OA12293A - 3-Azabicyclo(3.1.0)hexane derivatives having opioid receptor affinity. - Google Patents

Abstract

Compounds of formula (I), where the substituents are as defined herein, and the pharmaceutically or veterinarily acceptable derivatives or prodrugs thereof, are pharmaceutically and veterinarily useful, in particular they bind to opiate receptors (e.g. mu, kappa and delta opioid receptors). They are likely to be useful in the treatment of diseases or conditions modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; pruritic dermatoses, such as allergic dermatitis and atopy; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage; and head trauma.

Description

01 2293

3-AZABICÏCLO (3.1.0) HEXANE DERIVATIVES HAVIKG OPIOID RECEPTOR AEFINITÏ

This invention relates to pharmaceutically useful compounds, in particular compounds thatbind 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 opiatereceptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruriticdermatoses, such as allergie dermatitis and atopy in animais and humans. Compounds thatbind to opiate receptors hâve also been indicated in the treatment of eating disorders, opiateoverdoses, dépréssion, smoking and alcohol addiction, sexual dysfimetion, shock, stroke, 0 spinal damage and head tourna.

There is a particular need for an improved treatment of itching. Itehing, or pruritus, is acommon dermatological symptom that can give rise to considérable distress in both humansand animais. Pruritus ïs 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 envîronmental allergens, such as house dust mite or pollen; by bacterial and fungalinfections of the skin; orby ectoparasite infections.

Existmg treatments that hâve been employed in the treatment of pruritus include the use of 3 corticosteroids and antihistamines. However, both of fhese treatments are known to hâveundesirable side efîects. Other thérapies that hâve been employed include the use ofessential fatty acid dietary suppléments, though these hâve the disadvantages of being slow toact, and of offering only limited efficacy against allergie dermatitis. A varieiy of émollientssuch as soft paraffîn, gîycerine and lanolin are also employed, but with limited success. 5

Thus, there is a continuing need for alternative and/or improved treatments of pruritus.

Certain 4-arylpiperidine-based compounds are disclosed in «fer alla European patentapplications EP 287339, EP 506468 and EP 506478 as opioid antagoniste. In addition, 3 International Patent Application WO 95/15327 discloses azabicycloaîkane dérivatives usefulas neuroleptic agents.

International Patent Application WOOO/39089, fîled before the priority date of the instantapplication, but published thereafter, is herein incorporated by référencé in its entirety, and 012293 2 discloses azabicycloalkanes of similar structure to ihose described hereinbelow, withdifférent RA groups.

According to the invention there is provided a compound of formula I,

5 wherein the "Ar" ring représenta an optionally benzo-fused phenyl or 5- or 6-memberedheteroaryl ring; R1 when taken alone is H, halogen, NO2, NH2» NY2WY!, Het^, AD, COjR?, C(O)r8,C(=NOH)R8, or OE, 0 Y2 is H, Cj.6 alkyl, C3.6 alkenyl (each of which alkyl and alkenyl is optionally substitutedby aryl, aryloxy or Het1), W is SO2, CO, C(O)O, Ρ(Υΐ>0, P(Y1)=S, 5 Y1 is Ci_io alkyl (optionally substituted by one or more substituents independently selectedfrom halogen, OH, Ci_4 alkoxy, Ομβ alkanoyloxy, CONH2» cl-6 alkoxycarbonyl, NH2,aryl, mono- or di(Ci_4 alkyl)amino, C34 cycloalkyl, phthalimidyl, Het1), Het1, aryl(optionally substituted by one or more substituents independently selected from Cj_4 alkyl, 0 Cj_4 haloalkyl and halogen), NH2» N(Cj^ aîkyl)2 or NH(Ci_6 alkyl), .

Het1 is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, whichmay comprise up to 3 rings (preferably a heteroaryl group,optionally benzo- or pyrido-fused heteroaryl),

/i. 012293 optionally substituted by one or more substituents independently seleoted from Ci_g alkyl,Ci_g alkoxy, C3.6 cycloalkyl, Cj.g haloalkoxy, Cj.g haloalkyl, C3-5 halocycloaîkyl, =0,OH, halogen, NO2, SjRMWfc CON20aR20b NR20aR20b SR21a NR21bso2R22aNR21cç(Q)QR22b> NR21d£OR22d} and Ci_g alkoxycarbonyl, 5 and if a S atom is présent in a ring, it can be présent as part of a -S-, S(O)- or -S(O2)“ group, and carbon atoms in fhe ring can be présent as a part of a carbonyl moiety,

Rl9as Rl9b, Rl 9c each independently représente alkyl or aryl, 0 R20a and R20b eaCh independently represent H, Cpg alkyl, aiyl, alkyl)pbenyl, eachof which alkyl, aryl and alkylphenyl are optionally substituted by one or more Cj_4 alkyl,Ci_4 alkoxy, OH, NO2, NH2 and/or halogen, or and R20b Can be taken together with the N atom to which they are attached, to forma 4- to 6-merabered ring optionally substituted by one or more substitutuents independently 5 selected from one or more Ci_4 alkyl, C1.4 alkoxy, OH, «O, NO2, NH2 and/or halogen, R21a, b, c and d each independently represent H, Cj-g alkyl, aryl or C1.4 alkylphenyl, eachof which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Cj_4 alkyl,Cj _4. alkoxy, OH, NO2, halogen, NH2, ) <; R22a, b and c each independently represent alkyl, aryl or Cj-4 alkylphenyl, each ofwhich alkyl, aryl, and alkylphenyl are optionally substituted by one or more Ci_4 alkyl, C{_4alkoxy, OH, NO2, halogen, NH2, » A is C1.4 alkylene, C2-4 alkenylene or C2-4 alkynylene, each of which is optionallysubstituted by one or more Ci-4 alkyl, C1-4 alkoxy, halogen and/or OH, D is H, OH, CN, Nr25r265 c0NR25r26 nhr27 CO2R28, COR29, C(=NOH)R29 l or AD is CN, NR25r26 CONR25r26 where R25 and r26 either each independently H, Ci .3 alkyl, C3.8 cycloalkyl, aryl, Ci_4alkylphenyl (each of which C1.3 alkyl, C3_8 cycloalkyl, aryl and Cj_4 alkylphenyl areoptionally substituted by one or more NO2, halogen, Ci_4 alkyl and/or Ci_4 alkoxy, (each ofwhich latter Cj^j. alkyl and Ci .4 alkoxy is optionally substituted by one or more halogen)), 012293 4 or R25 and R2b are 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 furfher heteroatoms selected front N, O and S, and which ring is optionally substitnted by one or more Ci. 4 alkyl, OH, =0, NO2, NH2 and/or halogen, 5 R27 is COR30, CO2R31a, SC>2R31b, r28 and r29 âre each independently H, Ci_g alkyl, C3_8 cycloaîkyl, aryl or Ci.4alkyiphenyî, each of which Ci_g alkyl, C3.8 cycloaîkyl, aTyl and Cy_4 alkylphenyl are 0 optionally substituted by one or more NO2, halogen, Ci_4 alkyl, Ci .4 alkoxy (each of which latter Ci_4 alkyl and C{_4 alkoxy are optionally substituted by one or more halogen), R30 is H, Ci_4 alkyl, C3.8 cycloaîkyl, alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, C1-4alkylphenyl, phenyl(Ci_4 )alkoxy, (each of which Cj_4 alkyl, C3_g cycloaîkyl, Ci_4 alkoxy, 5 C3.8 cycloalkyloxy, aryl, aryloxy, Cj_4 alkylphenyl and phenyl(Cj_4 )alkoxy are optionally substituted by one or more NO2, halogen, Ci .4 alkyl, C}_4 alkoxy (which latter alkyl andalkoxy are optionally substituted by one or more halogen)), R31a and R^lb are each independently Cj_4 alkyl, C3_8 cycloaîkyl, aryl or Ci_4 0 alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, Cj_4alkyl or C|_4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by onemore halogen E is H, CONR32r33j CSNR32r33s COR34 CO2R34, COCH(R34a)NH2, R35, 5 CH2CO2R35a, CHR35bCO2R35a, CH2OCO2R35c, CHR35d0CC>2R35c,COCR36=CR37NH2i COCHR36cHR37nh2> or PO(OR38)2, R32 and R33 are. each independently H, C340 alkylalkenyl, C3.7 cycloaîkyl (optionallysubstituted by Ci_4 alkyl), phenyl (optionally substituted by (X)n), Ci_iq alkyl (optionally 0 substituted by C4.7 cycloaîkyl (optionally substituted by Cj_4 alkyl) or phenyl optionallysubstituted by (X)n), or R32 and R33 can be taken together with the N atom to which they are attached and canform a 5- to 8-membered heterocycle optionally comprising furfher hetero atoms selected Ο 7 229 3 5 from N, O and S, which heterocycle is optionally substituted by Ci_4 alkyl, optionallysubstituted by one or more halogen, * R.34 is h, C4.7 cycloalkyl (optionally substituted by one or more Ci_4 alkyl), phenyl . 5 (optionally substituted by (X)n, C[_4 aBcanoyloxy, NR32R33a CONR32r33 and/or OH), or

Cj_6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl (optionallysubstituted by one or moire C1.4 alkyl), or phenyl (optionally substituted by (3¾. C14 alkanoyloxy, NR32r33s CONR32r33 and/or OH)), 0 R34a is H, C1.6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl(optionally substituted by one or more Cj_4 alkyl), or phenyl (optionally substituted by (5¾Ci_4 alkanoyloxy, Nr32r33> CONR32r33 and/or OH)), C4.7 cycloalkyl (optionallysubstituted by one or more Ci_4 alkyl), phenyl (optionally substituted by (3¾. Ci_4alkanoyloxy, NR32r33, CONR32r33 and/or OH) or a naturally occuring amino acid 5 substituent, R35 is C4.7 cycloalkyl optionally substituted by one or more Cj4 alkyl, phenyl (optionallysubstituted by one or more (3¾. C14 alkanoyl, NHR33, CON(R32)2, and/or OH), Cj_6alkyl (optionally substituted by C4J7 cycloalkyl optionally substituted by one or more Οχ_4 0 alkyl, or phenyl (optionally substituted by one or more (3¾. Οχ_4 alkanoyl, NHR32,CON(R32)2, and/or OH)), C1-4 alkoxy(C}_4 alkyl), phenyl(Ci4)alkyloxy(Ci_4)aîkyl,tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, R35a,b,c and d are each independently H, C4-7 cycloalkyl optionally substituted by one or .5 more Cj_4 alkyl, phenyl optionally substituted by one or more (3¾ or Οχ_6 alkyl (optionallysubstituted by C4.7 cycloalkyl optionally substituted by one or more Cj_4 alkyl, or phenyloptionally substituted by one or more (3¾). r36 and R3? each independently represent H, C3.6 alkylalkenyl, C4.7 cycloalkyl, phenyl 0 optionally substituted by one or more (3¾. or Ci-g alkyl (optionally substituted by C4.7cycloalkyl optionally substituted by one or more C1-4 alkyl, or phenyl optionally substitutedby one or more (3¾). R38 is C4.7 cycloalkyl optionally substituted by one or more C14 alkyl, phenyl optionally 5 substituted by one or more (3¾ or Cj.g alkyl (optionally substituted by C4.7 cycloalkyl 012293 optionally substituted by one or more Ci_4 alkyl, or phenyl optionally substituted by one ormore(X)n), R2 when taken alone is H or halogen; 5 or Ri and R2, when attached to adjacent carbon atoms, can be taken together with the carbonatoms to which they are attached, and may represent Hetla;

Hetla is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, 0 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 moresubstituents independently selected from OH, =0, halogen, Ci_4 alkyl, Cj_4 haloalkyl, Cj_4 alkoxy and Cj _4 haloalkoxy, which Cj_4 alkyl, Cj_4 haloalkyl, Cy_4 alkoxy and Ci_4 haloalkoxy groups can be 5 optionally substituted by one or more C345 cycloalkyl, aryl(Cj_6)alkyl, which aryl group is optionally substituted by one or more halogen, Ci_4 alkyl, Ci_4haloalkyl, Ci_4 alkoxy and C1-4 haloalkoxy, which latter C1.4 alkyl, Ci_4 haloalkyl, Cj_4 alkoxy and Ci_4 haloalkoxy groups can beoptionally substituted by one or more NR23r24s NR23s(O)nR24> NR23ç(Q)mj^24) 0 and if a S atom is présent in a ring, it can be présent as part of a -S-, S(O)- or -S(C>2)- group, which R23 and R24 when taken alone independently represent H, Ci_4 alkyl, or Cj_4haloalkyl, 5 or R.23 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 heteroatomsselected from, N, O, or S, and which heterocyclic ring is optionally substituted by one ormore halogen, Cj_4 alkyl, Ci_4 haloalkyl, alkoxy and/or Οχ_4 haloalkoxy groups, 0 R3 is H, CN, halogen, Cj-g alkoxy, Ci_g alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy,C3.8 cycloalkyl, C3.8 cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturatedheterocycle, NR12R13, C0NR12r13j Ny2wy1, Cpô alkyl, C2-io alkenyl, C2.10 alkynyl,(each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or moreCN, halogen, OH, alkoxy, Çj_g alkoxycarbonyl, Ç2-6 alkyloxycaibonyloxy, C]_g 012293 7 alkanoyï, Ομ6 alkanoyloxy, C3-8 cycloalkyl, C3.8 cycloalkyloxy, C4.9 cycloalkanoyl, aryl,aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13 and/or NY^WY1),

R.4 is Ci_io alkyl, C3-10 alkenyl or C340 alkynyï, each of which groups is liriked to the N 5 atom via a sp3 carbon, and which group is substituted by one or more substituents selectedfrom: C2-6 alkoxy [substituted by one or more groups selected from OH, NR25R26, CONR25r26}halogen, Ci_g alkoxy, C24 alkynyï, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, 10 COÇheteroaryl1), COfaiyl1), CO2 (heteroaryl1), COCH^aiyl1), COCH2 (heteroaryl1),002^2(3^11). CX^CWheteroaiyl1), S(O)n(Ci^ aïkyl), SCO^Caiyî1),SiO^Oieteroaryl1), SO2NB.25r26 cycloalkyl1], S(O)nCi_6 alkyl [optionally substituted by one or more groups selected from OH, NR25R26, 5 C0NR25R2^, halogen, C}_g alkoxy, C2-4 alkynyï, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, COOieteroaryl1), COCaryl1), «^(heteroaryl1), COO^Caryl1),COCH2(heteroaryI1), Œ^CB^aryl1), CO2CH2(heteroaryI1), S(O)n(Ci_g alkyl),SCOjj/aryl1), S(0)n(heteroaryl1), SO2NR25R2i> and cycloalkyl1], 0 aryl2, C02CH2(heteroaryl !), 002012(0^11). cycloalkyl1, COÇheteroaryl1), 5 COÇaryl1), OCOCaryl1), OCOÇheteroaryl1), OCO(Ci_6 alkyl), OCOCH2CN, 0 CO2(heteroaiyl1), Œ^Caryl1), COCH2(heteroaryl1),

SiO^aryl1, SÇO^GB^axyll, 5 SCO^Oieteroaryl1), 012293

SiO^CH^Qieteroaryl1), ^802^11. NHSO2(Ci-6 alkyl), NHSO^eteroaiyl1), 5 NHSO2CH2(heteroaryl1), NHSO^H^aryl1), NHCOaryl1, NHCO(Ci.6 alkyl), NHCONHaryl1, 10 NHCONH(Ci_6 alkyl), NHCOheteroaryl1, NHCONHheteroaiyl1, NHCO2(aryl1), ΝΗΟΟ2(Ομ6 alkyl), 15 NHCO2(heteroaryl1),aryl^oxy,heteroaiylioxy,

