WO2010102663A1

WO2010102663A1 - Piperazine derivatives for use in therapy

Info

Publication number: WO2010102663A1
Application number: PCT/EP2009/052802
Authority: WO
Inventors: Paul John Beswick; Alister Campbell; Andrew Cridland; Robert James Gleave; Lee William Page
Original assignee: Glaxo Group Limited
Priority date: 2009-03-10
Filing date: 2009-03-10
Publication date: 2010-09-16

Abstract

The present invention relates to novel piperazine derivatives (I) with affinity for Ca_v2.2 calcium channels and which are capable of interfering with Ca_v2.2 calcium channels; to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.

Description

Compounds for Use in Therapy

The present invention relates to novel piperazine derivatives with affinity for Ca_v2.2 calcium channels and which are capable of interfering with Ca_v2.2 calcium channels; to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.

Presynaptic Ca_v2.2 (N-type) voltage-gated calcium channels in the dorsal horn of the spinal cord modulate the release of key pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP), indicating the potential therapeutic use of Ca_v2.2 calcium channel blockers as analgesics.

Peptidic ω-conotoxins, isolated from the venom of cone snails, are selective for Ca_v2.2 calcium channels and can block SP release in the spinal cord (Smith et al. (2002) Pain, 96: 119-127). Moreover, they are antinociceptive in animal models of chronic pain following intrathecal administration (Bowersox et al. (1996) Journal of Pharmacology and Experimental Therapeutics, 279: 1243-1249; Smith et al. (2002) supra), and are effective analgesics in clinical use, particularly in the treatment of neuropathic pain (Brose et al. (1997) Clinical Journal of Pain, 13: 256-259).

However, Ca_v2.2 calcium channels are also important for normal neuronal function. Therefore, the aim is to identify novel molecules that preferentially block Ca_v2.2 under conditions of increased neuronal excitability, so-called use-dependent blockers, as is the case in chronic pain syndromes (Winquist et al. (2005) Biochemical Pharmacology, 70: 489-499).

WO 2007/103456 (Trimeris, Inc) discloses a series of piperazine and piperidine derivatives for the treatment of HIV infection.

The present invention provides compounds with affinity for Ca_v2.2 calcium channels and which are capable of interfering with the affects of these channels. According to a first aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy:

(I) wherein R¹ is halogen, Ci_-4 alkyl, Ci_-3 alkoxy; n is 0, 1 , 2, 3, 4 or 5; m is 0, 1 , 2, 3 or 4;

X is a linker selected from -CO-, -XONH-, -XH₂-CONH-, -XH₂-CO-, -XO-CH₂-O-,

-XO-CH₂-, -XO-CH₂-S-, -XON(CH₃)-, -XH₂-CO-NH-CH₂-, -XH₂-CON(CH₃)- and -

XO-CH₂-NH- wherein ^* indicates bonding to the piperazine ring;

R² is Ci_-4 alkyl, Ci_-3 alkoxy Ci_-3 alkyl or hydroxy Ci_-4 alkyl; R³ is hydrogen, halogen, cyano, Ci_-4 alkyl, Ci_-4 alkoxy or halo Ci_-4 alkyl;

R⁴ is hydrogen, halogen, cyano, Ci_-4 alkoxy or halo Ci_-4 alkyl;

R⁵ is hydrogen, halogen, cyano, Ci_-4 alkyl or Ci_-4 alkoxy; wherein at least one of R³, R⁴ and R⁵ is a group other than hydrogen; and wherein when R³ or R⁴ are bromo, R⁵ is halogen, cyano, Ci_-4 alkyl or Ci_-4 alkoxy; with the proviso that the compound is not

Λ/-(4-bromo-2-chlorophenyl)-4-[(4-chlorophenyl)sulfonyl]-1-piperazinecarboxamide;

4-[(4-chlorophenyl)sulfonyl]-Λ/-(3-methylphenyl)-1-piperazinecarboxamide;

1-[(4-chlorophenyl)sulfonyl]-4-[(2-fluorophenyl)acetyl]piperazine;

1-[(4-chlorophenyl)sulfonyl]-4-[(4-fluorophenyl)carbonyl]piperazine; or 4-{[4-[(3-fluorophenyl)carbonyl]-3-(hydroxymethyl)-1-piperazinyl]sulfonyl}benzonitrile.

As used herein, the term "alkyl" (when used as a group or as part of a group) refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, Ci_-6 alkyl means a straight or branched hydrocarbon chain containing at least 1 and at most 6 carbon atoms. Examples of alkyl include, but are not limited to; methyl (Me), ethyl (Et), n-propyl, i-propyl, t-butyl, n-heptyl, n- hexyl and i-hexyl. As used herein, the term "C_1-3 alkoxy" and "C_1-4 alkoxy" (when used as a group or as part of a group) refers to an -O-alkyl group wherein alkyl is as defined herein. C_1-4 alkoxy groups are methoxy, ethoxy, propoxy and butoxy. As for alkyl unless a particular structure is specified the terms propoxy, butoxy etc. include all straight and branched chain forms having the appropriate number of carbon atoms, e.g. propoxy includes n-propoxy and isopropoxy.

As used herein, the term "C_1-3 alkoxy C_1-3 alkyl" as used herein refers to an -alkyl-O- alkyl group wherein alkyl is as defined herein. Examples of such groups include methoxyethyl, methoxypropyl and ethoxypropyl.

As used herein, the term "hydroxy C_1-4 alkyl" as used herein refers to an -alkyl-OH group wherein alkyl is as defined herein. Examples of such groups include hydroxymethyl and hydroxylethyl.

As used herein, the term "halo C_1-4 alkyl" as used herein refers an alkyl group as defined herein substituted with one or more halogen groups, for example CF₃, CF₂H or CF₃CH₂.

The term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluoro (fluorine), chloro (chlorine), bromo (bromine) and iodo (iodine).

In one embodiment of the first aspect, n is 0, 1 , 2 or 3. In a particular embodiment of the first aspect, n is 0, 1 or 2. In a more particular embodiment of the first aspect, n is 0 or 1. In a further embodiment of the first aspect, n is 0.

When present, in one embodiment of the first aspect, R¹ is selected from fluoro, chloro, bromo, methyl, methoxy, ethoxy and propoxy. In a particular embodiment of the first aspect, R¹ is selected from fluoro, chloro, ethoxy and methoxy. In a more particular embodiment of the first aspect, R¹ is fluoro.

In one embodiment of the first aspect, m is 0, 1 , 2 or 3. In another embodiment of the first aspect, m is 1 , 2 or 3. In a particular embodiment of the first aspect, m is 1 or 2. In a more particular embodiment of the first aspect, m is 1. In one embodiment of the first aspect, R² is C_1-3 alkyl. In another embodiment of the first aspect, R² is selected from methyl, ethyl, hydroxymethyl and methoxymethyl. In a particular embodiment of the fi rrsstt aspect, R² is methyl or ethyl. In a more particular embodiment of the first aspect, R² is methyl.

In one embodiment of the first aspect, X is selected from -CO-, -XONH-, -XH₂- CONH-, -XH₂-CO-, -XO-CH₂-O-, -XO-CH₂-, -XO-CH₂-S-, -XON(CH₃)- and -XH₂- CO-NH-CH₂- wherein ^* indicates bonding to the piperazine ring. In a particular embodiment of the first aspect, X is selected from -CO-, -XONH- and -XH₂-CONH- . In a more particular embodiment of the first aspect, X is -CO-.

In one embodiment of the first aspect, R³ is selected from hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, cyano and methoxy. In one particular embodiment of the first aspect, R³ is selected from hydrogen, chloro, bromo, trifluoromethyl, cyano and methoxy. In a more particular embodiment of the first aspect, R³ is selected from chloro, trifluoromethyl and cyano, In an even more particular embodiment of the first aspect, R³ is cyano.

In one embodiment of the first aspect, R⁴ is selected from hydrogen, methoxy, fluoro, chloro and cyano. In a particular embodiment of the first aspect, R⁴ is selected from hydrogen, fluoro, methoxy and cyano. In a more particular embodiment of the first aspect, R⁴ is selected from hydrogen and cyano, even more particularly, R⁴ is hydrogen.

In one embodiment of the first aspect, R⁵ is selected from hydrogen, methoxy, fluoro, methyl and cyano. In a particular embodiment of the first aspect, R⁵ is selected from hydrogen, methoxy and fluoro. In a more particular embodiment of the first aspect, R⁵ is hydrogen.

In one embodiment of the first aspect, R³ is selected from chloro, trifluoromethyl and cyano, R⁴ is selected from hydrogen and cyano and R⁵ is selected from hydrogen, methoxy and fluoro. In a further embodiment of the first aspect, R³ is selected from chloro, trifluoromethyl and cyano, and R⁴ and R⁵ both are hydrogen. In a more particular embodiment of the first aspect, R³ is cyano and R⁴ and R⁵ both are hydrogen. In one embodiment of the first aspect, m is 1 or 2 and R² is C_1-3 alkyl. In a particular embodiment of the first aspect, m is 1 and R² is C_1-3 alkyl. In a more particular embodiment o off the first aspect, m is 1 and R² is methyl or ethyl, even more particularly R² is methyl.

In one embodiment of the first aspect, n is 1 or 2 and R¹ is selected from fluoro, chloro, ethoxy and methoxy. In a particular embodiment of the first aspect, n is 1 or 2 and R¹ is fluoro. In a more particular embodiment of the first aspect, n is 1 and R¹ is fluoro.

In one embodiment of the first aspect, n is 0, X is selected from -CO-, -XONH-, - XH₂-CONH-, -XH₂-CO-, -XO-CH₂-O-, -XO-CH₂-, -XO-CH₂-S-, -XON(CH₃)- and - XH₂-CO-NH-CH₂- wherein ^* indicates bonding to the piperazine ring, m is 1 or 2, R² is C_1-3 alkyl, R³ is selected from chloro, trifluoromethyl and cyano, R⁴ is selected from hydrogen and cyano and R⁵ is selected from hydrogen, methoxy and fluoro. In a particular embodiment of the first aspect, n is O, X is selected from -CO-, -XONH- and -XH₂-CONH-, m is 1 , R² is methyl or ethyl, R³ is selected from chloro, trifluoromethyl and cyano, and R⁴ and R⁵ both are hydrogen.

In one embodiment of the first aspect, n is 1 or 2, R¹ is selected from fluoro, chloro, ethoxy and methoxy, X is selected from -CO-, -XONH- and -XH₂-CONH-, m is 1 or 2, R² is C_1-3 alkyl, R³ is selected from chloro, trifluoromethyl and cyano, R⁴ is selected from hydrogen and cyano and R⁵ is selected from hydrogen, methoxy and fluoro. In a particular embodiment of the first aspect, n is 1 or 2, R¹ is fluoro, m is 1 , R² is methyl or ethyl, R³ is selected from chloro, trifluoromethyl and cyano, and R⁴ and R⁵ both are hydrogen.

In one embodiment of the first aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided

(I) wherein R¹ represents halogen; m represents an integer from 1 or 2; n represents an integer from 0 to 2;

X represents a linker selected from -CO-, -CONH- or -CH₂-CONH-; R² represents C_1-4 alkyl;

R³ represents hydrogen, chloro (chlorine), fluoro (fluorine), bromo (bromine), cyano or trifluoromethyl;

R⁴ represents hydrogen, chloro (chlorine), fluoro (fluorine), cyano, methoxy or trifluoromethyl; such that at least one of R³, R⁴ and R⁵ represents a group other than hydrogen; and R⁵ represents hydrogen, methyl, chloro (chlorine) or fluoro (fluorine), such that when R⁵ represents a group other than hydrogen, R³ also represents a group other than hydrogen and such that when R³ represents bromo (bromine), R⁵ represents a group other than hydrogen.

In one embodiment of the first aspect, n represents 0 or 1. In an alternative embodiment of the first aspect, n represents 0 or 2. In a further embodiment of the first aspect, n represents 0.

When present, in one embodiment of the first aspect, R¹ represents fluoro (fluorine).

In one embodiment of the first aspect, m represents 1 or 2. In a further embodiment of the first aspect, m represents 1. In one embodiment of the first aspect, R² represents C_1-3 alkyl. In a further embodiment of the first aspect, R² represents methyl or ethyl. In a yet further embodiment of the first aspect, R² represents methyl.

In one embodiment of the first aspect, X represents -CO-.

In one embodiment of the first aspect, R³ represents chloro (chlorine), fluoro (fluorine), cyano or trifluoromethyl and R⁴ and R⁵ both represent hydrogen. In an alternative embodiment of the first aspect, R³ represents cyano, R⁴ represents hydrogen and R⁵ represents methyl. In a further alternative embodiment of the first aspect, R³ represents bromo (bromine), R⁴ represents hydrogen and R⁵ represents methyl.

In a further embodiment of the first aspect, R³ represents cyano and R⁴ and R⁵ both represent hydrogen.

In one embodiment of the first aspect, R⁴ represents fluoro (fluorine) or methoxy. In a further embodiment of the first aspect, R⁴ represents fluoro (fluorine) or methoxy and R³ and R⁵ both represent hydrogen.

In one embodiment of the first aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Examples 1 to 68, or a pharmaceutically acceptable salt thereof.

In one embodiment of the first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from:

(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1-piperazinecarboxamide (E1 ); (3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E2);

2-{(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1-piperazinyl}-Λ/-phenylacetamide (E3); (2/?)-1 -[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E4);

4-{[3-Ethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E5);

2-{(3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1-piperazinyl}-Λ/-phenylacetamide (E6);

(2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl) piperazine (E7);

(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1-(phenylcarbonyl)piperazine (E8); (2S)-1-[(4-Chlorophenyl)sulfonyl]-4-[(2-fluorophenyl)carbonyl]-2-methylpiperazine

(E9);

(2S)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E10); 2-{(3R)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1-piperazinyl}-Λ/-phenylacetamide

(E1 1 );

(2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1-piperazinecarboxamide (E12);

(3S)-4-[(4-Chlorophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-3-methyl-1- piperazinecarboxamide (E13);

(3S)-4-[(3-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E14);

(3S)-Λ/-(2,4-Difluorophenyl)-4-[(3-fluorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxamide (E15);

(3S)-4-[(4-Cyanophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (E16); (3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-1- piperazinecarboxamide (E17);

(3S)-3-Methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-Λ/-phenyl-1 -piperazinecarboxamide

(E18);

(3S)-4-[(4-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (E19); (3S)-4-[(4-Cyanophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-3-methyl-1- piperazinecarboxamide (E20);

(3S)-Λ/-(2,4-Difluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxamide (E21 );

(2S)-2-Methyl-1-(phenylcarbonyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl} piperazine (E22);

4-({(3S)-4-[(3-Fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl) benzonitrile

(E23);

4-({(3S)-4-[(4-Fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl) benzonitrile

(E24); (2/?)-2-Methyl-1-(phenylcarbonyl)-4-{[4 (trifluoromethyl)phenyl]sulfonyl} piperazine

(E25);

4-({(3S)-4-[(2-Fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl) benzonitrile

(E26);

4-{[(3S)-3-Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E27); 4-{[3,3-Dimethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E28);

4-{[(3R)-3-Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E29);

(2S)-4-[(4-Bromo-2-methylphenyl)sulfonyl]-2-methyl-1-(phenylcarbonyl)piperazine

(E30); and

3-Methyl-4-{[(3S)-3-methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E31 ). In one embodiment of the first aspect, the compound of formula (I) is 4-{[(3S)-3- Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E27), or a pharmaceutically acceptable salt thereof.

According to a second aspect, the invention provides a compound of formula (I) or a salt thereof, wherein

R¹ is halogen, Ci_-4 alkyl, Ci_-3 alkoxy; n is O, 1 , 2, 3, 4 or 5; m is 1 , 2 or 3; X is a linker selected from -CO-, -XONH-, -XH₂-CONH-, -XH₂-CO-, -XO-CH₂-O-,

XO-CH₂-NH- wherein ^* indicates bonding to the piperazine ring;

R² is Ci-₄ alkyl, Ci_-3 alkoxy Ci_-3 alkyl or hydroxy Ci_-4 alkyl;

R³ is hydrogen, halogen, cyano, Ci_-4 alkyl, Ci_-4 alkoxy or halo Ci_-4 alkyl; R⁴ is hydrogen, halogen, cyano, Ci_-4 alkoxy or halo Ci_-4 alkyl;

R⁵ is hydrogen, halogen, cyano, Ci_-4 alkyl or Ci_-4 alkoxy; wherein at least one of R³, R⁴ and R⁵ is a group other than hydrogen; and wherein when R³ or R⁴ are bromo, R⁵ is halogen, cyano, Ci_-4 alkyl or Ci_-4 alkoxy; with the proviso that the compound is not 4-{[4-[(3-fluorophenyl)carbonyl]-3- (hydroxymethyl)-1-piperazinyl]sulfonyl}benzonitrile.

In one embodiment of the second aspect, n is O, 1 , 2 or 3. In a particular embodiment of the second aspect, n is O, 1 or 2. In a more particular embodiment of the second aspect, n is O or 1. In a further embodiment of the second aspect, n is O.

When present, in one embodiment of the second aspect, R¹ is selected from fluoro, chloro, bromo, methyl, methoxy, ethoxy and propoxy. In a particular embodiment of the second aspect, R¹ is selected from fluoro, chloro, ethoxy and methoxy. In a more particular embodiment of the second aspect, R¹ is fluoro.

In one embodiment of the second aspect, m is 1 or 2. In a particular embodiment of the second aspect, m is 1.

In one embodiment of the second aspect, R² is Ci_-3 alkyl. In another embodiment of the second aspect, R² is selected from methyl, ethyl, hydroxymethyl and methoxymethyl. In a particular embodiment of the second aspect, R² is methyl or ethyl. In a more particular embodiment of the second aspect, R² is methyl. In one embodiment of the second aspect, X is selected from -CO-, -XONH-, -XH₂- CONH-, -XH₂-CO-, -XO-CH₂-O-, -XO-CH₂-, -XO-CH₂-S-, -XON(CH₃)- and -XH₂- CO-NH-CH₂- wherein ^* indicates bonding to the piperazine ring. In a particular embodiment of the second aspect, X is selected from -CO-, -XONH- and -XH₂- CONH-. In a more particular embodiment of the second aspect, X is -CO-.

In one embodiment of the second aspect, R³ is selected from hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, cyano and methoxy. In one particular embodiment of the second aspect, R³ is selected from hydrogen, chloro, bromo, trifluoromethyl, cyano and methoxy. In a more particular embodiment of the second aspect, R³ is selected from chloro, trifluoromethyl and cyano, In an even more particular embodiment of the second aspect, R³ is cyano.

In one embodiment of the second aspect, R⁴ is selected from hydrogen, methoxy, fluoro, chloro and cyano. In a particular embodiment of the second aspect, R⁴ is selected from hydrogen, fluoro, methoxy and cyano. In a more particular embodiment of the second aspect, R⁴ is selected from hydrogen and cyano, even more particularly, R⁴ is hydrogen.

In one embodiment of the second aspect, R⁵ is selected from hydrogen, methoxy, fluoro, methyl and cyano. In a particular embodiment of the second aspect, R⁵ is selected from hydrogen, methoxy and fluoro. In a more particular embodiment of the second aspect, R⁵ is hydrogen.

In one embodiment of the second aspect, R³ is selected from chloro, trifluoromethyl and cyano, R⁴ is selected from hydrogen and cyano and R⁵ is selected from hydrogen, methoxy and fluoro. In a further embodiment of the second aspect, R³ is selected from chloro, trifluoromethyl and cyano, and R⁴ and R⁵ both are hydrogen. In a more particular embodiment of the second aspect, R³ is cyano and R⁴ and R⁵ both are hydrogen.

