NZ523141A

NZ523141A - 3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity

Info

Publication number: NZ523141A
Application number: NZ523141A
Authority: NZ
Inventors: Bernard Joseph Banks; Douglas James Critcher; Ashley Edward Fenwick; David Morris Gethin; Stephen Paul Gibson; Graham Lunn
Original assignee: Pfizer
Priority date: 2000-06-23
Filing date: 2001-06-07
Publication date: 2005-06-24
Also published as: AR028969A1; BG107329A; HUP0301228A2; HUP0301228A3; YU91802A; PL365956A1; IS6637A; UY26787A1; EA200201269A1; DZ3368A1; PE20020253A1; IL153427A0; SK17172002A3; AU6259101A; BR0111867A; NO20026168L; MXPA02012878A; ZA200210278B; EA005117B1; AP2002002698A0

Abstract

A substance which is a compound of formula I, a process for its preparation and derivatives of compounds of formula I are disclosed. The substance is useful in the treatment of a condition mediated by opiate receptors.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 523141 52 WO 01/98267 PCT/IBO1/01035 3-AZABICYCLO (3.1.0) HEXANE DERIVATIVES HAVING OPIOID RECEPTOR AFFINITY This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors). Compounds that bind to 5 such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, 0 spinal damage and head trauma. There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be 5 caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections. Existing treatments that have been employed in the treatment of pruritus include the use of 3 corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatly acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success. j Thus, there is a continuing need for alternative and/or improved treatments of pruritus. Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. In addition, ) International Patent Application WO 95/15327 discloses azabieycloalkane derivatives useful as neuroleptic agents. International Patent Application WO00/39089, filed before the priority date of the instant application, but published thereafter, is herein incorporated by reference in its entirety, and WO 01/98267 2 PCT/IB01/01035 discloses azabicycloalkanes of similar structure to those described hereinbelow, with different R^ groups. According to the invention there is provided a compound of formula I, wherein the "Ar" ring represents an optionally benzo-fused phenyl or 5- or 6-membered heteroaryl ring; Rl when taken alone is H, halogen, NO2, NH2, NY2WYl, Hetl, AD, C02R7, C(0)r8, C(=NOH)R8, orOE, Y2 is H, Cj.g alkyl, C3.6 alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Hetl), W is SO2, CO, C(0)0, P(Yl)=0, P(Y1)=S, Yl is Cj.io alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, Ci_4 alkoxy, Ci_6 alkanoyloxy, CONH2, Cj.g alkoxycarbonyl. NH2, aryl, mono- or di(Ci_4 alkyl)amino, C3.8 cycloalkyl, phthalimidyl, Hetl), Hetl, gj-yi (optionally substituted by one or more substituents independently selected from Cj_4 alkyl, Cj.4 haloalkyl and halogen), NH2, N(Ci_g alkyl)2 or NH(Ci_6 alkyl), Hetl is a "heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-fosed heteroaryl), optionally substituted by one or more substituents independently selected from Ci_g alkyl, Cj-6 alkoxy, C3.6 cycloalkyl, Cj.6 baloalkoxy, Ci-g haloalkyl, C3.6 halocycloalkyl, -O, OH, halogen, N02, SiRl9aRl9bR19c, CONR20flR20b, NR20aR20b SR21a NR21bso2R22a NR21<?C(0)0R22b, NR21dcORm5 and Ci.g alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a -S-, S(0)- or -S(C>2)- group, and carbon atoms in the ring can be present as a part of a carbonyl moiety, Rl9a, Rl9b r19c each independently represent C1.6 alkyl or aiyl, R20a and R20b each independently represent H, Ci-6 alkyl, aryl, (Cj^ alkyl)phenyl, each of which alkyl, aiyl and alkylphenyl are optionally substituted by one or more Cj_4 alkyl, Ci_4 alkoxy, OH, NO2. NH2 and/or halogen, or R20a and R2^b can be taken together with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substitutuents independently selected from one or more Ci_4 alkyl, C1.4 alkoxy, OH, =0, NO2, NH2 and/or halogen, R21a, b, c and d each independently represent H, Cj-g alkyl, aryl or Cj_4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Cj_4 alkyl, Ci_4 alkoxy, OH, NO2, halogen, NH2, R22a, b and c each independently represent Cj-g alkyl, aryl or Ci_4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Cj-4 alkyl, Cj.4 alkoxy, OH, N02, halogen, NH2, A is Cj_4 alkylene, C2-4 alkenylene or C2_4 alkynylene, each of which is optionally substituted by one or more Ci-4 alkyl, C1.4 alkoxy, halogen and/or OH, D is H, OH, CN, NR25R26, c0NR25r26 NHR27, C02R28, COR29 C(==NOH)R29) or AD is CN, NR25r26, CONR^R2^, where R25 and R26 are either each independently H, Cj_3 alkyl, C3_g cycloalkyl, aryl, alkylphenyl (each of which c1.3 alkyl, C3_g cycloalkyl, aryl and C1.4 alkylphenyl are optionally substituted by one or more nq2, halogen, Cj-4 alkyl and/or C1.4 alkoxy, (each of which latter C1.4 alkyl and C1.4 alkoxy is optionally substituted by one or more halogen)), WO 01/98267 4 PCT/IBO1/01035 or and R26 aTe taken together with the N atom to which they are attached and can form a 4- to 7-membered heterocyclic ring optionally incorporating one or more further hetero atoms selected from N, O and S, and which ring is optionally substituted by one or more Ci_ 4 alkyl, OH, =0, NO2, NH2 and/or halogen, R27 is COR30, C02R31a, SO2R3113, R28 and R29 Ire each independently H, alkyl, C3_g cycloalkyl, aryl or Ci_ 4alkylphenyl, each of which Cj.6 alkyl, C3.§ cycloalkyl, aryl and Cj_4 alkylphenyl are optionally substituted by one or more NO2, halogen, C^_4 alkyl, C1.4 alkoxy (each of which latter C1.4 alkyl and Ci_4 alkoxy are optionally substituted by one or more halogen), R30 is H, Ci_4 alkyl, C3_g cycloalkyl, C1.4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, C1.4 alkylphenyl, phenyl(C 1.4 )alkoxy, (each of which Cj_4 alkyl, C3.8 cycloalkyl, Ci_4 alkoxy, C3-8 cycloalkyloxy, aiyl, aryloxy, C1.4 alkylphenyl and phenyl(Ci_4 )aIkoxy are optionally substituted by one or more NO2, halogen, C1.4 alkyl, Cj_4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)), R31a JR.3 lb are each independently Cj.4 alkyl, C3-8 cycloalkyl, aryl or C1.4 alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, C1.4 alkyl or C\j± alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen E is H, CONR32R33, CSNR32R33, COR34, C02R345 COCH(R34a)NH2, R35, CH2C02R35as CHR35bC02R35a, CH20C02R35c, CHR35d0C02R35c, COCR36=cr37nh2, COCHR36CHR37nh2j or PO(OR38)2, R32 and R33 are each independently H, C3.40 alkylalkenyl, C3.7 cycloalkyl (optionally substituted by Ci_4 alkyl), phenyl (optionally substituted by (X)n), alkyl (optionally substituted by C4.7 cycloalkyl (optionally substituted by Cj_4 alkyl) or phenyl optionally substituted by (X)n), or R32 and R33 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising further hetero atoms selected WO 01/98267 5 PCT/IB01/01035 from N, O and S, which heterocycle is optionally substituted by Ci-4 alkyl, optionally substituted by one or more halogen, R34 is H, C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), phenyl (optionally substituted by (X)n, C1.4 alkanoyloxy, NR.32r33; CONR32r33 and/or OH), or Ci_6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or mote Ci_4 alkyl), or phenyl (optionally substituted by (X)n, Cj_4 alkanoyloxy, NR32r33s coNR32r33 anj/or OH)), R34a is jj5 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), or phenyl (optionally substituted by (X)n, Cj_4 alkanoyloxy, NR32r33; G0NR32r33 and/or OH)), C4.7 cycloalkyl (optionally substituted by one or more Cj_4 alkyl), phenyl (optionally substituted by (X)n, Ci_4 alkanoyloxy, kr32r33= CONR32r33 and/or OH) or a naturally occuring amino acid substituent, R35 is C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl (optionally substituted by one or more (X)n, Cj_4 alkanoyl, NH0R.32, CON(R32)2, and/or OH), Ci_6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl (optionally substituted by one or more (X^, C1.4 alkanoyl, NHR32; CON(R32)2, and/or OH)), C1.4 alkoxy(Ci_4 alkyl), phenyl(C 1 _4)alkyloxy(C\ _4)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, R35a,b,c and d are each independently H, C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl optionally substituted by one or more (X)n or C\.q alkyl (optionally substituted by C4-7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl optionally substituted by one or more (X)n), R36 and R37 each independently represent H, C3.6 alkylalkenyl, C4.7 cycloalkyl, phenyl optionally substituted by one or more (X)n, or Ci_6 alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl optionally substituted by one or more (X)n), R38 is C4.7 cycloalkyl optionally substituted by one or more Cj_4 alkyl, phenyl optionally substituted by one or more (X)n, or alkyl (optionally substituted by C4.7 cycloalkyl WO 01/98267 6 PCT/IB01/01035 optionally substituted by one or more Cj_4 alkyl, or phenyl optionally substituted by one or more (X)n), R2 when taken alone is H or halogen; or R* and R2, when attached to adjacent Carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Het^a; Het*a is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5- to 7-membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, =0, halogen, Cj_4 alkyl, C}_4 haloalkyl, C1.4 alkoxy and Ci .4 haloalkoxy, which Ci_4 alkyl, C1.4 haloalkyl, Cj_4 alkoxy and C1.4 haloalkoxy groups can be optionally substituted by one or more C3.6 cycloalkyl, aryl(Ci_6)alkyl, which aryl group is optionally substituted by one or more halogen, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and C1.4 haloalkoxy, which latter C1.4 alkyl, C1.4 haloalkyl, Cj_4 alkoxy and Cj_4 haloalkoxy groups can be optionally substituted by one or more NR23r24 NR23s(0)nR24s NR23c(0)mR24, and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(02)- group, which R23 and r24 when taken alone independently represent H, C|_4 alkyl, or C1.4 haloalkyl, or r23 and R24 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, C1.4 alkyl, C|_4 haloalkyl, C1.4 alkoxy and/or C1.4 haloalkoxy groups, R3 is H, CN, halogen, Ci_g alkoxy, Ci_g alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3.8 cycloalkyl, C3_g cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12r13j CONR12r13j NY2WY1, Ci_6 alkyl, C2-10 alkenyl, C240 alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, Cj.g alkoxy, Ci_6 alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, C]_g 7 alkanoyl, C\-6 alkanoyloxy, C3.8 cycloalkyl, C3_g cycloalkyloxy, c4.9 cycloalkanoyl, aryl, aiyloxy, heteroaryl, saturated heterocycle, NR12r13, C0NR12r13 and/or NY^WY^), R4 is Ci_io alkyl, C3.10 alfeenyl or C3.10 alkynyl, each of which groups is linked to the N 5 atom via a sp3 carbon, and which group is substituted by one or more substituents selected from: C^alkoxy [substituted by one or more groups selected from OH, NR25r26> CONR25r26j halogen, Cj-g alkoxy, C2-4 alkynyl, C2-4 alfeenyl, heteroaryl1, aryl*, coch2cn, 10 COCheteroaryl1), COCaiyl1), c02(heteroaryll), coch2(aiyl1), coch2(heteroaryl1), c02ch2(aryll), c02ch2(heteroaryll), S(0)n(Ci_6 alkyl), S(0)n(aryll), S(0)n(heteroaryll), S02NR25R26 , a cycloalkyl group that is a C3.10 carbocyclic system with one or two rings and cycloalkyl1], S(0)nCi_6 alkyl [optionally substituted by one or more groups selected from OH, Nr25r26j .5 CONR.25r26j halogen, Cj.6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl*, aiyll, COCH2CN, CO(heteroaryl^), CO(aryU), C02(heteroaryll), COCH2(aryll), coch2(heteroaryll), CX>2CH2(aryl1), c02ch2(heteroaiyl 1), S(0)n(Ci_g alkyl), S(0)n(aryll), S(0)n(heteroaxyll), S02NR.25r26 an(i cycloalkyl I], 0 aryl2, C02CH2(heteroary 1 *), C02CE2(aiyl1), cycloalkyl^, a cycloalkyl group that is a C3_i0 carbocyclic system with one or two rings and cycloalkyl1], CO(heteroaryU), 5 CO(aiyll), OCO(aiyll), OCOfheteroarvll). "j'wiu^l PROPERTYQFFICE OF N.Z. 2 3 MAR 2005 I - REGPiwerp I 8 S(0)nCH2(heteroaiyl1)' NHS02aiyl1, NHS02(heteroaryll), S NHS02CH2(heteroaryll), NHS02CH2(aryll), NHCOaryll, NHCONHatyl1, nhconh(ci_6 alkyl), NHCOheteroaryl1, NHCONHheteroaiyll, NHC02(aryl1), 15 NHC02(heteroaryll), aryl2oxy, heteroaxylloxy, Ci_6 alkoxycarbonyl substituted by Ci-6 alkyl, aryl, Ci-g alkoxy, CH2(aryll), Cj.4 haloalkyl, halogen, OH, CN or NR25r26s iO C2-6 alkanoyl substituted by Ci„6 alkyl, aiyl, Cj.g alkoxy, CH2(aiyll), Ci_4 haloalkyl, halogen, OH, CN or NR25r26# C2-6 alkanoyloxy substituted by C\^ alkyl, aiyl, Cj_6 alkoxy, CH2(aiyl^), Cj^j haloalkyl, halogen, OH, CN or NR25r26 cycloalkyl^oxy, 15 COcycloalkyll, heterocycle substituted by one or more substituent selected from Ci_6 alkyl(substituted by OH), CONR25R26 CH2CONR25r26>nr25r26>nhCONR25r26 C0(Cj.6 alkyl), S02NR25r26 S02(Ci_6 alkyl), CO^Ci.6 alkyl), CH2C02(Cl.6 alkyl), OCH2C02(CU alkyl), aiyl, heterocyclyl, aryloxy, aryl(CH2)oxy, aiyl(CH2)» CN and c3.7 cycloalkyl, iO heterocyclyloxy substituted by one or more substituent selected from Ci_£ alkyl(substituted by OH), CONR25r26 CH2CONR25r26) NR25r26, NHC0NR25r26# CO(C W alkyl), S02NR25R26, S02(Ci_6 alkyl), C02(Ci_6 alkyl), CH2C02(Ci.6 alkyl), 0CH2C02(Ci^ alkyl), aiyl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, 5 1 '^TEUECTUAi PROPER] y , OF N.Z. ^ ^ mar 2005 V£D 9 WHEREIN aiyl1 is phenyl optionally fiised to a C5.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C].g alkyl(optionally substituted by OH, CN or halogen), Ci_g haloalkoxy, OH, <0, NY^WY 1, halogen, Ci-6 alkoxy, CONR25R26, CH2C0NR25r26 Nr25r26, NHC0NR2Sr26, C0(C^ alkyl), 5 COaiyl, COheteroaryl, S02NR25r26j S(0)n(Ci.g alkyl), S(0)n(aryl), S(0)n(heteroaryl), C02(Ci.6 alkyl), C02(aryl), C02(heteroaiyi), C02H, (CH2)l-4C02(Ci_6 alkyl), (CH2)i. 4CO2H, (CH2)i-4C02(aiyl), (CH2)MC02(heteroaiyl), 0(CH2)i-4C02(Ci-6 alkyl), 0(CH2)i^C02H; 0(CH2)i-4C02(aryl), 0(CH2)i^C02(heteroaryl), aryl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aiyl(CH2), CN, 0(CH2)i-4C0NR25r26 and C3.7 cycloalkyl, ) aiyl2 is phenyl optionally fused to a C5.7 carbocyclic ring, which group is substituted by one or more substituent selected from Cj.6 alkyl(substituted by OH), CONR25r26) CH2CONR25r26j nr25r26 NHCONR25r26j C0(Ci-6 alkyl), COaiyl, COheteroaryl, S02NR25r26 S(0)n(Ci.<5 alkyl), S(0)n(aiyl), S(0)n(heteroaryl), C02(Ci_6 alkyl), 5 C02(aryl), C02(heteroaryl), C02H, (CH2)i-4C02(Ci^ alkyl), (CH^a^H, (CH2)l-4C02(axyl), (CH2)i-4C02(heteroaryl)J 0(CH2)i_4C02(Ci_6 alkyl), 0(CH2)WC02H, 0(CH2)i^C02(aryl)s 0(CH2)i^C02(heteroaryl), aryl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aiyl(CH2), CN, 0(CH2)i^C0NR25r26 and C3.7 cycloalkyl, 3 heteroaryl^ is heteroaryl optionally fused to a C5.