CZ20023967A3 - 3-Azabicyclo[3,1,0]hexane derivatives exhibiting affinity for opiate receptors - Google Patents

Abstract

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

Description

Technical field

The present invention relates to pharmaceutically useful compounds, particularly compounds that bind to opiate receptors (e.g., mu, kappa, and delta opiate receptors). Compounds that bind to such receptors are likely to be effective in treating diseases modulated by opiate receptors, such as irritable bowel syndrome, constipation, nausea, vomiting, and itchy dermatoses, such as allergic dermatitis and atopy, in humans and animals. Compounds that bind to opiate receptors are also indicated in the treatment of eating disorders, opioid overdose, depression, alcohol and smoking addiction, sexual dysfunction, shock, stroke, spinal cord injury and head trauma.

BACKGROUND OF THE INVENTION

There is a significant need to improve the treatment of itching. Itching or pruritus is a common dermatological symptom that significantly stresses both humans and animals. Pruritus is often associated with inflammatory skin diseases that may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea, and to environmental allergens such as pollen or mites; bacterial and fungal infections of the skin; or ectoparasitic infections.

Existing treatments used to treat prurit include the use of corticosteroids and antihistamines. However, it is known that both types of treatment have undesirable side effects. Other therapies used include the administration of dietary supplements containing essential fatty acids, which have the disadvantage of having a slow onset of action and only limited efficacy against allergic dermatitis. Many plasticizers, such as soft paraffin, glycerin, and lanolin, are also used, but these have only a limited effect.

Therefore, there remains a need for alternative and / or better treatment of pruritus,

Some 4-arylpyperidine-based compounds are described in European Patent Applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. Further, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I,

wherein the ring "Ar" represents an optionally benzofused phenyl or a 5- or 6-membered heteroaryl ring;

R ¹ , when alone, is H, halogen, NO ₂ , NH ₂ , NY ² WY ¹ ,

Het ^1, AD, CO ₂ R ^7, C (O) R ^8, C (= NOH) ^R8, or OE,

Y ² is H, Ci_6 alkyl, _C3 _6 alkenyl (each of which alkyl and alkenyl may optionally be substituted by aryl, aryloxy or Het ^1),

W is SO ₂ CO, C (O) O, P (Y ² ) = OP (Y ¹ ) = S,

Y ¹ is C 1-10 alkyl (optionally substituted with one or more substituents independently selected from halogen, OH,

CI-4 alkoxy, 0χ- ₆ alkanoyloxy, CONH _2, C ₆ alkoxycarbonyl, _NH2, aryl, mono- or di (Ci_4alkyl) amino, C ₃ _ ₈ cycloalkyl, phthalimidyl, ^{Het1), Het1,} aryl (optionally substituted by one or more substituents independently selected from Ci-4 alkyl, C1-4 haloalkyl and halogen), NH _2, N (0χ_ ₆ alkyl) _2, NH (C 1-6 alkyl),

Het ¹ is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may consist of up to 3 rings (preferably heteroaryl groups, optionally, benzo- or pyrido-fused heteroaryl), optionally substituted with one or more substituents independently selected from

C 1-6 alkyl, C ₆ alkoxy, _C3 _6 cycloalkyl, C ₆ haloalkoxy, C1-6 haloalkyl, _C3 _6 halogencykloakylu, = 0, OH, halogen, N0 _2, SiR ^19a R ^19b R ^19c, R ^20a CON ^20b NR ^20a R ^20b , SR ^21a , NR ^21b SO 2 R ^22a , NR ^21c C (O) OR ^22b , NR ^21d COR ^22d and C 1-6 alkoxycarbonyl and if the ring contains an S atom, this atom is present as part of -S-, S (O - or - S (O ₂ ) - groups and carbon atoms in the ring may be present as part of a carbonyl group;

each independently represents C 1-8 alkyl or aryl;

R ^20a and R ^20b each independently represent H, C 1-8 alkyl, aryl, (C 1-4 alkyl) phenyl, wherein each of the alkyl, aryl and alkylphenyl groups is optionally substituted with one or more groups selected from the group consisting of C _1-4 alkyl ,

C 1-4 alkoxy, OH, NO ₂ , NH ₂ , and / or halogen, or

R ^20a _{and R} 20b _S p _O] _ _e CNE with the N atom to which they are attached form a 4- to β-membered ring optionally substituted with one or more substituents independently selected from the group consisting of C ₄ alkyl, C ₄ alkoxy, , OH, = O, NO ₂

NH ₂ and / or halogen,

R ^21a , R ^21b , R ^21c and R ^21d each independently represent H,

C 1-6 alkyl, aryl or C _1-4 alkylphenyl, wherein each of alkyl, aryl and alkylphenyl is optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, C _1-4 alkoxy, OH, NO ₂ , halogen, NH ₂ ,

R ^22a, R ^22b and R ^22c each independently represents 0χ_ ₆ alkyl, aryl or Cl 4 alkylphenyl, each of which is optionally substituted with one or more substituents selected from the group consisting of CI-4 alkyl, C1-4 alkoxy, OH, N0 ₂ , halogen, NH ₂ ,

A is C 1-4 alkylene, C ₂ _ ₄ akenylen, _C2 -4 akynylen, each of which is optionally substituted with one or more substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen and / or OH, ,

D is H, OH, CN, NR ²⁵ R ^2S, CONR ²⁵ R ^26, NHR ^27, CO ₂ R ^28,

COR ²⁹ , C (-NOH) R ²⁹ or Λ

AD is CN, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁶ each independently represent H, C 1-3 alkyl,

_C3 -8 cycloalkyl, aryl, C ₄ alkylphenyl, (wherein each of C 1-3 alkyl, C 3-8 cycloalkyl, aryl, C ₄ alkylphenyl optionally substituted by one or more groups selected from the group consisting of NO _2, halogen, C ₄ alkyl and / or C1-4 alkoxy (each of the last groups C ₄ alkyl, and

C 1-4 alkoxy is optionally substituted with one or more halogen atoms), or

R ²⁵ and R ²⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from the group consisting of N, O and S, which is optionally substituted with one or more a plurality of substituents from the group consisting of C 1-4 alkyl, OH, = O, NO ₂ , NH ₂ and / or halogen,

R ²⁷ is COR ³⁰ , CO2R ^31a , SO2R ^31b ,

R ²⁸ and R ²⁹ each independently represent H, C _1-6 alkyl,

_C3 -8 cycloalkyl, aryl and C ₄ alkylphenyl, wherein each of the groups C 1-6 alkyl, C _3-8 cycloalkyl, aryl, C 1-4 alkylphenyl optionally substituted by one or more groups selected from the group consisting of N0 _2, halogen , C 1-4 alkyl,

C 1-4 alkoxy, (each of the last C 1-4 alkyl and C 1-4 alkoxy groups being optionally substituted with one or more halogen atoms),

R ³⁰ is H, C 1-4 alkyl, C ₃ _ ₈ cycloalkyl, C 1-4 alkoxy,

C ₃ _ ₈ cycloalkoxy, aryl, aryloxy, C ₄ alkylphenyl, phenyl (Ci-4) alkoxy, (wherein each of C ₄ alkyl,

C 3-8 cycloalkyl, C ₄ alkoxy, C ₃ _G cycloalkoxy, aryl, aryloxy,

C 4 alkylphenyl and phenyl (C _C4) alkoxy, optionally substituted with one or more substituents selected from the group consisting of N0 _2, halogen, C _x _ ₄ alkyl or C _x _ ₄ alkoxy (which latter alkyl and alkoxy are optionally substituted with one or more halogen atoms)).

R ^31a and R ^31b each independently represents C _x _ ₄ alkyl,

_C3 _8 cycloalkyl, aryl or C _x - ₄ alkylphenyl, each of which is optionally substituted by one or more substituents selected from the group consisting of N0 _2, halogen, C _x _ ₄ alkyl or C _x _ ₄ alkoxy, where each of the last groups alkyl and alkoxy is optionally substituted with one or more halogen atoms.

