AU781837B2 - 3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity - Google Patents

Description

WO 01/98267 PCT/IB01/01035 3-AZABICYCLO HEXANE DERIVATIVES HAVING OPIOID RECEPTOR AFFINITY This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors mu, kappa and delta opioid receptors). Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, 0 spinal damage and head trauma.

There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.

Existing treatments that have been employed in the treatment of pruritus include the use of 3 corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.

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

Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. In addition, S International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.

International Patent Application WO00/39089, filed before the priority date of the instant application, but published thereafter, is herein incorporated by reference in its entirety, and WO 01/98267 PCT/IB01/01035 2 discloses azabicycloalkanes of similar structure to those described hereinbelow, with different R 4 groups.

According to the invention there is provided a compound of formula I, (X)nwherein the "Ar" ring represents an heteroaryl ring;

R

1 when taken alone is H, halogen,

C(=NOH)R

8 or OE, optionally benzo-fused phenyl or 5- or 6-membered

NO

2

NH

2

NY

2

WY

1 Hetl, AD, CO 2

R

7

C(O)R

8

Y

2 is H, C1- 6 alkyl, C 3 6 alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Hetl), W is SO2, CO, C(O)O, P(Yl)=O, P(Yl)=S, yl is C-.

10 alkyl (optionally substituted by one or more substituents independently selected from halogen, OH, C 1 -4 alkoxy, C1-6 alkanoyloxy, CONH 2 C1-6 alkoxycarbonyl, NH 2 aryl, mono- or di(C 1 4 alkyl)amino, C3-8 cycloalkyl, phthalimidyl, Hetl), Hetl, aryl (optionally substituted by one or more substituents independently selected from Ci-4 alkyl, 0 C1-4 haloalkyl and halogen), NH 2 N(C1-6 alkyl) 2 or NH(C1-6 alkyl), Het 1 is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryi group, optionally benzo- or pyrido-fused heteroaryl), optionally substituted by one or more substituents independently selected from C 1 alkyl, CI-6,alkoxy,

C

3 -6 cycloalkyl, C 1 -6 haloalkoxy, CI-6 haloalkyl, C 3 6 halocycloalkyl, OH, halogen, NO 2 SiR 1 9 aR 1 9 b R 9 c, CONR 2 aR 2 0b, NR 2 0aR 2 0b, SR 21 a NR 2 1bSO 2 R 2 2 a, NR 2 IcC(O)OR 2 2 b NR 2 ldCOR 22 1d, and C 1 6 alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a or -S(02)group, and carbon atoms in the ring can be present as a part of a carbonyl moiety; Rl9a, Rl9b, Rl 9 c each independently represent C1-6 alkyl or aryL,

R

2 Oa and R2Ob each independently represent Hi, CI..6 alyl, aryl, (C 1 4 allyl)phenyl, each of which alkyl, aryl and alkyiphenyl are optionally substituted by one or more CIA4 alkyl, C 14 ailcoxy, OH, NO 2

NH

2 and/or halogen or R 2 0a and R 2 Ob can be taken together with the N atom to which they are attached, to forma a 4- to 6-membered ring optionally substituted by one or more substitutuents independently 1 5 selected from one or more Cj..

4 alkyl, C 1 4 alkoxy, OH, NO 2

NH

2 and/or halogen, R2la, b, c and d each independently represent H, C1-.6 alkyl, aryl or CI- 4 alkylphenyl, each of which ailkyl, aryl, and alylphenyl are optionally substituted by One Or more C 1 4 alkyl,

C

1 4 alkoxy, OH1, NO 2 halogen, NH 2

R

2 2a, b and c each independently represent

C

1 _6 alkyL, aryl Or CI- 4 alklphenyl, each of which alkyl, aryl, and ailcyiphenyl are optionally substituted by one or more C 1 4 alkyl, C 1 4 alkoxy, OH, N02, halogen, NH 2 :25 A is C 1 4 alkylene, C 2 4 alkenylene or C 2 4 alkynylene, each of which is optionally .substituted by one Or more C 1 -4 alkyl, Cl 4 alkoxy, halogen and/or OH, D is H, OK, CN NR 25

R

2 6, CONR 2

SR

26

NHR

2 7, C02R 28 C0R 2 9

CC&NOH)R

2 9, 301 or is CN, NR 2

SR

2 6 C0NR 25

R

26 d where R 25 and R 2 6 are either each independently IL C1..3 alkyl, C 3 8 cycloakl, ayL, C 1 4 alk-Yipheny;. (each Of which Cl..

3 alkyl, C 3 8 cycloalkyl, azYl and Cl- 4 alkyihenyl ae optionally Substituted by one or more N0 2 halogen, C 14 alkyl and/or C 1 4 alkomiy, (each of *which latter C1 4 alkyl and CI 1 4 alkoxY is optionally substituted by one or more halogen)), WO 01/98267 PCT/IB01/01035 4 or R 2 5 and R 26 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 further hetero atoms selected from N, 0 and S, and which ring is optionally substituted by one or more C 1

.I

4 alkyl, OH, NO 2

NI{

2 and/or halogen,

R

27 is COR 3 0, C0 2

R

3 la, SO 2

R

3 lb,

R

28 and R 29 Are each independently H, Cl-6 alkyl, C3-8 cycloalkyl, aryl or C 1 4alkylphenyl, each of which Cl..6 alkyl, C3-8 cycloalkyl, aryl and C 1 4 alkylphenyl are 0 optionally substituted by one or more NO 2 halogen, C 1 4 ailkyl, C 1 alkoxy (each of which latter Ci1A- alkyl and Cl 1 4 alkoxy are optionally substituted by one or more halogen),

R

30 is H, CI-4 alkyl, C 3 -8g cycloalkyl, CI..4 alkoxy, C 3 8 cycloalicyloxy, aryl, aryloxy, C 1 4 alkyiphenyl, phenyl(CI-4 )alkoxy, (each of which CI.

4 alkyl, C3- 8 cycloalkyl, CI-4 alkoxy,

C

3 8 cycloalkyloxy, aryl, aryloxy, C 1 .4 alkyiphenyl and phenyl(C 1 4 )alkoxy are optionally substituted by one or more NO 2 halogen, C 1 4 alkyl, C- 1 -4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)),

R

3 1 a and R3lb are each independently C 1 4 alkyl, C3-.8 cycloalicyl, aryl or C 1 4 o alkylphenyl, each of which is optionally substituted by one or more NO 2 halogen, CI..

4 alkyl or C 1 .4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen E is H, C0NR 32

R

33

CSNR

32

R

3 3 C0R 34 C0 2

R

34

COCH(R

3 .4a)NH 2

R

3 5

CH

2

CO

2

R

3 5a, CHR 3 5bCO 2

R

3 Sa, CH2OCO2R 3 Sc, CHR 3 5dOCO 2

R

3

COCR

3 6

-CR

37

NH

2

COCHR

36

CHR

37

NH

2 or PO(0R 3 8)2,

R

32 and R 33 are. each independently H, C3-.

10 alkylalkenyl, C 3 7 cycloalkyl (optionally substituted by C 1 -4 alkyl), phenyl (optionally substituted by C 1 10 alkyl (optionally o substituted by C 4 7 cycloalkyl (optionally substituted by C 1 alkcyl) or phenyl optionally substituted by or R 32 arnd R 3 3 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising further hetero atoms selected WO 01/98267 PCT/IB01/01035 from N, O and S, which heterocycle is optionally substituted by Cl-4 alkyl, optionally substituted by one or more halogen,

R

34 is H, C4- 7 cycloalkyl (optionally substituted by one or more C 1 -4 alkyl), phenyl (optionally substituted by C1-4 alkanoyloxy, NR 3 2

R

33

CONR

3 2

R

3 3 and/or OH), or

C

1 6 alkyl (optionally substituted by one or more halogen, C4- 7 cycloalkyl (optionally substituted by one or more C1.4 alkyl), or phenyl (optionally substituted by CI-4 alkanoyloxy, NR 32

R

33

CONR

32

R

3 3 and/or OH)), 0 R 34 a is H, C 1 -6 alkyl (optionally substituted by one or more halogen, C4- 7 cycloalkyl (optionally substituted by one or more C1_4 alkyl), or phenyl (optionally substituted by (X)n,

CI-

4 alkanoyloxy, NR 32

R

33

CONR

32

R

33 and/or C4- 7 cycloalkyl (optionally substituted by one or more C1- 4 alkyl), phenyl (optionally substituted by C 1 -4 alkanoyloxy, NR 3 2

R

3 3

CONR

32

R

3 3 and/or OH) or a naturally occuring amino acid substituent,

R

35 is C4-7 cycloalkyl optionally substituted by one or more C1-4 alkyl, phenyl (optionally substituted by one or more C1-4 alkanoyl, NHR 32

CON(R

32 2 and/or OH), CI-6 alkyl (optionally substituted by C4- 7 cycloalkyl optionally substituted by one or more CI-4 0 alkyl, or phenyl (optionally substituted by one or more C 1 4 alkanoyl, NHR 32

CON(R

32 2 and/or C 1 -4 alkoxy(C1-4 alkyl), phenyl(C14)alkyloxy(C1.4)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, and d are each independently H, C4- 7 cycloalkyl optionally substituted by one or more C1- 4 alkyl, phenyl optionally substituted by one or more (X)n or C 1 -6 alkyl (optionally substituted by C4- 7 cycloalkyl optionally substituted by one or more C1- 4 alkyl, or phenyl optionally substituted by one or more (X)n, R3 6 and R 3 7 each independently represent H, C3-6 alkylalkenyl, C4- 7 cycloalkyl, phenyl 0 optionally substituted by one or more or C1-6 alkyl (optionally substituted by C 4 7 cycloalkyl optionally substituted by one or more C1-4 alkyl, or phenyl optionally substituted by one or more R38 is C 4 7 cycloalkyl optionally substituted by one or more C1.4 alkyl, phenyl optionally substituted by one or more or C 1 6 alkyl (optionally substituted by C 4 7 cycloalkyl WO 01/98267 PCT/IB01/01035 6 optionally substituted by one or more C 1 4 alkyl, or phenyl optionally substituted by one or more

R

2 when taken alone is H or halogen; or R 1 and R 2 when attached to adjacent carbon atoms, can be taken together with the carbon atoms to which they are attached, and may represent Hetla; Het l a 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 7membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, halogen, C -4 alkyl, C 1 .4 haloalkyl, C 1 -4 alkoxy and C1-4 haloalkoxy, which C 1 4 alkyl, C1- 4 haloalkyl, C1- 4 alkoxy and C1-4 haloalkoxy groups can be optionally substituted by one or more C3-6 cycloalkyl, aryl(C1-6)alkyl, which aryl group is optionally substituted by one or more halogen, C 1 -4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy, which latter C1- 4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy groups can be optionally substituted by one or more NR 2 3

R

2 4

NR

2 3 S(O)nR 2 4

NR

2 3 C(O)mR 2 4 0 and if a S atom is present in a ring, it can be present as part of a or -S(0 2 group, which R 2 3 and R 2 4 when taken alone independently represent H, C 1 4 alkyl, or C1-4 haloalkyl, or R 2 3 and R 2 4 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, C1-4 alkyl, C1-4 haloalkyl, C 1 -4 alkoxy and/or C 1 4 haloalkoxy groups, 0 R 3 is H, CN, halogen, C 1 -6 alkoxy, C1-6 alkoxycarbonyl, C 2 -6 alkanoyl, C 2 6 alkanoyloxy,

C

3 -8 cycloalkyl, C 3 -8 cycloalkyloxy, C 4 9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR 12

R

13

CONR

1 2

R

13

NY

2 wY 1 C1-6 alkyl, C2-10 alkenyl, C 2 1 0 alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, C1-6 alkanoyl, C 1 4 6 alkanoyloxy, C 3 8 cycloalkyl, C 3 -8 cycloalkyloxy, C 4 9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR1 2 R 1 3 CONR1 2 R 1 3 and/or NY 2 WY I), R 4 is CI- 1 o alkyl, C 3 10 alkenyl or C 3 10 alkynyl, each of which groups is linked to the N atom via a sp 3 carbon, and which group is substituted by one or more substituents selected from:

C

1 6 alkoxy [substituted by one or more groups selected from OH, NR 2 5 R 2 1, C0NR 2 5 R 1 6 halogen, C 1 6 alkoxy, C 2 4 alkynyl, C 2 4 alkenyl, heteroaryll, aryll, COCH 2

CN,

CO(heteroaryll), CO(aryll), C0 2 (heteroaryll), COCH 2 (aryll), COCH 2 (heteroaryll),

CO

2

CH

2 (aryll), CO 2

CH

2 (heteroaryl'), S(O)n(C 1 6 alkyl), S(O)r,(aryll), S(O),,(heteroaryll), S0 2 NR 25R 26, a cycloalkyl group that is a C 3 -1 0 carbocyclic system with one or two rings and cycloalkyl'], S(O)nC,.

6 alkyl [optionally substituted by one or more groups selected from OH, NR 'R 26 C0NR 25

R

26 halogen, C 1 6 alkoxy, C24 alkynyl, C 2 4 alkenyl, heteroaryl'1, aryl'1,

COCH

2 CN, CO(heteroaryl CO(aryl C0 2 (heteroaryl COCH 2 (aryl 1),

COCH

2 (heteroaryl'), CO 2

CH

2 (aryl'), CO 2

CH

2 (heteroaryll), 6 alkyl), S(O)J(aryl'), S(O),(heteroaryll), S0 2 NR 25R 26and cycloalkyl'], ary 1 2

CO

2

CH

2 (heteroaryl 1),

CO

2

CH

2 (aryl 1), cycloalkyl', a cycloalkyl group that is a C 3 -10 carbocyclic system with one or two rings, CO(heteroaryl 1), CO(aryl 1), OCO(aryll), :OCO(heteroaryl'1), 25 OCO(C 1 6 alkyl),

OCOCH

2

CN,

C0 2 (heteroaryl 1), C0 2 (aryl'),

COCH

2 (heteroaryl 1), S(O)naryll, S(O)nCH 2 arYi!1, *S(O),,(heteroaryll), *see 11 \AYLIB\LIBAJO6015 dm NSS S(O)nGH2(heteroaryl 1), NHiSO 2 aryll, NHSO2(heteroaryl 1), I NHSO2CH2(heteroaryll), NHSO2CH 2 (arYl 1), NHCOaryil, NHCONHaryll, L0 NHCOheteroaryl 1, NHCON~heteroaryl 1,

NHCO

2 (arYll), NIICO2(heteroaryl 1), aryl 2 oxy, heteroaryl ioxy, C1..6 alkoxycarbonyl substituted by CI-6 ailkyl, aryl, C1..6 ailcoxy, CH2(aryll), CI-4 haloalkyl, halogen, OH-L CN or N2R6

C

2 -6 alkanoyl substituted by C 1 6 alkyl, aryl, C 1 6 alkoxy, CH2(aryll), CliA haloalkyl, halogen, OH, CN or NR 25

R

2 6

C

2 6 alkanoyloxy substituted by CI-6 ailcyl, aryl, C 1 6 alkoxy, CH2(arYll), Cl- 4 haloalkyl, halogen, OH, CN or N2R6 cycloalcyl 1 oxy, COcycloalkyll, heterocycle substituted by one or more substituent selected from C, _6 alkyl(substjtuted by OH), CONR 2 5R 2 6, CH2CONR 2 5R26, NR 25

R

2 6

NHCONI(

25 R26, CO(C1..6 alkyD, S0 2

NR

25

R

2 6 S0 2

(C

1 6 alkyl), C0 2 (Cl.- 6 alkyl), CH12002(CI.-6 alky!)', OCH2CO 2 (cl..

6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH 2 CN and C 3 7 cycloalcyl, heterocyclyloxy substituted by one or more substituent selected from CI- alkyl(substjued by OH), CoNR 2 5R 2 6, cI200NR, 2

SR

2 6

NR,

2 5

R

26

NI{CONR

2 5R 2 6, C)O(Ci,.6 aikYl), S0 2

NR;

5

R

26 S0 2

(C

1 6 alkyl), CO2(Cp_6 alkyl), 0112002(Cl..6 alkyj). OCH 2

CO

2

(C

1 _6 alkyl), RAl heterocYclYl, aryloxy, arYI(CUE[)oxy, MACy(HO) ON and C3-.7 cyclOalkyl, WO 01/98267 PCTAB01/01035 9 WHEREIN aryl I is phenyl. optionally fused to a C 5 7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C 1 6 alkyl(optionally substituted by OH, CN or halogen), C 1 -6 haloalkoxy, OH, 0, NY 2 WY 1 halogen, C 1 -6 alkoxy, C0NR 2 5

R

26

CH

2

CONR

25

R

26

NR

25

R

26

NHCONR

25

R

26

CO(C

1 6 alkyl), COaryl, COheteroaryl, S02NR 2 5

R

2 6 S(O)n(Cl..6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), C0 2 (C 1 6 alkyl), C02(aryl), CO2(heteroaryl), C0 2 11, (CH2)1A4CO2(C 1-6 alkyl), (CH 2 1 2 H, (CH2)l 4 CO2(ary1), (GB 2 1 -4CO2(heteroaryl), O(CH2) 1 ACO2(CI-6'~alkyl),

O(CH

2 1 4 C0 2 H, O(CH2) 1-CO2(aryl), O(CH 2 1 .4CO2(heteroaryl), aryl, heterocytlyl, aryloxy, aryl(CH2)oxy, arYl(CH2), CN, O(CH 2 1 4 C0NR 25

R

26 and C 3 7 cycloalkyl, 0 aryl 2 is phenyl. optionally fused to a C 5 7 carbocyclic ring, which group is substituted by one or more substituent selected from C 1 -6 alkyl(substituted by OH), C0NR 2 5

R

26

CH

2 C0NR 2 5

R

26

NR

2 5

R

26 NH 'CONR 25

R

26

CO(C

1 6 ailcyl), COaryl, COheteroaryl, S0 2

NR

2 5

R

2 6 S(O)n(Cl.6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), C0 2

(C

1 6 alkyl), CO2(aryl), CO2(heteroaryl), CO 2 H, (CH2)14C02(C1.6 alkyl), (CH2) 1 4 C0 2 H, (GB 2 1 4C02(ary (CH2) 1 .4CO2(heteroaryl), O(CH2) 1 4 C0 2

(G

1 -6 alkyl), O(CH2) 1 ACO2H,

O(CH

2 1 4C02(aryI), O(CH2) 1 4CO2(heteroary1), aryl, heterocyclyl, aryloxy, ary](GH2)oxy, aryl(CH2), GN, O(CH 2 I 4 C0NR 2 5