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from Ci_6 alkyl(optionally substituted by OH, CN or halogen), Cj.g haloalkoxy, OH, =0, NY2WY1, halogen, Ci_6 alkoxy, CONR25R26 CH2C0NR25r26 nr25r26 NHCONR2%26 co(Ci.6 alkyl), COaryl, COheteroaryl, S02NR25r26j S(0)n(Ci_6 alkyl), S(0)n(aiyl), S(0)n(heteroaryI),' 5 C02(Ci.6 alkyl), C02(axyl), C02(heteroaryl), CO2H, (CH2)mC02(Ci^ alkyl), (CH2)i. 4CO2H, (CH2)i^C02(aiyI), (CH^ i^C02(heteroaryl), 0(CH2)i-4C02(Ci_6 alkyl), 0(CH2)i_4C02H, 0(CH2)i-4C%(aiyl), 0(CH2) 1 ^j.C02(heteroaiyl), aryl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aiyl(CH2), CN, 0(CH2)i^CONR25r26 and C3.7 cycloalkyl, ) cycloalkyl^ is a C3.10 carbocyclic system with one or two rings and which is substituted by Ci-6 alkyl, aiyl, alkoxy, CH2(aryll), Ci_4 haloalkyl, halogen, OH, CN otNR25r26s WITH THE PROVISO THAT THERE ARE NO N-R4 GROUTS WHEREIN THERE IS A HETERO-ATOM LINKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 MAR 2005 RECEIVED 10 Rl2 and Rl3 each independently represent H or Ci_4 alkyl, or Rl2 aad Rl3 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from NR16,0 and/or Si and which is optionally substituted by one or more C1-4 alkyl, r5 and R^ when taken separately are each independently H, alkyl, R5 and R^ can be taken together with the carbon atoms to which they are joined to form a s C3.8 cycloalkyl ring, r7> r9 and RW when taken separately are H, R5 and R*> orR^ can be taken together with (he carbon atoms to which they are joined to form a C3.8 cycloalkyl ring, X is halogen, C1-4 alkyl, C1.4 alkoxy, Cj_4 haloalkyl or Cj_4 haloalkoxy, mis 1 or 2; n is 0,1 or 2; q is 0 or 1; "Naturally occuring amino acid substituent" means the a-substituent that occurs in any (me of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline; "Heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part ©fas', S(0)- or -S(0)2- group, and which may be joined to the remainder of the compound via any available atom(s); "Heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected fromN, O and S and up to IB ring carbon atoms; INTELLECTUAL PROPERTY umut OF N.2 2 3 MAR 2005 Dcr.eiupn n "Aiyl", including in the definitions of "aiyloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.); "Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows; "Cycloalkyl" groups can be polycycHc if the number of carbon atoms allows; or a pharmaceutical^ or veterinarily acceptable derivative or prodrug thereof; provided that the one or more substituents on the group R4 include at least one group that is not one of the following: (i) Ci-6 alkoxy (substituted by a single substituent that is an unsubstituted aryl1 group); A A (ii) aryl oxy, aryl, heteroaryloxy, heterocycle (which latter four groups are substituted by one or more substituents which are NHCONR^R26 groups, wherein R25 and R26 are independently H or C1.3 alkyl, or R25 and R , together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring); (iii) CCXheteroaryl1), COCH2(heteroaryl1), S(0)n(heteroaryl1), S(0)nCH2(heteroaryl1) (in which latter four groups heteroaryl1 represents a 4- to 7-membered heterocycle comprising a N-atom (via which atom the heteroaryl1 group is attached) and optionally comprising a further hetero moiety selected from NH, N(Cj.6 alkyl), N(C3_7 cycloalkyl), O or S, which heterocycle is optionally substituted by one or more alkyl groups); (iv) heteroaryloxy, wherein heteroaryl1 is unsubstituted or substituted by one or more substituents which are alkyl (optionally substituted by one or more substituents which are CN and/or halogen), Cm alkoxy, CM haloalkoxy, OH, =0, NY2WY1 and/or NHCONR^R26 INTELLECTUAL PROPERTY OFFICE OF N.Z 2 3 MAR 2005 RICEiven 11a (wherein R25 and R26 are independently H or C1.3 alkyl, or R25 and R26, together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring)); (v) NHS(0)2(aryl1), NHCO(aryl1), NHC02(aryl1) (in which latter three groups aryl1 is unsubstituted or is substituted by one or more substituents which are alkyl, Cm haloalkyl and/or halogen); (vi) NHS(0)2CH2(aryl1) (in which aryl1 is unsubstituted); (vii) NHCOflieteroaryl1), NHC02(heteroaryl1), NHS(0)2(heteroaryl1), NHS(0)2CH2(heteroaryl1) (in which latter four groups heteroaryl1 is unsubstituted or is substituted by one or more substituents which are C1.6 alkyl, Cm haloalkyl, Cm alkoxy, C3.6 cycloalkyl, Cm haloalkoxy, =0, OH, halogen, S(aryl), S(Cm alkyl), C02(C,.5 alkyl), CONR25R26 and/or NR25R26 (in which latter two groups, the groups R25 and R26 are either each independently H, C1.3 alkyl, aryl, Cm alkylphenyl (each of which C1.3 alkyl, aryl and Cm alkylphenyl are optionally substituted by one or more substituents which are N02, halogen, Cm alkyl and/or Cm alkoxy), or R25 and R26 are taken together with the N atom to which they are attached and can form a 4- to 6-membered heterocyclic ring, which ring is optionally substituted by one or more Cm alkyl, OH, =0, N02, NH2 and/or halogen)). Where a fused heterocyclic group is present it can be attached to the remainder of the compound via any available atom(s). "Haloalkyl'1, "haloalkoxy" groups and the like can contain more than one halogen and for instance can be per-halogenated. WO 01/98267 12 PCT/IB01/01035 Certain of the compounds of the invention can exist in one or more geometric and/or stereoisomeric forms. The present invention includes all such individual isomers and salts and prodrugs thereof. 5 Certain compounds of the present invention may exist in more than one tautomeric form. Similarly certain compounds of the invention may have zwitterionic forms. It is to be understood that the invention embraces all such tautomers, zwitterions and their derivatives. The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid 10 addition and the base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate aiid g-toluenesulphonate salts. Suitable base salts are formed from bases 15 which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review on suitable salts see Berge et al> J. Phaim. Sci., 66, 1-19 (1977). It will be appreciated by those skilled in the art that certain protected derivatives of !0 compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be transformed after administration into or onto the body, for example by metabolism, to form compounds of formula (I) which are pharmacologically active. Such derivatives are included in the term "prodrug". It will further be appreciated by those skilled in the art that certain moieties .5 known to those skilled in the art as "pro-moieties", for example as described in "Design of Prodrugs" by H Bundgaard (Elsevier) 1985, may be placed on appropriate functionalities when such functionalities are present in compounds of formula (I), also to form a "prodrug". Further, certain compounds of formula I may act as prodrugs of other compounds of formula I. All protected derivatives, and prodrugs, of the compounds of formula I are included within the 0 scope of the invention. Preferably the " Ar" ring represents phenyl or pyridyl. Most preferably the " Ar" ring represents a group of formula: 5 WO 01/98267 13 PCT/IBO1/01035 R2 Preferably R* when taken alone is OH, CN, halogen, NO2, NH2, NY2WY1 or Hetl. More preferably Rl when taken alone is OH, CN, I, CI, NH2, NO2, optionally benzo-fused heteroaryl, NHS02Yl, NHCOYl or NHCO2Y1. Yet more preferably Rl when taken alone is OH, CN, I, CI, NH2, N02,l,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHS02(Ci_6 alkyl), NHS02(C]_6 alkyl substituted by methoxy, CONH2, OH, C02(C2-6 alkyl), phthalimido, NH2 or halogen), NHSO2NH2, NHS02NH(Ci_6 alkyl), NHS02N(Cj.6 alkyl)2, NHS02Hetia, NHCO(Ci_6 alky]) orNHC02(C1.6 alkyl). Even more preferably Rl is OH, NHSO2CH3, NHS02C2H5, NHS02(n-C3H7), NHS02(i-C3H7), NHS02(n-C4H7), NHS02NH(i-C3H7), NKS02(N-methyliTmdazol-4-yl), NHS02(CH2)20CH3, NHS02(CH2)2OH, 1,2,4-triazolyl or imidazol-2-yl. Most preferably Rl is OH, NHSO2CH3, NHSO2C2H5 or imidazol-2-yl. Preferably R2 when taken alone is H. Rl and R2 when taken together with the carbon atoms to which they are attached are preferably an optionally benzo-fused 5- to 7-membered heteroaiyl ring optionally substituted by C 1.4 alkyl or C 1.4 haloalkyl. More preferably Rl and r2 when taken together with the carbon atoms to which they are attached are a 5-membered heteroaryl moiety optionally substituted by C1.4 alkyl or C1.4 haloalkyl. Yet more preferably R* and R2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF3. Preferably X is CI. 14 Preferably n is 0. Preferably q is 0. Preferably R3 is H, CN, Ci_6 alkyl (optionally substituted by one or more halogen, OH, Ci> 6 alkoxy, alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C2-6 alkyloxycarbonyloxy, NR12R13, CONRl2R!3 and/or NY^WYl). More preferably R3 is H, CH3, C2H5, i-C3H7, n-C3H7 or CH20CH3-Most preferably is CH3. Preferably R4 is Cj.io alkyl substituted by one or more substituents selected from: C2-6 alkoxy [substituted by one or more groups selected from OH, NR2%269 C0NR25r26j halogen, Ci.<j alkoxy, C%4 alkynyl, C2-4 alkenyl, heteroaiyl 1, aiyl1, COCH2CN, CO(heteroaryll), CO(aiyll), C02(heteroaryl1), coch2(aryl!), coch2(heteroaryl 1), c02ch2(aryll), C02CH2(heteroaiyll), S(0)n(Ci.6 alkyl), S(0)n(aiyll), S(0)n(heteroaiy11), S02NR25R26 , a cycloalkyl group that is a C3.10 carbocyclic system with one or two rings and cycloalkyl'], S(0)aCi_6 alkyl [optionally substituted by one or more groups selected from OH, NR25R26) CONR25r26} halogen, Cj.6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaiyl!, aiyl!, coch2cn, CO(heteroaryll), CO(aryll), C02(heteroaryll), coch2(aryll), coch2(heteroaryll), C02CH2(aryl1)J C02CH2(heteroaryl!), S(0)n(Ci_6 alkyl), S(0)n(aryll), S(0)n(heteroaryll), S02NR25r26 and cycloalkyl!], aiyl2, C02CH2(heteroaiyl 1), C02CH2(aryll), cycloalkyl1, a cycloalkyl group that is a C3-10 carbocyclic system with one or two rings and cycloalkyl1], CO(heteroaiyl!), CO(aryll), OCO(aiyll), OCO(heteroaryl!), OCO(Ci.6 alkyl), OCOCH2CN. C02(heteroaryl!), 15 C02(aiyll), COCH2(heteroaryl1), S^aiyl1, S(0)nCH2aryll, S(0)n(heteroaiyl 1), SfOn^Cheteroaiyl1), NHS02aryll, NHS02(heteroaryl 1), NHS02CH2(heteroaiyll), NHS02CH2(aiyll), NHCOaiyll, NHCONHaiyll, NHCOheteroaiyl I, NHCONHheteroaryl 1, NHC02(aiyll), NHC02(heteroaryll), aryl2oxy, heteroaryl loxy, Ci-6 alkoxycarbonyl substituted by Ci-6 alkyl, aryl, Ci_g alkoxy, CH2(aryll), Ci_4 haloalkyl, halogen, OH, CN orNR25R26, C2-6 alkanoyl substituted by Ci_g alkyl, aiyl, Ci^ alkoxy, CH2(aiyll), Cj^j. haloalkyl, halogen, OH, CN or NR25r26s C2.6 alkanoyloxy substituted by Ci_g alkyl, aiyl, Cj-6 alkoxy, CH2(aiyll), Ci_4 haloalkyl, halogen, OH, CN or NR25r26( cycloalkyloxy, COcycloalkyll, heterocycle substituted by one or more substituent selected from C]_6 alkyl(substituted by OH), CONR25R26 CH2C0NR25r26, NR25r26, NHCONR25r26 CO(Ci.g alkyl), S02NR.25r26 S02(Ci_6 alkyl), COtfC^ alkyl), CH2C02(CW alkyl), 0CH2C02(Ci^ alkyl), aiyl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aryXm^V 2 3 MAR 2005 RECEIVED WO 01/98267 16 PCT/IB01/01035 heterocyclyloxy substituted by one or more substituent selected from Cj_6 alkyl(substituted by OH), CONR.25R26 CH2C0NR25r26; nr25r26 HHC0NR25r26 CO(Ci_6 alkyl), S02NR25R26, S02(Ci_6 alkyl), C02(Ci_6 alkyl), CH2C02(Ci_6 alkyl), 0CH2C02(Ci_6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryI(CH2), CN and C3.7 cycloalkyl, More preferably R4 is C]_io alkyl substituted by cycloalkyl 1. Yet more preferably R4 is C2-4 alkyl substituted by cycloalkyl^. Further more preferably R4 is propyl substituted by cycloalkyl 1. Furthet yet more preferably R4 is propyl substituted by a C3.10 carbocyclic system with one or two rings and which is substituted by OH. Even more preferably R4 is propyl substituted by (cyclohexyl substituted by OH) Most preferably R4 is (1 -hydroxycyclohexyl)prop-3 -yl. Another preferred group of compounds are those wherein R4 takes the values as specified in the Examples 145-203 below. Preferably R5, r65 r7, r8 r9 and r10 are each taken separately and are H. A preferred group of substances are those in which the" Ar" ring, Rl, R2, r3, R4, r5} r6} R?, R§, R^, r10, q and (X)n have the values as detailed in the Examples below. The invention further provides synthetic methods for the production of compounds and salts of the invention, which are described below and in the Examples and Preparations. The skilled man will appreciate that the compounds of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, VCH (1989 or later editions), WO 01/98267 17 PCT/IBO1/01035 "Advanced Organic Chemistry - Reactions, Mechanisms and Structure", J.March, Wiley-Interscience (3rd or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), 5 "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide. It is to be understood that the synthetic transformation methods mentioned herein are 0 exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound. For example, substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinafter in conjunction with a 5 particular reaction. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The 0 procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter. It will be apparent to those skilled in the art that sensitive functional groups may need to be 5 protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons hie (1999), and refernces therein. Functional groups which may desirable to protect include oxo, hydroxy, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (e.g. 0 ethylene ketals) and dithianes. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. fert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include Cj.g alkyl or benzyl esters. WO 01/98267 PCT/IB01/01035 18 In the Methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I). The invention provides a process for the preparation of compounds of formula I as defined 5 above, or a pharmacutically or veterinarily acceptable derivative thereof, which comprises: (a) for compounds of formula I in which q is 0 and Rl represents NY2WY1, reacting a compound of formula II, ' with a compound of formula III, ) Zl-WYl m wherein is a suitable leaving group, such as halogen or Y^S020-; (b) for compounds of formula I in which q is 0 and R*> and R? both represent H, reduction of a compound of formula IV, ; using a suitable reducing agent; (c) for compounds of formula I in which q is 0 and R^ and R^ both represent H, reduction of a compound of formula V, WO 01/98267 19 PCT/IBO1/01035 using a suitable reducing agent; (d) for compounds of formula I in which q is 0 and Rl and R2 are attached to adjacent carbon atoms and are taken together with the carbon atoms to which they are attached to 5 represent Het*a, in which Het*a represents an imidazolo unit, reaction of a corresponding compound of formula VI, VI with a compound of formula VII, Ryco2H vn 3 wherein Ry represents H or any of the optional substituents on Hetla (as defined above), preferably H, C \ .4 alkyl or C1.4 haloalkyl; (e) where q is 0, reacting a compound of formula VIII, WO 01/98267 20 PCT/IB01/01035 vin with a compound of formula IX, R4-Lg IX wherein Lg is a leaving group; 5 (f) for compounds of formula I in which q is 0 and R^, r7= r9 ancj rIO are au reduction of a compound of formula X, with a suitable reducing agent; (g) for compounds of formula I in which q is 0 and R^ represents OH, reacting a compound of formula II in which is H, as defined above, with fluoroboric acid and .0 isoamyl nitrite; WO 01/98267 21 PCT/IB01/01035 (h) for compounds of formula I in which q is 0 and Rl represents CI, reacting a compound of formula II in which Y2 is H, as defined above, with sodium nitrite in the presence of dilute acid, followed by reaction with copper (I) chloride in the presence of concentrated acid; 5 (i) for compounds of formula I in which q is 1, reacting a compound of formula I where q is 0 with a suitable oxidising agent such as aqueous hydrogen peroxide; (j) for compounds of formula I where q is 0, by reduction of a corresponding compound of formula XXXI, where R4aCH2 takes the same meaning as R4 as defined above; or (k) for compounds of formula (I) where q is 0, reductive amination reaction of the :o amine of formula VIII above with an aldehyde of formula R4a-CHO wherein R4aCH2 takes the same meaning as R4 as defined above, and where desired or necessary converting the resulting compound of formula I into a pharmaceutical^ or veterinarily acceptable derivative or vice versa. :5 In process (a), the reaction may be carried out at between 0°C and room temperature in the presence of a suitable base (e.g. pyridine) and an appropriate organic solvent (e.g. dichloromethane). .0 5 (X)n XXXI Compounds of formula II may be prepared by reduction of a corresponding compound of 0 formula XI or formula XII, WO 01/98267 22 PCT/IB01/01035 (X)n XI xn in the presence of a suitable reducing agent, such as lithium aluminium hydride. The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran). Compounds