E is H, CONR ³² R ^33, CSNR ³² R ^33, COR ^34, CO 2 R ^34, COCH (R ^34a) NH 2, R ^35, CH2CO2R ^35a, CHR ^35b CO 2 R ^35a, CH2OCO2R ^35c, CHR ^35d OCO2R ^35c CoCr ³⁶ = CR ³⁷ NH2, COCHR ³⁶ CHR ³⁷ NH2 or PO (OR ³⁸ ) ₂

R ³² and R ³³ each independently represents H, C ₃ _ _X the alkyl alkenyl, C 3-7 cycloalkyl (optionally substituted by C _x _ ₄ alkyl), phenyl (optionally substituted by (X) _n), C _{x. x} o alkyl (optionally substituted C ₄ _7 cycloalkyl (optionally substituted by C _x _ ₄ alkyl), or phenyl optionally substituted with (X) _n), or

R ³² and R ³³ may together with the N atom to which they are attached form a 5- to 8-membered heterocycle optionally containing further heteroatoms selected from N, 0 and S, which is optionally substituted by _C _ ₄ alkyl which is optionally substituted with one or more halogen atoms,

R ³⁴ is H, _C4 -7 cycloalkyl (optionally substituted by one or more C _x _ ₄ alkyl), phenyl (optionally substituted by (X) NR a C 1-4 alkanoyloxy, NR ³² R ^33, CONR ³² R ³³ and / or OH) • · · · or

C 1-6 alkyl (optionally substituted with one or more substituents selected from the group consisting of halogen, C 4-7 cycloalkyl (optionally substituted with one or more C 1-4 alkyl groups) or phenyl (optionally substituted with one or more groups selected from the group consisting of ( X) _n , C 1-4 alkanoyloxy, NR ³² R ³³ , CONR ³² R ³³ and / or OH)),

R ^34a is H, C 1-6 alkyl (optionally substituted with one or more substituents from the group consisting of halogen atoms,

C 4-7 cycloacyl (optionally substituted with one or more C 1-4 alkyl) or phenyl (optionally substituted with (X) _n , C 1-4 alkanoyloxy, NR ³² R ³³ , CONR ³² R ³³ and / or OH)),

C 4-7 cycloalkyl (optionally substituted with one or more C 1-4 alkyl) phenyl (optionally substituted with (X) _n ,

(C 1-4 alkanoyloxy, NR ³² R ³³ , CONR ³² R ³³ and / or OH) or a naturally occurring amino acid residue,

R ³⁵ is C 4-7 cycloalkyl, optionally substituted with one or more C 1-4 alkyl, phenyl (optionally substituted with one or more (X) n, C 1-4 alkanoyl, NHR ³² , CON (R ³² ) 2 and / or OH C 1-6 alkyl (optionally substituted with C 4-7 cycloalkyl optionally substituted with one or more C 1-4 alkyl or phenyl groups (optionally substituted with one or more (X) _n groups),

C 1-4 alkanoyl, NHR ³² , CON (R ³² ) ₂ and / or OH)),

C 1-4 alkoxy (C 1-4 alkyl), phenyl (C 1-4) alkyloxy (C 1-4) alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,

R ^35a , R ^35b , R ^35c and R ^35d each independently represent H,

_C4 _7 cycloalkyl, optionally substituted with one or more substituents selected from • · the group consisting of C ₄ alkyl, phenyl optionally substituted with one or more (X) _n or C 6 alkyl (optionally substituted C ₄ _ ₇ cycloalkyl which is optionally substituted with one or more C 1-4 alkyl or phenyl groups, optionally substituted with one or more (X) _n ),

R ₃₆ and R ₃₇ each independently represent H, C 3-6 alkylalkenyl, C 4-7 cycloalkyl, phenyl, optionally substituted with one or more (X) _n or C 1-6 alkyl (optionally substituted)

C 4-7 cycloalkyl optionally substituted with one or more C 1-4 alkyl or phenyl optionally substituted with one or more (X) _n ),

R ³⁸ is C 4-7 cycloalkyl optionally substituted with one or more C 1-4 alkyl, phenyl, optionally substituted with one or more (X) _n or C 1-6 alkyl (optionally substituted with C 4-7 cycloalkyl, optionally substituted with one or more groups C 1-4 alkyl or phenyl, optionally substituted with one or more (X) _n ),

R ² when independently represents H or halogen; or

R ¹ and R ² , when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached may represent Het ^{1 a} ;

Het ^1a is a heterocyclic group containing up to 4 heteroatoms selected from the group consisting of N, O and S, which may consist of up to 3 rings (and preferably represents a benzofused 5- to 7-membered heterocyclic ring) optionally substituted with one or more substituents independently selected from OH, = O, halogen, C _1-4 alkyl, C _1-4 haloalkyl,

C 1-4 alkoxy and C _1-4 haloalkoxy, wherein C _1-4 alkyl groups,

Ci-4 haloalkyl, C ₄ alkoxy and C ₄ haloalkoxy may be substituted with one or more substituents selected from the group consisting of C ₃ _ ₆ cycloalkyl, aryl (C ₆₎ alkyl, wherein aryl may be optionally substituted by one or more halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C 1-4 haloalkoxy, wherein the last C _1-4 alkyl,

C 1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy groups may be optionally substituted with one or more NR ²³ R ²⁴ , NR ²³ S (O) n R ²⁴ , NR ²³ C (O) m R ²⁴ , and when S is present in the ring , may be part of the groups -S-, S (O) -, -S (O ₂ ) -, wherein R ²³ and R ²⁴ , when independently represent, H,

C 1-4 alkyl or C _1-4 haloalkyl, or

R ²³ and R ²⁴ together with the N atom to which they are attached may form a 4- to 6-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from N, O and S, wherein the heterocyclic ring is optionally substituted one or more halo, C _1-4 alkyl, C _1-4 haloalkyl, C 1-4 alkoxy and / or C _1-4 haloalkoxy groups,

R ³ is H, CN, halogen, C 1-6 alkoxy, C _1-6 alkoxycarbonyl,

_C2 -6 alkanoyl, C ₂ _ ₆ alkanoyloxy, C ₃ _ ₈ cycloalkyl,

_C3 _8 cycloalkoxy, _C4 _9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR ¹² R ^13, CONR ¹² R ^13, NY ² WY ^1, C-C6 alkyl, _C2-IO alkenyl, _C2-IO alkynyl (wherein each of the alkyl, alkenyl, and alkynyl groups is optionally substituted with one or more CN, halogen, OH, C 1-8 alkoxy,

Ci_6 alkoxycarbonyl, C ₂ - $ alkoxycarbonyloxy, C 6 alkanoyl,

Ci_6 alkanoyloxy, C ₃ .g cycloalkyl, C ₃ -g cycloalkyloxy, · φ

C ₄ -g cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR ¹² R ^13, CONR ¹² R ¹³ and / or NZ ² WY ^1),

R ⁴ is C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, each of which is linked to the N atom via an sp ³ carbon, wherein the group is substituted with one or more substituents selected from the group consisting of:

C ₂ -6 alkoxy [substituted by one or more radicals selected from the group consisting of OH, NR ²⁵ R ^26, CONR ²⁵ R ^26, halogen, Ci_6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl ^1, aryl ^1, COCH2CN, CO ^{(heteroaryl1),} CO (aryl ^1), CO2 ^{(heteroaryl1),} COCH2 ^(aryl1), COCH2 (heteroaryl ^1), ₂ CO2CH (aryl ¹⁾

CO ₂ CH ₂ (heteroaryl ¹ ), S (O) _n (C _1-6 alkyl), S (O) _n (aryl ¹ ),

S (O) _n (aryl ¹ ), S (O) n (heteroaryl ¹ ), SO ² NR ²⁵ R ²⁶ and cycloalkyl ¹ ],

S (O) _n C 1-6 alkyl [optionally substituted with one or more groups selected from OH, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , halogen,

Ci_6 alkoxy, C ₂ _ ₄ alkinyl, _C2 -4 alkenyl, heteroaryl \ ^aryl1, COCH2CN, CO ^{(heteroaryl1),} CO (aryl ^1), CO2 (heteroaryl ¹⁾

COCH ₂ (aryl ¹ ), COCH ₂ (heteroaryl ¹ ), CO ₂ CH ₂ (aryl ¹ ),

CO ₂ CH ₂ (heteroaryl ¹ ), S (O) _n (C _1-6 alkyl), S (O) _n (aryl ¹ ),

S (O) _n (heteroaryl ¹ ), SO ₂ NR ²⁵ R ²⁶ and cycloalkyl ¹ ], aryl ² ,

CO ₂ CH ₂ (heteroaryl ¹ )

CO ₂ CH ₂ (aryl ¹ ), cycloalkyl ¹ ,

CO (heteroaryl ¹ ),

CO (aryl ¹ )

OCO (aryl ¹ )

OCO (heteroaryl ¹ )

OCO (C _X 6 alkyl),

ococh ₂ cn,

CO ₂ (heteroaryl ¹ ),

C0 ₂ (aryl ¹⁾

COCH ₂ (heteroaryl ¹ )

S (O) _n (aryl ¹ ),

S (O) _n CH ₂ (aryl ¹ ),

S (0) _n (heteroaryl ^1).