Ci_6 alkoxycarbonyl substituted by Cj_6 alkyl, aryl, Cj.g alkoxy, CB^Caiyl1), Cj_4haloalkyl, halogen, OH, CN or NR.25R26, '.0 C2-6 alkanoyl substituted by Ομ$ alkyl, aryl, Ci_g alkoxy, 0112(31711). haloalkyl, halogen, OH, CN or NR25r265 C2_6 alkanoyloxy substituted by Ci_6 alkyl, aryl, Ci_g alkoxy, Œ^aryl1), haloalkyl, halogen, OH, CN or NR25r26, cycloalky^oxy, ΰ COcycloalkyl1, heterocycle substituted by one or more substituent selected from Ci_6 alkyl(substituted byOH), CONR25r26 CH2C0NR25r26 Nr25r26 NHCONR25r26 CO(Ci_6 alkyl),SO2NR25r26 SO2(Ci_6 alkyl), CO2(Ci_6 alkyl), CH2CO2(Ci.6 alkyl), OCH2CO2(Ci_6alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3J7 cycloalkyl,

iO heterocycîyloxy substituted by one or more substituent selected from Cj.g alkyl(substitutedby OH), CONR25r26 CH2C0NR25r26j nr25r26 NHC0NR25r26 CO(Ci_6 alkyl),SO2NR25r26 SO2(Ci.6 alkyl), CO2(Ci_6 alkyl), CH2CO2(Ci.6 alkyl), OCH2CO2(Ci^alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, 5 01 2293 WHEREIN aryll is phenyl optionally fused to a C5.7 carbocyclic ring, which group isoptionally substituted by one or more substituent selected from Cj_g alkyl(optionallysubstituted by OH, CN or halogen), haloalkoxy, OH, =0, NY2WYl, halogen, Ci_galkoxy, CONR25r26) cH2CONR25r26 Nr25r26; nhC0NR.25r26 CO(Ci_g alkyl), 5 COaryl, COheteroaryl, SO2NR25r26) S(O)n(Ci„6 alkyl), S(O)n(aryl), S(O)n(heteroaryl),CO?(Ci.g alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)l-4CO2(Ci.g alkyl), (CH2)i-4CO2H, (CH2)i-4CÛ2(aryl), (CH2)l-4CO2(heteroaryl), O(CH2)i-4CO2(Ci_6 alkyl),O(CH2)mCO2H; O(CH2)i-4CO2(aiyl), O(CH2)i-4CO2(heteroaryl), aryl, heterocyclyl,aryloxy, aiyl(CH2)oxy, aryl(CH2), CN, O(CH2)mCONR25r26 <33.7 cycloalkyl, 0 aryl2 is phenyl optionally fused to a C5.7 carbocyclic ring, which group is substituted byone or more substituent selected from alkyl(sübstitutëdby OH), CONR25r26}CH2CONR25r26) Nr25r26 NHCONR25r26 CO(Ci.6 alkyl), COaryl, COheteroaryl,SO2NR25r265 S(O)n(Ci.6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), CO2(Ci_0 alkyl), 5 CO2(aryl), ÇO2(heteroaiyl), CO2H, (CH2)i-4CO2(C}_6 alkyl), (CH2)i-4CO2H, (CH2)l-4CO2(aryl), (CH2)l-4CO2(heteroaryl), O(CH2)i-4CO2(Ci-6 alkyl), 0(Œ2)i-4C02H,0(CH2)l-4CO2(aryl), O(CH2)MCO2(heteroaryl), aryl, heterocyclyl, aryloxy,aryl(CH2)oxy, aryl(CH2), CN, O(CH2)i-4CONR25r26 and C3.7 cycloalkyl, 3 heteroaryl1 is heteroaryl optionally fused to a C5.7 carbocyclic ring, which group isoptionally substituted by one or more substituent selected from Cj.g alkyl(optionallysubstituted by OH, CN or halogen), C^.g haloalkoxy, OH, =0, ΝΥ2ψγ1, halogen, Cj.galkoxy, CONR25r26} CH2CONR25r26 nr25r26 NHCONR25r26 ΟΟ(Ομ6 alkyl),COaryl, COheteroaryl, SO2NR25r26j S(O)n(Ci_6 alkyl), S(O)n(aryl), S(O)n(heteroaiyl),' 5 C02(Ci_g alkyl), CO2(aiyl), CO2(heteroaryl), CO2H, (CH2)i-4CO2(Ci_6 alkyl), (CHo) 1- 4CO2H, (CH2)i-4CÛ2(aiyI), (Œ2)MeO2(heteroaiyi), O(CH2)l-4CO2CCi.6 alkyl),O(CH2)i-4CO2H, 0(Œ2)l-4C02(aryl),0(CH2)MC02(heteroaryl), aryl, heterocyclyl,aryloxy, aryl(CH2)oxy, aryl(CH2), CN» O(CH2)i-4CONR25r26 and C3.7 cycloalkyl, } cycloalkyl^ is a C34Q carbocyclic System with one or two rings and which is substituted byCi_6 alkyl, aryl, Cj.g alkoxy, CE^iaryl1), Cm haloalkyl, halogen, OH, CN or NR25r26

WTÏH THE PROVISO THAT THERE ARE NO N-R4 GROUPS WHEREIN ISERE IS AHETERO-ATOM LINKED TO ANOTHER HETEROΑΊΌΜ VIA ONE SP3 CARBON Z is a direct bond, CO or S(O)n group, 012293 10 B is (GEÎ2)p,

Rl2 and r13 each independently represent H or C}-4 alkyl, 5 or Rl2 and Rl^ can be taken together with the N atom to which they are attached to form a4- to 7-membered heterocÿcle optionalîy comprising a further hetero moiety selected fromNRl6} o and/or Sj and which is optionalîy substituted by one or more Cj_4 alkyl, 0 Rl4 and R^ each independently represent H, Cj.iQ alkyl, C3.40 alkenyl, C3.40 alkynyl,C3.8 cycloalkyl, aryl or heteroaryl, or R.14 and R^ can be taken together with the N atom to which they are attached to form a4- to 7-membered heterocÿcle optionalîy comprising a further hetero moiety selected from 5 NRl^, O and/or S, and which is optionalîy substituted by one or more C1.4 alkyl, R16 is H, Cj.6 alkyl, C3_8 cycloalkyl, (Cj.g alkylene)(C3_8 cycloalkyl) or (Cj-galkylene)aryl, 0 R5 and RS when taken separately are each independently H, Ci«g alkyl, R5 and R&amp; can be taken together with the carbon atoms to which they are joined to form aC3.8 cycloalkyl ring, 5 R6, R?, R^ and Ri® when taken separately are H, R^ and R6 or R? can be taken together with the carbon atoms to which they are joined toform a C3.8 cycloalkyl ring, 0 Xishalogen, Ci_4 alkyl, Ci^aîkoxy,Ci_4 haloalkyl or Ci_4haloalkoxy, mis 1 or 2; n is 0,1 or 2; 5 012293 pis 0,1,2,3,4,5,6,7,8,9 or 10; q is 0 or 1; 5 "Naturaîly occuring amïno acid substituent" means the α-substituent that occurs in any oneof the following nataral amino acids, glycine, alanine, valine, leucine, isoleucine,phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, méthionine, cysteine,aspartic acid, glutàmic acid, asparagine, glutamine, lysine, arginine or proline; 0 "Heteroaryl" représente an aromatic ring containing up to four heteroatoms independentlyselected from N, O and S, and if a S atom is présent in the ring, it can be présent as part of a -S-, S(O)- or -S(O)2- group, and which may be joined to the remaînder of the compound viaany available atom(s); 5 "Heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ringheteroatoms selected from N, O and S and up to 18 ring carbon atoms; "Aiyl", including in the définitions of "aryloxy", etc., means a group comprising a pbenylring and which may incorporate a further carbocyclic ring fused to said phenyl ring and 0 which may be joined to the remaînder of the compound via any available atom(s) (examplesof such groups include napbthyl, indanyl, etc.); "Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbonatoms allows; "Çycloalkyl" groups can be polycyclic if the number of carbon atoms allows; or a pharmaceutically or veterinarily acceptable dérivative or prodrug thereof. 3 Where a fused heterocycüc group is présent it can be attached to the remaînder of thecompound via any available atom(s). "Haloalkyl", "baîoaîkoxy" groups and the like can contain more than one halogen atom, andfor instance can be per-halogenated. 012293 12

Certain of the compounds of the invention can exist in one or more géométrie and/orstereoisomeric forms. The présent invention includes ail such individual isomers and saltsand prodrugs thereof. 5 Certain compounds of the présent invention may exist in more than one tautomeric form.

Similarly certain compounds of the invention may hâve zwitterionic fonns. It is to beunderstood that the invention embraces ail such tautomers, zwitterions and their dérivatives.

The phannaceutically 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 and g-toluenesulphonate salts. Suitable base salts are formed 6om bases 15 which form non-toxic salts and examples are the aluminium, calcium, lithium, magnésium,potassium, sodium, zinc and diethanolamine salts. For a review on suitable salts see Berge etal, J. Phann. Sci., 66,1-19 (1977).

It will be appreciated by those skilled in the art that certain protected dérivatives of •.0 compounds of formula (J), which may be made prior to a final deprotection stage, may notpossess pharmacological activity as such, but may, in certain instances, be transformed afteradministration into or onto the body, for example by metabolism, to form compounds offormula (I) which are pharmacologically active. Such dérivatives are included in the tenn"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 descrîbed in "Design ofProdrugs" by H Bundgaard (Elsevier) 1985, may be placed on appropriate fimctionalitieswhen such fimctionalities are présent 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.AU protected dérivatives, and prodrugs, of the compounds of formula I are included within tire 0 scope of the invention.

Preferably the " Ar" ring represents phenÿl or pyridyl.

Most preferably the "Ar" ring represents a group of formula: 5 012293

13 R2 5 Preferably Rl when taken alone is OH, CN, halogen, NO2, NH2, Νγ2WY1 or Het^.

More preferably Rl when taken alone is OH, CN, I, Cl, NH2, NO2, optionally benzo-fusedheteroaryl, NHSO2Y1,NHCOY1 orNHCC^Y1.

Yet more preferably R1 when taken alone is OH, CN, I, Cl, 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, 0 NHS02(Ci-6 alkyl), NHSO2<Ci_6 alkyl substituted by methoxy, CONH2, OH, CO2(C2-6alkyl), phthalimido, NH2 or halogen), NHSO2NH2, NHSO2NH(Ci_g alkyl), NHSO2N(Ci.6alkyl)2, NHSO2Hetia, NHCO(Ci_6 alkyl) or NHCO2(Ci_6 alkyl).

Even more preferably Rl is OH, NHSO2CH3, NHSO2C2H5, NHSO2(n-C3H7), NHSO2(i-C3H7), NHSO2(n-C4H7), NHSO2NH(i-C3H7), NHSO20'î-methylimidazol-4-yl), 5 NHS02(CH2)2OCH3, NKS02(CH2)2OH,l,2,4-triazolyl or imidazol-2-ÿl.

Most preferably R1 is OH, NHSO2CH3, NHSO2C2H5 or imidazol-2-yl.

Preferably R^ when taken alone is H. 0 Rl and R^ when taken together with the carbon atoms to which they are attached are. preferably an optionally benzo-fused 5- to 7-membered heteroaryl ring optionally substituted by Ci_4 alkyl or Ci_4 haloalkyl.

More preferably Rl and R? when taken together with the carbon atoms to which they areattached are a 5-membered heteroaryl moiety optionally substituted by C1.4 alkyl or Cj^j. 5 haloalkyl.

Yet more preferably Rl and R2 when taken together with the carbon atoms to which they areattached are an imidazole group optionally 2-substituted by CF3.

Preferably X is Cl. 3 012293 14

Preferably n is 0.

Preferably q is 0. 5 Preferably R^ is H, CN, Ci_g alkyl (optionally substituted by one or more halogen, OH, Ci_ 6 alkoxy, Cj.6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C2-6alkyloxycarbonyloxy, NR12R13, CONR12r13 and/orNY^WY^).

More preferably R3 is H, CH3, C2H5, 1-C3H7, 11-C3H7 or CH2OCH3.

Most preferably R3 is CH3. 10

Preferably R4 is Cj-io alkyl substituted by one or more substituants selected from: C2_g alkoxy [substituted by one or more groups selected from OH, NR25r26s CONR?5r269halogen, Οχ-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryP, aiyll, COCH2CN, .5 CO(heteroaryll), CO(aryll), CO2(heteroaryll), COCH2(aryll), COCH2(heteroaryl1),CO2CH2(aryll), CO2CH2(heteroaryll), S(0)q(Ci^ alkyl), S(O)n(aryll),S(O)n(heteroaryll), SO2NR25r26 an(i cycloalkyll], δ(θ)ηθχ.6 alkyl [optionally substituted by one or more groups selected from OH, NR25r26j .0 CONR25r26> halogen, Cj_6 alkoxy, C2-4 alkynyl, C2_4 alkenyl, heteroaiyll, aiyll,COCH2CN, COCheteroaryll), CO(aiyll), CO2(heteroaryll), COCH2(aryll),COCH2(heteroaryll), CO2CH2(aryl1), CO2CH2(heteroaryll), S(O)n(Ci_6 alkyl)»S(O)n(aryll), S(O)n(heteroaryll), SO2NR25r26 cycloalkÿll], 5 aiyl2, CO2CH2(heteroaryl 1), CO2CH2(aryll), cycloalkyll, CO(heteroaryll), 0 CO(aryll), OCO(aryll), OCO(heteroaryll), OCO(Ci.6 alkyl)» OCOCH2CN, 5 CO2(heteroaryll), 01 2293 15 CO2(aryll), COCÏÏ^Cheteroaryl1), S(O)naryll, S^CH^ry!1, 5 S(O)n(heteroaiyll), S(O)nCH2(heteroarylb, NHSO2aryl!, NHSO2(Ci_6 alkyl), NHSO2(heteroaryll), .0 NHSO2CH2(heteroaiyll), NHSO2CH2(aryll), NHCOaryU, NHCO(Ci_6 alkyl), NHCONHaiyll, 5 NHCONH(Ci.6 alkyl), NHCOheteroaryl1, NHCONHheteroaryU, NHCO2(aryll), NHCO2(Ci_6 alkyl), 0 NHCO2(heteroaryll),aryl2oxy,heteroaryUoxy, C{_6 alkoxycarbonyl substituted by Ομ$ alkyl, aryl, Ci_6 alkoxy, CH2(aryÜ), Ci_4haloalkyl, halogen, OH, CN orNR25R26 5 C2-6 alkanoyl substituted by Ομζ alkyl, aryl, Ομβ alkoxy, CH2(axyll), Οχ_4 haloalkyl, halogen, OH, CN or NR25r26 C2-6 alkanoyloxy substituted by Ομ^ alkyl, aryl, Ομ6 alkoxy, CH2(aryll), Ci_4 haloalkyl, halogen, OH, CN or NR25r26, cycloalkylloxy, 0 COcycloalkyU, heterocycle substituted by one or more substituent selected from Ομβ alkyl(substituted byOH), CONR.25r26> CH2CONR25r26 Nr25r26>nhCONR25r26> ΟΟ(Ομβ alkyl),SO2NR25R26, SO2(Ci„6 alkyl), ΟΟ2(Ομ6 alkyl), CH2CO2(Ci^ alkyl), ΌΟΗ20Ο2(0μ6alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloaîkyl, 5 012293 16 heterocyclyloxy substituted by one or more substituent selected from Ci_6 alkyl(substitutedby OH), CONR25R26, CH2CONR2Sr26, Nr25r26, NHCONR25r26 ΟΟ(Ομ6 alkyl),SO2NR25R26 SO2(Ci-6 alkyl), CO2(Ci_6 alkyl), CH2CO2(Ci_6 alkyl), OCH2CO2(Ci_6alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, 5

More preferably R^ is Cj.io alkyl substituted by cycloalkyl 1.

Yet more preferably R^ is C2-4 alkyl substituted by cycloalkyl^.

0 Further more preferably R.4 is propyl substituted by cycloalkyl V

Furthet yet more preferably R4 is propyl substituted by a 03.10 carbocyclic System with oneor two rings and which. is substituted by OH. 5 Even more preferably R^ is propyl substituted by (cyclohexyl substituted by OH)

Most preferably R.4 is (l-hydroxycyclohexyl)prop-3-yl.

Anotber preferred group of compounds are those wherein R^ takes the values as specified in 0 the Examples 145-203 below.

Preferably R5, r6, r7, r8 r9 and RIO 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} 5 R^, r8, r9, r10> q pqQ hâve the values as detailed in the Examples below.

The invention further provides synthétic methods for the production of compounds and saltsof the invention, which axe described below and in the Examples and Préparations. Theskilled man will appreciate that the compounds of the invention could be made by methods 0 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 usingstandard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations",RC Larock, VGH (1989 or later éditions), 012293 17 "Advanced Organic Chemistry - Reactions, Mechanisms and Structure", JMarch, Wiley-Interscience (3rd or later éditions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later» éditions), 5 "Designing Organic Synthèses" S Warren (Wiley) (1983 or later éditions), "Guidébook ToOrganic Synthesis" RK. Mackie and DM Smith (Longman) (1982 or later éditions), etc.,and the référencés îherein 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 thedesired compounds can be efSciently assexnbled. The skilled chemist will exercise hisjudgement and skill as to the most efficient sequence of réactions for synthesis of a giventarget compound. For example, substituents may be added to and/or Chemical transformationsperformed upon, different intermediates to those mentioned hereinafter in conjuration with a 5 particular reaction. This will dépend inter alia on factors such as the nature of otherfunctional groups présent in a particular substrate, the availability of key intermediates andthe protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involvedwill 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 reactionparameters in a manner that will be évident to the skilled person by reference to standardtexfbooks 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 deprotseted during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as desenbed in “Protective Groups inOrganic Synthesis” by TW Greene and PGM Wuts, John Wiley &amp; Sons Inc (1999), andrefemees therein. Functional groups which may désirable to protect include oxo, hydroxy,amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (e.g. 0 efhylene ketals) and dithianes. Suitable protecting groups for hydroxy include trialkylsilyl anddiarylalkylsilyl groups (e.g. Zeri-butyldimethylsilyl, terf-butyldiphenylsilyl or frimethylsiiyl)and tetrahydropyranyl. Suitable protecting groups for amino include fcrt-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylicacid include Cj.g alkyl orbenzyl esters. 01 2293 18

In the Methods below, unless otherwise specifîed, the substituents are as defined above withréférencé to the compounds of formula (I).

