylpyridazine (Intermediate 78; 1.09 g, 3.42 mmol), tri-o-tolylphosphine (0.208 g, 0.685 mmol), palladium(II) acetate (0.038 g, 0.171 mmol), 5-bromo-1,3-difluoro(trifluoromethyl)benzene (1.07 g, 4.11 mmol), triethylamine (9.07 ml, 65.1 mmol) and acetonitrile (10 ml) was subjected to microwave irradiation at 120 °C for 2 hours. The on mixture was filtered through diatomaceous earth to remove the insoluble white precipitate and the filtrate partitioned between ethyl e and brine. The organics were dried (MgSO4) and concentrated in vacuo before the crude product was purified by column chromatography (silica, eluting with 0-30 % ethyl acetate in petrol) to afford, 3,4-bis(benzyloxy)[(E)[3,5-difluoro- 4-(trifluoromethyl)phenyl]ethenyl]pyridazine, the title compound as a yellow solid (1.21 g, 71 %). 1H NMR (CD 2Cl2) δ 7.56 (d, 2 H), 7.34 - 7.52 (m, 10 H), 7.27 (d, 2 H), 7.09 (s, 1 H), .67 (s, 2 H) and 5.28 (s, 2 H).
MS ES+: 499.
Intermediate 78: 3,4-bis(Benzyloxy)ethenylpyridazine A vessel containing 2,4,6-triethenyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (1.105 g, 4.59 mmol), s(benzyloxy)chloropyridazine (Intermediate 1, 3 g, 9.18 mmol) and potassium carbonate (3.17 g, 22.95 mmol) was evacuated and flushed with nitrogen. e (30 ml) and water (3 ml) were added in vacuo and the reaction was degassed before tetrakis(triphenyl-phosphine)palladium(0) (0.530 g, 0.459 mmol) was added. The resulting mixture was then heated at 80 °C for 18 hours and upon cooling, was diluted with ethyl e and washed with saturated aqueous sodium carbonate solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. This was purified by column chromatography (silica, eluting with 0-30 % ethyl acetate in petrol) to afford 3,4- bis(benzyloxy)ethenylpyridazine (1.1g, 38 % . 1H NMR (CDCl 3) δ 7.51 - 7.65 (m, 2 H), 7.29 - 7.49 (m, 8 H), 6.82 - 6.98 (m, 2 H), 5.89 - 6.03 (m, 1 H), 5.67 (s, 2 H), 5.45 - 5.59 (m, 1 H) and 5.24 (s, 2 H).
MS ES+: 319.
Intermediate 79: 3,4-bis(Benzyloxy)[(E)[3-fluoro(trifluoromethyl)- phenyl]ethenyl]pyridazine A vessel containing 3,4-bis(benzyloxy)ethenylpyridazine (Intermediate 78, 1.09 g, 3.42 mmol), tris-(2-methylphenyl)phosphane (0.208 g, 0.685 mmol), 2-fluoroiodo (trifluoromethyl)benzene (1.191 g, 4.11 mmol) and palladium(II) acetate (0.038 g, 0.171 mmol) was evacuated and acetonitrile (10 ml) and ylamine (9.07 ml, 65.1 mmol) were added in vacuo and then the mixture was flushed with nitrogen. The reaction was then heated in the ave at 80 °C for 4 hours and, upon cooling, was diluted with dichloromethane and washed with saturated aqueous ammonium chloride solution. The organics were dried (MgSO4), filtered and t removed in vacuo to give a brown oil which was purified by column chromatography (silica, eluting with 30- 100 % dichloromethane in petrol) to yield s(benzyloxy)[(E)[3-fluoro (trifluoromethyl)phenyl]ethenyl]pyridazine (1.1 g, 2.29 mmol, 67 % yield). 1H NMR (CDCl 3) δ 7.53 - 7.68 (m, 3 H), 7.31 - 7.53 (m, 12 H), 6.97 (s, 1 H), 5.71 (s, 2 H) and 5.28 (s, 2 H).
MS ES+: 481. 2. Examples Scheme A: Example 1: 4-Hydroxy(2-phenylethyl)pyridazin-3(2H)-one 3,4-bis(Benzyloxy)(phenylethynyl)pyridazine (Intermediate 2; 320 mg, 0.815 mmol) was ved in ethanol and palladium on carbon (87 mgs, 0.815 mmol) was added before the mixture was purged and subjected to hydrogen gas. The reaction was then filtered and evaporated and the residue was purified on silica using 0-10 % methanol in dichloromethane to yield a red solid. This was ated with ethanol to give the crude title compound as a white solid and the mother liquors were evaporated and dissolved in a minimum amount of dimethyl sulfoxide and purified by C18 reverse phase silica chromatography to yield 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (31 mg, 0.14 mmol, 17.6 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.80 (s, br, 1 H), 10.7 (s, br, 1 H), 7.15 - 7.30 (m, 6 H), 2.85 – 2.95 (m, 2 H) and 2.76 – 2.83 (s, 2 H).
MS ES+: 217.
Example 2: 6-[2-(4-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared as bed for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(4-fluorophenyl)ethynyl]pyridazine (Intermediate 3). 1H NMR (400 MHz, DMSO-d 6) δ 7.22-7.28 (m, 2 H), 7.05-7.13 (m, 2 H), 6.58 (s, 1 H), 2.85 - 2.94 (m, 2 H) and 2.73-2.79 (m, 2H) MS ES+: 236.
Example 3: 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin- 3(2H)-one 3,4-bis(benzyloxy){[5-(trifluoromethyl)pyridinyl]ethynyl}pyridazine (Intermediate 6; 460 mg, 0.997 mmol) was dissolved in ethanol and palladium on carbon was added before the mixture was purged and subjected to hydrogen gas. On completion of the reaction the solvent was removed in vacuo to yield a residue which was purified by reverse phase chromatography using 5-90 % acetonitrile in acidic water (0.05 % trifluoroacetic acid) to give, after recrystallisation from an ethanol-heptane e, 4-hydroxy(2-(5-(trifluoromethyl)pyridinyl)ethyl)pyridazin-3(2H)-one (136 mg, 0.48 mmol, 48 % . 1H NMR (400 MHz, DMSO-d 6) δ 12.66 (br s, 1 H), 10.72 (br s, 1 H), 8.89 (s, 1 H), 8.11 (s, 1 H), 7.54 (s, 1 H), 6.62 (s, 1 H), 3.13 - 3.19 (m, 2 H) and 2.90-2.98 (m, 2 H) MS ES+: 286.
Scheme B: Example 4: 6-[(4-Chlorobenzyl)sulfanyl]hydroxypyridazin-3(2H)-one To a solution of 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 8; 527 mg, 1.04 mmol) in methanol (5177 µl) was added a solution of hydrogen chloride in dioxane (4.0 M, 5177 µl, 20.71 mmol) and the reaction was allowed to stir at room temperature for 72 hours. The ing mixture was trated in vacuo to afford a yellow solid which was recrystallised from ethanol to afford 6-[(4-chlorobenzyl)sulfanyl]hydroxypyridazin-3(2H)-one as white crystals (153 mg, 56.9 mmol, 55 %). 1H NMR (400 MHz, DMSO-d 6): δ 12.99 (s, br, 1 H), 10.6 (s, br, 1 H), 7.35 - 7.46 (m, 4 H), 6.53 (s, 1 H) and 4.24 (s, 2 H).
MS ES+: 269.
Example 5: 4-Hydroxy{2-[6-(trifluoromethyl)pyridinyl]ethyl}pyridazin- 3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy){[6-(trifluoromethyl)pyridinyl]ethynyl}pyridazine (Intermediate 9) except that the on was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions to afford 4-hydroxy{2-[6-(trifluoromethyl)pyridin yl]ethyl}pyridazin-3(2H)-one as a cream solid (26 % yield).
H NMR (400 MHz, DMSO-d6): δ 12.68 (br s, 1 H), 10.80 (s, br, 1 H), 8.64 (s, 1 H), 7.92 – 7.98 (m, 1 H), 7.80 – 7.88 (m, 1 H), 6.61 (s, 1 H), 2.98 – 3.08 (m, 2 H) and 2.80 – 2.88 (m, 2 H).
MS ES : 286. e 6: 6-[2-(3-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one O N Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(3-fluorophenyl)ethynyl]pyridazine (Intermediate 10) except that the reaction was carried out in methanol. The resulting crude product was recrystallised from a mixture of ethanol and heptane to afford 6-[2-(3- fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one as cream crystals (yield = 63 %).
H NMR (400 MHz, DMSO-d6): δ 12.67 (br s, 1 H), 10.71 (br s, 1 H), 7.25 – 7.38 (s, 1 H), 6.95 – 7.15 (m, 3 H), 6.61 (s, 1 H), 2.88 – 2.95 (m, 2 H) and 2.73 – 2.81 (m, 2 H).
MS ES : 235. e 7: 6-[2-(2-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one ed as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy)[(2-fluorophenyl)ethynyl]pyridazine (Intermediate 11).