S (O) _n CH ₂ (heteroaryl ¹ ),

NHSO2 (aryl ¹ )

NHSO ₂ (C ₁ _6 alkyl),

NHSO ₂ (heteroaryl ¹ )

NHSO ₂ CH ₂ (heteroaryl ¹ ),

NHSO ₂ CH ₂ (aryl ¹ )

NHCO (aryl · ¹ )

NHCO (C _1-6 alkyl),

NHCONH (aryl ¹ )

NHCONH (C _1-6 alkyl),

NHCO (heteroaryl ¹ )

NHCONH (heteroaryl ¹ ),

NHCO ₂ (aryl ¹ )

NHCO ₂ (C _1-6 alkyl),

NHCO ₂ (heteroaryl ¹ ), aryl ² oxy, heteroaryl ¹ oxy,

C 1-6 alkoxycarbonyl substituted with C 1-6 alkyl, aryl,

C 1-6 alkoxy, CH ₂ (aryl ¹ ), C 1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ²⁶ ,

_C2 -6 alkanoyl substituted by C1-6 alkyl, aryl, C ₆ alkoxy, _CH2 ^(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ^26,

C ₂ -6 alkanoyloxy-substituted C 3-6 alkyl, aryl,

C 1-6 alkoxy, CH ₂ (aryl ¹ ), C 1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ²⁶ ,

cycloalkyl ¹ oxy,

Cycloalkyl ¹ , heterocyclyl substituted with one or more substituents selected from the group consisting of C 1-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , ch ₂ conr ²⁵ r ²⁶ , nr ²⁵ r ²⁶ , nhconr ²⁵ r ²⁶ ,

CO (C _1-6 alkyl), SO ₂ NR ²⁵ R ²⁶ , SO ₂ (C _1-6 alkyl), CO ₂ (C 1-6 alkyl), CH ₂ CO ₂ (C 1-6 alkyl), OCH ₂ CO ₂ (C 1-6 alkyl) alkyl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C ₃ _ ₇ cycloalkyl, heterocyclyloxy substituted by one or more substituents selected from the group consisting of _{Ci_6} alkyl (substituted by OH) , con ²⁵ r ²⁶ , ch ₂ con ²⁵ r ²⁶ , nr ²⁵ r ²⁶ , nhconr ²⁵ r ²⁶ ,

CO (C _1-6 alkyl), SO ₂ NR ²⁵ R ²⁶ , SO ₂ (C _1-6 alkyl), CO ₂ (C _1-6 alkyl), CH ₂ CO ₂ (C 1-6 alkyl), OCH ₂ CO ₂ (C _1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C ₃ _ ₇ cycloalkyl, wherein aryl ¹ is phenyl, optionally fused to a CS ₇ carbocyclic ring, which group is optionally substituted with one or a plurality of substituents selected from the group consisting of C 1-6 alkyl (optionally substituted with OH, CN or halogen), C _1-6 haloalkoxy, OH, = O, NY ² WY ¹ , halogen,

Ci-g alkoxy, CONR ²⁵ R ^26, CH ₂ C0NR ²⁵ R ^26, NR ²⁵ R ^26, R ²⁵ NHC0NR ²⁶

CO (C _1-6 alkyl), COaryl, COheteroaryl, SO ₂ NR ²⁵ R ²⁶ ,

S (O) _n (C _1-6 alkyl), S (O) _n (aryl), S (O) _n (heteroaryl),

C0 ₂ (C - _C6 alkyl), C0 ₂ (aryl) C0 ₂ (heteroaryl), CO ₂ H, (ΟΗ _2)! _ ₄ 00 ₂ (C-C6 alkyl), _(CH2)! - ₄ CO ₂ H, (CH ₂ ) _1-4 CO ₂ (aryl), (CH ₂ ) _1-4 CO ₂ (heteroaryl), 0 (CH ₂ ) _1-4 CO ₂ (C _1-6 alkyl), 0 (CH ₂ ) i- ₄ CO ₂ H, (CH ₂ ) i- ₄ CO ₂ (aryl), O (CH ₂ ) i- ₄ CO ₂ (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH ₂ ) oxy, aryl (CH _2), CN, O (CH _{2) 4} CONR ²⁵ R ²⁶ and

C _3-7 cycloalkyl.

aryl ² is phenyl, optionally fused to a C 5-7 carbocyclic ring, which group is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , CH ² CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NHCONR ²⁵ R ²⁶ , CO (C 1-6 alkyl), COaryl, CO heteroaryl, SO ₂ NR ²⁵ R ²⁶ , S (O) _n (C _1-6 alkyl), S (O) _n (aryl), S (O) _n (heteroaryl), CO ₂ (C _1-6 alkyl), CO ₂ (aryl), CO ₂ (heteroaryl), CO ₂ H, (CH ₂ ) 1-4002 (O 6 alkyl), (CH ₂ I- ₄ CO ₂ H, (CH ₂ ) _1-4 CO ₂ (aryl), (CH ₂ ) _1-4 CO ₂ (heteroaryl), 0 (CH ₂ ) _1-4 00 ₂ (C _1-6 alkyl), O (CH ₂ ) _1-4 CO ₂ H, O (CH ₂ ) _1-4 CO ₂ (aryl), O (CH ₂ ) _{X -4} CO ₂ (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH ₂ ) oxy , aryl (CH ₂ ), CN,

O (CH ₂ ) _{x -4} CONR ²⁵ R ²⁶ and C 3-7 cycloalkyl.

heteroaryl ¹ is heteroaryl optionally fused to

C5-7 carbocyclic ring, which group is optionally substituted with one or more substituents selected from the group consisting of C _x _6 alkyl (optionally substituted with OH, CN or halogen), C _x -6 haloalkoxy, OH, = 0, NY ² WY ^X , halogen, C 1-6 alkoxy, CONR ²⁵ R ²⁶ , CH ² CON ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NH ²⁵ R ²⁶ , CO (C 1-6 alkyl), COaryl, CO heteroaryl, SO ² NR ²⁵ R ²⁶ , S (O) n (C _1-6 alkyl), S (O) _n (aryl), S (O) _n (heteroaryl),

CO ₂ (C _1-6 alkyl), CO ₂ (aryl), CO ₂ (heteroaryl), CO ₂ H, (CH ₂ ) _1-4 CO ₂ (C 1-6 alkyl), (CH ₂ ) _X - ₄ CO ₂ H, (CH _{2) x} _ ₄ CO ₂ (aryl), (CH ₂₎ i _{4 CO2} (heteroaryl), 0 (CH ₂₎ i ₄ CO ₂ (C _x _ ₆ alkyl), 0 (CH ₂ ) _1-4 CO ₂ H, O (CH ₂ ) _1-4 CO ₂ (aryl), O (CH ₂ ) _X - ₄ CO ₂ (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH ₂ ) oxy, aryl ( CH ₂ ), CN,

0 _{(CH2) i-4} CONR ²⁵ R ²⁶ and C _3-7 cycloalkyl, cycloalkyl C ¹ is ₃ - _X0 carbocyclic ring system having one or two rings which is substituted by _C _6 alkyl, aryl,

C1-6 alkoxy, _CH2 (aryl ^1), C ₄ haloalkyl, halogen, OH,

CN or NR ²⁵ R ²⁶ '

provided that it does not contain NR ⁴ groups in which a heteroatom is linked to another heteroatom through one sp 3 carbon,

Z is a direct bond, CO or S (O) _n group,

B is (CH _{2) p,}

R ¹² and R ¹³ each independently represent H or C _1-4 alkyl, or

R ⁱ² and R ¹³ may together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle optionally containing another hetero moiety selected from ^NR16, 0 and / or S and which is optionally substituted by one or more groups