The invention provides a process for the préparation of compounds of formula I as defined5 above, or a pharmacutically or veterinarily acceptable dérivative thereof, which comprises: (a) for compounds of formula I in which q is 0 and R1 représente NY^WYl, reacting acompound of formula H, ’

with a compound of formula ΙΠ, ) zi-wyi 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^ and R? both represent H,réduction of a compound of formula IV,

(c) for compounds of formula I in which q is 0 and R9 and R10 both represent H,réduction of a compound of formula V, 01229b 19

using a suitable reducing agent; (d) for compounds of formula I in which. q is 0 and R1 and R2 are attached to adjacentcarbon atoxns and are taken together with the carbon atoms to which they are attached to 5 represent Het^a, in which Het^a représente an imidazolo unit, reaction of a coirespondingcompound of formula VI,

with a compound of formula VU,

Ryco2H vn D wherein Ry représente H or any of the optional substituents on Het^a (as defined above),preferably H, C}_4 alkyl or Ci_4 haloalkyl; (e) where q is 0, reacting a compound of formula VIH, 01 2293

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 and RIO are ail H, réduction of a compound of formula X,

with a suitable reducing agent; (g) for compounds of formula I in which q is 0 and Ri represents OH, reacting acompound of formula H in which is H, as defîned above, with fiuoroboric acid and .0 isoatnyl nitrite; 012293 21 (h) for compounds of formula I in which q is 0 and Rl represents Cl, reacting acompound of formula Π in which is H, as defined above, with sodium nitrite in thepresence of dilute acid, followed by reaction with copper (I) chloride in the presence ofconcentrated 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 réduction of a corresponding compoundof formula XXXI,

where R^aCH2 takes the same meaning as R^ as defined above; or (k) for compounds of formula (l) where q is 0, reductive amination reaction of the ;0 amine of formula VIII above with an aldéhyde of formula R4a-CHO wherein R^CHatakes the same meaning as R4 as defined above, and where desired or necessary converting the resulting compound of formula I into aphaimaceutically or veterinarily acceptable dérivative or vice versa. '3 In process (a), the reaction may be carried out at between 0°C and room température in thepresence of a suitable base (e.g. pyridine) and an appropriate organic solvent (e.g,dichloromethane).

Compounds of formula H may be prepared by réduction of a corresponding compound of 0 formula XI or formula XE, 012293 22

in the presen.ce of a suitable reducing agent, such as lithium aluminium hydride. Thereaction may be carried out at between room température and reflux température in thepresence of a suitable solvent (e.g. tetrahydrofuran). 5

Compounds of formula XI and ΧΠ may be prepared by réduction of the corresponding -NO2compounds trader conditions that are well known to those skilled in the art (e.g. usingH2/Raney Ni or in the presence of CaCl2 and iron powder, in the presence of a suitablesolvent System (e.g. EtOH, EtOAc and/or water)). The skilled person will appreciate that, in .0 preparing a compound of formula Π, in which is H, from such a corresponding -NO2compound, the two àbove-mentioned réduction steps may be performed in the same step orsequentially in any order.

The said corresponding -NO2 compounds may be prepared by reaction of a compound of15 formula ΧΠ or formula XIV, as appropriate,

ΧΠΙ

XIV 012293 23 wherein L1 représente a suitable leaving group [such as halo (e.g. chlore or bromo)], L2représente a suitable leaving group (such as Cj-3 alkoxy) and R8 is as defined above, with acompound of formula XV,

R4NH2 XV 5 The reaction may be carried out at between room température and reflux température in thepresence of a suitable base (e.g. NaHCC>3) and an appropriate organic solvent (e.g.dimethylformamide), or at a higher température (e.g. between 50 and 200°C, preferablybetween 100 and 160°C) in the presence of neat compound of formula XV. 0 Compounds of formula XJH and XIV may be prepared in accordance with standardtechniques. For example, compounds of formula ΧΙΠ and XTV may be prepared by reactinga corresponding compound of formula XVI or XVH,

with a compound of formula XVÏÏI or XIX respéctively, 5 N2CHR5COL2 XVffl N2CHRsCOL2 xk wherein L2 is as defined above. The reaction may be carried out at room température in thepresence of a suitable catalyst [e.g. Rh2(OAc)4] and an appropriate non-protic organicsolvent (e.g. dichloromethane).

Compounds of formula XVI and formula XVH are available or can be prepared using knowntechniques. Compounds of formula XVI and formula XVH may, for example, be preparedfrom corresponding compounds of formula XX, 01 2293 24

for example by performing a Wittig réaction using an appropriate provider of thenucleophilic group RO2C-CR5H· or RO2C-CR^H" (wherein R représente lower (e.g. Ci_3)alkyl), as appropriate, under conditions fhat are well known to those skilled in the art The - 5 CO2R group of the resulting compound may be converted to an appropriate -CHrLI groupusing standard techniques (e.g. réduction of the ester to the primary alcohol and conversionof the latter to an alkyl halide) under conditions fhat are well known to those skilled in theart. 0 In processes (b) and (c), suitable reducing agents include lithium aluminium hydride. Thereaction may be carried out at between room température and reflux température in thepresence of a suitable solvent (e.g. tetrahydrofuran).

Compounds of formula H may be prepared by réduction of the corresponding compound of 5 formula XXX,

XXX 012293 25 by analogy to the process steps mentioned above.

Compounds of formula IV and V may be prepared respectively from compounds of formula

wherein représente 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 TV and V in which RJ représente l,2,4-triazol-3-yl may beprepared by reaction of an appropriate compound of formula XXI or ΧΧΠ in whichreprésente -CN with HCl (gas) in the presence of an appropriate lower alkyl alcohol (e.g.éthanol), for example at between 0°C and room température, followed by reaction of the 5 résultant intermediate with formic acid hydrazide (e.g. at reflux température, with or withoutthe presence of a suitable organic solvent (e.g. methanol), followed by, if necessary,removing the solvent and heating the résultant residue to a high température (e.g. about150°C)). (2) Compounds of formula IV and V in which Rl représente imidazol-2-yl may be 3 prepared by reaction of an appropriate compound of formula XXI or ΧΧΠ in which représente -CN with HCl (gas) in the presence of an appropriate lower alkyl alcohol (e.g.éthanol), for example at between 0°C and room température, followed by reaction of therésultant intermediate with aminoacetaldehyde dialkylacetal (e.g. dimethylacetal) (e.g. at oraround reflux température in the presence of an appropriate solvent^ such as methanol). 5 (3) Compounds of formula IV and V in which Rl représente l,2,3-triazol-5-yl may be prepared by reaction of an appropriate compound of formula XXI or ΧΧΠ in which 012293 26 représente -CN with diazomethane, or a protected (e.g. trialkylsilyl) dérivative thereof, forexample at between 0°C and room température in the presence of a suitable base (e.g. n-BuLi) and, optionally, an appropriate organic solvent (e.g. THF), followed by removal of theprotecting group as necessary. (4) Compounds of formula IV and V in which R) représente benzimidazol-2-yl may beprepared by reaction of an appropriate compound of formula XXI or ΧΧΠ in which L3représente C=NH(OEt) with 1,2-diaminobenzene. The reaction may be carried out in asolvent such as mefhanol, at an elevated température (such as the reflux température of thesolvent). Préparations 81, etc. provide further details.

Sompounds of formula IV and V in which K1 représente Het* may also be prepared from;ompounds of formula XI and XH respectively according to the following schexne:

XXIV * 012293 27 A wherein Het^ is defined above. Further details may be found in Préparations 67, 68, etc. inWO00/39089, herein incorporated by référencé in its entirety. * 5 Compounds of formula XXI and ΧΧΠ may be prepared in analogous fashion to methodsdescribed herein, for example those described hereinbefore for préparation of compounds of formula H. 0 Other compounds of formula (TV) and (V) may be prepared by analogy with methodsdescribed herein (e.g. by analogy with meihods described hereinbefore for préparation of compounds of formula XI and ΧΠ (and especially the corresponding -NO2 compound)). 5 In process (d), the reaction may be carried out by heating under reflux, with or without thepresence of an appropriate organic solvent. 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 Π), which latter compound may be 0 activated by converting the 3-amino group to a 3-amido group, followed by hydroîysis of the amide and réduction of the 4-nitrobenzene compound. Ail of these reactions may beperformed using techniques that are familiar to the skilled person, and are illustrated in Préparations 45-48, etc. beîow. 5 In process (e), suitable leaving groups that Lg may represent include halogen, such asbrémine, or a. sulphonate group such as tosylate, mesylate or triflate. The reaction may becarried out in a polar solvent that does not adversely affect the reaction, at a suitabletempérature, e.g. 0-150°C, in the presence of a base. A catalyst such as sodium iodide mayoptionally be added. 0 Préférable choices are a slight excess of R^-Lg, where Lg = Cl or Br, an excess of base (2.0- 5 4.0 eq), such as K2CO3, NaHCÛ3, 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 thepresence of a catalyst such as Nal or Kl, for 2-24 hr. see RC Larrock in “Comprehensive Organic Transformations-A Guide to Functional GroupPréparations”, VCH, (1989), p 397, and référencés cited therein. 01 2293 28

Compounds of formula VUI may be prepared from compounds of formula XXV,

wherein Pg représente a suitable protecting group. Suitable protecting groupe include allyl,5 which may be removed using a palladium (0) cataîyst and Ν,Ν-dimethylbarbituric acid (see

Préparation 53, etc. below). Compounds of formula XXV may be prepared using analogousmethods to those described herein for the préparation of compounds of formula I.

In process (f), suitable reducing agente include lithium aluminium hydride. The reaction may10 be canied out in a solvent that does not adversely affect the reaction (for exampletetrahydrofuran), at an elevated température (for example the reflux température of the solvent).

Compounds of formula X may be prepared by reacting a compound of formula XXVI15 with a compound of formula XXVII in the presence of an oxidizing agent Suitable oxidizing agents include manganèse dioxide. The reaction may be canied out in a solventthat does not adversely affect the reaction (for example dioxan), at an elevated températuresuch as the reflux température of the solvent (for example see Préparation 77, WOOO/39089).The intennediate compounds XXIXa are isolatable using suitable conditions (e.g. see ÏO Préparation 5 8, WO00/39089). 012293 29

5 Compounds of formula XXVI may be prepared from compounds of formula XXVIII, byreaction of the corresponding ketone with hydrazine monohydrate using known techniques(and as described in Préparation 76, etc. WOOO/39089).

Process (f) is particularly useful when Ar représente an optionally benzo-fused 5- or 6- 0 membered heteroaryl ring. A similar methodology may be used to obtain compounds offormula Π: the precursor nitro compound may be prepared from a compound of formula XX,as defîned above, using the steps described above (see for example Préparations 57-61,WOOO/39089). 012293 30

In process (g), the reaction may be carried out in a solvent that does not adversely affect thereaction (for example éthanol), fïrst below room température and then at an elevatedtempérature (Examples 79, etc. WÛ00/39089, provides furfher details). 5 In process (h), suitable acids include dilute aqueous hydrochloric acid and concentratedhydrochloric acid, respectively. The reaction may be carried out at or around roomtempérature, fînishing at‘ an elevated température (for example 90°Ç). Example 51WO00/39089 provides furfher details. .0 In process (j), the compound of formula XXXI may be prepared by acylation of thecompound of formula VIH as defined above, with an acylating agent of the formula R^aCO-Lg, where Lg is a suitable leaving group as defined above with respect to (e), and includeshalogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR^a (j.e. an acid anhydride) and the like,well known to those practising in the art. See for example the conditions used for Préparation 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 Préparations”, second édition, (1999), pp 1941-1949, andréférencés cited therein. Preferably the carboxylic acid (0.9-1.1 eq), l-(3-dimethylaminopropyl)-3-etbylcarbodiimide. HCI (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 sait (1 eq) and base(NaHCO3 or organic base, Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24hratRT.

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 0-100°C to generate the desired tertiary amine, see RC Larrock in “Comprehensive Organic Transformations-AGuide to Functional Group Préparations", VCH, (1989), pp 432-434, and référencés citedtherein. Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at0°C-RT, in THF, for 1-24 hr. 0

In process (k) the appropriât© aldéhyde is reacted with an amine, optionally présent as an acidaddition sait, in the presence of a suitable reducing agent (such as sodium cyanoborohydride,sodium triacetoxyborohydride, or catalytic hydrogénation with Pd, Pt or Ni catalysts). Thereaction is suitably performed in the presence of acetic acid at 0-100°C in THF, methanol, 5 DCM (dichlorometfaane), or DCE (1,2 -dicMoroethane), for a suitable time such as 1-24 hr. 012293 10 10 15 15 10 10 15 15 31

Preferably the amine sait, such as the trifluoroacetic acid (TFA) sait, is treated with anorganic base (1-3 mole équivalents), such as triethylamine or Hunigs base, and then thealdéhyde (1-1.5 mole équivalents), followed by sodium triacetoxÿborohydride (1-2.0 moleéquivalents), in DCM or DCE, at room température for 2-24 hr. see RC Larrock;“Comprehensive Organic Transformations-A Guide to Functional Group Préparations”,second édition, (1999), p 835-842, and references cited therein, and Abdel-Magid et al, J.Org. Chem., 1996,61,3849.

The aldéhydes used in this process may be prepared from the corresponding aîcohols usingsuitable oxidising agents; see RC Larrock in “Comprehensive Organic Transformations-AGuide to Functional Group Préparations”, second édition, (1999), pp 1234-1236 and 1238-1247, and references cited therein. Preferred oxidants are tetrapropylammonium perruthenate(Ley, étal., Synthesis, 1994, 639-666), Swem 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).

Various functional group interconversions on compounds of formula (I), or intermediatesthereto, may be carried out to give different compounds of formula (I) or intermediates.Some of these are mentioned below.

Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueoussolution, see Cross et al., J. Med. Chem., 1985,28,1427-1432.

Esters can be converted to die corresponding aîcohols using a suitable reducing agent, seeLarock, Comprehensive Organic Transformations-A Guide to Functional GroupPréparations, second édition, (1999), pp 1117-1120 and references cited therein. Suitablereducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis,1975,617) and lithium aluminium hydride (LÎA1H4, see Brown, Org. Reactions, 1951,6,469) - viz. reaction of the type:

O

OH 012293 32

Alcohols can be prepared from a corresponding acid using a suitable reducing agent; seeLarock, Comprehensive Organic Transformations-A Guide to Functional GroupPréparations, second édition, (1999), pp 1114-1116. Preferably the reducing agent is eitherborane (BH3 (1-2 eq), L Org. Chem., 1973,38,2786), or LÎA1H4 (1-4 eq), in an ethereal 5 solvent, such as THF, 0-80°C, for 1-24 br. - viz. reaction of the type:

R

O

OH 0 Direct méthode to préparé alkyl halides and alyl sulphonates from their alcohols are described by RC Larrock, Comprehensive Organic Transformations-A Guide to FunctionalGroup Préparations, second édition, (1999), pp 689-700, and référencés cited therein. 5 Benzylacetals can be treated with a suitable reducing agent in the presence of a Lewis acid ororganic acid to give benyloxyalcohols.

For représentative examples see Organic Préparations and Procedures, hit., 1991,23,4,427-431, 2rC14/LiAlH4; J. Org. Chem., 1987,52,2594, Zn(BH4)2ZMe3SiCl; and OrganicPréparations and Procedures, Int, 1985, 17(1), 11-16, NaBH4/TFA 0 viz. reaction of the type: ΓΛ

5

It will be apparent to fhose skilled in the art that compounds of formula I may be convertedto other compounds of formula I using known techniques. For example, compounds offormula I in which γΐ represents aîkoxycarbonyl may be converted to compounds in whichΥΐ represents alkyl substituted by OH, by réduction using L1AIH4 (Example 57 provides 3 further details). Similarly, intermediate compounds may be interconverted using knowntechniques (see for example Préparation 85). 012293 33

The intennediate compounds such as those of formulae ΠΙ, XV, XVHI, XK, XX, VU, IX,XXVI, XXVII and XXVIII, and dérivatives thereof, when not commercially available or notsubsequentiy described, may be obtained either by analogy with the processes described 5 herein, or by conventional synthetic procedures, in accordance with standard techniques,from readily available starting materiàls using appropriai© reagents and reaction conditions.

The invention further provides the intennediate compounds of formulae H, IV, V, VI, X, Xa,XI, XH, XXI, ΧΧΠ, xxm, XXIV, XXIX, XXIXa, XXX, and XXXI as defined above. .0

Where desired or necessary, the compound of formula (I) can be converted into apharmaceutically acceptable sait thereof, conveniently by mixing together solutions of acompound of formula (I) and tire desired acid or base, as appropriate. The sait may beprecipitated from solution and collected by filtration, or may be collected by other means 5 such as by évaporation of the solvent Both types of sait may also be formed orinterconverted using ion-exchange resin techniques.

The compounds of the invention may be purified by conventional methods, for exampleséparation of diastereomers may be achieved by conventional techniques, e.g. by fractional 0 crystallisation, chromatography or H JP.L.C. of a stereoisomeric mixture of a compound of formula (I) or a sait thereof. An individual enantiomer of a compound of formula (I) mayalso be prepared from a corresponding optically pure intennediate or by resolution, such asby HJP.L.C. of the corresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereomeric salts formed by reaction of the corresponding racemate 5 with a suitably optically active base or acid.