R

26 and C 3 7 cycloalkyl, 3 heteroaryll is heteroaryl optionally fused to a C 5 7 carbocyclic ring, which group is optionally substituted by one or more substituent selected from C 1 -6 alkyl(optionally substituted by OH, CN or halogen), C 1 6 haloalkoxy, OH, N-y 2 WY 1 halogen, C 1 6 alkoxy, CONR 2 5R 26

CH

2

CONR

2 5

R

26

NR

25

R

26

NHCONR

2 5

R

26

CO(C

1 -6 alkyl), COaryl, COheteroaryl, SO 2

NR

2 5

R

26 S(O)n(C 1 -6 alkyl), S(O)n~alYl), S(O)n(heteroaryl),'

CO

2

(C

1 6 alkyl), G02(aryl), C02(heteroaryl), CO 2 (CH2)14CO2(C1..6 alkyl), (GB 2 1 2 H, (CH 2 )1-4~CO2(arY0), (CH 2 1 4CO2(heteroaryl), O(CH2) l..4CO2(C1 -6 alkyl), O(CH2) 1 .4C0 2 H, O(CH 2 1 4CO2(aryl), (CH 1 4C02(heteroarl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(C11 2 1 4 C0NR 2 5

R

26 and C3-.7 cycloalkyl, cycloalkyl 1 is a C 3 10 carbocyclic system with one or two rings and which is substituted by C 1 6 alkyl, aryl, C 1 6 alkoxy, CH 2 (aryl Ci1A- haloalkyl, halogen, OH, CN or NR 25

R

26 WITH THE PROVISO THAT THERE ARE No N-R4 GROUPS WHEFREIN THEEI HETERO-ATOM LINKED TO ANOTHER HETEROATOM VIA ONE SP3 CARBON Z is a direct bond, CO or S(O)n group, WO 01/98267 PCT/IB01/01035 B is (CH 2 )p,

R

12 and R 13 each independently represent H or CI-4 alkyl, or R 12 and R 13 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from

NR

16 O and/or and which is optionally substituted by one or more C1- 4 alkyl, O R1 4 and R 15 each independently represent H, C1- 10 alkyl, C3-10 alkenyl, C 3 -10 alkynyl,

C

3 8 cycloalkyl, aryl or heteroaryl, or R 14 and R 15 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a further hetero moiety selected from

NR

16 O and/or S, and which is optionally substituted by one or more C1-4 alkyl,

R

16 is H, C 1 -6 alkyl, C 3 8 cycloalkyl, (C 1 -6 alkylene)(C 3 8 cycloalkyl) or (C 1 .6 alkylene)aryl, 0 R 5 and R 8 when taken separately are each independently H, C1-6 alkyl,

R

5 and R 8 can be taken together with the carbon atoms to which they are joined to form a

C

3 .8 cycloalkyl ring,

R

6

R

7

R

9 and R 10 when taken separately are H,

R

5 and R 6 or R 7 can be taken together with the carbon atoms to which they are joined to form a C3- 8 cycloalkyl ring, 0 X is halogen, C 1 -4 alkyl, C1-4 alkoxy, C1- 4 haloalkyl or C 1 .4 haloalkoxy, m is 1 or 2; n is 0, 1 or 2; 11 p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or q is 0 or 1; "Naturally occuring amino acid substituent" means the a-substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline; "Heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if a S atom is present in the ring, it can be present as part of a or -S(0) 2 group, and which may be joined to the remainder of the compound via any available atom(s); "Heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms; "Aryl", including in the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.); "Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows; "Cycloalkyl" groups can be polycyclic if the number of carbon atoms allows; or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof; provided that the one or more substituents on the group R 4 include at least one group that is not one of the following: Ci-6 alkoxy (substituted by a single substituent that is an unsubstituted aryl' group); (ii) aryl2oxy, aryl 2 heteroaryloxy, heterocycle (which latter four groups are substituted by one or more substituents which are NHCONR25R 26 groups, wherein R 2 5 and R 26 are independently H or C.-3 alkyl, or R 25 and R 26 together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring); (iii) CO(heteroaryl'), COCH 2 (heteroaryl'), S(O),(heteroaryl'), S(O)nCH 2 (heteroaryl') (in which latter four groups heteroaryl' represents a 4- to 7-membered heterocycle comprising a N-atom (via which atom the heteroaryl' group is attached) and optionally comprising a further hetero moiety selected from NH, N(CI- 6 alkyl), N(C 3 7 cycloalkyl), O or S, which heterocycle is optionally substituted by one or more C-4 alkyl groups); (iv) heteroaryl'oxy, wherein heteroaryl' is unsubstituted or substituted by one or more substituents which are CI- 6 alkyl (optionally substituted by one or more substituents which are CN and/or halogen), CI-4 alkoxy, Ci- 4 haloalkoxy, OH, NY 2 WY' and/or NHCONR25R26 (wherein R 25 and R 26 are independently H or C1- 3 alkyl, or R 25 and R 26 together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring));

NHS(O)

2 (aryll), NHCO(aryl'), NHCO 2 (aryl l (in which latter three groups aryl' is unsubstituted or is substituted by one or more substituents which are C1-4 alkyl, CI-4 haloalkyl and/or halogen); (vi) NHS(O) 2

CH

2 (aryl') (in which aryl' is unsubstituted); (vii) NHCO(heteroaryl'),

NHCO

2 (heteroaryl'), NHS(O) 2 (heteroaryl'), NHS(0)2CH2(heteroaryl') (in which latter four groups heteroaryl is unsubstituted or is 25 substituted by one or more substituents which are CI-6 alkyl, C.-6 haloalkyl, C,-6 alkoxy,

C

3 6 cycloalkyl, C-.

6 haloalkoxy, OH, halogen, S(aryl), S(CI.

6 alkyl), CO 2 (C1- 5 alkyl),

CONR

2 5

R

26 andor NR 5

R

26 (i which latter two groups, the groups R 25 and R 2 are either each independently H, CI.

3 alkyl, aryl, Cl- 4 alkylphenyl (each of which CI- 3 alkyl, aryl and Ci 4 alkylphenyl are optionally substituted by one or more substituents which are NO 2 halogen, CI- 4 alkyl and/or CI- 4 alkoxy), or R 25 and R 26 are taken together with the N atom to which they are attached and can form a 4- to 6-membered heterocyclic ring, which ring is optionally substituted by one or more CI- 4 alkyl, OH, NO 2

NH

2 and/or halogen)).

11 \DAYLIB\LIBA]06015 doc NSS Ilb Where a fused heterocyclic group is present it can be attached to the remainder of the compound via any available atom(s).

"Haloalkyl", "haloalkoxy" groups and the like can contain more than one halogen atom, and for instance can be per-halogenated.

[[.\DAYLIB\LIBA]06015 doc NSS WO 01/98267 PCT/IB01/01035 12 Certain of the compounds of the invention can exist in one or more geometric and/or stereoisomeric forms. The present invention includes all such individual isomers and salts and prodrugs thereof.

Certain compounds of the present invention may exist in more than one tautomeric form.

Similarly certain compounds of the invention may have zwitterionic forms. It is to be understood that the invention embraces all such tautomers, zwitterions and their derivatives.

The pharmaceutically acceptable salts of the compounds of the formula include the acid 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 p-toluenesulphonate salts. Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).

It will be appreciated by those skilled in the art that certain protected derivatives of :0 compounds of formula which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be transformed after administration into or onto the body, for example by metabolism, to form compounds of formula which are pharmacologically active. Such derivatives are included in the term "prodrug". It will further be appreciated by those skilled in the art that certain moieties known to those skilled in the art as "pro-moieties", for example as described in "Design of Prodrugs" by H Bundgaard (Elsevier) 1985, may be placed on appropriate functionalities when such functionalities are present in compounds of formula also to form a "prodrug".

Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.

All protected derivatives, and prodrugs, of the compounds of formula I are included within the 0 scope of the invention.

Preferably the "Ar" ring represents phenyl or pyridyl.

Most preferably the "Ar" ring represents a group of formula: WO 01/98267 PCT/tBO1/01035 13 Preferably R 1 when taken alone is OH, CN, halogen, NO 2

NH

2 Ny 2 WY1 or Hetl.

More preferably RI when taken alone is OH, ON, I, Cl, NH 2

NO

2 optionally benzo-fused heteroaryl, NHSO 2

Y

1 NHCOYI or NHCO 2

YI.

Yet more preferably RI when taken alone is OH, CN, I, Cl, NH 2 N02,1,2,3-triazolyl, 1,2,4triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, o NHSO 2 (Cl..6 alkyl), NHSO 2 (C1..6 alkyl substituted by methoxy, CONH 2 OH, C0 2

(C

2 6 alkyl), phthalimido, NH 2 or halogen), NHSO 2

NH

2

NHSO

2 NH(C 1 6 alkyl), NHSO 2 N(C 1 6 alkyl)2, NHSO2Hetla, NHCO(C 1 6 alkyl) or NHCO2(Cl- 6 alkyl).

Even more preferably RI is OH, NHSO 2

CH

3 NHSO2C 2 H5, NHSO 2 (n-C 3

H

7 NHS0 2 (i-

C

3

H

7

NHSO

2 (n-C4H 7

NHSO

2 NH(i-C 3

H

7 NHSO2(N-methylimidazol.4-yl),

NHSO

2

(CH

2 2 0CH3, NHSO 2

(CH

2 2 0H, 1 ,2,4-triazolyl or imidazol-2-yl.

Most preferably RI is OH, NHSO 2

CH

3

NHSO

2

C

2

H

5 or imidazol-2-yl.

Preferably R 2 when taken alone is H.

o RI and R 2 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 Cl14 haloalkyl.

More preferably RI and R 2 when taken together with the carbon atoms to which they are attached are a 5-membered heteroaryl moiety optionally substituted by C1..4 alkcyl or Chaloalkyl.

Yet more preferably RI and R 2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF 3 Preferably X is Cl.

Preferably n is 0.

Preferably q is 0.

Preferably R 3 is H, CN, or CI- 6 alkyl (optionally substituted by one or more halogen, OH,

C

1 6 alkoxy, C 1 -6 alkoxycarbonyl, C 2 6 alkanoyl, C 2 6 alkanoyloxy, C 26 alkyloxycarbonyloxy, NR1 'R 1 3

CONR'

2 R 3 and/or Ny 2 WYl).

More preferably R 3 is H, CH 3

C

2

H

5 i-C 3

H

7 n-C 3

H

7 or CH 2

OCH

3 Most preferably R 3 is CH 3 Preferably R 4 is C 1 10 alkyl substituted by one or more substituents selected from:

C

1 6 alkoxy [substituted by one or more groups selected from OH, NR 25

R

26

CONR

2 5 R 26 halogen, C 1 6 alkoxy, C 2 4 alkynyl, C 2 A alkenyl, heteroaryll, aryl', COCH 2

CN,

CO(heteroaryll), CO(aryll), C0 2 (heteroaryll), COCH 2 (aryll), COCH 2 (heteroaryll),

CO

2

CH

2 (aryll), CO 2

CH

2 (heteroaryl'), 6 alkyl), S(O)n(aryl'), S(O)n(heteroaryl'), S0 2 NR 25

R

26 a cycloalkyl group that is a C 3 -1 0 carbocyclic system with one or two rings and cycloalkyl']1 alkyl [optionally substituted by one or more groups selected from OH, NR 25

R

2 C0NR 5 R 26 halogen, C 1.

6 alkoxy, C 2 A alkynyl, C 2 A alkenyl, heteroaryl'1, aryl'1,

COCH

2 CN, CO(heteroaryll), CO(aryll), C0 2 (heteroaryl'), COCH 2 (aryl'),

COCH

2 (heteroaryl'), CO 2

CH

2 (aryl'), CO 2

CH

2 (heteroaryl'), 6 alkyl), S(O)n(heteroaryll), S0 2 NR2R 26and cycloalkyl'I], aryl1 2

CO

2

CH

2 (heteroaryl 1),

CO

2

CH

2 (aryll), cycloalkyl', a cycloalkyl group that is a C 3 -1 0 carbocyclic system with one or two rings, :CO(heteroaryl'), 25 CO(aryl') OCO(aryl') OCO(heteroaryl 1), OCO(C 1.

6 alkyl),

OCOCH

2

CN,

C0 2 (heteroaryl 1), jIIDAYLB\LIBA)060OI.doc:NSS C02(aryll), COCH2(heteroaryl 1), S(O)flCH 2 aryll, S(O)n(heteroaxyl 1), S(O)nCH2(heteroaryll), NHSO2aryl l, NHSO2(heteroaryl 1), NHSO2CH2(heteroaryl 1), NHSO2CH 2 (arYl 1), NHCOaryl 1, NHCONHaryI 1, NilCOheteroaryl 1, NHCON~heteroaryl 1, NHCO2(arYIl), NHCO2(heteroaryll), ary1 2 oxy, heteroaaylloxy, Ci-6 alkoxycarbonyl substituted by 01.6 alkyl, aryl, 01.6 alkoxy, CH2(aryll), CI- :.seehaloallcy, halogen, OH. di or NR 25

R

26 s 60,19 25 C2-.6 alkanoyI substituted by 01.6 alkyl, aryl, 01.6 alkoxy, CH 2 (azyll), 0 1A alalkyl .00. :halogen, OIL CN or NR 25

R

2 0, :goe. 02.6 alkanoyloxy substituted b .Y C1-6 alkYl, ar.' C1-6 ailkoxy, CH2(aryll), C-4 haloalky), halogen, OH, CN or NR 2 5

R

26 cycloallcylloxy, COcycloalkyll, :0000,heterocycle substituted by one or more substituent selected from 016 alkyl(substituted by 0 0940OH),

CONR

2 5

R

2 6 CH2C0NR 2 5R 2 6, NR 25

R

26

NHCONR

2

SR

2 6, CO(C1..6 alkyl), 000:0 S0 2

NR

2 5

R

2 6

SO

2 (Cj..

6 alkyl), C02(CI..6 alkl), CH20_)0 2 (CI.6 aUlkyl), 0C11 2 00 2 (Cl._6 C04 alkyl), aryl, heterocyclyl, aryloxy, arYl(CH 2 )OXY, aryl(CHj), ON and C3-7 cycloaULkl se WO 01/98267 PCT/IB01/01035 16 heterocyclyloxy substituted by one or more substituent selected from C1-6 alkyl(substituted by OH), CONR 2 5

R

26

CH

2

CONR

2 5

R

26

NR

25

R

26

NHCONR

25

R

26 CO(C1.

6 alkyl),

SO

2

NR

2 5

R

26 S0 2 (C1-6 alkyl), C0 2

(C

1 .6 alkyl), CH 2 CO2(CI-6 alkyl), OCH2CO 2 (C1.6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH 2 )oxy, aryl(CH 2 CN and C3- 7 cycloalkyl, More preferably R 4 is C 1 10 alkyl substituted by cycloalkyll.

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

.0 Further more preferably R 4 is propyl substituted by cycloalkyll.

Furthet yet more preferably R 4 is propyl substituted by a C 3 -10 carbocyclic system with one or two rings and which is substituted by OH.

Even more preferably R 4 is propyl substituted by (cyclohexyl substituted by OH) Most preferably R 4 is (1-hydroxycyclohexyl)prop-3-yl.

Another preferred group of compounds are those wherein R 4 takes the values as specified in 0 the Examples 145-203 below.

Preferably R 5

R

6

R

7

R

8

R

9 and R 10 are each taken separately and are H.

A preferred group of substances are those in which the "Ar" ring, R 1

R

2

R

3

R

4

R

5

R

6

R

7

R

8

R

9

R

10 q and (X)n have the values as detailed in the Examples below.

The invention further provides synthetic methods for the production of compounds and salts of the invention, which are described below and in the Examples and Preparations. The skilled man will appreciate that the compounds of the invention could be made by methods 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 using standard textbooks such as "Comprehcnsive Organic Transformations A Guide to Functional Group Transformations", RC Larock, VCH (1989 or later editions), WO 01/98267 PCT/IB01/01035 17 "Advanced Organic Chemistry Reactions, Mechanisms and Structure", J.March, Wiley- Interscience (3rd or later editions), "Organic Synthesis The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

It is to be understood that the synthetic transformation methods mentioned herein are 0 exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactionis for synthesis of a given target compound. For example, substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinafter in conjunction with a particular reaction. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The 0 procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter.

It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley Sons Inc (1999), and refernces therein. Functional groups which may desirable to protect include oxo, hydroxy, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (e.g.

0 ethylene ketals) and dithianes. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C.-6 alkyl or benzyl esters.

WO 01/98267 PCT/IB01/01035 18 In the Methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula The invention provides a process for the preparation of compounds of formula I as defined above, or a pharmacutically or veterinarily acceptable derivative thereof, which comprises: for compounds of formula I in which q is 0 and R 1 represents NY 2 W YI, reacting a compound of formula II,.

R

2 (X)n Ar NHY 2

R

3 R 16

R

10 N R

II

R

4 with a compound of formula n, Zl-WY1 m wherein Z1 is a suitable leaving group, such as halogen or YlSO 2 0-; for compounds of formula I in which q is 0 and R 6 and R 7 both represent H, reduction of a compound of formula IV, S using a suitable reducing agent; for compounds of formula I in which reduction of a compound of formula V, q is 0 and R 9 and R 10 both represent H, WO 01/98267 PCT/IB01/01035 using a suitable reducing agent; for compounds of formula I in which q is 0 and R 1 and R 2 are attached to adjacent carbon atoms and are taken together with the carbon atoms to which they are attached to represent Hetla, in which Het l a represents an imidazolo unit, reaction of a corresponding compound of formula VI,

-NH

2 with a compound of formula VII,

RYCO

2 H VII 3 wherein RY represents H or any of the optional substituents on Hetla (as defined above), preferably H, C1-4 alkyi or C1-4 haloalkyl; where q is 0, reacting a compound of formula VIII, WO 01/98267 PTIO/13 PCT/IBOI/01035 with a compound of formula IX,

R

4 -Lg wherein Lg is a leaving group; for compounds of formula I in which q is 0 and R 6

R

7

R

9 and RIO are all H, reduction of a compound of formula X, with a suitable reducing agent; for compounds of formula I in which q is 0 and RI represents OH, reacting a cc'ou"d of fbrrn'alin I hiT u 2 iy H, asdfndaoc ihf brc aci and .0 isoamyl nitrite; WO 01/98267 PCT/IB01/01035 21 for compounds of formula I in which q is 0 and R1 represents Cl, reacting a compound of formula II in which Y 2 is H, as defined above, with sodium nitrite in the presence of dilute acid, followed by reaction with copper chloride in the presence of concentrated acid; 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; for compounds of formula I where q is 0, by reduction of a corresponding compound of formula XXXI, R2 .0 /R 1 (X)n Ar R R R s

R

10 N R 7 O R4a

XXXI

where R 4 aCH 2 takes the same meaning as R 4 as defined above; or for compounds of formula where q is 0, reductive amination reaction of the :0 amine of formula VIII above with an aldehyde of formula R 4 a-CHO wherein R 4 aCH takes the same meaning as R 4 as defined above, and where desired or necessary converting the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa.

