ZA200507920B

ZA200507920B - Piperazine derivatives and their use for the treatment of neurological and psychiatric diseases

Info

Publication number: ZA200507920B
Application number: ZA200507920A
Authority: ZA
Inventors: Bruton Gordon; Orlek Barry Sidney; Kishore K Rana
Original assignee: Glaxo Group Ltd
Priority date: 2003-04-23
Filing date: 2005-09-30
Publication date: 2007-03-28
Also published as: NO20055514L; CN1809553A; NO20055514D0; GB0309222D0

Description

PIPERAZINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF NEUROLOGICAL AND PSYC

HIATRIC DISEASES

The present invention relates to novel piperidine carbonyl piperazine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

WO 97/06802 (Zeneca Limited) describe a series of pyridyl and pyrimidyl derivatives as oxido-squalene cyclase inhibitors which are claimed to lower blood cholesterol.

WO 02/76925 (EJ; Lilly), WO 03/004480, WO 03/024928 and WO 03/024929 (all Novo

Nordisk A/S and Boehringer Ingelheim International) describe a series of substituted piperidines or piperazines which are claimed to bind selectively to the histamine H3 receptor. WO 03/62234 (Yamanouchi Pharmaceutical Co) describe a series of quinoxaline derivatives as poly(ADP-ribose) polymerase inhibitors. US2002115854 (Bristol Myers Squibb) describe a series of heterocyclic compounds as thrombin or factor

Xa inhibitors. WO 97/23462 (Pfizer Inc) describe a series of quinoline and quinoxaline derivatives for treating a range of indications including benign prostatic hyperplasia, hypertension and hyperlipidaemia. WO 96/10022 (Zeneca Ltd) describe a series of heterocyclic compounds containing amino-aza-cyclyl and aryl groups as factor Xa protease and blood coagulation inhibitors. WO 03/103669 and WO 03/088967 (both

Schering Corp) describe a series of piperidinyl benzimidazolone compounds as histamine H3 antagonists, WO 02/32893 and WO 02/72570 (both Schering Corp) describe a series of non-imidazole compounds as histamine H3 antagonists.

The histamine H3 receptor is predominantly expressed in the mammalian central nervous system (CNS), with minimal expression in peripheral tissues except on some sympathetic nerves (Leurs et al., (1998), Trends Pharmacol. Sci. 19, 177-183).

Activation of H3 receptors by selective agonists or histamine results in the inhibition of neurotransmitter release from a variety of different nerve populations, including histaminergic and cholinergic neurons (Schlicker et al., (1994), Fundam. Clin.

Pharmacol. 8, 128-137). Additionally, in vitro and in vivo studies have shown that H3 antagonists can facilitate neurotransmitter release in brain areas such as the cerebral cortex and hippocampus, relevant to cognition (Onodera et al., (1998), In: The Histamine

H3 receptor, ed Leurs and Timmerman, pp255-267, Elsevier Science B.V.). Moreover, a number of reports in the literature have demonstrated the cognitive enhancing properties of H3 antagonists (e.g. thioperamide, clobenpropit, ciproxifan and GT-2331) in rodent models including the five choice task, object recognition, elevated plus maze, acquisition of novel task and passive avoidance (Giovanni et al., (1999), Behav. Brain

Res. 104, 147-155). These data suggest that novel H3 antagonists and/or inverse agonists such as the current series could be useful for the treatment of cognitive 40 impairments in neurological diseases such as Alzheimer's disease and related neurodegenerative disorders.

The present invention provides, in a first aspect, a compound of formula (Hora pharmaceutically acceptable salt thereof: q 0 =

N R® oy C5 Jn

P Nos () wherein:

R' represents aryl, heteroaryl, -aryl-X-Ca7 cycloalkyl, -heteroaryl-X-Cs cycloalkyl, -aryi-

X-aryl, -aryl-X-heteroaryl, -aryl-X-heterocyclyl, -heteroaryl-X-heteroaryl, -heteroaryl-X- aryl or —heteroaryl-X-heterocyclyl; wherein said aryl, heteroaryl and heterocyclyl groups of R' may be optionally substituted by one or more (eg. 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloC alkyl, polyhaloC alkyl, haloC4.¢ alkoxy, polyhaloC. alkoxy, Ci. alkyl, Cis alkoxy, Cy.¢ alkylthio, Ci. alkoxyCi.e alkyl, Ca cycloalkylCy. alkoxy, -COC,5 alkyl, -

COCs alkyl-halogen,.-COC. alkyl-cyano, Cie alkoxycarbonyl, Ci. alkylsulfonyl, Cis alkylsulfinyl, C+. alkylsulfonyloxy, Ci. alkylsulfonylC,.¢ alkyl, C16 alkylsulfonamidoC,.¢ alkyl, C1.¢ alkylamidoCi.¢ alkyl, aryl, arylsulfonyl, arylsulfonyloxy, aryloxy, arylsulfonamido, arylcarboxamido, aroyl, or a group NR"R'®, -CONR™R?", -NR"*COR'", -C(R'®)=NOR'®, -NR'5SO,R® or -SO,NR"R'®, wherein R" and R'® independently represent hydrogen or C.. alkyl or together form a heterocyclic ring;

X represents a bond, O, CO, SO, OCH, or CH,0; each R? and R* independently represents C44 alkyl;

R® represents Cs alkyl, Css alkenyl, Css alkynyl, Css cycloalkyl, Css cycloalkenyl or -Cy. salkyl-Ca.6 cycloalkyl; wherein said Ca. cycloalkyl groups of R® may be optionally substituted by one or more (eg. 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, C1.4 alkyl or trifluoromethyl groups; m and n independently represent 0, 1 or 2; p and q independently represent 1 or 2; or a pharmaceutically acceptable salt thereof.

In one particular aspect of the present invention, there is provided a compound of formula (1) as defined above wherein:

R' represents aryl, heteroaryl, -aryl-X-aryl, -aryl-X-heteroaryl, -aryl-X-heterocyclyl, - heteroaryl-X-heteroaryl, -heteroaryl-X-aryl or —heteroaryl-X-heterocyclyl; and wherein said aryl, heteroaryl and heterocyclyl groups of R' may be optionally substituted by one or more (eg. 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloC,.5 alkyl, polyhaloCi.s alkyl, haloC1. alkoxy, polyhaloCi.g alkoxy, Cis alkyl, Cis alkoxy, Ci. alkylthio, Cie alkoxyCi.s alkyl, Caz cycloalkylC1s alkoxy, Ci alkanoyl, Cis alkoxycarbonyl, Ce alkylsulfonyl, Cis alkylsulfinyl, Cis alkylsulfonyloxy, Cie alkylsulfonylCy.¢ alkyl, C16 alkylsulfonamidoC.s alkyl, C1 alkylamidoC, alkyl, arylsulfonyl, arylsulfonyloxy, aryloxy, arylsulfonamido, arylcarboxamido, aroyl, or a group

NR'R™. -CONR®R'®, -NR'®COR'®, -NR"*SO.R" or _SO,NR'*R'®, wherein R" and R" independently represent hydrogen or Cy. alkyl or together form a heterocyclic ring; and q represents 1; and m represents 0.

In one particular aspect of the present invention, there is provided a compound of formula (1) as defined above wherein said ary}, heteroaryl and heterocyclyl groups of R' may be optionally substituted by one or more (eg. 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloC. alkyl, polyhaloCq.s alkyl, haloC1. alkoxy, polyhaloCi.e atkoxy, Cis alkyl, C15 alkoxy, Ci. alkylthio, Cy. alkoxyCi alkyl, C37 cycloalkylCs.s alkoxy, -COC. alkyl, C16 alkoxycarbonyl, C16 alkylsulfonyl, Ci. alkylsulfinyl, Cis alkylsulfonyloxy, Cs alkylsulfonylCy.e alkyl, C14 alkylsulfonamidoCi. alkyl, C16 alkylamidoCi.s alkyl, arylsulfonyl, aryisulfonyloxy, aryloxy, arylsulfonamido, arylcarboxamido, aroyl, or a group NR'R', -CONR™R, -NR"*COR"®, -C(R"®)=NOR'®, -

NR'*SO,R® or -SONR'’R'®, wherein R'® and R'® independently represent hydrogen or

C,.¢ alkyl or together form a heterocyclic ring.

Specific compounds of formula (1) which may be mentioned are those wherein R’ represents pyridyl or pyrimidyl optionally substituted by one or two hydrogen, amino, halogen, cyano, Ci. alkyl or Ci. alkoxy groups and R® represents Cs alkyl, Ca alkenyl,

Ca. alkynyl, Css cycloalkyl or Css cycloalkenyl.

Specific compounds of formula (I) which may be mentioned are those wherein R' represents quinoxalinyl substituted by a halogen, hydroxy, cyano, nitro, oxo, haloCy.¢ alkyl, polyhaloCy.¢ alkyl, haloCi. alkoxy, polyhaloCi alkoxy, C1 alkyl, Cis alkoxy, Cis alkylthio, C1. alkoxyCi.s alkyl, Ca cycloalkylCy.s alkoxy, -COCi.6 alkyl, -COC alkyl- halogen, -COC,. alkyl-cyano, Cs alkoxycarbonyl, Ci.s alkylsulfonyl, Cis alkylsulfinyl, C,. ¢ alkylsulfonyloxy, Cis alkylsulfonylCy.s alkyl, Cie alkylsulfonamidoCs.s alkyl, C1 alkylamidoCy.¢ alkyl, aryl, arylsulfonyl, arylsulfonyloxy, aryloxy, arylsulfonamido, arylcarboxamido, aroyl, or a group NR'R™®, -NR'*COR, -C(R'6)=NOR'®, -NR'*SO,R™ or -SO,NR'R', wherein R'® and R" independently represent hydrogen or C6 alkyl or together form a heterocyclic ring. 40

Specific compounds of formula (1) which may be mentioned are those wherein R® represents Cas alkyl, Cs alkenyl, Ca. alkynyl, Cas cycloalkyl or Css cycloalkenyl. -3- /i

Specific compounds of formula (1) which may be mentioned are those wherein R' represents quinolinyl or quinoxalinyl tri-substituted by a phenyl, amino and C 14 alkoxy group and R® represents Cs alkyl, Cas alkenyl, Css alkynyl, Ca cycloalkyl, Css cycloalkenyl or -C,4alkyl-Ca cycloalkyl.

Alky! groups, whether alone or as part of another group, may be straight chain or branched and the groups alkoxy and alkanoyl shall be interpreted similarly. The term ‘halogen’ is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine and the term ‘polyhalo' is used herein to refer to a moiety containing more than one (eg. 2-5) of said halogen atoms.

The term "aryl" includes single and fused rings wherein at least one ring is aromatic, for example, phenyl, naphthyl, indanone and tetrahydronaphthalenyl.

The term "heterocyclyl" is intended to mean a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur or a 4-7 membered saturated or partially unsaturated aliphatic ring fused to a benzene ring. Suitable examples of such monocyclic rings include pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, diazepanyl and azepanyl. Suitable examples of benzofused heterocyclic rings include indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl, dihydrobenzofurany! or dihydrobenzoxazinyl.

The term "heteroaryl" is intended to mean a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such monocyclic aromatic rings include thienyl, fury], pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazoliny, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridiny!l, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazoly! and the like.

Preferably, R' represents -aryl (eg. phenyl, naphthyl or indanone) optionally substituted by one or more (eg. 1, 2 or 3) halogen (eg. fluorine, chlorine or bromine), C1. alkyl (eg. isopropyl), polyhaloCy.¢ alkyl (eg. CFs), Ci. alkoxy (eg. methoxy or isopropyloxy), polyhaloC. 40 alkoxy (eg. trifluoromethoxy or difluoromethoxy), -COC,. alkyl (eg. -COMe or -COE), -

C(R'%)=NOR" (eg. ~C(Me)=NOMe or —C(Me)=NOE?), -NR'®*COR'® (eg. -NHCOMe), -

COC, alkyl-halogen (eg. —COCH_-F), -COC, alkyl-cyano (eg. ~COCH.CN), cyano or

C,. alkoxycarbonyl (eg. ethoxycarbonyl) groups; -aryl-X-Ca cycloalkyl (eg. —phenyl-CO-cyclopropyl or —phenyl-CO-cyclobutyl); -aryl-X-aryl (eg. —phenyl-CO-phenyl or —phenyl-O-phenyl); -aryl-X-heterocyclyl (eg. —phenyl-CO-morpholinyl or —phenyl-pyrrolidinyl) optionally substituted by one or more (eg. 1, 2 or 3) halogen (eg. —2-chlorophenyl-CO- morpholinyl) or oxo groups; -aryl-X-heteroaryl (eg. —phenyl-thiazolyl, -phenyl-oxadiazolyl (eg. -phenyl-1,2,4- oxadiazolyl or —phenyl-1 ,3,4-oxadiazolyl), -phenyl-pyrrolyl, —phenyl-oxazolyl or —phenyl- isoxazolyl) optionally substituted by a C, alkyl (eg. methyl) or aryl (eg. phenyl) group; -heterocycly! (eg. dihydrobenzofuranyl, dihydrobenzoxazinyl or indolinyl) optionally substituted by one or more (eg. 1, 2 or 3) C4 alkyl (eg. methyl) or -COC,¢ alkyl (eg. -COMe) groups; heteroaryl (eg. pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl or benzothiazolyl) optionally substituted by one or more (eg. 1, 2 or 3) cyano, halogen (eg. bromine or chlorine), polyhaloCy.¢ alkyl (eg. CFa), C16 alkyl (eg. methyl), Cy. alkoxy (eg. methoxy), Cs. alkoxycarbonyl (eg. methoxycarbonyl) or ~CONR™R" (eg. -CON(H)(Me) or —CON(Me),) groups; -heteroaryl-X-aryl (eg. —pyrimidinyl-phenyl) optionally substituted by one or more (eg. 1, 2 or 3) cyano or Cy alkylsulfonyl (eg. MeSO;) groups; -heteroaryl-X-heterocyclyl (eg. -pyrimidyl-morpholinyl, -pyrimidinyl- dihydrobenzofuranyl or —pyridyl-CO-pyrrolidinyl); or -heteroaryl-X-heteroaryl (eg. -pyrimidyl-pyridyl).