H NMR (400 MHz, DMSO-d6) δ 12.69 (br s, 1 H), 10.77 (br s, 1 H), 7.21-7.35 (m, 2 H), 7.08-7.21 (m, 2 H), 6.60 (s, 1 H), 2.85 - 2.95 (m, 2 H) and 2.72-2.79 (m, 2H) MS ES : 235.
Example 8: 6-[2-(3,5-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(3,5-difluorophenyl)ethynyl]pyridazine (Intermediate 12).
The crude material was purified by e phase column chromatography (10 g C18) cartridge eluting with 0-100 % methanol and water with acidic modifier to afford a pale orange oil solid. This was recrystallised from a mixture of ethanol and heptane to give a peach coloured solid (yield = 29 %).
H NMR (400 MHz, DMSO-d6): δ 12.69 (br s, 1 H), 10.74 (br s, 1 H), 6.95 – 7.05 (m, 3 H), 6.60 (s, 1 H), 2.88 – 2.95 (m, 2 H) and 2.74 – 2.81 (m, 2 H).
MS ES : 253.
Example 9: 3,4-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(3,4-difluorophenyl)ethynyl]pyridazine (Intermediate 13). The crude material was purified by reverse phase chromatography, eluting with 5- 100 % itrile in water with a 0.05 % formic acid modifier in the water.
H NMR (400 MHz, DMSO-d6): δ 12.6 (s, br, 1 H), 10.8 (s, br, 1 H), 7.24 – 7.38 (m, 2 H), 7.02 – 7.09 (m, 1 H), 6.64 (s, 1 H), 2.84 – 2.92 (m, 2 H) and 2.72 – 2.81 (m, 2 H).
MS ES : 253.
Example 10: 4-Hydroxy{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)- one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy){2-[3-(trifluoromethoxy)phenyl]ethynyl}pyridazine (Intermediate 14). The residue was purified by e phase column chromatography (30 g C18) cartridge eluting with 0-100 % methanol in water with acidic modifier and the appropriate fractions ed and concentrated. The crude product was recrystallised from ethyl acetate / heptane to give a white solid (yield = 23 %).
H NMR (400 MHz, DMSO-d6): δ 12.67 (br s, 1 H), 10.71 (br s, 1 H), 7.35 – 7.45 (m, 1 H), 7.15 – 7.30 (m, 3 H), 6.51 (s, 1 H), 2.92 – 2.98 (m, 2 H) and 2.74 – 2.84 (m, 2 H).
MS ES : 301.
Example 11: 4-Hydroxy{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)- O N Prepared as described for oxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy){2-[3-(trifluoromethyl)phenyl]ethynyl}pyridazine (Intermediate 15) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (2:1). The crude material was purified by reverse phase chromatography, eluting with 5-80 % acetonitrile / water with a 0.05 % formic acid modifier in the water. The crude product was recrystallised from ethanol / heptane to give a white solid (yield = 27 %).
H NMR (400 MHz, DMSO-d6): δ 12.7 (s, br, 1 H), 10.7 (s, br, 1 H), 7.59 (s, 1 H), 7.49 – 7.53 (m, 3 H), 6.61 (s, 1 H), 2.95 – 3.01 (m, 2 H) and 2.77 – 2.81 (m, 2 H).
MS ES : 285.
Example 12: oxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin- 3(2H)-one To a solution of 3,4-bis(benzyloxy){2-[5-(trifluoromethyl)pyridin yl]ethynyl}pyridazine (Intermediate 16, 1.5 g) in methanol (10 ml) was added 10 % palladium on carbon (0.04 g) slowly under nitrogen and the on mixture was stirred for 30 minutes at room temperature under a en atmosphere. The resulting mixture was filtered through a “Celite” (trade mark) diatomaceous earth bed under en atmosphere and washed with methanol before the filtrate was concentrated under vacuum to afford crude 3,4-bis (benzyloxy)(2-(5-(trifluoromethyl) pyridin yl) ethyl)pyridazine (0.4 g, 0.86 mmol). This was taken up in methanol (10 ml) at room temperature and 10 % palladium on carbon (0.04 g) was added slowly under nitrogen atmosphere. The mixture was then stirred under hydrogen (200 psi) at room temperature overnight before being filtered through a bed of “Celite” diatomaceous earth under nitrogen and washed with methanol. The c layer was concentrated in vacuo to afford the crude product (0.2 g) which was purified by the preparative HPLC to afford homogeneous 4-hydroxy{2-[5-(trifluoromethyl)pyridin yl}pyridazin-3(2H)-one (0.03 g, 81.6% yield).
H NMR (400 MHz, 6): δ 12.72 (s, br, 1 H), 10.81 (s, br, 1 H), 8.80 (s, 1 H), 8.75 (s, 1 H), 8.10 (s, 1 H), 6.63 (s, 1 H), 3.00 – 3.34 (m, 2 H) and 2.81 – 2.85 (m, 2 H).
MS ES : 286.
Example 13: 6-(2-Cyclohexylethyl)hydroxypyridazin-3(2H)-one O N Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)(cyclohexylethynyl)pyridazine (Intermediate 17) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1).
The resulting crude product was ed by preparative HPLC under acidic conditions.
The solid obtained was recrystallised from methyl tert-butyl ether and ethyl acetate to afford 6-(2-cyclohexylethyl)hydroxypyridazin-3(2H)-one as a cream solid (11 % yield).
H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1 H), 10.68 (br s, 1 H), 6.52 (s, 1 H), 2.39 - 2.48 (m, 2 H), 1.56 - 1.76 (m, 5 H), 1.38 - 1.49 (m, 2 H), 1.05 - 1.27 (m, 4 H), 0.80 - 0.97 (m, 2 H) MS ES : 223.
Example 14: 6-(2-Cyclopropylethyl)hydroxypyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one le 1) from 3,4-bis(benzyloxy)(cyclopropylethynyl)pyridazine (Intermediate 18) except that the reaction was d out in ethanol. The resulting crude t was purified by preparative HPLC under acidic conditions to afford 6-(2-cyclopropylethyl) hydroxypyridazin-3(2H)-one as a cream solid (14 % yield).
H NMR (400 MHz, MeOH-d6) δ 6.55 (s, 1 H), 2.55 - 2.63 (m, 2 H), 1.45 - 1.54 (m, 2 H), 0.67 - 0.75 (m, 1 H), 0.38 - 0.42 (m, 2 H) and - 0.04 - 0.06 (m, 2 H) MS ES : 181.
Example 15: yclopentylethyl)hydroxypyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)(cyclopentylethynyl)pyridazine (Intermediate 19) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1).
The resulting crude product was purified by preparative HPLC under acidic conditions to afford 6-(2-cyclopentylethyl)hydroxypyridazin-3(2H)-one after recrystallisation from ethanol and heptane as a white solid (51 % yield).
H NMR (400 MHz, DMSO-d6) δ 12.63 (br s, 1 H), 10.67 (br s, 1 H), 6.54 (s, 1 H), 2.41 - 2.48 (m, 2 H), 1.67 - 1.79 (m, 3 H), 1.41 - 1.63 (m, 6 H), 1.00-1.15 (m, 2 H).
MS ES : 209.
Example 16: 4-Hydroxy[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(4-methoxycyclohexenyl)ethynyl]pyridazine (Intermediate 20) except that the reaction was carried out in methanol. The ing crude product was purified by preparative HPLC under acidic ions to afford 4- hydroxy[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one (mixture of isomers) as a white solid (26 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.62 (s, 1 H), 10.66 (br s, 1 H), 6.52-6.55 (m, 1 H), 3.21 and 3.18 (2 singlets, total 3 H), 2.97 - 3.08 (m, 1 H), 2.40 - 2.47 (m, 2 H), 1.91 - 2.01 (m, 1 H), 1.70 - 1.80 (m, 2 H), 0.84 - 1.51 (m, 8 H) MS ES : 253.
Example 17: 6-[2-(2,4-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared as described for oxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(2,4-difluorophenyl)ethynyl]pyridazine (Intermediate 21) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100 % acetonitrile / water with acidic modifier and the appropriate fractions combined to give a yellow solid. This was recrystallised from ethanol to give a white solid (yield = 26 %).
H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1 H), 10.78 (br s, 1 H), 7.24 - 7.40 (m, 1 H), 7.09 - 7.26 (m, 1 H), 6.93 - 7.07 (m, 1 H), 6.58 (s, 1 H), 2.82 - 2.97 (m, 2 H), 2.63 - 2.80 (m, 2 H).
MS ES : 253.
Example 18: 3-(Difluoromethyl)phenyl]ethyl}hydroxypyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy)[(3-(difluoromethyl)phenyl)ethynyl]pyridazine (Intermediate 22) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge g with 5-100 % itrile / water with acidic modifier and the appropriate fractions combined to give a pale orange solid (yield = 32%).