In one embodiment of the second aspect, m is 1 or 2 and R² is C_1-3 alkyl. In a particular embodiment of the second aspect, m is 1 and R² is C_1-3 alkyl. In a more particular embodiment of the second aspect, m is 1 and R² is methyl or ethyl, even more particularly R² is methyl. In one embodiment of the second aspect, n is 1 or 2 and R¹ is selected from fluoro, chloro, ethoxy and methoxy. In a particular embodiment of the second aspect, n is 1 or 2 and R¹ is fluoro. In a more particular embodiment of the second aspect, n is 1 and R¹ is fluoro.

In one embodiment of the second aspect, n is 0, X is selected from -CO-, -XONH-, -XH₂-CONH-, -XH₂-CO-, -XO-CH₂-O-, -XO-CH₂-, -XO-CH₂-S-, -XON(CH₃)- and -XH₂-CO-NH-CH₂- wherein ^* indicates bonding to the piperazine ring, m is 1 or 2, R² is C-ι-3 alkyl, R³ is selected from chloro, trifluoromethyl and cyano, R⁴ is selected from hydrogen and cyano and R⁵ is selected from hydrogen, methoxy and fluoro. In a more particular embodiment of the second aspect, n is O, X is selected from -CO-, - XONH- and -XH₂-CONH-, m is 1 , R² is methyl or ethyl, R³ is selected from chloro, trifluoromethyl and cyano, and R⁴ and R⁵ both are hydrogen.

In one embodiment of the second aspect, n is 1 or 2, R¹ is selected from fluoro, chloro, ethoxy and methoxy, X is selected from -CO-, -XONH- and -XH₂-CONH-, m is 1 or 2, R² is C_1-3 alkyl, R³ is selected from chloro, trifluoromethyl and cyano, R⁴ is selected from hydrogen and cyano and R⁵ is selected from hydrogen, methoxy and fluoro. In a particular embodiment of the second aspect, n is 1 or 2, R¹ is fluoro, m is 1 , R² is methyl or ethyl, R³ is selected from chloro, trifluoromethyl and cyano, and R⁴ and R⁵ both are hydrogen.

In one embodiment of the second aspect, a compound of formula (I), or a salt thereof, is provided

X represents a linker selected from -CO-, -CONH- or -CH₂-CONH-; R² represents C_1-4 alkyl; R³ represents hydrogen, chloro (chlorine), fluoro (fluorine), bromo (bromine), cyano or trifluoromethyl;

In one embodiment of the second aspect, n represents 0 or 1. In an alternative embodiment of the second aspect, n represents 0 or 2. In a further embodiment of the second aspect, n represents 0.

When present, in one embodiment of the second aspect, R¹ represents fluoro (fluorine).

In one embodiment of the second aspect, m represents 1 or 2. In a further embodiment of the second aspect, m represents 1.

In one embodiment of the second aspect, R² represents Ci_-3 alkyl. In a further embodiment of the second aspect, R² represents methyl or ethyl. In a yet further embodiment of the second aspect, R² represents methyl.

In one embodiment of the second aspect, X represents -CO-.

In one embodiment of the second aspect, R³ represents chloro (chlorine), fluoro (fluorine), cyano or trifluoromethyl and R⁴ and R⁵ both represent hydrogen. In an alternative embodiment of the second aspect, R³ represents cyano, R⁴ represents hydrogen and R⁵ represents methyl. In a further alternative embodiment of the second aspect, R³ represents bromo (bromine), R⁴ represents hydrogen and R⁵ represents methyl. In a further embodiment of the second aspect, R³ represents cyano and R⁴ and R⁵ both represent hydrogen.

In one embodiment of the second aspect, R⁴ represents fluoro (fluorine) or methoxy. In a further embodiment of the second aspect, R⁴ represents fluoro (fluorine) or methoxy and R³ and R⁵ both represent hydrogen.

In one embodiment of the first aspect, a compound of formula (I), or a salt thereof, is selected from a compound of Examples 1 to 68, or a salt thereof.

In one embodiment of the second aspect, a compound of formula (I) or a salt thereof is selected from:

(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-/V-phenyl-1 -piperazinecarboxamide (E1 );

(3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E2); 2-{(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1-piperazinyl}-Λ/-phenylacetamide (E3);

(2/?)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E4);

4-{[3-Ethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E5);

(2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl) piperazine (E7); (2R)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl)piperazine (E8);

(2S)-1-[(4-Chlorophenyl)sulfonyl]-4-[(2-fluorophenyl)carbonyl]-2-methylpiperazine

(E9);

(2S)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E10);

2-{(3R)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1-piperazinyl}-Λ/-phenylacetamide (E1 1 );

(2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1-piperazinecarboxamide (E 12);

(3S)-4-[(3-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E14); (3S)-Λ/-(2,4-Difluorophenyl)-4-[(3-fluorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxamide (E15);

(3S)-4-[(4-Cyanophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (E16);

(3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-1- piperazinecarboxamide (E17); (3S)-3-Methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-Λ/-phenyl-1 -piperazinecarboxamide

(E18);

(3S)-4-[(4-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (E19); (3S)-4-[(4-Cyanophenyl)sulfonyl]-/V-(2,4-difluorophenyl)-3-methyl-1- piperazinecarboxamide (E20);

(3S)-/V-(2,4-Difluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxamide (E21 ); (2S)-2-Methyl-1-(phenylcarbonyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl} piperazine

(E22);

(E23);

4-({(3S)-4-[(4-Fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl) benzonitrile (E24);

(2/?)-2-Methyl-1 -(phenylcarbonyl)-4-{[4 (trifluoromethyl)phenyl]sulfonyl} piperazine

(E25);

(E26); 4-{[(3S)-3-Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E27);

4-{[3,3-Dimethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E28);

4-{[(3R)-3-Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E29);

(2S)-4-[(4-Bromo-2-methylphenyl)sulfonyl]-2-methyl-1-(phenylcarbonyl)piperazine

(E30); and 3-Methyl-4-{[(3S)-3-methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile

(E31 ).

In one embodiment of the second aspect, the compound of formula (I) is 4-{[(3S)-3- Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E27), or a salt thereof.

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

Certain compounds of formula (I) as defined in the first and second aspect may in some circumstances form acid addition salts thereof. It will be appreciated that for use in medicine compounds of formula (I) may be used as salts, in which case the salts should be pharmaceutically acceptable. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.

Examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated by those skilled in the art that certain protected derivatives of the compounds of formula (I) as defined in the first and second aspect, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds as defined in the first and second aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first and second aspect are included within the scope of the invention. Examples of suitable prodrugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds as defined in the first and second aspects. Therefore, in a further aspect, the invention provides a prodrug of a compound as defined in the first and second aspect.

It will be appreciated that certain compounds of formula (I) as defined in the first and second aspect, or their salts, may exist as solvates, such as hydrates. Where solvates exist, this invention includes within its scope stoichiometric and non- stoichiometric solvates.

It will be appreciated that certain compounds of formula (I) as defined in the first and second aspect, or their salts, may exist in more than one polymorphic form. The invention extends to all such forms whether in a pure polymorphic form or when admixed with any other material, such as another polymorphic form.

Certain compounds of formula (I) as defined in the first and second aspect are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. In particular, there is a chiral centre present within the compounds of formula (I) as defined in the first and second aspect as shown by the asterisk below:

(I)

Therefore, in one embodiment of the first and second aspect, the compound of formula (I) is a compound of formula (IA):

(IA) wherein R , R , R , R , R and n are as defined hereinbefore.

In an alternative embodiment of the first and second aspect, the compound of formula (I) is a compound of formula (IB):

(IB) wherein R , R , R , R , R and n are as defined hereinbefore.

The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluoro (fluorine), such as ³H, ¹¹C, ¹⁴C and ¹⁸F.

Compounds of formula (I) as defined in the first and second aspect and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In one embodiment, the compounds of formula (I) as defined in the first and second aspect or salts thereof are not isotopically labelled.

A compound of formula (I) as defined in the first and second aspect can be prepared as set forth in the following Schemes and in the examples. The following processes form another aspect of the present invention.

The present invention also provides a process for the preparation of a compound of formula (I) as defined in the first and second aspect or a salt thereof, which process comprises:

(a) preparing a compound of formula (I) wherein X represents -CO-, -CH₂- CONH- Or -CO-CH₂- which comprises reacting a compound of formula (II)

(H) or a protected derivative thereof, with a compound of formula (III)

(HI) wherein R¹, R², R³, R⁴, R⁵, m, n and X are as defined above and L¹ represents a suitable leaving group such as a halogen atom (e.g. chloro (chlorine) or bromo (bromine)); (b) preparing a compound of formula (I) wherein X represents -CONH- which comprises reacting a compound of formula (II) as defined above with a compound of formula (IV)

(IV) wherein R¹ and n are as defined above;

(c) reacting a compound of formula (V)

(V) or a protected derivative thereof, with a compound of formula (Vl)

(Vl) wherein R¹, R², R³, R⁴, R⁵, m, n and X are as defined above and L² represents a suitable leaving group such as a halogen atom (e.g. chloro (chlorine) or bromo (bromine));

(d) deprotecting a compound of formula (I) or converting groups which are protected; and optionally thereafter

(e) interconversion to other compounds of formula (I). When X represents -CH₂-CONH-, process (a) typically comprises reaction of a compound of formula (II) and (III) in the presence of a suitable solvent such as N, N- dimethylformamide) and a suitable base such as cesium carbonate optionally in the presence of an iodide source (such as potassium iodide) at a temperature between O⁰C and ambient temperature (for example ambient temperature).

When X represents -CO- or -CO-CH₂-, process (a) typically comprises reaction of a compound of formula (II) and (III) in the presence of a suitable solvent (such as acetonitrile, tetrahydrofuran or dichloromethane, in the presence of a suitable base, (for example, triethylamine, di-isopropylethylamine or PS-DIEA) at O⁰C to ambient temperature (for example, room temperature).

Process (b) typically comprises reaction of a compound of formula (II) and (IV) in the presence of a suitable solvent such as dichloromethane, in the presence of a suitable base (such as triethylamine) at a temperature between O⁰C and ambient temperature (for example room temperature).

Process (c) typically comprises reaction of a compound of formula (V) and (Vl) in the presence of a suitable solvent (such as dichloromethane or acetonitrile) in the presence of a suitable base, (for example triethylamine, di-isopropylethylamine or PS-DIEA) at O⁰C to ambient temperature (for example, ambient temperature). Alternatively, process (c) may typically comprise reaction of the intermediates in the presence of a suitable base as a solvent (for example pyridine).

In process (d), examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3^rd Ed. 1999). Suitable amine protecting groups include sulfonyl (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 (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid. Process (e) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution or amide bond formation. One such example of interconversion may be interconversion for a compound of formula (I) wherein R³ represents bromo (bromine) to a compound of formula (I) wherein R³ represents cyano. Such interconversion may be carried out by treating the bromo (bromine) compound with a cyanide salt (for example copper (I) cyanide) in a suitable solvent (such as N, N- dimethylformamide) at elevated temperatures (such as 200°C using microwave irradiation). Alternatively the interconversion may be carried out using a cyanide salt (for example zinc cyanide) in the presence of a source of a palladium catalyst (for example tris(dibenzylideneacetone)dipalladium(0) and ligand (for example 1 ,1 '- bis(diphenylphosphino)ferrocene) in a suitable solvent (such as N, N- dimethylformamide) at elevated temperatures (such as 12O⁰C). An alternative example of interconversion is for a compound of formula (I) wherein R² equals hydroxyalkyl to a compound of formula (I) where R² equals alkoxyalkyl. Such interconversion may be carried out by treating the hydroxyalkyl compound with an alkylating agent (for example methyl iodide) in the presence of a base (such as N- phenyl-tris(dimethylamino)iminophosphorane on polystyrene resin (PS-BEMP)). This conversion may be carried out in suitable solvent (such as tetrahydrofuran) at a selected temperature between ambient and elevated (for example ambient temperature).

Compounds of formula (II) may be prepared in accordance with the following Scheme:

Step (ii)

wherein R², R³, R⁴, R⁵, m and L² are as defined above and P¹ represents a suitable protecting group such as t-butoxycarbonyl.

Step (i) typically comprises reacting a compound of formula (Vl) and (VII) in a suitable solvent, such as dichloromethane or acetonitrile in the presence of a base, (for example triethylamine, di-isopropylethylamine or PS-DIEA) at O⁰C to ambient temperature (for example ambient temperature). Alternatively, step (i) may typically be carried out using a suitable base as a solvent, (for example pyridine).

Step (ii) typically comprises a deprotection reaction. For example, when P¹ represents t-butoxycarbonyl, step (ii) will typically comprise treatment with an acid, for example hydrochloric acid or trifluoroacetic acid, in a solvent (such as 1 ,4- dioxane, dichloromethane or a mixture of methanol and 1 ,4-dioxane). Compounds of formula (V) may be prepared in accordance with the following Scheme:

wherein R², m, R¹, n, X and P¹ are as defined above.

When X represents -NHCO-, step (i) typically comprises reacting a compound of formula (VII) with an appropriately substituted phenyl isocyanate derivative in the presence of a suitable solvent (such as dichloromethane) in the presence of a suitable base (such as triethylamine) at a temperature between O⁰C and ambient temperature (for example ambient temperature).

When X represents -CO-, -CH₂-CONH- or -CO-CH₂-, step (i) typically comprises reacting a compound of formula (VII) with a compound of formula (III) in a suitable solvent (such as acetonitrile, tetrahydrofuran or dichloromethane) in the presence of a suitable base (for example, triethylamine, di-isopropylethylamine or PS-DIEA) at O⁰C to ambient temperature (for example ambient temperature). Step (ii) typically comprises a deprotection reaction which may be carried out in an analogous manner to Step (ii) above.

Compounds of formula (III), (IV), (Vl) and (VII) are either commercially available, or may be prepared by known methods.

Compounds with affinity for Ca_v2.2 calcium channels may be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.

'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.

'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.

'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV- related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions. In addition, neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

Other conditions which could potentially be treated by compounds of the present invention include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence- inducing agent such as opiods (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.

Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.

The compounds of formula (I) as defined in the first and second aspect may also be useful for neuroprotection and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.

Another condition which could potentially be treated by compounds of formula (I) as defined in the first and second aspect is spasticity or muscular hypertonicity.

Thus, in an embodiment of the first aspect, the therapy is to treat any of the disorders described herein, in particular pain.

According to a further aspect, there is provided a use of a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of any of the disorders herein, in particular pain.

According to another aspect, there is provided a method of treatment of any of the disorders herein, in particular pain in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof.

The term "treatment" or "treating" as used herein includes the treatment of established disorders and also includes the prophylaxis thereof. The term "prophylaxis" is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrence of symptoms in an afflicted subject and is not limited to complete prevention of an affliction.

It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.

In order to use a compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.

In order to use the compounds of formula (I) as defined in the first and second aspect in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) as defined in the first and second aspect, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

When used in the treatment of pain, the compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine. Such therapeutic agents include for example COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor modulators, such as glycine receptor antagonists or memantine; ligands for the α₂δ- subunit of voltage gated calcium channels, such as gabapentin and pregabalin; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; cholinesterase inhibitors such as galantamine; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HT₁ agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetyl choline (nACh) receptor modulators; glutamate receptor modulators, for example modulators of the NR2B subtype; EP₄ receptor ligands; EP₂ receptor ligands; EP₃ receptor ligands; EP₄ agonists and EP₂ agonists; EP₄ antagonists; EP₂ antagonists and EP₃ antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor or Transient Receptor Potential (TRP) ligand; and purinergic receptor ligands, including antagonists at

P2X₃, P2X_2/3, P2X₄, P2X₇ or P2X_4/7. Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995, US5,633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691 , WO99/12930, WO00/26216, WO00/52008, WO00/38311 , WO01/58881 and WO02/18374.

When used in the treatment of Alzheimer's disease, the compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated 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-HT_1A antagonists, (e.g. lecozotan), 5-HT6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g. GSK189254 and GSK239512, 5-HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as β or v- secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators and Glycine Transporter Reuptake inhibitors.

When a compound of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof is used in combination with another therapeutic agent, 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 (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof together with a further therapeutic agent or agents.

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 infusable 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 colourants.

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 sterilization 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 of formula (I) as defined in the first and second aspect or a pharmaceutically acceptable salt thereof 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, months, years or even life.

A further aspect to the invention is a pharmaceutical composition comprising 0.05 to IOOOmg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Examples The preparation of a number of compounds of formula (I) as defined in the first and second aspect are described below.

Intermediate 1 : 1,1-Dimethylethyl (2/?)-4-[(4-chlorophenyl)sulfonyl]-2-methyl-1 - piperazinecarboxylate (D1)

To a solution of 1 ,1-dimethylethyl (2/?)-2-methyl-1-piperazinecarboxylate (294mg, 1.47 mmol) and triethylamine (0.51 ml_, 3.68 mmol) in DCM (5ml_) was added 4- chlorobenzenesulfonyl chloride (464 mg, 2.21 mmol). The reaction was stirred at room temperature under an argon atmosphere for 18hours. After this time, a further quantity of 4-chlorobenzenesulfonyl chloride (250mg, 1.19 mmol) was added and the sample was stirred for a further 2hours. The reaction was then evaporated and re- suspended in DCM (3OmL) to this was added PS-trisamine (2g) which was stirred gently for 2 hours and filtered. PS-isocyanate (2.5g) was then added and the solution and gently stirred for 72hours before again being filtered and evaporated. To the residue was added EtOAc (3OmL) and the organic solution was washed with water (2x 10OmL). The collected and separated organic layer was dried (MgSO₄), filtered and evaporated. The product was dried under vacuum at 40⁰C for 1 hour to yield the title compound (462mg, 85%).

¹H-NMR (CDCI₃) δ1.27 (3H, d, J= 6.8Hz), 1.42 (9H, s), 2.24 (1 H, dt, J=11.62, 3.29Hz), 2.42 (1 H, dd, J=11.4, 3.73), 3.16 (1 H, m), 3.49 (1 H, m), 3.68 (1 H, m), 3.92 (1 H, m), 4.34 (1 H, m), 7.52 (2H, m), 7.67 (2H, m). Intermediate 2: (3/?)-1-[(4-Chlorophenyl)sulfonyl]-3-methylpiperazine (D2)

To a solution of 1 ,1-dimethylethyl (2/?)-4-[(4-chlorophenyl)sulfonyl]-2-methyl-1- piperazinecarboxylate (462mg, 1.24 mmol) (Intermediate 1 ) in DCM (16ml_) was added TFA (4ml_). The solution was stirred at room temperature overnight (approx 17hrs). The reaction was concentrated in-vacuo and the residue was dissolved in EtOAc (3OmL). The solution was washed with saturated aqueous sodium bicarbonate (2x 10OmL) and water (10OmL). The collected and separated organic layer was dried (MgSO₄), filtered and evaporated. The product was dried under vacuum at 40⁰C for 18hours to yield the title compound (260mg, 77%).

¹H-NMR (CDCI₃) 51.03 (3H, d, J= 6.36Hz), 1.91 (1 H, t, J=10.63Hz), 2.29 (1 H, dt, J=11.18, 3.29Hz), 2.96 (3H, m), 3.61 (2H, m), 7.51 (2H, m), 7.69 (2H, m).