The compounds of the invention are useful because they possess pharmacological activity inanimais, especially mammals including humans. They are therefore indicated asphaimaceuticals and, in particular, for use as animal médicaments.

According to a further aspect of the invention there is provided the compounds of theinvention for use as médicaments, such as pharmaceuticals and animal médicaments, such asfor the treatment of opiate-mediated diseases and conditions. 3 012293 34

By the tenu “treatment”, this term includes both therapeutic (curative) and prophylactictreatment.

In particular, the substances of the invention hâve 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; dépréssion;smoking and alcohol addiction; sexual dysftmction; shock; stroke; spinal damage and/or headtrauma; and conditions characterised by having pruritis as a symptom. .0 Thus, according to a forther aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a médicament for the treatment of a ! disease modulated via an opiate receptor. There is forther provided the use of the compoundsof the invention in the manufacture of a médicament for the treatment of as irritable bowelsyndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; .5 dépréssion; smoking and alcohol addiction; sexual dysfonction; 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 orprophylactic treatment of pruritic dermatoses including allergie dermatitis and atopy in !0 animais and humans. Other diseases and conditions which may be mentioned include contactdermatitis, psoriasis, eczema and insect bites.

I

Thus, the invention provides a method of treating or preventing a disease modulated via anopiate receptor. There is forther provided a method of treating irritable bowel syndrome; :5 constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; dépréssion;smoking and alcohol addiction; sexual dysfonction; shock; stroke; spinal damage and/or headtrauma; or a medical condition characterised by pruritus as a symptom in an animal (e.g, amammal), which comprises administering a therapeutically effective amount of a compoundof the invention to an animal in need of such treatment 0

The compounds of the invention will nonnally be administered orally or by any parentéralroute, in the form of pharmaceutical préparations comprising the active ingrédient optionallyin the form of a non-toxic organic, or inorganic, acid, or base, addition sait, in apharmaceutically acceptable dosage form. Depending upon the disorder and patient to be 012293 35 treated, as well as the route of administration, fhe compositions may be administered atvarying doses (see below).

While it is possible to administer a compound of die invention directly without any 5 formulation, the compounds are preferably employed in the form of a pharmaceutical, orveterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier,diluent or excipient and a compound of the invention. The carrier, diluent or excipient maybe selected with' due regard to the intended route of administration and standardpharmaceutical, and/or veterinary, practice. Pharmaceutical compositions comprising the 10 compounds of the invention may contain from 0.1 percent by weight to 90.0 percent byweight of the active ingrédient.

The methods by which the compounds may be administered for veterinary use include oraladministration 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,altematively, they can be administered by injection (eg subcutaneously, intramuscularly orintravenously), or as an implant Such formulations may be prepared in a conventionalmanner 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 fhebody weight of the animal. For parentéral, topical and oral administration, typical doseranges of the active ingrédient 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, fhe veterinary practitioner, or the skilled person, wilï be abîe to déterminé the• actual dosage which will be most suitable for an individual patient, which may vary with thespecies, âge, weight and response of the particular patient The above dosages are exemplaryof fhe average case; there can, of course, be individual instances where higher or lower 0 dosage ranges are merited, and such are within the scopeofthis invention.

For veterinary use, the compounds of the invention are of particular value for treatingpruritus in domestic animais such as cats and dogs and in horses. 012293 36

As an alternative for treating animais, the compounds may be administered with the animal » feedstaff and for this purpose a concentcated feed additive or premix may be prepared formixing with the normal animal feed. * 5 For human use, the compounds are administered as a pharmaceutical formulation containingthe active ingrédient together with a pharmaceutically acceptable diluent or canier. Suchcompositions include conventional tablet, capsule and ointment préparations which areformulated in accôrdance with standard pharmaceutical practice. 10 Compounds of the invention may be administered either alone or in combination with one ormore agents used in the treatment or prophylaxis of disease or in the réduction or suppressionof symptoms. Examples of such agents (which are provided by way of illustration andshould net be construed as lïmiting) include antiparasitics, eg fipronil, lufenuron,imidacloprid, avermectins (eg abamectin, ivermectin, doramectin), milbemycins, .5 organophosphates, pyrethroids; antihistamines, eg chlorpheniramine, trimeprazine,diphenhydramine, doxylamine; antifungals, eg fluconazole, kétoconazole, itraconazole,griseofulvin, amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin, ampicillin,amoxycillin; anti-inflammatorïes eg prednisolone, betamethasone, dexamethasone,carprofen, ketoprofen; dietary suppléments, eg gamma-linoleic acid; and émollients. .0 Therefore, the invention further provides a product containing a compound of the inventionand one or more selected compounds from the above list as a combined préparation forsimultaneous, separate or sequentïal use in the treatment of diseases modulated via opiatereceptors 5 The skilled person will also appreciate that compounds of the invention may be taken as asingle 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, orveterinary, 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 hâve the advantage that, in the treatment of humanand/or animal patients, they may be more efficacious than, be less toxic than, hâve a broaderrange of activity than, be more potent than, produce fewer side effects than, be more easüly 012293 37 absorbed than, or they may hâve other useful pharmacological properties over, compoundsknown in the prior art.

The biological activities of the compounds of the présent invention were determined by the 5 followingtestmethod.

Biological Test

Compounds of the présent invention hâve been found to display activity in three opioid 0 receptor binding assays sélective 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. Animais wereeuthanaised, their brains removed and the cerebellum discarded. The remaining brain tissue 5 was sectioned into small pièces approximately 3 g in weight and homogenised in 50mM TrispH 7.4 buffer at 4°C using a Kinematica Polytron tissue homogeniser. The resultinghomogenate was centrifuged at 48,400 x g for 10 minutes and the supexnatant discarded. Thepellet 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 -8Q°C, Membrane material prepared in this mannercould be stored for up to four weeks prior to use.

For mu, kappa and delta assays, increasing concentrations of experimental compound (5 x10-12 t0 io-5m), Tris buffer and ligand, (mu = [D-Ala2,N-Me-Phe4,Gly-ol5j- 5 Enkephalin, DAMGO; kappa = U-69,593; delta = Enkephalin, [D-pen255] DPDPE), werecombined in polystyrène tubes. The reaction was initiated by the addition of tissue, and themixture was incubated at room température for 90 minutes, The reaction was terminated byrapid filtration using a Brandel Cell Harvester™ through Betaplate™ GF/A glass fibre filteispre-soaked in 50 mM Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then 0 washed three tïmes with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays, washedfilters 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 sealedand counted by a Betaplate™ 1204 beta counter. 012293 38

Duplicate samples were run for each experimental compound and the data generated wasanalysed using IC50 analysis software in Graphpad Prism. Ki values were caîculated usingGraphpad Prism according to the following formula: 5 Ki - IC50 / 1 + [3H ligand] / Kj) where IC50 is the concentration at which 50% of the 3H ligand is displaced by the testcompound and K£j is the dissociation constant for the 3H ligand at the receptor site. 0 Bioloeical Actrvitv

The Ki values of certain compounds of the présent invention in the opioid receptor bindingassays were determined, and were found to hâve Ki values of 4000 nM or less for the μreceptor. 5

It is believed that the methods used in the following Examples produce compounds havingthe relative stereochemistry shown below, and such compounds are preferred:

wherein Rl-4 and (X)n are as defined above. 3 The invention is illustrated by the following Examples and Préparations in which thefollowing abbreviations may be used: APCI = atmospheric pressure Chemical ianizationDMF - dimethylformamide 5 DMSO = dimethylsulphoxided (in relation to time) = dayd (in relation to NMR) = doubletES (in relation to MS) = electrospray 012293 39

EtOAc = ethyl acetateEtOH = éthanolh-hour

MeOH = methanol 5 min = minute MS = mass spectrumn-BuOH - n-butanolODS = octadecylsilylTHF - tetrahydrofuran 0 TSP - thermospray

Melting points were determined using a Gallenkamp melting point apparatus and areuncoirected. Nuclear magnetic résonance (NMR) spectral data relate ta and wereobtained using a Varian Unity 300 or 400 spectrometer, the observed Chemical shifts (δ)

5 being consistent with the proposed structures. Mass spectral (MS) data were obtained on aFisons Instruments Trio 1000, or a Fisons Instruments- Trio 1000 APCI, or a FinniganNavigator MS, or a Micromass Platform LC spectrometer. The calculated and observed ionsquoted refer to the isotopic composition of lowest mass. Room température means 20 to25°C. The mass spectrometer which is used as a detector on the analytical HPLC-MS 0 System is a Micromass VG Platform H, running on Masslynx/Openlynx software. The System can run positive and négative ion with either Eîectrospray or APCI probes and is calîbrated to1972 Daltons, it collects full Diode airay data from 190nm to 600nm. HPLC means high performance liquid chromatography. HPLC conditions used were: 5

Condition I: Rainin Dynamax™ column, 8μ ODS, 24 x 300 mm, column température 40°C,flow rate 45 ml/min, eluting with methanol : water (70: 30), UV détection of product at 246nm.

Condition 2: Rainin Dynamax™ column, 5μ ODS, 21.6 x 250 mm, column température 3 40°C, flow rate 5 ml/min, eluting with acetonitrile : water (50:50), UV détection of product at 246 nm.

Condition 3: Rainin Dynamax™ column, 8μ ODS, 41 x 250 mm, column température 40°C,flow rate 45 ml/min, eluting with acetonitrile : 0.1M aqueous ammonium acetate bufler (50 :50), UV détection of product at 235 nm. 012293 40

Condition 4: Phenomenex Magellan™ column, 5μ Ci g silica, 21.2 x 150 ram, columntempérature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueousammonium acetate buffer (30 : 70 to 95 : 5 over 10 min), UV détection of product at 220 nm.Condition 5: Phenomenex Magellan™ column, 5μ ODS, 21.2 x 150 ram, column température 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 détection of product at 215 nm.

Condition 6: Phenomenex Magellan™ column, 5μ Cjg silica, 4.6 x 150 mm, columntempérature 40°C, flow rate 1 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueousheptanesulphonic acid (10: 90 to 90 :10 over 30 min), UV détection of product at 220 nm. 0 Condition 7: Phenomenex Magellan™ column, 5μ Ci g silica, 21.2 x 150 mm, columntempérature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.05Maqueous ammonium acetate buffer (50 : 50 for 15 min then 50 : 50 to 90 : 10 over 5 min),UV détection of product at 220 nm.

Condition 8: Phenomenex MagelîenTM column, 5μ Cig silica, 21.2 x 150 mm, column 5 température 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 détection of product at 220 nm.

Condition 9: Phenomenex MagelîenTM column, 5μ ODS, 10 x 150 mm, column température40°C, flow rate 5ml/min, eluting with a gradient of acetonitrile : 0.1M aqueous ammoniumacetate buffer (5 :95 to 30:70 over 5 min then 30:70 for a further 20 min), UV détection of 0 product at 225nm.

Condition 10: Phenomenex Magellan^M column, 5μ Cjg silica, 212 x 150mm, columntempérature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile : 0.1M aqueousammonium acetate (5 : 95 to 40 : 60 over 5 min then 40 : 60 for a further 25 min), UVdétection of product at 210 nm. 5 Condition 11: Phenomenex MagellanTM column, 5μ ODS, 10 x 150mm, columntempérature 40°C, flow rate 5 ml/min, eluting with a gradient of acetonitrile : water (5 :95 to55 :45 over 5 min), UV détection of product at 210 nm.

The free base form of the szabicycles couïd be obtained from the hydrochloride or acetate 0 salts, for example, in the following way. The sait (0.3 mmol) was dissolved indichloromeihane (20 ml) and washed with saturated aqueous sodium hydrogai carbonatesolution (20 ml). The basic mixture was separated and the aqueous layer was extracted withdichloromethane (2 x 20 ml). The combined organic extracts were dried (Na2SC>4) andconcentrated in vacuo to give the free base. 5 012293 41

SPE cartridge refera to a solid phase extraction cartridge. These can be commercially» obtained from Varian (Mega Bond Elut ®) or Isolute^M 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 référencé in its entirety. A number of further Examples, such as those in the table below, can be made viao the processes A-K outlined below and in the experimental details following the table

Process A

Alkylation 5 Alkylation of the amine of formula VIII or a sait thereof with R4Lg, where Lg is asuitable leaving group, such as a halogen, trifiate, mesylate, etc., in the presence ofa base, optionally in the presence of a catalyst, in a polar solvent, at between 0 and150°C.

Preferably the alkylation is carried out with R4Lg (slight excess), where Lg =C! or Br, 0 an excess of base (2.0-4.0 eq), such as K2CO3, NaHCO3, or a tertiary amine, suchas triethylamine or Hunigs base, in a polar solvent, such as THF, DMF, or MeCN, atbetween 40 and 120°C, optionally in the presence of a catalyst such as Nal or Kl, for2-24 hr. see RC Larrock in “Comprehensive Organic Transformations-A Guide to Functional 5 Group Préparations", VCH, (1989), p 397, and référencés cited therein.

For Example: 012293

+ R4Lg TFA sait 42

SO2Me

Lg=Br or Cl

Conditions: Amine sait (1.0 eq), RX (1.1 eq), NaHCO3 (2-4.0 eq), DMF, Nal (cat), 4C

Process B 5 Reductive amination

Treating an appropriate aldéhyde R4aCH0 with an amine of formula VIH in thepresence of a suitable reducing agent (such as sodium cyanoborohydride, sodiumtriacetoxyborohydride, or catalytic hydrogénation with Pd, Pt or Ni catalysts). Thereaction is often performed in the presence of acetic acid at 0-100°C in THF, MeOH, D DCM, or DCE (1,2 -dichioroethane), for 1-24 hr.

Preferably the amine sait is treated with an organic base (1-3 eq), such astriethylamine or Hunigs base, and then the aldéhyde (1-1.5 eq), followed by sodiumtriacetoxyborohydride (1-2.0eq), in dichloromethane or DCE, at room température for 2-24 hr. see RC Larrock; “Comprehensive Organic Transformations-A Guide to s Functional Group Préparations”, second édition, (1999), p 835-842, and référencéscited therein, and Abdel-Magid et al, J. Org. Chem., 1996,61,3849.

For example: 072293 43

Conditions: Amine sait (1.0 eq), RCHO (1-1.5eq), Et3N (1-3 eq), Na(OAc)3BH (1-2 eq), DCMRT.

Process C

Réduction of Amide of Formula XXXI

The amide carbonyl can be reduced with a suitable reducing agent, for examplelithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°Cto generate the desired tertiary amine, see RC Larrôck in “Comprehensive OrganicTransformations-A Guide to Functional Group Préparations”, VCH, (1989), pp 432-434, and référencés 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. :

Process D

Oxidatlon

Aldéhydes used in process B can be prepared using suitable oxidising agents; seeRC Larrock in “Comprehensive Organic Transformations-A Guide to FunctionalGroup Préparations", second édition, (1999), pp 1234-1236 and 1238-1247, andréférencés cited therein. 012293 44

Preferred oxidants are tetrapropylammonium perruthenate (Ley, étal., 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 R4a

H

Process E

Acid/ amine sait coupling to give amides of formula XXXI 10 Either using an acid chloride + amine in a suitable solvent or the acid activated by asuitable agent, optionally in the presence of a catalyst, for example DMAP, in asuitable solvent; see RC Larrock in “Comprehensive Organic Transformations-AGuide to Functional Group Préparations”, second édition, (1999), pp 1941-1949, andréférencés cited therein. Preferably the carboxylic acid (0.9-1.1 eq), 1-(3- .5 dimethylaminopropyl)-3-ethylcarbodiimide. HCl (1-1.5 eq) and 1- hydroxybenzotriazofe (1.0 eq) are stirred in DMF or DCM at RT for 5-15 min andthen the amine sait (1 eq) and base (NaHCO3 or organic base , Et3N or Hunigsbase (2-4 eq)) are added, the reaction taking 2-24 hr at RT.

For Example:

Process FUrea formation

Anilines can be converted to a urea using potassium cyanate (excess) in an acidic5 aqueous solution, see Cross et al., J. Med. Chem., 1985,28,1427-1432. viz. reaction of the type: 012293 45 K o-

:N -N. 1NHCI.RT, 0.1-10 hr

5 Process G

Ester to an alcohoi

Esters can be converted to the corresponding alcohoi using a suitable reducingio agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional

Group Préparations, second édition, (1999), pp 1117-1120 and référencés citedtherein. Suitable reducing agents include diisobutyiaiuminium hydride (DIBAL, seeWinterfeldt, Synthesis, 1975,617) and lithium aluminium hydride (UA1K4, see Brown,Org. Reactions, 1951, 6,469). viz. réaction of the type:

O

Process H >0 Acid to alcohoi

It should be appreciated that the aicohols used in process D can be prepared fromthe corresponding acid using a suitable reducing agent; see Larock, ComprehensiveOrganic Transformations-A Guide to Functional Group Préparations, second édition, 15 (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973,38,2786), or LÎA1H4 (1-4 eq), in an ethereal solvent, such asTHF, 0-80°C, for 1-24 hr.

O

Process I

Alcohoi to halide 012293 46 lt should be appreciated that the R4Lg used in Process A can be prepared from thecorresponding alcohol R4aOH.