In process the reaction may be carried out at between 0 0 C and room temperature in the presence of a suitable base pyridine) and an appropriate organic solvent (e.g.

dichloromethane).

Compounds of formula II may be prepared by reduction of a corresponding compound of 0 formula XI or formula XII, WO 01/98267 PCT/IB01/01035 22

R

2

R

2 (X)n Ar NH 2 (X)n Ar NH 2

R

3 R 3

R

8 5

R

8

R/

R

9

RR

R N O O N R 14 4 R

R

XI XII in the presence of a suitable reducing agent, such as lithium aluminium hydride. The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent tetrahydrofuran).

Compounds of formula XI and XII may be prepared by reduction of the corresponding -NO 2 compounds under conditions that are well known to those skilled in the art using

H

2 /Raney Ni or in the presence of CaC12 and iron powder, in the presence of a suitable solvent system EtOH, EtOAc and/or water)). The skilled person will appreciate that, in 0 preparing a compound of formula II, in which Y 2 is H, from such a corresponding -NO 2 compound, the two above-mentioned reduction steps may be performed in the same step or sequentially in any order.

The said corresponding -NO 2 compounds may be prepared by reaction of a compound of formula XII or formula XIV, as appropriate,

-NO

2 III XIV WO 01/98267 PCT/IB01/01035 23 wherein L 1 represents a suitable leaving group [such as halo chloro or bromo)], L 2 represents a suitable leaving group (such as C1-3 alkoxy) and R 3 is as defined above, with a compound of formula XV,

R

4

NH

2

XV

The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable base NaHC03) and an appropriate organic solvent (e.g.

dimethylformamide), or at a higher temperature between 50 and 200°C, preferably between 100 and 160 0 C) in the presence of neat compound of formula XV.

0 Compounds of formula XIII and XIV may be prepared in accordance with standard techniques. For example, compounds of formula XIII and XIV may be prepared by reacting a corresponding compound of formula XVI or XVII,

R

2

R

2 (X)n Ar NO 2 (X)n Ar N2 R8/ y-R R3 R9 L -L1

R

XVI XVII with a compound of formula XVIII or XIX respectively,

N

2

CHR

5

COL

2

XVIII

N

2

CHR

8

COL

2

XIX

wherein L 2 is as defined above. The reaction may be carried out at room temperature in the presence of a suitable catalyst Rh 2 (OAc)4] and an appropriate non-prtic organic solvent dichloromethane).

Compounds of formula XVI and formula XVII are available or can be prepared using known techniques. Compounds of formula XVI and formula XVII may, for example, be prepared from corresponding compounds of formula XX, WO 01/98267 PCT/IB01/01035 24

R

2 (X)n Ar N2 7-R 3 0

XX

for example by performing a Wittig reaction using an appropriate provider of the nucleophilic group RO 2

C-CR

5 H- or RO 2

C-CR

8 H- (wherein R represents lower C 1 3 alkyl), as appropriate, under conditions that are well known to those skilled in the art. The

CO

2 R group of the resulting compound may be converted to an appropriate -CH 2

L

1 group using standard techniques reduction of the ester to the primary alcohol and conversion of the latter to an alkyl halide) under conditions that are well known to those skilled in the art.

O In processes and suitable reducing agents include lithium aluminium hydride. The reaction may be carried out at between room temperature and reflux temperature in the presence of a suitable solvent tetrahydrofuran).

Compounds of formula II may be prepared by reduction of the corresponding compound of formula XXX,

XXX

WO 01/98267 PCT/IB01/01035 by analogy to the process steps mentioned above.

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

R

2

R

2 (X)n Ar L3 (X)n Ar R3

R

3

R

9

R

R

8 5 RR /\R Ro 0 N 0 0 N R 7 14 4 R R XXI XXII wherein L 3 represents a group that is capable of undergoing functional group transformations cyano) using standard functional group substitution or conversion techniques.

0 For example: Compounds of formula IV and V in which R1 represents 1,2,4-triazol-3-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L 3 represents -CN with HCI (gas) in the presence of an appropriate lower alkyl alcohol (e.g.

ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with formic acid hydrazide at reflux temperature, with or without the presence of a suitable organic solvent methanol), followed by, if necessary, removing the solvent and heating the resultant residue to a high temperature about 150 0 Compounds of formula IV and V in which R1 represents imidazol-2-yl may be 3 prepared by reaction of an appropriate compound of formula XXI or XXII in which L 3 represents -CN with HCI (gas) in the presence of an appropriate lower alkyl alcohol (e.g.

ethanol), for example at between 0°C and room temperature, followed by reaction of the resultant intermediate with aminoacetaldehyde dialkylacetal dimethylacetal) at or around reflux temperature in the presence of an appropriate solvent, such as methanol).

Compounds of formula IV and V in which R 1 represents 1,2,3-triazol-5-yl may be prepared by reaction of an appropriate compound of formula XXI or XXII in which L 3 represents -CN with diazomethane, Or a Protected frialkylsilyl) derivative thereof; for example at between 000 and room temperature in the presence of a suitable base n- BuLi) and, optionally, an appropriate organic solvent THF), followed by removal of the protecting group as necessary.

Compounds of formula IV and V in which RI represents benzimidazol.2yl may be prepared by reaction of an appropriate compound of formula =X or XIM in which L 3 represents 0--NH(O~t) with l,2-diaminobenzene. Ile reaction may be carried out in a 3olvent such as methanol, at an elevated temperature (such as the reflux temperature of the ;olvent). Preparations 81, etc. provide further details.

:ompounds of formula IV and V in which RI represents fletl may also be prepared from ompounds of formula MI and X11 respectively according to the following scheme: Q) HC4 NRNO 2 fl 2 0 h) 10 H 2 0

XXIII

Pd2(dba) 3 ,Ph 3 As

BU

3 Sn-Het, -NH 2 XX~iV WO 01/98267 PCT/IB01/01035 27 wherein Hetl is defined above. Further details may be found in Preparations 67, 68, etc. in WO00/39089, herein incorporated by reference in its entirety.

Compounds of formula XXI and XXII may be prepared in analogous fashion to methods described herein, for example those described hereinbefore for preparation of compounds of formula II.

Other compounds of formula (IV) and may be prepared by analogy with methods 0 described herein by analogy with methods described hereinbefore for preparation of compounds of formula XI and XII (and especially the corresponding -NO 2 compound)).

In process the reaction may be carried out by heating under reflux, with or without the presence 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 II), which latter compound may be activated by converting the 3-amino group to a 3-amido group, followed by hydrolysis of the 0 amide and reduction of the 4-nitrobenzene compound. All of these reactions may be performed using techniques that are familiar to the skilled person, and are illustrated in Preparations 45-48, etc. below.

In process suitable leaving groups that Lg may represent include halogen, such as bromine, or a sulphonate group such as tosylate, mesylate or triflate. The reaction may be carried out in a polar solvent that does not adversely affect the reaction, at a suitable temperature, e.g. 0-1500C, in the presence of a base. A catalyst such as sodium iodide may optionally be added.

0 Preferable choices are a slight excess of R 4 -Lg, where Lg Cl or Br, an excess of base eq), such as K 2 CO3, NaHCO 3 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 0 C, optionally in the presence of a catalyst such as Nal or KI, for 2-24 hr.

see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), p 397, and references cited therein.

WO 01/98267 PCT/IB01/01035 28 Compounds of formula VII may be prepared from compounds of formula XXV,

R

2 Ar R

R

3 8 Re R 10 R 10 N R Pg

XXV

wherein Pg represents a suitable protecting group. Suitable protecting groups include allyl, which may be removed using a palladium catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc. below). Compounds of formula XXV may be prepared using analogous methods to those described herein for the preparation of compounds of formula I.

In process suitable reducing agents include lithium aluminium hydride. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), at an elevated temperature (for example the reflux temperature of the solvent).

Compounds of formula X may be prepared by reacting a compound of formula XXVI with a compound of formula XXVII in the presence of an oxidizing agent Suitable oxidizing agents include manganese dioxide. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example dioxan), at an elevated temperature such as the reflux temperature of the solvent (for example see Preparation 77, WO00/39089).

The intermediate compounds XXIXa are isolatable using suitable conditions see Preparation 58, WO00/39089).

WO 01/98267 PCT/IB01/01035 (X)n- (X)n

R

8

R

XXV0

XXVII

INH

2

XXVI

XXIXa (X)n-

XXIX

Compounds of formula XXVI may be prepared from compounds of formula XXVIII, by reaction of the corresponding ketone with hydrazine monohydrate using known techniques (and as described in Preparation 76, etc. WO00/39089).

Process is particularly useful when Ar represents an optionally benzo-fused 5- or 6- 0 membered heteroaryl ring. A similar methodology may be used to obtain compounds of formula II: the precursor nitro compound may be prepared from a compound of formula XX, as defined abovc, using the steps described above (see for example Preparations 57-61, WO00/39089).

WO 01/98267 PCT/lB01/01035 In process the reaction may be carried out in a solvent that does not adversely affect the reaction (for example ethanol), first below room temperature and then at an elevated temperature (Examples 79, etc. WO00/39089, provides further details).

In process suitable acids include dilute aqueous hydrochloric acid and concentrated hydrochloric acid, respectively. The reaction may be carried out at or around room temperature, finishing at an elevated temperature (for example 90 0 Example 51 WO00/39089 provides further details.

0 In process the compound of formula XXXI may be prepared by acylation of the compound of formula VIII as defined above, with an acylating agent of the formula R 4 aCO- Lg, where Lg is a suitable leaving group as defined above with respect to and includes halogen, (alkyl, haloalkyl or aryl)sulphonate, OCOR 4 a an acid anhydride) and the like, well known to those practising in the art. See for example the conditions used for Preparation 47. The coupling can optionally be carried out in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein. Preferably the carboxylic acid (0.9-1.1 eq), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide. HCI (1-1.5 eq) and 1-hydroxybenzotriazole 0 eq) are stirred in DMF or DCM at RT for 5-15 min and then the amine salt (1 eq) and base (NaHCO3 or organic base, Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr at RT.

The amide bond can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-1000C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432-434, and references cited therein. Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C-RT, in THF, for 1-24 hr.

D

In process the appropriate aldehyde is reacted with an amine, optionally present as an acid addition salt, in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is suitably performed in the presence of acetic acid at 0-100 0 C in THF, methanol, DCM (dichloromethane), or DCE (1,2 -dichloroethane), for a suitable time such as 1-24 hr.

WO 01/98267 PCT/IB01/01035 31 Preferably the amine salt, such as the trifluoroacetic acid (TFA) salt, is treated with an organic base (1-3 mole equivalents), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 mole equivalents), followed by sodium triacetoxyborohydride (1-2.0 mole equivalents), in DCM or DCE, at room temperature for 2-24 hr. see RC Larrock; "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), p 835-842, and references cited therein, and Abdel-Magid et al, J.

Org. Chem., 1996, 61, 3849.

The aldehydes used in this process may be prepared from the corresponding alcohols using suitable oxidising agents; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1234-1236 and 1238- 1247, and references cited therein. Preferred oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J.

Org. Chem., 1983, 48, 4155-4156).

Various functional group interconversions on compounds of formula or intermediates thereto, may be carried out to give different compounds of formula or intermediates.

Some of these are mentioned below.

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

Esters can be converted to the corresponding alcohols using a suitable reducing agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein. Suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride (LiAlH4, see Brown, Org. Reactions, 1951, 6, ;0 469) viz. reaction of the type: 0 R R1

R

rrH

^J

WO 01/98267 PCT/IB01/01035 32 Alcohols can be prepared from a corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAlH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80 0 C, for 1-24 hr. viz. reaction of the type: R OH ROH 0 Direct methods to prepare alkyl halides and alyl sulphonates from their alcohols are described by RC Larrock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 689-700, and references cited therein.

Benzylacetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give benyloxyalcohols.

For representative examples see Organic Preparations and Procedures, Int., 1991, 23, 4, 427- 431, ZrC14/LiAlH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCl; and Organic Preparations and Procedures, Int, 1985, 17(1), 11-16, NaBH4/TFA.

0 viz. reaction of the type: 00 SH R O O H

R

It will be apparent to those skilled in the art that compounds of formula I may be converted to other compounds of formula I using known techniques. For example, compounds of formula I in which Y1 represents alkoxycarbonyl may be converted to compounds in which Yl represents alkyl substituted by OH, by reduction using LiAlH 4 (Example 57 provides further details). Similarly, intermediate compounds may be interconverted using known techniques (see for example Preparation WO 01/98267 PCT/IB01/01035 33 The intermediate compounds such as those of formulae III, XV, XVIII, XIX, XX, VII, IX, XXVI, XXVII and XXVIII, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.

The invention further provides the intermediate compounds of formulae II, IV, V, VI, X, Xa, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, and XXXI as defined above.

0 Where desired or necessary, the compound of formula can be converted into a pharmaceutically acceptable salt thereof, conveniently by mixing together solutions of a compound of formula and the desired acid or base, as appropriate. The salt may be precipitated from solution and collected by filtration, or may be collected by other means such as by evaporation of the solvent. Both types of salt may also be formed or interconverted using ion-exchange resin techniques.

The compounds of the invention may be purified by conventional methods, for example separation of diastereomers may be achieved by conventional techniques, e.g. by fractional 0 crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of formula or a salt thereof. An individual enantiomer of a compound of formula may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereomeric salts formed by reaction of the corresponding racemate with a suitably optically active base or acid.

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

According to a further aspect of the invention there is provided the compounds of the invention for use as medicaments, such as pharmaceuticals and animal medicaments, such as for te treatment of opiate-mediated diseases and conditions.

WO 01/98267 PCT/IB01/01035 34 By the term "treatment", this term includes both therapeutic (curative) and prophylactic treatment.

In particular, the substances of the invention have been found to be useful in the treatment of diseases and conditions modulated via opiate receptors, such as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; and conditions characterised by having pruritis as a symptom.

.0 Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease modulated via an opiate receptor. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of as irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damageand/or head trauma; and conditions characterised by having pruritis as a symptom.

The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in :0 animals and humans. Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.

Thus, the invention provides a method of treating or preventing a disease modulated via an opiate receptor. There is further provided a method of treating irritable bowel syndrome; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; smoking and alcohol addiction; sexual dysfunction; shock; stroke; spinal damage and/or head trauma; or a medical condition characterised by pruritus as a symptom in an animal a mammal), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment.

.0 The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be WO 01/98267 PCT/IB01/01035 treated, as well as the route of administration, the compositions may be administered at varying doses (see below).

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

The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (eg subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.

.0 The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal.

Preferably the range is 0.1 to 10 mg per kg.

In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the averge case; there can, of course, be individual instances where higher or lower 0 dosage ranges are merited, and such are within the scope of this invention.

For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as and dogs and in horses.

WO 01/98267 PCT/IB01/01035 36 As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.

For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.

Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparasitics, eg fipronil, lufenuron, imidacloprid, avermectins (eg abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, eg chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, eg fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, eg enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories eg prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, eg gamma-linoleic acid; and emollients.

0 Therefore, the invention further provides a product containing a compound of the invention and one or more selected compounds from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases modulated via opiate receptors The skilled person will also appreciate that compounds of the invention may be taken as a single dose or on an "as required" basis as needed or desired).

Thus, according to a further aspect of the invention there is provided a pharmaceutical, or veterinary, formulation including a compound of the invention in admixture with a 0 pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier.

Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily WO 01/98267 PCT/IB01/01035 37 absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.

The biological activities of the compounds of the present invention were determined by the following test method.

Biological Test Compounds of the present invention have been found to display activity in three opioid 0 receptor binding assays selective for the mu, kappa and delta opioid receptors in dog brain.

The assays were conducted by the following procedure.

Laboratory bred beagles were used as a source of dog brain tissue. Animals were euthanaised, their brains removed and the cerebellum discarded. The remaining brain tissue was sectioned into small pieces approximately 3 g in weight and homogenised in 50mM Tris pH 7.4 buffer at 40C using a Kinematica Polytron tissue homoger.iser. The resulting homogenate was centrifuged at 48,400 x g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 370C 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 -800C. Membrane material prepared in this manner could be stored for up to four weeks prior to use.

For mu, kappa and delta assays, increasing concentrations of experimental compound (5 x 10-12 to 10- 5 Tris buffer and 3H ligand, (mu [D-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 Enkephalin, DAMGO; kappa U-69,593; delta Enkephalin, [D-pen 2 5 DPDPE), were combined in polystyrene tubes. The reaction was initiated by the addition of tissue, and the mixture was incubated at room temperature for 90 minutes. The reaction was terminated by rapid filtration using a Brandel Cell Harvester M through Betaplate T GF/A glass fibre filters pre-soaked in 50 mMi Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then 0 washed three times with 0.5 ml ice-cold Tris pH 7.4 buffer. For mu and delta assays, washed filters were placed in bags and StarscintTM scintillant added, for the kappa assay Meltilex

T

B/HS solid scintillant was used. Bags containing the filters and scintillant were heat sealed and co-unted by a Betaplate 1204 beta counter.

WO 01/98267 PCT/IB01/01035 38 Duplicate samples were run for each experimental compound and the data generated was analysed using IC50 analysis software in Graphpad Prism. Ki values were calculated using Graphpad Prism according to the following formula: Ki IC50 1 3 H ligand] KD where IC 50 is the concentration at which 50% of the 3 H ligand is displaced by the test compound and KD is the dissociation constant for the 3 H ligand at the receptor site.

0 Biological Activity The Ki values of certain compounds of the present invention in the opioid receptor binding assays were determined, and were found to have Ki values of 4000 nM or less for the g receptor.

It is believed that the methods used in the following Examples produce compounds having the relative stereochemistry shown below, and such compounds are preferred: R2

R

(X)n r

I

N

R4 wherein R1- 4 and (X)n are as defined above.