H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1 H), 10.77 (br s, 1 H), 7.33 - 7.47 (m, 5 H), 6.79 - 7.18 (m, 1 H), 6.61 (s, 1 H), 2.89 - 3.00 (m, 2 H), 2.71 - 2.83 (m, 2 H).
MS ES : 267.
Example 19: 6-Benzylhydroxypyridazin-3(2H)-one To a degassed solution of yl-3,4-bis(benzyloxy)pyridazine (Intermediate 23: 0.16 g, 0.418 mmol) in methanol (4.18 ml) was added 10 % palladium on carbon (0.045 g, 0.042 mmol). The mixture was degassed, evacuated and filled with hydrogen from a balloon. After 1 hour the reaction mixture was degassed and filtered through a pad of “Celite” diatomaceous earth, washing with methanol and concentrated to give a yellow oil. The crude oil was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100 % acetonitrile / water with acidic modifier and the appropriate fractions combined to give a cream solid (yield = 77 %).
H NMR (400 MHz, DMSO-d6) δ 12.72 (br s, 1 H), 10.78 (br s, 1 H), 7.15 - 7.40 (m, 5 H), 6.46 (s, 1 H), 3.79 (s, 2 H).
MS ES : 203.
Example 20: 6-[2-(3-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(3-chloromethyl)phenyl)ethynyl]pyridazine (Intermediate 24) except that the on was carried out in ethyl acetate. The crude material was purified by reverse phase chromatography (50 g C18) cartridge eluting with 5-100 % acetonitrile / water with acidic modifier and the appropriate fractions combined to give an orange solid. This was tallised from ethyl acetate to give a white solid (yield = 32 %).
H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1 H), 10.72 (br s, 1 H), 7.10 - 7.40 (m, 4 H), 6.60 (s, 1 H), 2.82 - 3.05 (m, 2 H), 2.71 - 2.82 (m, 2 H).
MS ES : 251.
Example 21: 4-Hydroxy(1-phenylcyclopropyl)pyridazin-3(2H)-one Prepared as described for 4-hydroxy(2-phenethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy)(1-phenylcyclopropyl)pyridazine (Intermediate 26) except that the reaction was carried out in ethyl acetate. The crude al was recrystallised from ethyl acetate to give a pink solid (yield = 27 %).
H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1 H), 10.74 (br s, 1 H), 7.13 - 7.39 (m, 5 H), 6.32 (s, 1 H), 1.27 - 1.39 (m, 2 H), 1.10 - 1.24 (m, 2 H).
MS ES : 229.
Example 22: 4-[2-(5-Hydroxyoxo-1,6-dihydropyridazinyl)ethyl]benzonitrile Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 4-{2-[5,6-bis(benzyloxy)pyridazinyl]ethynyl}benzonitrile (Intermediate 27) except that the solvent mixture used for the hydrogenation was made up from tetrahydrofuran and methanol (1:1) and the final nd was recrystallised from tetrahydrofuran. 1H NMR (400 MHz, DMSO-d6) δ 12.59 (br s, 1 H), 10.66 (br s, 1 H), 7.56 - 7.78 (m, 2 H), 7.27 - 7.44 (m, 2 H), 6.52 (s, 1 H), 2.82 - 3.01 (m, 2 H) and 2.56 - 2.82 (m, 2 H).
MS ES+: 242. e 23: 6-[2-(3-Fluoromethylphenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(3-fluoro methylphenyl)ethynyl]pyridazine (Intermediate 28) except that the solvent mixture used for the hydrogenation was ethyl acetate and methanol (1:1) and the final product was recrystallised from ethyl e. 1H NMR (400 MHz, DMSO-d 6) d 12.67 (s, 1 H), 10.71 (br s, 1 H), 7.09 - 7.24 (m, 1 H), 6.85 - 7.07 (m, 2 H), 6.59 (s, 1 H), 2.80 - 2.93 (m, 2 H), 2.68 - 2.77 (m, 2 H) and 2.18 (s, 3 H).
MS ES+: 249.
Example 24: 6-[2-(4-Fluoromethylphenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(4-fluoro methylphenyl)ethynyl]pyridazine mediate 29) except that the t mixture used for the hydrogenation was made up of ethyl acetate and methanol (1:1) and the final material was recrystallised from ethyl acetate. 1H NMR (400 MHz, DMSO-d 6) δ 12.67 (s, 1 H), 10.70 (br s, 1 H), 6.90 - 7.20 (m, 3 H), 6.58 (s, 1 H), 2.61 - 2.91 (m, 4 H) and 2.20 (s, 3 H).
MS ES+: 249.
Example 25: 6-[2-(3,4-Dimethoxyphenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(3,4-dimethoxyphenyl)ethynyl]pyridazine mediate 30) except that the solvent mixture used for the hydrogenation was ethanol and tetrahydrofuran (1:1) and the final material was recrystallised from a mixture of ethyl acetate and heptane. 1H NMR (400 MHz, DMSO-d 6) δ 12.66 (br s, 1 H), 10.69 (br s, 1 H), 6.76 - 6.94 (m, 2 H), 6.63 - 6.77 (m, 1 H), 6.58 (s, 1 H), 3.59 - 3.82 (m, 6 H) and 2.60 - 2.91 (m, 4 H).
MS ES+: 277.
Example 26: 4-Hydroxy{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)- Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from 3,4-bis(benzyloxy) ((3(trifluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 39) except that the t used for the hydrogenation was ethanol and the final compound was recrystallised from a mixture of ethyl acetate and heptane. 1H NMR (400 MHz, DMSO-d 6) δ 12.67 (s, 1 H), 10.71 (br s, 1 H), 7.36 - 7.45 (m, 1 H), 7.13 - 7.30 (m, 3 H), 6.60 (s, 1 H), 2.88 - 2.99 (m, 2 H) and 2.73 - 2.82 (m, 2 H).
MS ES+: 301.
Example 27: 6-[2-(4-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)((4-chlorophenyl)ethynyl)pyridazine (Intermediate 34) except that the solvent used for the enation was tetrahydrofuran and the final compound was recrystallised from a mixture of ethyl acetate and heptane. 1H NMR (400 MHz, DMSO-d 6) δ 12.66 (s, 1 H), 10.72 (br s, 1 H), 7.14 - 7.44 (m, 4 H), 6.58 (s, 1 H), 2.83 - 2.92 (m, 2 H) and 2.69 - 2.79 (m, 2 H).
MS ES+: 251, 253.
Example 28: 6-[2-(2-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)((2-chlorophenyl)ethynyl)pyridazine (Intermediate 35) except that the solvent used for the enation was ethyl acetate and the final material was recrystallised from a mixture of ethyl acetate and heptane 1H NMR (400 MHz, DMSO-d 6) δ 12.67 (s, 1 H), 10.73 (br s, 1 H), 7.14 - 7.46 (m, 4 H), 6.58 (s, 1 H), 2.91 - 3.05 (m, 2 H) and 2.70 - 2.81 (m, 2 H).
MS ES+: 251, 253.
Example 29: oxy{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)- Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)((2-trifluoromethylphenyl)ethynyl)pyridazine (Intermediate 40) except that the final product was recrystallised from a mixture of ethyl acetate and heptane. 1H NMR (400 MHz, DMSO-d 6) δ 12.66 (br s, 1 H), 10.79 (br s, 1 H), 7.35 - 7.74 (m, 4 H), 6.56 (s, 1 H), 2.97 - 3.11 (m, 2 H) and 2.71 - 2.82 (m, 2 H).
MS ES+: 285.
Example 30: 6-(4-(Difluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)((4- (difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 36) except that the solvent mixture used for the enation was made up of tetrahydrofuran and methanol and the final material was recrystallised from 2-propanol and heptanes. 1H NMR (400 MHz, CD 2Cl2) δ 7.17 - 7.24 (m, 2 H), 7.00 - 7.11 (m, 2 H), 6.55 (s, 1 H), 6.31 - 6.74 (m, 1 H), 2.91 - 3.00 (m, 2 H) and 2.81 - 2.91 (m, 2 H).
MS ES+ 283.
Example 31: 6-(4-(Trifluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one ed by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)((4- uoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 37) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from MTBE and e. 1H NMR (400 MHz, DMSO-d 6) δ 12.70 (s, 1 H), 10.75 (br s, 1 H), 7.21 - 7.41 (m, 4 H), 6.61 (s, 1 H) and 2.67 - 2.99 (m, 4 H).
MS ES+ 301.
Example 32: 6-(3-(Difluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)((3- (difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 38) except that the mixture of solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final compound was recrystallised from a mixture of ethanol and heptane. 1H NMR (400 MHz, DMSO-d 6) δ 12.65 (br s, 1 H), 6.92 - 7.43 (m, 6 H), 6.58 (s, 1 H), 2.83 - 2.97 (m, 2 H) and 2.70 - 2.84 (m, 2 H).
MS ES+ 283.