More preferably, R* represents -aryl (eg. phenyl, naphthyi or indanone) optionally substituted by one or more (eg. 1, 2 or 3) halogen (eg. fluorine, chlorine or bromine), C1. alkyl (eg. isopropyl), polyhaloC,.s alkyl (eg. CFs), C1 alkoxy (eg. methoxy or isopropyloxy), polyhaloCi.s alkoxy (eg. trifluoromethoxy or difluoromethoxy), -COC,¢ alkyl (eg. -COMe or -COEY), -

C(R')=NOR'™ (eg. -C(Me)=NOMe or —C(Me)=NOEY), -NR'®COR'® (eg. -NHCOMe), -

COC. alkyl-halogen (eg. ~COCH-F), -COC,.¢ alkyl-cyano (eg. -COCH,CN}), cyano or

C4. alkoxycarbonyl (eg. ethoxycarbonyl) groups; -aryl-X-Cs cycloalkyl (eg. —phenyl-CO-cyclopropyl or —phenyl-CO-cyclobutyt), -aryl-X-heteroaryl (eg. —phenyl-thiazolyl, -phenyl-oxadiazolyl, -phenyl-pyrrolyl, — phenyl-oxazolyl or —-phenykisoxazolyl) optionally substituted by a C.. alkyl (eg. methyl) or aryl (eg. phenyl) group; or -heteroaryl (eg. pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl or benzothiazolyl) optionally substituted by one or more (eg. 1, 2 or 3) cyano, halogen (eg. bromine or chlorine), polyhaloC, alkyl! (eg. CFs), Ci alkyl (eg. methyl), Cy alkoxy 40 (eg. methoxy), C1. alkoxycarbonyl (eg. methoxycarbonyl) or —~CONR™R" (eg. —

CON(H)(Me) or -CON(Me)z) groups.

Most preferably, R represents -aryl (eg. phenyl) optionally substituted by one or more (eg. 1, 2 or 3) halogen (eg. fluorine or chlorine), polyhaloCy.s alkyl (eg. CFs), -NR'COR'® (eg. -NHCOMe), -

COC, alkyl (eg. -COMe or -COEt) or cyano groups; -aryl-X-Cg cycloalkyl (eg. —phenyl-CO-cyclopropyl); -aryl-X-heteroaryl (eg. -phenyl-oxadiazolyl or ~phenyl-oxazolyl) optionally substituted by a Cy. alkyl (eg. methyl) or aryl (eg. phenyl) group; or -heteroaryl (eg. pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or quinolinyl) optionally substituted by one or more (eg. 1, 2 or 3) halogen (eg. bromine or chlorine), polyhaloCi.s alkyl (eg. CF3), Ci alkyl (eg. methyl) or cyano groups.

Especially preferably, R' represents -aryl (eg. phenyl) optionally substituted at the 4-position by a -COC. alkyl (eg. —

COMe or -COEt) or cyano group, or -heteroaryl (eg. pyridyl or quinofinyl) optionally substituted by one or more (eg. 1, 2 or 3) C4 alkyl (eg. methyl) or polyhaloCy alkyl (eg. CFs) groups.

Most especially preferably, R? represents -pyridyl (eg. —3-pyridyl) substituted at the 6-position by a polyhaloCy. alkyl (eg.

CF) group (eg. 6-CFs-pyridin-3-yl).

Preferably X represents a bond, O or CO, more preferably a bond or CO, most preferably a bond.

Preferably, m represents 0.

Preferably, n represents 0, 1 or 2, more preferably 0 or 1, especially 0.

Preferably, q represents 1.

When present, preferably R? represents methyl.

When R? represents methyl, said R? group is preferably attached to the carbon atom adjacent to the N-R® group. When RZ represents methyl, the stereochemistry of R? preferably has the S configuration.

Preferably, R® represents Css alkyl (eg. ethyl, isopropyl, n-propyl, isobutyl or isopentyl) or Cae cycloalkyl (eg. cyclobutyl or cyclopentyl), more preferably isopropyl, isobutyl or cyclobutyl, most preferably isopropyl or cyclobutyl, especially isopropyl. 40

Preferred compounds according to the invention include examples E1-E198 as shown below, or a pharmaceutically acceptable salt thereof.

More preferred compounds according to the invention include: 1-lsopropyl-4-[1 -(5-cyano-pyridin-2-yl)-piperidine-4-carbonyl]-piperazine (E1); 1-Isopropyl-4-[1 _(5-methoxycarbonyi-4-trifiuoromethyipyridin-2-yl)-piperidine-4-carbonyll-

piperazine (E4):1-Isopropyl-4-[1-(4-sthoxycarbonyipheny!)-piperidine~4-carbonyll-

piperazine (E8);1-Cyclobutyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyll-piperazine (E9):1-Cyclobutyl-4-[1-(4-cyano-3-fluorophenyl)-piperidine-4-carbonyl]-piperazine (E10);1-Cyclobutyl-4-{1 (4-cyano-2.6-difluorophenyl)-piperidine-4-carbonyl]-piperazine (E11);1-Cyclobutyl-4-[1 (4-cyano-3-trifluoromethylphenyl)-piperidine-4-carbonyl]-

piperazine (E12),1 -Cyclobutyl-4-[1 -(4-cyano-naphthalen-1 -yl)-piperidine-4-carbonyl]- piperazine (E 13);1-Cyclobutyl-4-[1 -(5-cyanopyridin-2-yl)-piperidine-4-carbonyl]- piperazine (E14);1-Cyclobutyl-4-[1 -(6-trifluoromethylpyridin-2-yi)-piperidine-4-carbonyll- piperazine (E15);1-Cyclobutyl-4-{1 -(5-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl}- piperazine (E16);1-Cyclobutyl-4-{1 -(3-chloro-5-trifluoromethylpyridin-2-yi)-piperidine-4-

carbonyl]-piperazine (E17); 1-Isopropyl-4-{1-{5-(4-methylsulfonyiphenyl)-pyrimidin-2-yi]- piperidine-4-carbonyl}-piperazine (E25); 1-Isopropyl-4-{1-[4-(morpholino-carbonyl)- phenyl]-piperidine-4-carbonyl}-piperazine (E30),

1-Cyclopentyl-4-[1 -(4-cyano-phenyl)-piperidine-4-carbonyl]-piperazine (E31); (2R,6S)-1-Cyclobutyl-4-{1 -(4-cyanophenyl)-piperidine-4-carbonyl}-2,6-

dimethylpiperazine (E33); 1-Isopentyl-4-[1-(5-cyano-pyridin-2-yl)-piperidine-4-carbonyi]-piperazine (E35); 1-Cyclobutyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbonyil-[1 ,Al-diazepane (E36); 1-Cyclobutyl-4-[1 -(5-cyanopyridin-2-yl)-piperidine-4-carbonyl}-[1 ,4]-diazepane (E37); 1-Isopropyl-4-[1 ~(4-cyano-2,5-difluorophenyl)-piperidine-4-carbonyl}-{1 ,4]-diazepane

(E39); 1-Isopropyl-4-[1 -(4-cyano-3-chlorophenyl)-piperidine-4-carbonyil-{1 ,4]-diazepane (E40); 1-Isopropyl-4-[1 -(4-cyano-3-fluoro-phenyl)-piperidine-4-carbonyl}-{1 ,4]-diazepane (E41); 1-Isopropyl-4-1 -(4-cyano-2,6-difluoro-phenyl)-piperidine-4-carbonyl}-[1 ,4]-diazepane (E42);

1-Isopropyl-4-[1 ~(4-cyano-2-fluoro-phenyl)-piperidine-4-carbonyl]-[1 ,4)-diazepane (E43); 1-1sopropyl-4-[1 -(4-cyano-3-trifluoromethyl-phenyl)-piperidine-4-carbonyl}-[t 4) diazepane (E44);

1-1sopropyl-4-[1 -(4-trifluoromethyl-phenyl)-piperidine-4-carbonyl}-[1 ,4)-diazepane (E45); 1-1sopropyl-4-[1 -(4-cyano-naphthalen-1-yl)-piperidine-4-carbonyl]-[1 ,4)-diazepane (E46);

1-lsopropyl-4-{1-(3,4-dichlorophenyl)-piperidine-4-carbonyf}-[1 ,4]-diazepane (E54); 1-Isopropyl-4-{1 -(4-trifluoromethoxyphenyl)-piperidine-4-carbonyf]-[1 ,4]-diazepane (E56); 1-Isopropyl-4-[1 -(4-difluoromethoxyphenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane (E59); 1-Isopropyl-4-[1 -(4-phenoxyphenyl)-piperidine-4-carbonyl]-[1 A}-diazepane (E61); 1-lsopropyl-4-[1 -(6-methoxypyridin-3-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane (E62),1-

40 Isopropyl-4-[1 -(4-cyano-2,3-diflucrophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane (E63); 1-lsopropyl-4-[1-(4-cyano-2-chlorophenyl)-piperidine-4-carbonyil-[1 ,4]-diazepane (E64), 1-Cyclobutyl-4-[1-(4-cyano-2-chlorophenyl)-piperidine-4-carbonyl]-{1 ,4]-diazepane (E65);

1-Cyclobutyt-4-{1 {4-cyano-3-chlorophenyl)-piperidine-4-carbonyl}-[1 ,A}-diazepane (E66); 1-Cyclobutyl-4-[1 (4-cyano-3-fluorophenyl)-piperidine-4-carbonyl}-{1 ,4]-diazepane (E67); 1-Cyclobutyl-4-{1 _{4-cyano-3-trifiuoromethylphenyl)-piperidine-4-carbonyl-{1 4] diazepane (E68);

1-Cyclobutyl-4-{1 {4-cyano-2,5-difiuorophenyl)-piperidine-4-carbonyf}-{1 ,4)-diazepane (E69); (S)-1-Isopropyt-4-{1 (4-cyanophenyl)-piperidine-4-carbonyll-2-methylpiperazine (E70); (S)-1-1sopropyl-4-[1 -(6-cyanopyridin-3-yl)-piperidi ne-4-carbonyl]-2-methyl piperazine (E78); (S)-1-lsopropyl-4-{1 -(5-cyanopyridin-2-yl)-piperidine-4-carbony]-2-methyl piperazine (E86); (S)-1-Isopropyl-4-[1 -(5-trifluoromethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-2-methyl piperazine (E87); (S)-1-Isopropyl-4-{1 (B-trifluoromethyl-pyridazin-3-yl)-piperidine-4-carbonyl}-2-methyl piperazine (E88), 1-lsopropyl-4-{1-[4-(5-pheny}-1 3,4-oxadiazol-2-yl)phenyl]-piperidine-4-carbonyl} piperazine (E90); 1-Isopropyl-4-[1 -(quinolin-6-y1)-piperidine-4-carbonyl] piperazine (E91); 1-Cyclobutyl-4-{1 -(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl] piperazine (E97); 1-lsopropyl-4-[1 _(5-trifluoromethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-piperazine (E102); (S)-1-1sobutyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbonyll-piperazine (E104), 1-Isopropyi-4-[1 -(4-cyclopropylcarbonylphenyl)-piperidine-4-carbonyl}-piperazine (E105), 1-lsopropyl-4-[1 -(2-methyl-quinolin-6-yl)-piperidine-4-carbonyl]-piperazine (E118), 1-Isopropyl-4-[1 (6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-piperazine (E129); 1-Cyclobutyl-4-[1 ~(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-{1 [A]-diazepane (E136); 1-Cyclobutyl-4-[1 -(2-cyanopyridin-4-yl)-piperidine-4-carbonyl]-{1 ,4]-diazepane (E137); 1-Isopropyl-4-[1 -(6-trifluoromethylpyridazi n-3-yl)-piperidine-4-carbonyl]-[1,4]-diazepane (E138); 1-lsopropyi-4-[1 ~(5-trifluoromethylpyrazin-2-yl)-piperidine-4-carbonyl]-{1 ,/4]-diazepane (E139); 1-Isopropyl-4-{1-[4-(2-methyl-1 ,3-oxazol-5-yl)phenyl]-piperidine-4-carbonyl}-[1 4- diazepane (E154); 1-lsopropyl-4-{1-[4-(3-methyl-1 2,4-oxadiazol-5-yl)phenyi]-piperidine-4-carbonyl}-{1 4) diazepane (E168); 1-isopropyl-4-{1 ~(4-acetamido-3-fluorophenyl)-piperidine-4-carbonyl]-{1 ,4]-diazepane (E169); 1-Cyclobutyl-4-[1 -(4-acetylphenyl)-piperidine-4-carbonyl]-[1 4)-diazepane (E170); 1-Cyclobutyl-4-[1 -(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-{1 ,4]-diazepane (E179), 40 1-lsopropyl-4-[1 ~(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl}-{1 ,4]-diazepane (E180); 1-1sopropyl-4-[1 -(2-methyl-quinalin-4-yl)-piperidine-4-carbony]-{1 ,4)-diazepane (E183);

1-isopropyl-4-{1-[4-(3-methy}-1 2 4-oxadiazol-5-yi)phenyll-piperidine-4-carbonyi}-piperazine (E185); 1-lsopropyl-4-{1 -(2-trifluoromethylpyrimidin-5-yl)-pi peridine-4-carbonyl]-{1,4]-diazepane (E198) or a pharmaceutically acceptable salt thereof.

Most preferred compounds according to the invention include: 1-Isopropyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyll-piperazine (E2); 1-Isopropyl-4-[1-(4-cyanopheny)-piperidine-4-carbonyl}-1 ,4]-diazepane (E38); (S)-1-1sopropyl-4-[1 _(6-triflucromethylpyridin-3-yi)-piperidine-4-carbonyil-2-methyl piperazine (E79); 1-lsopropyl-4-[1 -(4-acetylphenyl)-piperidine-4-carbonyil-[1 ,4]-diazepane (E150); 1-1sopropyl-4-{1 -(4-propanoylphenyl)-piperidine-4-carbonyil-{1 ,4)-diazepane (E151); or a pharmaceutically acceptable salt thereof.

Especially preferred compounds according to the invention include: 1-Isopropyl-4-[1 ~(6-trifluoromethylpyridin-3-yi)-piperidine-4-carbonyll-piperazine (E96), 1-Isopropyl-4-[1 ~(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl}-{1 ,4]-diazepane (E135); or a phamaceutically acceptable salt thereof.

Because of their potential use in medicine, the salts of the compounds of formula (1) are preferably pharmaceutically acceptable.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesuifonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (1) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (1) including hydrates and solvates. 40

Certain compounds of formula (I) are capable of existing in sterecisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention.

The present invention also provides a process for the preparation of a compound of formula (l)ora pharmaceutically acceptable salt thereof, which process comprises: (a) reacting a compound of formula (1) 5 0

H—N

N— AR),

Ra { S

N

P pect (mn or an optionally activated or protected derivative thereof, wherein R%, R*, m,n, pand q are as defined above and R* is as defined for R® above or a group convertible to R®, with a compound of formula R'-L', wherein R'is as defined above and L' represents a suitable leaving group, such as a halogen atom (eg. fluorine, chlorine, bromine or iodine) or triflate, followed by a deprotection reaction as necessary, or (b) reacting a compound of formula (Ill)

A oO

R—N 2

RY

(11) wherein R', R%, m and q are as defined above and L? represents OH or a suitable leaving group, such as a halogen atom (eg. chlorine), with a compound of formula (IV)

H

\ 2 i h

P N 3a

R

(IV) wherein R%, n and p are as defined above R* is as defined for R® above or a group convertible to R®; or

(c) deprotecting a compound of formula (1) or converting groups which are protected; and optionally thereafter (d) interconversion to other compounds of formula (I).

Process (a) typically comprises the use of a suitable base, such as potassium carbonate in a suitable solvent such as dimethylsulfoxide or N,N-dimethylformamide at elevated temperature. Alternatively process (a) may be carried out with a suitable catalyst such as ) tris(dibenzylideneacetone)dipaliadium(0) and 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl or bis(dibenzylideneacstone)palladium and 2- dicyciohexylphosphino-2'-(N,N-dimethylamino)biphenyl or acetato(2'-di-t-butylphosphin- 1,1’-biphenyl-2-yl)palladium Il in the presence of a suitable base such as sodium t- butoxide or potassium phosphate in a solvent such as o-xylene, dioxane or toluene, optionally at an elevated temperature.