Intermediate 3: 1,1-Dimethylethyl (3S)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxylate (D3)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (300mg, 1.5 mmol) and triethylamine (0.52ml_, 3.75 mmol) in DCM (1OmL) was added 4- chlorobenzenesulfonyl chloride (473 mg, 2.25 mmol). The reaction was stirred at room temperature under an argon atmosphere for δhours. After this time, a further quantity of 4-chlorobenzenesulfonyl chloride (473mg, 2.25 mmol) was added and the sample was stirred overnight (approx 18hrs). The reaction was then evaporated and re-suspended in DCM (3OmL) to this was added PS-trisamine (2g) which was stirred gently for 2hours. After this time, a further quantity of PS-trisamine (1.5g) and PS- isocyanate (3g) was added and the solution gently stirred for 4hours before being filtered and evaporated. To the residue was added EtOAc (3OmL) and the organic solution was washed with water (2x 10OmL). The collected and separated organic layer was dried (MgSO₄), filtered and evaporated. The product was dried under vacuum at 40⁰C for 12hour to yield the title compound (476mg, >100% crude).

¹H-NMR (CDCI₃) 51.02 (3H, d, J= 6.8Hz), 1.43 (9H, s), 2.70-3.15 (3H, br m), 3.60 (1 H, br, m), 3.81 (1 H, br m), 4.12 (2H, br m), 7.49 (2H, m), 7.75 (2H, m).

Intermediate 4: (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (D4)

To a solution of 1 ,1-dimethylethyl (3S)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxylate (476mg, 1.27 mmol) (Intermediate 3) in anhydrous DCM (16mL) was added TFA (4mL). The solution was stirred at room temperature over a weekend (approx 65hrs). The reaction was reduced in-vacuo and the residue was dissolved in DCM (3OmL). The solution was washed with saturated aqueous sodium bicarbonate (2x 10OmL) and water (10OmL). The collected and separated organic layer was dried (MgSO₄), filtered and evaporated. The product was dried under vacuum at 40⁰C for 2hours to yield the title compound (227mg, 65%). ¹H-NMR (CDCI₃) 51.15 (3H, d, J= 7.02Hz), 2.70 (2H, br m), 2.90 (2H, br m), 3.12 (1 H, dt, J=12.39, 3.29Hz), 3.54 (1 H, br m), 4.03 (1 H, br m), 7.48 (2H, m), 7.75 (2H, m).

Intermediate s: 1,1-Dimethylethyl (3/?)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1 - piperazinecarboxylate (D5)

To a solution of 1 ,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate (301 mg, 1.5 mmol) in anhydrous acetonitrile (1OmL) was added PS-DIEA (925mg) and the solution was stirred gently under an argon atmosphere at room temperature for 15mins. 4-chlorobenzenesulfonyl chloride (371 mg, 1.8 mmol) as a solution in acetonitrile (5ml_) was added and the reaction was stirred for 24hrs. After this time, the reaction was filtered and PS-isocyanate (3g) was added to the solution which was stirred at room temperature over a weekend (approx 64hrs). The reaction was again filtered and PS-trisamine (1.2g) was added to the solution mixture which was stirred for 2hrs at room temperature. Finally the reaction was filtered and reduced in- vacuo to yield the title compound (411 mg, 73%).

¹H-NMR (CDCI₃) 51.02 (3H, d, J= 6.8Hz), 1.43 (9H, s), 2.79 (1 H, br m), 2.97 (1 H, br m), 3.11 (1 H, dt J=12.5, 3.29Hz), 3.60 (1 H, m), 3.80 (1 H, br m), 4.1 1 (2H, br m), 7.48 (2H, m), 7.75 (2H, m). Intermediate 6: (2/?)-1-[(4-Chlorophenyl)sulfonyl]-2-methylpiperazine (D6)

To a solution of 1 ,1-dimethylethyl (3R)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxylate (411 mg, 1.1 mmol) (Intermediate 5) in DCM (8ml_) was added TFA (2ml_). The solution was stirred at room temperature overnight (approx 18hrs). The reaction was passed down a SCX-2 (2g) column washing with two column volumes of methanol and eluting the product with 2N ammonia solution in methanol (25ml). The product containing fractions were reduced in-vacuo and the white solid obtained was suspended in chloroform which was filtered and the solution evaporated to yield the title compound (328mg, >100%).

¹H-NMR (d6-DMSO) 51.07 (3H, d, J= 7.02Hz), 2.59 (1 H, m), 2.75 (1 H, m), 2.86 (1 H, m), 2.98 (1 H, m), 3.12 (1 H, m), 3.57 (1 H, m), 4.04 (1 H, br m), 7.70 (2H, m), 7.84 (2H, m).

Intermediate 7: 1,1-Dimethylethyl (2S)-4-[(4-chlorophenyl)sulfonyl]-2-methyl-1- piperazinecarboxylate (D7)

To a stirred solution of 1 ,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.2g, 1 mmol) in DCM (5mL) was added triethylamine (0.35ml_) and 4- chlorobenzenesulphonyl chloride (0.42g, 2mmol). The mixture was stirred overnight at ambient temperature under argon. To the reaction was added 4- chlorobenzenesulfonyl chloride (0.2g, 0.95mmol) and the reaction stirred for a further 2 hours. The solvent was evaporated and the crude taken up in DCM (25ml_). To the solution was added PS-trisamine (3g) and the mixture stirred at room temperature for 2hours. To the mixture was then added PS-isocyanate (1.5g) and the mixture stirred for a further 30minut.es. The reaction was filtered and the solvent removed by evaporation. The crude product was taken up in DCM, washed twice with water (2 x 5OmL), dried (MgSO₄) and filtered. The solvent was evaporated to yield crude product which was dried at 4O⁰C under vacuum for 1 hour to yield the title compound as an off-white solid (0.284g, 76%).

¹H NMR (CDCI₃) 51.27 (3H, d, J=I), 1.42 (9H, s), 2.24 (1 H, m), 2.42 (1 H, dd, J=11 ,4), 3.16 (1 H, m), 3.49 (1 H, dt, J=11 , 2), 3.67 (1 H, m), 3.93 (1 H, m), 4.34 (1 H, br s), 7.52 (2H, m), 7.67 (2H, m).

Intermediate 8: (3S)-1-[(4-Chlorophenyl)sulfonyl]-3-methylpiperazine (D8)

To a solution of 1 ,1-dimethylethyl (2S)-4-[(4-chlorophenyl)sulfonyl]-2-methyl-1- piperazinecarboxylate (0.284g, 0.76mmol) (Intermediate 7) in anhydrous DCM (12ml_) was added trifluroroacetic acid (3ml_). The solution was stirred at room temperature for 2hours. The solvent was then evaporated and the crude taken up in DCM (1OmL), washed with saturated aqueous NaHCO₃ (2 x 5OmL), water (5OmL), dried (MgSO₄), filtered and the solvent evaporated. The crude product was dried under vacuum at 4O⁰C for 30minut.es to yield the title compound as an off-white solid (0.147g, 70%). ¹H N MR (CDCI₃) OLOS (SH₁ CI₁ J=B), 1.90 (1 H, dd, J=H ₁ 10), 2.29 (1 H, td, J=11 , 3), 2.93 (2H₁ m), 3.00 (1 H ,m), 3.61 (2H₁ m), 7.51 (2H₁ m), 7.70 (2H₁ m)

MS ES+ve m/z 275 (M+H)

Intermediate 9: 1,1-Dimethylethyl (3S)-3-methyl-4-[(phenylamino)carbonyl]-1 - piperazinecarboxylate (D9)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (472mg, 2.357 mmol) in DCM (8m L) was added triethylamine (0.361 mL, 2.59 mmol) and phenyl isocyanate (0.309mL, 2.83 mmol) the sample was stirred under an argon atmosphere at room temperature for 18hrs. The reaction was evaporated and the residue was suspended in 2N aqueous HCI (8mL). The aqueous was extracted with DCM (3x 15mL) and the combined collected organic layer was passed through a hydrophobic frit and evaporated to yield the title compound as a white solid (700mg, 93%).

¹H NMR (CDCI₃) 51.25 (3H₁ d, J=7.0Hz), 1.48 (9H s), 2.84-3.30 (3H₁ br m), 3.66-3.94 (2H₁ br m), 4.12-4.33 (2H₁ br m), 6.32 (1 H₁ NH₁ br m), 7.07 (1 H₁ m), 7.27-7.39 (4H₁ m). Intermediate 10: 1,1 -Dimethylethyl (2S)-4-{[(2,4- difluorophenyl)amino]carbonyl}-2-methyl-1 -piperazinecarboxylate (D10)

To a solution of 1 ,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.5g, 7.5 mmol) in anhydrous DCM (3OmL) was added triethylamine (2.59ml_, 19 mmol) and 2,4-difluoro-1-isocyanatobenzene (0.88ml_, 7.5 mmol) the sample was stirred under an argon atmosphere at room temperature for 2hours. The reaction was evaporated and the residue was suspended DCM (3OmL) which was washed with 0.5M aqueous HCI (10OmL), and then water (10OmL). The collected organic layer was dried (MgSO₄), filtered and evaporated, the residue was dried in a vac-oven at 40⁰C overnight (approx 18hours) to yield the title compound as a white solid (2.41 g, 91%).

¹H NMR (CDCI₃) 51.22 (3H, d, J=6.58Hz), 1.48 (9H, s), 3.11 (1 H, m), 3.22 (1 H, m), 3.34 (1 H, dd, J=13.37, 3.95Hz), 3.71 (1 H, m), 3.92 (1 H, m), 4.31 (1 H, br m), 6.39 (1 H, NH, br m), 6.85 (2H, m), 7.99 (1 H, m).

Intermediate 11 : (3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-1 -piperazinecarboxamide (D11)

To a solution of 1 ,1-dimethylethyl (2S)-4-{[(2,4-difluorophenyl)amino]carbonyl}-2- methyl-1-piperazinecarboxylate (2.41 g, 5.4 mmol) (Intermediate 10) in anhydrous DCM (4OmL) was added TFA (1OmL). The solution was stirred at room temperature for 1 hour. The solvent was evaporated and the residue suspended in DCM (3OmL) which was washed with (saturated aqueous sodium bicarbonate solution (100ml) and water (100ml). The combined aqueous was concentrated and re-extracted with DCM (2x 4OmL) which was then added to the original organic layer. The combined DCM was dried (MgSO₄), filtered and evaporated to yield the title compound (1.25g, 72%).

¹H NMR (CDCI₃) 51.12 (3H, d, J=6.14Hz), 2.59 (1 H, dd, J=12.72,10.52Hz), 2.86 (2H, m), 2.95-3.09 (2H, m), 3.90 (2H, m), 6.42 (1 H, NH, br m), 6.84 (2H, m), 8.00 (1 H, m).

Intermediate 12: 1,1 -Dimethylethyl (2S)-2-methyl-4-[(phenylamino)carbonyl]-1 - piperazinecarboxylate (D12)

To a solution of 1 ,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.5g, 7.5 mmol) in anhydrous DCM (3OmL) was added triethylamine (2.59ml_, 19 mmol) and phenyl-isocyanate (0.814ml_, 7.5 mmol) the mixture was stirred under an argon atmosphere at room temperature for 2hours. The reaction was evaporated and the residue was suspended DCM (3OmL) which was washed with (0.5M, aq) HCI (10OmL), and then water (10OmL). The collected organic layer was dried (MgSO₄), filtered and evaporated to yield the title compound (1.96g, 82%)

¹H NMR (CDCI₃) 51.21 (3H, d, J=6.8Hz), 1.48 (9H, s), 3.07 (1 H, br m), 3.20 (1 H, m), 3.30 (1 H, dd, J=13.37, 4.17Hz), 3.72 (1 H, m), 3.90 (2H, m), 4.28 (1 H, br m), 6.36 (1 H, NH, br m), 7.05 (1 H, m), 7.30 (2H, m), 7.35 (2H, m).

Intermediate 13: (3S)-3-Methyl-Λ/-phenyl-1 -piperazinecarboxamide (D13)

To a solution of 1 ,1-dimethylethyl (2S)-2-methyl-4-[(phenylamino)carbonyl]-1- piperazinecarboxylate (1.96g, 6.14 mmol) (Intermediate 12) in anhydrous DCM (4OmL) was added TFA (1 OmL). The solution was stirred at room temperature overnight (approx 18hours). The solvent was evaporated and the residue suspended in DCM (4OmL) which was washed with saturated aqueous sodium bicarbonate solution (2x 150ml). The aqueous was concentrated and re-extracted with DCM (20OmL). All the combined organic layers were then dried (MgSO₄), filtered and evaporated, the residue was further dried in a vac-oven at 40⁰C for 2hours to yield the title compound (997mg, 74%).

¹H NMR (CDCI₃) 51.10 (3H, d, J=6.36Hz), 2.55 (1 H, dd, J=12.72, 10.3Hz), 2.77-3.06 (4H, m), 3.91 (2H, m), 6.38 (1 H, NH, br m), 7.03 (1 H, m), 7.29 (2H, m), 7.35 (2H, m).

Intermediate 14: (2/?)-2-Methyl-1 -(phenylcarbonyl)piperazine hydrochloride (D14)

To a solution of 1 ,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate (205mg, 1.024 mmol) in DCM (7mL) was added DIPEA (0.268mL, 1.535 mmol) at room temperature. Benzoyl chloride (0.131 mL, 1.126 mmol) was then added and the resultant mixture stirred overnight (approx 18hrs). The reaction was diluted with DCM (5mL) and washed with water (1 OmL), 2M aqueous HCI (1 OmL) and saturated sodium bicarbonate solution (1 OmL), then dried on a hydrophobic frit and concentrated to dryness. The residue was purified by silica chromatography (Biotage SP4), eluting with a gradient of 0%-10% EtOAc in iso-hexane (10 column volumes), then 10%-40% EtOAc in iso-hexane (10 column volumes) and the product containing fractions were collected and concentrated to dryness giving the desired 1 ,1- dimethylethyl (3R)-3-methyl-4-(phenylcarbonyl)-1-piperazinecarboxylate (347mg, 98 %),

MS ES+ve m/z 305 (M+H).

1 ,1 -dimethylethyl (3R)-3-methyl-4-(phenylcarbonyl)-1-piperazinecarboxylate (347mg, 1.0 mmol) was dissolved in 1 ,4-dioxane (4mL) and treated with HCI (4M solution in 1 ,4-dioxane) (1.254mL, 5.02 mmol) at room temperature and the resultant mixture stirred for 3hours. A further quantity of HCI (4M solution in 1 ,4-dioxane) (0.5mL) was added and the stirring was maintained for 1 hour. More HCI (4M solution in 1 ,4- dioxane) (0.3ml_) was added and the reaction mixture was stirred overnight (approx 18hrs). A further quantity of HCI (4M solution in 1 ,4-dioxane) (0.2ml_) was then added and stirring was maintained for 3hours. The reaction mixture was evaporated to dryness and the solid was triturated with diethyl ether to give (2R)-2-methyl-1-(phenylcarbonyl)piperazine hydrochloride (235mg, 97 %).

¹H NMR (d6-DMSO) 51.33 (3H, d, J=7Hz), 2.98 (1 H, m), 3.10-3.15 (3H, m), 3.15- 3.35 (1 H, m), 3.98 (1 H, br s), 4.43 (1 H, br s), 7.46 (5H, m).

MS ES+ve m/z 205 (M+H).

Intermediate 15: 1,1 -Dimethylethyl (3S)-3-methyl-4-(phenylcarbonyl)-1- piperazinecarboxylate (D15)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (2.08 g, 10.39 mmol) in dichloromethane (DCM) (75 ml) was added DIPEA (2.72 ml, 15.58 mmol) at room temperature and then benzoyl chloride (1.326 ml, 1 1.42 mmol) was added slowly and the resultant mixture stirred for 16 hours overnight. The reaction was then diluted with DCM (30ml) and 100ml of water was added and the layers separated. The organics were then washed with 2M HCI (50ml) and saturated NaHCO₃ (5OmL). The solution then dried (MgSO₄) and concentrated to dryness giving the title compound as a colourless oil (3.2 g, 10.41 mmol, 100 % yield).

MS ES+ve m/z 305 (M+H)

¹H NMR (CDCI₃) δ 1.25 (3H, d, J=6.6), 1.47 (9H, s), 2.7-3.3 (4H, br m), 3.8-4.2 (3H, br m), 7.37 (2H, m), 7.42 (3H, m) Intermediate 16: (2S)-2-Methyl-1-(phenylcarbonyl)piperazine hydrochloride (D16)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-4-(phenylcarbonyl)-1- piperazinecarboxylate (3.2 g, 10.51 mmol) (Intermediate 15) in 1 ,4-dioxane (50 ml) was added HCI (4M in 1 ,4-Dioxane) (5.26 ml, 21.03 mmol) at room temperature and the resultant mixture stirred for 1 hour. A further portion of HCI (4M in 1 ,4-dioxane) (5.26 ml, 21.03 mmol) was added and the mixture stirred for a further 17 hours. To the reaction was added HCI (4M in 1 ,4-dioxane) (5.26 ml, 21.03 mmol) was added along with methanol (10 ml) and the mixture stirred for a further 2 hours. The solution was concentrated to dryness under vacuum, the resulting solid triturated with diethyl ether and the solid isolated by filtration and dried in vacuum oven overnight to yield the title compound (2.32 g, 92 %).

¹H NMR (d6-DMSO) δ 1.34 (3H, t, J= 7.2Hz), 2.97 (1 H, td, J=3.7, 12), 3.15 (2H, d, J=2.6), 3.20 (1 H, br d, J=13), 3.30 (1 H, br d, J=13), 3.98 (1 H, br s), 4.43 (1 H, br s), 7.41-7.51 (5H, m), 9.49 (2H, br s). MS ES+ve m/z 205 (M+H)

Intermediate 17: 4-{[(3S)-3-methyl-1 -piperazinyl]sulfonyl}benzonitrile (D17)

To 1 ,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1g) in DCM (5OmL) was added DIPEA (1.74ml_). 4-cyanobenzenesulfonyl chloride (1.1g) was then added slowly and the reaction mixture was stirred for 1 hour. To the reaction was added DCM (5OmL) and the solution was washed with saturated sodium bicarbonate solution and water. The organic layer was collected and evaporated to dryness under vacuum. The resulting oil was dissolved in 1 ,4-dioxane (1OmL) before the addition of 4M HCI in 1 ,4-dioxane (1OmL) and a few drops of water. The reaction was stirred for 1.5 hours. The reaction mixture was evaporated to dryness under vacuum then dissolved in MeOH. The MeOH solution was loaded onto a 1Og SCX column. The loaded column was then washed with 2 column volumes of MeOH and the desired product was eluted from the column with 1 M ammonia in MeOH. The fraction containing eluted product was evaporated to dryness under vacuum to yield the title compound as a yellow oil (895mg, 68%).

MS ES+ve m/z 265 (M+H)

Intermediate 18: [1 -(phenylcarbonyl)-2-piperazinyl]methanol (D18)

1 ,1-dimethylethyl 3-(hydroxymethyl)-1-piperazinecarboxylate (commercially available, for example from ChemPacific Corp., Baltimore, USA, 200mg) was dissolved in THF (1OmL). Benzoyl chloride (143mg) and triethylamine (0.193mL) were added and the reaction stirred for 2 hours. The reaction mixture was diluted with DCM (5OmL) and washed twice with saturated sodium bicarbonate solution. The organic layer was collected and dried with magnesium sulphate. The solid was removed by filtration and the solution evaporated to dryness leaving a colourless oil. 1 M HCI in 1 ,4- dioxane solution (2OmL) was added to the oil and the reaction was stirred overnight. The reaction mixture was evaporated to dryness on the rotary evaporator and the residual white solid was triturated with ether. The ether was removed by filtration and the solid collected. The solid was dissolved in methanol and transferred onto a SCX column, washed with two column volumes of MeOH, then the desired product eluted with 1 M methanolic ammonia. The fraction containing product was collected and evaporated to dryness on the rotary evaporator to yield the title compound as a colourless oil (215mg).