Direct methods to préparé alkyl halides and alkyl sulphonates from their aicohois aredescribed by RC Larock, Comprehensive Organic Transformations-A Guide to 5 Functionai Group Préparations, second édition, (1999),pp 689-700, and référencés cited therein.

Process J

Benzyi haiides to benzyloxyaicohois .0 Benzyloxyaicohois can be prepared by refiuxing the appropriate benzyi halide withsodium or sodium hydride and a poiymethyiene giycol in xyiene, see J. Am. Chem.Soc., 1951,3159-3162.viz. reaction of the type:

X = halide

5 Process K

Acetals to benzyloxyaicohois

Acetals can be treated with a suitabie reducing agent in the presence of a Lewis acidor organic acid to give the benyioxyalcohols.

For représentative examples see Organic Préparations and Procedures, Int., 1991, 0 23,4,427-431, ZrCI4/LiAIH4; J. Org. Chem., 1987,52,2594, Zn(BH4)2ZMe3SiCI; and Organic Préparations and Procedures, Int., 1985,17(1), 11-16, NaBH4/TFA.viz.reaction of the type:

5 012293 47 H ij SO2Me H [ SO2Me JJ ^If I R L-—\ Coupling Processes /\ A-C /“À + R-Y -»- N TFA sait H Example Name Precursor(s) Coupling method -(CH2)nO(CH2)nR examples 145 N-(3-{6-ethyl-3-[2-(2- Yr hydroxyethoxy)etb.yl]-3- o azabicyclo[3.1.OJhex-6- O 's O O yl}phenyl)methanesulfonami de Process A Alkylation If kx °'X^XOH 146 H / JY-[3-(3-{2-[2- (dimethylamino)ethoxy]ethyl "*X sz }-6-ethyl-3- y I oz O azabicyclo[3.1.0]hex-6- U w yl)phenyl]methanesulfonami ProcessB de Reductive amination Q \ 1 Process D oxidation 147 2- [2-(6-ethyl-6-{3-[(methylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex- 3- yl)etboxy]acetamide 012293 48

'Ν' Q

frocess B ' leductive amination HO, 48

NK

' ?rocess D oxidation '°"Ύ

O NH,

JV-(3-{6-ethyl-3-[2-(2- pyridmylmethoxy)ethyl]-3-azabicyclo[3.1 -0]hex-6-yl}phenyl)methanesulfonaniide

Process B HO,

Process D 149

7/-(3-{6-ethy 1-3 - [2-(2,2,2-trifluoroefhoxÿ)ethyl]-3-azabicyclo(3.1.0]hex-6-yl}phenyl)methanesulfonamide °Y^o

N

N

Process C

Amide réduction v r Α,Ο,,Χ

HOProcess E 012293 49

Amide formation

2V-(3-{6-ethyl-3-[2-(2-propynyloxy)etih.yl]-3-azabicyclo[3.1.0]bex-6-yl}phenyl)methanesulfonamide °<y-\

H

Process B

Process D

Æ-(3-{3-[2-(allyloxy)ethyl]- 6-ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesuîfonarni de

Process B

HO'Process D

7Ç-(3-{6-ethyl-3-[2-(2- methoxyetboxy)ethyl]-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de

Process B and D 154 N-(3-{3-[2- (cyclohexylmethoxy)ethyl}6-ethyl-3- azabicyclo[3.1.0]hex-6-yl}phenyl)meihanesulfonamide

012293 50 H ÜJ Ο θ ΟΧ) (CH2)nO(Cîî2)nAr examples 155 H ιΓΎ ο o tf-[3-(3-{2-[(4- chlorôbenzyl)oxyje£hyl}-6- ethyl-3- azabicyclo[3.1 .Ojhex-6- yl)phenyl]methanesulfonami de Process B and D CojOr" 156 AM3-(6-ethvI-3-{2-iï4- fi J ο o methoxvbenzvBoxvlefhvll- 3-azabicvcfor3.1.01hex-6- Process B and D vllDhenvIlmethanesulfonami /\ de cxx “δΐ other (CH2)nO(CH2)nAr examples can be prepared viaa 2 step process from a benzylalcohol or benzyl chloride For a general proceduresee; J. Am. Chem. Soc.,1951,3159-3162. Aryl substituent (mix. of aryl and aryloxy examples) : Oî 2293 51

012293 160

161

52 JV-{3-[3-(2-{4-[(aminocarbonyl)aniino]phenoxy} ethyl)-6-etbyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide 2V-(3-{3-(3-(4- acetylphenyl)propyî]-6- ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de 4-[2-(6-etiiyl-6-{3- ((methylsulfony])amino}phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethoxy]benzenesulfonami de

Process A

Process A

Processes C and E 012293 53 H ?/-[3-(6-ethyl-3- {2-[4- (methyîsulfonyl)phenoxy]eth 1 J ° 0 yI}-3-azabicyclo[3.1.03hex- 6- yl)phenyl]methanesulfonami de 0 0 164 H methyl 4-[2-(6-ethyl-6-{3- [(methylsulfonyljaminoîphenyl}-3-azabicyclo[3.1 .Ojhex- 3-yl)ethoxy]benzoate v ..OMe M 0 ° Processes B and D 11 O /Λ 0 165 H ethyl {2-[2-(6-ethyl-6-{3- Js s. <"V [(methylsulfonyl)amino]phe £ 0 Ijj 0 0 nyl}-3-azabicyclo[3.1.Ojhex- 3-yl)ethoxy|phenyl) acetate 11 T Process A 'i? 166 Processes B and D methyl {4-[2-(6-ethyl-6-{3- 012293 54

[(methylsulfonyî)amino]phe nyl}-3-azabicyclo[3.1.0]hex-3 -yl)efhoxy]phenoxy) acetate 167

JV-[3-(6-ethyl-3-{2-[4-(hydroxymetbyl)phenoxy]ethyl} -3-azabicyclo[3.1.O]hex-6- yl)phenyl]methanesulfonami de

OH

HO

’rocesses CandE

or from réduction ofexample 19-Process G

168

JV-(3-{3-[2-([l,r4jiphenyl]-4-yloxy)ethyl]-6-efhyl-3-azabicyclo[3.1 .OJhex-6-yl}phenyl)methanesulfonamide HO'

Processes B and D 169 55

?/-[3-(3-{2-[4-(4,5-dihydro- l,3-oxazol-2- yl)phenoxy]ethyl}-6-ethyl-3-azabicyclo[3.1,0]hex-6-yl)phenyl]methanesulfonamide 170

Æ-(3-{6-ethyl-3-[2-(4-phenoxyphenoxy)etbyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide 171

/7434342- (benzvloxvlbenzvn-6- ethvl-3- azabicvcloO. 1 .Olhex-6- vftphenvDrnethanesulfona mide 1743-{3-(2-(4-benzylphenoxy)ethyl]-6- 072293

Processes B and D

Commercial aldéhyde

Processes B

172 012293 56 rr" Μ 0 -s'" ζΛο ethyl-3- azabicyclo [3.1.0)hex-6- yl}phenyl)methanesulfonami de k/O 173 H N-{3-[3-(4-cyanobenzyl)-6- ethyl-3- azabicyclo[3.1 .OJhex-6- Commercial aldehvde N-q'" <Λ\> yl]phenyl}methanesulfona mide Process B V O O -> II 174 Q H O O AT-(3-{3-(2-(4- cyclopropylpbenoxy)ethyl]- 6-efhyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de UK-180220 Process A ? <-°V% ÜK-419966 V Substitucnts ofthcbasic aîkyl/alkenyl/aDcynyl chains: 175 α^Λ0Χ) Process A phenyl 3-(6-ethyl-6-{3- 57

176 07 229 3 [(methylsulfonyl)ammo]phenyl}-3-azabicyclo[3.1 .Ojhex-3-yl)propanoate

benzyl 4-(6-ethyl-6-{3-[(methylsulfonyl)amino]phenyl} -3-azabicyclo[3.1.0]hex-3-yl)butanoate

ProcessA

jV-{3-[6-ethyl-3-(3-oxo-3-phenylpropyl)-3-azabicyclo [3.1 .Q]hex-6-yl]pbenyl)methanesulfonaniide ,-Xq

Process A

N-(3-{3-[3-(2,3-dihydro-lir- inden-5-yl)-3-oxopropyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6> yl}phenyl)methmesulfonami de c^Xo

Process A 012293 01 229 58 79

2- (6-ethyl-6-{3-Xmethylsulfonyl)amino]phenyl} -3-azabicyclo[3.1.0]hex- 3- yI)ethyl benzoate

O'

' frocess A .Br 80

N 2- (6-ethyl-6-{3-[(methylsulfonyl)amino]phenyl} -3-azabicyclo[3.1.0]hex- 3- yl)ethyl cyanoacetate

Br" ,0

' ^rocess A 181

O u 2-(6-ethvl-6-{3-rimethylsulfonvllaminolphen vI}-3-azabicvclor3.1 .Olhex-

ci

Process A 3-vBethvl l,5-dimethvl-3 oxo-2-phenvI-2.3-dihvdro- lH-pvrazole-4-carboxvlate 182

HO

Processes C and E ΛΓ-(3-{3-Κ4-/βζϊ- butylcycIohexyl)methylj-6- 012293

59 ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de 183

M(3-{6-ethyl-3-[<4-methoxycyclohexyl)methyl]-3-azabicyclo[3.1,0]hex-6-yl}phenyl)methanesulfonamide

HO λ-f

Processes C and E

O' 184

M(3-{3-[(2- benzylcyclohexyl)methyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonami de

Processes C and E

HO

185 012293 60

N- {3-[6-ethyl-3-(octahydro- lff-inden-2-ylmethyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfoiiamide

' 3rocessss C and E *r 86

2V-(3-{6-ethyl-3-[(2-phenylcyclopropyl)methyl3-3 -azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

Processes C and E

?/-(3-{6-ethyl-3-[2-(phenylsulfonyl)ethyl]-3-azabïcyclo[3.1 .Ojhex-6-yl}phenyl)methanesulfonamide

HO x>?

Processes C and E

Processes B and P 188

012293 61

2V-(3-{6-ethyl-3-[2- (ethylsulfonyl)ethyl]-3- azabicyclo[3.1.0]hex-6- yl}phenyl)mefhanesulfonami de 89

benzylsulfonyl)ethyl]-6- ethyl-3- azabicyclo[3.1.0]hex-6- yl}phenyl)methanesulfonanû de

190

JV-[2-(6-ethyl-6-{3-[(methylsulfonyl)annno]phenyl}-3-azabicyclo[3.1.0]hex-3- yl)ethyl]benzenesulfonaœide

XO °

Process C and E

OH A43-(6-ethyl-3-{2- [(methylsulfonyl)aniino]eihy l}-3-azabicyclo[3.1.0]hex-6- yl)phenyl]methanesulfonami de

191 012293 62

Q As- 0 O Usz A'o o 192 ç H <N. / O O N-[2-(6-ethyl-6-{3- '(metiiylsulfony])amino]phenyl}-3-azabicyclo[3.1.0]hex-3-yl)ethyl]acetamide 0 À /\χΟΗ H Processes B and D Ÿ H O 193 H fi T HJ O 0 ujO N-[2-(6-ethyl-6-{3- [(mefhylsulfonyl)amino]phenyl}-3-azabicyclo[3.1.0]hex-3-yl)etb.yl]benzamide O Process A δ 194 JV-[2-(6-etbyl-6-{3- [(metiiylsulfonyl)amino]phe nyl}-3-azabicyclo[3.1.0]hex- 3-yl)ethyl]isonicotinaniide Processes B and D 07 229 3 63

,OH 7^-[3-(3-{2- [(anilinocarbonyl)amino]e1hyl}-6-ethyl-3-azabicyclo[3.1.O]hex-6-yl)phenyl]methanesulfonamide

Processes B and D 196

ethyl 2-(6-etiiyi-6-{3-[(methylsulfonyl)anûno]phenyl}-3-azabicyclo[3.1.0]bex-3-yl)ethylcarbamate HO'

Processes B and D 27-(3-{6-eihyl-3-[2- (phenylsulfanyl)ethyl]-3- azabicyclo[3.1.0]hex-6- yl}phenyl)rnethanesulfonami de

Processes C and E 197 01 2293 64 K ίΐ I x/·' HJ ο o 198 H HJ ο o jV-(3-{6-ethyl-3-[2-(2-pyrimidmylsulfanyl)ethyl]-3-azabicyclo[3.1 .Ojhex-6- O H0^SY^ U Processes C and E yl}phenyl)methanesulfonamide '·

Example 199: ÎV-f3-f3-r3-f4-acetvIphenvl)propvH-6-ethvI-3-azabicvclor3.1.Qlhex-6- vIlphenvDmethanesulfonamide - and formate sait

O 01 2293 65 Το a solution of the trifluoroacetic acid sait of /V-[3-(6-ethyi-3-azabicyc!o[3.1.0]hex-6-yi)phenyllmethanesuifonamide (106 mg, 0.27 mmoi) in N,N- dimethylformamide (4ml) was added sodium hydrogen carbonate (90mg, 1,1 mmoi), 1-(4-(3-chioropropyi)phenyi]ethanone (58 mg, 0.29 mmoi) and sodium îodide (catalytic) andthe reaction mixture was heated at 70 °C for 20 h. After cooiing, the soivent wasremoved in-vacuo to give a crude residue. This was purified by silica (14 g) coiumnchromatography elutingwith ethyi acetate: hexane (75:25) and then with neat ethylacetate. Combination and évaporation of the appropriate fractions gave the partialiypurified product. This material was further purified by préparative HPLC (condition 1)to afford the formate sait of titie compound (16 mg, 12%) as a yeiiow oil. 1H-NMR (300MHz, CDCl3, data for formate sait) : 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). MS (Electrospray) : MZZ (M-H) 439; C^H^NAS - H requires 439.2.

Example 200 : AZ-(3-f3-f2-fbenzvloxv)benzvl1-6-ethvl-3-azabicvcloF3.1.01hex-6- vDphenvDmethanesulfonamide

To a solution of 2-benzyloxybenzaldehyde (27mg, O.13mmol) in dichloromethane (5mi) at room température was added the trifluoroacetic acid sait N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50mg, 0.13 mmoi) andtriethylamine (0.05 ml, 0.38 mmoi). The reaction was left to stir at room températurefor 2h. At this point sodium triacetoxyborohydride (40.8 mg, 0.19 mmoi) was addedand the reaction was left to stir at room température for 16 h. Water (5ml) was thenadded to the reaction mixture and the two layers were separated using a Whatmanfilter tube (hydrophobie polytetrafluoroethylene membrane). The organic layer wasthen blown down to dryness under a steam of nitrogen. The residue was purified by 012293 66 column chromatography using a Sep-Pak™ cartridge packed with silîca gel (10 g)eluting with hexane: ethyl acetate (100:0, 1:1, 1:3, 1:6, 1:9 and 0:100) to afford thetitle compound (28 mg, 46%) as an oil. 5 1H-NMR (300MHz, CDCl3): 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 (Electrospraÿ) : M/Z (M+H) 477; C^K^O-jS + H requires 477. θ Example 201 : A/-Î3-r3-(4-cvanobenzv0~6-ethvl-3-azabicycloi3.t .0~lhex-6- vnphenviïmethanesulfonamide

5 The compound above was prepared by a simllar method to that of Example 167,using the trifluoroacetic acid sait of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyQmethanesuIfonamide (100 mg, 0.25mmol) and 4-cyanobenzaldehyde(33mg, 0.25mmol) as the starting matériels. The product was purified usingpréparative HPLC (conditions 3) to afford the title compound (28 mg, 28 %) as an .0 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) .5 MS (Electrospray) : M/Z (M+H) 396; CaHasNaOzS-H requires 396.

Exampje-2Q2:-^-(3-(3-f2-(4-cvclopropvlphenoxv^ethvn-6-ethvl-3- azabicvclof3.1.Qlhex-6-vnphenvhmethanesulfnnamiriP> 67 072293

Το a solution of the trifluoroacetic acid sait of /V-[3-(6-ethy!-3-azabicyclo[3.1.0]hex-6-yl)phenyf|methanesulfonamide (75 mg, 0.19 mmol) in N, N- dimethylforrnamide (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 thereaction mixture was heated at 60 °C for 20 h. After cooling, the solvent wasremoved in-vacuo to give a crude residue. This was purified by préparative HPLC(condition 2) to afford the formate sait of the title compound (4 mg, 5%) as a brown 0 gum. 1H-NMR (300MHz, CDCI3, data for formate sait) : 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; CæHxiNzOsS - H requires 439.2.