An R* group convertible to R® may for example be a protecting group such as tert- butoxycarbonyl which may be removed under acidic conditions, eg trifluoroacetic acid or

HCI or a benzyloxycarbony! group which may be removed by hydrogenolysis, to give a compound where R? represents hydrogen. Subsequent conversion to a compound where R* represents R® may be carried out by reductive amination with a compound of formula R*=0 in the presence of sodium triacetoxyborohydride or alkylation with a compound of formula R®-L® where L®is a leaving group such as bromine or iodine.

When R? represents methyl at the carbon atom adjacent to N-R*, R* may represent hydrogen which may subsequently be converted to R?® as described above.

Process (b) typically comprises activation of the compound of formula (!il) wherein L2 represents OH with a coupling reagent such as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxybenzotriazole (HOBT) or 1-hydroxyazabenzotriazole (HOAT) in a suitable solvent such as dichloromethane or dimethylformamide followed by reaction with the compound of formula (IV).

Process (b) may also involve halogenation of the compound of formula (I1f) wherein L2 represents OH with a suitable halogenating agent (eg. thionyl chloride or oxalyl chloride) followed by reaction with the compound of formula (IV) in the presence of a suitable base such as triethylamine or a solid supported base such as diethylaminomethylpolystyrene in a sultable solvent such as dichloromethane

In process (c), examples of protecting groups and the means for their removal can be 40 found in T. W. Greene ‘Protective Groups in Organic Synthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2' 2" 2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl

(e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g. hydrogenolysis of a benzyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl! group using zinc in acetic acid) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF3) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Elliman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.

Process (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation. Examples of transition metal mediated coupling reactions useful as interconversion procedures include the following:

Palladium catalysed coupling reactions between organic electrophiles, such as aryl halides, and organometallic reagents, for example boronic acids (Suzuki cross-coupling reactions); Palladium catalysed amination and amidation reactions between organic electrophiles, such as aryl halides, and nucleophiles, such as amines and amides;

Copper catalysed amidation reactions between organic electrophiles (such as aryl halides) and nucleophiles such as amides; and Copper mediated coupling reactions between phenols and boronic acids.

Compounds of formula (iI) may be prepared in accordance with the following procedure:

0 C 0 ! PL—N

P*—N 3 Step (i) Oa rR) . L J — RY? n (R)n H

Vv) ®), 5 N \ 3a

S R*® (VI)

N

Re (IV)

Step (ii) a 0]

H—N

N R?

Rm ( 5 Fn

N

P pA (m wherein RZ, R*, m, n, p and q are as defined above, R* is as defined for R® above or a group convertible to R?, L® represents OH or a suitable leaving group such as a halogen atom (eg. chlorine), and P' represents a suitable protecting group such as t- butoxycarbonyl.

When L® represents OH, step (i) typically comprises the use of suitable coupling conditions eg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT).

When L® represents a suitable leaving group such as a halogen atom (eg. chlorine), step (i) typically comprises the use of a suitable base such as triethylamine in a suitable solvent such as dichloromethane.

Step (ii) typically comprises a suitable deprotection reaction using standard conditions such as those described above for process (c). Where P! is a tert butoxycarbonyl group this may involve a suitable acid such as HCl or trifluoroacetic acid

Compounds of formula (11) wherein L2 represents OH, may be prepared in accordance with the following procedure:

0 ! 2 x

H—N 2 Step (i) p? . P —_ ®) (Rn RI-L4 m

I (vin) vi) Step (il) oa

RI—

OH

RY) (nye wherein R!, R*, m and q are as defined above, L* represents a suitable leaving group such as a halogen atom or triflate and P2 represents a suitable protecting group such as methoxy, ethoxy, t-butoxy or benzyloxy.

Step (i) is typically carried out in a suitable solvent such as N,N-dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate. Alternatively step (i) may be carried out with a suitable catalyst such as tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)bipheny! or bis(dibenzylideneacetone)palladium and 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl or acetato(2'-di-t-butylphosphin- 1,1-biphenyl-2-yl)palladium Il in the presence of a suitable base such as sodium t- butoxide or potassium phosphate in a solvent such as o-xylene, dioxane or toluene, optionally at an elevated temperature.

Step (ii) typically comprises a suitable deprotection reaction using standard conditions such as those described above for process (c). Where P? is an alkoxy group such as ethoxy this may involve suitable acid or base catalysed hydrolysis eg. using aqueous hydrochloric acid or a base such as sodium hydroxide or lithium hydroxide.

Compounds of formula (lll) wherein L2 represents a suitable leaving group, such as a halogen atom (eg. chlorine) may be prepared by treating a compound of formula (IH)? with thionyl chloride or oxalyl chloride.

Compounds of formula (IV), (V), (VII) and R'-L* are either known in the literature or can be prepared by analogous methods.

Compounds of formula (1) and their pharmaceutically acceptable salts have affinity for and are antagonists and/or inverse agonists of the histamine H3 receptor and are believed to be of potential use in the treatment of neurological diseases including

Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, epilepsy, neuropathic pain, inflammatory pain, migraine,

Parkinson's disease, multiple sclerosis, stroke and sleep disorders including narcolepsy, psychiatric disorders including schizophrenia (particularly cognitive deficit of schizophrenia), attention deficit hypereactivity disorder, depression and addiction; and other diseases including obesity, asthma, allergic rhinitis, nasal congestion, chronic obstructive pulmonary disease and gastro-intestinal disorders.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders, in particular cognitive impairments in diseases such as Alzheimer's disease and related neurodegenerative disorders.

The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.

When used in therapy, the compounds of formula (1) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.

Thus, the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition which comprises the compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Compounds of formula (I) may be used in combination with other therapeutic agents, for example medicaments claimed to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HTs antagonists, M1 muscarinic agonists, M2 muscarinic antagonists or acetylcholinesterase inhibitors. 40 Compounds of formula (I) may also be used in combination with histamine H1 antagonists, such a combination has the potential to be useful in the treatment of various respiratory disorders, such as asthma, allergic rhinitis, nasal congestion or chronic obstructive pulmonary disease. When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (1) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (1) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants. 40 For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. in preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

The following Descriptions and Examples illustrate the preparation of compounds of the invention.

It will be appreciated that any of the following hydrochloride salt compounds may be converted into the corresponding free base compounds by treatment with saturated aqueous potassium carbonate solution followed by extraction into DCM using the procedure described in Description 8, step 4.

It will also be appreciated that *1,4-Diazepane’ is used throughout to refer to the ring system below which may also be referred to as *hexahydro-1H-1,4-diazepine’. 0,

Description 1 1-lsopropyl-4-(piperidine-4-carbonyl)-piperazine (D1)

Step 1: 1-sopropyl-4-(piperidine-4-carbonyl)-piperazine dihydrochloride 1-tert-Butoxycarbonyl-piperidine-4-carboxylate (5g) in DMF (60ml) was treated with EDC (5.59) followed by HOAT (0.1g). After 5min, N-isopropylpiperazine (2.8g) in DMF (5ml) was added and the reaction was left stirring for 18h. The reaction was then diluted with 40 EtOAc (150ml) and washed with saturated brine/sodium hydrogen carbonate (1:1,

200ml) followed by brine (3x200ml). The EtOAc layer was evaporated to near dryness and the residue treated with TFA/water (40m, 95:5) for 5h prior to evaporation and re- evaporation from toluene (3x60ml). The residue was taken up into a minimum volume of

EtOAc and treated with HCI (30m, 2N solution in diethyl ether) for 1h. The resulting sub- titled compound was filtered off and washed with diethyl ether before drying under vacuum (4.89).

Step 2: 14sopropyl-4-(piperidine-4-carbonyl)-piperazine

The product of D1, Step 1, was dissolved in water and basified with potassium carbonate, followed by extraction with EtOAc and evaporation gave the title compound (D1) as the free base (3.59). 'H NMR § [MeOH-d4]: 1.073 (6H, d, J= 6.4Hz), 1.69-1.75 (4H, m), 2.5-2.58 (4H, m), 2.69-2.82 (3H, m), 2.85-2.94 (1H, m), 3.13-3.22 (2H, m) and 3.54-3.65 (4H, m).

Description 2 1-Isopropyl-4-[1-(5-bromo-pyrimidin-2-yl)-piperidine-4-carbonyll-piperazine (D2)

Potassium carbonate (2.069) was added to a mixture of 5-bromo-2-chloropyrimidine (2.89g) and 1-isopropyl-4-(piperidine-4-carbonyl)-piperazine (D1) (3.57g) in DMF (60m).

The reaction mixture was allowed to stir at rt overnight. The DMF was removed by evaporation and the resulting residue was partitioned between H,O/EtOAc(20:20ml). The

EtOAc layer was dried (MgSO, ) and filtered, the filtrate was evaporated to dryness to give the title compound (D2) as a white solid (4g). 'H NMR § [DMSO-d6]: 0.98 (EH, d,

J=6.5), 1.4-1.5 (2H, m),1.6-1.7 (2H, m ), 2.30-2.35 (2H, m), 2.40-2.48 (2H, m), 2.64-2.70 (1H, m) 2.93-3.00 (3H, m), 3.4-3.55 (4H, m) 4.52-4.59 (2H,m) 8.45 (2H, s).

Description 3 1-(4-Cyanophenyl)-plperidine-4-carboxylic acid (D3)

Step 1 : Ethyl 1-{4-cyanophenyl)-piperidine-4-carboxylate

To 4-fluorobenzonitrile (11.56g) in DMSO (200ml) was added piperidine-4-carboxylic acid ethyl ester (15g) and potassium carbonate (14.4g) and the reaction was heated to 120°C for 4h. After cooling solvent was evaporated and the residue taken up into EtOAc (150ml) and washed with HCI (1 M, 2x100m!l), sodium hydrogen carbonate solution (2 x 100ml) and brine (100ml). Evaporation of the organic layer provided the subtitled compound (22.6g). LCMS electrospray(+ve) 259 (MH*).

Step2: 1-(4-Cyanophenyl)-piperidine-4-carboxylic acid

The product of D3, Step 1 (22.69) was dissolved in 1,4-dioxane (150ml) and 2M sodium hydroxide (87m). The reaction was then stirred at rt for 2h and then further 2M sodium hydroxide (87ml) was added and the reaction heated to 70°C for 2h. The reaction mixture was then evaporated and the residue acidified to pH-2 with aqueous 2N HCI. 40 The aqueous solution was then extracted with DCM (2 x 200ml) and the combined organic layers washed with brine (100ml), dried (MgSQ,) and evaporated to give the title compound (D3) as a white solid (14.89). LCMS electrospray(+ve) 231 (MH").

Description 4 1-1 -(4-Cyanophenyl)-piperidine-4-carbonyl]-{1 ,4]-dlazepane hydrochloride (D4)

Step 1: 1-tert-Butoxycarbonyl- 4-[1 -(4-cyanophenyl)-piperidine-4-carbonyl]- [1,4]diazepane 1 -(4-Cyanophenyl)-piperidine-4-carboxylic acid (D3) (3.94g), HOBT (1.01 9), TEA (2.7 ml) and 1-tert-butoxy-carbonyl-1,4-diazepane (3.0g) were stirred in DMF (25ml) and then

EDC (3.7g) was added and the reaction stirred at rt overnight. The solvent was evaporated and the residue re-dissolved in DCM (100ml) and washed with saturated sodium hydrogen carbonate (2 x 80ml), brine (75ml) and the organic layer dried (MgSO.) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient 0-10% MeOH in DCM]. Fractions containing the required product were evaporated to give the subtitled compound as a white solid (0.92g). LCMS electrospray(+ve) 413 (MH").

Step2: 1-[1 -(4-Cyanophenyl)-piperidine-4-carbonyi]-{1 ,4]diazepane hydrochloride

The product of D4, Step 1 (0.929) was dissolved in DCM (25ml) and 4N HCl in 1,4- dioxane (5ml) was added and the reaction stirred at rt for 2h. The solvent was then evaporated to give the title compound (D4) as a white solid (0.77g). LCMS electrospray(+ve) 313 (MH").

Description 5 1-Cyclopentyl-4-(piperidine-4-carbonyl)-piperazine di-hydrochloride (D5)

Step 1: 1-Cyclopentyl-4-[1 -tert-butoxycarbonyl-piperidine-4-carbonyl]-piperazine 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (2.2g) in dry DMF (40ml) was treated with EDC (3.71g) followed by HOAT (0.1g). After Smin, N-cyclopentylpiperazine (1.59) in dry DMF (5m) was added and the reaction mixture was stirred at rt for 18h. Excess DMF was removed by evaporation and the resulting residue was re-dissolved in DCM, adsorbed onto silica gel (10g) and purified by chromatography [silica gel 0-10% MeOH (containing 10% 0.88 ammonia solution/ DCM)). The pure fractions were combined and the solvent removed by evaporation to give the subtitled compound (2g). LCMS electrospray(+ve) 366(MH"). :

Step 2: 1-Cyclopentyl-4-(piperidine~4-carbonyl)-piperazine di-hydrochloride

The product of D5, Step 1 (2g) was dissolved in dry MeOH (30ml) and treated with 4N dioxan/HC! (5m). The reaction mixture was stired at rt for 18h. Excess solvent was removed by evaporation to give the title compound (D5) as a cream solid (2g). LCMS electrospray (+ve) 266(MH").

Description 6 1-Cyclobutyl-piperazine di-hydrochloride (D6) 40 Step 1: 1-tert-Butoxycarbonyl-4-cyclobutyl-piperazine 1-tert-Butoxycarbonyl-piperazine (5.6g) was dissolved in dry DCM (100m) followed by the addition of cyclobutanone (2.10g). The reaction mixture was stirred at rt for 30min.

Sodium triacetoxyborohydride (6.379) was added portion-wise over 15min. The mixture was then stirred at rt overnight to give a black solution. The reaction mixture was washed with 1N NaOH (70ml) and the DCM layer was separated, dried (MgSQ,) and filtered. The filtrate was evaporated to dryness fo give the subtitled compound as an oil (6.1g) 'H

NMR [DMSO-d]: 1.39 (6H, s), 1.68-1.87 (4H, m), 1.9-2.01 (2H, m), 2.15-2.2 (3H, m), 2.5 (1H, m),2.6-2.78 (1H, m), 3.18-3.3 (4H, m).

Step 2: 1-Cyclobutyl-piperazine di-hydrochloride

The product of D6, Step 1 (5.19) was dissolved in dry MeOH (150ml) followed by the addition of 4N HCI in dioxan (10ml). The reaction mixture was stirred at rt overnight before being evaporated to dryness to give the title compound as a white solid (D6) (4g).