Example 33: 6-[1-(4-Fluorophenyl)cyclopropyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for oxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[1-(4-fluorophenyl)cyclopropyl]pyridazine (Intermediate 42) except that the solvent used for the enation was ethyl acetate and the t was recrystallised from a mixture of ethyl acetate and MTBE. 1H NMR (400 MHz, DMSO-d 6) δ12.69 (s, 1 H), 10.77 (br s, 1 H), 7.26 - 7.42 (m, 2 H), 7.01 - 7.26 (m, 2 H), 6.32 (s, 1 H), 1.28 - 1.39 (m, 2 H) and 1.09 - 1.22 (m, 2 H).
MS ES+: 247.
Example 34: 6-[1-(4-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine (Intermediate 41) except that the solvent mixture used for the hydrogenation consisted of ethyl acetate and tetrahydrofuran and the product was recrystallised from a mixture of heptane and MTBE. 1H NMR (400 MHz, DMSO-d 6) δ 12.75 (s, 1 H), 10.74 (br s, 1 H), 7.24 - 7.35 (m, 2 H), 7.00 - 7.19 (m, 2 H), 6.43 (s, 1 H), 3.85 - 4.13 (m, 1 H) and 1.38 - 1.55 (m, 3 H).
MS ES+: 235.
Example 35: 4-Hydroxy{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)- O N Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)(3-methylbutynyl)pyridazine (Intermediate 43) except that the solvent e used for the hydrogenation was made up of ethyl acetate and tetrahydrofuran and the product was recrystallised from heptane and MTBE. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.80 (br. s., 1H), 7.47 - 7.66 (m, 4H), 6.51 (s, 1H), 4.02 - 4.25 (m, 1H), 1.41 - 1.60 (m, 3H) MS ES+: 285 Example 36: 4-Hydroxy{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)- Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from (E)-3,4-bis(benzyloxy)(4-(trifluoromethyl)styryl)pyridazine (Intermediate 44) except that the product was recrystallised from a mixture of heptane and ethyl acetate. 1H NMR (400 MHz, DMSO-d 6) δ 12.67 (s, 1 H), 10.73 (br s, 1 H), 7.58 - 7.68 (m, 2 H), 7.40 - 7.49 (m, 2 H), 6.61 (s, 1 H), 2.92 - 3.03 (m, 2 H) and 2.72 - 2.85 (m, 2 H) MS ES+: 285.
Example 37: 6-((Cyclopropylmethyl)(methyl)amino)hydroxypyridazin-3(2H)- A suspension of 5,6-bis(benzyloxy)-N-(cyclopropylmethyl)-N-methylpyridazin amine (Intermediate 46; 2.44 mmol) and palladium on carbon (10% wt loading, dry basis; 0.259 g, 0.244 mmol) in ethyl acetate (10 ml) was d under a hydrogen here for 2 hours. The reaction mixture was filtered through a diatomaceous earth cartridge commercially sold under the trade mark ‘Celite’, eluting with ethyl acetate, tetrahydrofuran and methanol. The filtrate was concentrated in vacuo to afford a brown solid, which was triturated from ethyl acetate to give the title compound as a pale brown solid (27.9 mg, 38 %). 1H NMR (400 MHz, DMSO-d 6) δ 11.81 - 11.98 (m, 1 H), 6.48 (s, 1 H), 3.12 (d, 2 H), 2.84 (s, 3 H), 0.84 - 1.01 (m, 1 H), 0.36 - 0.51 (m, 2 H) and 0.09 - 0.26 (m, 2H).
MS ES+ 196.
Example 38: 6-((Cyclohexylmethyl)(methyl)amino)hydroxypyridazin-3(2H)-one Prepared according to the procedure for 6-((cyclopropylmethyl)(methyl)amino) hydroxypyridazin-3(2H)-one (Example 37) using 5,6-bis(benzyloxy)-N- hexylmethyl)-N-methylpyridazinamine (Intermediate 47) but purified by reverse phase C18 chromatography, g with 5-100 % acetonitrile / water with a 0.1 % ammonia modifier in both the water and acetonitrile to give the title nd as a pale cream solid (45 mg, 26 %) . 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.88 (br s, 1 H), 6.44 (s, 1 H), 2.98 - 3.13 (m, 2 H), 2.82 (s, 3 H), 1.52 - 1.74 (m, 6 H), 1.04 - 1.26 (m, 3 H) and 0.82 - 0.99 (m, 2 H).
MS ES+ 238.
Example 39: 6-(3-Chlorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as oxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy)[(3-chlorophenyl)methyl]pyridazine (Intermediate 48) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from ethyl acetate. 1H NMR (400 MHz, DMSO-d 6) δ 12.75 (s, 1 H), 10.83 (br s, 1 H), 7.15 - 7.40 (m, 4 H), 6.52 (s, 1 H) and 3.81 (s, 2 H).
MS ES+: 237 and 239.
Example 40: 6-(4-Chlorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(4-chlorophenyl)methyl]pyridazine (Intermediate 49) except that the solvent used for the hydrogenation was ethyl acetate and tetrahydrofuran and the product was recrystallised from ethyl acetate. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1 H), 10.81 (br s, 1 H), 7.32 - 7.45 (m, 2 H), 7.16 - 7.32 (m, 2 H), 6.48 (s, 1 H) and 3.79 (s, 2 H).
MS ES+: 237 and 239. e 41: 6-(Cyclohexylmethyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)(cyclohexylmethyl)pyridazine (Intermediate 50) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of MTBE and heptanes. 1H NMR (400 MHz, DMSO-d 6) δ 12.64 (s, 1 H), 10.64 (br s, 1 H), 6.51 (s, 1 H), 2.21 - 2.39 (m, 2 H), 1.44 - 1.72 (m, 6 H), 1.03 - 1.25 (m, 3 H) and 0.75 - 1.05 (m, 2 H).
MS ES+: 209.
Example 42: luorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of MTBE and heptanes. 1H NMR (400 MHz, DMSO-d 6) δ 12.73 (s, 1 H), 10.79 (br s, 1 H), 7.22 - 7.33 (m, 2 H), 6.96 - 7.18 (m, 2 H), 6.47 (s, 1 H) and 3.79 (s, 2 H).
MS ES+: 221.
Example 43: 6-(2-Chlorofluorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from s(benzyloxy)[(2-chlorofluorophenyl)methyl]pyridazine (Intermediate 52) except that the solvent used for the hydrogenation was tetrahydrofuran and the product was recrystallised from a mixture of MTBE and heptanes. 1H NMR (400 MHz, DMSO-d 6) δ 12.66 (s, 1 H), 10.90 (br s, 1 H), 7.31 - 7.48 (m, 2), 7.05 - 7.32 (m, 1 H), 6.55 (s, 1) and 4.00 (s, 2 H).
MS ES+: 255, 257.
Example 44: 6-(2-Chlorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(2-chlorophenyl)methyl]pyridazine (Intermediate 53) except that the t used for the hydrogenation was tetrahydrofuran and the product was recrystallised from a mixture of MTBE and heptanes. 1H NMR (400 MHz, DMSO-d 6) δ 12.72 (s, 1 H), 10.80 (br s, 1 H), 7.40 - 7.57 (m, 1 H), 7.20 - 7.42 (m, 3 H), 6.48 (s, 1 H) and 3.95 (s, 2 H).
MS ES+: 237, 239.
Example 45: 6-(3-Fluorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(3-fluorophenyl)methyl]pyridazine (Intermediate 54) except that the solvent used for the hydrogenation was l and the product was recrystallised from a mixture of MTBE and es. 1H NMR (400 MHz, DMSO-d 6) δ 12.75 (s, 1 H), 10.82 (br s, 1 H), 7.25 - 7.44 (m, 1 H), 6.99 - 7.14 (m, 3 H), 6.41 - 6.58 (m, 1 H) and 3.68 - 3.89 (m, 2 H).
MS ES+: 221.
Example 46: 6-(2-Fluorobenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(2-fluorophenyl)methyl]pyridazine (Intermediate 55) except that the product was recrystallised from a mixture of ethyl acetate and heptanes. 1H NMR (400 MHz, DMSO-d 6) δ 12.71 (br s, 1 H), 10.85 (br s, 1 H), 7.26 - 7.37 (m, 2 H), 7.12 - 7.22 (m, 2 H), 6.48 (s, 1 H) and 3.85 (s, 2 H).
MS ES+: 221.
Example 47: 6-(4-Methylbenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(4-methylphenyl)methyl]pyridazine (Intermediate 56) except that the solvent e used for the hydrogenation was made up of tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes. 1H NMR (400 MHz, DMSO-d 6) δ 12.70 (br s, 1 H), 10.75 (br s, 1 H), 7.12 (s, 4 H), 6.42 (s, 1 H), 3.64 - 3.82 (s, 2 H) and 2.26 (s, 3 H).
MS ES+: 217. e 48: 6-(3-Methylbenzyl)hydroxypyridazin-3(2H)-one Prepared in the same way as oxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy)[(3-methylphenyl)methyl]pyridazine (Intermediate 57) except that the solvent mixture used for the hydrogenation was made up from tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptane. 1H NMR (400 MHz, DMSO-d 6) δ 12.71 (br s, 1 H), 10.78 (br s, 1 H), 7.14 - 7.25 (m, 1 H), 6.96 - 7.10 (m, 3 H), 6.44 (s, 1 H), 3.74 (s, 2 H) and 2.17 - 2.35 (m, 3 H).