C _1-4 alkyl,

R ¹⁴ and R ¹⁵ each independently represent H, C 1-10 alkyl,

_Io C ₃ alkenyl, C 3-10 alkynyl, C ₃ _ ₈ cycloalkyl, aryl or heteroaryl,

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached may form a 4- to 7-membered heterocycle which optionally contains an additional hetero group selected from NR ¹⁶ , O and / or S and which is optionally substituted with one or more groups

C _1-4 alkyl,

R ¹⁶ is H, C 1-6 alkyl, C ₃ _ ₈ cycloalkyl, (Ci_6 alkylene) (C _3-8 cycloalkyl) or (C ₆ alkylene) aryl,

R ⁵ and R ⁸ when independently, each independently represent H,

C 1-6 alkyl,

R ⁵ and R ⁸ together with the carbon atom to which they are

linked to form a C3-8 cycloalkyl ring,

R, R, R and R are each independently H

R ⁵ and R ⁶ or R ⁷ together with the carbon atom to which they are attached may form a C 3-8 cycloalkyl ring,

X is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy, m is 1 or 2;

n is 0, 1 or 2;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

q is 0 or 1;

"Naturally occurring amino acid residues means α-substituents derived from any of the following natural amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, asparginine , glutamine, lysine, arginine, proline;

"Heteroaryl means an aromatic ring containing up to four heteroatoms selected from N, O, and S, and if an S atom is present in the ring, it may be present as part of the group -S-, S (O) -, - S (O) ₂ -, wherein the ring may be attached to the remainder of the compound via any suitable atom or atoms;

"Heterocyclyl" is a group containing 1, 2 or 3 rings containing up to 4 ring heteroatoms selected from N, O and S and a maximum of 18 ring carbon atoms.

"Aryl, including the meaning of the definition of" aryloxy, etc., means a phenyl ring-containing group that may further comprise another carbocyclic ring fused to said phenyl, and the aryl may be attached to the remainder of the compound via any suitable atom or atoms (e.g. naphthyl, indanyl, etc.). );

The groups "alkyl," alkenyl, "alkynyl may be linear or branched if the number of atoms allows;

A "cycloalkyl" group may be polycyclic if the number of carbon atoms allows;

or a pharmaceutically or veterinarily acceptable derivative thereof and a prodrug thereof.

If a fused heterocyclic ring is present, it may be attached to the remainder of the compound via any suitable atom or atoms,

The groups "haloalkyl and" haloalkoxy and the like may contain more than one halogen atom and, for example, may be per-halogenated.

Some of the compounds of the invention may exist in one or more geometric and / or stereoisomeric forms. The present invention includes all individual isomers of their salts and prodrugs.

Some of the compounds of the present invention may exist in more than one tautomeric form. Likewise, certain compounds of the invention may be in the form of zwitterions. The present invention includes all tautomers, zwitterions and derivatives thereof

Pharmaceutically acceptable salts of the compounds of formula I include their acid addition salts and basic salts. Suitable addition salts are derived from acids that form non-toxic salts, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulfonate, benzenesulfonate and p-toluenesulfonate.

Suitable bases are those which form non-toxic salts, for example aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine. Suitable salts are described in Berge et al, J. Pharm. Sci., 66, 1-19 (1977).

One of skill in the art is aware that certain protected derivatives of compounds of formula I that may be formed prior to the final unprotected condition may not exhibit pharmacological activity per se, but may, in certain cases, be transformed upon administration in or on the body, for example by metabolism, to give compounds of formula I which are pharmacologically active. Such derivatives are encompassed by the term "prodrugs." It is believed that one skilled in the art is aware that certain groups, known as "progroups," for example, as described in "Design of Prodrugs,

H. Bundgaard (Elsevier) 1985, may be placed on suitable functional groups when present in the compound of formula

I, also to produce a "prodrug. Further, certain compounds of formula I may behave as prodrugs of other compounds of formula I. All protected derivatives and prodrugs of compounds of formula I are within the scope of the invention.

Preferably Ar is phenyl or pyridyl.

Most preferably, "Ar represents a group of the formula:

R y

Preferably R ¹ , when alone, is OH, CN, halogen, NO ₂ , NH ₂ , NY ² WY ^x or Het ¹ .

More preferably, R ¹ 'when alone, is OH, CN, I, Cl, NH ₂ ,

NO ₂ , optionally benzofused heteroaryl, NHSO ₂ Y ^X , NHCOY ¹ , NHCO ₂ Y ^X.

Even more preferably R ^x , when alone, is OH, CN, I, Cl, NH 2, NO 2, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO 2 (C 1-6 alkyl), NHSO 2 (C 1-6 alkyl substituted by methoxy, CONH 2, OH, CO 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, NHSO 2 Het ^Xa , NHCO (C 1-6 alkyl) or NHCO ₂ (C 1-6 alkyl).

More preferably, R ^x is OH, NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ (nC ₃ H ₇ ), NHSO ₂ (1-C ₃ H ₇ ), NHSO ₂ (nC ₄ H ₇ ), NHSO ₂ NH (1- C3H7),

NHSO ₂ (N-methylimidazol-4-yl), NHSO ₂ (CH ₂ ) ₂ OCH ₃ , NHSO ₂ (CH ₂ ) ₂ OH, 1,2,4-triazolyl or imidazol-2-yl.

Most preferably, R ¹ is OH, NHSO ₂ CH 3, NHSO ₂ C ₂ H ₅ or imidazol-2-yl.

Preferably R ² , when alone, is H.

R ¹ and R ² together with the carbon atoms to which they are attached represent a benzofused 5- to 7-membered heteroaryl optionally substituted with C _1-4 alkyl, or

C 1-4 haloalkyl.

More preferably, R ¹ and R ² together with the carbon atoms to which they are attached represent a 5-membered heteroaryl, optionally substituted with C 1-4 alkyl, or C 1-4 haloalkyl.

More preferably, R ¹ and R ² together with the carbon atoms to which they are attached represent imidazolyl optionally 2-substituted.CF ₃ .

Preferably X is Cl.

Preferably n is 0.

Preferably q is 0.

Preferably, R ³ represents H, CN, C 1-6 alkyl (optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkoxy,

C1-6 alkoxycarbonyl, _C2 -6 alkanoyl, C ₂ _ ₆ alkanoyloxy,

C ₂ -6 alkyloxycarbonyloxy, NR ¹² R ^13, CONR ¹² R ¹³ and / or NY ² WY ^1). Even more preferably, R ³ is H, CH ₃ , C ₂ H ₅ , IC ₃ H ₇ , n C ₃ H ₇ or CH ₂ OCH ₃ .

Most preferably, R ³ represents CH ₃ .

Preferably, R ⁴ represents Ο _χ - ₁₀ alkyl substituted with one or more substituents selected from the group consisting of:

C ₂ -6 alkoxy [substituted by one or more substituents selected from the group consisting of OH, NR ²⁵ R ^26, CONR ²⁵ R ²⁶ · • halogen, C ₆ alkoxy, C _2-4 alkynyl, C ₂ _ ₄ alkenyl, heteroaryl, ^1, aryl ^1, COCH ₂ CN, CO ^{(heteroaryl1),} CO (aryl ^1), CO2 ^{(heteroaryl1),} COCH2 ^(aryl1), COCH2 (heteroaryl ^1), ₂ CO2CH (aryl ¹⁾

CO ₂ CH ₂ (heteroaryl ^1), S (0) _n (C _x - _C6 alkyl), S (0) _N (aryl ¹⁾

S (O) _n (heteroaryl ¹ ), SO ₂ NR ²⁵ R ²⁶ and cycloalkyl ¹ ],

S (O) NC 1-6 alkyl [optionally substituted with one or more groups selected from OH, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , halogen,

C1-6 alkoxy, C2-4 alkynyl, _C2 -4 alkenyl, heteroaryl \ ^aryl1, COCH2CN, CO ^{(heteroaryl1),} CO (aryl ^1), C02 (heteroaryl ¹⁾

COCH ₂ (aryl ¹ ), COCH 2 (heteroaryl ¹ ), CO ₂ CH ₂ (aryl ¹ ),

CO 2 CH 2 (heteroaryl ¹ ), S (O) _n (C 1-6 alkyl), S (O) _n (aryl ¹ ),

S (O) _n (heteroaryl ¹ ), SO ₂ NR ²⁵ R ²⁶ and cycloalkyl ¹ ], aryl ² ,

CO ₂ CH ₂ (heteroaryl ¹ )

CO ₂ CH ₂ (aryl ¹ ), cycloalkyl ¹ ,

CO (heteroaryl ¹ ),

CO (aryl ¹ )

OC0 (aryl ¹ ),

OC0 (heteroaryl ¹ ),

OC (C _1-6 alkyl ¹ ),

OCOCH2CN,

CO ₂ (heteroaryl ¹ ),

C0 ₂ (aryl ¹⁾

COCH ₂ (heteroaryl ¹ ),

S (O) _n (aryl ¹ ),

S (O) _n CH ₂ (aryl ¹ ),

S (O) _n (heteroaryl ^1).