MS ES+ve m/z 221 (M+H), retention time (0.21 min) 5min LC/MS Example 1 : (2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1 - piperazinecarboxamide (E1)

To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (85mg, 0.317 mmol) (Intermediate 2) in DCM (5ml_) was added triethylamine (0.44ml_, 0.793 mmol) and phenyl isocyanate (38mg, 0.317 mmol). The reaction was stirred at room temperature under an argon atmosphere for 2hours. The solution was evaporated and re-dissolved in DCM (1OmL) which was washed with water (2x 100ml). The collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4), eluting with hexane (3 column volumes), a gradient from 0-50% EtOAc in hexane (15 column volumes) and 50% EtOAc in hexane (3 column volumes)) and the product containing fractions were evaporated to yield the title compound as a white solid (78mg, 64%).

¹H NMR (d6-DMSO) δ 1.21 (3H, d, J= 6.58Hz), 2.23 (1 H, dt, J= 11.62, 3.51 Hz), 2.37 (1 H, dd, J= 11.62, 3.73Hz), 3.14 (1 H, dt, J=1 1.62, 1.97Hz), 3.44 (1 H, m), 3.65 (1 H, m), 3.98 (1 H, m), 4.44 (1 H br m), 6.96 (1 H, m), 7.22 (2H, m), 7.36 (2H, m), 7.74 (4H, m), 8.49 (1 H NH, br s)

MS ES+ve m/z 394 (M+H) Example 2 : (3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1- piperazinecarboxamide (E2)

To a solution of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (110mg, 0.4 mmol) (Intermediate 4) in DCM (5ml_) was added triethylamine (1.37ml_, 1 mmol) and phenyl isocyanate (48mg, 0.4 mmol). The reaction was stirred at room temperature under an argon atmosphere for 2hours. To the reaction mixture was added water (25ml) and the organic layer was separated. The aqueous was then extracted with more DCM (2x 20ml). The collected and combined organic layer was dried (Na₂SO₄), filtered and evaporated.

The residue was purified by silica chromatography (Biotage SP4), eluting with hexane (2 column volumes), a gradient from 0-40% EtOAc in hexane (15 column volumes) and 50% EtOAc in hexane (3 column volumes)) and the product containing fractions were evaporated to yield the title compound (40.3mg, 26%)

¹H-NMR (CDCI₃) 51.12 (3H, d, J= 6.58Hz), 3.01 (1 H, m), 3.22 (2H, m), 3.71 (2H, m), 3.98 (1 H, m), 4.18 (1 H, m), 6.25 (1 H, NH, br m) 7.05 (1 H, m), 7.29 (4H, m), 7.50 (2H, m), 7.76 (2H, m).

MS ES+ve m/z 394 (M+H) Example 3: 2-{(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -piperazinyl}-Λ/- phenylacetamide (E3)

To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (99mg, 362 μmol) (Intermediate 2) in anhydrous DMF (5ml_) was added cesium carbonate (295mg, 904 μmol), potassium iodide (66mg, 398 μmol) and 2-bromo-/V- phenylacetamide (78mg, 364 μmol). The reaction was stirred at room temperature under an argon atmosphere for 2hours. A further addition of 2-bromo-/V- phenylacetamide (78mg, 364 μmol) was made and the reaction was stirred overnight (approx 18hrs). A final addition of 2-bromo-Λ/-phenylacetamide (78mg, 364 μmol) was made and the reaction was stirred for a further 3hours. The solution was evaporated and re-suspended in DCM which was filtered (this process was repeated twice). The DCM was finally evaporated and the residue was purified by silica chromatography (Biotage SP4), eluting with hexane (3 column volumes), a gradient from 0-80% EtOAc in hexane (15 column volumes) and 80% EtOAc in hexane (3 column volumes)) and the product containing fractions were evaporated. This material was re-purified by silica chromatography (Biotage SP4), eluting with 10% EtOAc in hexane (3 column volumes), a gradient from 10-70% EtOAc in hexane (15 column volumes) and 70% EtOAc in hexane (3 column volumes)) and the product containing fractions were evaporated and dried on a high-vac line for 72hrs to yield the title compound (35mg, 24%) ¹H-NMR (CDCI₃) 51.1 1 (3H, d, J= 6.36Hz), 2.43 (1 H, m), 2.71 (3H, m), 2.94 (1 H, m), 3.02-3.37 (2H, ABq J=MA Hz), 3.45 (2H, m), 7.1 1 (1 H, m), 7.31 (2H, m), 7.47 (2H, m), 7.57 (2H, m), 7.73 (2H, m), 8.78 (1 H NH, br m)

MS ES+ve m/z 408 (M+H)

Example 4: (2/?)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4- (phenylcarbonyl)piperazine (E4)

To a solution of (2/?)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (38mg, 0.139 mmol) (Intermediate 6) in acetonitrile (3ml_) was added PS-DIEA (87mg). The solution was stirred at room temperature under an argon atmosphere for 15mins. Benzoyl chloride (16.2μl, 0.139 mmol) was added to the stirred reaction which was continued to be stirred for a further 4hrs. The reaction was filtered, the solution concentrated in-vacuo and the residue purified by Mass Directed Auto-Purification (MDAP) and the product containing fractions were evaporated giving the desired title compound (18mg, 34%)

¹H-NMR (CDCI₃) 51.04 (3H, br m), 3.17 (3H, br m), 3.70 (2H, br m), 4.00-4.75 (2H, br m), 7.34 (2H, m), 7.41 (2H, m), 7.50 (2H, m), 7.75 (2H, m).

MS ES+ve m/z 379 (M+H) Example 5: 4-{[3-Ethyl-4-(phenylcarbonyl)-1 -piperazinyl]sulfonyl}benzonitrile (E5)

To a solution of 1 ,1-dimethylethyl 2-ethyl-1-piperazinecarboxylate (100mg, 0.467 mmol) in DCM (5ml_) was added di-isopropylethylamine (0.253mL, 1.447 mmol), followed by gradual addition of 4-cyanobenzenesulfonyl chloride (103mg, 0.513 mmol). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated aqueous sodium bicarbonate solution (1OmL, twice), then with distilled water (1OmL). The organic layer was dried (MgSO₄), filtered and reduced in vacuo to yield 1 ,1-dimethylethyl 4-[(4-cyanophenyl)sulfonyl]-2-ethyl-1-piperazinecarboxylate as a crude transparent oil (173mg), MS ES+ve m/z 280 (M+H-100). To 1 ,1-dimethylethyl 4-[(4-cyanophenyl)sulfonyl]-2-ethyl-1-piperazinecarboxylate (173mg, 0.456 mmol) was added hydrogen chloride 1 M solution in 1 ,4 dioxane (1OmL) solution, followed by the addition of 3 drops of water. The reaction mixture was allowed to stir for 14hours. After this time, 5M aqueous HCI (1 ml) was added and the mixture was stirred for 12hours. The reaction mixture was concentrated in vacuo to yield colourless oil. The colourless oil was dissolved in methanol (1 OmL) and passed down a SCX-2 column washing with two column volumes of methanol and eluting the product with 2N ammonia solution in methanol (three column volumes). The fraction containing eluted product was reduced in vacuo to yield 4-[(3-ethyl-1- piperazinyl)sulfonyl]benzonitrile (99mg) as a transparent oil, MS ES+ve m/z 280 (M+H).

To a solution of 4-[(3-ethyl-1-piperazinyl)sulfonyl]benzonitrile (99mg, 0.354mol) in tetrahydrofuran (1OmL) was added triethylamine (0.074mL, 0.532mmol) followed by drop wise addition of benzoyl chloride (0.045mL, 0.390mmol). The reaction mixture was allowed to stir for 30minut.es. The reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated aqueous sodium bicarbonate solution (1OmL, twice), then 0.1 M hydrochloric acid (1OmL). The organic layer was dried with (MgSO₄), filtered and concentrated in vacuo to yield 144mg colourless oil. The oil was dissolved in minimum volume of hot ethyl acetate (~2ml), hot iso-hexane (10ml) was then added and allowed to cool to room temperature. The supernatant was decanted off, and residual solid triturated with diethyl ether (50ml), to yield a white solid (67mg, 37%).

¹H-NMR (CDCI₃) δ 0.65-1.19 (3H, br m), 1.78-1.98 (2H, m), 2.20-2.40 (1 H, m), 2.40- 2.57 (1 H, m), 2.96-3.48 (1 H, m), 3.48-3.96 (3H, m), 4.21-5.01 (1 H, m), 7.28-7.31 (2H, m), 7.36-7.45 (3H, m), 7.81-7.89 (4H, m).

MS ES+ve m/z 384 (M+H).

The single enantiomers were isolated from the racemic 4-{[3-ethyl-4-

(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (53mg) via chiral preparative chromatography using the following conditions:

- Column: Chiralpak IC (20mm x 250mm, 5μm)

- Eluent: Heptane: Ethanol 50:50 v/v pump-mixed - Flow rate =17. Omls/min

- U.V. Absorbance (S) 215nm

- Autosampler injection (250μl of sample in 20%Heptane/30%EtOH/50%DMF on column)

- lsocratic Run time = 30 minutes

Isolated enantiomers were analysed via chiral analytical chromatography using the following conditions:

- Chiralpak IC (4.6mm x 250mm, 5μm)

- Heptane: Ethanol 50:50 v/v pump-mixed - Flow rate =1. Omls/min

- U.V. Absorbance @ 215nm

- Autosampler injection (1 Oμl of sample in mobile phase on column)

- lsocratic Run time = 30 minutes

Isolated compounds: Example 5a: Faster running enantiomer (4-{[(3S)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile or 4-{[(3R)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile, 16mg)

Retention time 19.37min

Example 5b: Slower running enantiomer (4-{[(3S)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile or 4-{[(3R)-3-ethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile, 16mg)

Retention time 23.35min

Example 6: 2-{(3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1 -piperazinyl}-Λ/- phenylacetamide (E6)

To a solution of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (20.5mg, 75 μmol) (Intermediate 4) in anhydrous DMF (3ml_) was added cesium carbonate (70mg, 215 μmol), potassium iodide (15mg, 91 μmol) and 2-bromo-/V- phenylacetamide (18mg, 83 μmol). The reaction was stirred at room temperature under an argon atmosphere for 18hours. The reaction was filtered, the solution concentrated in-vacuo and the residue purified by Mass Directed Auto-Purification (MDAP) and the product containing fractions were evaporated giving the desired title compound (10.5mg, 35%) ¹H-NMR (d6-DMSO) 51.19 (3H, d, J= 6.8Hz), 2.84-5.04 (9H, br m), 7.10 (1 H, t, J= 7.45Hz), 7.34 (2H, t, J= 7.78Hz), 7.57 (2H, d, J=8.11 Hz), 7.73 (2H, d, J=8.55Hz), 7.87 (2H, d, J=8.55Hz), 7.95 (1 H, NH br m).

MS ES+ve m/z 409 (M+H)

Example 7: (2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl) piperazine (E7)

To a stirred solution of (3S)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (0.147g, 0.54mmol) (Intermediate 8) in anhydrous DCM (8ml_) was added triethylamine (0.19ml_) and benzoyl chloride (0.075g, 0.54mmol). The mixture was stirred at room temperature under an atmosphere of argon for 2hours. The solvent was evaporated and the crude taken up in DCM (1OmL) and washed twice with water (2 x 5OmL), dried with MgSO₄, filtered and the solvent evaporated. The crude product was purified by silica chromatography (Biotage SP4), eluting a gradient from 10-80% ethyl acetate in hexane) and the product containing fractions were dried under vacuum to yield the title compound as a white solid (100mg, 49%).

¹H NMR (CDCI₃) 51.41 (3H, d, J=6.8), 2.30 (1 H, m), 2.45 (1 H, m), 3.53 (1 H, m), 3.55 (1 H, m), 3.74 (1 H, m), 4.0-4.8 (2H, br s), 7.29 (2H, m), 7.40 (3H, m), 7.53 (2H, m), 7.67 (2H, m). ¹H NMR (dθ-DMSO, 349K) δ 1.23 (3H, d, J= 6.8), 2.39 (1 H, dd, J=12, 3.5), 2.57 (1 H, dd, J=12, 3.7), 3.23 (1 H, m), 3.45 (1 H, dt, J=12, 1.9), 3.63 (1 H, m), 3.89 (1 H, m), 4.35 (1 H, br s), 7.31 (2H, m), 7.40 (3H, m), 7.71 (4H, m)

MS ES+ve m/z 379 (M+H)

Example 8: (2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1- (phenylcarbonyl)piperazine (E8)

To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (85mg, 0.317 mmol) (Intermediate 2) in acetonitrile was added triethylamine (0.44ml_, 3.18 mmol) and benzoyl chloride (440mg, 3.14 mmol). The reaction was stirred at room temperature under argon for 3hrs. The reaction was evaporated, suspended in DCM (1OmL) and washed with water (2x 3OmL). The separated organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4), eluting with hexane (3 column volumes), a gradient from 0-40% EtOAc in hexane (15 column volumes) and 40% EtOAc in hexane (3 column volumes) and the product containing fractions were evaporated. The solid was triturated with hexane (3mL) and the solid collected by filtration was dried using a high-vacuum line for 72hours to yield the title compound as a white solid (51 mg, 43%)

¹H NMR (CDCI₃) 51.41 (3H, d, J=6.8), 2.30 (1 H, m), 2.45 (1 H, m), 3.35 (1 H, m), 3.55 (1 H, m), 3.74 (1 H, m), 4.0-4.8 (2H br s), 7.30 (2H, m), 7.40 (3H, m), 7.53 (2H, m), 7.67 (2H, m). ¹H NMR (dθ-DMSO, 349K) δ 1.23 (3H, d, J= 6.8), 2.39 (1 H, dd, J=12, 3.5), 2.57 (1 H, dd, J=12, 3.7), 3.23 (1 H, m), 3.45 (1 H, dt, J=12, 1.9), 3.63 (1 H, m), 3.89 (1 H, m), 4.35 (1 H, br s), 7.31 (2H, m), 7.40 (3H, m), 7.71 (4H, m)

MS ES+ve m/z 379 (M+H)

Example 9: (2S)-1 -[(4-Chlorophenyl)sulfonyl]-4-[(2-fluorophenyl)carbonyl]-2- methylpiperazine (E9)

To a solution of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (150mg, 0.482 mmol) (Intermediate 4) and triethylamine (0.141 ml_, 1.012 mmol) in DCM (5 ml_), cooled to O⁰C in an ice bath under argon, was added 2-fluorobenzoyl chloride (0.063ml_, 0.530 mmol). The reaction was allowed to warm to room temperature and stirred for 18hours. To the reaction was added 2N HCI (2ml_) and the organic layer was separated using a hydrophobic frit and concentrated. The residue was purified by silica chromatography (Biotage SP4), eluting with 25% EtOAc in iso-hexane (3 column volumes) then a gradient from 25%-50% EtOAc in iso-hexane (over 10 column volumes) to yield the title compound as a white solid (0.136g, 71%)

¹H NMR (CDCI_3, rotomeric) δ 0.95 (d, J=I) and 1.10 (d, J=I) (together 3H), 2.93 (m) and 3.02 (m) (together 1 H), 3.25 (1 H, m), 3.17 (1 H, m), (3.37 (br d) and 3.49 ( br d) (together 1 H), 3.63 (m) and 3.74 (m) (together 1 H), 4.07 (m) and 4.30 (m) (together 1 H), 4.53 (br d) and 4.69 (br d) (together 1 H), 7.10 (1 H, m), 7.21 (1 H, m), 7.28-7.46 (2H, m), 7.50 (2H, m), 7.75 (2H, m) MS ES+ve m/z 397 (M+1)

Example 10: (2S)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4- (phenylcarbonyl)piperazine (E10)

To a solution of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (110mg, 0.4 mmol) (Intermediate 4) in acetonitrile (5ml_) was added triethylamine (1.57ml_, 1 mmol) and benzoyl chloride (562mg, 0.4 mmol). The reaction was stirred at room temperature under argon for 1.5hrs. The reaction was evaporated, suspended in DCM and washed with water and then (2N) HCI (aq). The separated organic layer was dried (Na₂SO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4), eluting with iso-hexane (3 column volumes), a gradient from 0-40% EtOAc in iso-hexane (15 column volumes) and 40% EtOAc in iso-hexane (3 column volumes) and the product containing fractions were evaporated to yield the title compound as a white solid (98mg, 65%).

¹H NMR (CDCI₃) 51.04 (3H, br m), 2.83-3.39 (3H, br m), 3.58-3.81 (2H, br m), 3.97- 4.77 (2H, br m), 7.34 (2H, m), 7.40 (3H, m), 7.50 (2H, m), 7.75 (2H, m).

MS ES+ve m/z 379 (M+H) Example 11 : 2-{(3/?)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1 -piperazinyl}-Λ/- phenylacetamide (E11)

To a solution of (2/?)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine (42mg, 153 μmol) (Intermediate 6) in anhydrous DMF (3ml_) was added cesium carbonate

(141 mg, 432 μmol) and potassium iodide (27.4mg, 165 μmol) the mixture was stirred for 15mins at room temperature under and argon atmosphere. To this was added 2- bromo-Λ/-phenylacetamide (32mg, 153 μmol) and the reaction was stirred at room temperature under an argon atmosphere for 3 hours. The reaction was reduced in- vacuo and the residue suspended in DCM which was washed with water (1OmL). The separated organic layer was dried (Na₂SO₄), filtered and evaporated. The residue was purified by Mass Directed Auto-Purification (MDAP) and the product containing fractions were evaporated giving the desired title compound (13.7mg, 23%)

¹H NMR (CDCI₃) 51.31 (3H, d, J=6.8Hz), 2.32-2.46 (2H m), 2.66 (1 H, m), 2.83 (1 H, m), 2.99-3.19 (2H, ABq, J=16.4Hz), 3.33 (1 H, m), 3.71 (1 H, m), 4.19 (1 H, br m), 7.1 1 (1 H, t, J=7.4Hz), 7.32 (2H, t, J=7.78Hz), 7.51 (4H, d, J=8.33Hz), 7.77 (2H, d, J=8.77Hz), 8.85 (1 H, NH, br m).