The invention is illustrated by the following Examples and Preparations in which the following abbreviations may be used: APCI atmospheric pressure chemical ionization DMF dimethylformamide S DMSO dimethylsulphoxide d (in relation to time) day d (in relation to NMR) doublet ES (in relation to MS) electrospray WO 01/98267 PCT/IB01/01035 39 EtOAc ethyl acetate EtOH ethanol h= hour MeOH methanol min minute MS mass spectrum n-BuOH n-butanol ODS octadecylsilyl THF tetrahydrofuran 0 TSP thermospray Melting points were determined using a Gallenkamp melting point apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectral data relate to 1 H and were obtained using a Varian Unity 300 or 400 spectrometer, the observed chemical shifts (6) being consistent with the proposed structures. Mass spectral (MS) data were obtained on a Fisons Instruments Trio 1000, or a Fisons Instruments Trio 1000 APCI, or a Finnigan Navigator MS, or a Micromass Platform LC spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. Room temperature means 20 to 250C. The mass spectrometer which is used as a detector on the analytical HPLC-MS 0 system is a Micromass VG Platform II, running on Masslynx/Openlynx software. The system can run positive and negative ion with either Electrospray or APCI probes and is calibrated to 1972 Daltons, it collects full Diode array data from 190nm to 600nm.

HPLC means high performance liquid chromatography. HPLC conditions used were: Condition 1: Rainin Dynamax

T

M column, 8L ODS, 24 x 300 mm, column temperature flow rate 45 ml/min, eluting with methanol water (70 30), UV detection of product at 246 nm.

Condition 2: Rainin Dynamax M column, 5g± ODS, 21.6 x 250 mm, column temperature 3 40 0 C, flow rate 5 ml/min, eluting with acetonitrile water (50 50), UV detection of product at 246 nm.

Condition 3: Rainin Dynamax T column, 8p ODS, 41 x 250 mm, column temperature 400C, flow rate 45 miimin, eluting with acetonitrile 0.1M aqueous ammonium acetate buffer (50 UV detection of product at 235 nm.

WO 01/98267 PCT/IB01/01035 Condition 4: Phenomenex MagellanT' column, 511 C18 silica, 21.2 x 150 mm, column temperature 40 0 C, flow rate 20 ml/min, eluting with a gradient ofacetonitrile 0.1M aqueous ammonium acetate buffer (30 70 to 95 5 over 10 min), UV detection of product at 220 nm.

Condition 5: Phenomenex Magellan T column, 5u ODS, 21.2 x 150 mm, column temperature 400C, flow rate 20 ml/min, eluting with a gradient of acetonitrile 0.1M aqueous ammonium acetate buffer (5 95 to 95 5 over 20 min), UV detection of product at 215 nm.

Condition 6: Phenomenex MagellanTM column, 5up C 1 8 silica, 4.6 x 150 mm, column temperature 400C, flow rate 1 ml/min, eluting with a gradient of acetonitrile 0.1M aqueous heptanesulphonic acid (10 90 to 90 10 over 30 min), UV detection of product at 220 nm.

0 Condition 7: Phenomenex MagellanTM column, 5. C1 8 silica, 21.2 x 150 mm, column temperature 40 0 C, flow rate 20 ml/min, eluting with a gradient of acetonitrile 0.05M aqueous ammonium acetate buffer (50 50 for 15 min then 50 50 to 90 10 over 5 min), UV detection of product at 220 nm.

Condition 8: Phenomenex MagellenTM column, 5.4 C 1 8 silica, 21.2 x 150 mm, column temperature 40°C, flow rate 20 ml/min, eluting with a gradient of acetonitrile 0.1M aqueous ammonium acetate buffer (15 85 to 85 15), UV detection of product at 220 nm.

Condition 9: Phenomenex MagellenTM column, 5ut ODS, 10 x 150 mm, column temperature 0 C, flow rate 5ml/min, eluting with a gradient of acetonitrile 0.1M aqueous ammonium acetate buffer (5 95 to 30 70 over 5 min then 30 70 for a further 20 min), UV detection of 0 product at 225nm.

Condition 10: Phenomenex MagellanTM column, 5j. C 1 8 silica, 21.2 x 150mm, column temperature 40 0 C, flow rate 20 ml/min, eluting with a gradient of acetonitrile 0.1M aqueous ammonium acetate (5 95 to 40 60 over 5 min then 40 60 for a further 25 min), UV detection of product at 210 nm.

Condition 11: Phenomenex MagellanTM column, 5A ODS, 10 x 150mm, column temperature 40 0 C, flow rate 5 ml/min, eluting with a gradient of acetonitrile water (5 95 to 45 over 5 min), UV detection of product at 210 nm.

The free base form of the azabicycles could be obtained from the hydrochloride or acetate 0 salts, for example, in the following way. The salt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (20 ml). The basic mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the free base.

WO 01/98267 PCT/IB01/01035 41 SPE cartridge refers to a solid phase extraction cartridge. These can be commercially obtained from Varian (Mega Bond Elut or IsoluteTM.

NB "Examples" numbered 1-144 are compounds related to the instant invention, but with different R 4 groups, and are disclosed as such in International Patent Application no.

WO00/39089, herein incorporated by reference in its entirety.

A number of further Examples, such as those in the table below, can be made via 0 the processes A-K outlined below and in the experimental details following the table Process A Alkvlation Alkylation of the amine of formula VIII or a salt thereof with R 4 Lg, where Lg is a suitable leaving group, such as a halogen, triflate, mesylate, etc., in the presence of a base, optionally in the presence of a catalyst, in a polar solvent, at between 0 and 1500C.

Preferably the alkylation is carried out with R 4 Lg (slight excess), where Lg =CI or Br, D an excess of base (2.0-4.0 eq), such as K 2

CO

3 NaHCO 3 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 0 C, optionally in the presence of a catalyst such as Nal or KI, for 2-24 hr.

see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), p 397, and references cited therein.

For Example: WO 01/98267 PCT/IB01/01035 42 H H

N'"SO

2 Me

SO

2 M e R4Lg N N TFA salt 14 H R Lg=Br or Cl Conditions: Amine salt (1.0 eq), RX (1.1 eq), NaHCO3 (2-4.0 eq), DMF, Nal (cat), 4( Process B Reductive amination Treating an appropriate aldehyde R4aCHO with an amine of formula VIII in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is often performed in the presence of acetic acid at 0-100 0 C in THF, MeOH, o DCM, or DCE (1,2 -dichloroethane), for 1-24 hr.

Preferably the amine salt is treated with an organic base (1-3 eq), such as triethylamine or Hunigs base, and then the aldehyde (1-1.5 eq), followed by sodium triacetoxyborohydride (1-2.0eq), in dichloromethane or DCE, at room temperature for 2-24 hr. see RC Larrock; "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), p 835-842, and references cited therein, and Abdel-Magid et al, J. Org. Chem., 1996, 61, 3849.

For example: WO 01/98267 PCT/IB01/01035 43 H

H

N'S2Me N'SOMe 0 R4aj

H

N

S TFA salt N H I

R

4 a Conditions: Amine salt (1.0 eq), RCHO (1-1.5eq), Et3N (1-3 eq), Na(OAc)3BH (1-2 eq), DCM

RT.

Process C Reduction of Amide of Formula XXXI The amide carbonyl can be reduced with a suitable reducing agent, for example lithium aluminium hydride or borane, in an ethereal solvent, such as THF, at 0-100°C to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", VCH, (1989), pp 432- 434, and references cited therein.

Preferably the amide (1.0 eq) is treated with lithium aluminium hydride (1.0-3 eq), at 0°C- RT, in THF, for 1-24 hr, e.g.:

SO

2M

M

e

'SO

2 Me LiAIH4 N

N

O R4a -R4a Process D Oxidation Aldehydes used in process B can be prepared using suitable oxidising agents; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1234-1236 and 1238-1247, and references cited therein.

WO 01/98267 PCT/IB01/01035 44 Preferred oxidants are tetrapropylammonium perruthenate (Ley, et.al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al., J. Org.

Chem., 1983, 48, 4155-4156).

H

R4a H oxidant .R OH R4a O Process E Acid/ amine salt coupling to give amides of formula XXXI to Either using an acid chloride amine in a suitable solvent or the acid activated by a suitable agent, optionally in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition, (1999), pp 1941-1949, and references cited therein. Preferably the carboxyllc acd (0.9-1.1 eq), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide. HCI (1-1.5 eq) and 1hydroxybenzotriazole (1.0 eq) are stirred in DMF or DCM at RT for 5-15 min and then the amine salt (1 eq) and base (NaHCO3 or organic base Et3N or Hunigs base (2-4 eq)) are added, the reaction taking 2-24 hr at RT.

For Example:

SO

2 Me

SO

2 Me R

OH

N

I TFA salt

H

O0 R Process F Urea formation Anilines can be converted to a urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432. viz.

reaction of the type: WO 01/98267 PCT/IB01/01035

SNH

2 K 0 N N N H2 1N HCI, RT, 0.1-10 hr O Process G Ester to an alcohol Esters can be converted to the corresponding alcohol using a suitable reducing [0 agent, see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1117-1120 and references cited therein. Suitable reducing agents include diisobutylaluminium hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminium hydride (LiAIH4, see Brown, Org. Reactions, 1951, 6, 469).viz. reaction of the type: O_

OH

Process H !0 Acid to alcohol It should be appreciated that the alcohols used in process D can be prepared from the corresponding acid using a suitable reducing agent; see Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 1114-1116. Preferably the reducing agent is either borane (BH3 (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAIH4 (1-4 eq), in an ethereal solvent, such as THF, 0-80 0 C, for 1-24 hr.

a R4a OH 0 Process I Alcohol to halide WO 01/98267 PCT/IB01/01035 46 It should be appreciated that the R 4 Lg used in Process A can be prepared from the corresponding alcohol R 4

OH.

Direct methods to prepare alkyl halides and alkyl sulphonates from their alcohols are described by RC Larock, Comprehensive Organic Transformations-A Guide to Functional Group Preparations, second edition, (1999), pp 689-700, and references cited therein.

Process J Benzyl halides to benzyloxyalcohols .0 Benzyloxyalcohols can be prepared by refluxing the appropriate benzyl halide with sodium or sodium hydride and a polymethylene glycol in xylene, see J. Am. Chem.

Soc., 1951, 3159-3162.viz. reaction of the type: R R )NaorNaH rf X HO(CH2)nOH NorH O OH Xylene n X halide Process K Acetals to benzyloxyalcohols Acetals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic acid to give the benyloxyalcohols.

For representative examples see Organic Preparations and Procedures, Int., 1991, 0 23, 4, 427-431, ZrCI4/LiAIH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCI; and Organic Preparations and Procedures, Int., 1985, 17(1), 11-16, NaBH4/TFA.viz.

reaction of the type: O O HO O R 0 R I I WO 01/98267 PTIO/13 PCT/EB01/01035 Coupling Processes

A-C

R-Y

TFA salt Example Name Precursor(s) Coupling method -(CH2)nO(CH2)nR examples 145 {6-ethyl-3.[2-(2- C1 OH hydroxyethoxy)ethyll-3azabicyclo[3. 1.O]hex-6- 0 0 yllphenyl)methanesulfonami de Process A Alkylation

N

146 Hr[-3{-2 H (diniethylaniino)ethoxylethyl 0 o azabicYclo[3.1.0]hex-6- 0 0yl)phenyl]metbanesulfonami Process B de Reductive amination N Process D N oxidation 147 2-[2-(6-ethyl-6. {3- I[(methylsulfonyl)arninolphe nyl)-3-azabicyclot3 .1 .Olhex- WO 01/98267 PCTAB01/01035 48 H 0 Process B Reductive amnination 0 Process D oxidation iyl- 3 2 2 ethoxy)ethyl]-3- [3.1.O]hex-6- 0 0~

H

Process B Process D 2 N-(3 6-et pyridinyim azabicyclol yl}phenyl) de trifluoroethoxy)ethyl]-3azabicyclo[3. I .0]hex-6yl~phenyl)methanesulfonami de

F

Process C Amide reduction 0 F Process E WO 01/98267PTIBO/13 PCT[IBOI/01035 Amide formation {6-ethyl-3-[2-(2propynyloxy)ethyl]-3azabicyclo[3. 1 .]hex-6.

yl~phenyl)methanesulfonami de Process B Process D

H

NS

:'0 {3-[2-(allyloxy)ethyl]- 6-ethyl-3azabicyclo[3.1 .O]hex-6yI~phenyl)methanesulfonami de 0rcs Process D 1153 1 1 {6-ethyl-3.[2-(2methoxyethoxy)ethyl]-3azabicyclo[3 .1 .0]hex-6yl~phenyl)methanesulfonami de Process B and D 154 N31 3-)e h1 I- 6-ethyl-3azabicyclo[3.1 yllphenyl)methanesulfonami de Process C and E WO 01/98267 PTIO/13 PCT/IBOI/01035 r (CH2)nO(C112)nAr examples T -Ichlorobenzyl)oxy]ethyl)-6ethyl-3azabicyclo[3.1 .O]hex-6yl)phenyl]methanesulfonami de

C)

Process B and D

CI

156 N-r3-(6-ethvl-3-j2-r(4-

HI

methoxybenzvl)oxylethvfl- 0 0 3-azabicyclof3. 1 .Olhex-6- Process B and D 0 vl~ohenvllmethanesulfonami de N-A C I__ All 1other (CH2)nO(CH2)nAr For a general procedure examples can be prepared via see; J. Am. Chem. Soc., a 2 step process from a benzyl 1951, 3159-3162.

alcohol or benzyl chloride Aryl substituents (mix. of aryl and aryloxy examples): WO 01/98267 PTTO/13 PCT/IB01/01035 157 2-[2-(6-ethyl-6- {3- H [(methylsulfonyl)amino]phe NSnyl} -3 -azabicyclo[3. 1.0]hex- H2N 0O C C 3-yl)ethoxy]benzamide Process B and D 1 4 158 2-f 42-(6-ethyl-6-f3f(methylsulfonyl)aminoiphen yll-3-azabigvclor3. 1. Olhex- 3- YI)ethoxylphenyllacetaniide Cl NNI 0

UNH

2 Process A aminophenoxy)ethyl]-6ethyl-3azabicyclof3 .1 .O)hex-6yl}phenyl)methanesulfonarni de 0 l

NH

2 Process C and E WO 01/98267PC(iO/13 PCT[IB01/01035

H

,N,

C S%0 N- {4- [(aminocarbonyl)amino]phen oxy) ethyl)-6-ethyl -3azabicyclo 1.0]hex-6yl]phenyl}niethanesulfonami de Process F acetylphenyl)propyl]-6.

ethyl-3 azabicyclo 1.0]hex-6yl} phenyl)methanesulfonami de UK-I156607 Process A [(methylsulfony])amino)phe nyl} -3-azabicyclo[3.1 .O]hex- 3yl)ethoxy]benzenesulfonami de Process A WO 01/98267 PTLO/13 PCTIIB01/01035 (methylsulfonyl)phenoxy]eth yl} -3-aiabicyclo [3.1 .O]hex- 6yl)phenyl]methanesulfonami methyl 4-[2-(6-ethyl-6. {3- [(methylsulfonyl)amino]phe nyl) -3-azabicyclo[3. 3-yl)ethoxy]benzoate

H

NS

C0 Processes B and D ethyl {2-[2-(6-ethyl-6-{3- [(niethylsulfonyl)amino]phe nyl} -3-azabicyclo[3. 3 -yl)ethoxy~phenyl) acetate Process A WO 01/98267 PTLO/13 PCT/lBOl/01035 nyl} -3 -azabicyclo[3 .1 .O]hex- 3-yl)ethoxy]phenoxy} acetate 0N N-[3-(6-ethyl-3- (hydroxymethyl)phenoxy]eth yl} -3 -azabicyclo[3. I .0]hex- 6yl)phenyllmethanesulfonami de Processes C and E or from reduction of example 1 9-Process G ,1'-biphenyll- 4-yloxy)ethyl]-6-ethyl-3azabicyclo[3.I .0]hex-6yllphenyl)medmaesulfonarmi Processes B and D WO 01/98267PCIBO/03 PCT/IBOI/01035 {2-[4-(4,5-dihydro- 1 ,3-oxazol-2yl)phenoxy]ethyl} -6-ethyl-3azabicyclo[3. 1 .0]hex-6yl)phenyllmethanesulfonami de Processes B and D {6-ethyl-3-[2-(4phenoxyphenoxy)ethyl]-3azabicyclo[3. .1 .Ohex-6yl~phenyl)methanesulfonamid de HO"" O Processes B and D (be ngylpxv)bengynl-6ethyl-3azabicvclo[3. I .Olhex-6vylhenvImethanesulfona mide Commercial aldehyde Processes B WO 01/98267 PCTJLBO1/01035 WO 01/98267PCfIO/13 PCT/IB01/01035 LI [(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3 .1 .O]hex- C 3-yl)propanoate N 0 176 0

H

benzyl 4-(6-ethyl-6-{3- z

,S:

o O [(nietbylsulfonyl)amino]phe nyl}-3-azabicyclo[3.1.O]hex- Process A 3-yl)butanoate

N

0 177 0

H

N-13 -[6-ethyl-3 -oxo-3- CI C 0 phenylpropyl)-3- 0azabicyclo[3. 1.O]hex-6yI]pbenyl~methanesulfonami de Process A N 0 Kz 178 0 N 1 1 ih d o CH 00 inden-5-yI)-3-oxopropyl]-6ethyl-3azabicYclo[3. 1.O]hex-6- Process A yl)phenyl)methanesulfonami N 0 WO 01/98267 PTTO/13 PCT/lBOl/01035 179 2-(6-ethyl-6- {3- H [(methylsulfonyl)amino]phe N N. nyl} -3-azabicyclo[3. 0 3-yl)ethyl benzoate Process A N .1i 0 01

H

.s, 0 ,0 0 Process A 2-(6-ethyl-6- (3- [(methylsulfonyl)amino]phe nyl}-3-azabicyclo[3. 1.0]hex- 3-yI)ethyl cyanoacetate r(methylsulfonyl)aminolp~hen yl}-3-azabicyclo[3. I .Olhex- 3-flekhl 1 .5-dimethyl-3oxo-2-p~henyl-2,3-dihydro- IH-ovrazole-4-carboxylate

I

Process A -e ~HO Processes C and E IN-(3- {3-[(4-tert- WO 01/98267 PTLO/13 PCT[IB01/01035 azabicyclo[3. 1 .O]hex-6yl }phenyl)methanesulfonami de 0o- 0 {6-ethyl-3-[(4methoxycyclohexyl)methyl]- 3-azabicyclo[3. .1 .]hex-6yl~phenyl)inetlianesulfonami de Processes C and E benzylcyclohexyl)methyl]-6ethyl-3-' azabicyclo[3. .1 .]hex-6yI}phenyl)methanesulfonaini de Processes C and E

HO

0 WO 01/98267PTIiO/13 PCT[IB01/01035 N- {3 -[6-ethyl-3-(octahydro- IH-inden-2-ylmethyl)-3azabicyclo[3. .1 .]hex-6yl]phenyl)methaesulfonami de Processes C and E 1* N-(3 6-ethyl-3-[(2phenylcyclopropyl)methyl]- 3-azabicyclo[3. 1 .O]hex-6yl )phenyl)methaesulfonami de

HO

Processes C and E 4 S {6-ethyl-3-[2- (phenylsulfonyl)ethyl]-3azabicyclo 1 .]hex-6yI }phenyl)methanesulfonami de

HO

Processes C and E 188 0 0 Processes B and D WO 01/98267 WO 0198267PCTIiBOI/01035 ,x, I %0 {6-ethyl-3-42- (ethylsulfonyl)ethyl]-3 azabicyclo[3.1 .0]hex-6yl~phenyl)methanesulfonami de 00 189 Process A (benzylsulfonyl)ethyl]-6ethyl-3azabicyclo[3. 1 .0]hex-6yl~phenyl)methanesulfonami de N-[2-(6-ethyl-6- (3- [(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3.1 .Olhex- 3yl)ethyl~benzenesulfonamide Process C and E [(niethylsulfonyl) amino) ethy 0 0 1) -3-azabicyclo[3. 1.0]hex-6- Process A de WO 01/98267 WO 0198267PCTJJIBOl/01035

H

N s

N

H

Ns.