MS ES+: 217.
Example 49: 4-Hydroxy(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from s(benzyloxy)(3-(trifluoromethyl)benzyl) pyridazine (Intermediate 58) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes. 1H NMR (400 MHz, CD2Cl2) δ ppm 10.68 (br s, 1 H), 7.40 - 7.70 (m, 4 H), 6.56 (s, 1 H) and 3.99 (s, 2 H).
MS ES+ 271.
Example 50: 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin- 3(2H)-one 3,4-bis(Benzyloxy){2-[5-(trifluoromethyl)pyridinyl]ethynyl}pyridazine (Intermediate 31; 1.5 g, 3.25 mmol) was dissolved in methanol (10 mL) and 10 % palladium on carbon (0.04 g) was added before the mixture was purged and subjected to hydrogen gas. The reaction mixture was stirred for 30 min at room temperature under a hydrogen atmosphere. The reaction mass was then filtered h a celite bed under nitrogen atmosphere and washed with methanol. The te was concentrated in vacuo before the crude was re-dissolved in methanol (10 mL) and 10 % palladium on carbon (0.04 g) was added before the mixture was purged and subjected to a pressure of hydrogen gas (200 psi), stirring at room temperature overnight. Upon completion the resulting mixture was filtered through celite under nitrogen and washed with methanol.
The filtrate was concentrated under vacuum to afford the crude nd (0.2 g) which was then purified by the ative HPLC to yield 4-hydroxy(2-(5-(trifluoromethyl) pyridinyl) ethyl) pyridazin-3(2H)-one (0.03 g, 82 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.72 (s, 1 H), 10.82 (s, 1 H), 8.75-8.80 (d, 2 H), 8.10 (s, 1 H), 6.63 (s, 1 H), .04 (t, 2 H) and 2.81-2.85 (t, 2 H).
LC-MS ES+: 286.
Example 51: 4-Hydroxy[2-(oxanyl)ethyl]pyridazin-3(2H)-one O N H Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(3,6-dihydro-2H-pyran yl)ethynyl]pyridazine (Intermediate 60) except that the pressure of hydrogen gas was 200 psi at room temperature overnight and the solvent used for the hydrogenation was ol and the product was purified by column chromatography (silica gel, eluting with 0 – 5 % methanol in dichloromethane to afford the title compound (0.1 g, 16 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.67 (s, 1 H), 10.72 (s, 1 H), 6.56 (s, 1 H), 3.802- 3.84 (q, 2 H), 3.22-3.34 (q, 2 H), 1.57-1.60 (d, 2 H), 1.43-1.52 (m, 4 H) and 1.19-1.24 (m, 3 H).
LC-MS ES+: 225.
Example 52: 6-{[(4-Fluorophenyl)methyl](methyl)amino}hydroxy-pyridazin- 3(2H)-one Prepared in the same way as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]-N-methylpyridazin- e (Intermediate 61) except that the solvent used for the hydrogenation was methanol and the product was purified by ating in n-pentane (0.15 g, 52 % yield) 1H NMR (400 MHz, DMSO-d 6) δ 12.07 (s, 1 H), 10.6 (s, 1 H), 7.2-7.34 (m, 2 H), 7.12- 7.18 (m, 2H), 4.49 (s, 2 H) and 2.84 (s, 3 H).
LC-MS ES+: 250.
Example 53: 2,6-Difluorophenyl)ethyl]hydroxy-pyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(2,6-difluorophenyl)ethynyl]pyridazine (Intermediate 33) except that the solvent mixture used for the hydrogenation was methanol and the final material was purified by preparative HPLC (0.035 g, 24.8% yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.68 (s, 1 H), 10.78 (s, 1 H), 7.27-7.35 (m, 1 H), 7.03-7.07 (m, 2 H), 6.55 (s, 1 H), 2.90-2.94 (t, 2 H) and 2.69-2.73 (t, 2 H).
LC-MS ES+: 253.
Example 54: 6-[2-(2-Chlorofluorophenyl)ethyl]hydroxy-pyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[2-(2-chlorofluorophenyl)ethynyl] pyridazine (Intermediate 32) except that the catalyst used for the enation was platinum oxide and the solvent was methanol and the final material was purified by ative HPLC (0.035 g, 24.8% . 1H NMR (400 MHz, DMSO-d 6) δ 12.68 (s, 1 H), 10.78 (s, 1 H), 7.27-7.35 (m, 1 H), 7.03-7.07 (m, 2 H), 6.55 (s, 1 H), 2.90-2.94 (t, 2 H) and 2.69-2.73 (t, 2 H).
LC-MS ES+: 253.
Example 55: 6-{[3,5-bis(Trifluoromethyl)phenyl]methyl}hydroxypyridazin- 3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy){[3,5-bis(trifluoromethyl)phenyl]- methyl}pyridazine (Intermediate 58a) except that the solvent used for the hydrogenation was tetrahydrofuran and the final compound was recrystallised from a mixture of ethyl acetate and es (27 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.80 (br s, 1 H), 10.95 (br s, 1 H), 7.93 - 8.02 (m, 3 H), 6.60 (s, 1 H) and 4.05 (s, 2 H).
MS ES+: 339.
Example 56: 6-(1-Phenylethyl)hydroxypyridazin-3(2H)-one Prepared by the same method as for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)(1-phenylethenyl)pyridazine (Intermediate ) except that upon completion of the reaction the resulting mixture was filtered h Celite g with ethanol and then concentrated in vacuo to afford an orange solid. This was purified initially by eluting on a reverse phase C18 chromatography column (0-60% methanol in water with an acidic modifier) and upon combining and concentrating the appropriate fractions the crude t was recrystallised from a mixture of ethyl acetate and heptanes to afford a white solid and the final compound was recrystallised from a mixture of ethyl acetate and heptanes (32 % yield). 1H NMR (400 MHz, DMSO-d 6) δ 12.90 (br s, 1 H), 10.80 (br s, 1 H), 7.13 - 7.35 (m, 6 H), 3.99 (q, 1 H) and 1.47 (d, 3 H).
MS ES+: 217.
Example 57: 6-(Cyclopropylmethyl)hydroxy-2,3-dihydropyridazinone Prepared in the same manner as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from 3,4-bis(benzyloxy)(cyclopropylidenemethyl)pyridazine mediate 65) except that methanol was used as the reaction solvent. The crude compound was ed by preparative HPLC to yield 6-(cyclopropylmethyl) hydroxypyridazin-3(2H)-one (46 % yield) 1H NMR (DMSO-d 6): δ 12.69 (s, 1 H), 10.75 (s, 1 H), 6.63 (s, 1 H), 2.09-2.34 (d, 2 H), 0.89-0.99 (m, 1 H), 0.43-0.49 (m, 2 H) and 0.16-0.17 (m, 2 H).
LC-MS ES+: 167.
Example 58: 4-Hydroxy{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-2,3- dihydropyridazinone Prepared in the same manner as 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy){1-[4-(trifluoromethyl)phenyl]-cyclopropyl}- pyridazine (Intermediate 68) in 20 % yield. 1H NMR (DMSO-d 6) δ 12.76 (s, 1 H), 10.87 (br. s., 1 H) 7.67 (m, 2 H), 7.47 (m, 2 H), 6.37 (s, 1 H), 1.38 - 1.42 (m, 2 H) and 1.23 - 1.28 (m, 2 H).
MS: ES+: 297.
Example 59: 6-{2-[2-Chloro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy){2-[2-chloro(trifluoromethyl)phenyl]- l}pyridazine (Intermediate 69) in 11 % yield. 1H NMR (DMSO-d 6) δ 12.68 (s, 1 H), 10.78 (br. s., 1 H), 7.83 (s, 1 H), 7.64 - 7.68 (m, 1 H), 7.55 - 7.59 (m, 1 H), 6.61 (s, 1 H), 3.05 - 3.11 (m, 2 H) and 2.80 (m, 2 H).
MS: ES+: 319.
Example 60: 6-{2-[2-Fluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy){2-[2-fluoro(trifluoromethyl)phenyl]- l}pyridazine (Intermediate 70) except that THF was used as the solvent. The reaction was filtered through diatomaceous earth flushing with further tetrahydrofuran and concentrated in vacuo. The residue was purified by column chromatography (silica C18 cartridge; g with 0-65 % acetonitrile in water with acid er). The appropriate fractions were combined and concentrated in vacuo to remove the acetonitrile before the aqueous portion was extracted with ethyl acetate (x2), dried (MgSO4) and concentrated in vacuo. The resulting solid was recrystallised from a mixture of methyl tert-butyl ether and heptane to afford 6-{2-[2-fluoro (trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazinone as a cream solid (29 % yield). 1H NMR (DMSO-d 6) δ 12.67 (s, 1 H), 10.76 (br. s., 1 H), 7.60 (m, 1 H), 7.48 - 7.57 (m, 2 H), 6.61 (s, 1 H), 2.95 - 3.04 (m, 2 H) and 2.75 - 2.83 (m, 2 H) MS: ES+: 303.