Example 203: A/-(3-i6-ethvl-3-F(2-phenvlcvc!opropvnmethvn-3-azabicvclof3.1 .Olhex- 6-vftphenvi)methanesulfonamide

0 012293 68

To a mixture of frans-2-phenylcyclopropylcarboxa!dehyde {ref. J. Qrg. Chem., 1992, 57, 1526} (30 mg, 0.2 mmol) and the trifiuoroacetic acid sait of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesuIfonamide (50 mg, 0.13 mmol) in dry 1,2- 5 dichioroethane was added Hunigs' base (0.02ml, 0.12mmol). The mixture wassonicated for 3 minutes and then stirred for a further 30 minutes foilowed by theaddition of sodium triadetoxyborohydride (50 mg, 0.25mmol). After stirring for 72hours, the reaction was diiuted with ethyl acetate (50ml) and partitioned betweensaturated sodium bicarbonate (2 x 25ml). The organic iayer was washed with brine 10 (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 ) dissoived in the minimum of quantity of dichloromethane and purified using aBiotage™ 6 g cartridge eluting with a gradient of ethyl acetate:hexane (30:70) toethyl 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; C24H30SO2N2 + H requires 411

:0 PREPARATIONS NB Préparations 1 to 148 from International Patent Application publication no. WO00/39089 are herein incorporated by référencé in their entirety, and the samenumbering is adhered to herein. 5 Préparation 149 1-i4-f3-chioropropvl)phenvnethanone

Cl >

Cl

O

Aluminium chloride (15.0 g, 0.11 moles) and aœtyl chloride (16.0 g, 0.20 moles) o were dissoived in dichloromethane (50 ml) at room température. This mixture wasthen added dropwise to a solution 1-chioro-3-phenylprepane (15.5 g, 0.10 moles) in 012293 69 dichloromethane (25 ml) at room température over 15 minutes. The mixture wasstirred for 1 hr and then poured cautlously onto ice. The aqueous layer was extractedwith dichloromethane (450 ml). The organics were washed with water and brine, andthen dried (MgSO4) and concentrated in-vacuo to give the titïe compound (19.2 g,98%) as an oil. <H-NMR (300MHz, CDCI3): 2.10 (quintet, 2H), 2.60 (s, 3H), 2.85 (t, 2H), 3.55 (t, 2H),7.30 (cf, 2H), 7.90 (d, 2H). MS (thermospray) : M/Z [M+NH4f 214; C^H^CIO + NH4 requires 214.1.

Préparation 150 1-(2-chloroethoxv)-4-cvclopropylbenzene

HO

Ci 4-Cyclopropyiphenol (6.75 g, 50.3 mmoi, référencé: Horrom et. al., Qrg. Prep.Proceed. Int., 1992,24 (6), 696-698), 2-chioroethyl p-toluenesulfonate (17.71 g, 75.5mmol), and potassium carbonate (10.4 g, 75.4 mmol) in anhydrous acetonitrile (500ml) were stirred together under a nitrogen atmosphère at reflux for 30 hours. Thereaction was aliowed to cool to room température and dîluted with ethyl acetate(1000 ml). The organics were washed with water (3 x 250 ml), dried (MgSO4),fiitered and concentrated in vacuo. This crude matériel was purified by silica columnchromatography eluting with hexane : dichloromethane (4:1) and then with hexane :dichloromethane (3:1) to afford the titïe compound (8.7 g, 88%) as a solid.

Mpt: 47-48°C 1H-NMR (300MHz, CDCIa): 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; CnH13OCI requires 196.1.

Préparation 151 1-Allvl-1H-pvrolie-2,5-dione (see J, Oro. Chem., 1997.62.2652) 012293 70

5 To a solution of. tnaleic anhydride (98 g, 1.00 moi) in dry toluene (3000 ml) at roomtempérature under a nitrogen atmosphère was added dropwise a solution ofallylamine (57.1 g, 1.00 mol) in toluene (1000 ml) over one hour. The mixture wasstirred at room température 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-HexamethyIdisîlazane .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 roomtempérature and then poured onto 1N HCl (4000 ml). The two layers wereseparated and the organic layerwas washed with water (2000 ml), saturated sodiumbicarbonate (2000 ml) and brine (2000 ml). The organics were concentrated in vacuo 5 to give the title compound (74 g, 54%) as a solid. ’H-NMR (300MHz, CDCIS): 4.05 (d, 2H), 5.00-5.15 (m, 2H), 5.60-5.80 (m, 1H), 6.65(2H, s).

Préparation 152 0 1 -(3-nitrophenvl)-1 -oropanone hvdrazone

P N.

01 2293 71 Το a solution of 3-nitropropiophenone (168 g, 0.93 mol) in éthanol (830 ml) at roomtempérature was slowly added hydrazine monohydrate (96.8 g, 1.93 mol) via adropping funneî. The reaction mixture was heated at reflux for 4 hours and thencooled to room température. The solvent was removed in vacuo and the residue was 5 partitioned between dichloromethane (750 ml) and water (750 ml). The two layerswere separated and the organic layer was washed with brine (250 mi), drîed(Na2SO4), filtered and concentrated in-vacuo to give an orange oil. This residue wascrystallised fromdiisopropyl ether at-20°C to afford the title compound (110 g, 61%)as a yeliow 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; CSH11N3O2 + H requires 194.1. 5 Préparation 153 3-Allvl-6-ethvl-6-f3-nitrophenvl]-3-azabicyclof3.1.01hexane-2.4-dione

To a stirred solution of 1-(3-nitrophenyl)-1-propanone hydrazone (84.7 g, 439 mmol)o in 1,4-dioxane (1000 ml) was rapidly added manganèse dioxide (grade CMD-1 from

Sumltromo, 175 g, 2.01 mol)fbllowed by a saturated solution of ethanolic potassiumhydroxide (40 ml) at room température. The mixture was stirred at room températurefor 18 minutes and during this period the réaction température had risen from 19°Cto 25°C. Stirring was then stopped and the mixture was allowed to settie. This 5 mixture was then filtered through a pad of Ceîite® dropwise, directiy into a solution of 01 2293 72 T-aiiyï-1 H-pyrolle-2,5-dione (57.3 g, 418 mmol) in 1,4-dioxane (200 ml). The Celite®pad was washed with 1,4-dixane (100 ml) to ensure complété addition of thereactants. After stirring at room température for one hour the mixture was heated atreflux for 20 hours. The mixture was cooled to room température and the solvent 5 was removed in vacuo. The residue was then crystallised from dîisopropyl ether(1000 ml) at 0°C to afford the title compound (83 g, 66%) as an off-white crystallinesolid.

MPt: 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).

Préparation 154 3-aHyl-6-(3-aminophenvD-6-ethvl-3-azabicvclor3.1.01hexane-2,4-dione

To a stirred suspension of 3-allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicycio[3.1.0Jhexane-2,4-dione (93 g, 310 mmol) and iron powder (151 g, 2.70 0 mol) in éthanol (6.75 L) was added calcium chloride (16.7 g, 0.15 mol) in water (1.2L). The mixture was heated at reflux for three hours and then cooled to roomtempérature before being filtered through Celite®. The filtrats was concentrated invacuo to glve a wet solid. This matériel was dissolved in dichloromethane (500 ml)and the two layers were separated. The organic layer was dried (MgSO4), filtered 012293 73 and concentrated in vacuo to give a pale yellow solid (81 g). Thîs material wascrystallised from ethyi acetate and hexane (1:1; 6ml per gram) at room températureto 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, 1 H), 5.35 (d, 1 H), 5.75-5.85 (m, 1 H), 6.65 (d, 1 H), 6.70 (s, 1H), 6.75 (d, 1H), 7.10 (t, 1H).

Préparation 155 3-(3-Allvl-6-ethvl-3-azabicvclor3.1 .OIhex-6-yQaniline

To a solution of lithium aluminium hydride (1M solution in THF; 400 ml, 400 mmol) intetrahydrofuran (400 ml) under a nitrogen atmosphère at -15°C was added 3-allyl-6- 15 (3-aminophenyI)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 mi) via a dropping funnel over 0.5 hours. The mixture was thenallowed to siowly warm to room température over one hour. The mixture was heatedat 50°C for 3 hours and then cooled to 5®C. Water (400 ml) was then cautiouslyadded to the cooled (5°C) reaction mixture. The solids were removed by filtration 20 through a pad of Celite®, washing with ethyi acetate (400 ml). The filtrate was dried(MgSO4), filtered, and concentrated in vacuo to afford the title compound (38.1 g,96%) as a golden oil. 1H-NMR (300MHz, CDCI3): 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). 012293 74 MS (AP+) MZZ [MH]+ 243; + H requires 243.2.

Préparation 156 /V-f3-f3-allvl-6-ethvI-3-azabicvclor3.1.01hex-6-vl)phenvnmethanesulfonamide

To a solution of 3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (41 g, 169 mmoi)10 and tiiethylamine (34 g, 337 mmol) in dichloromethane (750 mi) at -40°C was added dropwise methanesulfonyl chloride (23.7 g, 206 mmol) via a dropping funnel. The .reaction mixture was siowly allowed to warm to room température over 2 hours andwas then stirred at room température for 20 hours. The organics were then washedwith water (4 x 500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford 15 the titïe compound (59.0 g) as a crude gum. 1H-NMR (300MHz, CDC!3): 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, 1 H), 7.00-7.40 (m, 4H).

Préparation 157 20 /V-f3-(6-ethvl-3-azabicvclor3.1.01hex-6-vl)phenvnmethanesulfonamide 012293 75

Το a degassed solution of A/-[3-(3-alIyi-6-ethy!-3-azabicyclo[3.1.03hex-6-yl)phenyI3methanesulfonamide (54.0 g, 169 mmol) and 1,3-dimethyibait,ituric acid(80.0 g, 512 mmol) in dichioromethane (500 ml) under a nitrogen atmosphère wasadded tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol). The mixture washeated at reflux for 8 hours and then stirred at room température for 20 hours. Theorganics were then extracted with 2M HCl (2 x 100 ml) and water (100 ml). Thecombined aqueous layers were then washed with dichioromethane (4 x 100 ml) andfreeze dried to give a crude solid. This material was purified by préparative HPLC(condition 4) to afford the trifiuoroacetic acid sait of tiüe compound (25.2 g, 53%) asa grey solid. ’H-NMR (300MHz, CD3OD): 0.90 (t, 3H), 1.65 (q, 2H), 2.30-2.40 (m, 2H), 2.90 (s,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; C14H20N2O2S + H requires 281.1.

Préparation 158:3-Benzvl-6-methvl-6-(3-nitrophenvl)-3-azabicvcior3.1.01hexane- 2.4-dione

To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone (100g, 0.56mol), in dioxan (1L) was added MnO2 (350g, 2.3mol) and the reactionmixture stirred at room température for 30mins. The slurry was fiitered through celiteand the celite pad washed with dioxan (200mis). The filtrate was retumed to a potand N-benzy! maleîmide (110g.) added portionwise over a period of 20mins. The 012293 76 reaction mixture was stirred at room température for 4hrs before being heated underreflux for 16hrs. The reaction mixture was cooled to room température and thesolvent removed in vacuo. The residue was triturated in methanol (500mls) and theproduct isolated by filtration as a white crystalline solid ( 56%). NMR (CDCIs) 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) MS (APCI): m/z [MH+] 337.5 +H requires 337.3

Préparation 159: 6-(3-Aminophenvl)-3-benzvl-6-methyi-3-azabicvclof3.1.01hexane- 2,4-dione

To a slurry of 3-benzyl-6-methyi-6-(3-nitrophenyI)-3-azabicyclo[3.1.0]hexane-2,4-dione (30g, 89mmol) in ethyl acetate (600mls) was added 5%Pt/C (1.5g, 5wt%). Themixture was hydrogenated at4 atm. (=60p.s.i.) Z room température for 18hrs. Theslurry was fiitered through arbacel and the resulting solution evaporated in vacuo toyield the product as a white crystalline solid (24g, 88%). 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

Préparation 160: N-f3-i3-Benzvl-6-rnethvl-2.4-dioxo-3-azabicvclol3.1 .Olhex-6- yjphenvnmethanesulfonamide

To a solution of 6-(3-aminopheny!)-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 température for 2.5hrs. The reactionmixture was washed sequentially wlth 1M HCl solution (120mls) and water (120mls). 012293 77

The ethyi acetate was dried over MgSO4 and evaporated in vacuo to yield theproduct 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.3H), 7.26-7.32 (m, 4H), 7.41-7.42 (d, 2H). MS (APCI): m/z [MH+] 385.7 +H requires 385.5

Préparation 161: N-f3-Benzvl-6-methvi-3-azabivciof3.1.01hex-6-vnphenvB methanesulfonamide

To a solution of N-{3-[3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0lhex-6-yi]phenyl}methanesulfonamide (150g, 391mmol), under nitrogen was added sodiumborohydride (31g, 820mmol). The reaction mixture was cooled to <10°C and theBFa.OEt2 (138.6mis, 1094mmol) added dropwise maintaining the température at<10°C. The reaction mixture was allowed to warm to room température over 2hrsbefore being heated under reflux for a further 8.5hrs. The reaction mixture wascooled 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 underreflux for a period of 18hrs. The THF was removed under vacuum, ethyi acetate(900mls) added, and the phases were separated. The aqueous phase was extractedwith a second portion of ethyi acetate (450mls). The organic phases were combinedand washed with water (750mls). The organics were dried over MgSO4 andevaporated in vacuo to yield the product as a white crystalline solid (129g, 93%). 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). MS (APCI): m/z [MH+J357.5 +H requires 357.5

Préparation 162: N-f3-r6-methvl-3-azabicvclof3.1,01hex-6- vnphenvllmethanesulfonamide 012293 78 Το a solution of N-{3-benzyi-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 addedand the resulting mixture heated at reflux for 16hrs. The mixture was aliowed to cooland the cataiyst removed by filtration through ceiite. The solvent was removed invacuo to yieid the product as a paie yeiiow oil, which soiidified on standing (15.2g,85%). 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

Preoaration 163:3-Benzvl-6-ethvl-6-(3-nitrophenvl)-3-azabicvclor3.1.01hexane-2.4- dione

To a solution of 1-(3-nitrophenyi)-1-propanone hydrazone (42.1gg, 217mmol), in dioxan (630mls) was added MnO2 (126g, 1440mmol) and thereaction mixture stirred at room température for 20mins. The slurry was fiiteredthrough ceiite and the ceiite pad washed with dioxan (200mls). The filtrate wasretumed to a pot and N-benzyi maieimide (44.9g, 239mmol) added portionwise overa period of 20mins. The reaction mixture was stirred at room température for 60hrsbefore being heated under reflux for 16hrs. The reaction mixture was cooled to roomtempérature and the solvent removed in vacuo. The residue was heated to reflux inmethanol (1200mls) for 3 hours and then cooied to room température. The productwas isoiated by filtration as a white crystalline soiid (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), 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 [MH+]351.5 +H requires 351.3 01 2293 79

Préparation 164: S-fS-AminophenvO-S-benzvi-O-ethvl-S-azabicvcioiS.1.01hexane-2.4- dione

To a slurry of 3-benzyl-6-ethyl-6-(3-nitrophenyi)-3-azabicycio[3.1.0]hexane-2,4-dione(42.1g, 12Qmmol) in ethyl acetate (850mis) was added 5%Pt/C (2.1g, 5wt%). Themixture was hydrogenated at 60psiZ room température for 18hrs. The siurry wasfiltered through arbace! and the resulting solution evaporated in vacuo to yieîd theproduct as a white crystalline soiid (34.1g, 89%). NMR (CDC13) d: 0.70-0.74 (t, 3K), 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 (APCl): m/z [MH+] 321.4 +H requires 321.4

Préparation 165: N-Î3-f3-Benzvl-6-ethvl-2.4-dioxo-3-azabicvclor3.1 .QIhex-6- vllphenvUmethanesulfonamide

To a solution of 6-(3-aminophenyl)~3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (31.5g, 98mmoi) in dichioromethane (250mls) was added pyridine (9.5mis, 118mmol) followed by the slow addition of methane sulfonyl chloride (9.1 mis, 118mmol). The reaction was stirred at room température for 16hrs. The reactionmixture was washed sequentially with 1M HCl solution (250mls) and water (120mis).The dichioromethane was dried over MgSO4 and evaporated in vacuo to yield theproduct as a waxy pink soiid (38.2g, 98%). . 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 (APCl): m/z [MH+] 399.6 +H requires 399.5

Préparation 166: N-f3-Benzvl-6-ethvi-3-azabicvdof3.1.0lhex-6-vllphenvB methanesulfonamide

To a solution of N-{3-[3-benzyl-6-ethyi-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yflphenyljmethanesulfonamide (38.2g, 95mmoi), in THF (200mls) under nitrogen wasadded sodium borohydride (7.46g, 201mmoi). The reaction mixture was cooled to<10 C and the BF3.OEt2 (38.1 mis, 268mmol) added dropwise maintaining the 80 072293 température at <10 C. The reaction mixture was allowed to warm to room température 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 320mls of water) added. The reaction mixture was then heated under reflux for a period of 18hrs. The THF was removed under vacuum, ethyi acetate (200mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyi acetate (200mis). The organic phases were combined and washed with 3 separate portions of water (3x400mls). The organics were dried over MgSO4 and evaporated in vacuo to yield the product as a white crystalline solid (33.5g, 94%). i 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). MS (APCI): m/z [MH+] 371.3 +H requires 371.5

Préparation 167: N-f3-l5-Ethvl-3-azabicvciof3.1.01hex-6- vflphenvllmethanesulfonamide - à

To a solution of N-{3-benzyl-6-ethyl-3-azabiyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (500mg, 1.34mmol), in methanol (30mls), was addedammonium formate (255mg, 4.05mmol) and the reaction stirred for 5minutes. 10%

Pd/C (200mg) was added and the resulting mixture heated at reflux for 2hrs. Themixture was allowed to cool and the catalyst removed by filtration through celite. Thesolvent was removed in vacuo to yield the product as a pale yellow oil, whichsolidified 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), 7.25-7.28 (m, 1 H). MS (APCI): m/z [MH+] 281.7 +H requires 281.4 012293 81

Other building block materiais useful in synthesising compounds of formula (I) w'rthvarious different R4 groups are available from the sources indicated in the tablebelow, and routine derivatisation thereof, or anaiogy synthesis. R4 Substructure Example of commercial source Literature reference -(CH2)nO(CH2)nR exampies Ck χχ,ΟΗ ALDRICH 1 HO. .N. ALDRICH HO. χ x .NH9 0 SALOR Λγ 1. Org.Magn.Reson., 1975, Vol 7, 488-495. 01 2293

82 WO 8707270

HO

Alcohol US 5157159

MAYBRIDGE HO,

ALDRICH HO,

ALDRICH

HO (CH2)nO(CH2)nAryl examples

Bull. Soc. Chim. Fr.;1947,616.