MS ES+ve m/z 409 (M+H) Example 12: (2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1 - piperazinecarboxamide (E12)

1 ,1-dimethylethyl (3S)-3-methyl-4-[(phenylamino)carbonyl]-1-piperazinecarboxylate (700mg, 2.19 mmol) (Intermediate 9) was suspended in 4M HCI in 1 ,4-dioxane (5ml_) and stirred vigorously at room temperature for 5hours. The sample was evaporated to yield (2S)-2-methyl-N-phenyl-1- piperazinecarboxamide hydrochloride as a hygroscopic white solid (620mg, >100%), MS ES+ve m/z 220 (M+H). To a solution of (2S)-2-methyl-N-phenyl-1-piperazinecarboxamide hydrochloride (620mg, 2.831 mmol) in pyridine (5ml_) was added in a portionwise fashion 4- chlorobenzenesulfonyl chloride (776mg, 3.687 mmol). The yellow solution was stirred under an argon atmosphere at room temperature for 18hrs. The reaction mixture was evaporated and the residue was suspended in 2N HCI (8ml_). The aqueous was extracted with DCM (3x 15ml_) and the combined collected organic layer was passed through a hydrophobic frit and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with hexane (1 column volumes), a gradient from 10-50% EtOAc in hexane (10 column volumes) and the product containing fractions were evaporated, triturated with ether and evaporated to yield the title compound as a white solid (114mg, 10%)

¹H NMR (CDCI₃) 51.36 (3H, d, J=6.72Hz), 2.31 (1 H dt, J=11.8, 3.57Hz), 2.48 (1 H, dd, J=11.46, 3.64Hz), 3.30 (1 H, dt, J=12.35, 3.29Hz), 3.53 (1 H, m), 3.71 (1 H, m), 3.88 (1 H, m), 4.33 (1 H, br m), 6.40 (1 H, NH, br m), 7.04 (1 H, m), 7.26 (4H, m), 7.52 (2H, m), 7.67 (2H, m). MS ES+ve m/z 394 (M+H).

Example 13: (3S)-4-[(4-Chlorophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-3-methyl- 1-piperazinecarboxamide (E13)

To a solution of (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-1-piperazinecarboxamide (110mg, 0.431 mmol) (Intermediate 1 1 ) in anhydrous DCM (8ml_) was added triethylamine (0.15ml_, 1.1 mmmol) and 4-chlorobenzenesulfonyl chloride (181 mg, 0.863 mmol). The reaction was stirred under an argon atmosphere at room temperature for 90mins. PS-trisamine (0.5g) was then added to the reaction mixture which was gently stirred for 12hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with hexane (3 column volumes), a gradient from 20-85% EtOAc in hexane (15 column volumes) and 85% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was finally dried in a vac- oven at 40⁰C for 72hours. (101 mg, 55%)

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.58Hz), 3.04 (1 H, m), 3.24 (2H, m), 3.72 (2H, m), 3.98 (1 H, m), 4.21 (1 H, m), 6.29 (1 H, NH, br m), 6.84 (2H, m), 7.50 (2H, m), 7.77 (2H, m), 7.90 (1 H, m). MS ES+ve m/z 430 (M+H)

Example 14: (3S)-4-[(3-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 - piperazinecarboxamide (E14)

To a solution of (3S)-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (1 10mg, 0.5 mmol) (Intermediate 13) in anhydrous DCM (12ml_) was added triethylamine (0.17ml_, 1.25 mmmol) and 3-fluorobenzenesulfonyl chloride (195mg, 1.0 mmol). The reaction was stirred under an argon atmosphere at room temperature for 12hours. PS-trisamine (0.7g) was then added to the reaction mixture which was gently stirred for 2hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with hexane (3 column volumes), a gradient from 20-85% EtOAc in hexane (15 column volumes) and 85% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The residue was triturated with hexane, evaporated and dried under high vacuum overnight (approx 18hours) to yield the title compound as white crystals (97.8mg, 52%).

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.03 (1 H, m), 3.25 (2H, m), 3.73 (2H, m), 3.98 (1 H, m), 4.21 (1 H, m), 6.20 (1 H, NH, br m), 7.05 (1 H, m), 7.29 (5H, m), 7.52 (2H, m), 7.63 (1 H, m).

MS ES+ve m/z 378 (M+H) Example 15: (3S)-Λ/-(2,4-Difluorophenyl)-4-[(3-fluorophenyl)sulfonyl]-3-methyl- 1-piperazinecarboxamide (E15)

To a solution of (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-1-piperazinecarboxamide (110mg, 0.431 mmol) (Intermediate 1 1 in anhydrous DCM (8ml_) was added triethylamine (0.15ml_, 1.1 mmmol) and 3-fluorobenzenesulfonyl chloride (167mg, 0.863 mmol). The reaction was stirred under an argon atmosphere at room temperature for 90mins. PS-trisamine (0.5g) was then added to the reaction mixture which was gently stirred for 12hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 15% EtOAc in hexane (3 column volumes), a gradient from 15-80% EtOAc in hexane (15 column volumes) and 80% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was dried in a vac-oven at 40⁰C for 72hours to afford white crystals (102.9mg, 58%).

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.05 (1 H, m), 3.26 (2H, m), 3.74 (2H, m), 3.99 (1 H, m), 4.23 (1 H, m), 6.29 (1 H, NH, br m), 6.84 (2H, m), 7.29 (1 H, m), 7.53 (2H, m), 7.63 (1 H, m), 7.90 (1 H, m).

MS ES+ve m/z 414 (M+H) Example 16: (3S)-4-[(4-Cyanophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1- piperazinecarboxamide (E16)

To a solution of (3S)-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (1 10mg, 0.5 mmol) (Intermediate 13) in anhydrous DCM (5ml_) was added triethylamine (0.17ml_, 1.25 mmmol) and 4-cyanobenzenesulfonyl chloride (201 mg, 1.0 mmol). The reaction was stirred under an argon atmosphere at room temperature for 2hours. The reaction was evaporated and re-suspended in DCM (12ml) to this was added PS-trisamine (0.7g) which was gently stirred for 2hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 30% EtOAc in hexane (3 column volumes), a gradient from 30-90% EtOAc in hexane (15 column volumes) and 90% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was dried in a vac-oven at 40⁰C overnight (approx 18hrs) to afford white crystals (32.5mg, 17%).

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.03 (1 H, m), 3.25 (2H, m), 3.74 (2H, m), 4.01 (1 H, m), 4.22 (1 H, m), 6.19 (1 H, NH, br m), 7.06 (1 H, m), 7.29 (4H, m), 7.83 (2H, m), 7.94 (2H, m).

MS ES+ve m/z 385 (M+H) Example 17: (3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-4-{[3- (methyloxy)phenyl]sulfonyl}-1 -piperazinecarboxamide (E17)

To a solution of (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-1-piperazinecarboxamide (110mg, 0.431 mmol) (Intermediate 1 1 ) in anhydrous DCM (8ml_) was added triethylamine (0.15ml_, 1.1 mmmol) and 3-(methyloxy)benzenesulfonyl chloride (178mg, 0.863 mmol). The reaction was stirred under an argon atmosphere at room temperature for 90mins. PS-trisamine (0.5g) was added to the reaction which was gently stirred for 12hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (3 column volumes), a gradient from 20-80% EtOAc in hexane (15 column volumes) and 80% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was dried in a vac- oven at 40⁰C for 72hours to afford white crystals (90.1 mg, 49%).

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.04 (1 H, m), 3.26 (2H, m), 3.72 (2H, m), 3.86 (3H, s), 3.95 (1 H, m), 4.22 (1 H, m), 6.28 (1 H, NH, br m), 6.84 (2H, m), 7.09 (1 H, m), 7.33 (1 H, m), 7.42 (2H, m), 7.91 (1 H, m).

MS ES+ve m/z 426 (M+H) Example 18: (3S)-3-Methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-Λ/-phenyl-1 - piperazinecarboxamide (E18)

To a solution of (3S)-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (106mg, 0.48 mmol) (Intermediate 13) in anhydrous DCM (8ml_) was added triethylamine (0.17ml_, 1.2 mmmol) and 3-(methyloxy)benzenesulfonyl chloride (198mg, 0.96 mmol). The reaction was stirred under an argon atmosphere at room temperature overnight (approx 18hrs). PS-trisamine (0.7g) was added to the reaction which was gently stirred for 2hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (3 column volumes), a gradient from 20-85% EtOAc in hexane (15 column volumes) and 85% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was dried in a vac-oven at 40⁰C for 5days to afford white crystals (80.1 mg, 43%).

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.01 (1 H, m), 3.25 (2H, m), 3.71 (2H, m), 3.85 (3H, s), 3.95 (1 H, m), 4.20 (1 H, m), 6.20 (1 H, NH, br m), 7.07 (2H, m), 7.28 (4H, m), 7.33 (1 H, m), 7.41 (2H, m).

MS ES+ve m/z 390 (M+H) Example 19: (3S)-4-[(4-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 - piperazinecarboxamide (E19)

To a solution of (3S)-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (1 10mg, 0.5 mmol) (Intermediate 13) in anhydrous DCM (12ml_) was added triethylamine (0.17ml_, 1.25 mmmol) and 4-fluorobenzenesulfonyl chloride (195mg, 1.0 mmol). The reaction was stirred under an argon atmosphere at room temperature for 12hours. PS-trisamine (0.7g) was then added to the reaction mixture which was gently stirred for 2hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with hexane (3 column volumes), a gradient from 20-85% EtOAc in hexane (15 column volumes) and 85% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The residue was triturated with hexane, evaporated and dried under high vacuum overnight (approx 18hours) to yield the title compound as white crystals (78.5mg, 41%)

¹H NMR (CDCI₃) 51.12 (3H, d, J=6.8Hz), 3.02 (1 H, m), 3.23 (2H, m), 3.69 (2H, m), 3.98 (1 H, m), 4.19 (1 H, m), 6.21 (1 H, NH, br m), 7.05 (1 H, m), 7.20 (2H, m), 7.29 (4H, m), 7.84 (2H, m).

MS ES+ve m/z 378 (M+H) Example 20: (3S)-4-[(4-Cyanophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-3-methyl- 1-piperazinecarboxamide (E20)

To a solution of (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-1-piperazinecarboxamide (110mg, 0.431 mmol) (Intermediate 1 1 ) in anhydrous DCM (8ml_) was added triethylamine (0.15ml_, 1.1 mmmol) and 4-cyanobenzenesulfonyl chloride (173mg, 0.863 mmol). The reaction was stirred under an argon atmosphere at room temperature for 90mins. PS-trisamine (0.5g) was then added to the reaction mixture which was gently stirred for 12hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (3 column volumes), a gradient from 20-85% EtOAc in hexane (15 column volumes) and 85% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was then dried in a vac-oven at 40⁰C for 48hours to afford white crystals (93.1 mg, 51%)

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.05 (1 H, m), 3.27 (2H, m), 3.75 (2H, m), 4.01 (1 H, m), 4.24 (1 H, m), 6.28 (1 H, NH, br m), 6.85 (2H, m), 7.83 (2H, m), 7.89 (1 H, m), 7.95 (2H, m).

MS ES+ve m/z 421 (M+H) Example 21 : (3S)-Λ/-(2,4-Difluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-3-methyl- 1-piperazinecarboxamide (E21)

To a solution of (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-1-piperazinecarboxamide (110mg, 0.431 mmol) (Intermediate 1 1 ) in anhydrous DCM (8ml_) was added triethylamine (0.15ml_, 1.1 mmol) and 4-fluorobenzenesulfonyl chloride (167mg, 0.863 mmol). The reaction was stirred under an argon atmosphere at room temperature for 90mins. PS-trisamine (0.5g) was then added to the reaction mixture which was gently stirred for 12hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 15% EtOAc in hexane (3 column volumes), a gradient from 15-80% EtOAc in hexane (15 column volumes) and 80% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was dried in a vac-oven at 40⁰C for 72hours to afford white crystals (83.3mg, 47%)

¹H NMR (CDCI₃) 51.13 (3H, d, J=6.8Hz), 3.05 (1 H, m), 3.24 (2H, m), 3.72 (2H, m), 3.98 (1 H, m), 4.21 (1 H, m), 6.29 (1 H, NH, br m), 6.84 (2H, m), 7.20 (2H, m), 7.82- 7.93 (3H, m).

MS ES+ve m/z 414 (M+H) Example 22: (2S)-2-Methyl-1-(phenylcarbonyl)-4-{[4- (trifluoromethyl)phenyl]sulfonyl} piperazine (E22)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (100mg, 0.499 mmol) in tetrahydrofuran (1OmL) was added triethylamine (0.104ml_, 0.749 mmol) followed by dropwise addition of benzoyl chloride (0.058ml_, 0.499 mmol). The reaction mixture was allowed to stir for 30minut.es. The reaction mixture was diluted with DCM (1OmL) and the solution was washed with saturated sodium bicarbonate solution (10ml, twice), then (0.1 M, aq) HCI (1 OmL). The organic layer was dried (MgSO₄), filtered and reduced in vacuo to yield 1 ,1-dimethylethyl (3S)-3-methyl-4-

(phenylcarbonyl)-i-piperazinecarboxylate as a colourless oil (153mg), MS ES+ve m/z 305 (M+H).

To 1 ,1-dimethylethyl (3S)-3-methyl-4-(phenylcarbonyl)-1-piperazinecarboxylate (153mg, 0.503 mmol) was added 1 M hydrochloric acid in 1 ,4 dioxane solution (1OmL), followed by the addition of 3 drops of water. The reaction mixture was allowed to stir for 14hours. The reaction mixture was reduced in vacuo to yield colourless oil.

The colourless oil was dissolved in methanol (1 OmL) and passed down a SCX-2 column washing with two column volumes of methanol and eluting the product with 2N ammonia solution in methanol (three column volumes). The fraction containing eluted product was concentrated in vacuo to yield (2S)-2-methyl-1- (phenylcarbonyl)piperazine 99mg as a white solid, MS ES+ve m/z 205 (M+H). To a solution of (2S)-2-methyl-1-(phenylcarbonyl)piperazine (99mg, 0.411 mmol) in DCM (5mL) was added di-isopropylethylamine (0.233mL, 1.275 mmol), followed by gradual addition of 4-(trifluoromethyl)benzenesulfonyl chloride (11 1 mg, 0.452 mmol). The reaction mixture was allowed to stir for 30minutes.

The reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated sodium bicarbonate solution (1 OmL, twice), then with distilled water (1OmL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo to yield 197 mg of transparent oil.

The oil was dissolved in minimum volume of hot ethyl acetate (5ml_); hot iso-hexane (2OmL) was then added and allowed to cool to room temperature. The supernatant was decanted into a beaker, where crystals formed spontaneously. The remaining supernatant was removed and crystals air dried, to yield the title compound as white needle-like crystals (74mg, 36%)

¹H-NMR (CDCI₃) δ1.42 (3H, d, J=6.8Hz), 2.27-2.42 (1 H, m), 2.42-2.58 (1 H, m), 3.29- 3.42 (1 H, m), 3.52-3.63 (1 H, m), 3.65-5.10 (2H, m), 3.69-3.83 (1 H, m), 7.28-7.37 (2H, m), 7.37-7.46 (3H, m), 7.79-7.90 (4H, m).

MS ES+ve m/z 413 (M+H)

Example 23: 4-({(3S)-4-[(3-Fluorophenyl)carbonyl]-3-methyl-1- piperazinyl}sulfonyl) benzonitrile (E23)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (120mg, 0.599 mmol) in DCM (3.5 ml) was added DIPEA (0.157mL, 0.899 mmol) followed by 3-fluorobenzoyl chloride (0.072mL, 0.599 mmol) and the reaction mixture stirred for 1.δhours. After this time, DCM (2mL) and water (5mL) were added and the layers separated. The organic layer was then washed with 2M aqueous HCI (5mL) and saturated aqueous sodium bicarbonate solution (5mL) then passed through a hydrophobic frit and concentrated to dryness giving the desired 1 ,1-dimethylethyl (3S)-4-[(3-fluorophenyl)carbonyl]-3-methyl-1-piperazinecarboxylate (157mg, 81 %), MS ES+ve m/z 223 (M+H).

1 , 1 -dimethylethyl (3S)-4-[(3-fluorophenyl)carbonyl]-3-methyl-1 -piperazinecarboxylate (157mg, 0.487 mmol) was dissolved in dioxane (2ml_) and treated with HCI (4M solution in 1 ,4-dioxane) (0.609ml_, 2.435 mmol) overnight (approx 18hours) at room temperature. A further addition of HCI (4M solution in 1 ,4-dioxane) (0.2ml_) was added and the reaction mixture was stirred for 4hours. (4M, aqueous) HCI (0.2ml_) was added and stirring was maintained for 2hours. (4M, aqueous) HCI (0.2ml_) was added and the resultant mixture was stirred overnight (approx 18hrs). The reaction mixture was evaporated to dryness and the solid was triturated with diethyl ether to give (2S)-1-[(3-fluorophenyl)carbonyl]-2-methylpiperazine hydrochloride (126 mg, >100 %), MS ES+ve m/z 223 (M+H).

To a solution of (2S)-1-[(3-fluorophenyl)carbonyl]-2-methylpiperazine hydrochloride (126mg, 0.487 mmol) in DCM (5ml_) was added DIPEA (0.264mL, 1.510 mmol) at room temperature and to it was slowly added 4-cyanobenzenesulfonyl chloride (108mg, 0.536 mmol) and the resultant mixture was then stirred for 3hours. The reaction was diluted with DCM (1OmL) and washed with water (1 OmL). The organic layer was passed through a hydrophobic frit and then concentrated in-vacuo. The residue was purified by silica chromatography (Biotage SP4), eluting with a gradient of 10%-40% EtOAc in iso-hexane (10 column volumes) and the product containing fractions were concentrated to dryness giving the title compound as a white solid (11 1 mg, 58%).

¹H-NMR (CDCI₃) 51.42 (3H, d, J=7Hz), 2.35 (1 H, t, J=9Hz), 2.50 (1 H, d, J=9Hz), 3.36 (1 H, m), 3.60 (1 H, d_! J=H Hz), 3.79 (1 H, d, J=IOHz), 3.90-5.10 (2H, br s), 7.01 (1 H, dd, J=10, 2Hz), 7.07 (1 H, d, J=IOHz), 7.12 (1 H, m), 7.38 (1 H, m), 7.86 (4H, m).

MS ES+ve m/z 388 (M+H).

Example 24: 4-({(3S)-4-[(4-Fluorophenyl)carbonyl]-3-methyl-1- piperazinyl}sulfonyl) benzonitrile (E24)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (106mg, 0.529 mmol) in DCM (3.5 ml) was added DIPEA (0.139mL, 0.794 mmol) followed by 4-fluorobenzoyl chloride (0.063ml_, 0.529 mmol) and the resultant mixture was stirred for 3.5hours at room temperature. The reaction was diluted with DCM (2ml_) and washed with water (5ml_), (2M, aqueous) HCI (5ml_) and saturated sodium bicarbonate solution (5ml_). The organic layer was dried through a hydrophobic frit and concentrated to dryness giving the desired 1 ,1-dimethylethyl (3S)-4-[(4- fluorophenyl)carbonyl]-3-methyl-1-piperazinecarboxylate as a colourless oil, (135 mg, 79 %) MS ES+ve m/z 223 (M+H-100).

1 , 1 -dimethylethyl (3S)-4-[(4-fluorophenyl)carbonyl]-3-methyl-1 -piperazinecarboxylate (135mg, 0.419 mmol) was dissolved in 1 ,4-dioxane (2ml_) and treated with HCI (4M solution in 1 ,4-dioxane) (0.419ml_, 1.675 mmol) and the resultant mixture was stirred at room temperature overnight (approx 18hrs). A further quantity of HCI (4M solution in 1 ,4-dioxane) (0.1 ml.) and methanol (0.2ml_) were added and the reaction mixture was stirred for 2hours. More HCI (4M solution in 1 ,4-dioxane) (0.2ml_) was then added and the resultant mixture was stirred for a further 2hours. The reaction mixture was evaporated to dryness and the residue was triturated with diethyl ether to give (2S)-1-[(4-fluorophenyl)carbonyl]-2-methylpiperazine hydrochloride (101 mg, 93 %) MS ES+ve m/z 223 (M+H).