Example 61: 6-{2-[3,5-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy)[(E)[3,5-bis(trifluoromethyl)phenyl]- ethenyl]pyridazine (Intermediate 71) in 49 % yield. 1H NMR d 6) δ 12.69 (s, 1 H), 10.75 (br. s., 1 H), 7.96 (s, 2 H), 7.91 (s, 1 H), 6.64 (s, 1 H), 3.06 - 3.14 (m, 2 H) and 2.84 (m, 2 H) MS: ES+: 353.
Example 62: 6-{2-[2,4-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydro- pyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(E)[2,4-bis(trifluoromethyl)phenyl]- ethenyl]pyridazine (Intermediate 72) in 31 % yield. 1H NMR (DMSO-d 6) δ 12.71 (s, 1 H), 10.80 (br. s., 1 H), 8.03 (m, 1 H), 7.97 (s, 1 H), 7.79 (m, 1 H), 6.62 (s, 1 H), 3.14 (m, 2 H), 2.77 - 2.86 (m, 2 H) MS: ES+: 353.
Example 63: 6-{2-[3,4-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone To a solution of 3,4-bis(benzyloxy)[(E)[3,4-bis(trifluoromethyl)phenyl]- ethenyl]pyridazine (Intermediate 73, 227 mg, 0.428 mmol) in THF (4279 µl) was added palladium on carbon (45.5 mg, 0.043 mmol) and the reaction vessel evacuated and purged with nitrogen (x 3). The reaction was stirred under a hydrogen atmosphere for 4 hours and the resulting mixture was filtered through a short pad of diatomacious earth and concentrated in vacuo. The residue was purified by chromatography (C18 silica cartridge eluting with 0-50 % acetonitrile in water with basic modifier). The appropriate fractions were combined and concentrated to remove the organics and the aqueous fractions were acidified with hydrochloric acid (2 N) and extracted with ethyl e (x 2), dried (MgSO4) and trated in vacuo to yield 6-{2-[3,4- bis(trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazinone as a cream solid (39 mg, 26 %) 1H NMR (DMSO-d 6) δ 12.69 (s, 1 H), 10.76 (br. s., 1 H), 7.95 (m, 1 H), 7.88 - 7.93 (m, 1 H), 7.76 (m, 1 H), 6.65 (s, 1 H), 3.04 - 3.12 (m, 2 H) and 2.83 (m, 2 H).
MS: ES+: 353 Example 64: 4-Hydroxy(3-methyl(trifluoromethyl)phenethyl)pyridazin- 3(2H)-one O N Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from 3,4-bis(benzyloxy)((3-methyl(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) except THF was used as the solvent. The reaction mixture was filtered through a diatomacious earth cartridge, eluting with further THF and methanol.
The filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (eluting with 5-100 % aqueous itrile with acid modifier).
The d fractions were combined and freeze dried to give a pale yellow solid, which was recrystallised from methyl tert-butyl ether to give a white solid. The filtrate was concentrated under reduced pressure, and the filtrate and ls ed separately by ative HPLC. The two batches were combined and recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 4-hydroxy(3-methyl (trifluoromethyl)-phenethyl)pyridazin-3(2H)-one as a white solid (31 mg, 4 %). 1H NMR (CD 3OD) δ 7.51 (d, 1 H), 7.22 (s, 1 H), 7.16 (d, 1 H), 6.57 (s, 1 H), 2.94 - 3.02 (m, 2 H), 2.81 - 2.90 (m, 2 H) and 2.44 (s, 3 H).
MS ES+: 299 M. p. = 174-175 °C.
Example 65: 3,4-bis(Benzyloxy)((3-chloro(trifluoromethyl)phenyl)ethyl)- pyridazine Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from s(benzyloxy){2-[3-chloro(trifluoromethyl)phenyl]- ethynyl}pyridazine (Intermediate 75) except that THF was used as the solvent. The crude product was ed by reverse phase tography (eluting with 5-100 % acetonitrile in water with acid modifier) to give a pale yellow solid. The solid was recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 3,4- bis(benzyloxy)((3-chloro(trifluoromethyl)phenyl)ethyl)-pyridazine as a white solid (0.182 g, 17 %). 1H NMR (CD 3OD) δ 7.67 (d, 1 H), 7.50 (s, 1 H), 7.33 (d, 1 H), 6.63 (s, 1 H), 3.00 - 3.09 (m, 2 H) and 2.85 - 2.93 (m, 2 H).
MS ES+: 319.
M. p. = 169-170°C.
Example 66: 4-Hydroxy{2-[2-methyl(trifluoromethyl)phenyl]ethyl}-2,3- dihydropyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(E)[2-methyl(trifluoromethyl)phenyl]- l]pyridazine (Intermediate 76) except that THF was used as the solvent. The crude t was purified by reverse phase chromatography, eluting with 5-100 % acetonitrile with acid modifier) and then recrystallised from a mixture of methyl tertbutyl ether and ethyl acetate to afford 4-hydroxy{2-[2-methyl (trifluoromethyl)phenyl]ethyl}-2,3-dihydropyridazinone as a white powder (0.23g, 36 %). 1H NMR (CD 2Cl2) δ, 7.42 (s, 1 H), 7.39 (d, 1 H), 7.25 (d, 1 H), 6.60 (s, 1 H), 2.96 - 3.08 (m, 2 H), 2.77 - 2.90 (m, 2 H), and 2.38 (s, 3 H).
MS ES+: 299.
M. p. = 170-172 °C e 67: 6-{2-[3,5-Difluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one le 1) from 3,4-bis(benzyloxy)[(E)[3,5-difluoro(trifluoromethyl)phenyl]ethenyl]- pyridazine (Intermediate 77) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography (silica, eluting with 5-100 % acetonitrile in water with acid modifier) to afford a white solid, which was recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 6-{2-[3,5-difluoro- 4-(trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazinone as a white solid (0.079 g, 10 %). 1H NMR (CD 3OD) δ 7.09 (d, 2 H), 6.64 (s, 1 H), 3.00 - 3.10 (m, 2 H) and 2.82 - 2.96 (m, 2 H).
MS ES+: 321.
M.p. = 211-212°C.
Example 68: 6-{2-[3-Fluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone Prepared as described for 4-hydroxy(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)[(E)[3-fluoro (trifluoromethyl)phenyl]ethenyl]pyridazine (Intermediate 79) in 60 % yield. The solid was purified by e phase chromatography, eluting with 5-100 % acetonitrile in water with acid er to yield 6-{2-[3-fluoro(trifluoromethyl)phenyl]ethyl} hydroxy-2,3-dihydropyridazinone in 60 % yield. 1H NMR (DMSO-d 6) δ 12.68 (s, 1 H), 10.76 (br. s., 1 H), 7.68 (m, 1 H), 7.42 (m, 1 H), 7.27 (m, 1 H), 6.61 (s, 1 H), 2.93 - 3.04 (m, 2 H) and 2.73 - 2.87 (m, 2 H).
MS ES+: 303. 3. Biological efficacy of compounds of the invention In Vitro DAAO Enzyme Assay The functional activity of compounds inhibiting the DAAO enzyme was determined by utilizing the co-product of the catalysis of D-Serine, H2O2 which can be quantitatively measured using the ‘Amplex’ (trade mark) Red (Invitrogen) detection. x’ Red reagent is a colorless substrate that reacts with en peroxide (H2O2) with a 1:1 stoichiometry in the presence of hydrogen peroxide to produce highly scent resorufin (excitation/emission maxima=570/585 nm). The changes in fluorescence were red by a fluorescence plate reader, Envision (Perkin Elmer) and increases in DAAO activity were readily detected upon addition of ne and suppression of this response observed with the application of test compounds.
Human DAAO enzyme was supplied by the Takeda ceutical Company (Osaka) and each batch was tested and used at concentrations giving comparable levels of activity. The Km of D-Serine was measured for each enzyme batch to maintain consistency; this Km was used in subsequent assays.
On the day of the assay compounds were serially diluted in DMSO before being diluted 1:20 with assay buffer (20mM Tris ph 7.4). A 5µl portion of assay buffer was added to the wells of a 384 clear base black-walled plate (Corning), 5µl of diluted nd was then added via automated plate to plate transfer using the Bravo liquid r (Agilent technologies) ed by 5µl of human DAAO enzyme and then 5µl D-Serine 50mM was added to all but the negative control wells (final concentration of 10mM). Finally 5µl ‘Amplex’ red reagent (Invitrogen) was added to all wells as per manufacturer’s ol. The plate was incubated for 60 minutes in the dark at 25 ºC and the fluorescence in each well was measured in the Envision plate .