Description 7 1-Cyclobutyl-4-(piperidine-4-carbonyl)-piperazine di-hydrochloride (D7) 1-Cyclobutyl-piperazine di-hydrochloride (D6) (1.89) in DMF (15ml) was stirred with sodium hydrogen carbonate (1.53g) for Smin before being added to a DMF (15m) solution of 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (1.949), EDCI (3.2¢g) and

HOAT (0.05g). After 4h the reaction was diluted with EtOAc and washed with saturated sodium hydrogen carbonate solution and brine (3x), before being evaporated. The residue was dissolved in a small volume of EtOAc and treated with TFA (90%

TFA/water). After 2h toluene was added and the reaction evaporated and re-evaporated from toluene. The residue was taken up into EtOAc and treated with 2N HCl in diethyl : ether. The precipitate was filtered, washed with diethyl ether and dried under vacuum.

Crystallisation from ethanol/diethy! ether afforded the title compound (D7) (1.749).

LCMS electrospray (+ve) 252(MH").

Description 8 1-Isopropyl-4-(piperidine-4-carbonyl)-[1,4]-diazepane (D8)

Step 1: 1-Benzyl-4-(1-tert-butoxycarbonyl-piperidine-4-carbonyl)-[1,4]-diazepane 1-Benzyl-[1,4]-diazepane (3.789) and 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (5.0g) were dissolved in DCM (150 ml) and TEA (3.6ml) was added followed by HOBT (1.34q) and finally EDC (4.90g). The reaction was stirred at rt overnight. The reaction mixture was then evaporated to a minimum, re-dissolved in DCM (50 ml) and washed with saturated sodium hydrogen carbonate solution (3 x 50ml) and brine (50ml). The organic layer was dried (MgSO,) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing pure desired product were combined and evaporated to give the subtitled compound as a pale brown solid (7.1 g).

Step 2: 1-(1-tert-Butoxycarbonyl-piperidine<4-carbonyl)-[1,4]-diazepane

The product of D8, Step 1 (7.1g) was dissolved in ethanol (100ml) and 10% palladium on 40 charcoal (1.0g) was added and the reaction hydrogenated for 18h. The catalyst was then removed by filtration and the filtrate evaporated to give the subtitled compound as a clear oil (5.09).

Step 3: 1-sopropyi-4-(1 -tert-butoxycarbonyl-piperidine-4-carbonyl)-{1 A4]-diazepane

The product of D8, Step 2 (2.0g) was dissolved in DCM (50 ml) and acetone (0.94ml) added and the mixture stirred for 5Smin. Sodium triacetoxyborohydride (2.79) was then added and the reaction stirred at rt for 1.5h. The reaction mixture was then washed with saturated potassium carbonate solution (50 mi), sodium hydrogen carbonate solution (3x 50m) and brine (50m). The organic layer was dried (MgSO) and evaporated to give the subtitled compound as a white solid (1.50 g).

Step 4: 1-Isopropyl-4-(piperidine-4-carbonyi]-{1 ,A]-dlazepane

The product of D8, Step 3 (1.5g) was dissolved in methanol (30ml) and 4N HCl in dioxane (10ml) added. The reaction was stirred at rt for 16h. The reaction mixture was then evaporated to a minimum and the residue basified with saturated potassium carbonate solution (50 ml) and extracted with DCM (3 x 50ml). The organic layer was dried (MgSO.) and evaporated to give the title compound (D8) as a white solid (0.759).

MS electrospray (+ve) 254 (MH).

Description 9 1-Isopropyi-4-[1 -(4-carboxy-phenyl)-piperidin~4-carbonyl]-piperazine hydrochloride (D9)

Step 1: 1-Isopropyl-4-{1 -(4-ethoxycarbonyl-phenyl)-piperidin-4-carbonyi]- piperazine 1-Isopropyl-4-(piperidine-4-carbonyl)piperazine (D1) (2.59), ethyl 4-fluorobenzoate (1.39g) and potassium carbonate (3.55g) was stirred in DMSO (50ml) and heated to 1200C for 2h. The reaction was then heated to 140°C for a further 2h. The reaction was then evaporated to a minimum and the residue re-dissolved in DCM (50m) and washed with sodium hydrogen carbonate (3 x 50ml) and brine (50ml). The organic layer was dried (MgSO,) and evaporated. The crude product was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the subtitled compound as a white solid (1.209). MS electrospray (+ve) 388 (MH™).

Step 2: 1-Isopropyl-4-[1-(4-carboxy-phenyl)-piperidin-4-carbonyl]-piperazine hydrochloride

The product of D9, Step 1 (1.22g) was dissolved in dioxane (20mi) and 2M lithium hydroxide (3.1ml) added and the mixture heated to reflux for 2h. The reaction mixture was then evaporated to a minimum, re-dissolved in DCM (50m) and treated with 4N HCI in dioxane (20ml). The mixture was then evaporated (co-evaporated with toluene) to give the title compound (D9) as a white solid (1.51g, contains 2eq. LiCl). MS electrospray (+ve) 360 (MH*).

Description 10 40 1-Cyclobutyl-4-(piperidine-4-carbonyi)-[1 ,4]-diazepane (D10)

Step 1: 1-Cyclobutyl-4-(1 -tert-butoxycarbonyl-piperidine-4-carbonyl)-{1,4]- diazepane

1-(1-tert-Butoxycarbonyl-piperidine-4-carbonyl)-[1 [4}-diazepane (2.0 g) (D8, Step 2) was dissolved in DCM (50ml) and cyclobutanone (0.96 ml) added and the mixture stirred for

Smin. Sodium triacetoxyborohydride (2.7g) was then added and the reaction stirred at rt for 1.5h. The reaction mixture was then washed with saturated potassium carbonate solution (50ml), sodium hydrogen carbonate solution (3x 50ml) and brine (50ml). The organic layer was dried (MgSOs) and evaporated to give the subtitled compound as a white solid (1.679).

Step 2: 1-Cyclobutyl-d-(piperidine-4-carbonyl)-{1,4]-diazepane

The product of D10, Step 1 (1 .67g) was dissolved in methanol (30ml) and 4N HCl in dioxane (10ml) added. The reaction was then stirred at rt for 16h. The reaction mixture was then evaporated to a minimum and the residue basified with saturated potassium carbonate solution (50ml) and extracted with DCM (3 x 50ml). The organic layer was then dried (MgSO,) and evaporated to give the title compound (D10) as a white solid (1.50g). MS electrospray (+ve) 266 (MH*). TH NMR 5 [DMSO-d6]: 3.60 (5H, m), 3.30 (1H, m), 3.10-2.65 (4H, m), 2.41 (4H, m), 2.05-1.58 (12H, m).

Description 11 1-(5-Cyano-pyridin-2-yl)-piperidine-4-carboxylic acid (D11)

Step 1: Ethyl 1-(5-cyano-pyridin-2-yl)-piperidine-4-carboxylic acid

Piperidine-4-carboxylic acid ethyl ester (5.7g) was dissolved in DMSO (100ml) and potassium carbonate added followed by 6-chloronicotinitrile (5.0g). The reaction was heated to 50°C for 4h under argon. The reaction mixture was then evaporated to a minimum and the residue acidified to pH-2 with aqueous 1N HCI solution. The aqueous mixture was then extracted with DCM (2 x 50ml). The combined organic layers were then washed with sodium hydrogen carbonate (2 x 50m), brine (50ml) and then dried (MgSO0,) and evaporated to give the subtitled compound as a white solid (8.969).

Step 2: 1-(5-Cyano-pyridin-2-yl)-piperidine-4-carboxylic acid

The product of D11, Step 1 (8.969) was dissolved in 1,4-dioxane (50ml) and 1M LiOH solution (38ml) added and the solution stirred at rt for 4h. The reaction mixture was then evaporated to a minimum and the residue acidified to pH-2 with aqueous 2N HCl acid and extracted with DCM (2 x 100ml). The combined organic extracts were then washed with brine (50m), dried (MgSO,) and evaporated to give the title compound (D11) as a white powder (6.609).

Description 12 1-(5-Cyano-pyridin-2-yl)-piperidine-4-carbonyl chloride (D12) 1-(5-Cyano-pyridin-2-yl)-piperidine~4-carboxylic acld (D11) (5.59) was heated to reflux in thionyl chloride (50m) for 1.5h and then allowed to stand at rt under argon overnight.

The reaction was then evaporated (co-evaporated 3 x with DCM) to give the title 40 compound (D12) as a yellow solid (5.70g).

Description 13

(2R,6S)-4-[1 -{4-Cyanophenyl)-piperidine-4-carbonyl]-2,6-dimethylpiperazine hydrochloride (D13) 1-(4-Cyanophenyl)-piperidine-4-carboxylic acid (D3) (6.929), HOBT (1.779), TEA (4.7 mi) and (2R,6S)-2,6-dimethylpiperazine (3.0g) were stirred in DMF (25m) and then EDC (3.79) was added and the reaction stirred at rt ovemight. The solvent was evaporated and the residue redissolved in DCM (100ml) and washed with saturated sodium hydrogen carbonate (2 x 80m), brine (75ml) and the organic layer dried (MgSO,) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM].

Fractions containing the required product were evaporated to give the free base compound which was dissolved in DCM (10m) and treated with 1N HCl in diethyl ether to give the title compound (D13) as a white precipitate which was filtered off (1 .80g). MS electrospray (+ve) 327 (MH).

Description 14 111 -(5-Cyanopyridin-2-yl)-piperidine-4-carbonyl]-[1 ,4]-diazepane hydrochloride (D14) 1-tert-Butoxy-carbonyl-[1,4]-diazepane (4.0g) and TEA (3.63mi) were stirred in DCM (15 ml). 1-(5-Cyano-pyridin-2-yl)-piperidine-4-carbonyl chloride (D142) (5.70g) in DCM (15m) was then added and the reaction stirred at rt under argon overnight. The reaction mixture was then washed with sodium hydrogen carbonate (2 x 50m) and brine (50m).

The organic layer was dried (MgSO,) and evaporated to give a crude product which was purified by column chromatography [silica gel, gradient elution 0-100% EtOAc in hexane]. Pure product fractions were combined and evaporated to give a pale yellow solid (1.10g) which was dissolved in 1,4-dioxane (30m) treated with 4N HCl in 1,4- dioxane (5ml) and then stirred at rt for 2h. The solvent was evaporated to give the title compound (D14) as a yellow solid (0.929).

Description 15 (S)-1-[1 -(4-Cyanophenyl)-piperidine-4-carbonyl]-3-methylpiperazine (D15)

A stirred solution of 1-(4-cyanophenyl)-piperidine-4-carboxylic acid (D3) (230mg) in DCM (10m) at rt was treated with oxalyl chloride (0.13mi) and 10% DMF in DCM (1 drop).

After 1h the solution was evaporated and then re-evaporated from DCM (2x 5ml). The acid chloride was redissolved in DCM (10m!) at rt and treated with diethylaminomethylpolystyrene (780mg, 3.2 mmol/g) and (S)-2-methyipiperazine (100mg) and stirred overnight. The mixture was flash chromatographed [silica gel, step gradient 4-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the title compound (D15) (248mg). MS electrospray (+ve) 313 (MH*). 'H NMR 8 (CDCly): 7.47 (2H, d, J=9Hz), 40 6.85 (2H, d, J=9 Hz), 4.47 (1H, m), 4.60-4.40 (1H, m), 3.97-3.65 (3H, m), 3.24-2.55 (8H, m), 2.28 (1H, m), 2.03-1.61 (4H, m), 1.80-1.45 (4H, m), 1.08 (3H, m)

Description 16 (R)-1-[1 -{4-Cyanophenyl)-plperidine-4-carbonyl]-3-methylpiperazine (D16)

The title compound (D16) was prepared from 1-(4-cyanophenyl)-piperidine-4-carboxylic acid (D3) and (R)-2-methylpiperazine using the procedure of Description D15.

Description 17 (2R, 58) and (2S, 5R)-1-{1 -(4-Cyanophenyl)-piperidine-4-carbonyl]-2,5- dimethylpiperazine (D17)

The tittle compound (D17) was prepared from 1-(4-cyanophenyl)-piperidine-4-carboxylic acid (D3) and (2S, 5R)-2,5-dimethylpiperazine using the procedure of Description D15.

Description 18 (3S, 5S)-1-[1 -{4-Cyanophenyl)-piperidine-4-carbonyl]-3,5-dimethylpiperazine (D18)

The title compound (D18) was prepared using a similar procedure to Description 4 step1 from 1-(4-cyanophenyl)-piperidine-4-carboxylic acid (D3), (2S, 6S)-2,6- dimethylpiperazine dihydrochloride (J.W. Mickleson, K.L. Belonga and E.J. Jacobsen, J.

Org. Chem., 1995, 60(13), 4177-4183), EDC, HOBT and N-methy! morpholine in DMF.

Description 19 (S)-1-Benzyloxycarbonyl-3-methylpiperazine (D19)

Benzyl chloroformate (16.3mi) in DCM (30ml) was added dropwise to a cooled solution at 00C of (S)-2-methylpiperazine (10g) in DCM (200ml) and triethylamine (14.5ml). The temperature was allowed to rise from 0°C to rt and the reaction mixture was stirred at rt for 3h. The mixture was washed with saturated aqueous NaHCO; (2x100ml). The DCM layer was dried (MgSQ,) and filtered. The filtrate was absorbed onto silica and then purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM] to give the title compound (D19) as an oil (10.189).

LCMS electrospray (+ve) 235 (MH").

Description 20 (S)-1 -Benzyloxycarbonyl-4-[1-(tert-butoxycarbonyl)-piperidine-4-carbonyl]-3- methylpiperazine (D20) 1-(tert-Butoxycarbonyl)-piperidine-4-carboxylic acid (0.53g), (S)-1-benzyloxycarbonyl-3- methylpiperazine (D19) (0.5g), HOBt (0.29g) and diethylaminomethy! polystyrene (1.789) were stirred in DCM (30m), then EDC (0.53g) was added and the reaction was stirred at rt overnight. The mixture was filtered and washed with saturated sodium hydrogen carbonate solution (3 x 50mi) and brine (30ml). The organic layer was dried (MgSO.) and evaporated to give a crude yellow oil which was purified by chromatography [silica gel; 0-100% ethyl acetate / hexane) to give the title compound (D20) as a clear oil which 40 crystallised on standing (0.88g).

Description 21

(S)-1-[1 L{tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methylpiperazine (D21) (S)-1-Benzyloxycarbonyl-4-[1 -(tert-butoxycarbonyl)-piperidine-4-carbonyt]-3- methylpiperazine (D20) (0.38g) was dissolved in ethanol (10 ml) and hydrogenated at atmospheric pressure over 10% Palladium on charcoal (10% water paste, catalytic quantity). After 16h the catalyst was removed by filtration and the filtrate was evaporated to give the title compound (D21) as a white powder (0.269).