To a solution of (2S)-1-[(4-fluorophenyl)carbonyl]-2-methylpiperazine hydrochloride (101 mg, 0.390 mmol) in DCM (5ml_) was added DIPEA (0.21 1 mL, 1.210 mmol) at room temperature and to it was slowly added 4-cyanobenzenesulfonyl chloride

(87mg, 0.429 mmol) and the resultant mixture then stirred for 2hours. The reaction was diluted with DCM (1OmL) and washed with water (1OmL). The organic layer was passed through a hydrophobic frit and then concentrated in-vacuo. The residue was purified by silica chromatography (Biotage SP4), eluting with a gradient of 10%-40% EtOAc in iso-hexane (10 column volumes) and the product containing fractions were concentrated to dryness giving the title compound, 4-({(3S)-4-[(4- fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl)benzonitrile as a white solid. (54mg, 36%)

¹H NMR (CDCI₃) 51.42 (3H, d, J=7Hz), 2.34 (1 H, dt, J=12, 3Hz), 2.50 (1 H, dd, J=12, 3Hz), 3.37 (1 H, m), 3.59 (1 H, d, J=12Hz), 3.78 (1 H, d, J=12Hz), 4.09 (1 H, br s), 4.52 (1 H, br s), 7.10 (2H, m), 7.32 (2H, m), 7.86 (4H, m).

MS ES+ve m/z 388 (M+H).

Example 25: (2/?)-2-Methyl-1 -(phenylcarbonyl)-4-{[4 (trifluoromethyl)phenyl]sulfonyl} piperazine (E25)

To a solution of (2R)-2-methyl-1-(phenylcarbonyl)piperazine hydrochloride (120mg,

0.498 mmol) (Intermediate 14) in DCM (5mL) was added DIPEA (0.27OmL, 1.545 mmol) at room temperature and to it was slowly added 4-

(trifluoromethyl)benzenesulfonyl chloride (134mg, 0.548 mmol) and the resultant mixture then stirred for 1.5hours.

The reaction was diluted with DCM (1 OmL) and washed with water (1OmL). The organic layer was passed through a hydrophobic frit and then concentrated in-vacuo. The residue was purified by silica chromatography (Biotage SP4), eluting with a gradient of 10%-40% EtOAc in iso-hexane (10 column volumes) and the product containing fractions were collected and concentrated to dryness giving the desired (2R)-2-methyl-1-(phenylcarbonyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (146 mg, 71%)

¹H NMR (CDCI₃) 51.42 (3H, d, J=7Hz), 2.34 (1 H, t, J=IOHz), 2.49 (1 H, d, J=IOHz), 3.36 (1 H, m), 3.59 (1 H, d, J=IOHz), 3.77 (1 H, d, J=IOHz), 3.80-5.00 (2H, br s), 7.30 (2H, m), 7.40 (3H, m), 7.85 (4H, m).

MS ES+ve m/z 413 (M+H).

Example 26: 4-({(3S)-4-[(2-Fluorophenyl)carbonyl]-3-methyl-1- piperazinyl}sulfonyl) benzonitrile (E26)

To a solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (104mg, 0.519 mmol) in DCM (3.5ml_) was added DIPEA (0.136ml_, 0.779 mmol) at room temperature followed by 2-fluorobenzoyl chloride (0.062ml_, 0.519 mmol). The resultant mixture was stirred at room temperature for 3.5hours. DCM (2m L) and water (5mL) were then added and the layers separated. The organics were washed with 2M aqueous HCI (5m L) and saturated sodium bicarbonate solution (5m L) then passed though a hydrophobic frit and concentrated to dryness giving the desired 1 ,1- dimethylethyl (3S)-4-[(2-fluorophenyl)carbonyl]-3-methyl-1-piperazinecarboxylate as a colourless oil (147mg, 88 %), MS ES+ve m/z 345 (M+Na).

1 , 1 -dimethylethyl (3S)-4-[(2-fluorophenyl)carbonyl]-3-methyl-1 -piperazinecarboxylate (147mg, 0.456 mmol) was dissolved in 1 ,4-dioxane (2mL) and treated with HCI (4M solution in 1 ,4-dioxane) (0.456mL, 1.824 mmol) and stirred overnight (approx 18hrs) at room temperature. A further quantity of HCI (4M solution in 1 ,4-dioxane) (0.1 mL) was added and the reaction mixture was stirred for 2hours. 4M aqueous HCI (0.1 mL) was added and stirring maintained for 2hours. The reaction mixture was concentrated to dryness and the residue was triturated with diethyl ether to yield the (2S)-1-[(2-fluorophenyl)carbonyl]-2-methylpiperazine hydrochloride (118 mg, 100 %), MS ES+ve m/z 223 (M+H).

To a solution of (2S)-1-[(2-fluorophenyl)carbonyl]-2-methylpiperazine hydrochloride (118mg, 0.456 mmol) in DCM (5ml_) was added DIPEA (0.247mL, 1.414 mmol) at room temperature and to it was slowly added 4-cyanobenzenesulfonyl chloride (101 mg, 0.502 mmol) and the resultant mixture then stirred for 2hours. The reaction was diluted with DCM (1OmL) and washed with water (1OmL). The organic layer was passed through a hydrophobic frit and then concentrated in-vacuo. The residue was purified by silica chromatography (Biotage SP4), eluting with a gradient of 10%-40% EtOAc in iso-hexane (10 column volumes) and the product containing fractions were collected and concentrated to dryness giving the desired 4-({(3S)-4-[(2- fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl)benzonitrile as a white solid (126mg, 71%)

¹H NMR (CDCI₃) δ1.35-1.43 (3H, br m), 2.43 (1 H, br m), 2.59 (1 H, br m), 3.24, 3.39 (1 H, br m), 3.54 (1 H, br m), 3.67 (1 H, m), 3.86 (1 H, br m), 4.66, 5.06 (1 H, br m), 7.07 (1 H, m), 7.20 (1 H, m), 7.38 (1 H, m), 7.42 (1 H, m), 7.86 (4H, m).

MS ES+ve m/z 388 (M+H).

Example 27: 4-{[(3S)-3-Methyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E27)

A solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (250mg, 1.248 mmol) in tetrahydrofuran (1 OmL) was treated with triethylamine (0.338ml_, 2.497 mmol) followed by benzoyl chloride (0.146ml_, 1.248 mmol). The reaction was stirred at room temperature for 3hours then concentrated in vacuo, and dissolved in 1 ,4- dioxane.

A solution of 1 ,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (3.Og, 14.98 mmol) in tetrahydrofuran (1 OmL) was treated with triethylamine (4.06mL, 30 mmol) followed by benzoyl chloride (1.76mL, 14.98 mmol). The reaction was stirred at room temperature for 5mins. Ethyl acetate was added and the solution washed with a saturated aqueous sodium chloride solution. The organic layer was dried (MgSO₄) and filtered.

The above two solutions were combined and evaporated under reduced pressure to obtain a residue (5.1g) which was dissolved in 1 ,4-dioxane and stirred at room temperature with a solution of HCI (4M solution in 1 ,4-dioxane) (30ml) for 3hours. Evaporation of the solvent gave a residue which was chromatographed over an SCX column (2x 5Og) eluting with 1 M methanolic ammonia. Evaporation of the solvent gave (2S)-2-methyl-1-(phenylcarbonyl)piperazine as a white solid (3.1g, 94%) which was used without further purification; MS ES+ve m/z 205 (M+H). (2S)-2-methyl-1-(phenylcarbonyl)piperazine (3.1g, 15.2 mmol) was dissolved in DCM (10OmL) and treated with DIPEA (8.22mL, 47.0 mmol) and 4-cyanobenzenesulfonyl chloride (3.37g, 16.7 mmol) and stirred at room temperature overnight (approx 18hrs). The reaction mixture was evaporated to dryness, the residue azeotroped with toluene and the resulting orange gum dissolved in ethyl acetate and washed with 2 M HCI, aqueous sodium carbonate and saturated aqueous sodium chloride. The organic layer was dried (MgSO₄), filtered and evaporated to dryness and the residue was recrystalised from a mixture of ethyl acetate and iso-hexane to provide the title compound as a crystalline solid (2.8g, 40%).

¹H NMR (CDCI₃) δ 1.41 (3H, d, J = 6.8Hz), 2.34 (1 H, br t, J = 10.6Hz), 2.50 (1 H, br d, J = 10.4Hz), 3.29-3.42 (1 H, m), 3.58 (1 H, br d, J = 11.6Hz), 3.70-4.90 (2H, m),

3.77 (1 H, br d, J = 10.8Hz), 7.27-7.31 (2H, m), 7.35-7.47 (3H, m), 7.80-7.90 (4H, m).

MS ES+ve m/z 370 (M+H)

Example 27 (Alternative Procedure): 4-{[(3S)-3-Methyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E27)

To a solution of (2S)-2-methyl-1-(phenylcarbonyl)piperazine hydrochloride (500 mg, 2.077 mmol) (Intermediate 16) in dichloromethane (DCM) (35ml) was added DIPEA (1.125 ml, 6.44 mmol) at room temperature and to it was slowly added 4- cyanobenzenesulfonyl chloride (461 mg, 2.285 mmol) and the resultant mixture then stirred for 16 hours overnight. The reaction was worked up by addition of 2M HCI solution (75 ml.) and dichloromethane (100 ml.) and the organic layer separated and washed again with saturated brine solution (50 ml_). The organics were then separated, dried (MgSO₄) and concentrated to dryness. The crude material was then purified by silica chromatography (Biotage SP-4, eluting a linear gradient of ethyl acetate in isohexane). The desired fractions were then combined and concentrated to dryness under reduced pressure. The sample was dried in a vacuum oven for 6 hours giving the title compound as a white foam (721 mg, 94 %)

¹H NMR (CDCI₃) δ 1.41 (3H, d, J=6.8Hz), 2.35 (1 H, br t, J= 11 Hz), 2.49 (1 H, br d, J= 11 Hz), 3.36 (1 H, m), 3.58 (1 H, br d, J= 11 Hz), 3.77 (1 H, br d, J= 11 Hz), 3.9-4.9 (2H, br s), 7.30 (2H, m), 7.40 (3H, m), 7.86 (4H, m)

MS ES+ve m/z 370 (M+H)

Example 28: 4-{[3,3-Dimethyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E28)

To a solution of 1 ,1-dimethylethyl 3,3-dimethyl-1-piperazinecarboxylate (100mg, 0.467mol) in tetrahydrofuran (1 OmL) was added triethylamine (0.098ml_, 0.700 mmol) followed by dropwise addition of benzoyl chloride (0.06OmL, 0.513mmol). The reaction mixture was allowed to stir for 30 minutes. The reaction mixture was diluted with DCM (1OmL) and the solution was washed with saturated sodium bicarbonate solution (1OmL, twice), then (0.1 M, aq) HCI (1OmL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo to yield 1 ,1-dimethylethyl 3,3-dimethyl-4- (phenylcarbonyl)-i-piperazinecarboxylate as a colourless oil (162mg, 100%), MS ES+ve m/z 319 (M+H)

To 1 , 1 -dimethylethyl 3,3-dimethyl-4-(phenylcarbonyl)-1 -piperazinecarboxylate (162mg, 0.509 mmol) was added 1 M hydrochloric acid in 1 ,4 dioxane (1 OmL), followed by the addition of 3 drops of water. The reaction mixture was allowed to stir for 62hours. The reaction mixture was reduced in vacuo to yield colourless oil. The colourless oil was dissolved in methanol (1 OmL) and passed down a SCX-2 column washing with two column volumes methanol and eluting the product with three column volumes of 2N ammonia solution in methanol The fraction containing eluted product was reduced in vacuo to yield 2,2-dimethyl-1-

(phenylcarbonyl)piperazine as a white solid (81 mg, 63%), MS ES+ve m/z 219 (M+H). To a solution of 2,2-dimethyl-1-(phenylcarbonyl)piperazine (81 mg, 0.318 mmol) in DCM (5m L) was added DIPEA (0.172mL, 0.986 mmol), followed by gradual addition of 4-cyanobenzenesulfonyl chloride (70.5mg, 0.350 mmol). The reaction mixture was allowed to stir for 1 hour.

The reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated sodium bicarbonate solution (1 OmL, twice), then with distilled water (1OmL). The organic layer was dried (MgSO₄), filtered and reduced in vacuo to yield a transparent oil (160mg).

The oil was then dissolved in 1 :1 MeCN/DMSO (0.9ml) and purified using MDAP (over 3 batches). The fractions containing product were combined and reduced in vacuo to yield the title compound as a white solid (48mg, 32%)

¹H-NMR (CDCI₃) 51.58 (6H, s), 3.00 (2H, s), 3.15 (2H, t, J=5.6Hz), 3.47 (2H, t, J=5.6Hz), 7.31-7.48 (5H, m), 7.84-7.93 (4H, m).

MS ES+ve m/z 384 (M+H).

Example 29: 4-{[(3/?)-3-Methyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E29)

To a solution of (2R)-2-methyl-1-(phenylcarbonyl)piperazine hydrochloride (1 15mg, 0.478 mmol) (Intermediate 14) in DCM (5mL) was added DIPEA (0.259mL, 1.481 mmol) at room temperature and to it was slowly added 4-cyanobenzenesulfonyl chloride (106mg, 0.525 mmol) and the resultant mixture then stirred for 1.5hours. The reaction was diluted with DCM (1 OmL) and washed with water (1OmL). The organic layer was passed through a hydrophobic frit and then concentrated in-vacuo. The residue was purified by silica chromatography (Biotage SP4), eluting with a gradient of 10%-50% EtOAc in iso-hexane (10 column volumes) and the product containing fractions were collected and concentrated to dryness giving the desired 4- {[(3R)-3-methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile as a white solid (153mg, 87%).

¹H NMR (CDCI₃) 51.41 (3H, d, J=7Hz), 2.34 (1 H, t, J=IOHz), 2.50 (1 H, d, J=IOHz), 3.36 (1 H, m), 3.58 (1 H, d, J=IOHz), 3.77 (1 H, d, J=IOHz), 3.80-4.80 (2H, br s), 7.30 (2H, m), 7.40 (3H, m), 7.85 (4H, m). MS ES+ve m/z 370 (M+H).

Example 30: (2S)-4-[(4-Bromo-2-methylphenyl)sulfonyl]-2-methyl-1 - (phenylcarbonyl)piperazine (E30)

To a solution of (2S)-2-methyl-1-(phenylcarbonyl)piperazine hydrochloride (150 mg, 0.623 mmol) (Intermediate 16) and DIPEA (0.348 ml, 1.994 mmol) in dry dichloromethane (DCM) (5 ml) was added a solution of 4-bromo-2- methylbenzenesulfonyl chloride (202 mg, 0.748 mmol) in dry DCM (1 ml) and the resulting colourless solution was stirred at ambient temperature for 18 hours. The solution was diluted with DCM (20 ml), and washed with 2M aqueous HCI (10 ml), saturated aqueous NaHCO₃ (10 ml), brine (10 ml), dried (MgSO₄), filtered and concentrated in vacuo to give a white foam. Silica chromatography (Biotage SP4; linear gradient (8-66%) EtOAc in isohexane) gave the title compound as a clear oil (256 mg, 94 % yield).

¹H NMR (CDCI₃) δ 1.32 (3H, d, J=7Hz), 2.66 (1 H, m), 2.82 (1 H, br d, J=IOHz), 3.30 (1 H, m), 3.50 (1 H, br d, J=12Hz), 3.66 (1 H, br d, J= 11 Hz), 3.80-4.90 ( 2H, br s), 7.33 (2H, m), 7.41 (3H, m), 7.48 (2H, m), 7.71 (1 H, d, J=8Hz)

MS ES+ve m/z 439 (M+H) Example 31 : 3-Methyl-4-{[(3S)-3-methyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E31)

A suspension of (2S)-4-[(4-bromo-2-methylphenyl)sulfonyl]-2-methyl-1- (phenylcarbonyl)piperazine (210 mg, 0.480 mmol) (Example 30) and copper (I) cyanide (165 mg, 1.842 mmol) in dry N,N-Dimethylformamide (DMF) (2.5 ml) was irradiated in the microwave at 175 ⁰C for 1 h followed by irradiation in the microwave at 200 ⁰C for 30 min. The reaction mixture added to water (20 ml), then extracted with EtOAc (3 x 20 ml). The organics were washed with concentrated ammonia solution (20 ml), brine (20 ml), dried (MgSO₄), filtered and concentrated in vacuo to give a pale yellow oil. Silica chromatography (Biotage SP4; linear gradient (12-100 %) EtOAc in isohexane) gave the title compound as a white solid (107 mg, 58 % yield).

¹H NMR (CDCI₃) δ 1.34 (1 H, d, J=7Hz), 2.72 (1 H, dd, J= 3, 12Hz), 2.89 (1 H, dd, J= 2,12Hz), 3.33 (1 H, m), 3.56 (1 H, br d, J= 12Hz), 3.71 (1 H, br d, J= 11 Hz), 3.80-4.30 (1 H, br s), 4.30-4.80 (1 H, br s), 7.34 (2H, m), 7.41 (3H, m) 7.63 (2H, m), 7.95 (1 H, m) MS ES+ve m/z 384 (M+H)

Example 32: (3S)-4-[(2-fluorophenyl)sulfonyl]-3-methyl-N-phenyl-1- piperazinecarboxamide (E32)

To a solution of (3S)-3-Methyl-Λ/-phenyl-1-piperazinecarboxamide (Intermediate 13, D13, 0.110g) in dry dichloromethane (12ml_) was added triethylamine (0.17ml_) then 2-fluorobenzenesulfonyl chloride (0.195g). The reaction was stirred at room temperature for 12 hours. To the reaction was added PS-trisamine (0.7g) and the reaction stirred for 2 hours. The mixture was filtered and washed with water (5OmL). The organic phase was dried with magnesium sulphate and the solvent removed in vacuo. The crude product was purified by column chromatography (Biotage SP4, eluting a gradient from 20-85% ethyl acetate in hexane). Fractions containing the desired product were combined and the solvent removed. The residue was taken up in hexane, sonicated for one minute then the solvent evaporated. The resulting product was dried under high vacuum overnight to yield the title compound as a white crystalline solid (85mg)

¹H NMR (400 MHz, Chloroform-D) δ ppm 1.18 (d, J=6.80 Hz, 3 H) 3.03 (td, J=MAA, 3.84 Hz, 1 H) 3.19 (dd, J=13.37, 3.51 Hz, 1 H) 3.38 (m, 1 H) 3.79 (m, 1 H) 3.84 (m, 1 H) 4.00 (m, 1 H) 4.23 (m, 1 H) 6.23 (s, 1 H) 7.06 (ddd, 1 H) 7.21 (ddd, J=10.36, 8.28, 1.10 Hz, 1 H) 7.29 (m, 2 H) 7.30 (m, 3 H) 7.58 (m, 1 H) 7.93 (td, J=7.45, 1.75 Hz, 1 H)

Example 33: (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-4-{[2- (methyloxy)phenyl]sulfonyl}-1 -piperazinecarboxamide (E33)

To a stirred solution of (3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-1- piperazinecarboxamide (Intermediate 1 1 , D11 ) (0.11 g) in dry DCM (8ml_) was added triethylamine (0.15ml_) and 2-(methyloxy)benzenesulfonyl chloride (0.178g). The reaction was stirred under argon for 90 minutes. To the reaction was added polymer supported trisamine (commercially available, for example from Biotage, Uppsala, Sweden, 0.5g) and the reaction stirred for a further 12 hours. The reaction was filtered, the solution washed with water (5OmL), dried (MgSO₄) and the solvent removed under vacuum. The crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 20-80% ethyl acetate in hexane) and the purified product dried at 40⁰C under vacuum for 72 hours to yield the title compound as a white crystalline solid (59mg).