of formula XI and XII may be prepared by reduction of the corresponding -NO2 compounds under conditions that are well known to those skilled in the art (e.g. using H2/Raney Ni or in the presence of CaCl2 and iron powder, in the presence of a suitable solvent system (e.g. EtOH, EtOAc and/or water)). The skilled person will appreciate that, in 0 preparing a compound of formula II, in which is H, from such a corresponding -NO2 compound, the two above-mentioned reduction steps may be performed in the same step or sequentially in any order. The said corresponding -NO2 compounds may be prepared by reaction of a compound of [5 formula XII or formula XTV, as appropriate, 5 (X)n L. L xm XIV WO 01/98267 23 PCT/IBO1/01035 wherein L* represents a suitable leaving group [such as halo (e.g. chloro or bromo)], \2-represents a suitable leaving group (such as Ci-3 alkoxy) and is as defined above, with a compound of formula XV, R4NH2 XV 5 The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable base (e.g. NaHC03) and an appropriate organic solvent (e.g. dimethylformamide), or at a higher temperature (e.g. between 50 and 200°C, preferably between 100 and 160°C) in the presence of neat compound of formula XV. 0 Compounds of formula XIII and XIV may be prepared in accordance with standard techniques. For example, compounds of formula XIH and XIV may be prepared by reacting a corresponding compound of formula XVI or XVII, XVI XVH with a compound of formula XVIII or XIX respectively, 5 N2CHR5COL2 XVIII N2CHR8COL2 XIX wherein L2 is as defined above. The reaction may be carried out at room temperature in the presence of a suitable catalyst [e.g. Rh2(OAc)4] and an appropriate non-protic organic solvent (e.g. dichloromethane). ) Compounds of formula XVI and formula XVII are available or can be prepared using known techniques. Compounds of formula XVI and formula XVH may, for example, be prepared from corresponding compounds of formula XX, WO 01/98267 24 PCT/IBO1/01035 (X)n O XX for example by performing a Wittig reaction using an appropriate provider of the nucleophilic group RC^C-CR^H" or RO2C-CR8H- (wherein R represents lower (e.g. C1.3) alkyl), as appropriate, under conditions that are well known to those skilled in the art. The - 5 C02R group of the resulting compound may be converted to an appropriate -CH2Ll group using standard techniques (e.g. reduction of the ester to the primary alcohol and conversion of the latter to an alkyl halide) under conditions that are well known to those skilled in the art. 0 In processes (b) and (c), suitable reducing agents include lithium aluminium hydride. The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran). Compounds of formula H may be prepared by reduction of the corresponding compound of 5 formula XXX, (X)n N l XXX WO 01/98267 25 PCT/IBO1/01035 by analogy to the process steps mentioned above. Compounds of formula IV and V may be prepared respectively from compounds of formula xxi xxn wherein represents a group that is capable of undergoing functional group transformations (e.g. cyano) using standard functional group substitution or conversion techniques. 0 For example: (1) Compounds of formula IV and V in which Rl represents l,2,4-triazol-3-yl may be prepared by reaction of an appropriate compound of formula XXI or XXH in which L3 represents -CN with HC1 (gas) in the presence of an appropriate lower alkyl alcohol (e.g. ethanol), for example at between 0°C and room temperature, followed by reaction of the 5 resultant intermediate with formic acid hydrazide (e.g. at reflux temperature, with or without the presence of a suitable organic solvent (e.g. methanol), followed by, if necessary, removing the solvent and heating the resultant residue to a high temperature (e.g. about 150°C)). (2) Compounds of formula IV and V in which Rl represents imidazol-2-yl may be 3 prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents -CN with HC1 (gas) in the presence of an appropriate lower alkyl alcohol (e.g. ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with aminoacetaldehyde dialkylacetal (e.g. dimethylacetal) (e.g. at or around reflux temperature in the presence of an appropriate solvent, such as methanol). 5 (3) Compounds of formula IV and V in which Rl represents l,2,3-triazol-5-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 WO 01/98267 26 PCT/IB01/01035 represents -CN with diazomethane, or a protected (e.g. trialkylsilyl) derivative thereof, for example at between 0°C and room temperature in the presence of a suitable base (e.g. n-BuLi) and, optionally, an appropriate organic solvent (e.g. THF), followed by removal of the protecting group as necessary. (4) Compounds of formula IV and V in which R* represents benzixnidazol-2-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L3 represents C=NH(OEt) with 1,2-diaminobenzene. The reaction may be carried out in a solvent such as methanol, at an elevated temperature (such as the reflux temperature of the solvent). Preparations 81, etc. provide further details. Compounds of formula IV and V in which Rl represents Hetl may also be prepared from ;ompounds of formula XI and XII respectively according to the following scheme: i)HCl,NaN02JH20 ii) KI, HzO XXIII Pd2aba3, PhAs Bu3Sn-HeP FT TV xn R XXIV R V WO 01/98267 27 PCT/IB01/01035 wherein Het^ is defined above. Further details may be found in Preparations 67, 68, etc. in W000/39089, herein incorporated by reference in its entirety. 5 Compounds of formula XXI and XXII may be prepared in analogous fashion to methods described herein, for example those described hereinbefore for preparation of compounds of formula II. Other compounds of formula (IV) and (V) may be prepared by analogy with methods 0 described herein (e.g. by analogy with methods described hereinbefore for preparation of compounds of formula XI and XII (and especially the corresponding -NO2 compound)). In process (d), the reaction may be carried out by heating under reflux, with or without the presence of an appropriate organic solvent. 5 Compounds of formula VI may be prepared using known techniques. For example, compounds of formula VI may be prepared by nitration (at the 4-position) of a corresponding 3-aminobenzene compound (a compound of formula II), which latter compound may be activated by converting the 3-amino group to a 3-amido group, followed by hydrolysis of the 0 amide and reduction of the 4-nitrobenzene compound. All of these reactions may be performed using techniques that are familiar to the skilled person, and are illustrated in Preparations 45-48, etc. below. In process (e), suitable leaving groups that Lg may represent include halogen, such as 5 bromine, or a sulphonate group such as tosylate, mesylate or triflate. The reaction may be carried out in a polar solvent that does not adversely affect the reaction, at a suitable temperature, e.g. 0-150°C, in the presence of a base. A catalyst such as sodium iodide may optionally be added. 0 Preferable choices are a slight excess of R^-Lg, where Lg = CI or Br, an excess of base (2.0-4.0 eq), such as K2CO3, NaHC03, or a tertiary amine, such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF, or MeCN, at between 40 and 120°C, optionally in the presence of a catalyst such as Nal or KI, for 2-24 hr. see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group 5 Preparations", VCH, (1989), p 397, and references cited therein. WO 01/98267 28 PCT/IBO1/01035 Compounds of formula VIII may be prepared from compounds of formula XXV, I Pg XXV wherein Pg represents a suitable protecting group. Suitable protecting groups include allyl, 5 which may be removed using a palladium (0) catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc. below). Compounds of formula XXV may be prepared using analogous methods to those described herein for the preparation of compounds of formula I. In process (f), suitable reducing agents include lithium aluminium hydride. The reaction may 10 be carried out in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), at an elevated temperature (for example the reflux temperature of the solvent). Compounds of formula X may be prepared by reacting a compound of formula XXVI 15 with a compound of formula XXVH in the presence of an oxidizing agent. Suitable oxidizing agents include manganese dioxide. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example dioxan). at an elevated temperature such as the reflux temperature of the solvent (for example see Preparation 77, W000/39089). The intermediate compounds XXIXa are isolatable using suitable conditions (e.g. see JO Preparation 58, W000/39089). WO 01/98267 29 PCT/IB01/01035 XXVI cr^N^o k> XXVII N' .N, R ,R* ■R CT A* XXIXa R4 XXIX 5 Compounds of formula XXVI may be prepared from compounds of formula XXVIII, by reaction of the corresponding ketone with hydrazine monohydrate using known techniques (and as described in Preparation 76, etc. WO00/39089). Process (f) is particularly useful when Ar represents an optionally benzo-fused 5- or 6-0 membered heteroaryl ring. A similar methodology may be used to obtain compounds of formula II: the precursor nitro compound may be prepared from a compound of formula XX, as defined above, using the steps described above (see for example Preparations 57-61, WQ00/39089). WO 01/98267 30 PCT/IB01/01035 In process (g), the reaction may be carried out in a solvent that does not adversely affect the reaction (for example ethanol), first below room temperature and then at an elevated temperature (Examples 79, etc. W000/39089, provides further details). 5 In process (h), suitable acids include dilute aqueous hydrochloric acid and concentrated hydrochloric acid, respectively. The reaction may be carried out at or around room temperature, finishing at' an elevated temperature (for example 90°C). Example 51 W000/39089 provides further details. 0 In process (j), the compound of formula XXXI may be prepared by acylation of the compound of formula VIH as defined above, with an acylating agent of the formula R.4acO-Lg, where Lg is a suitable leaving group as defined above with respect to (e), and includes halogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR4a (i.e. an acid anhydride) and the like, well known to those practising in the art. See for example the conditions used for Preparation 5 47. The coupling can optionally be carried out in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein. Preferably the carboxylic acid (0.9-1.1 eq), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HC1 (1-1.5 eq) and 1-hydroxybenzotriazole (1.0 0 eq) are stirred in DMF or DCM at RT for 5-15 min and then the amine salt (1 eq) and base (NaHC03 or organic base , Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr at RT. The amide bond can be reduced with a suitable reducing agent, for example lithium 5 aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-l00°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432-434, and references cited therein. Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C-RT, in THF, for 1-24 hr. 0 In process (k) the appropriate aldehyde is reacted with an amine, optionally present as an acid addition salt, in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is suitably performed in the presence of acetic acid at 0-100°C in THF, methanol, 5 DCM (dichloroxnethane), or DCE (1,2 -dichloroethane), for a suitable time such as 1-24 hr. WO 01/98267 PCT/IBO1/01035 31 Preferably the amine salt, such as the trifluoroacetic acid (TFA) salt, is treated with an organic base (1-3 mole equivalents), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 mole equivalents), followed by sodium triacetoxyborohydride (1-2.0 mole equivalents), in DCM or DCE, at room temperature for 2-24 hr. see RC Larrock; 5 "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), p 835-842, and references cited therein, and Abdel-Magid et al, J. Org. Chem., 1996, 61, 3849. The aldehydes used in this process may be prepared from the corresponding alcohols using 10 suitable oxidising agents; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1234-1236 and 1238-1247, and references cited therein. Preferred oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. 15 Org. Chem., 1983, 48, 4155-4156). Various functional group interconversions on compounds of formula (I), or intermediates thereto, may be carried out to give different compounds of formula (I) or intermediates. Some of these are mentioned below. !0 Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985,28,1427-1432. !5 Esters can be converted to the corresponding alcohols using a suitable reducing agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein. Suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium ahiminium hydride (LiAlH4, see Brown, Org. Reactions, 1951, 6, 10 469) - viz. reaction of the type: O WO 01/98267 32 PCT/IBO1/01035 Alcohols can be prepared from a corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973,38,2786), or LiAlH4 (1-4 eq), in an ethereal 5 solvent, such as THF, 0-80°C, for 1-24 hr. - viz. reaction of the type: xOH Rs^OH T " o 0 Direct methods to prepare alkyl halides and aiyl sulphonates from their alcohols are described by RC Larrock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 689-700, and references cited therein. 5 Benzylacetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give benyloxyalcohols. For representative examples see Organic Preparations and Procedures, Int., 1991,23,4, 427-431, ZrC14/LiAlH4; J. Org. Chem., 1987,52,2594, Zn(BH4)2/Me3SiCl; and Organic Preparations and Procedures, Int., 1985,17(1), 11-16, NaBH4/TFA. 0 viz. reaction of the type: r~\ V 0^ It will be apparent to those skilled in the art that compounds of formula I may be converted to other compounds of formula I using known techniques. For example, compounds of formula I in which Yl represents alkoxycarbonyl may be converted to compounds in which Yl represents alkyl substituted by OH, by reduction using LiAlH4 (Example 57 provides further details). Similarly, intermediate compounds may be interconverted using known techniques (see for example Preparation 85). WO 01/98267 33 PCT/IBO1/01035 The intermediate compounds such as those of formulae III, XV, XVIII, XfX, XX, VII, IX, XXVI, XXVII and XXVIII, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. The invention further provides the intermediate compounds of formulae II, IV, V, VI, X, Xa, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, and XXXI as defined above. Where desired or necessary, the compound of formula (I) can be converted into a pharmaceutical acceptable salt thereof, conveniently by mixing together solutions of a compound of formula (I) and the desired acid or base, as appropriate. The salt may be precipitated from solution and collected by filtration, or may be collected by other means such as by evaporation of the solvent. Both types of salt may also be formed or interconverted using ion-exchange resin techniques. The compounds of the invention may be purified by conventional methods, for example separation of diastereomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or a salt thereof. An individual enantiomer of a compound of formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereomeric salts formed by reaction of the corresponding racemate with a suitably optically active base or acid. The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. They are therefore indicated as pharmaceuticals and, in particular, for use as animal medicaments. According to a further aspect of the invention there is provided the compounds of the invention for use as medicaments, such as pharmaceuticals and animal medicaments, such as for the treatment of opiate-mediated diseases and conditions. WO 01/98267 34 PCT/IB01/01035 By the term "treatment", this term includes both therapeutic (curative) and prophylactic treatment. In particular, the substances of the invention have been found to be useful in the treatment of 5 diseases and conditions modulated via opiate receptors, such as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; and conditions characterised by having pruritis as a symptom. .0 Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease modulated via an opiate receptor. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; .5 depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage-and/or head trauma; and conditions characterised by having pruritis as a symptom. The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in :0 animals and humans. Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites. Thus, the invention provides a method of treating or preventing a disease modulated via an opiate receptor. There is further provided a method of treating irritable bowel syndrome; :5 constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; or a medical condition characterised by pruritus as a symptom in an animal (e.g. a mammal), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment. 0 The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be WO 01/98267 35 PCT/IB01/01035 treated, as well as the route of administration, the compositions may be administered at varying doses (see below). While it is possible to administer a compound of the invention directly without any 5 formulation, the compounds are preferably employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier, diluent or excipient and a compound of the invention. The carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical, and/or veterinary, practice, Pharmaceutical compositions comprising the [0 compounds of the invention may contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient. The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a 5 pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (eg subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice. .0 The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg. 5 In any event, the veterinary practitioner, or the skilled person, will be able to determine the ■ actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower 0 dosage ranges are merited, and such are within the scope of this invention. For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses. WO 01/98267 36 PCT/IB01/01035 As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed. 5 For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice. 10 Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparasitics, eg fipronil, lufenuron, imidacloprid, avermectins (eg abamectin, ivermectin, doramectin), milbemycins, 5 organophosphates, pyrethroids; antihistamines, eg chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, eg fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories eg prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, eg gamma-linoleic acid; and emollients. 0 Therefore, the invention further provides a product containing a compound of the invention and one or more selected compounds from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases modulated via opiate receptors 5 The skilled person will also appreciate that compounds of the invention may be taken as a single dose or on an "as required" basis (i.e. as needed or desired). Thus, according to a further aspect of the invention there is provided a pharmaceutical, or veterinary, formulation including a compound of the invention in admixture with a 0 pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier. Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily WO 01/98267 37 PCT/IB01/01035 absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art. The biological activities of the compounds of the present invention were determined by the 5 following test method. Biological Test Compounds of the present invention have been found to display activity in three opioid 0 receptor binding assays selective for the mu, kappa and delta opioid receptors in dog brain. The assays were conducted by the following procedure. Laboratory bred beagles were used as a source of dog brain tissue. Animals were euthanaised, their brains removed and the cerebellum discarded. The remaining brain tissue 5 was sectioned into small pieces approximately 3 g in weight and homogenised in 50mM Tris pH 7.4 buffer at 4°C using a Kinematica Polytron tissue homogeriser. The resulting homogenate was centrifuged at 48,400 x g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 37°C for 10 minutes. Centrifugation, resuspension and incubation steps were repeated twice more, and the final pellet was 0 resuspended in Tris buffer and stored at -80°C. Membrane material prepared in this maimer could be stored for up to four weeks prior to use. For mu, kappa and delta assays, increasing concentrations of experimental compound (5 x 10'12 to 10"5M), Tris buffer and 3H ligand, (mu = [D-Ala2,N-Me-Phe4JGly-ol53-5 Enkephalin, DAMGO; kappa = U-69,593; delta = Enkephalin, [D-pen2^] DPDPE), were combined in polystyrene tubes. The reaction was initiated by the addition of tissue, and -the mixture was incubated at room temperature for 90 minutes. The reaction was terminated by rapid filtration using a Brandel Cell Harvester™ through Betaplate™ GF/A glass fibre filters pre-soaked in 50 mM Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then 0 washed three times with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays, washed filters were placed in bags and Starscint™ scintillant added, for the kappa assay Meltilex™ B/HS solid scintillant was used. Bags containing the filters and scintillant were heat sealed and counted by a Betaplate™ 1204 beta counter. WO 01/98267 38 PCT/IB01/01035 Duplicate samples were run for each experimental compound and the data generated was analysed using IC50 analysis software in Graphpad Prism. Ki values were calculated using Graphpad Prism according to the following formula: 5 Ki = IC50 /1 + [3H ligand] / KD where IC50 is the concentration at which 50% of the ligand is displaced by the test compound and KD is the dissociation constant for the 3H ligand at the receptor site. 0 Biological Activity The Ki values of certain compounds of the present invention in the opioid receptor binding assays were determined, and were found to have Ki values of 4000 nM or less for the p. receptor. 5 It is believed that the methods used in the following Examples produce compounds having the relative stereochemistry shown below, and such compounds are preferred: R2 } The invention is illustrated by the following Examples and Preparations in which the following abbreviations may be used: APCI = atmospheric pressure chemical ionization DMF - dimethylformamide > DMSO = dimethylsulphoxide d (in relation to time) = day d (in relation to NMR) = doublet ES (in relation to MS) = electrospray WO 01/98267 39 PCT/IBO1/01035 EtOAc = ethyl acetate EtOH = ethanol h = hour MeOH = methanol 5 min = minute MS = mass spectrum ti-BuOH = n-butanol ODS = octadecylsilyl THF = tetrahydrofuran 0 TSP = thermospray Melting points were determined using a Gallenkamp melting point apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectral data relate to *H and were obtained using a Varian Unity 300 or 400 spectrometer, the observed chemical shifts (6) 5 being consistent with the proposed structures. Mass spectral (MS) data were obtained on a Fisons Instruments Trio 1000, or a Fisons Instruments- Trio 1000 APCI, or a Finnigan Navigator MS, or a Micromass Platform LC spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. Room temperature means 20 to 25°C. The mass spectrometer which is used as a detector on the analytical HPLC-MS 0 system is a Micromass VG Platform II, running on Masslynx/Openlynx software. The system can run positive and negative ion with either Electrospray or APCI probes and is calibrated to 1972 Daltons, it collects full Diode array data from 190nm to 600nm. HPLC means high performance liquid chromatography. HPLC conditions used were: 5 Condition 1: Rainin Dynamax™ column, 8jx ODS, 24 x 300 mm, column temperature 40°C, flow rate 45 ml/min, eluting with methanol: water (70 : 30), UV detection of product at 246 nm. Condition 2: Rainin Dynamax™ column, 5>x ODS, 21.6 x 250 mm, column temperature 3 40°C, flow rate 5 ml/min, eluting with acetonitrile : water (50 : 50), UV detection of product at 246 nm. Condition 3: Rainin Dynamax™ column, 8p. ODS, 41 x 250 mm, column temperature 40°C, flow rate 45 ml/min, eluting with acetonitrile : 0.1M aqueous ammonium acetate buffer (50 : 50), UV detection of product at 235 nm. WO 01/98267 PCT/IB01/01035 40 Condition 4: Phenomenex Magellan™ column, 5p. C^g silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (30 : 70 to 95 : 5 over 10 min), UV detection of product at 220 nm. Condition 5: Phenomenex Magellan™ column, 5p, ODS, 21.2 x 150 mm, column temperature 5 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile: 0.1M aqueous ammonium acetate buffer (5 : 95 to 95 : 5 over 20 min), UV detection of product at 215 nm. Condition 6: Phenomenex Magellan™ column, 5/J, Cjg silica, 4.6 x 150 mm, column temperature 40°C, flow rate 1 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous heptanesulphonic acid (10 : 90 to 90 : 10 over 30 min), UV detection of product at 220 nm. 0 Condition 7: Phenomenex Magellan™ column, 5p. C^g silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.05M aqueous ammonium acetate buffer (50 : 50 for 15 min then 50 : 50 to 90 : 10 over 5 min), UV detection of product at 220 nm. Condition 8: Phenomenex MagellenPM column, 5p. C^g silica, 21.2 x 150 mm, column 5 temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium'acetate buffer (15 : 85 to 85 : 15), UV detection of product at 220 nm. Condition 9: Phenomenex MagellenTM column, 5jli ODS, 10 x 150 mm, column temperature 40°C, flow rate 5ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate buffer (5 : 95 to 30 : 70 over 5 min then 30 : 70 for a further 20 min), UV detection of 0 product at 225nm. Condition 10: Phenomenex Magellan^M column, 5p. C]8 silica, 21.2 x 150mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammonium acetate (5 : 95 to 40 ; 60 over 5 min then 40 : 60 for a further 25 min), UV detection of product at 210 nm. 5 Condition 11: Phenomenex Magellan^ column, 5p ODS, 10 x 150mm, column temperature 40°C, flow rate 5 ml/min, eluting with a gradient of acetonitrile: water (5 : 95 to 55 :45 over 5 min), UV detection of product at 210 nm. The free base form of the azabicycles could be obtained from (he hydrochloride or acetate 0 salts, for example, in the following way. The salt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (20 ml). The basic mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (Na2S04) and concentrated in vacuo to give the free base. 5 WO 01/98267 41 PCT/IBO1/01035 SPE cartridge refers to a solid phase extraction cartridge. These can be commercially obtained from Varian (Mega Bond Elut ®) or IsoluteTM, NB "Examples" numbered 1-144 are compounds related to the instant invention, but with 5 different R4 groups, and are disclosed as such in International Patent Application no. WO00/39089, herein incorporated by reference in its entirety. A number of further Examples, such as those in the table below, can be made via 0 the processes A-K outlined below and in the experimental details following the table Process A Alleviation 5 Alkylation of the amine of formula VI1J or a salt thereof with R4Lg, where Lg is a suitable leaving group, such as a halogen, triflate, mesylate, etc., in the presence of a base, optionally in the presence of a catalyst, in a polar solvent, at between 0 and 150°C. Preferably the alkylation is carried out with R"Lg (slight excess), where Lg =Ci or Br, D an excess of base (2.0-4.0 eq), such as K2C03, NaHC03, or a tertiary amine, such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF, or MeCN, at between 40 and 120°C, optionally in the presence of a catalyst such as Nal or KI, for 2-24 hr. see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional 5 Group Preparations", VCH, (1989), p 397, and references cited therein. For Example: WO 01/98267 42 PCT/IB01/01035 S02Me S02Me f TFA salt H + R4Lg Lg=Br or CI Conditions: Amine salt (1.0 eq), RX (1.1 eq), NaHC03 (2-4.0 eq), DMF, Nal (cat), 4( Process B 5 Reductive amination Treating an appropriate aldehyde R4aCHO with an amine of formula VIII in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is often performed in the presence of acetic acid at 0-100°C in THF, MeOH, 0 DCM, or DCE (1,2 -dichloroethane), for 1-24 hr. Preferably the amine salt is treated with an organic base (1-3 eq), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 eq), followed by sodium triacetoxyborohydride (1-2.0eq), in dichloromethane or DCE, at room temperature for 2-24 hr. see RC Larrock: "Comprehensive Organic Transformations-A Guide to 5 Functional Group Preparations", second edition, (1999), p 835-842, and references cited therein, and Abdel-Magid etal, J. Org. Chem., 1996, 61,3849. For example: WO 01/98267 PCT/IBO1/01035 43 S02Me H S02Me ^ TFA salt H O N Conditions: Amine salt (1.0 eq), RCHO (1-1.5eq), Et3N (1-3 eq), Na(OAc)3BH (1-2 eq), DCM RT. Process C Reduction of Amide of Formula XXXI The amide carbonyl can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432-434, and references cited therein. Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C-RT, in THF, for 1-24 hr, e.g.: Aldehydes used in process B can be prepared using suitable oxidising agents; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1234-1236 and 1238-1247, and references cited therein. H Process D Oxidation WO 01/98267 44 PCT/IB01/01035 Preferred oxidants are tetrapropyiammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. Org. Chem., 1983, 48, 4155-4156). .R4a-"^OH oxidant i4a H A o 10 ',0 Process E Acid/ amine salt coupling to give amides of formula XXXI Either using an acid chloride + amine in a suitable solvent or the acid activated by a suitable agent, optionally in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein. Preferably the carboxylic acid (0.9-1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HCI (1-1.5 eq) and 1-hydroxybenzotriazole (1.0 eq) are stirred in DMF or DCM at RT for 5-15 min and then the amine salt (1 eq) and base (NaHC03 or organic base , Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr at RT. For Example: S02Me R O ,A OH TFA salt "S02Me Process F Urea formation Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985,28,1427-1432. viz. reaction of the type: WO 01/98267 45 PCT/IB01/01035 R NH, K+ 0; :N R H 1NHCI, RT, 0.1-10 hr Y O NH„ io [5 >0 15 Process G Ester to an alcohol Esters can be converted to the corresponding alcohol using a suitable reducing agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein. Suitable reducing agents include diisobutylaluminium hydride (DiBAL, see Winterfeldt, Synthesis, 1975,617) and lithium aluminium hydride (LiAIH4, see Brown, Org. Reactions, 1951, 6, 469).viz. reaction of the type: O R -R1 R Process H Acid to alcohol It should be appreciated that the alcohols used in process D can be prepared from the corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAIH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80°C, for 1-24 hr. 50 R4a\^OH O -fc4a ,OH Process I Alcohol to halide WO 01/98267 PCT/IB01/01035 46 It should be appreciated that the R4Lg used in Process A can be prepared from the corresponding alcohol R4aOH. Direct methods to prepare alkyl halides and alkyl sulphonates from their alcohols are described by RC Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 689-700, and references cited therein. Process J Benzyl halides to benzyloxyalcohols Benzyloxyalcohols can be prepared by refluxing the appropriate benzyl halide with sodium or sodium hydride and a polymethylene glycol in xylene, see J. Am. Chem. Soc., 1951, 3159-3162.viz. reaction of the type: R R Na or NaH + HO(CH2)nOH » 0 r ,0H Xylene X = halide Process K Acetals to benzyloxyalcohols Acetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give the benyloxyalcohois. For representative examples see Organic Preparations and Procedures, int., 1991, 23,4, 427-431, ZrCI4/LiAIH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCI; and Organic Preparations and Procedures, Int., 1985,17(1), 11-16, NaBH4/TFA.viz. reaction of the type: r\ HO O 5 WO 01/98267 47 PCT/IB01/01035 H H S02Me S02Me L-—\ Coupling Processes 1-—\ A A-C /\ f~\ + R-Y *- r~\ V TFA salt V H R Example Name Precursor(s) Coupling method -(CH2)nO(CH2)nR examples 145 H rrN;< 11 J o o N N-(3- {6-ethyl-3-[2-(2-hydroxyethoxy)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonami de Process A Alkylation 146 9^° Q N- l JV-[3-(3-{2-[2- (dimethylamino)ethoxy]ethyl }-6-ethyl-3- azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonami de l Process B Reductive amination 1 HCX ,N. Process D oxidation 147 2-[2-(6-ethyl-6-{3-t(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3.1.0]hex- 3-yl)etboxy]acetamide WO 01/98267 48 PCT/IB01/01035 WO 01/98267 49 PCT/IB01/01035 WO 01/98267 50 PCT/IBO1/01035 H / rr k 1 ^ 0 0 & (CH2)nO(CH2)nAr examples 155 H (T o" *0 iV-[3-(3-{2-[(4-chlorobenzyl)oxy]ethyl} -6-ethyl-3- azabicyc!o[3.1.0]hex-6- yl)phenyl]methanesulfonami de Process B and D 156 H f] T [1 J 0 0 JV-f3-f6-ethvI-3-f2-R4- HCX _ Process B and D methoxvbenzvDoxvlethvD-3-azabicvclor3.1.01hex-6-vDohenvllmethanesulfonami de All other (CH2)nO(CH2)nAr examples can be prepared via a 2 step process from a benzyl alcohol or benzyl chloride For a general procedure see; J Am. Chem. Soc., 1951,3159-3162. Aryl substituents (mix. of aiyl and aiyloxy examples): WO 01/98267 51 PCT/IBO1/01035 157 H \\ T 1^00 O h2nN^O N \ 2-[2-(6-ethyl-6-{3-[(methylsulfony])amino]phe nyl} -3-azabicyclo[3.1.0]hex- 3-yl)ethoxy]benzamide •Vw) Process B and D 158 H ifY JK KJ 0 ° ■"tu. 2-( 4-r2-f6-ethvl-6-( 3-rfmethvlsulfonvnaminolDlien Process A vH-3-azabicvclor3.1. Olhex- 3^ vDethoxvlDhenvUacetamide 159 H li T ^ |i J 0 o ^°TX ^%H2 W-(3-{3-[2-(4-aminophenoxy)ethyl] -6-ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de 0 ^^NH2 Process C and E WO 01/98267 PCT/IB01/01035 52 160 H (i T * <L ° 0 H 2 iV-{3-[3-(2-{4-[(aminocarbonyl)amino]phen oxy} ethyl)-6-ethyl-3-azabicyclo[3.1.0]hex-6-yI]phenyI}methanesuIfonami de H fj T H J o o Process F 161 H |l J 0 o H 0 iV-(3-{3-[3-(4- acetylphenyl)propyl]-6- ethyl-3- azabieyclo[3.1.0}hex-6- y 1} phenyl)methanesulfonami de UK-156607 0 Process A 162 H r^V'S-" (T 0 A O I °Y\ A^v^NH2 // "Vl 0 0 4-[2-(6-ethyl-6- (3-[(rnethylsulfony])amino]phe nyl} -3-azabicyclo[3.1.0]hex-3- yl)ethoxy]benzenesulfonami de •>% 0 o Process A 163 o 0 Processes C and E WO 01/98267 53 PCT/IB01/01035 H (T o'A0 N oy N° Ar-[3-(6-ethyl-3- {2- [4-(methylsulfony])phenoxy]eth yl} -3 -azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonami de 164 H fl | 'A- M J O 0 LXv o methyl 4-[2-(6-ethyl-6-{3-[(methylsulfonyl)amino]phe nyl} -3-azabicycIo[3.1.0]hex-3-yl)ethoxy]benzoate H0^°Tl 0 Processes B and D 165 H fl T XV. y j o o /\ n r^o ethyl {2-[2-(6-ethyl-6-{3-[(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3.1.0]hex-3-yl)ethoxy]phenyl} acetate Process A 166 methyl {4-[2-(6-ethyl-6-{3- Processes B and D WO 01/98267 PCT/IB01/01035 54 H \\ T [I J o o [(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3.1.0]hex-3-yl)ethoxy]phenoxy} acetate r° o :') o -A ■ o / 167 H fl T 'A-n j o o L°tCU. N-[3 -(6-ethyl-3- {2-[4-(hydroxymethyl)phenoxy]eth yl}-3-azabicyclo[3.1 .Ojhex-6- yl)phenyl]methanesulfonami de Processes C and E or from reduction of example 19-Process G H (J o* *o 0 168 H rf XT (IJ iV-(3- {3 -[2-(f 1,1 -biphenyl]-4-yloxy)ethyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonami de Processes B and D 169 WO 01/98267 55 PCT/IB01/01035 H U N-V JV-[3-(3-{2-[4-(4,5-dih.ydro-l,3-oxazol-2- yl)phenoxy]ethyl} -6-ethyl-3-azabicyclo[3.1,0]hex-6-yl)phenyl]methanesulfonami de ^V> Processes B and D 170 11J 0' 0 N JO N-(3-{6-ethyl-3-[2-(4-phenoxyphenoxy)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonami de H°^ Processes B and D 171 H kJ ° s° N-( 3-13-12- (benzvloxvtaenzvll-6- Commercial aldehvde ethvl-3- azabicvclor3.1. Olhex-6- Processes B vltohenvBmethanesulfona mide 172 iV-(3-{3-[2-(4-benzylphenoxy)ethyl]-6- OH °^°XXO Processes C and E WO 01/98267 PCT/IBO1/01035 56 H '*V O O ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de 173 /V-{3-[3-{4-cyanobenzyl)-6-ethyl-3- azabicyclo[3.1.0]hex-6- yl]phenyI}methanesulfona mide Commercial aldehyde Process B 174 UK-419966 AT-(3-{3-[2-(4- cyclopropylphenoxy)ethyl]- 6-ethyl-3- azabicyclo[3.1,0]hex-6- yl}phenyl)methanesulfonami de UK-180220 Process A Substituents of the basic alkyl/alkenyl/alkynyl chains: 175 O CI Process A phenyl 3-(6-ethyl-6-{3- WO 01/98267 57 PCT/IBO1/01035 H /NV' <5 fl 1 <- N> |l J o 0 [(methylsulfonyl)amino]phe nyl}-3-azabicyclo[3.1.0]hex- 3-yl)propanoate n o kA0AJ- 176 H rV «*SC y j o o ben2yl 4-(6-ethyl-6-{3-[(methylsulfonyl)amino]phe nyl}-3-azabicyclo[3.1.0]hex-3-yl)butanoate O Process A U..JD II 0 177 H (To-° A" A/-{3-[6-ethyl-3-(3-oxo-3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonami de O Process A V 0 178 ,Vv fl T 'An lisJ o 0 N O O N-(3- {3-[3-(2,3-dihydro-lff- inden-5-yl)-3-oxopropyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de Process A WO 01/98267 58 PCT/IBO1/01035 179 2-(6-ethyl-6-{3-[(methylsulfonyl)amino]phe nyl} -3 -azabicyclo[3.1.0]hex- 3-yl)ethyl benzoate 2-(6-ethyl-6-{3-[(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3.1.0]hex- 3-yl)etbyl cyanoacetate Process A 181 ii x 2-(6-ethvl-6-(3- r(methvlsulfonvl>aminolphen vll-3-azabicvclof3.1 .Olhex-3-vDethvl l.S-dimethvl-3- / Process A oxo-2-phenvl-2.3-dihvdro-liJ-pvrazole-4-carboxvIate o O 182 ho' Processes C and E X> N~(3- {3-[(4-tert-butylcyclohexyl)methyl]-6- WO 01/98267 59 PCT/IBO1/01035 WO 01/98267 60 PCT/IB01/01035 WO 01/98267 61 PCT/IB01/01035 WO 01/98267 PCT/IB01/01035 62 WO 01/98267 PCT/IBO1/01035 63 WO 01/98267 64 PCT/IBO1/01035 H (T o"% N 198 H (Yo'% Q AT-(3-{6-ethyl-3-[2-(2-pyrimidinylsulfanyl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonami de 0 JL /S. ,NX HO Y ^"| N^J Processes C and E Example 199: iV-('3-f3-r3-f4-acetylphenvl')propvfl-6-ethvI-3-azabicvclor3.1.01hex-6-vlVphenvl>methanesulfonamide - and formate salt WO 01/98267 65 PCT/IBO1/01035 To a solution of the trifluoroacetic acid salt of A/-[3-(6-ethyl-3-azabicyclo[3.1,0]hex-6-yl)phenyl]methanesulfonamide (106 mg, 0.27 mmol) in n,n- dimethylformamide (4 ml) was added sodium hydrogen carbonate (90mg, 1.1 mmol), 1-[4-(3-chloropropyl)phenyl]ethanone (58 mg, 0.29 mmol) and sodium iodide (catalytic) and 5 the reaction mixture was heated at 70 °C for 20 h. After cooling, the solvent was removed in-vacuo to give a crude residue. This was purified by silica (14 g) column chromatography eluting with ethyl acetate: hexane (75:25) and then with neat ethyl acetate. Combination and evaporation of the appropriate fractions gave the partially purified product. This material was further purified by preparative HPLC (condition 1) 10 to afford the formate salt of title compound (16 mg, 12%) as a yellow oil. 1H-NMR (300MHz, CDCl3, data for formate salt) : 0.85 (t, 3H), 1.70 (q, 2H), 2.05 (quintet, 2H), 2.15 (s, 2H), 2.55 (s, 3H), 2.70 (t, 2H), 2.80-2.85 (m, 4H), 2.95 (s, 3H), 3.70-3.80 (m, 2H), 7.00 (d, 1H), 7.05-7.10 (m, 2H), 7.20-7.28 (m, 3H), 7.90 (d, 2H), 8.40 (s, 1H). 15 MS (Electrospray): M/Z (M-H) 439; C25H32N203S - H requires 439.2. Example 200 : A/-(3-(3-r2-(benzvioxv)benzvl1-6-ethvl-3-azabicvclor3.1.0'lhex-6-vllphenvPmethanesulfonamide To a solution of 2-benzyloxybenzaldehyde (27mg, 0.13mmol) in dichloromethane (5 ml) at room temperature was added the trifluoroacetic acid salt N-[3-(6-ethyI-3-azabicyclo[3.1.0]hex-6-yl)phenyl]nnethanesulfonamide (50mg, 0.13 mmol) and triethylamine (0.05 ml, 0.38 mmol). The reaction was left to stir at room temperature 25 for 2h. At this point sodium triacetoxyborohydride (40.8 mg, 0.19 mmol) was added and the reaction was left to stir at room temperature for 16 h. Water (5ml) was then added to the reaction mixture and the two layers were separated using a Whatman filter tube (hydrophobic polytetrafluoroethylene membrane). The organic layer was then blown down to dryness under a steam of nitrogen. The residue was purified by 20 WO 01/98267 66 PCT/IBO1/01035 column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with hexane: ethyl acetate (100:0, 1:1, 1:3, 1:6, 1:9 and 0:100) to afford the title compound (28 mg, 46%) as an oil. 1H-NMR (300MHz, CDCI3): 0.85 (t, 3H), 2.80 (s, 2H), 2.00-2.10 (m, 2H), 2.85 (d, 2H), 3.00 (s, 3H), 3.10-3.20 (dd, 2H), 3.80 (s, 2H), 5.10 (s, 2H), 6.90-7.05 (m, 3H), 7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.40-7.50 (m, 6H). MS (Electrospray): M/Z (M+H) 477; C28H32N203S + H requires 477. Example 201 : ft/-(3-r3-(4-cvanobenzv0-6-ethvl-3-azabicvclo[3.1.01hex-6-vllDhenvl)methanesulfonamide The compound above was prepared by a similar method to that of Example 167, using the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yI)phenyl]methanesulfonamide (100 mg, 0.25mmol) and 4-cyanobenzaldehyde (33mg, 0.25mmo!) as the starting materials. The product was purified using preparative HPLC (conditions 3) to afford the title compound (28 mg, 28 %) as an off-white solid. 1H-NMR (300MHz, CDCI3): 0.85(t, 3H), 1.80 (s, 2H), 2.05 (q, 2H), 2.80 (d, 2H), 3.00 (s, 3H), 3.10 (d, 2H), 3.70 (s, 2H), 7.00-7.20 (m, 3H), 7.20 (m, 1H), 7.40 (d, 2H), 7.60 (d, 2H) MS (Electrospray): M/Z (M+H) 396; C22H25N302S-H requires 396. .H. .0 N Example 202: /V-(3-(3-r2-(4-cvclopropy|phenoxv)ethvn-6-ethvl-3- azabicvclor3.1.01hex-6-vl)phenvl)methanesulfonamide WO 01/98267 67 PCT/IBO1/01035 TFA salt H N To a solution of the trifluoroacetic acid salt of A/-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (75 mg, 0.19 mmol) in n,n- dimethylformamide (3 ml) 5 was added sodium hydrogen carbonate (64 mg, 0.8 mmol), 1-(2-chloroethoxy)-4-cyclopropylbenzene (41 mg, 0.21 mmol) and sodium iodide (3 mg, catalytic) and the reaction mixture was heated at 60 °C for 20 h. After cooling, the solvent was removed in-vacuo to give a crude residue. This was purified by preparative HPLC (condition 2) to afford the formate salt of the title compound (4 mg, 5%) as a brown 1H-NMR (300MHz, CDCI3, data for formate salt) : 0.55-0.60 (m, 2H), 0.80-0.95 (m, 5H), 1.80-1.90 (m, 3H), 2.25 (bs, 2H), 2.95 (s, 3H), 3.15 (d, 2H), 3.45 (t, 2H), 3.80-3.90 (m, 2H), 4.20 (t, 2H), 6.90 (d, 2H), 7.00 (d, 2H), 7.05-7.15 (t, 2H), 7.20 (s, 1H), 7.30 (t, 1H). 5 MS (Electrospray): M/Z (M-H) 439; C25H32N203S - H requires 439.2. Example 203: /V-(3-f6-ethvi-3-f(2-phenvlcvclopropvnmethvn-3-azabicvclof3.1 .Olhex-6-yl}phenvhmethanesulfonamide o gum. o WO 01/98267 68 PCT/IBO1/01035 To a mixture of frans-2-phenylcyclopropylcarboxa!dehyde {ref. J. Org. Chem., 1992, 57, 1526} (30 mg, 0.2 mmol) and the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50 mg, 0.13 mmol) in dry 1,2-5 dichioroethane was added Hunigs' base (0.02ml, 0.12mmol). The mixture was sonicated for 3 minutes and then stirred for a further 30 minutes followed by the addition of sodium triacetoxyborohydride (50 mg, 0.25mmol). After stirring for 72 hours, the reaction was diluted with ethyl acetate (50ml) and partitioned between saturated sodium bicarbonate (2 x 25ml). The organic layer was washed with brine o (2 x 20ml), dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure to produce a yellow/brown oil. This oil was dissolved in the minimum of quantity of dichloromethane and purified using a Biotage™ 6 g cartridge eluting with a gradient of ethyl acetate:hexane (30:70) to ethyl acetate (100%) to afford the title compound (32 mg 62%) as an oil. 5 1H-NMR (300MHz, CDCI3): 0.78-0.90 (m, 3H), 0.97 (m, 1H), 1.24 (m, 1H), 1.72 (m, 1H), 1.76-1.79 (m, 2H) 1.90-2.05 (m, 2H) 2.45 (dd, 1H), 2.60 (dd, 1H), 2.84-2.95 (m, 2H), 2.99 (s, 3H), 3.02-3.08 (m, 2H) 6.89-7.3 (m, 9H), MS (Electrospray): M/Z (M+H) 411; C24H3oS02N2 + H requires 411 0 PREPARATIONS NB Preparations 1 to 148 from International Patent Application publication no. W000/39089 are herein incorporated by reference in their entirety, and the same numbering is adhered to herein. 5 Preparation 149 1-r4-(3-chloropropyl)phenvllethanone Aluminium chloride (15.0 g, 0.11 moles) and acetyl chloride (16.0 g, 0.20 moles) 0 were dissolved in dichloromethane (50 ml) at room temperature. This mixture was then added dropwise to a solution 1-chloro-3-phenylpropane (15.5 g, 0.10 moles) in O WO 01/98267 PCT/IBO1/01035 69 dichloromethane (25 ml) at room temperature over 15 minutes. The mixture was stirred for 1 hr and then poured cautiously onto ice. The aqueous layer was extracted with dichloromethane (450 ml). The organics were washed with water and brine, and then dried (MgS04) and concentrated in-vacuo to give the title compound (19.2 g, 5 98%) as an oil. 1H-NMR (300MHz, CDCl3): 2.10 (quintet, 2H), 2.60 (s, 3H), 2.85 (t, 2H), 3.55 (t, 2H), 7.30 (d, 2H), 7.90 (d, 2H). MS (thermospray): M/Z [M+NH4]+ 214; C^H^CIO + NH4 requires 214.1. .0 Preparation 150 1-f2-chloroethoxv)-4-cvclopropvlbenzene 4-Cyclopropylphenol (6.75 g, 50.3 mmol, reference: Horrom et. al., Org. Prep. Proceed. Int., 1992, 24 (6), 696-698), 2-chloroethy! p-toluenesulfonate (17.71 g, 75.5 mmol), and potassium carbonate (10.4 g, 75.4 mmol) in anhydrous acetonitrile (500 ml) were stirred together under a nitrogen atmosphere at reflux for 30 hours. The 20 reaction was allowed to cool to room temperature and diluted with ethyl acetate (1000 ml). The organics were washed with water (3 x 250 ml), dried (MgS04), filtered and concentrated in vacuo. This crude material was purified by silica column chromatography eluting with hexane : dichloromethane (4:1) and then with hexane : dichloromethane (3:1) to afford the title compound (8.7 g, 88%) as a solid. is Mpt: 47-48°C 1H-NMR (300MHz, CDCI3): 0.60-0.70 (m, 2H), 0.85-0.95 (m, 2H), 1.80-1.95 (m, 1H), 3.81 (t, 2H), 4.21 (t, 2H), 6.82 (d, 2H), 7.02 (d, 2H). MS (thermospray) M/Z (M) 196; C^H^OCI requires 196.1. 15 30 Preparation 151 1 -Allvl-1 H-pyrolle-2,5-dione (see J. Org. Chem.. 1997.62. WO 01/98267 70 PCT/BB01/01035 fy=o y-o + H2N' oHj 5 To a solution otmaleic anhydride (98 g, 1.00 mol) in dry toluene (3000 ml) at room temperature under a nitrogen atmosphere was added dropwise a solution of allylamine (57.1 g, 1.00 mol) in toluene (1000 ml) over one hour. The mixture was stirred at room temperature for 20 hours and then zinc chloride (136.3 g, 1.00 mol) was added and the reaction was heated to 80°C. 1,1,1,3,3,3-Hexamethyldisilazane .0 (242 g, 1.5 mol) in toluene (1000 ml) was then added dropwise over one hour and the mixture was stirred at 80°C for another 4 hours. The mixture was cooled to room temperature and then poured onto 1N HCI (4000 ml). The two layers were separated and the organic Jayer was washed with water (2000 ml), saturated sodium bicarbonate (2000 ml) and brine (2000 ml). The organics were concentrated in vacuo 5 to give the title compound (74 g, 54%) as a solid. 