S (O) _n CH ₂ (heteroaryl ¹ ),

NHSO ₂ (aryl ¹ ),

NHSO ₂ (C 1-6 alkyl),

NHSO ₂ (heteroaryl ¹ )

NHSO ₂ CH ₂ (heteroaryl · ¹ ),

NHSO ₂ CH ₂ (aryl ¹ )

NHCOaryl ¹

NHCO (C 1-6 alkyl),

NHCONHaryl ¹

NHCONH _{(Ci_6} alkyl)

NHCOheteroaryl ¹

NHCONHheteroaryl ¹ ,

NHCO ₂ (aryl ¹ )

NHCO ₂ (C 1-6 alkyl),

NHCO ₂ (heteroaryl ¹ ), aryl ² oxy, heteroaryl ¹ oxy,

C 1-6 alkoxycarbonyl substituted with C 1-6 alkyl, aryl,

C 1-6 alkoxy, CH ₂ (aryl ¹ ), C 1-4 haloalkyl, halogen, OH,

CN or NR ²⁵ R ²⁵ ,

_C2 -6 alkanoyl substituted with C ₆ alkyl, aryl, C ₆ alkoxy, _CH2 (aryl ¹⁾ Cx_ ₄ haloalkyl, halogen, OH, CN or NR ²⁵ R ^26,

C _2-6 alkanoyloxy-substituted Cx_6 alkyl, aryl,

C 1-6 alkoxy, CH ₂ (aryl ¹ ), C 1-4 haloalkyl, halogen, OH,

CN or NR ²⁵ R ²⁶ , cycloalkyl ¹ oxy,

COcycloalkyl ¹ , heterocyclyl substituted with one or more substituents selected from the group consisting of O6-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , CH ₂ CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NHCNNR ²⁵ R ²⁶ ,

CO _{(Ci_6} alkyl), SO ₂ NR ²⁵ R ^26, S0 ₂ (Cx_ ₆ alkyl), CO ₂ (Cx_ ₅ alkyl), CH ₂ CO ₂ (C-C6 alkyl), OCH ₂ CO ₂ (Cx_6 alkyl) , aryl, heterocyclyl, aryloxy, aryl (CH ₂ ) oxy, aryl (CH ₂ ), CN and C 3-7 cycloalkyl heterocyclyloxy substituted with one or more substituents selected from the group consisting of C _1-5 alkyl (substituted)

OH), con ²⁵ r ²⁶ , ch ₂ con ²⁵ r ²⁵ , nr ²⁵ r ²⁶ , nhconr ²⁵ r ²⁶ ,

CO (C 1-6 alkyl), SO ₂ NR ²⁵ R ²⁶ , SO ₂ (C _1-6 alkyl), CO 2 C 1-6 alkyl), CH ₂ CO ₂ (C _1-6 alkyl), OCH ₂ CO ₂ (C _1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C3-7 cycloalkyl,

Even more preferably, R ⁴ represents C 1-10 alkyl substituted with cycloalkyl ¹ .

Even more preferably, R ⁴ represents a _C2 -4 alkyl substituted cycloalkyls ^first

Even more preferably, R ⁴ is propyl substituted with cycloalkyl ¹ .

More preferably, R ⁴ is propyl substituted with a C 3-10 carbocyclic system with one or two rings substituted with OH.

Even more preferably, R ⁴ is propyl substituted (cyclohexyl ¹ substituted with OH).

Most preferably, R ⁴ is (1-hydroxycyclohexyl) prop-3-yl.

Other preferred compounds are those in which R ⁴ is as defined in Examples 145-203 below.

Preferred groups of compounds are those wherein the ring, Ar, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , q and (X) _n are as defined above. in the Examples below.

The invention further provides a synthetic method for preparing the compounds and salts of the present invention, which are described below and in the Examples. It will be understood by those skilled in the art that the compounds of the present invention may also be prepared by methods other than those described herein, by adapting the methods described herein or by adapting methods described in the prior art, for example described in standard textbooks such as the Comprehensive Organic Transformations

Functional Group Transformations, RC Larock, VCH (1989 and later editions);

Advanced Organic Chemistry-Reactions, Mechanisms and Structure, J. Mark, Wiley-Interscience (3rd or later edition);

"Organic Synthesis-The Disconnection Approach, S. Warren (Willey)," (1982 or later);

Designing Organic Syntheses, S. Warren (Willey), (1983 or later edition);

"Guide book To Organic Synthesis by RK Mackie and DM Smith (Longman) (1982 or later edition; etc.), and references cited therein.

It is to be understood that the synthesis methods described herein are exemplary only and that the transformations may be performed in different order to produce the desired compound. Those skilled in the art will be able to select the most efficient reaction sequence for the synthesis of a given target compound. Substituents may be added and / or chemical transformations may be performed via intermediates other than those mentioned herein, using specific reactions. This depends inter alia on factors such as the nature of the other functional groups present on the substance, the availability of key intermediates and the protecting group strategy (if any) used. It is clear that the type of reactions selected affects the choice of reagents used at a particular stage of the synthesis, the need and type of protecting groups used, and the order of synthesis. The procedure may be adapted for particular reactants, reagents and other reaction parameters in a manner known to those skilled in the art by reference to standard literature and the examples below.

It will be appreciated by those skilled in the art that sensitive functional groups sometimes need to be coupled and deprotected during the synthesis of a compound of the present invention. This can be accomplished using conventional methods, as described, for example, in "Protective Groups in Organic Synthesis, TWGreen and PGM Wuts, John Willey & Sons, Inc., 1999," including references cited therein. Functional groups that may be desirable to protect include oxy, hydroxy, amino, and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (e.g., ethylene ketals) and dithianes. Suitable hydroxyl protecting groups are trialkylsilyl and diarylalkylsilyl, for example tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for the amino group are tert-butyloxycarbonyl,

9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid are C 1-6 alkyl or benzyl esters.

In the methods below, unless otherwise indicated, the substituents are as defined above for the compound of Formula I.

The invention provides a process for the preparation of compounds of formula I as defined above, or a pharmaceutically or veterinarily acceptable derivative thereof, said process comprising:

(A) for compounds of formula I wherein q is 0 and R ¹ is NY ² WY ¹ , reacting a compound of formula II,

(II), with a compound of formula III,

Z ¹ WY ¹ (III), wherein Z ¹ represents a suitable leaving group such as halogen or Y ¹ SO ₂ O-;

(b) for compounds of formula I wherein q is 0 and R ⁶ and R ⁷ both represent H, a reduction of the compound of formula IV,

(IV), using a suitable reducing agent;

(c) for compounds of formula I wherein q is 0 and R ⁹ and R ¹⁰ both represent H, a reduction of the compound of formula V

(V) using a suitable reducing agent;

(d) for compounds of formula I wherein q is 0 and R ¹ and R ² are attached to adjacent carbon atoms and together with the carbon atoms to which they are attached, Het ^{1 a} , wherein Het ^{1 a} represents an imidazole unit, reacts with the corresponding compound of formula VI,

(VII), with a compound of formula VII

R ^y CO ₂ H (VII) wherein R ^y represents H or any optional substituent Het ^{1 a} (as defined above), preferably H, C 1-4 alkyl or

C 1-4 haloalkyl.

with a compound of formula IX

(VIII),

R-Lg (1X).

wherein Lg is a leaving group;