N-[2-(6-ethyl-6- {3- [(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3. 1.Olhex- 3-yl)ethyl]acetamide 0~0

H

Processes B and D 193 N-[2-(6-ethyl-6- {3- [(methylsulfonyl)aminolphe nyl)-3-azabicyclo[3. 1 .]hex- 3-yl)ethyllbenzamide 0 Process A 194 N-[2-(6-ethyl-6- {3- [(methylsulfonyl)amino]phe nyl} -3-azabicyclo[3. .1 .]hex- 3-yl)ethyl]isonicotinamide Processes B and D WO 01/98267 WO 0198267PCTJIBOI/0 1035

H

S%

0

NN

H

N0* H I Processes B and D {2- [(anilinocarbonyl)amino]eth yl} -6-ethyl-3azabicyclo[3. 1 .01hex-6yl)phenyl]methanesulfonami de ethyl 2-(6-ethyl-6-(3 [(methylsulfonyl)aminolphe nyl) -3-azabicyclo[3. I .O]hex- 3-yl)ethylcarbarnate H0~'H Processes B and D Ho 0 HO)

KS-

{6-ethyl-3-[2- (phenylsulfanyl)ethyl]-3azabicyclo[3 .1 .0]hex-6yl)phenyl)methariesulfonami de Processes C and E WO 01/98267 PTIO/13 PCT/IBO1/01035 I r

S

N-(3 {6-ethyl-3 pyrimidinylsulfanyl)ethyl]-3azabicyclo[3. .1 .]hex-6yl)phenyl)methanesulfonami de Processes C and E S YN

N,,

Examplie 199: f 3-r3-(4-acetylphenflpropyll-6-ethvl-3-azabicyrlor3. 1.O1hex-6yllpheaft~ethanesulfonamide and formnate salt a"' ci" 0 TFA salt WO 01/98267 PCT/IB01/01035 To a solution of the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6yl)phenyllmethanesulfonamide (106 mg, 0.27 mmol) in N,N- dimethylformamide (4 ml) was added sodium hydrogen carbonate (90mg, 1.1 mmol), chloropropyl)phenyl]ethanone (58 mg, 0.29 mmol) and sodium iodide (catalytic) and the reaction mixture was heated at 70 "C for 20 h. After cooling, the solvent was removed in-vacuo to give a crude residue. This was purified by silica (14 g) column chromatography eluting with ethyl acetate: hexane (75:25) and then with neat ethyl acetate. Combination and evaporation of the appropriate fractions gave the partially purified product. This material was further purified by preparative HPLC (condition 1) to afford the formate salt of title compound (16 mg, 12%) as a yellow oil.

1 H-NMR (300MHz, CDCla, data for formate salt) 0.85 3H), 1.70 2H), 2.05 (quintet, 2H), 2.15 2H), 2.55 3H), 2.70 2H), 2.80-2.85 4H), 2.95 3H), 3.70-3.80 2H), 7.00 1H), 7.05-7.10 2H), 7.20-7.28 3H), 7.90 2H), 8.40 1H).

MS (Electrospray): M/Z 439; CzsH3N 2 0 3 S H requires 439.2.

Example 200: N-(3-{3-[2-(benzvloxv)benzyn-6-ethvl-3-azabicyclof3.1.01hex-6yl}phenvl)methanesulfonamide 00 No N TFA salt

H

To a solution of 2-benzyloxybenzaldehyde (27mg, 0.13mmol) in dichloromethane ml) at room temperature was added the trifluoroacetic acid salt N-[3-(6-ethy!-3azabicydo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (50mg, 0.13 mmol) and triethylamine (0.05 ml, 0.38 mmol). The reaction was left to stir at room temperature for 2h. At this point sodium triacetoxyborohydride (40.8 mg, 0.19 mmol) was added and the reaction was left to stir at room temperature for 16 h. Water (5ml) was then added to the reaction mixture and the two layers were separated using a Whatman filter tube (hydrophobic polytetrafluoroethylene membrane). The organic layer was then blown down to dryness under a steam of nitrogen. The residue was purified by WO 01/98267 PCTIEB01/01035 66 column chromatography using a Sep-Paklv cartridge packed with silica gel (10 g) eluting with hexane: ethyl acetate (100:0, 1:1, 1:3, 1:6, 1:9 and 0:100) to afford the title compound (28 mg, 46%) as an oil.

'H-NMR (300MHz, CDCI 3 0.85 3H), 2.80 2H), 2.00-2.10 (in, 2H), 2.85 2H), 3.00 3H), 3.10-3.20 (dd, 3.80 2H), 5.10 6.90-7.05 (in, 3H), 7.10 (in, 2H), 7.20-7.30 (in, 3H), 7.40-7.50 (mn, 6H).

MS (Electrospray) M/Z 477; C 2 ,3H3N 2

O

3 S H requires 477.

o Example 201 N-3-f3-(4-cvanobenzvl)-6-ethvl-3-azabicvclof3.1I.Olhex-6yllphenyllmethanesulfonainide 0:

~N

N

The compound above was prepared by a similar method to that of Example 167, using the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1 .0]hex-6yl)phenyl]methanesulfonamide (100 mg, 0.2Sinmol) and 4-cyanobenzaldehyde (33mg, 0.25iniol) as the starting materials. The product was purified using preparative HPLC (conditions 3) to afford the title compound (28 ing, 28 as an o off-white solid.

1 H-NMR (300rAHz, CDCi 3 0 .85(tM, 3H), 1.80 2H), 2.05 2H), 2.80 2H), 3.00 3H), 3.10 2H), 3.70 2H), 7.00-7.20 (in, 3H), 7.20 (in, 1IH), 7.40 2H), 7.60 2H) MS (Electrospray) M/Z 396; C22H 25

N.

3

O

2 S-H requires 396.

Example 202: N-(3-43-r2-(4-cvclopropvylphenoxv~ethvfl-6-ethvl-3azabicvclo[3. 1.01 hex-6-yllphenvl)methanesulfonainide WO 01/98267 PCT/IB01/01035 67 H H N, N N, N TFA salt N

H

To a solution of the trifluoroacetic acid salt of N-[3-(6-ethyl-3-azabicyclo[3.1 .Olhex-6yI)phenyllmethanesulfonamide (75 mg, 0.19 mmol) in NN- dimethyiformamide (3 ml) was added sodium hydrogen carbonate (64 mg, 0.8 mmol), 1-(2-chloroethoxy)-4cyclopropylbenzene (41 mg, 0.21 mmol) and sodium iodide (3 mg, catalytic) and the reaction mixture was heated at 60 0 C for 20 h. After cooling, the solvent was removed in-vacuo to give a crude residue. This was purified by preparative HPLC (condition 2) to afford the formate salt of the title compound (4 mg, as a brown 0 gum.

'H-NMR (300MHz, CDC 3 data for formate salt) 0.55-0.60 (in, 0.80-0.95 (mn, 1.80-1.90 (in, 3H), 2.25 (bs, 2H), 2.95 3H), 3.15 2H), 3.45 2H), 3.80- 3.90 (in, 2H), 4.20 6.90 7.00 2H), 7.05-7.15 2H), 7.20 1H), 7.30 1H).

MS (Electrospray): M/Z 439; C 25

H

32

N

2 0 3 S H requires 439.2.

Example 203: N-(3-(6-ethvl-3-R(2-phenvlcvdoproovl)methvfl-3-azabicvclo[3. 1. 01 hex- 6-Allhenvl~inethanesuffonamide

H

S

C O TFA salt WO 01/98267 PCT/IB01/01035 68 To a mixture of trans-2-phenylcyclopropylcarboxaldehyde {ref. J. Org. Chem., 1992, 57, 1526} (30 mg, 0.2 mmol) and the trifluoroacetic acid salt of N-[3-(6-ethyl-3azabicyclo[3.1.0]hex-6-yl)phenyl]methanesuffonamide (50 mg, 0.13 mmol) in dry 1,2dichloroethane was added Hunigs' base (0.02ml, 0.12mmol). The mixture was sonicated for 3 minutes and then stirred for a further 30 minutes followed by the addition of sodium triadetoxyborohydride (50 mg, 0.25mmol). After stirring for 72 hours, the reaction was diluted with ethyl acetate (50ml) and partitioned between saturated sodium bicarbonate (2 x 25ml). The organic layer was washed with brine (2 x 20ml), dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure to produce a yellow/brown oil. This oil was dissolved in the minimum of quantity of dichloromethane and purified using a Biotage T M 6 g cartridge eluting with a gradient of ethyl acetate:hexane (30:70) to ethyl acetate (100%) to afford the title compound (32 mg 62%) as an oil.

1 H-NMR (300MHz, CDCI 3 0.78-0.90 3H), 0.97 1H), 1.24 1H), 1.72 (m, 1H), 1.76-1.79 2H) 1.90-2.05 2H) 2.45 (dd, 1H), 2.60 (dd, 1H), 2.84-2.95 (m, 2H), 2.99 3H), 3.02-3.08 2H) 6.89-7.3 9H).

MS (Electrospray): M/Z 411; C 2 4

H~SO,

2 N H requires 411 :0 PREPARATIONS NB Preparations 1 to 148 from International Patent Application publication no.

WO00/39089 are herein incorporated by reference in their entirety, and the same numbering is adhered to herein.

Preparation 149 1 -4-(3-chloropropyl)phenyllethanone C! CI' 0 Aluminium chloride (15.0 g, 0.11 moles) and acetyl chloride (16.0 g, 0,20 moles) o were dissolved in dichloromethane (50 ml) at room temperature. This mixture was then added dropwise to a solution 1-chloro-3-phenylpropane (15.5 g, 0.10 moles) in WO 01/98267 PCT/IB01/01035 69 dichloromethane (25 ml) at room temperature over 15 minutes. The mixture was stirred for 1 hr and then poured cautiously onto ice. The aqueous layer was extracted with dichloromethane (450 ml). The organics were washed with water and brine, and then dried (MgSO 4 and concentrated in-vacuo to give the title compound (19.2 g, 98%) as an oil.

'H-NMR (300MHz, CDCI 3 2.10 (quintet, 2H), 2.60 3H), 2.85 2H), 3.55 2H), 7.30 2H), 7.90 2H).

MS (thermospray): M/Z [M+NH4] 214; C 1

,H,

1 CIO NH 4 requires 214.1.

Preparation 150 1-(2-chloroethoxv)-4-cyclopropylbenzene

HO

4-Cydopropylphenol (6.75 g, 50.3 mmol, reference: Horrom et. al., Org. Prep.

Proceed. Int., 1992, 24 696-698), 2-chloroethyl p-toluenesulfonate (17.71 g, 75.5 mmol), and potassium carbonate (10.4 g, 75.4 mmol) in anhydrous acetonitrile (500 ml) were stirred together under a nitrogen atmosphere at reflux for 30 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (1000 ml). The organics were washed with water (3 x 250 ml), dried (MgSO4), filtered and concentrated in vacuo. This crude material was purified by silica column chromatography eluting with hexane dichloromethane and then with hexane dichloromethane to afford the title compound (8.7 g, 88%) as a solid.

Mpt: 47-48 0

C

'H-NMR (300MHz, CDCIl): 0.60-0.70 2H), 0.85-0.95 2H), 1.80-1.95 1H), 3.81 2H), 4.21 2H), 6.82 2H), 7.02 2H).

MS (thermospray) M/Z 196; C 1

,H,

3 OCI requires 196.1.

Preparation 151 1-Allyl-1H-pyrolle-2.5-dione (see J. Ora. Chem., 1997, 62, 2652) WO 01/98267 PCT/IB01/01035 0^ To a solution ofmaleic anhydride (98 g, 1.00 mol) in dry toluene (3000 ml) at room temperature under a nitrogen atmosphere was added dropwise a solution of allylamine (57.1 g, 1.00 mol) in toluene (1000 ml) over one hour. The mixture was stirred at room temperature for 20 hours and then zinc chloride (136.3 g, 1.00 mol) was added and the reaction was heated to 80°C. 1,1,1,3,3,3-Hexamethyldisilazane .0 (242 g, 1.5 mol) in toluene (1000 ml) was then added dropwise over one hour and the mixture was stirred at 80 0 C for another 4 hours. The mixture was cooled to room temperature and then poured onto 1N HCI (4000 ml). The two layers were separated and the organic layer was washed with water (2000 ml), saturated sodium bicarbonate (2000 ml) and brine (2000 ml). The organics were concentrated in vacuo to give the title compound (74 g, 54%) as a solid.

'H-NMR (300MHz, CDCI,): 4.05 2H), 5.00-5.15 2H), 5.60-5.80 1H), 6.65 (2H, s).

Preparation 152 0 1-(3-nitrophenvl)-1-proDanone hvdrazone O O O-N O-

N"

O

O ,NH2 0 2 WO 01/98267 PCT/IB01/01035 71 To a solution of 3-nitropropiophenone (168 g, 0.93 mol) in ethanol (830 ml) at room temperature was slowly added hydrazine monohydrate (96.8 g, 1.93 mol) via a dropping funnel. The reaction mixture was heated at reflux for 4 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (750 ml) and water (750 ml). The two layers were separated and the organic layer was washed with brine (250 ml), dried (Na2SO4), filtered and concentrated in-vacuo to give an orange oil. This residue was crystallised from diisopropyl ether at -20 0 C to afford the title compound (110 g, 61%) as a yellow crystalline solid.

Mpt: 32 0

C

'H-NMR (300MHz, CDCI 3 1.20 3H), 2.70 2H), 5.65 (broad s, 2H), 7.50 1H), 7.95 1H), 8.10 1H), 8.50 1H).

MS (Electrospray) M/Z 194; CgHNO 3 2 H requires 194.1.

SPreparation 153 3-Allvl-6-ethvl-6-(3-nitrophenvl)-3-azabicyclo[3.1. 0hexane-2,4-dione 0 S 11+ 0 N

N

O O NH2 0 NO To a stirred solution of i-(3-nitrophenyi)-1-propanone hydrazone (84.7 g, 439 mmol) o in 1,4-dioxane (1000 ml) was rapidly added manganese dioxide (grade CMD-1 from Sumitromo, 175 g, 2.01 mol) followed by a saturated solution of ethanolic potassium hydroxide (40 ml) at room temperature. The mixture was stirred at room temperature for 18 minutes and during this period the reaction temperature had risen from 19 0

C

to 250C. Stirring was then stopped and the mixture was allowed to settle. This mixture was then filtered through a pad of Celite® dropwise, directly into a solution of WO 01/98267 PCT/IB01/01035 72 1-allyl-1H-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 complete addition of the reactants. After stirring at room temperature for one hour the mixture was heated at reflux for 20 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was then crystallised from dlisopropyl ether (1000 ml) at 0°C to afford the title compound (83 g, 66%) as an off-white crystalline solid.

MPt: 128-1290C 'H-NMR (300MHz, CDCI 3 0.90 3H), 1.80 2H), 2.80 2H), 4.05 2H), 5.20 0 1H), 5.30 1H), 5.75-5.85 1H), 7.55 1H), 7.70 (dd, 1H), 8.20 (dd, 1H), 8.25 1H).

Preparation 154 3-allyl-6-(3-amlnophenvl)-6-ethvl-3-azabicyclor3.1.0]hexane-2,4-dione 0 11+ N, 0-

NH

2 N O O To a stirred suspension of 3-allyl-6-ethyl-6-(3-nitrophenyl)-3azabicyclo[3.1.0]hexane-2,4-dione (93 g, 310 mmol) and iron powder (151 g, 2.70 0 mol) in ethanol (6.75 L) was added calcium chloride (16.7 g, 0.15 mol) in water (1.2 The mixture was heated at reflux for three hours and then cooled to room temperature before being filtered through Celite®. The filtrate was concentrated in vacuo to give a wet solid. This material was dissolved in dichloromethane (500 ml) and the two layers were separated. The organic layer was dried (MgSO4), filtered WO 01/98267 PCT/IB01/01035 73 and concentrated In vacuo to give a pale yellow solid (81 This material was crystallised from ethyl acetate and hexane 6ml per gram) at room temperature to afford the title compound (54 g, 65%) as a pale yellow crystalline solid.

'H-NMR (300MHz, CDCI 3 0.90 3H), 1.75 2H), 2.75 2H), 3.95 (broad s, 2H), 4.05 2H), 5.25 1H), 5.35 1H), 5.75-5.85 1H), 6.65 1H), 6.70 (s, 1H), 6.75 1H), 7.10 1H).

Preparation 155 3-(3-Allyl-6-ethvl-3-azabicvclo[3.1.0]hex-6-vl)aniline

NH

2 NH 2 N N To a solution of lithium aluminium hydride (1M solution in THF; 400 ml, 400 mmol) in tetrahydrofuran (400 ml) under a nitrogen atmosphere at -15°C was added 3-allyl-6- (3-aminophenyl)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 ml) via a dropping funnel over 0.5 hours. The mixture was then allowed to slowly warm to room temperature over one hour. The mixture was heated at 50 0 C for 3 hours and then cooled to 5 0 C. Water (400 ml) was then cautiously added to the cooled reaction mixture. The solids were removed by filtration through a pad of Celite®, washing with ethyl acetate (400 ml). The filtrate was dried (MgSO 4 filtered, and concentrated in vacuo to afford the title compound (38.1 g, 96%) as a golden oil.