The IC50 values for compounds were determined from ten point half log scale doseresponse studies and represent the concentration of compound required to prevent 50% inhibition of DAAO activity in the presence of 10mM D-Serine. Concentration response curves were generated using the average of duplicate wells for each data point and analyzed using non-linear regression and four parameter curve fit.
Results Example No. Mean IC50 (nM) Example No. Mean IC50 (nM) 1 10 2 10 3 21 4 3.7 30 6 9.7 7 13 8 11 9 10 10 22 11 16 12 23 13 31 14 41 16 16 52 17 13 18 14 19 12 20 8.4 21 21 22 13 23 14 24 6 e No. Mean IC50 (nM) Example No. Mean IC50 (nM) 45 26 22 27 13 28 20 29 45 30 18 31 20 32 16 33 23 34 26 41 36 19 37 220 38 20 39 13 40 12 41 99 42 15 43 26 44 22 45 18 46 15 47 26 48 12 49 23 50 23 51 30 52 130 53 19 54 14 55 760 56 32 57 380 58 61 59 19 60 15 61 57 62 29 63 15 64 13 65 13 66 12 67 10 68 19 These s indicate that compounds of the invention have potent inhibitory activity against the DAAO enzyme. The compounds tested above exhibit IC50 values significantly less than 5 µM, with the most potent compounds showing activity at the DAAO enzyme with IC50 values < 250 nM. ingly, the compounds of the invention are expected to have usefulness in the prevention or treatment of conditions, such as those discussed above, in which DAAO enzyme activity is implicated.
In addition, the compounds of the present invention possess variously advantageous pharmacological and/or toxicological profiles, when tested in a variety of standard tests for such parameters. For example, the compounds of the invention exhibit one or more ially useful properties for in vivo use, when characterised by pharmacological and/or toxicological tests including: hERG interaction (which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether- o-related gene, using for example the PatchXpress 7000A platform); CypP450 ctions (which may be measured in accordance with the FDA draft guidelines for drug interaction s (study design, data analysis and ations for dosing and labeling) (Sep. 2006), see www.fda.gov ); phototoxicity (for example using a protocol in accordance with assay details outlined in the OECD guidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptake phototoxicity test, April 2004); determination of pharmacokinetic parameters (for example following in vivo dosing via le routes, with plasma concentrations of compounds being determined from venous blood samples using an LC-MS/MS protocol); and in vivo receptor occupancy mined, for example, using protocols based on Medhurst et al., Journal of Pharmacology and Experimental Therapeutics, 2007, 321 , 1032). These standard tests for the characterisation of drug molecules are well known to the skilled person.
The term “comprising” as used in this specification and claims means sting at least in part of”. When interpreting statements in this ication, and claims which include the term “comprising”, it is to be understood that other features that are additional to the features ed by this term in each statement or claim may also be present. d terms such as ise” and “comprised” are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

Claims (22)

1. A compound of formula (I) 5 n R represents a en or fluorine atom or a trifluoromethyl group; 2 3 R represents a group –X-Y-R ; X and Y each independently represent a bond, an oxygen atom or a group -C(O), 4 4, -S(O)n, -C(O)NR , -S(O)2NR -NR4, , or 4 5 10 -CR R -, provided that X and Y cannot both simultaneously represent a bond and provided that if X and Y are both other than a bond, then at least one of X and Y 4 5 represents -CR R -; n is 0, 1 or 2; each R independently represents a hydrogen atom or a C1-C6 alkyl or C1-C6 15 haloalkyl group; each R independently represents a hydrogen atom, a C1-C6 alkyl or C1-C6 haloalkyl group or =CH-; R represents a 3- to 10-membered ted or unsaturated carbocyclic or heterocyclic ring , the ring system itself being optionally substituted by at least 20 one substituent selected from halogen, hydroxyl, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 yalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylsulphinyl, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxycarbonyl, amino (-NH2), -CON(R )2, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylmethyl, -[O]p-(CH2)q-O-R and a 4- to 6-membered saturated or unsaturated heterocyclic ring (optionally substituted with at least one substituent selected from C1-C4 alkyl and C1-C4 alkoxy); 5 each R independently represents a hydrogen atom or a C1-C6 alkyl group; p is 0 or 1; q is 1, 2, 3 or 4; and R represents a C1-C6 alkyl group; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R represents a hydrogen atom.
3. A compound according to claim 1 or claim 2, wherein X represents a bond, an 4 4, oxygen atom or a group -C(O), , R , -S(O)2NR -NR4, 4 5 4 5 15 , or -CR R -, and Y represents a bond or –CR R -.
4. A nd ing to claim 3, wherein X represents a group -S(O)n , - 4 4 4 NR , -CHR or and Y represents a bond or a group -CHR . 20
5. A compound according to claim 4, wherein each R independently represents a hydrogen atom or methyl group.
6. A compound according to any one of claims 1 to 5, wherein, in R , the 3- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system is 25 ed from phenyl, nyl, oxazolyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, 2,3-dihydrobenzofuranyl, pyrimidinyl, o[1,2- a]pyridinyl, pyrazolyl, thiazolyl and piperidinyl.
7. A compound according to any one of claims 1 to 5, wherein R ents an 5 optionally substituted 3- to 6-membered ted or unsaturated yclic or heterocyclic ring .
8. A compound according to claim 7, wherein R represents a 5- or 6-membered unsaturated carbocyclic or heterocyclic ring system, the heterocyclic ring system 10 comprising one or two ring heteroatoms independently selected from nitrogen and oxygen, wherein the carbocyclic or heterocyclic ring system is optionally substituted by one, two, three or four substituents independently selected from fluorine, chlorine, bromine, hydroxyl, cyano, oxo, C1-C4 alkyl, C2-C4 alkenyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C4 alkoxy, C1-C2 haloalkoxy, C1-C4 alkylthio, 15 C1-C4 alkylsulphinyl, C1-C4 alkylsulphonyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkoxycarbonyl, amino, carboxamido, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylmethyl, -[O]p-(CH 2)q-O-R and a 4- to ered saturated or unsaturated heterocyclic ring optionally substituted by methyl or methoxy.
9. A compound according to claim 7 or claim 8, wherein the optional substituents are selected from cyano, fluorine, chlorine, difluoromethyl, difluoromethoxy, oromethyl, trifluoromethoxy, methyl and methoxy. 25 10. A compound of formula (I) as defined in claim 1 selected from the group ting of: 4-Hydroxy(2-phenylethyl)pyridazin-3(2H)-one, 4-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 30 6-[(4-Chlorobenzyl)sulfanyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[6-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 6-[2-(3-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(2-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(3,5-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 5 6-[2-(3,4-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 6-(2-Cyclohexylethyl)hydroxypyridazin-3(2H)-one, 10 6-(2-Cyclopropylethyl)hydroxypyridazin-3(2H)-one, yclopentylethyl)hydroxypyridazin-3(2H)-one, 4-Hydroxy[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one, 6-[2-(2,4-Difluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-{2-[3-(Difluoromethyl)phenyl]ethyl}hydroxypyridazin-3(2H)-one, 15 6-Benzylhydroxypyridazin-3(2H)-one, 6-[2-(3-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy(1-phenylcyclopropyl)pyridazin-3(2H)-one, 4-[2-(5-Hydroxyoxo-1,6-dihydropyridazinyl)ethyl]benzonitrile, 6-[2-(3-Fluoromethylphenyl)ethyl]hydroxypyridazin-3(2H)-one, 20 6-[2-(4-Fluoromethylphenyl)ethyl]hydroxypyridazin-3(2H)-one, 6-[2-(3,4-Dimethoxyphenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one, 6-[2-(4-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 2-Chlorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 25 4-Hydroxy{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 6-(4-(Difluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one, 6-(4-(Trifluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one, Difluoromethoxy)phenethyl)hydroxypyridazin-3(2H)-one, 6-[1-(4-Fluorophenyl)cyclopropyl]hydroxypyridazin-3(2H)-one, 30 6-[1-(4-Fluorophenyl)ethyl]hydroxypyridazin-3(2H)-one, 4-Hydroxy{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, 6-((Cyclopropylmethyl)(methyl)amino)hydroxypyridazin-3(2H)-one, clohexylmethyl)(methyl)amino)hydroxypyridazin-3(2H)-one, 6-(3-Chlorobenzyl)hydroxypyridazin-3(2H)-one, 6-(4-Chlorobenzyl)hydroxypyridazin-3(2H)-one, 6-(Cyclohexylmethyl)hydroxypyridazin-3(2H)-one, 5 6-(4-Fluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(2-Chlorofluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(2-Chlorobenzyl)hydroxypyridazin-3(2H)-one, 6-(3-Fluorobenzyl)hydroxypyridazin-3(2H)-one, 6-(2-Fluorobenzyl)hydroxypyridazin-3(2H)-one, 10 6-(4-Methylbenzyl)hydroxypyridazin-3(2H)-one, 6-(3-Methylbenzyl)hydroxypyridazin-3(2H)-one, oxy(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one, 4-Hydroxy{2-[5-(trifluoromethyl)pyridinyl]ethyl}pyridazin-3(2H)-one, 4-Hydroxy[2-(oxanyl)ethyl]pyridazin-3(2H)-one, 15 6-{[(4-Fluorophenyl)methyl](methyl)amino}hydroxy-pyridazin-3(2H)-one, 6-[2-(2,6-Difluorophenyl)ethyl]hydroxy-pyridazin-3(2H)-one, 6-[2-(2-Chlorofluorophenyl)ethyl]hydroxy-pyridazin-3(2H)-one, 6-{[3,5-bis(Trifluoromethyl)phenyl]methyl}hydroxypyridazin-3(2H)-one, 6-(1-Phenylethyl)hydroxypyridazin-3(2H)-one, 20 6-(Cyclopropylmethyl)hydroxy-2,3-dihydropyridazinone , 4-Hydroxy{1-[4-(trifluoromethyl)phenyl]cyclopropyl}-2,3-dihydropyridazin- 3-one, 6-{2-[2-Chloro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, 25 6-{2-[2-Fluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, 6-{2-[3,5-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazin one, 6-{2-[2,4-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydro-pyridazin- 30 3-one, 6-{2-[3,4-bis(Trifluoromethyl)phenyl]ethyl}hydroxy-2,3-dihydropyridazin one, 4-Hydroxy(3-methyl(trifluoromethyl)phenethyl)pyridazin-3(2H)-one, 3,4-bis(Benzyloxy)((3-chloro(trifluoromethyl)phenyl)ethyl)-pyridazine, 4-Hydroxy{2-[2-methyl(trifluoromethyl)phenyl]ethyl}-2,3- dihydropyridazinone, 6-{2-[3,5-Difluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- 5 opyridazinone, 3-Fluoro(trifluoromethyl)phenyl]ethyl}hydroxy-2,3- dihydropyridazinone, and pharmaceutically acceptable salts thereof.