MS ES+ve m/z 426 (M+H)

¹H NMR (400 MHz, Chloroform-D) δ ppm 1.14 (d, J=7.23 Hz, 3 H) 3.01 (ddd, 1 H) 3.23 (dd, J=13.15, 3.51 Hz, 1 H) 3.37 (ddd, J=13.65, 12.00, 3.29 Hz, 1 H) 3.72 (dt, J=13.26, 2.08, 1.97 Hz, 1 H) 3.87 (dt, 1 H) 3.95 (s, 3 H) 3.99 (m, 1 H) 4.21 (m, 1 H) 6.32 (m, 1 H) 6.84 (m, 2 H) 7.00 (dd, J=8.33, 1.10 Hz, 1 H) 7.05 (ddd, J=8.22, 7.13, 1.10 Hz, 1 H) 7.53 (m, 1 H) 7.94 (m, 2 H)

Example 34: (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-4-{[4- (methyloxy)phenyl]sulfonyl}-1 -piperazinecarboxamide (E 34)

To a stirred solution of (3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-1- piperazinecarboxamide (Intermediate 1 1 , D11 ) (0.11 g) in dry DCM (8ml_) was added triethylamine (0.15ml_) and 4-(methyloxy)benzenesulfonyl chloride (0.178g). The reaction was stirred under argon for 90 minutes. To the reaction was added polymer supported trisamine (0.5g) and the reaction stirred for a further 12 hours. The reaction was filtered, the solution washed with water (5OmL), dried (MgSO₄) and the solvent removed under vacuum. The crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 20-80% ethyl acetate in hexane) and the purified product dried at 40⁰C under vacuum for 72 hours to yield the title compound as a white crystalline solid (99mg).

¹H NMR (400 MHz, Chloroform-D) δ ppm 1.13 (d, J=6.36 Hz, 3 H) 3.04 (ddd, J=12.72, 11.62, 3.73 Hz, 1 H) 3.23 (m, 2 H) 3.68 (m, 2 H) 3.86 (s, 3 H) 3.94 (m, 1 H) 4.18 (m, 1 H) 6.28 (m, 1 H) 6.83 (m, 2 H) 6.98 (m, 2 H) 7.76 (m, 2 H) 7.91 (m, 1 H) MS ES+ve m/z 426 (M+H)

Example 35: (3S)-4-[(3-cyanophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-3-methyl-1 - piperazinecarboxamide (E35)

To a solution of (3S)-Λ/-(2,4-difluorophenyl)-3-methyl-1 -piperazinecarboxamide (110mg, 0.431 mmol) (Intermediate 1 1 , D11 ) in anhydrous DCM (8ml_) was added triethylamine (0.15ml_, 1.1 mmmol) and 3-cyanobenzenesulfonyl chloride (173mg, 0.863 mmol). The reaction was stirred under an argon atmosphere at room temperature for 90mins. Polymer supported trisamine (0.5g) was then added to the reaction mixture which was gently stirred for 12hours and the solution filtered. The organic layer was washed with water (5OmL) and the collected organic layer was dried (MgSO₄), filtered and evaporated. The residue was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (3 column volumes), a gradient from 20-85% EtOAc in hexane (15 column volumes) and 85% EtOAc in hexane (3 column volumes) the product containing fractions were evaporated. The title compound was then dried in a vacuum oven at 40⁰C for 48hours to afford white crystals (104mg).

MS ES+ve m/z 421 (M+H)

¹H NMR (400 MHz, Chloroform-D) δ ppm 1.14 (d, J=6.36 Hz, 3 H) 3.06 (ddd, J=12.94, 11.84, 3.73 Hz, 1 H) 3.27 (m, 2 H) 3.75 (m, 2 H) 4.02 (m, 1 H) 4.24 (m, 1 H) 6.30 (m, 1 H) 6.85 (m, 2 H) 7.68 (ddd, J=7.89, 0.66 Hz, 1 H) 7.86 (ddd, J=7.84, 1.59, 1.10 Hz, 1 H) 7.90 (m, 1 H) 8.05 (ddd, J=8.00, 1.86, 1.32 Hz, 1 H) 8.12 (dt, J=1.75, 0.44 Hz, 1 H) Example 36: 4-{[3-(hydroxymethyl)-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E36)

1 ,1-dimethylethyl 3-(hydroxymethyl)-1-piperazinecarboxylate (0.3g), triethylamine (0.446 ml) and benzoyl chloride (0.419 ml) in tetrahydrofuran (2OmL) were stirred for 2 hours. The reaction was diluted with dichloromethane (100 ml). The solution was extracted twice with saturated aqueous NaHCO₃ then the solvent removed under vacuum. To the residue was added 1 M HCI in 1 ,4-dioxane and the reaction stirred overnight. The solvent was removed under vacuum and the resulting residue triturated with ether to yield the desired intermediate, [1-(phenylcarbonyl)-2- piperazinyl]methanol hydrochloride, as a white solid (0.541 mg)

To [1-(phenylcarbonyl)-2-piperazinyl]methanol hydrochloride (250mg) and di- idopropylethylamine (0.51OmL) in dichloromethane (2OmL) was added 4- cyanobenzenesulfonyl chloride (0.196g) and the reaction stirred for 2 hours. To the reaction was added dichloromethane and the solution extracted with 2M HCI then water. The solvent was removed under vacuum and the residue purified by silica chromatography using ethyl acetate as an eluent to yield the title compound (103mg)

MS ES+ve m/z 386 (M+H)

¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.28 (dd, J=10.85, 9.98 Hz, 1 H) 2.49 (td, J= 11.02, 3.18 Hz, 1 H) 2.96 (m, 1 H) 3.10 (dt, J=12.11 , 3.04 Hz, 1 H) 3.25 (m, 1 H) 3.63 (m, 1 H) 3.74 (m, 1 H) 4.21 (dd, J=11.18, 6.58 Hz, 1 H) 4.28 (dd, J=11.18, 5.26 Hz, 1 H) 7.46 (m, 2 H) 7.60 (m, 1 H) 7.85 (m, 2 H) 7.89 (m, 2 H) 8.01 (m, 2 H) Example 37: (3S)-4-[(3-cyanophenyl)sulfonyl]-3-methyl-N-phenyl-1 - piperazinecarboxamide (E37)

To a stirred solution of (3S)-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (Intermediate 13, D13) (0.1 1Og) in anhydrous dichloromethane (5ml_) was added 3- cyanobenzene sulfonylchloride (0.201g) and triethylamine (0.17ml_). The reaction was stirred at room temperature under argon for 2 hours. The solvent was evaporated and the crude product taken up in dichloromethane (12ml_). To this was added polymer supported trisamine (0.7g) and the mixture was stirred for 2 hours then filtered. The solvent was evaporated and the crude product taken up in dichloromethane (1OmL) and washed with water (5OmL). The organic phase was seperated, dried (MgSO₄) and filtered. The solvent was evaportaed and the crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 30-90% ethyl acetate in hexane) to yield the title compound as a white solid (83mg).

¹H NMR (400 MHz, Chloroform-D) δ ppm 1.13 (d, J=6.80 Hz, 3 H) 3.03 (ddd, J=12.83, 11.73, 3.73 Hz, 1 H) 3.22 (dd, J=12.72, 3.29 Hz, 1 H) 3.28 (m, 1 H) 3.71 (m, 1 H) 3.77 (m, 1 H) 4.01 (m, 1 H) 4.22 (m, 1 H) 6.22 (s, 1 H) 7.06 (m, 1 H) 7.29 (s, 2 H) 7.30 (s, 2 H) 7.68 (td, J=7.89, 0.44 Hz, 1 H) 7.86 (ddd, J=7.67, 1.53, 1.10 Hz, 1 H) 8.05 (ddd, J=8.00, 1.86, 1.10 Hz, 1 H) 8.12 (m, 1 H)

MS ES+ve m/z 385 (M+H)

Example 38: (3S)-3-methyl-4-{[4-(methyloxy)phenyl]sulfonyl}-Λ/-phenyl-1- piperazinecarboxamide (E38)

To a stirred solution of (3S)-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (Intermediate 13, D13) (0.106g) in anhydrous dichloromethane (8ml_) was added triethylamine (0.17ml_) and 4-(methyloxy)benzenesulfonyl chloride (0.198g). The reaction was stirred at room temperature under argon for overnight. To the reaction was added polymer supported trisamine (0.7g) and the mixture was stirred for 2 hours then filtered. The filtrate was washed with water (5OmL), dried (MgSO₄) and the solvent was evaporated. The crude product was purified by silica chromatography (Biotage SP4, eluting with a gradient from 20-85% ethyl acetate in hexane) and the purified product dried at 40⁰C under vacuum for five days to yield the title compound as a white crystalline solid (86mg).

MS ES+ve m/z 390 (M+H)

¹H NMR (400 MHz, Chloroform-D) δ ppm 1.12 (d, J=6.36 Hz, 3 H) 3.01 (ddd,

J=12.66, 11.67, 3.73 Hz, 1 H) 3.23 (m, 2 H) 3.66 (m, 1 H) 3.70 (m, 1 H) 3.85 (s, 3 H) 3.93 (m, 1 H) 4.17 (m, 1 H) 6.19 (m, 1 H) 6.98 (m, 2 H) 7.04 (m, 1 H) 7.28 (m, 4 H) 7.76 (m, 2 H)

Example 39: 4-{[3-[(methyloxy)methyl]-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E39)

A suspension of 4-{[3-(hydroxymethyl)-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl} benzonitrile (Example 36) (75mg), methyl iodide (100μl_) and polymer supported N2- (1 ,1-dimethylethyl)-N2,N2-diethyl-1 ,4,5,6-tetrahydro-1 ,3,2λ⁵-diazaphosphorine-2,2- diamine (BEMP, 2.2 mmol/g, 442mg) in tetrahydrofuran (2OmL) was stirred overnight. To the reaction was added methyl iodide (200μl_) and Λ/-phenyl- tris(dimethylamino)iminophosphorane on polystyrene resin (PS-BEMP) (500mg) and the reaction stirred for a further 24 hours. The reaction was filtered and the solvent removed. The crude product was purified by silica chromatography using ethyl acetate as a solvent to yield the title compound (35mg, 36%)

MS ES+ve m/z 400 (M+H)

¹H NMR (400 MHz, Chloroform-D) δ ppm 2.40 (s, 3 H) 2.47 (m, 1 H) 2.58 (m, 1 H) 2.64 (m, 1 H) 2.72 (td, J=10.52, 2.85 Hz, 1 H) 2.85 (dt, J= 11.73, 3.51 , 3.40 Hz, 1 H) 3.49 (m, 1 H) 3.64 (m, 1 H) 4.27 (dd, J= 11.62, 5.92 Hz, 1 H) 4.49 (dd, J= 11.51 , 3.84 Hz, 1 H) 7.47 (m, 2 H) 7.60 (tt, J=7.45, 1.32 Hz, 1 H) 7.83 (m, 2 H) 7.88 (m, 2 H) 8.00 (m, 2 H)

The single enantiomers were isolated from the racemic 4-{[3-[(methyloxy)methyl]-4- (phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (23mg) via chiral preparative chromatography using the following conditions:

- Column: Chiralpak IC (20mm x 250mm, 5μm) - Eluent: Heptane : Ethanol 70:30 v/v pump-mixed

- Flow rate =17.0mls/min

- U.V. Absorbance (S) 230nm

- Autosampler injection (500μl of sample in 95%Absolute ethanol/5%DMF on column) - lsocratic Run time = 30 minutes

- Column: Chiralpak IC (4.6mm x 250mm, 5μm)

- Heptane : Ethanol 70:30 v/v pump-mixed

- Flow rate =1.0mls/min

- U.V. Absorbance @ 215nm or 254nm (see chromatograms)

- Autosampler injection (1 Oμl of sample in Absolute ethanol on column)

- lsocratic Run time = 30 minutes

Isolated compounds:

Example 39a: Faster running enantiomer (4-{[(3R)-3-[(methyloxy)methyl]-4- (phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile or 4-{[(3S)-3-[(methyloxy)methyl]- 4-(phenylcarbonyl)-1 -piperazinyl]sulfonyl}benzonitrile, 9mg)

Retention time 21.36min

Example 39b: Slower running enantiomer (4-{[(3R)-3-[(methyloxy)methyl]-4-

(phenylcarbonyl)-i -piperazinyl]sulfonyl}benzonitrile or 4-{[(3S)-3-[(methyloxy)methyl]- 4-(phenylcarbonyl)-1 -piperazinyl]sulfonyl}benzonitrile, 9mg)

Retention time 23.76min

Example 40: 4-[(4-chlorophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-1 ■ piperazinecarboxamide (E40)

1-[(4-chlorophenyl)sulfonyl]piperazine (commercially available, for example from Matrix Scientific, Columbia, USA, 250 mg, 0.96mmol) was suspended in DCM (5ml). To this was added triethylamine (0.147 ml, 1.06mmol) and then 2,4-difluorophenyl isocyanate (0.149 ml, 1.25mmol). The yellow solution was stirred under argon for 3hrs. The sample was evaporated and purified using the MDAP. The fractions containing the desired product were evaporated and freeze dried from 1 ,4-dioxane to yield the title compound as a white solid (0.233g)

¹H NMR (250 MHz, Chloroform-D) δ ppm 3.09 (t, J=5.21 Hz, 4 H) 3.61 (t, J=4.94 Hz, 4 H) 6.35 (m, 1 H) 6.83 (m, 2 H) 7.54 (m, 2 H) 7.70 (m, 2 H) 7.87 (m, 1 H)

MS ES+ve m/z 416

Example 41 : (1 -(phenyl carbonyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-2- piperazinyl)methanol (E41)

[1-(phenylcarbonyl)-2-piperazinyl]methanol (0.215mg, Intermediate 18) was dissolved in DCM (1OmL). DIPEA (0.341 ml_) was then added while stirring. 4- (trifluoromethyl)benzenesulfonyl chloride (0.239mg) was then added slowly and the reaction mixture was stirred overnight. DCM (5OmL) was added to reaction mixture. The solution was washed with 1 M HCI, then with distilled water. The organic layer was collected and evaporated to dryness using a rotary evaporator. This gave 300mg of a transparent oil. A third of the residual material was dissolved in 1 :1 acetonitrile / DMSO and purified using MDAP. The fractions containing desired product were combined and evaporated to dryness on the rotary evaporator to yield the title compound as a white solid (64mg).

¹H NMR (400 MHz, MeOD) δ ppm 2.79 (m, 2 H) 3.33 (m, integration obscured by solvent, assume 1 H) 3.53 (dt, J=12.99, 3.04 Hz, 1 H) 3.89 (m, 2 H) 4.06 (m, 1 H) 4.50 (dd, J=12.72, 6.58 Hz, 1 H) 4.62 (dd, J=12.72, 3.95 Hz, 1 H) 7.50 (m, 2 H) 7.65 (m, 1 H) 8.00 (m, 2 H) 8.07 (m, 4 H)

MS ES+ve m/z 429

Example 42: 4-{[(3S)-3-methyl-4-(phenylacetyl)-1 - piperazinyl]sulfonyl}benzonitrile (E41)

Phenylacetyl chloride (70mg), 4-{[(3S)-3-methyl-1-piperazinyl]sulfonyl}benzonitrile (Intermediate 17) (106mg) and triethylamine (84μl_) in tetrahydrofuran (1OmL) were combined and stirred for 30 minutes. To the reaction was added DCM (5OmL) and the solution washed twice with a saturated solution of sodium bicarbonate. The organic layer was dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue was dissolved in DCM (5mL) and was purified by silica chromatography (eluting with a 0-15% gradient EtOAc in DCM). Fractions containing the desired product were combined and evaporated to dryness under vacuum. The product was triturated with ether to yield the title compound as a white solid (120mg, 80%).

MS ES+ve m/z 384 (M+H)

¹H NMR (500 MHz, DMSOd₆) δ ppm 8.14 (m, J = 8.6 Hz, 2H) 7.88 (d, J = 8.6 Hz, 2H) 7.25 (t, J = 7.5 Hz, 2H) 7.19 (t, J = 7.3 Hz, 1 H) 7.14 (m, 2H) 4.69 (br.s., 1 H) 4.31 (d, J = 11.5 Hz, 2H) 3.84 (d, J = 13.7 Hz, 1 H) 3.66 (m, 3H) 3.54 (d, J = 11 Hz, 1 H) 3.45 (d, J = 11.7 Hz, 1 H) 3.38 (d, J = 11.2 Hz, 1 H) 3.25 (t, J = 12.1 Hz, 1 H) 2.89 (t, J = 12.6 Hz, 1 H) 2.33 (dd, J = 12.6 Hz, 1 H) 2.16 (m, 2H) 1.10 (d, J = 6.2 Hz, 3H) Example 43: (2S)-2-methyl-4-{[4-(methyloxy)phenyl]sulfonyl}-1- (phenylcarbonyl)piperazine (E43)

To a solution of (2S)-2-methyl-1-(phenylcarbonyl)piperazine hydrochloride (Intermediate 16) (100 mg, 0.415 mmol) in dichloromethane (5 ml) was added DIPEA (0.225 ml, 1.288 mmol) at room temperature and to it was slowly added 4- Methoxybenzenesulfonyl chloride (94 mg, 0.457 mmol) and the resultant mixture then stirred for 2 hours. The reaction was worked up by addition of water (1 OmI) and dichloromethane (10ml) and the organic layer separated with a phase separation cartridge and then concentrated under a stream of argon. The crude material was then dissolved in dimethyl sulfoxide and purified by reverse phase Mass-Directed Autopurification (MDAP). The desired fractions were then collected and concentrated to dryness under vacuum to yield the title compound as a white solid (110 mg, 71%).

MS ES+ve m/z 375 (M+H)

¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.41 (d, J=6.80 Hz, 3 H) 2.25 (m, 1 H) 2.40 (m, 1 H) 3.35 (m, 1 H) 3.54 (m, 1 H) 3.72 (m, 1 H) 3.89 (s, 3 H) 5.0-4.0 (br.s., 2 H) 7.01 (m, 2 H) 7.30 (m, 2 H) 7.39 (m, 3 H) 7.67 (m, 2 H)

Examples 44 to 47:

The compounds of Table 1 were prepared by a similar procedure to that described for Example 13 using the appropriate substituted piperazine intermediate and sulphonyl chloride. Table 1.

Examples 48 and 49:

The compounds of Table 2 were prepared by a similar procedure to that described for Example 27 (alternative procedure) using Intermediate 16 and the appropriate sulphonyl chloride. Table 2.

Examples 50 to 68:

The compounds of Table 3 are commercially available and support the first aspect of the invention. The compounds are commercially available from at least one of the following suppliers: a) Enamine Ltd, Kiev, Ukraine; b) Life Chemicals Inc., (formerly I. F. Lab Inc.) Burlington, Canada; c) Asinex Ltd., Moscow, Russia; d) Chem.Div. Inc, San Diego, USA; e) Vitas-M, Moscow, Russia; f) ChemBridge Corporation, San Diego, USA; g) Zelinsky Institute of Organic Chemistry, Moscow, Russia.

Table 3.