'H-NMR (300MHz, CDCIl): 0,85 3H), 1.80-1.95 4H), 2.85-3.00 4H), 3.15 2H), 3.60 (broad s, 2H), 5.10 1H), 5.20 1H), 5.80-5.95 1H), 6.50 (d, 1 6.60 1H), 6.65 1H), 7.05 1H).

WO 01/98267 PCT/FBOI/01035 74 MS M/Z 243; C 16 H22N 2 H requires 243.2.

Preparation 156 N-[3-(3-allvl-6-ethvl-3-azabicvclo[3. 1. Olhex-6-vl)ohenvflmethanesuffonamide To a solution of 3-(3-allyl-6-ethyl-3-azabicydo3.1.0]hex-6-yl)anllne (41 g, 169 mmol) and triethylamine (34 g, 337 mmol) in dichloromethane (750 ml) at -40 0 C was added dropwise methanesulfonyl chloride (23.7 g, 206 mmol) via a dropping funnel. The reaction mixture was slowly allowed to warm to room temperature over 2 hours and was then stirred at room temperature for 20 hours. The organics were then washed with water (4 x 500 ml), dried (MgSO 4 filtered and concentrated In vacuo to afford the title compound (59.0 g) as a crude gum.

1 H-NMR (300MHz, CDCI 3 0.85 3H), 1.85 2H), 1.95 2.80-3.20 (in, 9H), 5.10-5.25 (mn, 5.80-5.95 (in, I 7.00-7.40 (in, 4H).

Preparation 157 N-[3-(6-ethvl-3-azabicvclo[3. 1.Olhex-6-vl)ohenvflmethanesulfonamlde WO 01/98267 PCT/IBO1/01035

H

H

N

s

N

To a degassed solution of N-[3-(3-allyl-6-ethyl-3-azabicyclo[3. 1. 0]hex-6yl)phenyl]methanesulfonamlde (54.0 g, 169 mmol) and 1,3-dimethylbarbituric acid (80.0 g, 512 mmol) in dichloromethane (500 ml) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium (2.0 g, 1.73 mmol). The mixture was heated at reflux for 8 hours and then stirred at room temperature for 20 hours. The organics were then extracted with 2M HCI (2 x 100 ml) and water (100 ml). The combined aqueous l ayers were then washed with dichloromethane (4 x 100 ml) and freeze dried to give a crude solid. This material was purified by preparative HPLC (condition 4) to afford the trifluoroacetic acid salt of title compound (25.2 g, 53%) as a grey solid.

'H-NMR (300MHz, CD 3 OD): 0.90 3H), 1.65 2H), 2.30-2.40 (in, 2H), 2.90 (s, 3.25-3.35 (in, 2H), 3.70-3.80 (in, 2H), 7.10-7.15 (in, 2H), 7.20 1H), 7.30 (t, 1 H).

MS M/Z 281; C14H20N202S H requires 281.1.

Preparation 158 3-Benzvl-6-methvl-6-(3-nitroohenyl)-3-azabicvcloi3. I.Olhexane- 2.4-ione To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone (1 0g, 0.56mol), in dioxan (I L) was added MnQ 2 (350g, 2.3mol) and the reaction mixture stirred at room temperature for 3omins. The slurry was filtered through celite and the celite pad washed with dloxan (200mls). The filtrate was returned to a pot and N-benzyl maleimide (1 10g,) added portionwise over a period of 20mins. The WO 01/98267 PCTlIB01/01035 76 reaction mixture was stirred at room temperature for 4hrs before being heated under reflux for l6hrs. The reaction mixture was cooled to room temperature and the solvent removed in vacua. The residue was triturated in methanol (5O0mls) and the product Isolated by filtration as a white crystalline solid 56%).

NMR (CDCI 3 d: 1.31 3H), 1.55 2.80 2H), 4.63 2H), 7.28-7.34 (in, 7.43-7.45 2H), 7.52-7.56 1IH), 7.63-7.65 1 8.13-8.16 1IH), 8.17 1IH) MS (APCI): m/z 337.5 +H requires 337.3 Preparation 159: 6-(3-Aminorphenvl)-3-benzvl-6-methvl-3-azabicvclor3.1I.Olhexane- 2.4-done To a slurry of 3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabcyclo[3.1I.0]hexane-2,4dione (30g, 89mmol) in ethyl acetate (600mls) was added 5%PtIC (1 .5g, 5wt 0 The mixture was hydrogenated at 4 atm. room temperature for l8hrs. The slurry was filtered through arbacel and the resulting solution evaporated in vacuo to yield the product as a white crystalline solid (24g, 88%).

NMR (CDCI3) d: 1.26 3H), 2.74 2H), 3.7 bs), 4.60 2H), 6.56-6.58 (d, 1H), 6.60 1 6.65-6.67 1 7.07-7.11 1IH), 7.26-7.33 (in, 3H), 7.42-7.44 (mn, 2H-).

MS (APCI): in/z 307.5 +H requires 307.4 Preparation 160: N-13-r3-Benzvl-6-methvl-2 .4-dioxo-3-azablcvclof 3.1 .Olhex-6villhenvllmetha nesulfonamlde To a solution of 6-(3-aminophenyl )-3-benzyl-6-methyl-3-azabicyclo[3. 1. 0]hexane- 2,4-dione (24g, 78mmol) In ethyl acetate (480mls) was added pyridine 11 8mmol) followed by the slow addition of methane sulfonyl chloride (9.l1mls, "14 l~mrnoI). The react ion was stirred at room temperature for 2.5hrs. The reaction mixture was washed sequentially with IM HCI solution (l2Oinls) and water (l2Oinls).

WO 01/98267 PCTAB01/01035 77 The ethyl acetate was dried over MgSO 4 and evaporated in vacua to yield the product as an orange solid (30g, 99%).

NMR (CDCI3) d: 1.27 2.77 3.02 4.61 7.08-7.14 (in, 7.26-7.32 (in, 7.41-7.42 2H-).

MS (APCI): m/z 385.7 +H requires 385.5 Preparation 161: N-43-Benzvl-6-methvl-3-azabivclor3. 1.Olhex-6-vllohenvlI methanesulfonamide To a solution of N-{3-[3benzyl-6-methyl.2,4-dioxo-3-azabicyIoE3. 1. 0]hex-6yl]phenyl~methanesulfonamide (1 50g, 391 mmol), under nitrogen was added sodium borohydride (31g, 82Ommol). The reaction mixture was cooled to <10 0 C and the

BF

3 .OEt 2 (138.6mls, lO94mmoI) added dropwise maintaining the temperature at 0 C. The reaction mixture was allowed to warm to room temperature over 2hrs before being heated under reflux for a further 8.5hrs. The reaction mixture was cooled to between 0 0 C and 50C and an aqueous solution of piperazine (198.5g, 2304mmol in 1.26L of water) added. The reaction mixture was then heated under reflux for a period of l8hrs. The THE was removed under vacuum, ethyl acetate (900mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (450mis). The organic phases were combined and washed with water (750mis). The organics were dried over MgSO 4 and evaporated In vacuo to yield the product as a white crystalline solid (1 29g, 93%).

NMR (CDCI3) d: 2.62 2.80-2.83 2.99 3.03-3.07 2H), 3.68 7.01-7.02 1 7.06-7.08 (in, 2H), 7.22-7.26 (in, 7.30-7.32 (in, 31-).

MS (APCI): m/z [MH+]357.5 +H requires 357.5 Preparation 162: N4f3-[6-mnethvy!-3-azablcvclo[3. 1 .lhex-6vllohenyllmethanesulfonainide WO 01/98267 PCT/IB01/01035 78 To a solution of N-{3-benzyl-6-methyl-3-azabiyclo[3.1.0]hex-6-ylphenyl} methanesulfonamide (20g, 56mmol), in methanol, was added ammonium formate (10.6g, 168mmol) and the reaction stirred for 5minutes. 10% Pd/C (8g) was added and the resulting mixture heated at reflux for 16hrs. The mixture was allowed to cool and the catalyst removed by filtration through celite. The solvent was removed in vacuo to yield the product as a pale yellow oil, which solidified on standing (15.2g, NMR (CDC13) d: 1.27 3H), 1.85-1.88 2H), 2.93 3H), 3.07-3.10 2H), 3.39-3.44 2H), 6.92-6.97 2H), 7.06 1H), 7.20-7.23 1H).

MS (APCI): m/z 267.4 +H requires 267.3 Preparation 163 3-Benzvl-6-ethyl-6-(3-nitrophenvl)-3-azabiccdo[3.1.01hexane-2,4dione To a solution of 1-(3-nitrophenyl)-1-propanone hydrazone (42.1gg, 217mmol), in dioxan (630mls) was added MnO2 (126g, 1440mmol) and the reaction mixture stirred at room temperature for 20mins. The slurry was filtered through celite and the celite pad washed with dioxan (200mls). The filtrate was returned to a pot and N-benzyl maleimide (44.9g, 239mmol) added portionwise over a period of 20mins. The reaction mixture was stirred at room temperature for before being heated under reflux for 16hrs. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was heated to reflux in methanol (1200mls) for 3 hours and then cooled to room temperature. The product was isolated by filtration as a white crystalline solid (42.4g, 56%).

NMR (CDCi3) d: 0.69-0.73 3H), 1.47-1.49 2H), 2.78 2H), 4.64 2H), 7.3-7.32 2H), 7.43-7.44 1H), 7.52-7.55 1H), 7.62-7.65 2H), 8.17-8.18 3H).

MS (APCI): m/z 351.5 +H requires 351.3 WO 01/98267 PCTfEB01/01035 79 Preparation 164: 6-(3-Amlnoohenyl)-3-benzvl-6-ethvl-3-azabicvclo3. 1.Olhexane-2.4dione To a slurry of 3-benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3. 1.0]hexane-2,4-dione (42.1g, l2OmmoI) in ethyl acetate (850mls) was added 5%PtIC (2.1g, 5wt%). The mixture was hydrogenated at 6Opsl/ room temperature for 18hrs. The slurry was filtered through arbacel and the resulting solution evaporated in vacuo to yield the product as a white crystalline solid (34.1g, 89%).

NMVR (CDCI3) d: 0.70-0.74 3H), 1.41-1.47 2H), 2.73 Cs, 2H), 3.68 (bs, 2H), 4.61 2H), 6.55-6.57 1IH), 6.60 1 6.66-6.68 1IH), 7.07-7.10 Ct, 1IH), 7.28-7.32 3H), 7.41 -7.43 2H).

MS (APCI): mlz 321.4 +H requires 321.4 Preparation 165: N-{3-f3-Benzvl-6-ethyl-2,4-dloxo-3-azablcvclo[3.1 .Olhex-6vii phenvllmethanesu Ifonamide To a solution of 6-(3-amlnophenyl)-3-benzyl-6-ethyl-3-azabcyclo[3. 1 .Ohexane-2 ,4dione C31 .5g, 98mmol) In dichloromethane C25Omls) was added pyridine 11 8mmol) followed by the slow addition of methane sulfonyl chloride (9.1lmls, 11 8mmol). The reaction was stirred at room temperature for l6hrs. The reaction mixture was washed sequentially with 1IM HCI solution C25Omls) and water (1l2Omls).

The dichioromethane was dried over MgSO 4 and evaporated in vacua to yield the product as a waxy pink solid (38.2g, NMR CCDC13) d: 0.68-0.72 Ct, 3H), 1.42-i1.47 2H), 2.75 Cs, 2H), 3.02 Cs, 3H), 4.62 Cs, 2H), 7.13-7.18 Cm, 3H), 7.29-7.42 Cm, 4H), 7.41-7.43 Cd, 2H).

MVS (APOI): m/z 399.6 +H requires 399.5 Preparation 166: N-(3-Benzvl-6-ethvl-3-a-zabicvclo[3.1I Olhex-6-vllo~henvll methanesulfonamide To a solution of N-{3-[3-benzyl-6-ethyl-2,4-dioxo-3-azabicycdo[3.1I.0]hex-6yljphenyllmethanesulfonamide (38.2g, 9 5mmol), in THIF C200mls) under nitrogen was added sodium borohydride (7.46g, 201 Mrrol). The reaction mixture was cooled to <10 C and the BF 3 -OEt 2 C38.lmls, 268mmol) added dropwise maintaining the WO 01/98267 PCT/IB01/01035 temperature at <10 C. The reaction mixture was allowed to warm to room temperature over 2hrs before being heated under reflux for a further 12hrs. The reaction mixture was cooled to between 0°C and 5°C and an aqueous solution of piperazine (48.7g, 565mmol in 320mls of water) added. The reaction mixture was then heated under reflux for a period of 18hrs. The THF was removed under vacuum, ethyl acetate (200mls) added, and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (200mls). The organic phases were combined and washed with 3 separate portions of water (3x400mls). The organics were dried over MgSO 4 and evaporated in vacuo to yield the product as a white crystalline solid (33.5g, 94%).

NMR (CDCI3) d: 0.84-0.88 3H), 1.76-1.77 2H), 2.06-2.12 2H), 2.79-2.81 2H), 2.99 3H), 3.06-3.08 2H), 3.67 2H), 7.01-7.03 1H), 7.08-7.10 (d, 2H), 7.22-7.26 3H), 7.30-7.32 3H).

MS (APCI): m/z 371.3 +H requires 371.5 Preparation 167: N-{3-r6-Ethvl-3-azabicvclo[3.1.0hex-6vlpDhenvl}methanesulfonamide 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 added ammonium formate (255mg, 4.05mmol) and the reaction stirred for 5minutes. Pd/C (200mg) was added and the resulting mixture heated at reflux for 2hrs. The mixture was allowed to cool and the catalyst removed by filtration through celite. The solvent was removed in vacuo to yield the product as a pale yellow oil, which solidified on standing (15.2g, NMR (CDCI3) d: 0.80-0.84 3H), 1.64-1.69 3H), 1.82-1.86 2H), 2.98 (s, 3H), 3.12-3.18 2H), 3.21-3.26 2H), 7.01-7.06 1H), 7.10-7.14 2H), 7.25- 7.28 1H).

MS (APCI): m/z 281.7 +H requires 281.4 WO 01/98267 PCT/IB01/01035 81 Other building block materials useful in synthesising compounds of formula with various different R 4 groups are available from the sources Indicated in the table below, and routine derivatisation thereof, or analogy synthesis.

R

4 Substructure Example of commercial Literature reference source -(CH2)nO(CH2)nR examples

ALDRICH

Cl o./fOH

ALDRICH

HO ~o N

SALOR

HO oNH2 1. Org.Magn.Reson., FHO s 1975. Vol 7; 488-495.

N

WO 01/98267 PTIO/13 PCT[IB01/01035 0 IF WO 8707270 HO') k FAlcohol US 5157159

MAYBRIDGE

ALDRICH

HONI- 0',N ALDRICH HO Bull. Soc. Chim. Fr.; 1947, 616.

Alcohol-EP-081 1621 (CH2)nO(CH2)nAryl examples

BIONET

1. J. Org. Chem., 1987, 52 2594.

-0 2. Org. Prep. Proceed.

I nt; 23,4; 1991, 427.

All other For a general procedure (CH2)nO(CH2)nAryl see; J. Am. Chem. Soc., examples could be 1951, 3159-3162.

prepared via 2 step process WO 01/98267 WO 0198267PCTIIB01/01035

SALOR

83 J. Med. Che 1427.

J. Med. Chei 1985, 14 ation of the we.

DE 2135678; DE 3636333 in., 1985, 28,

SALOR

'S0 2

M

product abc

SNH

Rev. Med.-Chiv., 1985, 89 316-20.

WO 01/98267PTIBO/03 PCT/lBOl/01035 *Cl- OMe 0

APIN

J. Med. Chem., 28, 1985, 1427 1985, 1427 O 0

HO

Ic-

OH

LANCASTER

HO

'CIO

ICN-RF

MAYBRIDG E HO oIllz

NI

WO 01/98267PTIiO013 PCT/IBOI/01035

MAYBRIDGE

9

H'

NI

1767.

WO 9611192 (alcohol) WO 9610999 Imidlazole analogue: J.