Description 22 (S)-1-1sopropyl-4-[1 -(tert-butoxycarbonyl)-piperidine-4-carbonyl}-3- methylpiperazine (D22) (S)-1-[1 (tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methylpiperazine (D21) (0.13g), 2-iodopropane (0.08mi) and potassium carbonate (0.11g) in acetonitrile (2ml) were heated at 120°C in an Emerys Optimiser microwave for 45min. The mixture was then filtered and evaporated. The crude product was redissolved in DCM (30ml) and washed with saturated sodium hydrogen carbonate solution (3 x 20ml) and brine (20ml). The organic layer was dried (MgSO) and evaporated to give the title compound (D22)as a clear oil (0.11g)

Description 23 (8S) -isopropyl-4-(piperidine-4-carbonyl)-3-methylpiperazine dihydrochloride (D23) (S)-1-Isopropyl-4-[1-(tert-butoxycarbonyl)-piperidine-4-carbonyl]-3-methylpiperazine (D22) (0.11g) was dissolved in methanol (1 Om) and treated with HCI (4N HCI in diethyl ether; 10ml). After being stirred at rt overnight the reaction mixture was evaporated to a minimum, co-evaporated from methanol, and then dried at 50°C to give the title compound (D23) as a pale brown solid (0.10g)

Description 24 (S)-1-Cyclobutyl-4-[1 «{tert-butoxycarbonyl)-piperidine-4-carbonyl]-3- methylipiperazine (D24) (SH11 -(tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methylpiperazine (D21) (0.139) and cyclobutanone (0.1ml) were stirred in methanol (10m) at rt for 10min and then sodium triacetoxyborohydride (0.26g) was added and the reaction stirred at rt overnight.

The reaction mixture was evaporated to a minimum and then redissolved in DCM (30m), and washed with saturated potassium carbonate solution (3 x 25ml). The organic layer was dried (MgSO,) and evaporated to give the title compound (D24) as a clear oil (0.13g).

Description 25 (S)1 -Cyclobutyl)-4-(piperidine~4-carbonyl)-3-methylpiperazine dihydrochloride 40 (D25)

The title compound (D25) was prepared from (S)-1-cyclobutyl-4-[1-(tert-butoxycarbonyl)- piperidine-4-carbonyl}-3-methylpiperazine (D24) using the procedure of Description 23.

Description 26 (S)-1 -Isopropyl-4-(benzyloxycarbonyl)-2-methylpiperazine (D26)

Potassium carbonate (11.29) was added to a solution of (S)-1-benzyloxycarbony!-3- methylpiperazine (D19) (10.18g) in CHsCN (60m), followed by isopropyl iodide (11.3ml) and the mixture was heated at reflux overnight. The reaction mixture was then allowed to cool to rt and the inorganics were filtered off. The filtrate was evaporated to give an oil which was taken up in EtOAc (100ml) and washed with water (2X50ml). The EtOAc layer was dried (MgSO,) and concentrated to give the title compound (D26) as an oil (8g). LCMS electrospray (+ve) 277 (MH).

Description 27 (S)-1-Isopropyl-2-methylpiperazine hydrochloride (D27) (S)-1-isopropyl-4-(benzyloxycarbonyl)-2-methylpiperazine (D26) (7.69) was dissolved in

EtOH (120ml) and treated with 10%Pd/C (2g) and hydrogenated under atmospheric conditions overnight. The catalyst was filtered off and washed with EtOH (30ml). The filtrate was treated with ethereal HCI (10m, 1N HCl in diethyl ether) and evaporated to dryness to give the title compound (D27) as a solid (2g). LCMS electrospray (+ve) 143 (MH*).

Description 28 (S)-1-isopropyl-4-[1-(tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methyl piperazine (D28) 1-(tert-Butoxycarbonyl)-piperidine-4-carboxylic acid (3.2g) in dry DMF (30ml) was treated first with EDC (5.4g) and catalytic HOAt followed by (S)-1-isopropyi-2-methyl piperazine hydrochloride (D27) (2g) and N,N-diisopropylethylamine (5m). After the reaction mixture was stirred overnight, water (50ml) was added and the cloudy precipitate was extracted into EtOAc (2x25ml), dried (MgSO,) and filtered. The filtrate was absorbed on silica and purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The fractions containing the required product were evaporated to give the title compound (D28) as an oil (3.8g). LCMS electrospray (+ve) 354 (MH).

Description 29 (S)-1-isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride (D29) (S)-1-Isopropyl-4-{ 1-(tert-butoxycarbonyl)-piperidine-4-carbonyl]-2-methyl-piperazine (D28) (3.8g) was treated with HCI as described in Description 8 step 4 to give the title dihydrochloride (D29) as a white solid (2.5g). LCMS electrospray (+ve) 254 (MH+). 40

Description 30 5-Bromo-2-trifluoromethylpyrimidine (D30)

A mixture of potassium fluoride (1.779) and cuprous iodide (5.799) was stirred and heated together using a heat gun under vacuum (~1 mm) for 20min. After cooling, dimethyl formamide (20ml) and N-methyl pyrrolidinone (20ml) were added followed by (trifluoromethyl)trimethylsilane (4.1ml) and 5-bromo-2-iodopyrimidine (6.5g). The mixture was stirred at rt for 5h and then the brown solution was poured into 6N ammonia solution. The product was extracted into ethyl acetate and the extracts were washed with sodium bicarbonate solution and brine and then dried (Na,S0O.) and evaporated.

Chromatography on silica gel (elution with 20-50% dichloromethane in pentane) gave the title compound (D30) as a white solid (2.49). 1H NMR (CDCl): 8.97 (2H, s).

Description 31 2-Chloro-5-trifluoromethylpyrazine (D31) 2-Amino-5-triflucromethylpyrazine (Miesel, US 4 203 552) was converted into 5- trifluoromethylpyrazin-2-one (Fitzjohn, EP 408196). 5-Trifluoromethylpyrazin-2-one (0.5g) was heated at reflux in POCls (3mi) containing 1 drop of conc. H,S0, for 3h. The cooled mixture was poured onto ice and brought to pH 5 by addition of solid NaHCO4 and extracted (3x) with diethyl ether. The ethereal extracts were washed with water and brine, dried (Na,SO,) and evaporated to give the title compound (D31) as a light yellow oil (0.2g) which was sufficiently pure for use without further purification. '"H NMR § [CDCl 8.72 (1H, s), 8.76 (1H, s).

Description 32 (S)-1-Methyipropyl methanesulfonate (D32)

An ice cold solution of (S)-2-butanol (888mg) in DCM (15m) was treated with Et;N (1.26mi) and followed by dropwise addition of methanesulfonyl chloride (0.52ml). After 1h the solution was washed with saturated sodium hydrogen carbonate solution (5ml), water (2x5ml), brine (5m), dried (MgSO) and evaporated to give the title compound (D32) (1.01g). 'H NMR 5 (CDCl): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d,

J=6.5Hz), 0.99 (3H, t, J=7.5Hz).

Description 33 (R)-1-Methylpropyl methanesulfonate (D33)

An ice cold solution of (R)-2-butanol (888mg) in DCM (15ml) was treated with EtzN (1.26ml) and followed by dropwise addition of methanesulfonyl chloride (0.52mi). After 1h the solution was washed with saturated sodium hydrogen carbonate solution (5ml), water (2x5ml), brine (5m), dried (MgSO,) and evaporated to give the title compound (D33) (0.99). "MH NMR & (CDCl): 4.74 (1H, m), 3.00 (3H, 5), 1.67 (2H, m), 1.41 (1H, d,

J=6.5Hz), 0.99 (3H, t, J=7.5Hz). 40 Description 34 11 +4-Cyanophenyl)-piperidine-4-carbonyl]-piperazine hydrochloride (D34)

The title compound (D34) was prepared from 1-(4-cyanophenyi)-piperidine-4-carboxylic acid (D3) and 1-tert-butoxycarbonylpiperazine in a similar manner to Description 4.

Description 35 2-Chloro-5-(1 -pyrrolidinylcarbonyl)pyridine (D35) 6-Chloronicotinic acid (1g) in DMF (30ml) was treated with EDC (2.439) followed by

HOA (10mg). After 15min N,N-diisopropylethylamine (2.2m) followed by pyrrolidine (0.53mi) was added. The reaction mixture was allowed to stir at rt overnight. The DMF was removed by evaporation and the resulting residue was partitioned between saturated NaHCO;and DCM. The DCM layer was dried (MgSO,) and filtered, the filtrate was absorbed on silica gel and purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the title compound (D35)as a solid (0.289). MS electrospray (+ve ion) 211 (MH™).

Description 36 2-Chloro-5-(dimethylaminocarbonyl)pyridine (D36)

The title compound (D36) was prepared from dimethylamine and 6-chloronicotinic acid according to the procedure described for Description 35. MS electrospray (+ve ion) 185 (MH).

Description 37 4-(4-Bromophenyl)-2-methyl-oxazole (D37) 4-Bromophenacyl bromide (21.3g) and acetamide (11.3g) were heated together at 130°C under argon. After 2.5h the reaction mixture was allowed to cool, and partitioned between water (150ml) and Et;O (150ml). The organic phase was washed with aqueous

NaOH (0.5N), aqueous HCI (0.5M) and saturated aqueous NaCl solution (100ml of : each), dried (MgSO,) and evaporated to give a brown solid which was recrystallised from hexanes to give the title compound (D37) as an orange solid (4.1g). LCMS electrospray (+ve) 239 (MH).

Description 38 5-(4-Bromophenyl)-2-methyl-oxazole (D38)

Trifluoromethanesulfonic acid (6.6ml) was added to a flask containing iodobenzene diacetate (12.2g) and MeCN (200ml) at rt. After 25min. a solution of 4'- bromoacetophenone (5g) in MeCN (50ml) was added and the resultant mixture heated at reflux for 6h. The reaction was allowed to cool to rt before the solvent was evaporated and the residue partitioned between saturated aqueous Na,COs (1 50m) and EtOAc (150ml). The organic phase was washed with saturated brine (150ml), dried (MgSO) 40 and evaporated to give an orange solid. The crude product was purified by column chromatography (silica gel, 50% EtOAc in hexane) to give the title compound (D38) as a pale yellow solid (3.59). LCMS electrospray (+ve) 239 (MH").

Description 39 5-(4-Bromophenyl)-3-methyl isoxazole (D39)

A solution of n-BuLi (81m of a 1.6M solution in hexanes) was added to a solution of acetone oxime (4.85g) in THF (100ml) at 0°C. The reaction mixture was allowed to warm to rt over 1h. A solution of methyl 4-bromobenzoate (8.4g) in THF (30ml) was then added to the reaction mixture and allowed to stir for 24h. Water (50ml) was added to the reaction, the organics were extracted and evaporated to give a brown oil, which was further evaporated from toluene (2x25ml). The crude product was purified by column chromatography (silica gel, 10-25% gradient of EtOAc in hexane) to give the title compound (D39) as a pale yellow solid (5.4g). LCMS electrospray (+ve) 239 (MH).

Description 40 3-(4-Bromophenyl)-5-methyl-1,2,4-oxadlazole (D40)

Step 1: 4-Bromo-N-hydroxy-benzenecarboximidamide 4-Bromophenylcarbonitrile (10.29), hydroxylamine hydrochloride (7.8g) and Et;N (11.39) were dissolved in EtOH (250ml) and the reaction mixture was heated at reflux for 3h, after which it was evaporated to form a white precipitate of the desired amidoxime, which was filtered off and washed with water (25m). The filtrate was extracted into EtOAc (2x25ml), and the combined organic extracts were dried (Na,SO,) and evaporated to give a second crop of the subtitle compound (combined yield = 11.1g). LCMS electrospray (+ve) 216 (MH").

Step 2: 3-(4-Bromophenyl)-5-methyi-1 ,2,4-oxadiazole

The product from D40, step 1 was suspended in acetic anhydride and heated to 100°C for 4h, then 120°C for 3h. After cooling the reaction mixture was evaporated to give a brown solid. This was partitioned between saturated aqueous NaHCO; and EtOAc. The organic phase was washed with saturated aqueous NaCl, dried (Na,SO,) and evaporated to give a yellow solid. The crude product was purified by column chromatography (silica gel, 10-100% gradient of EtOAc in hexane) to give the title compound (D40) as a white solid (6.2g). LCMS electrospray (+ve) 240 (MH).

Description 41 5-(4-Bromophenyl)-3-methyl-1 ,2,4-oxadiazole (D41) 4-Bromobenzamide (5.3g) and dimethylformamide dimethoxyacetal (35ml) were heated together at 125°C for 2h. The reaction was allowed to cool to rt and the liquid evaporated to give a pale yellow solid. Hydroxylamine hydrochloride (2.2g) in 1N NaOH solution (36ml) was added, followed by dioxane (36ml) then AcOH (48ml). The reaction mixture was stirred at rt for 30min then heated at 90°C for 3h. The reaction was allowed to cool to rt and saturated aqueous K,COj, solution (100ml) was added followed by DCM 40 (200ml) before filtering. The organic phase was separated from the mixture, then saturated brine (100ml) was added and the aqueous phase was extracted into EtOAc (200ml). The combined organic phases were dried (Na,SO,) and evaporated to give a brown solid. The crude product was purified by column chromatography (silica gel, step gradient 10-50% EtOAC in hexane) to give the title compound (D41) as a white solid (2.99). LCMS electrospray (+ve) 240 (MH).

Description 42 2-Chloro-5-{methylaminocarbonyi)pyridine (D42)

The title compound (D42) was prepared from methylamine and 6-chloronicotinic acid according to the procedure described for Description 35.

Example 1 1-Isopropyl-4-{1 (5-cyano-pyridin-2-yl)-piperidine-4-carbonyl]-piperazine hydrochloride (E1) o

OOO

To 1-isopropyl-4-(piperidine-4-carbonyl)-piperazine (0.239g) (D1) and 2-chloro-5-cyano- pyridine (0.1389), dissolved in DMSO (5ml), was added potassium carbonate (0.149).

The reaction was heated to 80°C for 4h before cooling and dilution with saturated sodium hydrogen carbonate (50m!) and EtOAc (80mi). The EtOAc layer was washed further with brine (3x80ml) and then extracted with iN HCl. The aqueous HCI extract was basified and back-extracted with EtOAc which was concentrated under vacuum. A solution of 2N

HCI in diethy! ether (1ml) was then added and the precipitate filtered and washed with diethyl ether. Crystallisation from methanol afforded the title compound (E1) (0.15g). H

NMR & [DMSO-d6]:1.29 (6H, d, J= 6.4H2), 1.4-1.6 (2H, m), 1.7-1.85 (2H, m), 2.8-3.27 (6H, m), 3.32-3.52 (3H, m), 3.69 (1H, m), 4.24 (1H, brd, J=13Hz), 4.35-4.55 (3H, m), 6.96 (1H, d, J=9.1Hz), 7.84 (1H, dd, J=9.1Hz and 1.5Hz), 8.47 (1H, d, J=1.5Hz) and 11.36 (1H, brs). MS electrospray; (+ve ion) 342 (MH+).