Kiev,

Inc, USA.

of

Abbreviations Table:

Equipment:

¹H NMR spectra

Chemical shifts are expressed in parts per million (ppm, units). Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

Mass-directed automated HPLC/Mass-directed automated preparation (MDAP)

Where indicated in the above examples, purification by mass-directed automated HPLC was carried out using the following apparatus and conditions:

Hardware - Waters 2525 Binary Gradient Module - Waters 515 Makeup Pump

- Waters Pump Control Module

- Waters 2767 Inject Collect - Waters Column Fluidics Manager - Waters 2996 Photodiode Array Detector

- Waters ZQ Mass Spectrometer

- Gilson 202 fraction collector

- Gilson Aspec waste collector

Software

Waters MassLynx version 4 SP2

Column

The columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm (small scale) and 30mm x 100mm (large scale). The stationary phase particle size is 5μm.

Solvents

A : Aqueous solvent = Water + 0.1% Formic Acid B : Organic solvent = Acetonitrile + 0.1 % Formic Acid Make up solvent = Methanol : Water 80:20 Needle rinse solvent = Methanol Methods

There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10- minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 = 5-30% B Large/Small Scale 1.5-2.2 = 15-55% B Large/Small Scale 2.2-2.9 = 30-85% B Large/Small Scale 2.9-3.6 = 50-99% B Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate

All of the above methods have a flow rate of either 20mls/min (Small Scale) or 40mls/min (Large Scale).

Liquid Chromatography / Mass Spectrometry (2 min method)

Analysis of the above Examples by Liquid Chromatography / Mass Spectrometry (LC/MS) was carried out using the following apparatus and conditions:

Hardware

- Waters Acquity Binary Solvent Manager

- Waters Acquity Sample Manager - Waters Acquity PDA

- Waters ZQ Mass Spectrometer

- Sedere Sedex 75

Software Waters MassLynx version 4.1

Column

The column used is a Waters Acquity BEH UPLC C18, the dimensions of which are 2.1 mm x 50mm. The stationary phase particle size is 1.7μ m.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid B : Organic solvent = Acetonitrile + 0.05% Formic Acid Weak Wash = 1 :1 Methanol : Water Strong Wash = Water

Method

The generic method used has a 2 minute runtime.

- The above method has a flow rate of 1 ml/min. - The injection volume for the generic method is 0.5ul

- The column temperature is 40deg

- The UV detection range is from 220 to 330nm

Liquid Chromatography / Mass Spectrometry (5 minute method)

Hardware

- Agilent 1100 Gradient Pump

- Agilent 1100 Autosampler - Agilent 1100 DAD Detector

- Agilent 1100 Degasser - Agilent 1100 Oven - Agilent 1100 Controller

- Waters ZQ Mass Spectrometer, Waters ZMD Mass Spectrometer, Waters ZQ2000 Mass Spectrometer or Agilent MSD Mass Spectrometer

- Sedere Sedex 55 / 75 / 85

Software

ZQ1 uses Waters MassLynx version 4.0 SP2 MSD systems use Agilent ChemStation Rev. B.01.01

Column

The column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm. The stationary phase particle size is 3μ m.

Solvents

A1 : Aqueous solvent = Water + 0.1% Formic Acid

B1 : Organic solvent = Acetonitrile + 0.1% Formic Acid A2 : Aqueous solvent = Water + 0.1% TFA B2 : Organic solvent = Acetonitrile + 0.1% TFA

Methods

The generic formic and TFA methods have a 5.5 minute runtime.

Standard 5.5 minute method

- The above method has a flow rate of 3ml/mins.

- The injection volume for the generic method is 5ul

- The column temperature is 30deg

- The UV detection range is from 210 to 350nm

Biotaqe SP4® Biotage - SP4® is an automated purification system. It uses preloaded silica gel columns. The user applies their material to the top of the column and chooses solvents, gradients, flow rates, column size, collection method and eluting volumes.

Phase Separators (Hydrophobic frit)

Phase separators are a range of ISOLUTE® columns fitted with an optimized frit material that easily separates aqueous phase from chlorinated solvents under gravity.

SCX - Strong Cation Exchange cartridge

Where indicated in the examples, an SCX cartridge was used as part of the compound purification process. Typically an ISOLUTE SCX-2 cartridge was used. ISOLUTE SCX-2 is a silica-based sorbent with a chemically bonded propylsulfonic acid functional group.

ISOLUTE SCX-2 Chemical Data Base Material: Silica, 50 μm Functional Group: Propylsulfonic acid Capacity: 0.6 meq/g Counter Ion: Proton

Pharmacological data Compounds of the invention may be tested for in vitro biological activity in the hCay2.2 assay in accordance with the following studies:

Methods Cell biology Stable cell lines expressing the human Cay2.2 α (α1 β) subunit, along with the human β3 and α2δ1 auxiliary subunits were created following sequential transfection and selection of human embryonic kidney (HEK293) cells. HEK293 cells were cultured in Dulbecco's modified Eagles media/F12 media (Invitrogen, Cat # 041 -95750V) containing 10% fetal bovine serum, with added L-glutamine (2 mM; Invitrogen, Cat # 25030-024) and non-essential amino acids (5%; Invitrogen, Cat # 1 1140-035).

Initially HEK293 cells were transfected with two plasmid vectors for expression of the hCa_v2.2 α subunit (pCIN5- hCa_v2.2 which carries a neomycin resistance marker) and the hCa_v β3 subunit (pCIH-hCa_v β3 which carries a hygromycin resistance marker). Clonal cell lines were isolated following selection in media supplemented with 0.4 mg ml^"1 Geneticin G418 (Invitrogen, Cat # 10131-027) and 0.1 mg ml^"1 hygromycin (Invitrogen, Cat # 10687-010). These clonal cell lines were assessed for Ca_v2.2 α/ β3-mediated current expression using the IonWorks planar array electrophysiology technology (described below). A clonal line was identified that gave a reasonable level of functional Ca_v2.2 α/ β3 current expression. This cell line was transfected with a plasmid vector for expression of the human α2δ1 subunit (pCIP-α2δ1 which carries a puromycin resistance marker) and clonal cell lines isolated following selection in media containing 0.62 μg ml^"1 puromycin (Sigma, Cat # P-7255), in addition to 0.4 mg ml^"1 Geneticin G418 and 0.1 mg ml^"1 hygromycin. Several cell lines were identified that gave robust levels of Ca_v2.2 α/ β3/α2δ1 -mediated current expression and one of these was selected for compound profiling. Expression of all three subunits within this cell line was continuously maintained by the inclusion of G418 (0.4 mg ml^"1), hygromycin (0.1 mg ml^"1) and puromycin (0.62 μg ml^"1). Cells were maintained at

37°C in a humidified environment containing 5% CO₂ in air. Cells were liberated from the T175 culture flasks for passage and harvesting using TrpLE (Invitrogen, Cat # 12604-013).

Cell preparation

Cells were grown to 30-60% confluence in T175 flasks and maintained at 30⁰C for 24 hrs prior to recording. Cells were lifted by removing the growth media, washing with Ca²⁺ free PBS (Invitrogen, Cat #14190-094) and incubating with 3 ml of warmed (37°C) TrpLE (Invitrogen, Cat # 12604-013) for 6 minutes. Lifted cells were suspended in 10 ml of extracellular buffer. Cell suspension was then placed into a 15 ml tube and centrifuged for 2 minutes at 700 rpm. After centrifugation, the supernatant was removed and the cell pellet was resuspended in 4.5 ml of extracellular solution.

Electrophysiology

Currents were recorded at room temperature (21-23°C) using the IonWorks planar array electrophysiology technology (Molecular Devices Corp.). Stimulation protocols and data acquisition were carried out using a microcomputer (Dell Pentium 4). In order to determine planar electrode hole resistances (Rp), a 10 mV, 160 ms potential difference was applied across each hole. These measurements were performed before cell addition. After cell addition a seal test was performed prior to antibiotic (amphotericin) circulation to achieve intracellular access. Leak subtraction was conducted in all experiments by applying a 160 ms hyperpolarizing (10 mV) prepulse 200 ms before the test pulses to measure leak conductance. Test pulses stepping from the holding potential (V_H) of -90 mV to +10 mV were applied for 20 ms and repeated 10 times at a frequency of 10 Hz. In all experiments, the test pulse protocol was performed in the absence (pre-read) and presence (post-read) of a compound. Pre- and post-reads were separated by a compound addition followed by a 3-3.5 min incubation.

Solutions and drugs The intracellular solution contained the following (in mM): K-gluconate 120, KCI 2OmM, MgCI₂ 5, EGTA 5, HEPES 10, adjusted to pH 7.3. Amphotericin was prepared as 30 mg/ml stock solution and diluted to a final working concentration of 0.2 mg ml^"1 in intracellular buffer solution. The extracellular solution contained the following (in mΛf): Na-gluconate 120, NaCI 20, MgCI₂ 1 , HEPES 10, BaCI₂ 5, adjusted to pH 7.4.

Compounds were prepared in DMSO as 1OmM stock solutions and subsequent 1 :3 serial dilutions performed. Finally the compounds were diluted 1 :100 in external solution resulting in a final DMSO concentration of 1%.

Data analysis

The recordings were analysed and filtered using seal resistance (>40 MΩ), resistance reduction (>35%) and peak current amplitude (>200pA) in the absence of compound to eliminate unsuitable cells from further analysis. Paired comparisons between pre-compound and post-compound additions were used to determine the inhibitory effect of each compound. The concentrations of compounds required to inhibit current elicited by the 1^st depolarising pulse by 50% (tonic plC50) were determined by fitting of the Hill equation to the concentration response data. In addition the use-dependent inhibitory properties of the compounds were determined by assessing the effect of compounds on the 10^th versus 1^st depolarising pulse. The ratio of the 10^th over 1^st pulse was determined in the absence and presence of drug and the % use-dependent inhibition calculated. The data was fitted using the same equation as for the tonic plC₅₀ and the concentration producing 30% inhibition (use- dependent pUD₃₀) determined.

The compounds of Examples 1 to 68 were tested in the hCa_v2.2 assay in the version as shown in the Examples. The compounds of Examples 1 to 68 exhibited a pUD₃₀ value of 4.5 or more than 4.5. The compounds of Examples 1 to 28, 30, 31 , 34 to 42, and 50 to 67 exhibited a pUD₃₀ value of 5.0 or more than 5.0. The compounds of Examples 1 to 3, 12, 22, 30, 31 and 50 to 53 exhibited a pUD₃₀ value of 5.5 or more than 5.5.

The compounds of Examples 1 to 67 exhibited a mean plC₅o value of 5.0 or less than 5.0. The compounds of Examples 1 to 10, 12, 14 to 21 , 23 to 29, 31 to 67 exhibited a mean plC₅o value of 4.5 or less than 4.5.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

(I) wherein R¹ is halogen, C_1-4 alkyl, C_1-3 alkoxy; n is 0, 1 , 2, 3, 4 or 5; m is 0, 1 , 2, 3 or 4;

XO-CH₂-NH- wherein ^* indicates bonding to the piperazine ring;

R² is C_1-4 alkyl, C_1-3 alkoxy C_1-3 alkyl or hydroxy C_1-4 alkyl;

R³ is hydrogen, halogen, cyano, C_1-4 alkyl, C_1-4 alkoxy or halo C_1-4 alkyl;

R⁴ is hydrogen, halogen, cyano, C_1-4 alkoxy or halo C_1-4 alkyl;

R⁵ is hydrogen, halogen, cyano, C_1-4 alkyl or C_1-4 alkoxy; wherein at least one of R³, R⁴ and R⁵ is a group other than hydrogen; and wherein when R³ or R⁴ are bromo, R⁵ is halogen, cyano, C_1-4 alkyl or C_1-4 alkoxy; with the proviso that the compound is not

4-[(4-chlorophenyl)sulfonyl]-Λ/-(3-methylphenyl)-1-piperazinecarboxamide;

1-[(4-chlorophenyl)sulfonyl]-4-[(2-fluorophenyl)acetyl]piperazine; 1-[(4-chlorophenyl)sulfonyl]-4-[(4-fluorophenyl)carbonyl]piperazine; or

4-{[4-[(3-fluorophenyl)carbonyl]-3-(hydroxymethyl)-1-piperazinyl]sulfonyl}benzonitrile; for use in therapy.

2. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 wherein n is 0, 1 , 2 or 3.

3. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 2 wherein n is 0 or 1 , particularly 0.

4. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 wherein R¹ is selected from fluoro, chloro, bromo, methyl, methoxy, ethoxy and propoxy.

5. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 4 wherein R¹ is selected from fluoro, chloro, ethoxy and methoxy, particularly fluoro.

6. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 wherein R² is C_1-3 alkyl.

7. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 6 wherein R² is selected from methyl, ethyl, hydroxymethyl and methoxymethyl.

8. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 7 wherein R² is methyl or ethyl, particularly methyl.

9. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 wherein X is selected from -CO-, -XONH-, - XH₂-CONH-, -XH₂-CO-, -XO-CH₂-O-, -XO-CH₂-, -XO-CH₂-S-, -XON(CH₃)- and - XH₂-CO-NH-CH₂- wherein ^* indicates bonding to the piperazine ring.

10. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 9 wherein X is selected from -CO-, -XONH- and -XH₂-CONH-, particularly -CO-.

11. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 wherein R³ is selected from hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, cyano and methoxy.

12. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 11 wherein R³ is selected from chloro, trifluoromethyl and cyano, particularly cyano.

13. A compound of formula (I) or pharmaceutically acceptable salt thereof aaccccoorrddiinngg ttoo aannyy oonnee ooff ccllaaiimmss 11 ttoo 12 wherein R⁴ is selected from hydrogen, methoxy, fluoro, chloro and cyano.

14. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 13 wherein R⁴ is selected from hydrogen and cyano, particularly hydrogen.

15. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 wherein R⁵ is selected from hydrogen, methoxy, fluoro, methyl and cyano.

16. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 15 wherein R⁵ is selected from hydrogen, methoxy and fluoro, particularly R⁵ is hydrogen.

17. A compound of formula (I) or pharmaceutically acceptable salt according to any one of claims 1 to 16 wherein m is 0, 1 , 2 or 3.

18. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 17 wherein m is 1 , 2 or 3.

19. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 18 wherein m is 1 or 2, particularly 1.

20. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 wherein

R¹ represents halogen; m represents an integer from 1 or 2; n represents an integer from 0 to 2; X represents a linker selected from -CO-, -XONH- or -XH₂-CONH- wherein ^* indicates bonding to the piperazine ring;

R² represents C_1-4 alkyl; R³ represents hydrogen, chloro (chlorine), fluoro (fluorine), bromo (bromine), cyano or trifluoromethyl;

21. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 wherein a compound or a pharmaceutically acceptable salt thereof is selected from a compound of Examples 1 to 68, or a pharmaceutically acceptable salt thereof.

22. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 wherein the compound is selected from (2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1-piperazinecarboxamide (E1 );

(3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E2); 2-{(2R)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -piperazinyl}-Λ/-phenylacetamide (E3);

(2/?)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E4);

4-{[3-Ethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E5);

(2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl) piperazine (E7); (2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl)piperazine (E8);

(E9);

(2S)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E10);

(3S)-4-[(3-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E 14); (3S)-Λ/-(2,4-Difluorophenyl)-4-[(3-fluorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxamide (E15);

(3S)-3-Methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-Λ/-phenyl-1-piperazinecarboxamide

(E18); (3S)-4-[(4-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E19);

(3S)-4-[(4-Cyanophenyl)sulfonyl]-Λ/-(2,4-difluorophenyl)-3-methyl-1- piperazinecarboxamide (E20);

(3S)-Λ/-(2,4-Difluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-3-methyl-1- piperazinecarboxamide (E21 ); (2S)-2-Methyl-1-(phenylcarbonyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl} piperazine

(E22);

(E23);

(E25);

4-{[3,3-Dimethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E28);

4-{[(3R)-3-Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E29);

(2S)-4-[(4-Bromo-2-methylphenyl)sulfonyl]-2-methyl-1-(phenylcarbonyl)piperazine

(E31 ), or a pharmaceutically acceptable salt thereof.

23. A compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 which is 4-{[(3S)-3-Methyl-4-(phenylcarbonyl)-1- piperazinyl]sulfonyl}benzonitrile (E27) of formula

, or a pharmaceutically acceptable salt thereof.

24. A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 for use in the treatment of pain.

25. Use of A compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 in the manufacture of a medicament for the treatment of pain.

26. A method for the treatment of pain in a human in need thereof comprising administering to said human a therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23.

27. A pharmaceutical composition comprising (a) a compound of formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 and (b) a pharmaceutically acceptable excipient.

28. A compound of formula (I), or a salt thereof, according to claim 18 or 19.

29. A compound of formula (I) or salt thereof according to claim 28 wherein R¹ represents halogen; m represents an integer from 1 or 2; n represents an integer from 0 to 2; X represents a linker selected from -CO-, -XONH- Or -XH₂-CONH- wherein ^* indicates bonding to the piperazine ring; R² represents C_1-4 alkyl;

30. A compound of formula (I) or salt thereof according to claim 28 wherein a compound or a salt thereof is selected from a compound of Examples 1 to 68, or a salt thereof.

31. A compound of formula (I) or salt thereof according to claim 28 wherein the compound is selected from (2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-Λ/-phenyl-1-piperazinecarboxamide (E1 ); (3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1-piperazinecarboxamide (E2);

2-{(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1-piperazinyl}-Λ/-phenylacetamide (E3);

(2/?)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E4);

4-{[3-Ethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E5); 2-{(3S)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1-piperazinyl}-Λ/-phenylacetamide (E6);

(2S)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1 -(phenylcarbonyl) piperazine (E7);

(2/?)-4-[(4-Chlorophenyl)sulfonyl]-2-methyl-1-(phenylcarbonyl)piperazine (E8);

(E9); (2S)-1-[(4-Chlorophenyl)sulfonyl]-2-methyl-4-(phenylcarbonyl)piperazine (E10);

2-{(3R)-4-[(4-Chlorophenyl)sulfonyl]-3-methyl-1-piperazinyl}-Λ/-phenylacetamide

(E1 1 );

(3S)-Λ/-(2,4-Difluorophenyl)-3-methyl-4-{[3-(methyloxy)phenyl]sulfonyl}-1- piperazinecarboxamide (E17);

(E18);

(3S)-4-[(4-Fluorophenyl)sulfonyl]-3-methyl-Λ/-phenyl-1 -piperazinecarboxamide (E19);

(2S)-2-Methyl-1-(phenylcarbonyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl} piperazine

(E22); 4-({(3S)-4-[(3-Fluorophenyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl) benzonitrile

(E23);

(E24);

(2/?)-2-Methyl-1 -(phenylcarbonyl)-4-{[4 (trifluoromethyl)phenyl]sulfonyl} piperazine (E25);

(E26);

4-{[(3S)-3-Methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E27);

4-{[3,3-Dimethyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile (E28); 4-{[(3R)-3-Methyl-4-(phenylcarbonyl)-1 -piperazinyl]sulfonyl}benzonitrile (E29);

(2S)-4-[(4-Bromo-2-methylphenyl)sulfonyl]-2-methyl-1-(phenylcarbonyl)piperazine

(E30); and

3-Methyl-4-{[(3S)-3-methyl-4-(phenylcarbonyl)-1-piperazinyl]sulfonyl}benzonitrile

(E31 ), or a salt thereof.

32. A compound of formula (I) or salt thereof according to claim 28 which is 4-

{[(3S)-3-Methyl-4-(phenylcarbonyl)-1 -piperazinyl]sulfonyl}benzonitrile (E27) of formula

, or a salt thereof.

33. A compound of formula (I) or salt thereof according to any one of claims 28 to 32 wherein the salt is a pharmaceutically acceptable salt.