Alcohol-EP-0811621

BIONET HO,

Cl HO, 1. J. Org. Chem., 1987,52 (12), 2594. 2. Org. Prep. Proceed.Int; 23,4; 1991,427.

Ail other (CH2)nO(CH2)nAryIexamples could beprepared via 2 step process

For a general proceduresee; J. Am. Chem. Soc.,1951,3159-3162. 01 2293 83

from a benzyl alcohol or benzyl chîoride Aryl substituants on R4 (mix. of aryl and aryioxyexamples} : H2N^0 SALOR J. Med. Chem., 1985,28, 1427. J. Med. Chem., EN; 28, 10,1985,1427. 0 SALOR H ^°TXX By manipulation of the product above. zz \\ 0 0 DE 2135678; DE 3636333 Rev. Med.-Chiv., 1985, 89 (2), 316-20. SPECS 01 2293 84

lî^L.OMe 0 ΑΡΙΝ J. Med. Chem., 28,10, 1985,1427 J. Med. Chem., 28,10, 1985,1427 '"η?1 EP-0171760 J. Med. Chem., 28,10, 1985,1427. Λ°ιχ« LANCASTER ηο"χ~'^Οχ'ιΓ^^ ICN-RF N-V MAYBRIDGE 012293 85

SALOR 0 Ηο'^'θγ^ι MAYBRIDGE Agric. Biol. Chem., 1978, OH 1767. WO 9611192 faicohon ΑΑΜ WO 9610999 Imidazole analogue: J. Med Chem., 1981, 24(10),1139 US-4713387 MAYBRIDGE XX J. Med. Chem., 28,10, 1985,1427. Substitueras of the basic R4 alkyl/alkenyl/alkynyl chains: α^Λο-Ο fCN-RF O WYCHEM ALDRICH 012293 86 Ο SALOR ALDRICH Ο J. Àm. Chem. Soc., 78, 1956,4944. Alcohol: EP-136260 Â^A SALOR „χ>^ ALDRICH XX ALDRICH Ο^ΟΗ œô SALOR χο J. Org. Chem., 1954, 1449. 012293 87

012293 88

Claims (33)

012293 89 CLAIMS

1. A substance which is a compound of formula I,

wherein the "Ar" ring represents an optionally benzo-fused phenyl or 5- or 6-memberedheteroaryl ring; Rl when taken alone is H, halogen, NO2, NH2, NY^WY1, Hetl, AD, COjR?, C(O)R8,C(=NOH)R8, or OE, γ2 is H, Ci_g alkyl, C3.6 alkenyl (each of which alkyl and alkenyl is optionally substitutedby aryl, aiyloxy or Hetl), W is SO2, CO, C(O)O, P(Yl>0, P(Y1)=S, Y* is Cj-io alkyl (optionally substituted by one or more snbstituents independently selectedfrom halogen, OH, C1.4 alkoxy, Ci-6 alkanoyloxy, CONH2» ^1-6 alkoxycarbonyl, NH2,aryl, mono- or di(C^ alkyl)amino, C3.8 cycloalkyl, phthalimidyl, Hetl), Hetl, aiyl(optionally substituted by one or more substituents independently selected from Οχ_4 alkyl,Cj_4 haloalkyl and halogen), NH2, N(Ci.g alkyl)2 or NH(Ci_g alkyl), Hetl is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, whichmay comprise up to 3 rings (preferably a heteroaryl group,optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from Cj.g alkyl,Ci_6 alkoxy, C3_g cycloalkyl, Ci_$ haloalkoxy, Ci-6 haloalkyl, C3.6 halocycloalkyl, «O, 012293 90 OH, halogen, NO2, SiRl^R^bR^c, CON20aR20bs NR20aR20b; gRÎla NR21bSO2R22a,NR21cc(O)OR22b, NR21dC0R22d and Ci_g alkoxycarbonyl, and if a S atom is présent in a ring, it can be présent as part of a -S-, S(O)- or -S(O2)- group,and carbon atoms in the ring can be présent as a part of a carbonyl moiety; R 19a, R 19b, Rl9c earfi independently represent Ομβ alkyl or aryl, R20a and R20b each independently represent H, Ci_g alkyl, aryl, (Ci_4 alkyl)phenyl, eachof which alkyl aryl and alkylphenyl are optionally substituted by one or more Cj_4 alkyl,Ci_4 alkoxy, OH, NO2, NH2 and/or halogen, or R20a and R^Ob can be taken together with the N atom to which they are attached, to forma 4- to 6-membered ring optionally substituted by one or more substitutuents independentlyselected from one or more Cy_4 alkyl, Ci_4 alkoxy, OH, =0, NO2, NH2 and/or halogen, R2 la, b, c and d each independently represent H, Ci_g alkyl, aryl or C1-4 alkylphenyl, eachof which alkyl, aryl, and alkylphenyl are optionally substituted by one or more Cp_4 alkyl,Ci_4 alkoxy, OH, NO2, halogen, NH2, R22a» b and c each independently represent alkyl, aryl or Ci_4 alkylphenyl, each ofwhich alkyl, aryl, and alkylphenyl are optionally substituted by one or more Cj_4 alkyl, Cj_4alkoxy, OH, NO2, halogen, NH2, A is Cj_4 alkylene, C2-4 alkenylene or C2.4 alkynylene, each of which is optionallysubstituted by one or more C}_4 alkyl, Cj_4 alkoxy, halogen and/or OH, D is H, OH, CN, NR25r26 CONR25r26j nhr27, CO2R28, COR29, C(=NOH)R29, or AD is CN, NR25r26 CONR25r26s where r25 and r26 are either each independently Η,Όμ3 alkyl, c3-8 cycloalkyl, aryl, Cj_4alkylphenyl (each of which Ομ3 alkyl, C3.8 cycloalkyl, aryl and Ci_4 alkylphenyl areoptionally substituted by one or more NO2, halogen, Ci_4 alkyl and/or Cj_4 alkoxy, (each ofwhich latter Cj_4 alkyl and Ci_4 alkoxy is optionally substituted by one or more halogen)),or R25 and R2^ are taken together with the N atom to which they are attached and can fofm a 4- to 7-membered heterocyclic ring optionally incorporating one or more fin-fh»· hetero 01 2293 91 atoms selected from N, O and S, and which ring is optionally sübstituted by one or more Ομ4 alkyl, OH, =0, NC>2, NH2 and/or halogen, R27 is COR30, CO2R31a, SO2R31b, r28 r29 each independentiy H, Ομβ alkyl, C3.8 cycloalkyl, aryl or Ομ 4alkylphenyl, each of which Ομζ alkyl, C3_g cycloalkyl, aryl and Ci_4 alkylphenyl areoptionally substituted by one or more NO2, halogen, C1-4 alkyl, C|_4 alkoxy (each of whichlatter Cj_4 alkyl and C1-4 alkoxy are optionally substituted by one or more halogen), R30 is H, C1-4 alkyl» C3.8 cycloalkyl, Ci_4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, C1-4alkylphenyl, phenyl(Ci_4 )alkoxy, (each of which C{_4 alkyl, C3_g cycloalkyl, Ci_4 alkoxy,C3.8 cycloalkyloxy, aiyl, aryloxy, Cj_4 alkylphenyl and phenyl(Ci_4 )alkoxy are optionallysubstituted by one or more NO2, halogen, C{_4 alkyl, Ci_4 alkoxy (which latter alkyl andalkoxy are optionally substituted by one or more halogen)), p31a and R.31b are each independentiy Ci_4 alkyl, C3_g cycloalkyl, aryl or Cj_4alkylphenyl, each of which is optionally substituted by one or more NO2, halogen, Cj-4alkyl or C1-4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by onemore halogen E is H, CONR32R33, CSNR32r33, COR34 CO2R34. COCH(R34a)NH2, R35,CH2CO2R35a, CHR35bCO2R35a, CH2OCO2R35c, ŒR35dOCO2R35c,COCR36=CR37NH2, COCHR36CHR37nH2, or PO(OR38)2, r32 and R33 are each independentiy H, C340 alkyîalkenyl, C3.7 cycloalkyl (optionallysubstituted by Ci_4 alkyl), phenyl (optionally substituted by (X)n). Ομχθ alkyl (optionallysubstituted by C4.7 cycloalkyl (optionally substituted by Cj_4 alkyl) or phenyl optionallysübstituted by (X)n), or R32 and R33 can be taken together with the N atom to which they are attached and canform a 5- to 8-menibered heterocycle optionally comprising further hetero atoms selectedfrom N, O and S, which heterocycle is optionally substituted by Ci_4 alkyl, optionallysubstituted by one or more halogen, 012293 92 R34 is H, C4_7 cycloalkyl (optionally substituted by one or more Cj_4 alkyl), phenyl(optionally substituted by (X)n, Ci_4 alkanoyloxy, NR32R33, CONR32R33 and/or OH), orCi_6 alkyl (optionally substituted by one or more balogen, C4-7 cycloalkyl (optionallysubstituted by one or more C1-4 alkyl), or phenyl (optionally substituted by (X)n> C1-4alkanoyloxy, NR32R33, CONR32R33 and/or OH)), R34a is h, Ci-6 alkyl (optionally substituted by one or more halogen, C4.7 cycloalkyl(optionally substituted by one or more Cj_4 alkyl), or phenyl (optionally substituted by (X)n,C1.4 alkanoyloxy, NR32R33, CONR32R33 and/or OH)), C4.7 cycloalkyl (optionallysubstituted by one or more Cj_4 alkyl), phenyl (optionally substituted by (X)n, Cj-4alkanoyloxy, NR32R33, CONR32R33 and/or OH) or a naturally occuring amino acidsubstituent, R33 is C4.7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl (optionallysubstituted by one or more (X)n, Ci_4 alkanoyl, NHR32, CON(R32)2, and/or OH); Ομβalkyl (optionally substituted by C4.7 cycloalkyl optionally substituted by one or more Ci _4alkyl, or phenyl (optionally substituted by one or more (X)n, Cj_4 alkanoyl, NHR32,CONÇR.32)2, and/or OH)), Ci .4 alkoxy(Ci_4 alkyl), phenyl(Ci^)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 ormore Cj_4 alkyl, phenyl optionally substituted by one or more (X)n or Cpg alkyl (optionallysubstituted by C4.7 cycloalkyl optionally substituted by one or more C1-4 alkyl, or phenyloptionally substituted by one or more (X)n), r36 and r37 each independently represent H, C3.6 alkylalkenyl, C4J7 cycloalkyl, phenyloptionally substituted by one or more (X)n, or Cj.g alkyl (optionally substituted by C4.7cycloalkyl optionally substituted by one or more Cj_4 alkyl, or phenyl optionally substitutedby one or more (X)n), R38 is C4.7 cycloalkyl optionally substituted by one or more Cj_4 alkyl, phenyl optionallysubstituted by one or more (X^, or alkyl (optionally substituted by 04.7 cycloalkyloptionally substituted by one or more Ci_4 alkyl, or phenyl optionally substituted by one ormore(X)n), 012293 93 R2 when taken alone is H or halogen; or Rl and r2, when attached to adjacent carbon atoms, can be taken together with the carbon 5 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 10 substituents independently selected from OH, =0, halogen, Οχ_4 alkyl, Cm haloalkyl, Cmalkoxy and Cm haloalkoxy, which Ci_4 alkyl, Cm haloalkyl, Cm alkoxy and Cm haloalkoxy groupe can be optionally substituted by one or more C3.6 cycloalkyl, aryl(Ci_g)aIkyl, which aryl group is optionally substituted by one or more halogen, Cm alkyl, Cm 15 haloalkyl, alkoxy and Cj4 haloalkoxy, which latter Cm alkyl, Cm haloalkyl, C1.4 alkoxy and Cm haloalkoxy groups can be optionally substituted by one or more NR23r24> nr23 S(O)nR243 NR23c(0)mR24> and if a S atom is présent in a ring, it can be présent as part of a -S-, S(O)- or -S(Û2)- group, 20 which R23 and R24 when taken alone independently represent H, Cm alkyl, or Cmhaloalkyl, or R.23 and R24 can be taken together with the N atom to which they are attached, to form a4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms 25 selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one ormore halogen, Cm alkyl, Cm haloalkyl, Cm alkoxy and/or Cm haloalkoxy groups, R3 is H, CN, halogen, Cm alkoxy, Cm alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy,C3-8 cycloalkyl, C3_g cycloalkyloxy, C4.9 cycloalkanoyl, aryl, aiyloxy, heteroaryl, saturated •30 heterocycle, NR12r13s CONR12r13} NY2WY1, Cm alkyl, C2-10 alkenyl, C2-10 alkynyl,(each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or moreCN, halogen, OH, Cm alkoxy, Cm alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, Cmalkanoyl, Cm alkanoyloxy, C3.8 cycloalkyl, C3_g cycloalkyloxy, C4.9 cycloalkanoyl, aryl,aryloxy, heteroaryl, saturated heterocycle, NR^2r13j CONR12r13 and/or NY2WY1), 35 012293 94 R.4 is Ci_io alkyl, C3.40 alkenyl or C340 alkynyl, each ofwhich groups is linked to the Natom via a sp3 carbon, and which group is sùbstituted by one or more sübstituents selectedfrom: C2-6 alkoxy [substituted by one or more groups selected from OH, NR25r26j CONR~5r26;halogen, Ci_g alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaiyll, aiyll, COCH2CN,CO(heteroaiyll), CO(aryli), CO2(heteroaiyll), COCH2(aryll), COCH2(heteroaryll),CO2CH2(aryl1),’CO2CH2(heteroaryll), S(O)n(Ci_6 S(O)n(aiyll),S(û)n(heteroaiyU), SO2NR25r26 cycloalkyll], S(O)nCi_6 alkyl [optionally substituted by one or more groups selected from OH, NR25r26jCONR25R26, halogen, Cj_6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryi^, aryll,COCH2CN, CO(heteroaryll), CO(aryll), CO2(heteroaryll), COCH2(aiyll),COCH2(heteroaryll), CO2CH2(aiyll), CO2CH2(heteroaiyll), S(O)n(Ci^ alkyl),S(O)n(aiyll), S(O)n(heteroaryll), SO2NR.25r26 and cycloalkyll], aiyl2, CO2CH2(heteroaryll), CO2CH2(aryll), cycloalkyll, CO(heteroaryll), CO(aiyll), OCO(aiyll), OCO(heteroaryll), OCO(Ci_6 alkyl), OCOCH2CN, CO2(heteroaryll), CO2(aryll), COCH2(heteroaryll), S(O)naryll, S(O)nCH2aiyll, S(O)n(heteroaiyll), S(O)nCH2(heteroaryll), NHSO2aiyll, NHSO2(Cj^ alkyl), 012293 95 NHSÛ2(heteroaryll), NHSÛ2CH2(heteroaryll), NHSO2CH2(aryll), NHCOaryll, 5 NHCO(Ci_6 alkyl), NHCONHaryll, NHCONH^g alkyl), NHCOheteroaryl^, NHCONHheteroaryll, 10 NHCC^aiyl1), NHCO2(Ci-6 alkyl), NHCO2(heteroaryll), aryl^oxy, heteroaryl^oxy, 15 Cj.g alkoxycarbonyl substituted by alkyl, aryl, Ομβ alkoxy, CH2(aryll), Ci_4haloalkyl, halogen, OH, CN or NR25r26 C2-6 alkanoyl substituted by Ομβ alkyl, aryl, Cj-6 alkoxy, CH2(aryl^), Ci_4 haloalkyl,halogen, OH, CN or NR25r26 C2-6 alkanoyloxy substituted by Ομβ alkyl, aryl, Ομ6 alkoxy, CH2(aryll), C1-4 haloalkyl, 20 halogen, OH, CN or NR25r26cycloalkyl ^oxy, COcycloalkyll, heterocycle substituted by one or more substituent selected from Ομ^ alkyl(sübstituted byOH), CONR25R26, CH2C0NR25r26, NR25r26 NHCONR25r26 ΟΟ(ϋμ6 alkyl), 25 SO2NR25r26 SO2(Ci_6 alkyl), ΟΟ2^μ6 alkyl), 0Η20Ο2(0μ6 alkyl), OCH2CO2(Ci_6alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3J7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from Ομ§ alkyl(substitutedby OH), CONR25R26 CH2CONR25r26 nr25r26 NHCONR25r26> 0Ο(Ομ6 alkyl), 30 SO2NR25r26 SO2(Ci_6 alkyl), CO2(Ci^ alkyl), CH2CO2e^-6 alkyl), OCH2CO2(Ci^alkyl), aryl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl, WHEREIN aryll is phenyl optionally fused to a C5J7 carbocyclic ring, which group isoptionally substituted by one or more substituent selected from Ομβ aîkyl(optionally 35 substituted by OH, CN or halogen), Ομβ haloalkoxy, OH, =0, NY2WY1, halogen, Cμ6 012293 96 alkoxy, CONR25R26, CH2CONR25R26, NR.25r26> NHCONR25r26} CO(Ci-6 alkyl),COaryl, COheteroaryl, SO2NR25R26, S(O)n(Ci.g alkyl), S(O)n(aryl), S(O)nÇheteroaryl),CC>2(Ci_6 alkyl), CO2(aryl), CO2<heteroaryi), CO2H, (CH2)mCO2(Ci_6 alkyl), (CH2)i-4CO2H, (CH2)l-4CC>2(aiyl), (CH2)i-4CO2(heteroaryl), O(CH2)mCO2(Ci-6 alkyl),O(CH2)l-4CO2H, O(CH2)i-4CO2(aryl), O(CH2)i-4CO2(heteroaryl), aryl, heierocyclyl,aryloxy, aryl(CH2)oxy, aiyl(CH2), CN, O(CH2)i-4CONR25r26 and C3.7 cycloalkyl, aryl2 is phenyl optionally fused to a 05,7 carbocyclic ring, which group is substituted byone or more substituent selected from C]_6 alkyl(substituted by OH), CONR25R26,CH2CONR25R26 nr25r26 NHCONR25r26 ΟΟ(Ομ6 alkyl), COaryl, COheteroaryl,SO2NR25r26, S(O)n(Ci_6 alkyl), S(O)n(aryl), S(0)n(heteroaryl), CO2(Ci.6 alkyl),CO2(aryl), C02(heteroaryl), CO2H, (CH2)l-4CO2(Ci.g alkyl), (CH2)l-4CO2H, (CH2)i-4CO2(aryl), (CH2)i-4CO2(heteroaryl), O(CH2)mCO2(Ci-6 alkyl), O(CH2)l-4CO2H,O(CH2)l-4CO2(aiyl), O(CH2)l-4CO2(heteroaryl), aryl, heierocyclyl, aryloxy,aryl(CH2)oxy, aryl(CH2), CN, O(CH2)i_4CONR25r26 C3.7 cycloalkyl, heteroaryl 1 is heteroaryl optionally fused to a C5.7 carbocyclic ring, which group isoptionally substituted by one or more substituent selected from C-, .5 alkyl(optionallysubstituted by OH, CN or halogen), Ci_g haloalkoxy, OH, =0, NY2WYl, halogen, Ci_6alkoxy, CONR25R26, CH2CONR25R26, NR25r26, NHCONR25R26, CO(Ci„6 alkyl),COaryl, COheteroaryl, SO2NR25R26, S(O)n(Ci_6 alkyl), S(O)n(aryl), S(O)n(heteroaryl),CO2(Ci_6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)l-4CO2(Cj_6 alkyl), (CH2)i-4CO2H, (CH2)l-4CO2(aryl), (CH2)l-4CO2(heteroaryl), O(CH2)i-4CO2(Ci_6 alkyl),O(CH2)mCO2H, O(CH2)i-4CO2(aryl), O(CH2)i^CO2(heteroaryl), aryl, heierocyclyl,aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)i_4CONR25R26 and C3.7 cycloalkyl, cycloalkyl^ is a C3.4Q carbocyclic System with one or two rings and which is substituted bycl-6 aUcyk aryl, Cj-g alkoxy, CH2(aryll), C^ haloalkyl, halogen, OH, CN or NR25R26, WITH THE PROVISO ΊΗΑ.Τ THERE ARE NO N-R4 GROUPS WHEREIN THKRP. IS AHETERO-ATOM UNKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON Z is a direct bond, CO or S(O)n group, Bis(CH2)p, 012293 97 Rl2 and Rl3 each independenüy represent H or alkyl, or Rl2 and Rl3 can be taken together with the N atom to which they are attached to form a4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from 5 NR16, o and/or S, and which is optionally substituted by one or more Ci_4 alkyl, Rl4 and R^ each indeperidently represent H, Ομχθ alkyl, C340 alkenyl, Cj.jo alkynyl,C3.8 cycloalkyl, aryl or heteroaiyl, 10 or Rl4 and Rl 5 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 fromNR16, o and/or S, and which is optionally substituted by one or more Cj_4 alkyl, Rl6 is H, Ci_6 alkyl, C3_g cycloalkyl, (Cj-g àlkylene)(C3-8 cycloalkyl) or (Ci_g 15 alkylene)aryl, RS and r8 when taken separately are each independenüy H, Cj.g alkyl, R5 and RS can be taken together with the carbon atoms to which they are joined to form a 20 C3.8 cycloalkyl ring, R^, r7; r9 and rIO when taken separately are H, R5 and R6 or R7 can be taken together with the carbon atoms to which they are joined to 25 form a C3.8 cycloalkyl ring, X is halogen, Cj_4 alkyl, C1-4 alkoxy, Cj_4 haloalkyl or C}_4 haloalkoxy, mis 1 or 2; 30 nisO, 1 or2; p is 0,1,2,3,4,5,6,7,8,9 or 10; 35 qisOorl; 01 2293 98 "Naturally occuring amino acid substituent" means the α-substituent tiiat occurs in any oneof the following natural amino acids, glycine, alanine, valine, leucine, isoleucine,phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, méthionine, cysteine,aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline; "Heteroaryl" represents an aromatic ring containing up to four heteroatoms independentlyselected from N, Ô and S, and if a S atom is présent in the ring, it can be présent as part of a -S-, S(O)- or -S(O)2- group, and which may be joined to the remainder of the compound viaany available atom(s); "Heterocycle" is a group containing 1, 2 or 3 rings, and whish contains up to 4 ringheteroatoms selected from N, O and S and up to 18 ring carbon atoms; "Aryl", including in the définitions of "aiyloxy", etc., means a group comprising a phenylring and which may incorporate a further carbocyclic ring fused to said phenyl ring andwhich may be joined to the remainder of the compound via any available atom(s) (examplesof such groups include naphthyl, indanyl, etc.); "Alkyl”, "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbonatoms allows; "Cycloalkyl" groups can be polycyclic if the number of carbon atoms allows; or a pharmaceutically or veterinarily acceptable dérivative or prodrug thereof.