10
11. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which comprises (i) when X represents a sulphur atom or when X is a bond and Y represents a sulphur atom, reacting a compound of formula (II) in which Hal ents a halogen atom and R is as defined in formula (I), with a 3 3 nd of formula (III), HS-[Y]t-R , where t is 0 or 1 and Y and R are as defined in formula (I); or 20 (ii) when X represents SO or when X is a bond and Y represents SO, oxidising a compound of formula (IV) (IV) 1 1 in which P represents a protecting group and R is as defined in formula (I), with a suitable oxidising agent, followed by reaction with a nd of formula (V), 1 3 1 3 L R , where w is 0 or 1, L represents a leaving group and Y and R are as 5 d in formula (I); or (iii) when X represents SO2 or when X is a bond and Y represents SO2, oxidising a compound of formula (IV) as defined in (ii) above with a le oxidising agent, ed by reaction with a compound of formula (V) as defined in (ii) above; or (iv) when X represents an oxygen atom or when X is a bond and Y represents an oxygen atom, reacting a compound of formula (II) as defined in (i) above, with a 3 3 compound of formula (VI), HO-[Y]z-R , where z is 0 or 1 and Y and R are as defined in formula (I); or (v) when X represents C(O) or when X is a bond and Y represents C(O), reacting a compound of a (II) as defined in (i) above with carbon dioxide, followed by addition of an activating agent and reaction with a compound of formula (Va), M-[Y]w- 3 20 20 3 R , where M is Li or MgR , R represents a halogen atom and w, Y and R are as 20 defined in formula (V) in (ii) above; or 4 4 (vi) when X represents -C(O)NR or when X is a bond and Y represents -C(O)NR , reacting a compound of formula (VII) 25 (VII) in which R is as defined in formula (I), with a compound of formula (VIII), 4 3 3 4 R HN-[Y] g-R , where g is 0 or 1 and Y, R and R are as defined in a (I); or (vii) when X represents -S(O)2NR or when X is a bond and Y represents 5 -S(O) 2NR , reacting a compound of formula (II) as defined in (i) above with sulphur dioxide, ed by addition of an oxidising-chlorinating agent and then reaction with a compound of formula (VIII) as defined in (vi) above; or 4 4 (viii) when X represents -NR or when X is a bond and Y represents -NR , reacting a 10 compound of formula (II) as defined in (i) above, with a compound of formula (VIII) as defined in (vi) above; or 4 5 4 5 4 (ix) when X ents -CR R - or when X is a bond and Y ents -CR R - and R and R each independently represent a C1-C6 alkyl group, reacting a compound of 15 a (II) as defined in (i) above with a nd of formula (IX), L - 4’ 5’ 3 2 4’ 5’ CR R -[Y] h-R , where h is 0 or 1, L represents a leaving group, R and R each independently represent a C1-C6 alkyl group and Y and R are as defined in formula (I); 4 5 4 5 20 (x) when X represents -CR R - or when X is a bond and Y represents -CR R - and 4 5 R and R each independently represent a hydrogen atom or a C 1-C6 alkyl group but do not both simultaneously represent a C1-C6 alkyl group, reacting a compound of formula 4 3 (II) as defined in (i) above with a compound of formula (IXa), R C(O)-[Y] h-R , 3 4 wherein h, Y, and R are as defined in formula (IX) in (ix) above and R is as defined in 25 formula (I) above, ed by a hydrogenation reaction; or (xi) when X and Y each represent -CHR , hydrogenating a compound of a 1 3 4 5 n R , R and R are as defined in formula (I); or 4 5 4 5 (xii) when X represents -CR R - or when X is a bond and Y represents -CR R - and R is =CH, reacting a compound of formula (XI) 10 (XI) 22 1 wherein R represents a hydrogen atom or a C1-C6 alkyl group and R is as defined in 24 26 3 24 formula (I), with a compound of formula (IXb), R -CH(R -R , wherein R represents a phosphonate moiety, R represents a hydrogen atom or a C1-C6 alkyl group and h, Y and R are as defined in formula (IX) in (ix) above; or (xiii) when X represents a group or when X is a bond and Y represents a group , reacting a compound of formula (XII) (XII) 1 3 where k is 0 or 1 and Y, R and R are as defined in formula (I), with diiodomethane 5 and zinc-copper couple; or (xiv) when X represents a group or when X is a bond and Y represents a group , reacting a nd of formula (XIII) 10 (XIII) 1 3 where l is 0 or 1 and Y, R and R are as defined in formula (I), with diiodomethane and zinc-copper couple; and optionally thereafter carrying out one or more of the following procedures: 15 ● ting a compound of formula (I) into another compound of formula (I) ● removing any protecting groups ● forming a ceutically acceptable salt.
12. A pharmaceutical composition comprising a compound of a (I) or a ceutically acceptable salt thereof as claimed in any one of claims 1 to 10, in ation with a pharmaceutically acceptable adjuvant, diluent or r. 5
13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10 for use in treating a ion whose development or ms are linked to D-amino acid oxidase (DAAO) enzyme activity.
14. A compound of formula (I) or a pharmaceutically acceptable salt thereof as 10 claimed in any one of claims 1 to 10 for use in treating schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain.
15. A combination of a compound of formula (I) or a ceutically acceptable salt thereof as claimed in any one of claims 1 to 10 and one or more agents selected 15 from carbamazepine, olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole, ziprasidone and lithium.
16. A compound of formula (XXX) (XXX) 1 2 20 20 wherein P and P each independently represent a benzyl protecting group, R represents a hydrogen atom or a trimethylsilane leaving group and R is as defined in formula (I) of claim 1.
17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof 25 as defined in any one of claims 1 to 10 in the manufacture of a medicament for ng a condition whose development or symptoms are linked to D-amino acid oxidase (DAAO) enzyme activity.
18. Use of a compound of formula (I) or a ceutically acceptable salt thereof as defined in any one of claims 1 to 10 in the manufacture of a medicament for treating schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders or pain.
19. A compound as defined in any one of claims 1 to 10, 13, 14 and 16 substantially as herein bed with reference to any example thereof.
20. A process as defined in claim 11 substantially as herein described with reference 10 to any example thereof.
21. A pharmaceutical ition as defined in claim 12 substantially as herein described with reference to any example thereof. 15
22. A ation as defined in claim 15 substantially as herein described with reference to any example thereof.
NZ620239A 2011-08-22 2012-08-21 Pyridazinone compounds and their use as daao inhibitors NZ620239B2 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB1114399.7 2011-08-22
GBGB1114399.7A GB201114399D0 (en) 2011-08-22 2011-08-22 Novel compounds
GB201118658A GB201118658D0 (en) 2011-10-27 2011-10-27 Novel compounds
GB1118658.2 2011-10-27
GB1203533.3 2012-02-29
GBGB1203533.3A GB201203533D0 (en) 2012-02-29 2012-02-29 Novel compounds
PCT/GB2012/000672 WO2013027000A1 (en) 2011-08-22 2012-08-21 Pyridazinone compounds and their use as daao inhibitors

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NZ620239B2 true NZ620239B2 (en) 2016-02-02

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