1H-NMR (300MHz. CDCI3): 4.05 (d, 2H), 5.00-5.15 (m, 2H), 5.60-5.80 (m, 1H), 6.65 (2H, s). Preparation 152 0 1 -(3-nitrophenvl)-1 -propanone hvdrazone _ s N 2 WO 01/98267 71 PCT/IBO1/01035 To a solution of 3-nitropropiophenone (168 g, 0.93 mol) in ethanol (830 ml) at room temperature was slowly added hydrazine monohydrate (96.8 g, 1.93 mol) via a dropping funnel. The reaction mixture was heated at reflux for 4 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (750 ml) and water (750 ml). The two layers were separated and the organic layer was washed with brine (250 ml), dried (Na2S04), filtered and concentrated in-vacuo to give an orange oil. This residue was crystallised from diisopropyl ether at -20°C to afford the title compound (110 g, 61%) as a yellow crystalline solid. Mpt: 32°C 1H-NMR (300MHz, CDCI3): 1.20 (t, 3H), 2.70 (q, 2H), 5.65 (broad s, 2H), 7.50 (t, 1H), 7.95 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H). MS (Electrospray) M/Z [MH]+194; QH^NaOj + H requires 194.1. Preparation 153 3-AII vl-6-eth vl-6-f 3-nitrophenvl )-3-aza bicvclor3.1.01 h exane-2,4-d ione fl. Nr N To a stirred solution of 1-(3-nitrophenyi)-1-propanone hydrazone (84.7 g, 439 mmol) 0 in 1,4-dioxane (1000 mt) was rapidly added manganese dioxide (grade CMD-1 from Sumitromo, 175 g, 2.01 mo!) followed by a saturated solution of ethanolic potassium hydroxide (40 ml) at room temperature. The mixture was stirred at room temperature for 18 minutes and during this period the reaction temperature had risen from 19°C to 25°C. Stirring was then stopped and the mixture was allowed to settle. This 5 mixture was then filtered through a pad of Ceiite® dropwise, directly into a solution of WO 01/98267 72 PCT/IB01/01035 1-a!lyI-1H-pyrolle-2,5-dione (57.3 g, 418 mmol) in 1,4-dioxane (200 ml). The Ceiite® pad was washed with 1,4-dixane (100 ml) to ensure complete addition of the reactants. After stirring at room temperature for one hour the mixture was heated at reflux for 20 hours. The mixture was cooled to room temperature and the solvent 5 was removed in vacuo. The residue was then crystallised from diisopropyl ether (1000 m!) at 0°C to afford the title compound (83 g, 66%) as an off-white crystalline solid. MR: 128-129°C 1H-NMR (300MHz, CDCI3): 0.90 (t, 3H), 1.80 (q, 2H), 2.80 (s, 2H), 4.05 (d. 2H), 5.20 0 (d, 1H), 5.30 (d, 1H), 5.75-5.85 (m, 1H), 7.55 (t, 1H), 7.70 (dd, 1H), 8.20 (dd, 1H), 8.25 (s, 1H). Preparation 154 3-allvl-6-f3-aminophenvl)-6-ethvl-3-azabicvdor3.1.0lhexane-2.4-dione 5 To a stirred suspension of 3-allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1,0]hexane-2,4-dione (93 g, 310 mmof) and iron powder (151 g, 2.70 0 moi) in ethanol (6.75 L) was added calcium chloride (16.7 g, 0.15 mol) in water (1.2 L). The mixture was heated at reflux for three hours and then cooled to room temperature before being filtered through Ceiite®. The filtrate was concentrated in vacuo to give a wet solid. This material was dissolved in dichloromethane (500 ml) and the two layers were separated. The organic layer was dried (MgS04), filtered WO 01/98267 PCT/IB01/01035 73 and concentrated in vacuo to give a pale yellow solid (81 g). This material was crystallised from ethyl acetate and hexane (1:1; 6ml per gram) at room temperature to afford the title compound (54 g, 65%) as a pale yellow crystalline solid. 1H-NMR (300MHz, CDCI3): 0.90 (t, 3H), 1.75 (q, 2H), 2.75 (s, 2H), 3.95 (broad s, 5 2H), 4.05 (d, 2H), 5.25 (d, 1H), 5.35 (d, 1H), 5.75-5.85 (m, 1H), 6.65 (d, 1H), 6.70 (s, 1H), 6.75 (d, 1H), 7.10 (t, 1H). Preparation 155 3-(3-Allvl-6-ethvl-3-azabicvclof3.1 .Olhex-6-vnaniline 10 To a solution of lithium aluminium hydride (1M solution in THF; 400 ml, 400 mmol) in tetrahydrofuran (400 ml) under a nitrogen atmosphere at -15°C was added 3-ally!-6-15 (3-aminopheny!)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 ml) via a dropping funnel over 0.5 hours. The mixture was then allowed to slowly warm to room temperature over one hour. The mixture was heated at 50°C for 3 hours and then cooled to 5°C. Water (400 ml) was then cautiously added to the cooled (5°C) reaction mixture. The solids were removed by filtration 20 through a pad of Ceiite®, washing with ethyl acetate (400 ml). The filtrate was dried (MgS04), filtered, and concentrated in vacuo to afford the title compound (38.1 g, 96%) as a golden oil. 1H-NMR (300MHz, CDCl3): 0.85 (t, 3H), 1.80-1.95 (m, 4H), 2.85-3.00 (m, 4H), 3.15 (d, 2H), 3.60 (broad s, 2H), 5.10 (d, 1H), 5.20 (d, 1H), 5.80-5.95 (m, 1H), 6.50 (d, 25 1H), 6.60 (s, 1H), 6.65 (d, 1H), 7.05 (t, 1H). WO 01/98267 PCT/IB01/01035 74 MS (AP+) M/Z [MH]+ 243; C16H2ZN2 + H requires 243.2. Preparation 156 A/-r3-f3-allvl-6-ethvl-3-azabicvclor3.1.01hex-6-vlbhenvnmethanesulfonamide To a solution of 3-{3-aIlyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniiine (41 g, 169 mmo!) 10 and triethylamine (34 g, 337 mmol) in dichloromethane (750 ml) at -40°C was added dropwise methanesulfonyl chloride (23.7 g, 206 mmol) via a dropping funnel. The . reaction mixture was slowly allowed to warm to room temperature over 2 hours and was then stirred at room temperature for 20 hours. The organics were then washed with water (4 x 500 ml), dried (MgS04), filtered and concentrated in vacuo to afford 15 the title compound (59.0 g) as a crude gum. 1H-NMR (300MHz, CDCl3): 0.85 (t, 3H), 1.85 (s, 2H), 1.95 (q, 2H), 2.80-3.20 (m, 9H), 5.10-5.25 (m, 2H), 5.80-5.95 (m, 1H), 7.00-7.40 (m, 4H). Preparation 157 20 /V-r3-(6-ethvl-3-azabicvclof3.1.01hex-6-vi)phenvnmethanesulfonamide WO 01/98267 75 PCT/IBO1/01035 IU <r° 10 To a degassed solution of A/-[3-(3-allyI-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesuIfonamide (54.0 g, 169 mmol) and 1,3-dimethylbarbituric acid (80.0 g, 512 mmol) in dichloromethane (500 ml) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol). The mixture was heated at reflux for 8 hours and then stirred at room temperature for 20 hours. The organics were then extracted with 2M HCI (2 x 100 ml) and water (100 ml). The combined aqueous layers were then washed with dichloromethane (4 x 100 ml) and freeze dried to give a crude solid. This material was purified by preparative HPLC (condition 4) to afford the trifluoroacetic acid salt of title compound (25.2 g, 53%) as a grey solid. 1H-NMR (300MHz, CD3OD): 0.90 (t, 3H), 1.65 (q, 2H), 2.30-2.40 (m, 2H), 2.90 (s, 15 3H), 3.25-3.35 (m, 2H), 3.70-3.80 (m, 2H), 7.10-7.15 (m, 2H), 7.20 (s, 1H), 7.30 (t, 1H). MS (AP+): M/Z [MH]+ 281; C14H20N2Q2S + H requires 281.1. 20 Preparation 158:3-Benzvl-6-methvl-6-(3-nitrophenvl)-3-azabicvclor3.1.01hexane-2.4-dione To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone (100g, 0.56mol), in dioxan (1L) was added Mn02 (350g, 2.3moi) and the reaction mixture stirred at room temperature for 30mins. The slurry was filtered through ceiite 25 and the ceiite pad washed with dioxan (200mls). The filtrate was returned to a pot and N-benzyl maleimide (110g,) added portionwise over a period of 20mins. The WO 01/98267 76 PCT/IBO1/01035 reaction mixture was stirred at room temperature for 4hrs before being heated under reflux for 16hrs. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was triturated in methanol (500mls) and the product isolated by filtration as a white crystalline solid ( 56%). 5 NMR (CDCI3) d: 1.31 (s, 3H), 1.55 (s, 3H), 2.80 (s, 2H), 4.63 (s, 2H), 7.28-7.34 (m, 3H), 7.43-7.45 (d, 2H), 7.52-7.56 (t, 1H), 7.63-7.65 (d, 1H), 8.13-8.16 (d, 1H), 8.17 (s, 1H) 10 MS (APCI): m/z [MH+] 337.5 +H requires 337.3 Preparation 159: 6-(3-Aminophenvl)-3-benzvl-6-methvl-3-azabicvclor3.1 .Olhexane-2.4-dione 15 To a slurry of 3-benzyl-6-methy!-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (30g, 89mmol) in ethyl acetate (600mls) was added 5%Pt/C (1.5g, 5wt%). The mixture was hydrogenated at 4 atm. (=60p.s.i.) / room temperature for 18hrs. The slurry was filtered through arbacel and the resulting solution evaporated in vacuo to yield the product as a white crystalline solid (24g, 88%). 20 NMR (CDCI3) d: 1.26 (s, 3H), 2.74 (s, 2H), 3.7 (2H, bs), 4.60 (s, 2H), 6.56-6.58 (d, 1H), 6.60 (s, 1H), 6.65-6.67 (d, 1H), 7.07-7.11 (t, 1H), 7.26-7.33 (m, 3H), 7.42-7.44 (m, 2H). MS (APCI): m/z [MH+] 307.5 +H requires 307.4 25 Preparation 160: N-(3-r3-Benzvi-6-methvl-2.4-dioxo-3-azabicvcloI3.1.01hex-6-vriphenvllmethanesulfonamide 30 To a solution of 6-(3-aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione (24g, 78mmol) in ethyl acetate (480mls) was added pyridine (9.5mls, 118mmol) followed by the slow addition of methane sulfonyl chloride (9.1 mis, 118mmol). The reaction was stirred at room temperature for 2.5hrs. The reaction mixture was washed sequentially with 1M HCl solution (120m!s) and water (120mls). WO 01/98267 77 PCT/IBO1/01035 The ethyl acetate was dried over MgS04 and evaporated in vacuo to yield the product as an orange solid (30g, 99%). NMR (CDC13) d: 1.27 (s, 3H), 2.77 (s, 2H), 3.02 (s, 3H), 4.61 (s, 2H), 7.08-7.14 (m. 5 3H), 7.26-7.32 (m, 4H), 7.41-7.42 (d, 2H). MS (APCI): m/z [MH+] 385.7 +H requires 385.5 Preparation 161: N-f3-Benzvl-6-methvl-3-azabivclor3.1.OIhex-6-vnphenvfl io methanesuifonamide To a solution of N-{3-[3-benzyl-6-methyI-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yljphenyljmethanesulfonamide (150g, 391mmo[), under nitrogen was added sodium borohydride (31 g, 820mmol). The reaction mixture was cooled to <10°C and the 15 BF3.OEt2 (138.6mls, 1094mmol) added dropwise maintaining the temperature at <10°C. The reaction mixture was allowed to warm to room temperature over 2hrs before being heated under reflux for a further 8.5hrs. The reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (198.5g, 2304mmol in 1.26L of water) added. The reaction mixture was then heated under 20 reflux for a period of 18hrs. The THF was removed under vacuum, ethyl acetate (900mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (450m!s). The organic phases were combined and washed with water (750mls). The organics were dried over MgS04 and evaporated in vacuo to yield the product as a white crystalline solid (129g, 93%). 25 NMR (CDCI3) d: 2.62 (s, 3H), 2.80-2.83 (d, 2H), 2.99 (s, 3H), 3.03-3.07 (d, 2H), 3.68 (s, 2H), 7.01-7.02 (s, 1H), 7.06-7.08 (m, 2H), 7.22-7.26 (m, 3H), 7.30-7.32 (m, 3H). 30 MS (APCI): m/z [MH+]357.5 +H requires 357.5 Preparation 162: N-f3-f6-methvl-3-azabicvclof3.1.0lhey-B-vHphenvDmethanesulfonamide 35 WO 01/98267 78 PCT/1B01/01035 To a solution of N-{3-benzyl-6-methyl-3-azabiycio[3.1.0]hex-6-yl]phenyl} methanesulfonamide (20g, 56mmol), in methanol, was added ammonium formate (10.6g, 168mmoi) and the reaction stirred for 5minutes. 10% Pd/C (8g) was added 5 and the resulting mixture heated at reflux for 16hrs. The mixture was allowed to cool and the catalyst removed by filtration through ceiite. The solvent was removed in vacuo to yield the product as a pale yellow oil, which solidified on standing (15.2g, 85%). 10 NMR (CDCI3) d: 1.27 (s, 3H), 1.85-1.88 (d, 2H), 2.93 (s, 3H), 3.07-3.10 (d, 2H), 3.39-3.44 (d, 2H), 6.92-6.97 (m, 2H), 7.06 (s, 1H), 7.20-7.23 (m, 1H). MS (APCI): m/z [MH+] 267.4 +H requires 267.3 15 Preparation 163 : 3-Benzvl-6-ethvl-6-(3-nitrophenvl)-3-azabicvclor3.1.01hexane-2.4-dione To a solution of 1-(3-nitrophenyl)-1-propanone hydrazone (42.1 gg, 217mmoi), in dioxan (630mls) was added Mn02 (126g, 1440mmol) and the 20 reaction mixture stirred at room temperature for 20mins. The slurry was filtered through ceiite and the ceiite pad washed with dioxan (200mls). The filtrate was returned to a pot and N-benzyl maleimide (44.9g, 239mmol) added portionwise over a period of 20mins. The reaction mixture was stirred at room temperature for 60hrs before being heated under reflux for 16hrs. The reaction mixture was cooled to room 25 temperature and the solvent removed in vacuo. The residue was heated to reflux in methanol (1200mls) for 3 hours and then cooled to room temperature. The product was isolated by filtration as a white crystalline solid (42.4g, 56%). NMR (CDCI3) d: 0.69-0.73 (t, 3H), 1.47-1.49 (q, 2H), 2.78 (s, 2H), 4.64 (s, 2H), 30 7.3-7.32 (m, 2H), 7.43-7.44 (d, 1H), 7.52-7.55 (t, 1H), 7.62-7.65 (d, 2H), 8.17-8.18 (m, 3H). MS (APCI): m/z IMH+]351.5 +H requires 351.3 WO 01/98267 79 PCT/IB01/01035 Preparation 164:6-f3-AminophenvlV3-benzv1-6-ethvl-3-azabicvelof3.1 .Olhexane-2.4-dione To a slurry of 3-benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyc!o[3.1.0]hexane-2,4-dione 5 (42.1g, 120mmol) in ethyl acetate (850mls) was added 5%Pt/C (2.1g, 5wt%). The mixture was hydrogenated at 60psi/ room temperature for 18hrs. The slurry was filtered through arbacel and the resulting solution evaporated in vacuo to yield the product as a white crystalline solid (34.1g, 89%). 10 NMR (CDCI3) d: 0.70-0.74 (t, 3H), 1.41-1.47 (q, 2H), 2.73 (s, 2H), 3.68 (bs, 2H), 4.61 (s, 2H), 6.55-6.57 (d, 1H), 6.60 (s, 1H), 6.66-6.68 (d, 1H), 7.07-7.10 (t, 1H), 7.28-7.32 (m, 3H), 7.41-7.43 (d, 2H). MS (APCI): m/z [MH+] 321.4 +H requires 321.4 15 Preparation 165: N-f3-r3-Benzvl-6-ethvl-2.4-dioxo-3-azabicvclor3.1 .Olhex-6-vllphenvflmethanesulfonamide To a solution of 6-(3-aminophenyl)-3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (31.5g, 98mmol) in dichloromethane (250mls) was added pyridine (9.5mls, 20 118mmol) followed by the slow addition of methane sulfonyi chloride (9.1 mis, 118mmol). The reaction was stirred at room temperature for 16hrs. The reaction mixture was washed sequentially with 1M HCi solution (250mls) and water (120mls). The dichloromethane was dried over MgS04 and evaporated in vacuo to yield the product as a waxy pink solid (38.2g, 98%). 25 NMR (CDCI3) d: 0.68-0.72 (t, 3H), 1.42-1.47 (q, 2H), 2.75 (s, 2H), 3.02 (s, 3H), 4.62 (s, 2H), 7.13-7.18 (m, 3H), 7.29-7.42 (m, 4H), 7.41-7.43 (d, 2H). MS (APCI): m/z [MH+] 399.6 +H requires 399.5 Preparation 166: N-{3-Benzvl-6-ethvl-3-azabicvclor3.1 .Olhex-6-vnphenvl) 30 methanesulfonamide To a solution of N-{3-[3-benzyl-6-ethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (38.2g, 95mmol), in THF (200mls) under nitrogen was added sodium borohydride (7.46g, 201 mmol). The reaction mixture was cooled to 35 <10 C and the BF3.OEt2 (38.1 mis, 268mmol) added dropwise maintaining the WO 01/98267 80 PCT/IB01/01035 temperature at <10 C. The reaction mixture was allowed to warm to room temperature over 2hrs before being heated under reflux for a further 12hrs. The reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (48.7g, 565mmoI in 320m!s of water) added. The reaction mixture was 5 then heated under reflux for a period of 18hrs. The THF was removed under vacuum, ethyl acetate (200mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (200mls). The organic phases were combined and washed with 3 separate portions of water (3x400mls). The organics were dried over MgS04 and evaporated in vacuo to yield 10 the product as a white crystalline solid (33.5g, 94%). NMR (CDCI3) d: 0.84-0.88 (t, 3H), 1.76-1.77 (d, 2H), 2.06-2-.12 (q, 2H), 2.79-2.81 (d, 2H), 2.99 (s, 3H), 3.06-3.08 (d, 2H), 3.67 (s, 2H), 7.01-7.03 (d, 1H), 7.08-7.10 (d, 2H), 7.22-7.26 (m, 3H), 7.30-7.32 (m, 3H). 15 MS (APCI): m/z [MH+] 371.3 +H requires 371.5 Preparation 167: N-(3-r6-Ethvl-3-azabicvclo[3.1.01hex-6-vllphenvDmethanesulfonamide 20 To a solution of N-{3-benzyl-6-ethyl-3-azabiyclo[3.1.0]hex-6-y!]phenyl} methanesulfonamide (500mg, 1.34mmol), in methanol (30mls), was added ammonium formate (255mg, 4.05mmo!) and the reaction stirred for 5minutes. 