Med Chem., 1981, 24(10), 1139 US-471 3387

MAYBRIDGE

J. Med. Chem., 28, 1985, 1427.

ICN-RF

WYCHEM

WO 01/98267 PCTI/iBOI/01035 WO 01/98267 WO 0198267PCT/EB01/01035 0

H

WO 01/98267 WO 0198267PCT/IBOl/01035 0

MAYBRIDGE

N

H H

HOH

0 ALDRICH H OS

I

Claims (24)

1. A substance which is a compound of formula I, PCTAJB01/01035 (X)n- wherein the "Ar" ring represents an optionally benzo-fused phenyl or 5- or 6-membered heteroaryl. ring; RI when taken alone is H, halogen, N02, NIT 2 NY 2 WYI, Hetl, AD, C0 2 R 7 C(O)R 8 C(=NOH)R 8 or OE, Y 2 is H, C 1 6 alkyl, C 3 6 alkenyl (each of which alkyl and alkenyl is optionally substituted by aryl, aryloxy or Het I), W is SO2, CO, C(O)O, P(yl)=O, P(yI)=S, YI is Cl.-10 ailkyl (optionally substituted by one or more substituents independently selected from halogen, OHf, C 1 A alkoxy, C 1 -6 alkanoyloxy, CONH 2 C 1 .6 alkoxycarbonyl, NH 2 aryl, mono- or di(Cl 1 4 alkyl)amino, C 3 cycloallcyl, phthalimnidyl, Hetl), Hetl, aryl (optionally substituted by one or more substituents independently selected from CIA4 alkyl, C 1A- haloallcyl and halogen), NH2, N(C 1 6 alkyl)2 or NH(Cl1 6 ailkyl), Het 1 I is a heterocyclic group containing up to 4 heteroatoms selected from N, 0 and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally benzo- or pyrido-flised heteroaryl), optionally substituted by one or more substituents independently selected from C 1 -6 alkyl, CI- alkoxy, C 3 -6 cycloallcyl, C 1 6 haloalkoxy, Cl.6 haloalkyl, C 3 -6 halocycloaUcyl, =O, OH, halogen, NO 2 SiP 19aRI9bol9c, CONR 2 aR 2 0b, NR 2 OaR 2 0b, SR 2 NR 2 IbSO 2 R 22 a, NR 2 1cC(O)OR 9b, NR 2 1dCOR 2 2 c, and C, alkoxycarbonyl, and if a S atom is present in a ring, it can be present as part of a or -S(0 2 group, and carbon atoms in the ring can be present as a part of a carbonyl moiety-, Rl9a, RI9b, R 19 c each independently represent 01.6 alkyl or aryl, R 2 0a and R2Ob each independently represent HL 01.6 alkyl, aryl, (Ci-4 alkyl)phenyi, each of which alkyl, aryl and alkyiphenyl are optionally substituted by one or more CiA- alkyl, C 0 aikoxy, OIL NO 2 NH 2 and/or halogen, or R 2 0a and R2Ob can be taken together* with the N atom to which they are attached, to form a 4- to 6-membered ring optionally substituted by one or more substitutuents independently selected from one or more Cl alkcyl, Cl A alkoxy, OH, 0O, N 2, NH 2 and/or halogen, is1 R 2 la, b, c and d each independently represent H1, C1..6 alkyl, aryl or CIA4 allIyphenyl, each of which alkyl, aryL, and alkyiphenyl are optionally substituted by one or more C14A alkyl, C14 alkoxy, OH, NO 2 halogen, NH1 2 R 2 2 a, b and C each independently represent CI-6 alkyl, aryl or CI-4 alkyiphenyl, each of which alkyl, aryl, and alicyiphenyl are optionally substituted by one or more CI4 alkyl, C[.4 :alkoxy, OH1, NO 2 halogen, NH 2 A is CIA4 alkylene, C2A alkenylene or C2A4 alkcynylene, each of which is optionally substituted by one or more C1A alkyl, C14 alkoxy, halogen and/or OH, D is K, 01H, N, NR 25 R 2 6 CONR 2 5R 26 NHgR 2 7, 00 2 R 2 8 C0R 29 C&=NOH)R 29 or AD is CN, NR 2 5 R 26 C0NR 25 R 26 where R 25 and R 26 are either each independently ILCI3 alkyl, C3-.8 cy0loalkYL, arYI, C1.4 alkylphenyl (each of which 01.3 alkyl, 03.8 cycloalkyl, aryl and 01.4 ailcyiphenyl are optionally substituted by one or more N02, halogen, CiA4 alkyl and/or 01.4 alkoXy, (each of which latter 01.4 alkyl and C1i4 alkoxy is optionally substituted by one or more halogen)), or R 2 5 and R 2 6 ametaken together with the Natom to which themattached and can fofn a

4- to 7-membered. heterocyclic ring optionally incorporating one or more further hetero, WO 01/98267 PCT/EB01/01035 91 atoms selected f-rm N, 0 and S, and which ring is optionally substituted by one or more C 1 I 4 alkyl, OH, NO 2 NI{2 and/or halogen, R 27 is C0R 30 CO 2 R 3 1 a, S0 2 R 3 I b, R 28 and R 29 are each. independently H, C 1 6 alkyl, C3-8 cycloalkyl, aryl or C 1 4alkylphenyl, each of which CI.6 ailkyl, C3-8~ cycloalkyl, aryl and CIA4 ailcyiphenyl are optionally substituted by one or more N0 2 halogen, C 1 4 alkyl, C 1 4 alkoxy (each of which latter C 1 4 alkyl and C 1 -4 alkoxy are optionally substituted by one or more halogen), R 30 is H, C 1 4 alkyl, C 3 8 cycloalkyl, C 1 4 alkoxy, C3-8 cycloalkyloxy, aryl, aryloxy, C 1 4 alkylphenyl, phenyl(C-4 )alkoxy, (each of which CI-4 alkyl, C 3 8 cycloalkyl, Cl..4 alkoxy, C3-8~ cycloalkyloxy, aryl, aryloxy, C 1 4 alkylphenyl and phenyl(C 14 )alkoxy are optionally substituted by one or more N0 2 halogen, CI-4 alkyl, CI-4 alkoxy (which latter alkyl and alkoxy are optionally substituted by one or more halogen)), R 3 la and R3lb are each independently CIA4 alkyl, C 3 8 cycloalkyl, aryl or C1-4 alkylphenyl, each of which is optionally substituted by one or more N0 2 halogen, C 1 4 alkyl or C 1 4 alkoxy, each of which latter alkyl and alkoxy is optionally substituted by one more halogen E is H, C0NR 32 R 33 CSNR 32 R 3 3 C0R 34 C02R 3 4 COCH(R 3 4 a)NH 2 R 35 CH 2 CO 2 R 3 5a, CHR 3 5bCO 2 R 3 5a, CH 2 OCO 2 R 3 5c, CHR 3 5dOCO 2 R 3 COCR 36 =CR 37 NH 2 COCHR 36 CHR 37 NH 2 Or PO(0R 38 )2, R 32 and R 33 are each independently H, C 3 10 alkylalkenyl, C 3 7 cycloalkyl (optionally substituted by C 1 4 alkyl), phenyl (optionally substituted by C 1 10 alkyl (optionally substituted by C 4 7 cycloallcyl (optionally substituted by Cl- 4 alkcyl) or phenyl optionally substituted by or R 32 and R 33 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising further hetero atoms selected from N, 0 and S, which heterocycle is optionally substituted by C 1 4 alkyl, optionally substituted by one or more halogen, WO 01/98267 PCT/IB01/01035 92 R 3 4 is H, C 4 .7 cycloalkyl (optionally substituted by one or more C1-4 alkyl), phenyl (optionally substituted by C1- 4 alkanoyloxy, NR 3 2 R 3 3 CONR 3 2 R 3 3 and/or OH), or C 1 -6 alkyl (optionally substituted by one or more halogen, C 4 7 cycloalkyl (optionally substituted by one or more C1-4 alkyl), or phenyl (optionally substituted by C1-4 alkanoyloxy, NR 3 2 R 3 3 CONR 3 2 R 3 3 and/or OH)), R 3 4 a is H, C 1 -6 alkyl (optionally substituted by one or more halogen, C 4 7 cycloalkyl (optionally substituted by one or more C1- 4 alkyl), or phenyl (optionally substituted by (X)n, C1- 4 alkanoyloxy, NR 3 2 R 3 3 CONR 3 2 R 3 3 and/or C 4 7 cycloalkyl (optionally substituted by one or more C1-4 alkyl), phenyl (optionally substituted by C 1 -4 alkanoyloxy, NR 3 2 R 3 3 CONR 3 2 R 3 3 and/or OH) or a naturally occuring amino acid substituent, R 3 5 is C 4 7 cycloalkyl optionally substituted by one or more C 1 4 alkyl, phenyl (optionally substituted by one or more C 1 -4 alkanoyl, NHR 3 2 CON(R 3 2 2 and/or OH), C 1 -6 alkyl (optionally substituted by C4- 7 cycloalkyl optionally substituted by one or more C1-4 alkyl, or phenyl (optionally substituted by one or more C1-4 alkanoyl, NHR 3 2 CON(R 3 2 2 and/or C1-4 alkoxy(C1-4 alkyl), phenyl(C1-4)alkyloxy(C14)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, and d are each independently C4-7 cycloalkyl optionally substituted by one or more C1- 4 alkyl, phenyl optionally substituted by one or more (X)n or C 1 -6 alkyl (optionally substituted by C4-7 cycloalkyl optionally substituted by one or more C1- 4 alkyl, or phenyl optionally substituted by one or more R 3 6 and R 3 7 each independently represent H, C3-6 alkylalkenyl, C4-7 cycloalkyl, phenyl optionally substituted by one or more or C1-6 alkyl (optionally substituted by C4-7 cycloalkyl optionally substituted by one or more C 1-4 alkyl, or phenyl optionally substituted by one or more R 3 8 is C 4 7 cycloalkyl optionally substituted by one or more C1- 4 alkyl, phenyl optionally substituted by one or more or C 1 6 alkyl (optionally substituted by C4- 7 cycloalkyl optionally substituted by one or more C1- 4 alkyl, or phenyl optionally substituted by one or more WO 01/98267 PCT/IB01/01035 93 R 2 when taken alone is H or halogen; or R 1 and R 2 when attached to adjacent carbon atoms, can be taken together with the carbon atoms 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,. which may comprise up to 3 rings (and is preferably an optionally benzo-fused 5- to 7- membered heterocyclic ring) and which group is optionally substituted by one or more substituents independently selected from OH, halogen, C1-4 alkyl, C 1 -4 haloalkyl, C 1 -4 alkoxy and C1-4 haloalkoxy, which C1-4 alkyl, CI- 4 haloalkyl, C 1 -4 alkoxy and C1-4 haloalkoxy groups can be optionally substituted by one or more C3-6 cycloalkyl, aryl(C 16)alkyl, which aryl group is optionally substituted by one or more halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C 1 4 haloalkoxy, which latter C1- 4 alkyl, CI- 4 haloalkyl, C1- 4 alkoxy and C1-4 haloalkoxy groups can be optionally substituted by one or more NR 23 R 24 NR 23 S(O)nR 24 NR 23 C(O)mR 24 and ifa S atom is present in a ring, it can be present as part of a or -S(0 2 group, which R 2 3 and R2 4 when taken alone independently represent H, C 1 4 alkyl, or CI-4 haloalkyl, or R 23 and R 24 can be taken together with the N atom to which they are attached, to form a 4- to 6-membered heterocyclic ring optionally comprising one or more further heteroatoms selected from, N, O, or S, and which heterocyclic ring is optionally substituted by one or more halogen, C 1-4 alkyl, C 1 4 haloalkyl, C 1 -4 alkoxy and/or CI-4 haloalkoxy groups, R 3 is H, CN, halogen, C 1 -6 alkoxy, C 1 -6 alkoxycarbonyl, C 2 -6 alkanoyl, C 2 6 alkanoyloxy, C3-8 cycloalkyl, C3- 8 cycloalkyloxy, C4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR 12 R 13 CONR 12 R 13 NY 2 WY 1 C 1 -6 alkyl, C 2 10 alkenyl, C2- 10 alkynyl, (each of which alkyl, alkenyl and alkynyl groups is optionally substituted by one or more CN, halogen, OH, C 1 -6 alkoxy, C 1 6 alkoxycarbonyl, C 2 6 alkyloxycarbonyloxy, C 1 -6 alkanoyl, C 1 -6 alkanoyloxy, C 3 8 cycloaikyi, C 3 -8 cycloalkyloxy, C 4 9 cycloalkanoyl, aryi, aryloxy, heteroaryl, saturated heterocycle, NR 12 R 13 CONR1 2 R 1 3 and/or NY 2 WYl), R 4is CI- 10 alkyl, C 3 10 alkenyl or C 3 10 alkynyl, each of which groups is linked to the N atom via a sp 3 carbon, and which group is substituted by one or more substituents selected from: CI- 6 alkoxy [substituted by one or more groups selected from OH, NR 25 R 6 C0NR1 5 R 26 halogen, C 1 6 alkoxy, C 24 alkynyl, C 24 alkenyl, heteroaryll, aryll, COCH 2 CN, CO(heteroaryl'), CO(aryll), C0 2 (heteroaryll), COCH 2 (aryll), COCH 2 (heteroaryll), CO 2 CH 2 (aryl'), CO 2 CH 2 (heteroaryl'), S(O).(C 1 -6 alkyl), S(O),,(heteroaryl S0 2 NR 25 R 26 a cycloalkyl group that is a C 3 1 0 carbocyclic system with one or two rings and cycloalkyl'], S(O),C 1 6 alkyl [optionally substituted by one or more groups selected from OH, NR 'R 26 C0NR 25 R 26 halogen, C 1 6 alkoxy, C 2 4 alkynyl, C 2 4 alkenyl, heteroaryl 1, aryl'1, COCH 2 CN, CO(heteroaryll), CO(aryl'), C0 2 (heteroaryll), COCH 2 (aryl I), COCH 2 (heteroaryll), CO 2 CH 2 (aryll), CO 2 CH 2 (heteroaryll), 6 alkyl), S(O)J(aryll), S(O)n(heteroaryll), S0 2 NR2R 26and cycloalkyl'], aryl1 2 CO 2 CH 2 (heteroaryl 1), CO 2 CH 2 (aryl I), cycloalkyll, a cycloalkyl group that is a C 3 -1 0 carbocyclic system with one or two rings, CO(heteroaryl 1), CO(aryl 1), OCO(aryl 1), OCO(heteroaryl 1), OCO(C,. 6 alkyl), ~:OCOCH 2 CN, 25 C0 2 (heteroaryl 1), C0 2 (aryl 1), A.OC 2 (hctcroary 1 1,, S(O),,CH 2 aryl 1, 30 S(O),,(heteroaryll), S(O),,CH 2 (heteroaryl'), NHSO 2 aryll, [I \DAYLIB\LIBA]0601I.doc NSS NHSO2(heteroaryll), NHSO2CH2(heteroaryl 1), NHSO2CH 2 (arYll), NHCOaryll, NHCONHaryll, NHCOheteroaryll 1 NHCON~lheteroaryl 1, NHCO2(arYll), NHCO2(heteroaryl 1), aryl 2 oxy, heteroarylloxy, Cl-6 alkoxycarbonyl substituted by C 1 -6 alkyl, aryl, Cl..6 alkoxy, CH12(aryll), CI-4 haloallcyl, halogen, OK, CN or N2R6 C 2 -6 alkanoyl substituted by C 1 alkl, aryl, C 1 -6 ailkoxy, CH 2 (aryl CiA- haloalkyl, halogen, OH, (ZN or NR 25 R 2 6 C2- alcanoyloxy substituted by CI-6 alkyL, aryl, CI- alkoxy, CH2(aryli), C1-4 haloalicyl, halogen, OH, CN or N2R6 cycloallcyll oxy, COcycloalkyll, heterocycle substituted by one or more substituent selected from CI- alkcyl(substituted by OH), CONR 2 5R 26 CH 2 00NR 2 5 R 2 6 NR 2 5 R 26 NHCONR 2 5R 26 CO(Cj-6 alkyl), 25 S02NR 25 R 2 6 S0 2 (CI- 6 alkyl), C02(CI-6 alkyl), CH2CO2(Ci.. 6 alkyl), 0CH 2 00 2 (0 1 6 *alkyl). aryL, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3- 7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from CI- allcyl(substituted by CONR 2 5R26, CH2CONRZ 2 5 Rh 6 NR 2 5R 2 6 NHCONR 2 5R 26 CO(CI_6 alkyl), S0 2 NR 25 R 2 6, SO 2 (C 1 _6 alkl), CO2(C1_6 alkyl), CH2C02(Cl..6 alkyl), OCH 2 CO 2 (C 1 -6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CI12)oxy, aryl(CH2), CN and C3- 7 cycloalkyL, WHEREIN aryl 11 is wf ph lOptionally ii4'e to a C5-.7 carbocyclic ring, which go pi optionally substituted by one or more substituent selected from CI-6 alkl(optionally 35 substituted by OH, CN or halogen), C1-6 halonilcoxy, OH, 0, NY 2 WYI, halogen, C 1 6 alkoxy, C0NR 25 R 2 6 C112C0NR 25 R 26 NR 2 5 R 26 NHCONR 25 R 26 OQ(O alkyl), Coaryl, COheteroaryl, S02NR 2 5 R 2 6 S(O)n(O 1.6 alkyl), S(O).(arYl), S(0)a(heteroaryl), C0 2 (0 1 6 alkyl), C02(aryl), C0 2 (heteroarYl), 00211 (01 2 )l00 2 (Cl. 6 alkyl), (OH 2 1 400211, (CH2)l-4OO2(arYl), (CH2)l..4CQ2(heteioaxYl), O(CH2)14Z02(Cl..6 alkyl), O(CH2)1-CO2K1 O(CH2)14C02(zYl), O(CH2)1..4002(heteroaryl), aryL, heterocyclyl, aryloxY, aIYI(CH2)oxy, arYl(0112), CN, O(CH2)l-tONR 25 R 26 and C3-7 cycloalkyl, aryi 2 is phenyl optionally fused to a C5-.7 carbocyclic ring, which group is substituted by one or more substituent selected from C1-.6 alkyl(substituted by OH), C0NR 2 5 R 2 6 C11 2 C0NR 25 R 2 6 NR 2 5 R 2 6 NHCONR 25 R 26 00(0146 alkyl), Coaryl, CoheteroaryL, S0 2 NR 25 R 2 6 S(O)n(0146 alkyl), S(0)n(aryl), S(0)n(heteroaryl), 002(C1._6 ailkyl), C02(arYl), C02(heteroarYl), 00211, (CH2)4OO 2 (CI-6 ailcyl), (CH2)14CiO21L (CH2)i.. 4CO(arY1), (OH 2 1 00O2(heteroarYl), O(C12)14CO2(Cl -6 alkYl), 0(0112)1 4~C02H O(CH2)100C2(arYI), 0(0112) l..t02(heter~arYl), aryl, heterocyclyl. aryloxy, 1s aryl(0112)oxy, aryl(CH2), ON, O(CH2) 1 4CONR 2 5 R 2 6 and 03-7 cycloalkyl, heteroaryl 1 is heteroaryl optionally fused to a 05-7 carbocyclic ring, which group is *optionally substituted by one or more substituent selected from 0 1 allcyl(optionally substituted by OH, ON or halogen), Cl- haloalkoxy, OH, 0O, NY 2 WY 1 halogen, 0146 *20 alkoxy, 00NR 2 5 R 26 011 2 00NR 2 5 R 2 NR 25 R 2 6 N1100NR 25 R 26 00(01.6 ailkyl), Coaryl, Coheteroaryl, S0 2 NR 2 5 R 2 6 S(O)n(Cl16 alkyl), S(O)n(aryl), S(O)n(heteroary1), 002(01..6 alkyl), C02(aryl), C02(heteroarl). 00211 (0112)14002(0146 alkyl). (0112)1. 400211 (0112)lOO2(aryl), (CH2)1~02htray) -4O2) 1 0 2 (0-6 alkyl) 0(0H2)l.4002K1 O(0112)1..4002(arYl), O(OH2)1.4002(heteroarYl), arYl, heterocyclyl, aryloxy, aryl(cH2)oxy, aryl(cH2), ON, 0(OH2)1_OONR 2 5 R 2 6 and C3-.7 cycloalkyl, cycloalkyll is a C3-10 carbocycic system with one or two rings and which is substituted by 01.6 alkYL, aryL l, 16 alkoxy, O112)(aryll), 01-4 haloalkyl.halogenOH ON orNR 2 5 R 2 6 WITH THE PROVISO THAT THERE ARE NO N-R4 GROUPS WHEREIN THERE IS A IIETERO-ATOM LIKE TO ANOTHE3R BETEROATOM VIA ONE SP3 CAPBON 97 R 12 and R 13 each independently represent H or CI-4 alkyl, or R 12 and R 13 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising a fuirther hetero moiety selected from NR 16 0 and/or S, and which is optionally substituted by one or more CI-4 alkyl, R 5 and R 8 when taken separately are each independently H, Cl 1 6 alkyl, R 5 and R 8 can be taken together with the carbon atoms to which they are joined to form a C3-.8 cycloalkyl. ring, R 6 R 7 R 9 and RIO when taken separately are H, R 5 and R 6 or R7can be taken together with the carbon atoms to which they are joined to form a C3-8 cycloalkyl ring, X is halogen, CM- alkyl, CM- alkoxy, CI-4 haloalkyl Or CM- baloalkoxy, mis 1 or2; n isO0, 1or2;It q is 0 or 1; "Naturally occuring amino acid substituent" means the a-substituent that occurs in any one of the following natural amino acids, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine or proline; "Heteroaryl" represents ai aromatic ring containing up to four heteroatoms independently selected from N, 0 and S, and if a S atom is present in the ring, it can be present as part ofa or -S(0) 2 group, and which may be joined to the remainder of the compound via any available atom(s); "Heterocycle" is a group containing 1, 2 or 3 rings, and which contains up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms; 15 "Aryl", including in the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate a further carbocyclic ring fused to said phenyl ring and which may be joined to the remainder of the compound via any available atom(s) (examples of such groups include naphthyl, indanyl, etc.); "Alkyl", "alkenyl" and "alkynyl" groups can be linear or branched if the number of carbon atoms allows; *"Cycloalkyl" groups can be polycyclic if the number of carbon atoms allows; *2 25 or a pharmaceutically acceptable salt or prodrug thereof; 99 provided that the one or more substituents on the group R 4 include at least one group that is not one of the following: C 1 6 alkoxy (substituted by a single substituent that is an unsubstituted aryl' group); (ii) aryl 2 oxy, aryl 2 heterocycloxy, heterocycle (which latter four groups are substituted by one or more substituents which are NHCONR25R 26 groups, wherein R 25 and R 2 6 are independently H or C 1 3 alkyl, or R 25 and R 26 together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring); (iii) CO(heteroaryl'), COCH 2 (heteroaryl'), S(O)n(heteroaryl'), S(O)nCH 2 (heteroaryl') (in which latter four groups heteroaryl' represents a 4- to 7-membered heterocycle to comprising a N-atom (via which atom the heteroaryl' group is attached) and optionally comprising a further hetero moiety selected from NH, N(CI.6 alkyl), N(C 3 7 cycloalkyl), O or S, which heterocycle is optionally substituted by one or more C-4 alkyl groups); (iv) heteroarylloxy, wherein heteroaryl' is unsubstituted or substituted by one or more substituents which are CI. 6 alkyl (optionally substituted by one or more substituents which are CN and/or halogen), C-4 alkoxy, CI-4 haloalkoxy, OH, NY2WY' and/or NHCONR 2 5 R 26 (wherein R 25 and R 26 are independently H or CI-3 alkyl, or R 25 and R 26 together with the N-atom to which they are attached, represent a 4- to 7-membered heterocyclic ring)); NHS(O) 2 (aryl'), NHCO(aryl'), NHCO 2 (aryl') (in which latter three groups aryl' is unsubstituted or is substituted by one or more substituents which are C-4 alkyl, Ci-4 Shaloalkyl and/or halogen); (vi) NHS(O) 2 CH 2 (aryl') (in which aryl' is unsubstituted); (vii) NHCO(heteroaryl'), NHCO 2 (heteroaryl'), NHS(0) 2 (heteroaryl'), NHS(0) 2 CH 2 (heteroaryl') (in which latter four groups heteroaryl' is unsubstituted or is 25 substituted by one or more substituents which are Ci-6 alkyl, CI- 6 haloalkyl, CI-6 alkoxy, *C 3 6 cycloalkyl, CI- 6 haloalkoxy, OH, halogen, S(aryl), S(CI. 6 alkyl), CO 2 5 alkyl), CONR R 26 and/or NR25R (in which latter two groups, the groups R 25 and R 26 are either each independently H, CI- 3 alkyl, aryl, C-4 alkylphenyl (each of which C-. 3 alkyl, aryl and C-4 alkylphenyl are optionally substituted by one or more substituents which are NO 2 halogen, C14 alkyl and/or Cl-4 alkoxy), or R25 and R 26 are taken together with the N atom to which they are attached and can form a 4- to 6-membered heterocyclic ring, which ring is optionally substituted by one or more C-4 alkyl, OH, NO 2 NH 2 and/or halogen)). [R:\LIBZ106196spcci.doc:NJC 100 2. A substance according to claim I wherein the "Ar" ring represents phenyl or pyridyl. 3. A substance according to claim 1 or claim 2 wherein R' when taken alone is OH, CN, halogen, NO 2 N- 2 NY 2 WY' or Het'. 4. A substance according to any one of claims 1 to 3 wherein R 2 when taken alone is H. A substance according to claim 1 or 2 wherein R' and R 2 are taken together with the carbon atoms to which they are attached and represent an optionally benzo-fused to 7-membered heteroaryl ring optionally substituted by CI-4 alkyl or CI-4 haloalkyl.