Example 2 1-sopropyl-4-[1 -(4-cyanophenyl)-piperidine~4-carbonyl]-piperazi ne hydrochloride (E2) to)

OOO

The title compound (E2) was prepared from 4-fluorobenzonitrile and 1-isopropyl-4- (piperidine-4-carbonyl)-piperazine (D1) according to the procedure described in Example 1, except that the reaction was carried out at 120°C for 8h. 'H NMR & [DMSO-d6]: 1.29 (6H, d, J= 6.5 Hz), 1.4-1.8 (4H, m), 2.8-3.1 (5H, m), 3.11-3.22 (1H, m), 3.31-3.5 (3H, m), 3.62-3.77 (1H, m), 3.89-4 (2H, m), 4.2 (1H, brd, J=13.5Hz), 7.03 (2H, d, J=9Hz), 7.56 (2H, d, J=9Hz) and 11.43 (1H, brs). MS electrospray; (+ve ion) 341 (MH+).

Examples 3-5 (E3-E5)

Example 3 was prepared as described for D2. Examples 4 and 5 were prepared from 1- isopropy!-4-(piperidine-4-carbonyl)-piperazine (D1) and the appropriate heteroaryl chloride using the procedure described in Example 1 and displayed 1H NMR and mass spectral data that were consistent with structure.

TaN

AAO

Example Heteroaryl Mass Spectrum = +

Ee Sl ae 2 i) woe) woo [MH* 443

F.C F,C

EE

NC NC

Examples 6-8 (E6-E8)

Examples 6 and 7 were prepared from 1-isopropyl-4-(piperidine-4-carbonyl)-piperazine (D1) and the appropriate aryl fluoride using the procedure described in Example 2.

Example 8 was prepared using the procedure described in D9, Step 1. Compounds displayed 1H NMR and mass spectral data that were consistent with structure. 0

OHO

EL

No Spectrum

Es*

Ea

CN : CN

NC NC

TE [2D [Oe [rw

Examples 9-19 (E9-E19)

Examples 9 - 19 were prepared from 1-cyclobutyl-4-(piperidine-4-carbonyl)-piperazine di-hydrochloride (D7) and the appropriate aryl halide, using the procedures described in

Example 1 (for E14-E19) and Example 2 (for E9-E13), and displayed 1H NMR and mass spectral data that were consistent with structure. i

OOo al va

No ES*

CN

EE me

CN

F

CN

CF. +

Cl . & [MH]* 397

CF{

Ee [On mere

S

Example 20 1-Isopropyl-4-[1 -(5-cyano-pyrimidin-2-yl)-piperidine-4-carbonyl}-piperazine hydrochloride (E20) =O OX

N

0 1-Isopropyl-4-[1 -(5-bromo-pyrimidin-2-yl)-piperidine-4-carbonyl]-piperazine (D2) (0.59) in

DMF (10ml) was treated with CUCN (0.1g) and the reaction mixture was refluxed overnight. The DMF was removed by evaporation and the residue was partitioned between H,O/EtOAc (20:20mi). The EtOAc layer was dried (MgSO0,) and evaporated to dryness and purified first by chromatography [ silica gel 0-10% MeOH (containing 10%

0.88 ammonia solution)! DCM] followed by further purification on a Waters Mass

Directed Auto Preparative HPLC eluting with (0.1% formic acid in water and 0.1% formic acid acetonitrile gradient 10-100%). The isolated product peaks were combined and evaporated to give the desired product as the formate salt which was converted to the

HCI salt in MeOH/ethereal 1N HCI (2m). The solvents were removed by evaporation to give the title compound (E20) as a white solid (17mg).'H NMR & [DMSO-d6): 1.29 (6H, d,

J=6.5), 1.40-1.58 (2H, m),1.70-1.81 (2H, m ), 2.90-3.5 (10H, m), 4.25-4.8 (4H, m), 8.74 (2H, 5),10.9 (1H, bs). LCMS electrospray (+ve) 343 (MH").

Example 21 1-Isopropyl-4-{1 .[5(pyridin-3-yl)-pyrimidin-2-yl]-piperidine-4-carbonyl}-piperazine hydrochloride (E21)

O-CrOpO<

NJ I N_/

A mixture of 1-isopropyl-4-[1 -(5-bromo-pyrimidin-2-yl)-piperidine-4-carbonyl]-piperazine (D2) (0.25g), 3-pyridyl boronic acid (0.1g), 2M K,CO3 (1.5ml) and EtOH (1.5ml) in toluene (10m) were stirred under a stream of argon for 30min. After this time Pd(PPhs)s (50mg) was added and the reaction mixture was refluxed overnight. Water (1ml) was added and the reaction mixture was stirred at rt for Smin. The mixture was passed through a 20g Varian Hydromatrix disposable liquid/liquid extraction cartridge and washed with EtOAc (30ml). The EtOAc layer was absorbed on silica (4g) and purified by chromatography [silica gel 0-10% MeOH (containing 10% 0.88 ammonia solution)/

DCM]. The free base was dissolved in MeOH (5mi) and treated with 1N ethereal HCI (2m). The solvents were removed by evaporation to give the title compound (E21) as a white solid (150mg)."H NMR § [DMSO-d6]: 1.29 (6H, d, J=6.5), 1.4-1.6 (2H, m),1.7-1.8 (2H, mm), 2.8-2.9 (1H, m),3.0-3.2 (6H, m),3.38-3.44 (2H, m), 3.42-3.5 (1H, m), 3.66-3.73 (1H, m), 4.25-4.3 (1H, s), 4.47-4.5 (1H, m) ,4.7-4.8 (2H, m), 8.0-8.08 (1H, m), 8.78-8.81 (2H, dd, J=2.5), 8.90 (1H, s), 9.23 (1H, d, J=1.5), 11.20 (1H, brs); LCMS electrospray (+ve) 395(MH").

Example 22 1-Isopropyi-4-[1 -(5-morpholino-pyrimidin-2-yl)-piperidine-4-carbonyl]-piperazine hydrochloride (E22) {3p {

NEAR \_/ 0

Bis(tri-t-butylphosphine)palladium(0) (20mg) was added to o-xylene(10ml) and the reaction mixture was stirred at rt for 10min to give an orange coloured solution. 1-

Isopropyl-4-[1-(5-bromo-pyrimidin-2-yl)-piperidine-4-carbonyl]-piperazine (D2) (0.25g) in o-xylene (10ml) was added to the orange solution followed by addition of NaO'Bu (84mg) and morpholine (0.12g) The reaction mixture was refluxed for 1h. After cooling the reaction mixture was partitioned between H,O/EtOAc (30:20ml), the EtOAc layer was dried (MgSO,) and filtered, the filtrate was absorbed onto silica gel (3g) and purified by chromatography [silica gel 0-1 0% MeOH (containing 10% 0.88 ammonia solution)/

DCM]. The free base was taken up in dry MeOH (3m) and treated with ethereal HCL.

The solvents were removed by evaporation to give the title compound (E22) as a white solid (67mg)."H NMR 3 [DMSO-d6]: 1.29 (6H, d, J=6.5), 1.4-1.6 (2H, m),1.68-1.7 (2H, m), 2.92-3.16 (10H, m),3.37-3.65 (4H, m),3.74-3.76 (4H, m),4.22-4.25(1H, m), 4.47- 4.60(3H, m), 8.26 (2H, 5),10.85 (1H, bs). LCMS electrospray (+ve) 403 (MH").

Example 23 1-isopropyl-4-[1 -(2-morpholino-pyrimidin-5-yl)-piperidine-4-carbonyll-piperazine hydrochloride (E23) 7 = /~\ {OHO OX [eo]

Step 1: 4-(5-Bromo-pyrimidin-2-yl)-morpholine

Potassium carbonate (0.34g) was added to a solution of 2-chioro-5-bromo-pyrimidine (0.5g) in DMF (20ml). The reaction mixture was stirred at rt for 15min. Morpholine (0.29) was added and the reaction mixture was stirred at rt for 2h. The excess DMF was removed by evaporation and the residue was partitioned between H,O/EtOAc (30:30ml)

The EtOAc layer was dried (MgSOs) and evaporated to dryness to give the sub-title compound as a cream solid (0.2g). LCMS electrospray(+ve) 246 (MH™).

Step2: 14sopropyl-4-(2-morpholino-pyrimidin-5-yl)-piperidine-4-carbonyl)- piperazine hydrochloride

The title compound was prepared by reacting the product of E23, Step 1 with 1- isopropyl-4-(piperidine-4-carbonyl)-piperazine (D1) using the conditions described in

Example 22 . 'H NMR 8 [DMSO-d6]; 1.29 (6H, d, J=6.5), 1.78 (4H,m), 2.80-3.1 (4H,m),3.2-4.7 (18H,m), 8.35 (2H, 5),10.65 (m, 1H). LCMS electrospray(+ve) 403 (MH").

Examples 24-26 (E24-E26)

Examples 24 - 26 were prepared from 1-isopropy!-4-[1 -(5-bromo-pyrimidin-2-yl)- piperidine-4-carbonyl]-piperazine (D2) and an appropriate aryl boronic acid using the procedure described in Example 21 and displayed "H NMR and mass spectral data that were consistent with structure. 0

R—

NN

No ES* "es [OC wer 472

E26 [=OCr [Mar ar

Examples 27 and 28 (E27-E28)

Examples 27 - 28 were prepared and isolated as for Example 1, from 1-isopropyl-4- (piperidine-4-carbonyl)-piperazine (D1) (0.239g) and 4-fluoro-acetophenone at 120°C for 2h, followed by condensation of the product with the corresponding hydroxylamine hydrochloride in refluxing methanol for 1h. Conversion to the HCl salts, by precipitation from ethyl acetate with 2N HCl in diethyl ether, and crystallisation from ethanol afforded the examples which displayed H NMR and mass spectral data that were consistent with structure. o /~\

NN

Era

No ESt

Ce [THO [mrt

Example 29 14sopropyl-4-{1-[2-chloro-4-(morpholino-carbonyl)-phenyi}-piperidine-4-carbonyl}- piperazine hydrochloride (E29) » CL

Step 1: 14sopropyl-4-[1 -(2-chloro-~4-chlorocarbonyl-phenyl)-piperidin-4-carbonyl]- piperazine hydrochloride 1-lsopropyl-4-[1-(4-carboxy-phenyl)-piperidin-4-carbonyl}-piperazine hydrochloride (D9) (0.25g) was dissolved in thionyl chloride (10ml) and heated at reflux for 1.5h. The reaction mixture was then evaporated to a minimum (co-evaporated with DCM, 3 x 10mi) to give the subtitled compound as a yellow oil (0.259).

Step 2: 1-Isopropyl-4-{1 -[2-chloro-4-{morpholino-carbonyl)-phenyl]-piperidine-4- carbonyl}-piperazine hydrochloride

A stirred mixture of the product of E29, Step 1 (0.25 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.45 g) in DCM (10m) at rt was treated with morpholine (0.035 g) and stirred for 16h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM].

Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated and the residue crystallised from acetone to yield the title compound (E29) as a white powder

(0.018 g). MS electrospray (+ion) 464 (MH). 14 NMR 8 [DMSO-d6}: 10.30 (1H, s), 7.45 (1H, s), 7.32 (1H, d, J=8.0H2), 7.17 (1H, d, J=8.4Hz), 4.55 (1H, m), 4.20 (1H, m), 3.62- 3.28 (15H, m), 3.15-2.67 (5H, m), 1.77 (4H, m), 1.28 (6H, d, J=6.4Hz).

Example 30 1-Isoprapyl-4-{1-[4-{morpholino-carbonyi)-phenyil-piperidine-4-carbonyi}- piperazine hydrochloride (E30)

Iatata o C 9 a

To a stirred solution of 1-isopropyl-4-[1 ~(4-carboxy-phenyl)-piperidin-4-carbony}- piperazine hydrochloride (D9) (0.25g), morpholine (0.035ml), HOBT (0.03g), TEA (0.16 ml) in DCM (10 ml) was added EDC (0.10g). DMF (2ml) was added and the reaction stirred under argon overnight. The reaction mixture was then evaporated to a minimum and residue dissolved in DCM (50ml) and washed with sodium hydrogen carbonate (3 x 50 ml) and then brine (50ml). The organic layer was then dried (MgSO0,) and evaporated to give the free base product. Free base was converted to the HCl salt by dissolving in DCM (5ml) and treating with excess 1 HCI in diethyl ether, evaporated and then crystallised from acetone to give the title compound (E30) as a white solid (0.03g).

MS electrospray (+ve) 429 (MH). 1H NMR [DMSO-d6]: 10.85 (1H, s), 7.38 (2H, d,

J=8.4Hz), 7.08 (2H, m), 4.51 (1H, m), 4.22 (1H, m), 3.81 (2H, m), 3.68-3.35 (12H, m), 3.20-2.81 (6H, m), 1.74 (4H, m), 1.29 (6H, d, J=6.4Hz).

Example 31 1-Cyclopentyl-4-[1 .(4-cyano-phenyl)-piperidine-4-carbonyl]-piperazine hydrochloride (E31) lo]

OOOO

Potassium carbonate (0.8g) was added to a stirred solution of 1-cyclopentyl-4- (piperidine-4-carbonyl)-piperazine di-hydrochloride (D5) (0.5g) in dry DMSO (15m) followed by the addition of 4-benzonitrile (0.35g). The reaction mixture was heated at 140°C for 2h. After cooling the reaction mixture was partitioned between H,O/EtOAC (30:30ml). The EtOAc layer was dried (MgSO) filtered and the filtrate was absorbed onto silica gel (4g) and purified by chromatography [silica gel 0-10% MeOH ( containing 10% 0.88 ammonia solution)/ DCM]. The free base was dissolved in MeOH (3ml) and treated with 1N ethereal HCI (2m). The solvents were removed by evaporation to give the title compound (E31) as a white solid (63mg)."H NMR 8 [DMSO-d6]; 1.5-1.9 (12H,

m), 2.9-3.06 (4H, m) 3.9-3.96 (2H, m), 4.18-4.45 (2H, m), 7.01 (2H, d J=9.2), 7.55 (2H, d

J=0.2), 11.28 (1H, brs). LCMS electrospray(+ve) 356 (MH).

Example 32 1-Cyclopentyl-4-{1-{5-cyano-pyridin-2-yl)-piperidine-4-carbonyi]-piperazine hydrochloride (E32) \ =O OC 0

The title compound (E32) was prepared from 2-chloro-5-cyano-pyridine and 1- cyclopentyl-4-(piperidine-4-carbonyl)-piperazine di-hydrochloride (D5) according to the procedure described in Example 31. "H NMR 8 [DMSO-d6} 1.5 (4H, m), 1.67-1.88 (6H, m),1.98-2.02 (2H, m), 2.87-2.97 (6H, m), 3.4-3.7 (4H, m), 4.17-4.7 (4H, m) 6.94 (1H, d,

J=9Hz), 7.8 (1H, d, J=0Hz), 8.4 (1H, s) 11.5 (1H, brs). LCMS electrospray (+ve) 368 (MH+).