(f) for compounds of formula I wherein q is 0 and R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are all H, a reduction of the compound of formula X,

(g) for compounds of formula I wherein q is 0 and R ¹ is OH, reacting a compound of formula II as defined above, wherein Y ² · · * represents H, with fluoroboric acid and isoamyl nitrite;

(h) for compounds of formula I wherein q is 0 and R ¹ represents a Cl reaction of a compound of formula II wherein Y ² is H as defined above with sodium nitrite in the presence of dilute acid, followed by reaction with cuprous chloride in the presence of concentrated acids;

(i) for compounds of formula I wherein q is 1 by reacting a compound of formula I wherein q is 0 with a suitable oxidizing agent such as aqueous hydrogen peroxide;

(j) for compounds of formula I wherein q is 0, by reducing the corresponding compound of formula XXXI,

(XXXI), wherein R ^{4 and} CH ₂ have the same meaning as R ⁴ as defined above;

(k) for compounds of formula I wherein q is 0, a reductive amination reaction of an amine of formula VIII as defined above with an aldehyde of formula R ^4a CHO wherein R ^4a CH ₂ has the same meaning as R ⁴ as defined above;

and, if desired or appropriate, converting a compound of Formula I into a pharmaceutically or veterinarily acceptable derivative, and vice versa.

«· ····

In process (a), the reaction may be carried out at a temperature of 0 ° C to room temperature, in the presence of a suitable base (for example pyridine) and a suitable organic solvent (for example dichloromethane).

Compounds of formula II may be prepared by reduction of the corresponding compound of formula XI or formula XII

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

Compounds of formula XI and XII may be prepared by reduction of the corresponding -NO ₂ compounds under conditions well known to those skilled in the art (e.g. using H ₂ / Raney Ni or in the presence of CaCl ₂ and iron powder) in the presence of a suitable solvent system (e.g. (or water)). Those skilled in the art will appreciate that in the preparation of a compound of formula II, wherein Y ² is H, from the corresponding -NO ₂ compound, the two abovementioned reduction steps may be performed in one step or sequentially in any order.

Said corresponding -NO ₂ compounds may be prepared by reacting a compound of Formula XII or Formula XIV, as appropriate,

(XIII) (XIV) wherein L ¹ is a suitable leaving group (such as halogen (e.g. chlorine or bromine)), L ² represents a suitable leaving group (such as C _1-3 alkoxy) and R ³ has the same meaning as above, with a compound of formula XV

R ⁴ NH ₂

The reaction may be carried out at a temperature between room temperature and reflux temperature, in the presence of a suitable base (e.g. NaHCO 3) and a suitable organic solvent (e.g. dimethylformamide), or at a higher temperature (e.g. between 50 and 200 ° C, preferably between 100 and 160 ° C) in the presence of a compound of formula XV,

Compounds of formula XIII and XIV can be prepared using standard techniques. For example, compounds XIII and XIV can be prepared by reacting the corresponding compound of formula XVI or XVII

(XVI)

with a compound of formula XIX, respectively,

N ₂ CHR ⁵ COL ²

N ₂ CHR ® COL ² (XIX) wherein L ² has the same meaning as defined above. The reaction may be carried out at room temperature in the presence of a suitable catalyst (e.g. Rh ₂ (OAc) ₄ ) and a suitable aprotic organic solvent (e.g. dichloromethane).

Compounds of formulas XVI and XVII are available or can be prepared using known techniques. For example, compounds of formulas XVI and XVII can be prepared from the corresponding compounds of formula XX (XX) by, for example, carrying out a Wittig reaction using a suitable reagent delivering the nucleophilic group RO ₂ C-CR ⁵ H- or RO ₂ C-CR ⁸ H- ( . C1-3) alkyl, under conditions well known to those skilled in the art. -CO2R group of the resulting compound may be converted to a suitable Cf ^ L ¹ group using standard techniques (e.g. reduction of the ester to the primary alcohol and conversion of the primary alcohol to an alkyl halide) to conditions well known to those skilled in the art.

In methods (b) and (c), suitable reducing agents include lithium aluminum hydride. The reaction may be carried out at a temperature between room temperature and reflux temperature, in the presence of a suitable solvent (e.g. tetrahydrofuran).

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

(XXX) analogously to the procedures above.

Compounds of formulas IV and V may be prepared from the corresponding compounds of formulas XXI and XXII,

wherein L ³ is a group that is capable of transforming functional groups (e.g., a cyano group) using standard functional group substitution or conversion techniques.

For example:

(1) Compounds of formulas IV and V wherein R ¹ is 1,2,4-triazol-3-yl may be prepared by reacting a suitable compound of formula XXI or XXII, wherein L ³ is -CN, with HCl (gas) in the presence of a suitable lower alkyl alcohol (e.g. ethanol), at a temperature between 0 ° C and room temperature, and then reacting the obtained intermediate with formic hydrazide (e.g. at reflux temperature, with or without a suitable organic solvent (e.g. methanol) and heating the residue to higher temperature (e.g. about 150 ° C)).

(2) Compounds of formula IV and V wherein R ¹ is imidazol-2-yl may be prepared by reacting a suitable compound of formula XXI or XXII, wherein L ³ is -CN, with HCl (gas) in the presence of a suitable lower alkyl alcohol ( (e.g. ethanol) at a temperature between 0 ° C and room temperature, and then reacting the obtained intermediate with aminoacetaldehyde dialkylacetal (e.g. dimethylacetal) (e.g. at reflux temperature in the presence of a suitable solvent such as methanol).

(3) Compounds of formula IV and V wherein R ¹ is 1,2,3-triazol-5-yl may be prepared by reacting a suitable compound of formula XXI or XXII, wherein L ³ is -CN with diazomethane or a protected (for example, trialkylsilyl) ) a derivative, at a temperature between 0 ° C and room temperature, in the presence of a suitable base (e.g. n-BuLi) and optionally a suitable organic solvent (e.g. THF), and then, if necessary, deprotecting.

(4) Compounds of formula IV and V wherein R ¹ is benzimidazol-2-yl can be prepared by reacting a compound of formula XXI or XXII, wherein L ³ is -C =NH (Oet), with 1,2-diaminobenzene. The reaction may be carried out in a solvent such as methanol at an elevated temperature (such as the reflux temperature of the solvent). Further details are provided in Preparation 81, etc..

Compounds of formulas IV and V wherein R ¹ is Het ¹ may also be prepared from the corresponding compounds of formulas XI and XII according to the following reaction scheme:

(X) n

(i) HCl, NaNO ₂ , H ₂ O fi) ΚΙ, HO

Pd ₂ aba ₃ , PhA-S Pu ₃ Sa-HeU

wherein Het ¹ is the same as defined above. Further details are given in Preparations 67 and 68 etc. in WO 00/39089, which are incorporated herein by reference.

Compounds of formula XXI and XXII may be prepared in a manner analogous to that described herein, for example, the method described for the preparation of compounds of formula II.

Other compounds of formulas IV and V may be prepared analogously to the methods described herein (for example, analogously to the methods described for the preparation of compounds of formulas XI and XII (and in particular the corresponding -NO ₂ compounds)).

In process (d), the reaction may be carried out by heating at reflux, with or without the presence of a suitable organic solvent.

Compounds of formula VI may be prepared using known techniques. For example, compounds of formula VI can be prepared by nitrating (at the 4-position) the corresponding 3-aminobenzene compound (compounds of formula II), which can be activated by converting the 3-amino group to a 3-amido group and then hydrolyzing the amide and reducing the 4-nitrobenzene compound. All of these reactions can be carried out by techniques known to those skilled in the art and described in Preparations 45-48 etc. below.

In process (e), suitable leaving groups which may be Lg are halogen, such as bromine, a sulfone group, such as tosylate, mesylate or triflate. The reaction may be carried out in a polar solvent which does not adversely affect the reaction at a suitable temperature, for example 0 to 150 ° C, in the presence of a base. Sodium iodide can be added as catalyst.

A preferred embodiment is a slight excess of R ⁴ -Lg, wherein Lg = Cl or Br, an excess of base (2.0-4 equivalents) such as Κ ₂ ΟΟ ₃ , NaHCO ₃ or a tertiary amine such as triethylamine or Hunig's base in a polar solvent such as THF, DMF or MeCN at a temperature between 40 and 120 ° C, optionally in the presence of a catalyst such as NaI or KI for 2 to 24 hours, see RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparations VCH, (1989) p.397, and references cited therein.