2. A substance according to claim 1 wherein the "Ar" ring represents phenyl or pyridyl.

3. A substance according to any preceding claim wherein Rl when taken alone is OH, CN,halogen, NÔ2, NH2, NY2WY1 or Hetl.

4. A substance according to any preceding claim wherein r2 when taken alone is H. 012293 99

5. A substance according to claim 1 or 2 wherein Rl and R2 are taken together with thecarbon atoms to which they are attached and represent an optionally benzo-fused 5- to 7-membered heteroaryl ring optionally substituted by Ci_4 alkyl or Cj_4 haloalkyl. 5

6. A substance according to any preceding claim wherein X is Cl.

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 alkyl 10 (optionally substituted by one or more halogen, OH, Ομ§ alkoxy, Cj.g alkoxycarbonyl, C2_ g alkanoyl, C2-6 alkanoyloxy, C2-g alkyloxycarbonyloxy, NR12r13} C0NR12r13 and/orNY2WYl).

9. A substance according to any preceding claim wherein R4 is Ci_iq alkyl substituted by 15 one or more substituents selected from: C2-6 alkoxy [substituted by one or more groups selected from OH, NR25R26, CONR25r265halogen, Cj_g alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl^, aryll, COCH2CN,CO(heteroaryll), CO(aryll), CO2(heteroaryP), COCHyCaryll), COCH2(heteroaiyll), 20 CO2CH2(aryll), CO2CH2(heteroaryll), 8(Ο)η(Ομ6 alkyl), S(O)n(aryll),S(O)n(heteroaryll), S02NR.25r26 and cycloalkyll], S(O)nCi.6 alkyl [optionally substituted by one or more groups selected from OH, NR25r26>CONR25r26j halogen, Ci_g alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaiyll, aryll, 25 COCH2CN, CO(heteroaryll), CO(aryU), CÛ2(heteroaryll), COCH2(aryll), COCH2(heteroaryll), CO2CH2(aryll), CO2CH2(heteroaryll), S(O)n(Ci_g alkyl),S(O)n(aryll), S(O)n(heteroaryil), SO2NR25r26 cycloalkyll], aryl2, 30 CO2CH2(heteroaryll), CO2CH2(aryll), cycloalkyll, CO(heteroaryll), CO(aryll), 35 OCO(aryll), 01229 100 01 2293 OCO(heteroaryll), OCO(Ci_6 alkyl), OCOCH2CN, CO2(heteroaryl1), 5 CO2(aryl1), COCH2(heteroaryll), S(O)naryll, S(O)nCH2aryl1,’ S(O)n(heteroaryll), 10 S(0)nCH2(heteroaryl1), NHSO2aiyll, NHSO2(CT.6 alkyl), NHSO2(heteroaiyl 1), NHSO2CH2(heteroaryll), 15 NHSO2CH2(aiyll), NHCOaryll, NHCO(Ci_6 alkyl), NHCONHaryll, NHCONH(Ci_6 alkyl), 20 NHCOheteroaiyll, NHCONHheteroaiyll, NHCO2(aiyll), NHCO2(C!.6 alkyl), NHCO2(heteroaryll), 25 aryl2oxy, heteroarylloxy, Ci„6 alkoxycarbonyl substituted by Ci .g alkyl, aiyl· Ci_g alkoxy, CH2(aryll), C1.4haloalkyl· halogen, OH, CN or NR25R26, C2-6 alkanoyl substituted by Ci-$ alkyl, aryl, Ci_6 alkoxy, CH2(aryll), Ci_4 haloalkyl· 30 halogen, OH, CN or NR25r26. C2-6 alkanoyloxy substituted by Ci_g alkyl· aiyl, alkoxy, CH2(aryll), C1-4 haloalkyl· halogen, OH, CN or NR25r26> cycloalkyl^oxy, COcycloalkyll, 01 2293 101 heterocycle substituted by one or more substituent selected from Cj_6 alkyl(substituted byOH), CONR25r26 CH2CONR25r26} NR25r26 NHCONR25r26s CO(Ci_6 alkyl),SO2NR25r26 SO2(Ci_6 alkyl), CO2(Ci_6 alkyl), CH2CO2(Ci„6 alkyl), ΟΟΗ20Ο2(0μ6alkyl), aiyl, heterocyclyl, aryloxy, aiyl(CH2)oxy, aryl(CH2), CN and C3J7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from Cj_g alkyl(substituÎedby OH), CONR25r26 CH2CONR25r26 nr25r26 NHCONR25r26 00(0^ alkyl),SO2NR25r26 SO2(Ci.6 alkyl), CO2(Ci_6 alkyl), CH2CO2(Ci_6 alkyl), OCH2CO2(Ci_6alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3.7 cycloalkyl,

10. A substance according to any preceding daim wherein R5, r6s R7, r8 r9 rIO areeach taken separately and are ail H.

11. A substance according to any preceding claim wherein the "Ar" ring représente a groupof formula:

12. A substance according to any preceding claim wherein R3 is H, CH3, C2H5,1-C3H7, n-C3H7 or CH2OCH3·

13. A substance according to any preceding claim except claim 5 wherein Rl is OH, CN, I,Cl, NH2, NO2, optionally benzo-fused heteroaryl, NHSO2Y1, NHCOY1 or NHC02Yl.

14. A substance according to any preceding claim wherein R4 is Ci_io substituted by cycloalkyl 1.

15 with a suitabie reducing agent; (g) for compounds of formula Σ in which q is 0 and RJ represents OH, reacting acompound of formula Π, where is H, as defined àbove, with fluoroboric acid and isoamylnitrite; (h) for compounds of formula I in which q is 0 and R1 représente Cl, reacting a20 compound of formula Π, where Y2 is H, as defined àbove, with sodium nitrite in the presence 107 012293 of dilute acid, followed by reaction with copper (I) cbloride in the presence of concentratedacid; * • (i) for compounds of formula I in wbich q is 1, reacting a compound of formula ï where f q is 0 with a suitable oxidising agent such as aqueous hydrogen peroxide; or i 5 (J) for compounds of formula I where q is 0, by réduction of a corresponding compound of formula XXXI,

XXXI where R^CHg takes the sams meaning as R^ as defîned above, (K) for compounds of formula (I) where q is 0, reductive amination reaction of the amine of20 formula VIH above with an aldéhyde of formula R4a-CHO wherein R4aCH2 the same meaning as R4 as defîned above, and where desired or necessary converting the resulting compound of formula î into aphannaceutically or veterinarily acceptable dérivative or vice versa. 25

15. A substance according to any preceding claim except daims 3,4 and 13 wherein R1 andR2 are taken together with the carbon atoms to which they are attached are a 5-memberedheteroaryl moiety optionally substituted by Ci_4 alkyl or Ci_4 haloalkyl. 012293 102

16. A substance according to any preceding claim wherein R^ is CH3 or C2H5.

17. A substance according to any preceding claim except daims 5 and 15 wherein Rl whentaken alone is OH, CN, I, Cl, NH2, N02,l,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, 5 pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO2(Ci_g alkyl), NHSO2(Ci-6 alkyl substituted by methoxy, CONH2, OH, CO2(C2-6 alkyl), phthalimido, NH2 orhalogen), NHSO2NH2, NHSO2NH(Ci_6 alkyl), NHSO2N(Ci.6 alkyl)2, NHSO2Hetia,NHCO(Ci_6 alkyl) or NHCO2(Ci_6 alkyl). 10

18. A substance according to claim 17 wherein Rl is OH, NHSO2CH3, NHSO2C2H5, NHSO2(n-C3H7), NHSO2O-C3H7), NHSO2(n-C4H7), NHSO2NH(i-C3H7), NHSO2(N-methylimidazol-4-yl), NHSO2(CH2)2OCH3, NHSO2(CH2)2OH, 1,2,4-triazolyl or imidazol-2-yl. 15

19. A substance according to claim 18 wherein Rl is OH, NHSO2CH3, NHSO2C2H5 or imidazol-2-yl.

20. A substance according to claim 15 wherein Rl and R^ when taken together wifh thécarbon atoms to which they are attached are an imidazole group optionally 2-substituted by 20 CF3.

21. A substance according to any preceding claim wherein R4 is C2-4 alkyl substituted bycycloalkyll. 25

22. Â 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. 30

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-yl. 072293 103

26. A substance according to daim 1 which has the fcllowing relative stereochemistry:

27. A substance according to claim 1 which is selected from the compounds of the Examplesas described herein, and the salts and prodrugs thereof.

28. A pharmaceutical or veterinary composition comprising a substance according to anyone of the preceding daims, and a pharmacutically or veterinariîy acceptable carrier.

29. A substance according to any of daims 1 to 26 for use in medicine.

30. À substance according to any of daims 1 to 26 for use as a médicament usefuî for thetreatment of an opiate-mediated disease or condition.

31. The use of a substance according to any one of daims 1 to 26 in the manufacture of amédicament for the treatment of a disease or condition mediated by opiats receptors.

32. A process for the préparation of a substance according to claim 1 which comprises: (a) for compounds of formula I in which q is 0 and RJ représente NY^WYl, reacting acompound of formula Π, 104 01 2293

with a compound of formula ΙΠ, Zl-WYl ni wherein is a suitable leaving group, such as halogen or YISO2O- ; 5 (b) for çompounds of formula I in which q is 0 and and R? bofh represent H, réduction of a compound of formula TV,

(c) for çompounds of formula I in which q is 0 and R® and R10 bofh represent H,10 réduction of a compound of formula V, 012283 105

using a suitable reducing agent; (d) for compounds of formula I in which q is 0 and Ri and R2 are attached to adjacentcarbon atoms and are taken togefher with the carbon atoms to which. they are attached to 5 represent Het^a, in which Het^a représenta an imidazolo unit, reaction of a correspondingcompound of formula VI,

with a compound of formula Vïï, RyCÛ2H VH 10 wherein RY represents H or any of the optionaî substitaents on Hefla (as defîned above),. preferably H, Cj_4 alkyl or Ci^j. haloalkyl; (e) where q is 0, reacting a compound of formula VUE, 012293

with a compound of formula IX, R*-Lg IX wherein Lg is a leaving group; 5 (f) for compounds of formula I in which q is 0 and RA r7, r9 anj RIO are ail H, réduction of a compound of formula X,

33. A compound of formula Π, IV, V, VI, X, χη XI, χπ, XXI, ΧΧΠ, ΧΧ1Π, XXIV, XXIX,XXLXa, XXX, or XXXI, or sait thereof, as described herein. * w