10% Pd/C (200mg) was added and the resulting mixture heated at reflux for 2hrs. The 25 mixture was allowed to cool and the catalyst removed by filtration through ceiite. The solvent was removed in vacuo to yield the product as a pale yellow oil, which solidified on standing (15.2g, 85%). NMR (CDCI3) d: 0.80-0.84 (t, 3H), 1.64-1.69 (q, 3H), 1.82-1.86 (d, 2H), 2.98 (s, 3H), 3.12-3.18 (d, 2H), 3.21-3.26 (d, 2H), 7.01-7.06 (d, 1H), 7.10-7.14 (m, 2H), 7.25-30 7.28 (m,1H). MS (APCI): m/z [MH+] 281.7 +H requires 281.4 WO 01/98267 81 PCT/IBO1/01035 Other building block materials useful in synthesising compounds of formula (I) with various different R4 groups are available from the sources indicated in the table below, and routine derivatisation thereof, or analogy synthesis. R4 Substructure Example of commercial source Literature reference -(CH2)nO(CH2)nR examples Ck .OH ALDRICH 1 ALDR1CH H0^0^NH2 0 SALOR 1. Org.Magn.Reson., 1975, Vol 7, 488-495. WO 01/98267 82 PCT/IB01/01035 WO 8707270 Alcohol US 5157159 HO. MAYBRiDGE ALDRICH HCL ^ n ALDRICH HOvY^°'^nV^xi 0 Bull. Soc. Chim. Fr.; 1947,616. Alcohol-EP-0811621 (CH2)nO(CH2)nAryl examples BIONET 1. J. Org. Chem., 1987, 52 (12), 2594. 2. Org. Prep. Proceed, int; 23,4; 1991, 427. All other (CH2)nO(CH2)nAryl examples could be prepared via 2 step process For a general procedure see; J. Am. Chem. Soc., 1951,3159-3162. WO 01/98267 83 PCT/IB01/01035 from a benzyl alcohol or benzyl chloride Aryl substituents on R4 (mix. of aryl and aryloxy examples): H2N^0 SALOR J. Med. Chem., 1985, 28, 1427. J. Med. Chem., EN; 28, 10, 1985, 1427. 0 SALOR H j^^j^^SQ2Me H 2 By manipulation of the product above. ci^V^ <- N\ 0 o DE 2135678; DE 3636333 Rev. Med.-Chiv., 1985, 89 (2), 316-20. SPECS WO 01/98267 84 PCT/IB01/01035 \\ o o .0. ho ^ 0 APIN J. Med. Chem., 28, 10, 1985,1427 J. Med. Chem., 28,10, 1985, 1427 ""^ax EP-0171760 J. Med. Chem., 28, 10, 1985, 1427. ■^tX- LANCASTER ICN-RF HO"^^0,vrr^] kA^o n -/ MAYBRIDGE WO 01/98267 85 PCT/IBO1/01035 H0^°TXX) SALOR 0 MAYBRIDGH OH Agric. Biol. Chem., 1978, 1767. WO 9611192 falcohoh WO 9610999 Imidazole analogue: J. Med Chem., 1981, 24(10), 1139 US-4713387 MAYBRIDGE J. Med. Chem., 28,10, 1985, 1427. Substituents of the basic R4 alkyl/alkenyl/alkynyl chains: ICN-RF 0 WYCHEM ALDRICH WO 01/98267 86 PCT/IB01/01035 WO 01/98267 87 PCT/IB01/01035 ^ H HO /I ] r<^ 0 ALDRICH X V LANCASTER AIcohol-ALDRICH °w° \\// LANCASTER LANCASTER '/ vV\ 0 O SPECS H sC '' r\ 0 0 MDA O /\/OH H ALDRICH Qy>^ 0 ALDRICH MAYBRIDGE 0^ ALDRICH </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 01/98267 88 PCT/IBO1/01035 a x ^°h H H MAYBRIDGE H0^ Y 0 SALOR 0 HO ^ ALDRICH O JL /S. J\L HO Y ALDRICH WO 01/98267 89 PCT/IBO1/01035 CLAIMS wherein the "Ar" ring represents an optionally benzo-fused phenyl or 5- or 6-membered 15 heteroaryl ring; Rl when taken alone is H, halogen, N02, NH2, NY2WY1, Hetl, AD, CO2R7, C(0)R8, C(=N0H)R8, or OE, 20 Y2 is H, C|.g alkyl, C3.5 alkenyl (each of which alkyl and alkenyl is optionally substituted by aiyl, aryloxy or Hetl), W is S02, CO, C(0)0, P(Yl)=0, P(Yl)=S, 25 YlisCj-io alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, Ci_4 alkoxy, Cj-g alkanoyloxy, CONH2, alkoxycarbonyl, NH2, aiyl, mono- or di(Cj_4 alkyl)amino, C3.3 cycloalkyl, phthalimidyl, Hetl), Hetl, aiyl (optionally substituted by one or more substituents independently selected from C1.4 alkyl, Cj_4 haloalkyl and halogen), NH2, N(Ci_6 alkyl)2 or NH(C]_6 alkyl), 30 Hetl {s a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaiyl group, optionally benzo- or pyrido-fosed heteroaryl), optionally substituted by one or more substituents independently selected from Ci_g alkyl, 35 Ci_6 alkoxy, C3.6 cycloalkyl, Ci_6 haloalkoxy, Cj_6 haloalkyl, C3-6 halocycloalkyl, =0, 90 OH, halogen, NC>2, SiRl9aR19bR19c cONR20aR20b, NR20aR20K SR2**, NR21bSo2R22a> nr210C(O)OR22b NR2ldC0R22b, and Ci-g alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a -S-, S(O)- or -S(C>2)- group, and carbon atoms in the ring can be present as a part of a carbonyl moiety; 5 Rl9af Rl9b9 R19c each independently represent Ci-g alkyl or aryl, R20a ^ R20b each independently represent H, Ci-6 alkyl, aryl, (Ci_4 alkyl)phenyl, each of which alkyl, aryl and alkylphenyl are optionally substituted by one or more Ci_4 alkyl, 10 Ci_4 alkoxy, OH, NO2, NH2 and/or halogen, or R20a and R20b can be taken together with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substitutuents independently selected from one or more Cj_4 alkyl, C1.4 alkoxy, OH, =0, NO2, NH2 and/or halogen, ^^15 R21a> b, c and d each independently represent H, Ci-6 alkyl, aryl or C1-4 alkylphenyl, each of which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Cj_4 alkyl, Ci-4 alkoxy, OH, NO2, halogen, NH2. R22a, b and c each independently represent Ci.g alkyl, aiyl or C|_4 alkylphenyl, each of 20 which alkyl, aiyl, and alkylphenyl are optionally substituted by one or more Ci_4 alkyl, Cj_4 alkoxy, OH, NO2, halogen, NH2, A is Cj_4 alkylene, C2-4 alkenylene or C2-4 alkynylene, each of which is optionally substituted by one or more Ci_4 alkyl, Cj_4 alkoxy, halogen and/or OH, 25 D is H, OH, CN, NR25r26 OONR25r26 nhr27 C02R28, COR2?, c(=noh)R29 or AD is CN, NR25r26, C0NR25r26 30 where r25 and R26 are either each independently H,'Ci_3 alkyl, C3_g cycloalkyl, aiyl, Cj.4 alkylphenyl (each of which C1.3 alkyl, C3.8 cycloalkyl, aryl and Cj_4 alkylphenyl are optionally substituted by one or more N02, halogen, Cj_4 alkyl and/or C\_4 alkoxy, (each of which latter Cj_4 alkyl and C1.4 alkoxy is optionally substituted by one or more halogen)), or R25 and R26 are taken together with the N atom to which they are attached and can fofm a 35 4- to 7-membered heterocyclic ring optionally incorporating one or more further hetero INTEL! ^ 2 3 MAR 2005 RECElVPr WO 01/98267 91 PCT/IB01/01035 atoms selected from N, 0 and S, and which ring is optionally substituted by one or more Cj. 4 alkyl, OH, =0, NO2, NH2 and/or halogen, R27 is COR30, CO2R31 a, S02R3 lb, r28 an{j r29 are each independently H, Ci_g alkyl, 03.3 cycloalkyl, aryl or Ci_ 4alkylphenyl, each of which Cj-g alkyl, C3.3 cycloalkyl, aryl and Cj_4 alkylphenyl are optionally substituted by one or more N02, halogen, C1.4 alkyl, C1.4 alkoxy (each of which latter C1.4 alkyl and Cj_4 alkoxy are optionally substituted by one or more halogen), R30 is H, C\_4 alkyl, C3.8 cycloalkyl, C4.4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, C\_4 alkylphenyl, phenyl(Ci_4 )alkoxy, (each of which (4.4 alkyl, C3.8 cycloalkyl, Ci_4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, Ci_4 alkylphenyl and phenyl(Ci_4 )alkoxy are optionally substituted by one or more NO2, halogen, C1.4 alkyl, C1.4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)), R31a and R31b are each independently C1.4 alkyl, C3.8 cycloalkyl, aryl or Ci_4 alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, Ci_4 alkyl or C1-4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen E is H, COHR32r33) CSNR32r33j COR34 CO2R34, COCH(R34a)NH2, r35; CH2C02R35a, CHR35bc02R35a, CH20C02R35c CHR35d0C02R35c, COCR36=CR37nH2, COCHR36cHR37nh2i or PO(OR38)2, r32 and r33 are each independently H, C3.10 alkylalkenyl, C3.7 cycloalkyl (optionally substituted by C1.4 alkyl), phenyl (optionally substituted by (X)n), Ci.jo alkyl (optionally substituted by C4.7 cycloalkyl (optionally substituted by C1.4 alkyl) or phenyl optionally substituted by (X)n), or R32 and R33 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising further hetero atoms selected from N, O and S, which heterocycle is optionally substituted by C1.4 alkyl, optionally substituted by one or more halogen, WO 01/98267 92 PCT/IB01/01035 R.34 is H, C4.7 cycloalkyl (optionally substituted by one or more C}_4 alkyl), phenyl (optionally substituted by (X)n, C1.4 alkanoyloxy, NR32r33; C0NR32r33 and/or OH), or Ci.g alkyl (optionally substituted by one or more halogen, 04.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), or phenyl (optionally substituted by (X)n, C]-4 alkanoyloxy, NR32R339 CONR.32r33 and/or OH)), R34a is h, C 1.6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), or phenyl (optionally substituted by (X)n, Ci_4 alkanoyloxy, Nr32r33! CONR32r33 ancJ/or OH)), C4.7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), phenyl (optionally substituted by (X)n, Cj-4 alkanoyloxy, NR.32r33j CONR3^r33 and/or OH) or a naturally occuring amino acid substituent, R35 is C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl (optionally substituted by one or more (X)n, Cj.4 alkanoyl, NHR32, CON(r32)2, and/or OH); alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Cj-4 alkyl, or phenyl (optionally substituted by one or more (X)n, C1.4 alkanoyl, NHR32, CON(R32)2, and/or OH)), C1.4 alkoxy(Ci_4 alkyl), phenyl(Ci_4)alkyloxy(Ci_4)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, R35a,b,c and d are each independently H, C4.7 cycloalkyl optionally substituted by one or more C1-4 alkyl, phenyl optionally substituted by one or more (X)n or alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C^.4 alkyl, or phenyl optionally substituted by one or more (X)n), R36 and R37 each independently represent H, C3-6 alkylalkenyl, C4.7 cycloalkyl, phenyl optionally substituted by one or more (X)n, or Ci_g alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl optionally substituted by one or more (X)n), R3® is C4.7 cycloalkyl optionally substituted by one or more C}_4 alkyl, phenyl optionally substituted by one or more (X)n, or Cj.g alkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, or phenyl optionally substituted by one or more (X)n), WO 01/98267 93 PCT/IB01/01035 when taken alone is H or halogen; or Rl and R2, when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Het^a; Het^3 is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S,. which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5- to 7-membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, =0, halogen, Ci_4 alkyl, Cx-4 haloalkyl, C1.4 alkoxy and C1-4 haloalkoxy, which Cj_4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and Cj_4 haloalkoxy groups can be optionally substituted by one or more C3.6 cycloalkyl, atyl(Ci_6)alkyl, which aiyl group is optionally substituted by one or more halogen, Ci_4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and C1.4 haloalkoxy, which latter Cj_4 alkyl, C1.4 haloalkyl, Cj_4 alkoxy and C1.4 haloalkoxy groups can be optionally substituted by one or more NR23r24 NR23S(0)nR24 NR23c(0)mR24 and if a S atom is present in a ring, it can be present as part of a -S-, S(0)- or -S(02)- group, which R23 and R24 when taken alone independently represent H, Ci_4 alkyl, or C1.4 haloalkyl, or R23 and R^4 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, C1.4 alkyl, C1.4 haloalkyl, C}_4 alkoxy and/or C1.4 haloalkoxy groups, R3 is H, CN, halogen, Ci_6 alkoxy, C]_6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C3.8 cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12r135 CONR12r13j NY^WY*, Cj.g alkyl, C2-I0 alkenyl, C2-10 alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, Cj_6 alkoxy, Cj.g alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, Ci_g alkanoyl, Ci-6 alkanoyloxy, C3_g cycloalkyl, C3_g cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12r13 and/or NY2^1), 94 R4 is Ci.io alkyl, C340 alkenyl or C3.10 alkynyl, each of which groups is linked to flie N atom via a sp3 carbon, and which group is substituted by one or more substituents selected from: C^alkoxy [substituted by one or more groups selected from OH, NR25r26j CONR25r26j halogen, Ci_6 alkoxy, C2.4 alkynyl, C2.4 alkenyl, heteroaiyl1, aiyl1, COOE^CN, CO(heteroaryll), COCaryl1), C02(heteroaryll), CQCH^Caryl1), CXXH2(Meroaiyll), C02CH2(aryll);C02CH2(heteroaiyll), S(0)n(Ci^ alkyl), S(0)n(aiyll), S(0)n(heteroaryl), S02NR25R26, a cycloalkyl group that is a C3.10 carbocyclic system with one or two rings and cycloalkyl1], S(0)nCi.g alkyl [optionally substituted by one or more groups selected from OH, NR25r265 CONR25r2^, halogen, alkoxy, C2_4 alkynyl, C2^ alkenyl, heteroaryl 1, aryll, COCH2CN, CO(heteroaryll), CO(aiyll), C02(heteroaiyll), COCH2(aiyll), COCH2(heteroaryl1), C02CH2(aiyll), CX^CH^eteroaiyl1), S(0)n(Ci_6 alkyl), S(0)n(aiyll), S(0)n(heteroaiyll), S02NR25r26 and cycloalkyll], aryl2, CX)2CH2(heteroaiyl1), C02CH2(aryl1), cycloalkyl^, a cycloalkyl group that is a C3.10 carbocyclic system with one or two rings and cycloalkyl1], CO(heteroaiyll), CO(aiyll), OCO(aiyll), OCOCheteroaiyl1), OCO(Ci^ alkyl), OCOCH2CN, C02(heteroaryll), C02(aryll), COCH2(heteroaryll), SCOJnaryl1, S(0)nCH2aiyll, SCO^Oieteroaiyll), S(0)nCH2Cheteroaryll), NHS02«iyll, INTELLECTUAL PROPERTY OFFICE OF N.2. 2 3 MAR 2005 RECEIVED 95 NHS02(heteroaryll), NHS02CH2(heteroaryll), NHS02CH2(aiyll), NHCOaryll, 5 NHCONHaiyll, NHCOheteroaryl1, NHCONHheteroaryll, 10 NHC02(aiyli), NHC02(heteroaryl *), aiyl2oxy, heteroaiylloxy, 15 Cj.6 alkoxycarbonyl substituted by Ci-g alkyl, aryl, Ci_6 alkoxy, GB^aryl1), C1.4 haloalkyl, halogen, OH, CN or NR25r269 C2-6 alkanoyl substituted by Ci-g alkyl, aiyl, Cj_6 alkoxy, GH^Caryl1), C1-4 haloalkyl, halogen, OH, CN or NR25r26 C2-6 alkanoyloxy substituted by Cj-g alkyl, aryl, Ci-6 alkoxy, CH2(aryll), C1-4 haloalkyl, 20 halogen, OH, CN or NR25r26, cycloalkylloxy, COcycloalkyll, heterocycle substituted by one or more substituent selected from Cj-g alkyl(substituted by OH), CONR25R26 CH2CONR25r26, NR25r26, NHC0NR25r26 CO(Ci_6 alkyl), 25 S02NR25R26 SO^C^ alkyl), C02(Ci^ alkyl), CH2C02(Ci.6 alkyl), 0CH2C02(Ci^ alkyl), aryl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aiyl(CH2), CN and C3.7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from Ci„6 alkyl(substituted by OH), CONR25r26 ch2c0nr25r26t nr25r26, NHCONR25r26, CO(Ci^ alkyl), 30 S02NR.25R26 S02(CW alkyl), C02(Ci^ alkyl), CH2C02(Ci^ alkyl), 0CH2CQ2(Ci.6 alkyl), aiyl, heterocyclyl, aiyloxy, axyl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, WHEREIN aryll is phenyl optionally fused to a C5.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from Ci_6 alkyl(optionally 35 substituted by OH, CN or halogen), Ci .5 haloalkoxy, OH, =0, NY2WY1, halogen, Ci_fi intellectual property office OF N.Z. 2 3 MAR 2005 RECEIVED 96 alkoxy, CONR^R26, CH2CONR25r26} nr25r26, nhC0NR25r26, CO(Ci-g alkyl), COaryl, COheteroaryl, SOjNR^R26, S(0)n(Ci_6 alkyl), S(0)n(aryl), S(0)n(heteroaryl), C02(Ci_6 alkyl), C02(aiyl), C02(heteroaryl), C02H, (CH2)i_4C02(Ci.6 alkyl), (CH2)i-4CO2H, (CH2>l-4C02(aryl), (CH^j^CO^eteroaryl), 0(CH2)i_4C02(Ci.6 alkyl), 5 0(CH2) 1-4CO2H, 0(CH2)l-4c02(ary1). 