Compounds of formula VIII may be prepared from compounds of formula XXV

(XXV)

wherein Pg represents a suitable protecting group. Suitable protecting groups include allyl, which can be removed using a palladium (0) catalyst and N, N-dimethylbarbituric acid (see Preparation 53, etc. below). Compounds of formula XXV may be prepared analogously to the methods described for the preparation of compounds of formula I.

In process (f), a suitable reducing agent is lithium aluminum hydride. The reaction may be carried out in a solvent that does not adversely affect the reaction (such as tetrahydrofuran) at an elevated temperature (such as 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. The reaction may be carried out in a solvent that does not adversely affect the reaction (such as dioxane) at an elevated temperature (e.g., the reflux temperature of the solvent) (see, for example, Preparation 77, WO00 / 39089). Intermediates of formula XXIXa are isolated using suitable conditions (see, for example, Preparation 58, WO 00/39089).

Compounds of formula XXVI can be prepared from compounds of formula XXVIII by reacting the corresponding ketone with hydrazine monohydrate using known techniques (as described in Preparation 76 etc. WO 0/39089).

Process (f) is particularly suitable when Ar is an optionally benzofused 5- or β-membered heteroaryl ring. A similar method can be used to prepare compounds of formula II: a precursor nitro compound can be prepared from a compound of formula XX as defined above using the steps described above (see Preparations 57-61 etc. WO 00/39089).

In process (g), the reaction may be carried out in a solvent that does not adversely affect the reaction (such as ethanol), first at a temperature below room temperature and then at a higher temperature (in Example 79 etc. WO 0039089 further details are given) .

In process (h), suitable acids include a solution of hydrochloric acid and concentrated hydrochloric acid, respectively. The reaction may be carried out at room temperature and finally at a higher temperature (e.g. 90 ° C).

Further details are given in Example 51 of WO 0039089.

In process (j), a compound of formula XXXI can be prepared by acylating a compound of formula VIII as described above using an acylating agent of formula R ^4a CO-Lg, wherein Lg is a suitable leaving group as defined for (e), which may be halogen , (alkyl, haloalkyl or aryl) sulfonate, OCOR ^4a (i.e., acid anhydride) and the like, as well known to those skilled in the art. See, for example, the conditions used for preparation 47. The reaction may 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 equivalents), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. HCl (1-1.5 eq.) And 1-hydroxybenzotriazole (1.0 eq.) Are stirred in DMF or DCM at room temperature for 5-15 min. and then the amino salt (1 eq) and the base (NAHCO3) or the organic base, Et3N or Huning base (2-4 eq) are added, the reaction lasts 2-24 hours at room temperature.

The amide bond may be reduced with a suitable reducing agent, for example lithium aluminum hydride or borane, in an ether solvent such as THF at 100 ° C to give the desired tertiary amine, see RC Larrock in Comprehensive Organic Transformations-A. Guide to

Functional Group Preparations VCH, (1989) pp. 434-434, and references cited therein. Preferably, the amide (1.0 eq.) Is treated with lithium aluminum hydride (1.1-3 eq.) At 0 ° C-room temperature, in THF, for 1-24 hours.

• · · · · ·

In process (k), a suitable 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 may be carried out in the presence of acetic acid at 0 to 100 ° C in THF, methanol, DCM (dichloromethane) or DCE (1,2-dichloroethane) for about 1-24 hours.

Preferably, an amino salt such as trifluoroacetic acid (TFA) is reacted with an organic base (1-3 mol equivalents) such as triethylamine or Hunig's base and then with an aldehyde (1-1.5 mol equivalents) and further with sodium triacetoxyorohydride (1-2.0 mol equivalents) in DCM or DCE at room temperature for 2-24 hours, see RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) pp. 835-842, and references cited therein and Abdel-Magid et al., J. org. Chem., 1996, GI, 3849.

The aldehydes used in this process can be prepared from the corresponding oxidizing 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 oxidizing agents are tetrapropylammonium perruthenate (Ley, et al., Synthesis, 1994, 639-666), Swern oxidation and related methods (Tidwell, Organic Reactions, 1990, 39, 297572) and the Dess-Martin Periodinane reagent (Dess et al., J.

Org. Chem., 1983, 48, 415-4156).

Conversions of various functional groups on the compounds of formula I, or on intermediates, may be carried out.

Some of them are described below.

Anilines can be converted to 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 RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) pp.1117-1120 and references cited therein. Suitable reducing agents are diisobutylaluminum hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminum hydride (LiAlH ₄ , see Brown, Org. Reactions, 1951, 6, 469) - see reactions of the type:

OH

Alcohols may be prepared from the corresponding acids using a suitable reducing agent, see RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) pp. 1114-1116. A preferred reducing agent is borane (BH ₃ (1-2 eq), J. Org. Chem., 1973, 38, 2786), or LiAlH ₄ (1-4 eq), in an ether solvent such as THF 0-80 ° C, after 1-24 hours - see reaction type:

Fk SOH

Fk .OH

Direct methods for preparing alkyl halides and alkyl sulfonates from their alcohols are described in RC Larrock " Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) pp. 689-700, including references cited therein.

The benzylacetals can be reacted with a suitable reducing agent in the presence of a Lewis acid or an organic acid to form benzyloxy alcohols.

For representative examples, see Organic Preparations and Procedures, Int., 1991, 23, 4, 427-431, ZrCl ₄ / LiAlH ₄ , J. Org. Chem., 1987, 52, 2594, Zn (BH ₄₎ / MeaSiCl; and Organic Preparations and Procedures, Int., 1985, 17 (1), 11-16, NaBH 4 / TFA, see reactions of the type:

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, a compound of formula I wherein Y ¹ represents alkoxycarbonyl can be converted to compounds wherein Y ¹ represents alkyl substituted with OH by reduction using LiAlH 4 (Example 57 provides further details). Similarly, intermediates can be interconverted using known techniques (see, for example, Preparation 85).

Intermediates, such as intermediates of formulas III, XV, XVIII, XIX XX, VII, IX, XXVI, XXVII and XXVIII, and derivatives thereof, if not commercially available, can be obtained by analogous methods described or conventional synthesis methods using standard techniques. of available starting materials, using appropriate reagents and reaction conditions.

The invention further provides intermediates of formulas II, IV, V, VI,

X, ^X, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, _XXIX, XXX, XXXI as defined above.

If necessary or desired, the compounds of formula I may be converted into their pharmaceutically acceptable salts by mixing a solution of the compound of formula I and a selected acid or base. The salt may precipitate out of solution and be recovered by filtration or may be recovered by other means such as evaporation of the solvent. Both types of salts can also be prepared by interconversion using an ion exchange resin.

The compounds of the present invention can be purified by conventional techniques, such as fractional crystallization by chromatography or HPLC, of a stereoisomeric mixture of a compound of formula I or a salt thereof. The individual enantiomers of the compound of formula I may also be prepared from the corresponding optically pure intermediates or by resolution, such as HPLC of the appropriate racemate using a suitable chiral carrier or fractional crystallization of the diastereomeric salt formed by reacting the corresponding racemate with a suitable optically active acid or base.

The compounds of the present invention are useful because they have pharmacological activity in animals, particularly mammals, including humans. Therefore, they are useful as pharmaceutical agents in animals.

In another aspect, the invention provides a compound of

of the present invention for use as a medicament, such as a pharmaceutical and animal medicament, for treatment, for example, in the treatment of diseases and conditions modulated by opiate receptors.

The term "treatment" refers to both therapeutic (curative) and prophylactic treatment.

In particular, the compounds of the present invention have been found to be useful in the treatment of opiate receptor mediated diseases and conditions such as irritable bowel syndrome, constipation, nausea, vomiting, pruritus, eating disorders, opioid overdose, depression, alcohol and smoking addiction, sexual dysfunction, shock, stroke, spinal cord and / or head injury.and conditions characterized by pruritus as a symptom.