Example 33 (2R,6S)-1-Cyclobutyl-4-{1 -(4-cyanophenyl)-piperidine-4-carbonyi]-2,6- dimethylpiperazine hydrochloride (E33) 0 ~ -O-OLC0 (2R,6S)4-[1 _(4-Cyanophenyl)-piperidine-4-carbonyl-2,6-dimethylpiperazine hydrochloride (D13) (0.30g), TEA (0.4mt), cyclobutanone (0.13g) and sodium triacetoxyborohydride (0.40g) in DCM (5ml) were heated to 100°C in a microwave reactor for 5min. The reaction mixture was then washed with saturated potassium carbonate solution (2 x 30mi), and brine (30ml). The organic layer was then dried (MgSO.) and evaporated give the crude product which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base compound which was converted to the HCI salt by redissolving in DCM and then treating with excess hydrogen chloride (1M solution in diethyl ether), evaporating and then crystallising from acetone to give the title compound (E33) as a pale grey solid (0.053g). MS electrospray (+ve) 381 (MH). 1H NMR & [DMSO-d6]: 11.28 pilus 10.10 (1H, m, rotomers), 7.59 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=8.0Hz), 4.31-3.73 (6H, m), 3.60-3.22 (3H, m), 2.97 (3H, m), 2.50-2.08 (4H, m), 1.78-1.61 (6H, m), 1.50 -1.10 (6H, m).

Example 34 1-1sopropyl-4-[1 -phenyl-piperidine-4-carbonyl]-[1 ,4]-diazepane hydrochloride (E34)

OO le}

The title compound (E34) was prepared from 1-isopropyl-4-(piperidine-4-carbonyl)-{1 4)- diazepane (D8) and bromobenzene following the procedure of Example 45. LCMS electrospray (+ve) 330 (MH").

Example 35 1-isopentyl-4-[1 -(5-cyano-pyridin-2-yl)-piperidine-4-carbonyl}-piperazine hydrochloride (E35) °

N /\ Et -O end NM

The title compound (E35) was prepared from N-isopentylpiperazine using the procedure described in Example 1. MS electrospray; (+ve ion) 370 (MH+).

Example 36 1-Cyclobutyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane hydrochloride (E36) 0 { > -O-OH

NC N N J

1-[1 -(4-Cyanophenyl)-piperidine-4-carbonyl]-[1 ,4)-diazepane hydrochloride (D4) (0.309) was dissolved in DCM (10m). TEA (0.4 ml) and cyclobutanone (0.14mi) were added and stirred for 5 min. Sodium triacetoxyborohydride (0.40g) was then added and the reaction stirred at rt overnight. The reaction was then washed with aqueous saturated potassium carbonate solution (2 x 30ml), brine (30m), dried (MgS0,) and evaporated. The free base was redissolved in DCM and treated with excess hydrogen chloride (1M solution in diethyl ether) and concentrated to yield the title compound (E36) as a white solid (0.169).

MS electrospray (+ve) 367 (MH). 1H NMR & [DMSO-d6]: 10.95-10.78 (1H, m), 7.56 (2H, d, J=9.2Hz), 7.02 (2H, d, J=8.8Hz), 4.20-3.95 (3H, m), 3.62-3.39 (5H m), 3.07 (1H, m), 2.98-2.70 (5H, m), 2.49-2.01 (6H, m), 1.72-1 .57 (6H, m).

Example 37 1-Cyclobutyl-4-[1-(5-cyanopyridin-2-yl)-piperidine-4-carbonyl]-[1,4]-diazepane hydrochloride (E37) [o]

OL

1-{1-(5-Cyanopyridin-2-yl)-piperidine-4-carbony(l-[1 4)-diazepane hydrochloride (D14) (0.30g) was dissolved in DCM (10ml) and TEA (0.4ml) was added followed by cyclobutanone (0.14mi). The reaction was stirred for 5min under argon and then sodium triacetoxyborohydride (0.41g) was added and the reaction stirred at rt for 4h. The reaction mixture was washed with saturated aqueous potassium carbonate (2 x 30m), saturated sodium hydrogen carbonate (2 x 50mi) and brine (50m). The organic layer was then dried (MgSO.) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM] to give the free base product which was converted to the HCl salt by redissolving in DCM and then treating with excess hydrogen chloride (1M solution in diethy! ether) and concentrating to yield the title compound (E37) as a pale yellow solid (0.047g). MS electrospray (+ve) 368 (MH™). 1TH NMR § [DMSO-d6]: 10.80-10.50 (1H, m), 8.47 (1H, s), 7.83 (1H, d, J=8.8Hz), 6.95 (2H, d, J=8.8Hz), 4.44 (2H, m), 4.05 (1H, m), 3.85-3.28 (6H, m), 3.07-2.72 (5H, m), 2.41-2.01 (6H, m), 1.82-1.41 (6H, m).

Example 38 1-isopropyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbony}-{1 ,4]-dlazepane- hydrochloride (E38) a =O [¢]

Triethylamine (0.18mi) was added to a solution of 1-[1-(4-cyanophenyl)-piperidine-4- carbonyl)-[1,4]-diazepane hydrochloride (D4) (0.3g) in dry DCM (15m) followed by the addition of acetone (0.15g). The reaction was stirred at rt for 30min followed by the addition of sodium triacetoxyborohydride (0.4g). After 18h 1N NaOH (2ml) was added and stirring continued for a further 15min. The reaction was then washed with water and the DCM layer was separated, dried (MgSOs ), absorbed onto silica gel (4g) and purified by chromatography [silica gel 0-10% MeOH (containing 10% 0.88 ammonia solution)

DCM]. The free base was dissolved in MeOH (3m) and treated with 1N ethereal HCI (2m). The solvent was removed by evaporation to give the title compound (E38) as a white solid (0.1g)."H NMR § [DMSO-d6]; 1.27 (6H, d J=6.5Hz), 1.58 (2H, m), 1.74 (2H, m), 2.08 (1H, m), 2.32 (1H, m), 2.75-3.25 (6H, m), 3.35-3.76 (6H, m), 3.94.08 (2H, m), 7.0 (2H,d, J=8.8), 7.54 (2H, d J=8.8), 10.38-10.58 (1H, m). LCMS electrospray (+ve) 355 (MH*).

Example 39 1-Isopropyl-4-[1-(4-cyano-2,5-difluorophenyl)-piperidine-4-carbonyl}-[1,4]- diazepane hydrochloride (E39)

F = = Ori lo

K,COs (0.59) was added to a solution of 1-isopropyl-4-(piperidine-4-carbonyi}-[1 4]- diazepane (D8) (0.29) in dry DMSO (2m), and the resulting mixture was stirred at rt for 15min, followed by the addition of 2 4 5-triflucrobenzonitrile (0.24g) in dry DMF (1ml).

The reaction was then heated at 140°C for 2h before cooling to rt. Excess potassium carbonate was removed by filtration and the crude reaction mixture was purified first by adding the crude reaction toa Varian 10g SCX column and eluting with MeOH (40m), then eluting with 10% 0.88 ammonia solution in MeOH (20ml) which was evaporated to afford a residue that was further purified using a Waters mass directed auto preparative

HPLC. The purified fractions were combined and the aqueous solvents were removed by evaporation and the residue re-dissolved in MeOH (2ml) and treated with 1N ethereal

HCI (1ml) which gave a white solid which was washed with diethyl ether to give the title compound (E39) (34mg)."H NMR 3 [MeOH-d4]; 1.37 (6H, m),1.87 (4H, m), 2.19-2.29 (2H, m), 2.94-3.00 (3H, m), 3.29-3.3 (2H, m), 3.53-3.58 (7H, m), 3.86-3.98 (1H, m), 4.04- 4.1 (1H, m), 6.9 (1H, dd, J=11.6Hz), 7.4 (1H, dd, J=12.4hZ). LCMS electrospray (+ve) 391 (MH").

Example 40 1-Isopropyl-4-[1 -(4-cyano-3-chiorophenyl)-piperidine-4-carbonyl]-[1 4]-diazepane hydrochloride (E40)

Ci = Ono lo}

The title compound (E40) was prepared using 2-chloro-4-fluorobenzonitrile and the procedure described in Example 39. 'H NMR 8 [MeOH-d4]; 1.37 (6H, m),1.78-1.9 (4H, m), 2.29 (2H, m), 2.99-3.00 (3H, m), 3.04-3.31 (2H, m), 3.47-3.58 (5H, m), 3.87 (1H, m), 3.97-4.07 (2H, m), 4.07-4.09 (1H), 6.96 (1H, d, J=8.8Hz), 7.08 (1H, d, J=2Hz), 7.51 (1H,

J=8.8Hz). LCMS electrospray (+ve) 389 (MH").

Example 41 1-isopropyl-4-[1 -(4-cyano-3-fluoro-phenyl)-piperidine-4-carbonyl]-{1 ,A}-dlazepane hydrochloride (E41) . = {Oni 0

The title compound (E41) was prepared using 2,4-difluorobenzonitrile and the procedure described in Example 39. 'H NMR § [MeOH-d4]: 1.37 (6H, m),1.9 (4H, m), 2.19-2.33 (2H, m), 2.89-2.98 (3H, m), 3.27-3.3 (2H, m), 3.5-3.78 (6H, m), 3.80-3.90 (1H, m), 4.07-

4.15 (1H, m), 4.07-4.09 (1H), 7.15 (1H, t, J=8.4Hz), 7.44 (2H, dd J=6.4Hz). LCMS electrospray (+ve) 373 (MH").

Example 42 1-isopropyl-4-[1-{4-cyano-2,6-difluoro-phenyl)-piperidine-4-carbonyl}-{1 4)- diazepane hydrochloride (E42)

F

= Cr

F [¢)

The title compound (E42) was prepared using 3,4,5-trifluorobenzonitrile and the procedure described in Example 39. 'H NMR § [MeOH-d4]: 1.37 (6H, m), 1.78-1.92 (4H, m), 2.15-2.38 (2H, m), 2.80-2.93 (1H, m), 3.17-3.27 (4H, m), 3.4-3.78 (7TH, m), 3.80-3.90 (1H, m), 4.07-4.15 (1H, m), 7.35 (2H, dd, J= 2.4Hz). LCMS electrospray (+ve) 391 (MH")

Example 43 14sopropyi-4-[1 -(4-cyano-2-fluoro-phenyl)-piperidine-4-carbonyl]-[1 ,4]-diazepane hydrochloride (E43)

F

CO lo)

The title compound (E43) was prepared using 3,4-difluorobenzonitrile and the procedure described in Example 39. 'H NMR & [MeOH-d4]: 1.37 (6H, m),1.73-1.89 (4H, m), 2.18- 2.37 (2H, m), 2.98-3.08 (3H, m), 3.15-3.27 (2H, m), 3.48-3.78 (5H, m), 3.80-3.90 (1H, m), 3.98-4.12 (2H, m), 4.054.12 (1 H), 6.7-6.8 (2H, m), 7.45 (1H, t, J=8Hz). LCMS electrospray (+ve) 373 (MH").

Example 44 1-Isopropyl-4-[1 -(4-cyano-3-triflucromethyl-phenyl)-piperidine-4-carbonyl]-[1 A] diazepane hydrochloride (E44)

F

2 FOI

N= No 0

The title compound (E44) was prepared using 2-trifluoromethyl-4-fluorobenzonitrile and the procedure described in Example 39. 'H NMR & [MeOH-d4]: 1.38 (6H, m), 1.75-1.91 (4H, m), 2.23-2.37 (2H, m), 2.80-3.08 (4H, m), 3.34.08 (10H, m), 7.18 (1H, d, J=8.8Hz), 7.25 (1H, d, J=2.4), 7.68 (1H, d, J=8.8Hz). LCMS electrospray (+ve) 423 (MH).

Example 45 1-Isopropyl-4-[1 -(4-trifluoromethyl-phenyl)-piperidine-4-carbonyl]-{1 ,4]-dlazepane hydrochloride (E45)

F On ~

Fo — N_/

F 0

To 4-trifluoromethyi-iodobenzene (0.2g) under argon in dry degassed dioxane (1.5m) was added bis(dibenzylideneacetone)paliadium (0.02g) followed by 2- dicyclohexylphosphine-2'-(N,N-dimethylamino)-bipheny! (0.0559). After 15min this solution was added to 1-isopropyl-4-(piperidine-4-carbonyl]-{1 ,4]-diazepane (D8) (0.159) as a slurry in dry degassed dioxane (1 .5ml) under argon. This was followed by addition of sodium-t-butoxide (0.06g) and heating to 100°C for 2h. After cooling, saturated ammonium chloride solution (10ml) was added along with EtOAc (20ml). The reaction was filtered and washed with brine (2x) before being extracted with 1N HCI and then neutralised with potassium carbonate solution and back extracted into EtOAc.

Concentration to low volume and addition of 2N HCl in diethyl ether caused the title hydrochloride salt to precipitate. Decantation of the supernatant and repeated trituration of the residue with diethyl ether afforded crude product that was crystallised from acetonitrile to afford the title compound (E45) (0.078g). H NMR & [MeOH-d4]: 1.38 (6H, 15m), 2.0-2.34 (6H, m), 2.86-4.11 (14H, m), 7.5-7.6 (2H, m) and 7.71-7.77 (2H, m). LCMS electrospray (+ve) 398 (MH").

Examples 46-69 (E46-E69)

Example 46 and Examples 63-69 were prepared from either 1-isopropyl-4-(piperidine-4- carbonyl)-[1,4]-dlazepane (D8) or 1-cyclobutyl-4-(piperidine-4-carbonyl)-[1 A]-diazepane (D10) and the appropriate aryl fluoride using the procedure described in Example 39.

Examples 47- 62 were prepared by coupling 1-isopropyl-4-(piperidine-4-carbonyl)-[1 4]- diazepane (D8) with the appropriate aryl halide (bromide or iodide) using the conditions described in Example 45. The products displayed 1TH NMR and mass spectral data that were consistent with structure. a

MN

Sa.