0(CH2)i_4C02(heteroaiyl), aiyl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aiyl(CH2), CN, 0(CH2)i_4C0NR25r26 and C3.7 cycloalkyl, aiyl2 is phenyl optionally fused to a C5.7 carbocyclic ring, which group is substituted by one or more substituent selected from Cj_6 alkyl(substituted by OH), CONR25r26; 10 CH2conr25R26, nr25r26 nhconr25r26, C0(Ci_6 alkyl), COaryl, COheteroaryl, S02NR25r26j S(0)n(Ci^ alkyl), S(0)n(aiyl), S(0)n(heteroaiyl), C02(Ci.6 alkyl), C02(aiyl), C02(heteroaryl), C02H, (CH2)l-4C02(Ci^ alkyl), (CH2)l-4C02H, (CH2)i-4CX)2Caiyl)1 (CH2)l-4C02(heteroaiyl), 0(CH2)i_4C02(Ci_6 alkyl), 0(CH2)i_4C02H, 0(CH2) 1 -4C02(aryl), 0(CH2) 1 -4C02(heteroaiyl), aryl, heterocyclyl, aryloxy, 15 aiyl(CH2)oxy, aiyl(CH2)» CN. 0(CH2)1-4C0NR25r26 md C3.7 cycloalkyl, heteroaryl 1 is heteroaryl optionally fused to a C5.7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C^g alkyl(optionally substituted by OH, CN or halogen), Cj-6 haloalkoxy, OH, =0, NY^WYl, halogen, Ci-g 20 alkoxy, CONR25R26, CH2CONR25r26 nr25r26 NHC0NR25r26) CO(Ci„6 alkyl), COaiyl, COheteroaryl, S02NR25r26} S(0)n(Ci.6 alkyl), S(0)n(aryl), S(0)n(heteroaiyl), C02(Ci^ alkyl), C02(aiyl), C02(heteroaiyl), C02H, (CH2)i-4C02(Ci_6 alkyl), (CH2)i-4C02H, (CH2)i-4C02(aiyl), (CH2)i^4C02(heteroaxyl), 0(CH2)i.4C02(Ci.6 alkyl), 0(CH2)i^C02H, 0(CH2)i_4CXD2(aiyl), 0(CH2)i.4C02(heteroaiyl), aryl, heterocyclyl, 25 aryloxy, atyl(CH2)oxy, aryl(CH2), CN, 0(CH2)i^C0NR25R26 and C3.7 cycloalkyl, cycloalkyll is a C340 carbocyclic system with one or two rings and which is substituted by Ci_6 alkyl, aryl, Ci^ alkoxy, CH2(aryll), Cj^ haloalkyl, halogen, OH, CN orNR^R26, 30 WITH THE PROVISO THAT THERE ARE NO N-R4 GROUPS WHEREIN THERE IS A HETERO-ATOM LINKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON 35 97 rl2 and r13 each independently represent H or Cj-4 alkyl, or and can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from 5 NR16,0 and/or S, and which is optionally substituted by one or more C\^ alkyl, 15 R5 and-R^ when taken separately are each independently H, Cj.6 alkyl, R5 and R*> can be taken together with the carbon atoms to which they are joined to form a 20 C3.8 cycloalkyl ring, r6, r7, r9 and R*0 when taken separately are H, R5 and R*> or R? can be taken together with the caxbon atoms to which they are joined to 25 form a C3„g cycloalkyl ring, X is halogen, Ci_4 alkyl, Cj-4 alkoxy, C1.4 haloalkyl or Ci_4 haloalkoxy, mis lor 2; 30 nisO, lor 2; ^ 10 35 qisOorl; 98 "Naturally occuring amino acid substituent" means the a-substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, 5 aspartic add, glutamic acid, asparagine, glutamine, lysine, arginine or proline; "Heteroaryl11 represents an aromatic ring containing up to four heteroatoms independently selected from N, 0 and S, and if a S atom is present in the ring, it can be present as part of a -S-, S(0)- or -S(0)2- group, and which may be joined to the remainder of the compound via 10 any available atom(s); "Heterocycle" is a group containing 1, 2 or 3 rings, and which contains 15) to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms; 15 "Aiyl", including in the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.); 20 ' "Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows; "Cycloalkyr groups can be polycyclic if fee number of carbon atoms allows; 25 or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof. provided that the one or more substituents on the group R4 include at least one group that is not one of die following: (i) Ci„6 alkoxy (substituted by a single substituent that is an unsubstituted aryl1 group); (ii) aryl2oxy, aryl2, heteroaryloxy, heterocycle (which latter four groups are substituted by one or more substituents which are NHCONR^R26 groups, wherein R25 and R26 are independently H or C1.3 alkyl, or R25 and R26, together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring); i r—UAL phupstiy OFF/CTI OF N.Z. 2 3 MAR 2005 I _ RECFU/Pn I 98a (iii) COheteroaryl1), COCH2(heteroaryl'), S^nOieteroaryl1), S(0)nCH2(heteroaryl1) (in which latter four groups heteroaryl1 represents a 4- to 7-membered heterocycle comprising a N-atom (via which atom the heteroaryl1 group is attached) and optionally comprising a further hetero moiety selected from NH, N(Ci^ alkyl), N(C3.7 cycloalkyl), O or S, which heterocycle is optionally substituted by one or more Cm alkyl groups); (iv) heteroaryl'oxy, wherein heteroaryl1 is unsubstituted or substituted by one or more substituents which are alkyl (optionally substituted by one or more substituents which are CN and/or halogen), Cm 25t>26 alkoxy, CM haloalkoxy, OH, =0, NY WY and/or NHCONR R (wherein R25 and are independently H or Ci.3 alkyl, or R" and ,26 25 R , together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring)); (v) NHS(0)2(aryl1), NHCO(aryl1), NHCO^aryl1) (in which latter three groups aiyl1 is unsubstituted or is substituted by one or more substituents which are C^ alkyl, Cm haloalkyl and/or halogen); (vi) NHS(0)2CH2(aryl1) (in which aryl1 is unsubstituted); (vii) NHCOOieteroaryl1), NHC02(heteroaryl1), NHS(0)2(heteroaryl1), NHS(0)2CH2(heteroaryl1) (in which latter four groups heteroaryl1 is unsubstituted or is substituted by one or more substituents which are Ci_<5 alkyl, Ci_6 haloalkyl, Cj^ alkoxy, C3.6 cycloalkyl, C\* haloalkoxy, =0, OH, halogen, S(aryl), S(CW alkyl), CO^Q.s alkyl), CONR25R26 and/or NR25R26 (in which latter two groups, the groups R25 and R26 are either each independently H, C1.3 alkyl, aryl, Cm alkylphenyl (each of which Ci_3 alkyl, aryl and Cm alkylphenyl are optionally substituted by one or more substituents which are N02, halogen, Cm alkyl and/or Cm alkoxy), or R25 and R26 are taken together with the N atom to which they are attached and can form a 4- to 6-membered heterocyclic ring, which ring is optionally substituted by one or more Cm alkyl, OH, =0, N02, NH2 and/or halogen)). 2. A substance according to daim 1 wherein the "Ar" ring represents phenyl or pyridyl. 3. A substance according to any preceding claim wherein Rl whoa taken alone is OH, CN, halogen, N02,NH2»NY2WY1 or Hetl. 4. A substance according to any preceding claim wherein R2 when taken alone is H. WO 01/98267 PCT/IB01/01035 99 5. A substance according to claim 1 or 2 wherein Rl and R2 are taken together with the carbon atoms to which they are attached and represent an optionally benzo-fused 5- to 7-membered heteroaryl ring optionally substituted by C 1.4 alkyl or Cj_4 haloalkyl. 5 6. A substance according to any preceding claim wherein X is CI. 7. A substance according to any preceding claim wherein n is 0 and q is 0. 8. A substance according to any preceding claim wherein R3 is H, CN, or Cj.g alkyl 10 (optionally substituted by one or more halogen, OH, Cj.g alkoxy, Cj_6 alkoxycarbonyl, C2- g alkanoyl, C2-6 alkanoyloxy, C2-6 alkyloxycarbonyloxy, NR12r13; CONR*2r13 and/or NY2WY1). 9. A substance according to any preceding claim wherein R4 is Cj-io alkyl substituted by 15 one or more substituents selected from: C2_6 alkoxy [substituted by one or more groups selected from OH, NR.25r26; CONR.25r26) halogen, Cj.g alkoxy, C2.4 alkynyl, C2-4 alkenyl, heteroaryl 1, aryl^, COCH2CN, CO(heteroaryll), CO(aryl^), C02(heteroaryll), COCH2(aryll), COCH2(heteroaryl^), 20 C02CH2(aryll), C02CH2(heteroaryll), S(0)n(Ci.6 alkyl), S(0)n(aiyll), S(0)n(heteroaryll), S02NR.25r26 and cycloalkyl^], S(0)nCi_6 alkyl [optionally substituted by one or more groups selected from OH, NR25r26; CONR25r26s halogen, Cj.g alkoxy, C2_4 alkynyl, C2.4 alkenyl, heteroaryl 1, aiyll, 25 COCH2CN, CO(heteroaryll), CO(aryll), C02(heteroaiyll), COCH2(aiyll), COCH2(heteroaryll), C02CH2(aryll), C02CH2(heteroaryl 1), S(0)n(Ci_6 alkyl), S(0)n(aryll), S(O)n(heteroaryl1), S02NR25r26 an(j cycloalkyl^], aiyl2, 30 C02CH2(heteroaryll), C02CH2(aryll), cycloalkyl^, CO(heteroaryll), CO(aryll), 35 OCO(aryll), WO 01/98267 100 PCT/IB01/01035 OCO(heteroaryl 1), OCO(C i-6 alkyl), OCOCH2CN, C02(heteroaryl1), C02(aryl1), COCH2(heteroaryl 1), S(0)naryl^, S(0)nCH2aryll,* S(0)n(heteroaryll), S(0)nCH2(heteroaryl 1), NHS02aryll, NHS02(C1-6 alkyl), NHS02(heteroaryll), NHS02CH2(heteroaryll), NHS02CH2(aryl1), NHCOaiyl1, NHCO(Ci_6 alkyl), NHCONHaryl1, NHCONH(Ci-6 alkyl), NHCOheteroaryl1, NHCONHheteroaiyl 1, NHC02(aryll), NHC02(Ci-6 alkyl), NHC02(heteroaryl 1), aryl^oxy, heteroaryl^ oxy, Ci_6 alkoxycarbonyl substituted by Ci_6 alkyl, aryl, Ci.g alkoxy, C^Caryl1), C1-4 haloalkyl, halogen, OH, CN or NR2^r26j C2-6 alkanoyl substituted by Ci_g alkyl, aryl, C\.q alkoxy, CH^Caryl1), C1.4 haloalkyl, halogen, OH, CN or NR25r26. C2-6 alkanoyloxy substituted by Ci_g alkyl, aryl, Ci_g alkoxy, CH2(aryll), C1.4 haloalkyl, halogen, OH, CN or NR25r26, cycloalkyl1 oxy, COcycloalkyl1, WO 01/98267 101 PCT/IB01/01035 heterocycle substituted by one or more substituent selected from Ci_g alkyl(substituted by OH), CONR25R26, CH2C0NR25r26) Nr25r265 HHCONR25r26) C0(Ci_6 alkyl), S02NR25r26; S02(Ci_6 alkyl), C02(Ci_6 alkyl), CH2C02(Ci_6 alkyl), 0CH2C02(Ci-6 alkyl), aiyl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from Cj.g alkyl(substituted by OH), CONR25r26j CH2CONR25r26} nr25r26 NHCONR25r26> CO(Ci.6 alkyl), S02NR25r26} S02(Ci„6 alkyl), C02(Ci_6 alkyl), CH2C02(Ci_6 alkyl), 0CH2C02(Ci_6 alkyl), aiyl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, 10. A substance according to any preceding claim wherein R^, r6: r7; r8 r9 and r10 are each taken separately and are all H. 11. A substance according to any preceding claim wherein the "Ar" ring represents a group of formula: 12. A substance according to any preceding claim wherein R3 is H, CH3, C2H5, i-C3H7, n-C3H7 or CH2OCH3. 13. A substance according to any preceding claim except claim 5 wherein Rl is OH, CN, I, CI, NH2, N02, optionally benzo-fused heteroaryl, NHS02Y*, NHCOY1 or NHC02Yl. 14. A substance according to any preceding claim wherein R4 is Cj.io alkyl substituted by cycloalkyl^. 15. A substance according to any preceding claim except claims 3,4 and 13 wherein Rl and R2 are taken together with the carbon atoms to which they are attached are a 5-membered heteroaryl moiety optionally substituted by C1.4 alkyl or C1.4 haloalkyl. WO 01/98267 102 PCT/IBO1/01035 16. A substance according to any preceding claim wherein R3 is CH3 or C2H5. 17. A substance according to any preceding claim except claims 5 and 15 wherein R* when taken alone is OH, CN, I, CI, NH2, N02,1,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHS02(Ci_6 alkyl), NHS02(Ci_ 6 alkyl substituted by methoxy, CONH2, OH, C02(C2_6 alkyl), phthalimido, NH2 or halogen), NHS02NH2, NHS02NH(Ci-6 alkyl), NHS02N(Ci_6 alkyl)2, NHS02Hetia, NHCO(Ci_6 alkyl) or NHC02(Ci_6 alkyl). 18. A substance according to claim 17 wherein Rl is OH, NHSO2CH3, NHSO2C2H5, NHS02(n-C3H7), NHS02(i-C3H7), NHS02(n-C4H7), NHS02NH(i-C3H7), NHS02(N-methylimidazol-4-yl), NHS02(CH2)20CH3, NHS02(CH2)20H, 1,2,4-triazolyl or irnidazol-2-yl. 19. A substance according to claim 18 wherein Rl is OH, NHS02CH3, NHSO2C2H5 or imidazol-2-yl. 20. A substance according to claim 15 wherein Rl and R2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF3. 21. A substance according to any preceding claim wherein R4 is C2_4 alkyl substituted by cycloalkyll. 22. A substance according to any preceding claim wherein R4 is propyl substituted by cycloalkyll. 23. A substance according to any preceding claim wherein R4 is propyl substituted by a C3. 10 carbocyclic system with one or two rings and which is substituted by OH. 24. A substance according to any preceding claim wherein R4 is propyl substituted by (cyclohexyl substituted by OH). 25. A substance according to any preceding claim wherein R4 is (l-hydroxycyclohexyl)prop-3-yI. WO 01/98267 PCT/IB01/01035 103 26. A substance according to claim 1 which has the following relative stereochemisfcty: 5 27. A substance according to claim 1 which is selected from the compounds of the Examples as described herein, and the salts and prodrugs thereof. 28. A pharmaceutical or veterinary composition comprising a substance according to any 10 one of the preceding claims, and a pharmacutically or veterinarily acceptable carrier. 29. A substance according to any of claims 1 to 26 for use in medicine. 30. A substance according to any of claims 1 to 26 for use as a medicament useful for the 15 treatment of an opiate-mediated disease or condition. 31. Hie use of a substance according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of a disease or condition mediated by opiate receptors. 20 32. A method of treatment of a condition mediated by an opiate receptor or receptors comprising administration of a therapeutically active amount of a substance according to any one of claims 1 to 26 to a non-human animal. 33. A process for the preparation of a substance according to claim 1 which comprises: 25 (a) for compounds of formula I in which q is 0 and Rl represents NY^WYl, reacting a compound of formula II, lms^prroFtli7j 2 7 APR 2005 WO 01/98267 PCT/IB01/01035 with a compound of formula III, Zl-WY1 m wherein is a suitable leaving group, such as halogen or YISO2O-; (b) for compounds of formula I in which q is 0 and R.6 and R? both represent H, reduction of a compound of formula IV, r-,2 -R' R R8-. R\ R1°/ Sr 1 1 a R4 IV using a suitable reducing agent; (c) for compounds of formula I in which q is 0 and R^ and R*0 both represent H, 10 reduction of a compound of formula V, WO 01/98267 105 PCT/IB01/01035 using a suitable reducing agent; (d) for compounds of formula I in which q is 0 and Rl and R2 are attached to adjacent carbon atoms and are taken together with the carbon atoms to which they are attached to 5 represent Het^3, in which Hetla represents an imidazolo unit, reaction of a corresponding compound of formula VI, with a compound of formula VII, RyC02H VII 10 wherein Ry represents H or any of the optional substituents on Hetla (as defined above), preferably H, C1.4 alkyl or C 1.4 haloalkyl; (e) where q is 0, reacting a compound of formula VIII, WO

01/98267 106 PCT/IBO1/01035 with a compound of formula IX, R4-Lg IX wherein Lg is a leaving group; 5 (f) for compounds of formula I in which q is 0 and r6, r7, r9 and r^° are all H, reduction of a compound of formula X, 15 with a suitable reducing agent; (g) for compounds of formula I in which q is 0 and R1 represents OH, reacting a compound of formula II, where Y2 is H, as defined above, with fluoroboric acid and isoamyl nitrite; (h) for compounds of formula I in which q is 0 and R* represents CI, reacting a 20 compound of formula II, where Y2 is H, as defined above, with sodium nitrite in the presence 107 of dilute acid, followed by reaction with copper (I) chloride in the presence of concentrated acid; (i) for compounds of formula I in which q is 1, reacting a compound of formula I where q is 0 with a suitable oxidising agent such as aqueous hydrogen peroxide; or (j) for compounds of formula I where q is 0, by reduction of a corresponding compound of formula XXXI, XXXI where R4aCH2 takes fee same meaning as R4 as defined above, (K) for compounds of formula 00 where q is 0, reductive amination reaction of the amine, of formula VHI above wife an aldehyde of formula R^-CHO wherein R4aCH2 takes fee Rama meaning as R4 as defined above, and where desired or necessary converting fee resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa. intellectual PROPERTY OFFICE OF N.Z 2 3 MAR 2005 RECEIVED 108 IV wherein R1 to R5, R8 to R10, X and n are as defined in Claim 1, a compound of formula V, intellectual property office of n.z. 2 3 MAR 2005 I RECEIVED _ 109 wherein R1 to R8, X and n are as defined in Claim 1, VI wherein R3 to R10, X and n are as defined in Claim 1, a compound of formula X, INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 MAR 2005 RECEIVED 110 wherein R1 to R®, R8, X and n are as defined in Claim 1, 5 wherein R2 to R5, R8 to R10, X and n are as defined in Claim 1, a compound of formula XII, R2 Ill XXI wherein L3 represents a group that is capable of undergoing functional group transformations using standard functional group substitution or conversion techniques and R2 to R5, R8 to R10, X and n are as defined in Claim 1, XXII wherein L3 is as defined above and R2 to R8, X and n are as defined in Claim 1, a compound of formula XXIII, intellectual property OFFICE of n.z. 2 3 MAR 2005 RECEIVED 112 wherein R2, R4, R5, R8 to R10, X and n are as defined in Claim 1, a compound of formula XXIV, intellectual property office of n.z. 2 3 MAR 2005 RECEIVED a compound of formula XXX, wherein R2 to R8, X and n are as defined in Claim 1, XXIXa wherein R1 to R5, R8, X and n are as defined in Claim 1, 113 XXX wherein R2 to R10, X and n are as defined in Claim 1, or a compound of formula XXXI, XXXI wherein R4aCH2 takes the same meaning as R4, as defined in Claim 1, and R1 to R3, R5 to R10, X and n are as defined in Claim 1, or salt thereof. -INTELLECTUAL WJHbHK UllW. OF N.Z. 2 3 MAR 2005 RECEIVED, 114 35. A substance according to claim 1 substantially as herein described with reference to any example thereof. 36. A substance according to claim 26 substantially as herein described with reference to any example thereof. A composition according to claim 28 substantially as herein described with reference to any example thereof. A use according to claim 31 substantially as herein described with reference to any example thereof. 39. A process according to claim 33 substantially as herein described with reference to any example thereof. 37. 38. </div>