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 R 3 is H, CN, or C.-6 alkyl (optionally substituted by one or more halogen, OH, C,-6 alkoxy, C.-6 alkoxycarbonyl, C2- 6 alkanoyl, C 2 6 alkanoyloxy, C2- 6 alkyloxycarbonyloxy, NR' 2 R' 3 is CONR' 2 R' 3 and/or NY 2 WY').

9. A substance according to any preceding claim wherein R 4 is CI-10 alkyl substituted by one or more substituents selected from: CI- 6 alkoxy [substituted by one or more groups selected from OH, NR 25 R 2 6 CONR 2 5 R 26 halogen, C,. 6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl', aryl', COCH 2 CN, CO(heteroaryl'), CO(aryl'), C0 2 (heteroaryl'), COCH 2 (aryl1), COCH 2 (heteroaryl'), CO 2 CH 2 (aryl'), CO 2 CH 2 (heteroaryl'), S(O)n(C,- 6 alkyl), S(O)n(aryl'), S(O)n(heteroaryl'), S S0 2 NR 25 R 26 a cycloalkyl group that is a C 3 -lo carbocyclic system with one or two rings and cycloalkyl'], S S(O)nC.I-6 alkyl [optionally substituted by one or more groups selected from OH, NR 2 5 R 2 6 25 CONR 25 R 26 halogen, Ci- 6 alkoxy, C 24 alkynyl, C2-4 alkenyl, heteroaryl', aryl', COCH 2 CN, CO(heteroaryl'), CO(aryl'), C0 2 (heteroaryl'), COCH 2 (aryl'), COCH 2 (heteroaryll), CO 2 CH 2 (aryll), C0 2 CH 2 (heteroaryl'), S(O)n(Cl- 6 aikyl), S(O)n(aryl'), S(O),(heteroaryl'), SO 2 NR25R26 and cycloalkyl'], aryl 2 CO 2 CH 2 (heteroaryl CO 2 CH 2 (aryl'), cycloalkyl', a cycloalkyl group that is a C 3 -1 0 carbocyclic system with one or two rings, CO(heteroaryl'), CO(aryl'), OCO(aryl'), [(I:\DAYLIB\IBA)6015.doc NSS OCO~heteroaryl 1), OCO(C 1 6 alkyl), OCOCH 2 CN, C02(heteroarYl 1), CO2(aryll), COCH2(heteroaryll), S(O)nCH2aryli,' S(O)n(heteroaryll), S(O)nCH2(heteroaryll), NIISO2aryll, NHSO 2 (heteroaryll), NHSO2CH2(heteroarYl 1), NHSO 2 CH 2 (arYl 1), NHCOaryll, NHCONHaryl 1, NHCOheteroaryll, NHCONl~heteroaryll, NHCO2(heteroarYl *25 sryi 2 oxy, heteroarylloxy, C 1 alkoxycarbonyl substituted by C 1 alkyl, aryl, C 1 6 alkoxy, CH2(aryll), CiA- haloalkyl, halogen, OH, CN or NR7L5R 26 C 2 -6 alkanoyl substituted by CI-6 alkyl, aryl, C1-6 alkoxy, CH2(arYI'), CI-4 haloalkyl, halogen, OH, CN or N2R6 C2-6 alkanoyloxy substituted by CI-6 alkyl, aryl, CI-6 ailcoxy, CH2(aryll)- CI-4 baloalkyl, haiogcn, OH, C-N or NR, 25 R 2 ,74 cycloalkyiloxy, COcycloalicyll, 102 heterocycle substituted by one or more substituent selected from C 1 6 alkcyl(substituted by OHI), C0NR 2 5 R 26 CII 2 CONR 25 R 2 6 NR25R 26 NHCONR 25 R 26 CO(C 1 6 alkyl), S0 2 NR 25 R 26 S0 2 (CI- 6 alkyl), C02(C1..6 alkyl), (2H200 2 (Cl. 6 alkyl), OCH 2 002(Cl.. 6 all), aryl, heterocyclyl, axyloxy, ary](CH 2 )oxy, ary](C11 2 CN and C 3 7 cycloalkyl, heterocyclyloxy substituted by one or more substituent selected from C1..6 alkyl(substituted by OM, C0NR 25 R 26 CH200NR 2 5 R 26 NR 25 R 2 6 NHCONR 2 5 R 26 CO(Cl 1 6 alkYl), S0 2 NR 25 R 2 6 S0 2 (Cl 1 6 ailcl), C0 2 (CI- 6 alkyl). CH2CO 2 (Cl..6 ailcyl), 0CH 2 C0 2 (CI- 6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH 2 CN and C 3 7 cycloalkyl, A substance according to any preceding claim wherein R 5 R 6 R 7 R 8 R 9 and RIO are each taken separately and are all H.

11. A substance according to any preceding claim wherein the "Ar" ring represents a group of formula: R

12. A substance according to any preceding claim wherein R 3 is H, Gi 3 C 2 H 5 i-C 3 H 7 n- 03H 7 Or CH 2 0CH 3

13. A substance according to any preceding claim except claim 5 wherein RI is OH, CN, I, Cl, NH 2 NO 2 optionally benzo-fused heteroaryl, rHS0 2 YI, NHCOYI or NHCO 2 YI.

14.- A substance according to any preceding claim wherein R 4 is CI-. 10 alkyl substituted by cycloalkyll. *I1. A substance according to any Preceding claim except claims 3, 4 and 13 wherein RI and* R2are taken together wifth the carbon atoms towhich they are attached are a ~heteroaryl moiety optionally substituted by C 1 ,aklo iAhlakl 103

16. A substance according to any preceding claim wherein R 3 is CH 3 or C 2

17. A substance according to any preceding claim except claims 5 and 15 wherein RI when taken alone is OIL, MN I, CTh NH 2 N02,,2,3-riazolyl, 1,2,4-triazolyL, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzinidazol-2-yl, NHSO2(Cl_6 alkyl), NHSO 2 (Cl.. 6 ailkyl substituted by methoxy, CONH2, OK, CO 2 (C 2 _6 alkyl), phtbalimido, NH 2 or halogen), NHSO 2 NH 2 NHSO 2 NH(C 1 6 alkyl), NHISO 2 N(C 1 -6 alkyl)2, NHSO2Hetla, NHCO(C1..6 ailkyl) or NIICO 2 (Cl..6 alkyl).

18. A substance according to claim 17 wherein RI is OH 1 NHSO 2 CH 3 NHSO 2 C 2 ]E 5 NHISO2(n-C 3 H7), NHSO 2 (i-C 3 H 7 NHSO2(n-04H 7 NHSO 2 bIH(i-C 3 H 7 NHSO 2 (N- niethylimidazol-4-yl), NHSO 2 (CH 2 2 00H 3 NHSO 2 (CH 2 2 0H.L 1,2,4-triazolyl or imidazol- 2-yl.

19. A substance according to claim 18 wherein R1 is OH,, NHSO 2 CH 3 NHSO 2 C 2 H 5 Or imidazol-2-yl. A substance according to claim 15 wherein RI and R 2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally 2-substituted by CF 3

21. A substance according to any preceding claim wherein R 4 is C2-4 alkyl substituted by cycloalkyll. 25 22. A substance according to any preceding claim wherein R 4 is propyl substituted by cycloalkl.

23. A substance according to any preceding claim- wherein PA is propyl. substituted by a 03. carbocyclic system with one or two rings and which is substituted by OH.

24. A substance according to any preceding claim wherein R 4 is propyl substituted by (cyclohexyl substituted by OH). A substance according to any pre Iceding claim wherein R 4 is (l-hydroxycyclohexyl)prop- 3-yl. 104

26. A substance according to claim 1 which has the following relative stereochernistry:

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

28. A pharmaceutical or veterinary composition comprising a substance acc-ording to any one of the preceding claims, and a pharmacutically or veterinarily acceptable carrier.

29. A substance according to any of claims 1 to 26 for use in medicine. A substance according to any of claims I to 26 for use as a medicament useful for the treatment of an opiate-mediated disease or condition. 3 1. The use of a substance according to any one of claims I to 27 in the manufacture of a medicament for the treatment of a disease or condition mediated by opiate receptors.

32. A method of treatment of a condition mediated by an opiate receptor or receptors comprising administration of a therapeutically active amount of a substance according to any one of claimslIto26. or of a composition as claimed in claim 28.

33. A process for the preparation of a substance according to claim 1 'which comprises: 25 for compounds of formula I in which q is 0 and RI represents NY 2 W, YI, reacting a compound of formula 114 105 with a compound of formula III, Z 1 -WYI Mf wherein ZI is a suitable leaving group, such as halogen or YlSO 2 O-; fo opud ffruaIi hc i n 6adR ohrpeetI reduction of a compound of formula IV, ~6 OS 6* 6 IV using a suitable reducing agent; for compounds of formula I in wha~ch q is 0 and R 9 and R 10 both represent H, reduction of a compoun-d of formula V, 66 66 6 6 6 6 6*66

666. 6* 66 6 6 6666 66 66 6 6 6 6 106 V using a suitable reducing agent; for compounds of formula I in which q is 0 and RI and R 2 are attached to adjacent carbon atoms and are taken together with the carbon atoms to which they are attached to represent Hetla, in which Hetla represents an inidazolo unit, reaction of a correponding compound of formula VI, H2 9 4. 9 9. 9 9 9 .4 9 9* 9 9 with a compound of formula VII, RYC0 2 H wherein RY represents H or any of the optional preferably H,CL4ailcy!or C- 4 haloak-.y14 VII substituents on Hetla (as defined above), (e) 9 9 9 9 9. 99 0 9 9999 *9*9 0* 99 9 9 9 9 where q is 0, reacting a compound of formula VIII viaf with a compound of formula KX R 4 -Lg wherein Lg is a leaving group; for compounds of formula I in which q is 0 and R 6 R 7 R 9 and RIO are all HIL reduction of a compound of formula X, Ar R 1 S C with a n-tabie reducing agent; C. CC for compounds of formula I in which q is 0 and RI represents OH, reacting a compound of formula I1, where Y2 is H, as defined above, with fluoroboric acid and isoamyl nitrite; for compounds of formula I in which q is 0 and kl repre-sents CL, reacting a compound of formula IL, where Y2 is K, as defined above, with sodium nitrite in the presence 108 of dilute acid, followed by reaction with copper chloride in the presence of concentrated acid; for compounds of formula I in which q is 1, reacting a compound of formula I where q is 0 with a suitable oxidising agent such as aqueous hydrogen peroxide; or for compounds of formula I where q is 0, by reduction of a corresponding compound of formula XXXI, R 2 R 1 O (X)n Ar R R3 R 8 A\ R" R R 1 o N R O R 4 XXXI where R 4 aCH 2 takes the same meaning as R4 as defined above, for compounds of formula where q is 0, reductive amination reaction of the amine of formula VIII above with an aldehyde of formula R"-CHO wherein R 4 aCH 2 takes the same meaning as R4 as defined above, and where desired or necessary converting the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa. r a .a a a 34. A compound of formula 11, (X)n. II wherein R 2 to R1 0 y 2 Xand nare as defined in Claim 1, a compound of formula IV, IV wherein R' to R 5 R 8 to R1 0 X and n are as defined in Claim 1, a compound of formula V, (X)n [I \DAYLIB\LIBA10601S doc NSS 110 wherein R' to R 8 X and n are as defined in Claim 1, a compound of formula VI, NH 2 (X)n Ar N H 2 R 3 R 4 R VI wherein R 3 to R' 1 X and n are as defined in Claim 1, a compound of formula X, R 2 (X)n Ar R R 3 R' R' R 4 x X wherein R' to R R 8 X and n are as defined in Claim 1, a compound of formula XI, R 2 r XI wherein R 2 to R 5 R 8 to RI 1 X and n are as defined in Claim 1, SI:\DAYLI B\LIBA06015 doc:NSS a compound of formula XII, X11 2 8 wherein R to R X and n are as defined in Claim I, a compound of formula XXI, 0 *,0000 0 0000 0 00 @0 0 0 .0 0 0. 00 0* *0 0 0 0 *0 00 0 b 000 0 0e~0 0 0 Jo.. 00. 0000 0 0 0 0 0000 00 0 *09 0 00 00 0 ~0 XXI wherein L0 represents a group that undergoes functional group transformations using standard functional group substitution or conversion techniques and R 2to R 5, R' to R O, X and n are as defined in Claim I, a compound of formula XXII, (X)n- XXII rR:\LIBzj06I96speci.doc:NJC 112 wherein L 3 is as defined above and R 2 to R 8 X and n are as defined in Claim 1, a compound of formula XXIII, R 2 4 R XXIII wherein R 2 R 4 R 5 R 8 to R 1 0 X and n are as defined in Claim 1, a compound of formula XXIV, XXIV wherein R 2 to R 8 X and n are as defined in Claim 1, a compound of formula XXIXa, r r 10 wherein R' to R 5 R 8 X and n are as defined in Claim 1, a compound of formula XXX, [I.\DAYLIB\LIBA]06015.doc NSS 113 (X)n Ar NO 2 R3 R'8 R R FR Rio N R 14 R XXX wherein R 2 to R I o, X and n are as defined in Claim 1, or a compound of formula XXXI, R 2 Ar R9 LR 6 O0 R4a XXXI 5 wherein R 4 aCH 2 takes the same meaning as R 4 as defined in Claim 1, and R' to R 3 R 5 to R X and n are as defined in Claim 1, or salt thereof. :35. A substance which is a compound of Formula I as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples. 36. A process for the preparation of a substance according to any one of claims 1 o0 to 27 which process is as defined in steps a) to k) of claim 33, substantially as hereinbefore described with reference to processes A to K at pages 41 to 46. 37. A substance according to any one of claims 1 to 27 when prepared according to the process of claim 33 or claim 36. Dated 30 September, 2003 S 15i Pfizer Inc. Patent Attorneys for the Applicant/Nominated Person S: SPRUSON FERGUSON [I \DAYLIB\LIBA]06015 doc NSS