Example Ar Mass Spectrum (ES*) =e = ad) ®ve 405 a Me

E47 | {*® met seo a Me | [MNa]* 402

FX En oN Me | [MNa]* 395

)— elmer 372

Me | [MNa]t 394

Or {mH 388

Yo Me | [2MNa]* 797

O- Love 414

CFO Me [MNa]* 436 8 el NS emt 348 = Me | [MNa]* 370 @ | imHpr 382384 > Me | [MNa]t 404/406 “ 0° [mH 398/400/402

LN Me | rMNa]t 420/422

Cl =n [A wm cl

Me | 1oMNalt 741 = wo _® |iMH* 304/396 o Me | [MNa]* 416/418 e = Me | [MNa]* 418

CHF, Me | iMNa]t 418

Me | roMNal* 865 meo—¢ ® | MH* 361 em Oa

MNa]* 383 on a [MH]* 391

Me

FF oy Me ae —> | [MH]* 401/403 cl “ — —> | MHI* 401/403

Cl [FO =

F

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: 0 (0] 4 N R? RY Ww; oh P Neo () wherein: R' represents aryl, heteroaryl, -aryl-X-Cs7 cycloalkyl, -heteroaryl-X-Cs; cycloalkyl, -aryl- X-aryl, -aryl-X-heteroaryl, -aryl-X-heterocyclyl, -heteroaryl-X-heteroaryl, -heteroaryl-X- aryl or —heteroaryl-X-heterocyclyl; wherein said aryl, heteroaryl and heterocyclyl groups of R' may be optionally substituted by one or more (eg. 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloCs alkyl, polyhaloC, alkyl, haloC,. alkoxy, polyhaloC,. alkoxy, Ci. alkyl, Cy.6 alkoxy, Ci alkylthio, Cy. alkoxyCi.g alkyl, Cs; cycloalkylC,.s alkoxy, -COC,.6 alkyl, - COC; alkyl-halogen, -COC,.5 alkyl-cyano, Cy alkoxycarbonyl, Ci alkylsulfonyl, Ci. alkylsulfinyl, C1 alkylsulfonyloxy, Ci. alkylsulfonylC,.¢ alkyl, Cis alkylsulfonamidoCi.¢ alkyl, C16 alkylamidoC,.g alkyl, aryl, arylsulfonyl, arylsulfonyloxy, aryloxy, arylsulfonamido, arylcarboxamido, aroyl, or a group NR™®R'®, -CONR™R", -NR'COR", -C(R'®)=NOR?, -NR"SO,R'"® or -SO.NR"R'®, wherein R' and R" independently represent hydrogen or C, alkyl or together form a heterocyclic ring; X represents a bond, O, CO, SO,, OCH; or CHO; each R? and R* independently represents Cy alkyl; R® represents Cys alkyl, Ca alkenyl, Cs, alkynyl, Cas cycloalkyl, Cs¢ cycloalkenyl or -C;. 4alkyl-Cae cycloalkyl; wherein said Ca cycloalkyl groups of R* may be optionally substituted by one or more

(eg. 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, C4 alky! or trifluoromethy! groups; m and n independently represent 0, 1 or 2; p and q independently represent 1 or 2; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (1) as defined in claim 1 wherein R' represents -aryl optionally substituted by 1, 2 or 3 halogen, Cs alkyl, polyhaloC,.s alkyl, C;¢ alkoxy, polyhaloC, alkoxy, -COC.¢ alkyl, -C(R'®)=NOR'®, -NR'* COR", -COC,.¢ alkyl- halogen, -COC,.¢ alkyl-cyano, cyano or Cy. alkoxycarbonyl groups; -aryl-X-Cs 7 cycloalkyl;

-aryl-X-aryl, -aryl-X-heterocyclyl optionally substituted by 1, 2 or 3 halogen or oxo groups; -aryl-X-heteroary! optionally substituted by a Cs alkyl or aryl group; -heterocyclyl optionally substituted by 1, 2 or 3 Cy alkyl or -COC, alkyl groups; heteroaryl optionally substituted by 1, 2 or 3 cyano, halogen, polyhaloC,.¢ alkyl,

Cs.6 alkyl, C15 alkoxy, C1. alkoxycarbonyl or -CONR'R' groups; -heteroaryl-X-aryl optionally substituted by 1, 2 or 3 cyano or C, alkylsulfonyl groups; -heteroaryl-X-heterocyclyl; or -heteroaryi-X-heteroaryl.

3. A compound of formula (1) as defined in claim 2 wherein R! represents phenyl, naphthyl or indanone optionally substituted by 1, 2 or 3 halogen, Cy alkyl, polyhaloC,.s alkyl, C1 alkoxy, polyhaloC_ alkoxy, -COC,¢ alkyl, -C(R'®)=NOR'®, - NR"COR?', -COC,s alkyl-halogen, -COC, alkyl-cyano, cyano or C, alkoxycarbonyl groups; —phenyl-CO-cyclopropyl or —phenyl-CO-cyclobutyl; —phenyl-thiazolyl, -phenyl-oxadiazolyl, -phenyl-pyrrolyl, -phenyl-oxazolyl or — phenyl-isoxaxolyl optionally substituted by a C,.¢ alkyl or aryl group; or pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyi, isoquinolinyl or benzothiazoly! optionally substituted by 1, 2 or 3 cyano, halogen, polyhaloC,.s alkyl, C+. alkyl, Ci alkoxy, C,. alkoxycarbonyl or ~CONR'™R"® groups.

4. A compound of formula (I) as defined in claim 3 wherein R' represents phenyl! optionally substituted by 1, 2 or 3 halogen, polyhaloCi. alkyl, - : NR' COR, -COC, alkyl or cyano groups; —phenyl-CO-cyclopropyl; -phenyi-oxadiazolyl or —phenyl-oxazolyl optionally substituted by a C, alkyl or aryl group; or pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or quinolinyl optionally substituted by 1, 2 or 3 halogen, polyhaloC,.¢ alkyl, Cy. alkyl or cyano groups.

5. A compound of formula (1) as defined in claim 4 wherein R' represents phenyl optionally substituted at the 4-position by a —-COMe, -COEt or cyano group; or pyridyl or quinolinyl optionally substituted by a methyl or CF; group.

6. A compound of formula (1) as defined in claim 5 wherein R' represents - 6-CF3-pyridin-3-yl. 40

7. A compound of formula (l) as defined in any one of claims 1 to 6 wherein X represents a bond, O or CO.

8. A compound of formula (1) as defined in claim 7, wherein X represents a bond or

Co. 9 A compound of formula (I) as defined in any one of claims 1 to 8 wherein m represents 0.

10. A compound of formula (1) as defined in any one of claims 1 to 9 wherein n represents 0, 1 or 2.

11. A compound of formula (I) as defined in claim 10 wherein n represents 0 or 1.

12. A compound of formula (I) as defined in claim 10 or claim 11 wherein R? represents methyl.

13. A compound of formula (I) as defined in claim 11 wherein n represents 0.

14. A compound of formula (1) as defined in any one of claims 1 to 13 wherein q represents 1.

15. A compound of formula (I) as defined in any one of claims 1 to 14 wherein R® represents Cs. alkyl or Cs cycloalkyl.

16. A compound of formula (I) as defined in claim 15 wherein R® represents isopropyl, isobutyl or cyclobutyl.

17. A compound of formula (I) as defined in claim 16 wherein R® represents isopropyl or cyclobutyl.

18. A compound of formula (1) as defined in claim 17 wherein R® represents isopropyl.

19. A compound of formula (I) as defined in claim 1 which is a compound of E1-E198 or a pharmaceutically acceptable salt thereof.

20. A compound of formula (1) as defined in claim 1 which is 1-1sopropyl-4-[1-{5-cyano-pyridin-2-yl)-piperidine-4-carbonyi]-piperazine; 1-Isopropyl-4-[1-(5-methoxycarbonyl-4-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]- piperazine; 40 1-lsopropyl-4-[1-(4-ethoxycarbonylphenyl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(4-cyano-3-fluorophenyl)-piperidine-4-carbonyl}-piperazine;

1-Cyclobutyl-4-[1-(4-cyano-2,6-difluorophenyl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(4-cyano-3-trifluoromethylpheny!)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(4-cyano-naphthalen-1-yl)-piperidine-4-carbonyl}-piperazine; 1-Cyclobutyl-4-[1-(5-cyanopyridin-2-yl)-piperidine-4-carbonyl}-piperazine;

1-Cyclobutyl-4-[1-(6-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(5-triflucromethylpyridin-2-yl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(3-chloro-5-trifluoromethylpyridin-2-yl)-piperidine-4-carbonyl]- piperazine; 1-lsopropyl-4-{1-[5-(4-methylsulfonylphenyl)-pyrimidin-2-yl]-piperidine-4-carbonyl}-

piperazine; 1-Isopropyl-4-{1-[4-(morpholino-carbony!}-phenyl]-piperidine-4-carbonyl}-piperazine; 1-Cyclopentyl-4-[1-(4-cyano-phenyl)-piperidine-4-carbonyl]-piperazine;

(2R,6S8)-1-Cyclobutyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-2,6- dimethylpiperazine;

1-Isopentyl-4-[1-(5-cyano-pyridin-2-yl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(4-cyanophenyi)-piperidine-4-carbonyl]-{1,4]-diazepane; 1-Cyclobutyl-4-[1-(5-cyanopyridin-2-yl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-cyano-2,5-difluorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-cyano-3-chlorophenyl)-piperidine-4-carbonyl(]-[1,4]-diazepane;

1-lsopropyl-4-[1-(4-cyano-3-fluoro-phenyl)-piperidine-4-carbonyl}-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-cyano-2,6-difluoro-phenyl)-piperidine-4-carbonyl]-{1,4]-diazepane; 1-Isopropyl-4-[1-(4-cyano-2-fluoro-phenyl)-piperidine-4-carbonyl}-[1,4]-diazepane; 1-1sopropyl-4-[1-(4-cyano-3-trifluoromethyl-phenyl)-piperidine-4-carbonyl]-[1,4]}- diazepane;

1-Isopropyl-4-[1-(4-trifluoromethyl-phenyl}-piperidine-4-carbonyi]-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-cyano-naphthalen-1-yl)-piperidine-4-carbonyl]-{1,4]-diazepane; 1-Isopropyl-4-[1-(3,4-dichlorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-trifluoromethoxyphenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-difluoromethoxyphenyl)-piperidine-4-carbonyl]-[1,4]-diazepane;

1-Isopropyl-4-[1-(4-phenoxyphenyl)-piperidine-4-carbonyi]-[1,4]-diazepane; 1-Isopropyl-4-[1-(6-methoxypyridin-3-yl)-piperidine-4-carbonyl]-[1,4]-diazepane;1- Isopropyl-4-[1-(4-cyano-2,3-difluorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-cyano-2-chlorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Cyclobutyl-4-[1-(4-cyano-2-chlorophenyl)-piperidine-4-carbonyi}-[1,4])-diazepane;

1-Cyclobutyl-4-[1-(4-cyano-3-chlorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Cyclobutyl-4-[1-(4-cyano-3-fluorophenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Cyclobutyl-4-[1-(4-cyano-3-trifluoromethylphenyl)-piperidine-4-carbonyl}-[1,4]- diazepane; 1-Cyclobutyt-4-[1-(4-cyano-2,5-difluorophenyl)-piperidine-4-carbonyl]{1,4]-diazepane;

40 (S)-1-Isopropyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-2-methylpiperazine; (S)-1-Isopropyl-4-{1-(6-cyanopyridin-3-yl)-piperidine—4-carbonyl]-2-methyl piperazine; (8)-1-Isopropyl-4-[1-(5-cyanopyridin-2-yl}-piperidine-4-carbonyl]-2-methyl piperazine;

(S)-1-Isopropyl-4-[1 -(5-trifluoromethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-2-methyl piperazine; (S)-1-Isopropyl-4-[1-(6-trifluoromethyl-pyridazin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine; 1-lsopropyl-4-{1-[4-(5-phenyl-1 ,3,4-oxadiazol-2-yl)phenyl]-piperidine-4-carbonyl} piperazine; 1-1sopropyl-4-[1-(quinolin-6-y1)-piperidine-4-carbonyl] piperazine; 1-Cyclobutyl-4-[1-(6-triflucromethyipyridin-3-yl)-piperidine-4-carbonyl] piperazine; 1-Isopropyl-4-[1 -(5-trifluoromethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-piperazine; (S)-1-Isobutyl-4-[1 -(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine; 1-Isopropyl-4-[1 -(4-cyclopropylcarbonylphenyl)-piperidine-4-carbonyl]-piperazine; 1-Isopropyl-4-[1-(2-methyl-quinolin-6-yl)-piperidine-4-carbonyl]-piperazine; 1-1sopropyl-4-[1-(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-piperazine; 1-Cyclobutyl-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-[1 4]-diazepane; 1-Cyclobutyl4-[{1-(2-cyanopyridin-4-yl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(6-trifluoromethylpyridazin-3-yl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(5-trifluoromethylpyrazin-2-yl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-isopropyl-4-{1-[4-(2-methyl-1,3-oxazol-5-yl)phenyl]-piperidine-4-carbonyl}-[1,4]- diazepane; 1-lsopropyl-4-{1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-piperidine-4-carbonyl}-[1,4]- diazepane; 1-Isopropyl-4-[1-(4-acetamido-3-fluorophenyl)-piperidine-4-carbonyl]{ 1,4]-diazepane; 1-Cyclobutyl-4-[1-(4-acetylphenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Cyclobutyl-4-[1-(6-cyano-pyridin-3-yi)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-lsopropyl-4-[1-(6-cyano-pyridin-3-yl)-piperidine-4-carbonyl]-[1,4]-diazepane; 1-Isopropyl-4-[1-(2-methyl-quinolin-4-yl)-piperidine-4-carbonyl}-[1,4]-diazepane; 1-Isopropyl-4-{1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-piperidine-4-carbonyl}-piperazine; 1-Isopropyl-4-[1-(2-trifluoromethylpyrimidin-5-yl)-piperidine-4-carbonyl]-[1,4]-diazepane; or a pharmaceutically acceptable salt thereof.

21. A compound of formula (I) as defined in claim 1 which is 1-Isopropyl-4-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine; 1-Isopropyi-4-[1-(4-cyanophenyi}-piperidine-4-carbonyl]-[1,4]-diazepane; (S)-1-Isopropyl-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine; 1-Isopropyi-4-[1-(4-acetylphenyl)-piperidine-4-carbonyl}-[1,4]-diazepane; 1-Isopropyl-4-[1-(4-propanoylphenyl)-piperidine-4-carbonyl]-[1,4]-diazepane; or a pharmaceutically acceptable salt thereof. 40 22. A compound of formula (I) as defined in claim 1 which is 1-Isopropyi-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyi}-piperazine; 1-Isopropyl-4-[1-(6-trifluoromethylpyridin-3-yl)-piperidine-4-carbonyl]-{1,4]-diazepane;

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition which comprises the compound of formula (I) as defined in any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

24. A compound as defined in any one of claims 1 to 22 for use in therapy.

25. A compound as defined in any one of claims1 to 22 for use in the treatment of neurological diseases.

26. Use of a compound as defined in any one of claims 1 to 22 in the manufacture of a medicament for the treatment of neurological diseases.

27. A pharmaceutical composition for use in the treatment of neurological diseases which comprises the compound of formula (I) as defined in any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. A process for the preparation of a compound of formula (lI) or a pharmaceutically acceptable salt thereof, which process comprises: (a) reacting a compound of formula (ll) oO H— N rR’ py = Jn - ? pS (0) or an optionally activated or protected derivative thereof, wherein R?, R*, m, n, p and q are as defined in claim 1 and R* is as defined for Rin claim 1 or a group convertible to R®, with a compound of formula R'-L', wherein R' is as defined in claim 1 and L' represents a suitable leaving group, such as a halogen atom followed by a deprotection reaction as necessary; or

84. AMENDED SHEET

(b) reacting a compound of formula (lll) o (-] =) 2 (Rx WL) wherein R', R*, m and q are as defined in claim 1 and L® represents OH or a suitable leaving group, such as a halogen atom, with a compound of formula (IV) H \ C N (4 ps 0) wherein R%, n and p are as defined in claim 1 R* is as defined for R*in claim 1 or a group convertible to R%; or (c) deprotecting a compound of formula (I) or converting groups which are protected; and optionally thereafter (d) interconversion to other compounds of formula (1).

29. A compound of formula | as defined in claim 1, substantially as herein described and exemplified.

30. A pharmaceutical composition as defined in claim 23, substantially as herein described and exemplified.

31. A process as defined in claim 28, substantially as herein described and exemplified. 85 AMENDED SHEET