In another aspect, the invention provides the use of the compounds of the present invention for the manufacture of a medicament for the treatment of opiate receptor mediated diseases. The invention provides the use of the compounds of the present invention for the manufacture of a medicament for the treatment of irritable bowel syndrome; constipation; nausea, vomiting, pruritus, eating disorders, opioid overdose, depression, alcohol and smoking addiction, sexual dysfunction, shock, stroke, spinal cord and / or head injury.and conditions characterized by pruritus as a symptom.

Thus, the compounds of the present invention are believed to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans. Other diseases and conditions that may be mentioned include contact dermatitis, psoriasis eczema and insect bites.

• · · ·

Thus, the invention provides a method for treating or preventing diseases modulated by opioid receptors. The invention provides a method of treating irritable bowel syndrome constipation, nausea, vomiting, pruritus, eating disorders, opioid overdose, depression, alcohol and smoking addiction, sexual dysfunction, shock, stroke, spinal cord and / or head injury, and conditions characterized by pruritus such as a symptom in animals (e.g., mammals), said method comprising administering a therapeutically effective amount of a compound of the present invention to an animal in need of such treatment.

The compounds of the present invention will usually be administered orally or parenterally, in the form of pharmaceutical compositions containing 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 on the disease and the patient. route of administration, the compositions may be administered at various dosages (see below).

Although it is possible to administer the compound of the present invention directly into the form of a pharmaceutical composition, it is preferable to use it in the form of pharmaceutical or veterinary compositions containing pharmaceutically or veterinarily acceptable carriers, diluents or excipients and the compound of the present invention. Carriers, diluents or additives may be selected with regard to the intended route of administration according to standard pharmaceutical and / or veterinary practice. Pharmaceutical compositions containing the compounds of the present invention may contain from 0.1% to 90% by weight of the active ingredient.

Methods by which the compounds may be administered for veterinary use include oral administration in the form of capsules, boluses, tablets or liquids, topical administration in the form of ointments, sprays or screeds, disinfectant baths, sprays, foam, shampoos, ophthalmic agents, or alternatively, in the form of injections (for example subcutaneous, intramuscular or intravenous) or in the form of implants. Such compositions may be prepared in conventional manner according to standard veterinary practice.

The compositions will vary considerably with respect to the weight of the active compound contained in the composition, which will depend on the species of animal being treated, the severity and type of disease and the animal's body weight. For parenteral, topical and oral administration, typical doses of active ingredient are in the range of 0.01 to 100 mg per kg of animal body weight. A preferred range is 0.1 to 10 mg per kg.

In any case, the veterinarian or one skilled in the art will be able to determine the actual dosage that will be most suitable for an individual patient. The above doses are exemplary of average cases; in some cases, such doses may be higher or lower, and such doses are within the scope of the present invention.

In veterinary use, the compounds of the present invention are particularly useful for treating prurit in domestic animals such as cats, dogs and horses.

In the treatment of animals, the compounds may be administered in an animal feed and may be prepared for this purpose.

a concentrated dietary supplement or pre-formulated mixture which is then mixed with normal animal food.

For use in humans, the compounds are administered as pharmaceutical compositions comprising the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablets, capsules, and ointments that are consistent with conventional pharmaceutical practice.

The compounds of the present invention may be administered alone or in combination with one or more agents used in the treatment or prophylaxis of disease or suppression of symptoms. Examples of such non-limiting agents are antiparasitic agents such as fipronil, lufenuron, imidacloprid, avermectins (for example, abamectin, ivermectin, doramectin) milbemycins, organophosphates, pyrethroids, antihistamines such as chlorophenyramine, diphadrine, trimeprazine; antifungals such as fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterial agents such as enrofloxacin, marbofoxacin, ampicillin, amoxycillin; anti-inflammatory agents such as prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen ,; dietary supplements such as γ-linoleic acid; and emollients. The invention further provides compositions comprising a compound of the present invention and one or more selected compounds from the above list as combined compositions for simultaneous, separate or sequential use in the treatment of diseases modulated by opiate receptors.

It will be apparent to those skilled in the art that the compounds of the present invention may be administered as a single dose or as required (e.g., if necessary or desired).

Thus, in a further aspect, the invention provides a pharmaceutical or veterinary composition comprising a compound of the present invention in admixture with a pharmaceutically or veterinarily acceptable excipient, diluent or carrier.

The compounds of the present invention may also be advantageous in that they may be more potent, less toxic, have a broader spectrum of activity, have fewer side effects, be better absorbed, or have more favorable pharmacological properties than those previously known in human or animal treatment. in the field.

The biological activities of the compounds of the present invention were determined in the following assay.

Biological test

The compounds of the present invention were found to exhibit activity in three opiate receptor binding assays that were selective for mu, kappa, and delta opioid receptors in canine brain. The tests were performed as follows.

Laboratory beagle dogs were used as a source of canine brain tissue. The animals were sacrificed, their brains removed and the brains removed. The remainder of the brain tissue was cut into small pieces of approximately 3 g, which were homogenized in 50 mM Tris, pH 7.4, at 4 ° C using a Kinematica Polytron tissue homogenizer. The obtained homogenate was centrifuged at 48400 xg for 10 minutes.

and the supernatant was discarded. The pellet was resuspended in Tris buffer and incubated at 37 ° C for 10 minutes.

The resuspension centrifugation and incubation were repeated two more times and the final pellet was resuspended in Tris buffer and stored at -80 ° C. The membrane material prepared in this way was stored for up to 4 weeks until use.

For mu, kappa, delta assays, increasing concentrations of test compound (5x10 ^-12 to 10 ⁵ M), Tris buffer and ³ H ligand (mu = [D-Ala ² , N-Me-Phe ⁴ , Gly-ol] encaphaline) , DAMAGO; kappa = U-69593; delta (enkephalin [D-pen ^2.5 ] DPDE) mixed in polystyrene tubes The reaction was initiated by the addition of tissue and the mixture was incubated at room temperature for 90 minutes. using Brandel Cell Harwester ™ through Betaplate ™ GF / A glass fiber filters pre-immersed in 50 mM Tris pH 7.4, 0.1% polyethyleneimine buffer, and then washed three times with 0.5 mL ice-cold Tris buffer, pH 7, 4. For mu and delta assays, washed filters were placed in bags and Starscint ™ scintillant added, Meltilex ™ B / HS solid scintillant was used for kappa assay, bags containing filters and scintillant were heated sealed and read on Betaplate ™ 1204 beta-counter.

Two samples were processed for each compound and the obtained data were analyzed using IC ₅₀ analysis software in Graphpad Prism. Ki values were calculated using Graphpad Prism. according to the following formula:

K i = IC _50/1 + [ ³ H ligand] / K _D where IC ₅₀ is the concentration at which 50% of the ³ H ligand is removed by the test compound and K _D is the dissociation constant for the ³ H ligand at the receptor site.

Biological activity

Ki values for some compounds of the present invention were determined in an opiate receptor binding assay and it was found that for the µ receptor certain compounds of the present invention had Ki values of 4000nM or less.

It is believed that in the methods used in the following examples, compounds having the following stereochemistry are obtained and these compounds are preferred:

wherein R ¹⁴ and (X) _n are the same as defined above.

The invention is illustrated by the following examples and preparations in which the following abbreviations are used.

APCI = atmospheric pressure chemical ionization DMF = dimethylformamide

DMSO = dimethylsulfoxide d (time-related) = day d (NMR-related) = doublet

ES (MS-related) = electrospray

EtOAc = ethyl acetate

EtOH = ethanol h = hour

MeOH = methanol min. = minute

MS = mass spectrum of n-BuOH = n-butanol

ODS = octadecylsilyl

THF = tetrahydrofuran

TSP = thermospray

Melting points were determined using a Gallenkamp and are uncorrected. Nuclear Magnetic Resonance (NMR) spectral data refers to ^X H and was obtained using a Varian Unity 300 or 400 spectrometer and the observed chemical shifts (δ) are consistent with the predicted structures. Mass spectral data (MS) was obtained using Fisons Instruments Trio 1000 APCI or Finnigan Navigator MS or Micromass Platform LC spectrometer. The calculated and observed ions refer to the isotopic composition of the lowest weight. Room temperature means 20-25 ° C. The mass spectrometer used as a detector on an analytical HPLC system is Micromass VG Platform II, working with Masslynx / Openlynx software.

The system can be used for positive and negative ions with either electrospray ionization or APCI ionization and is calibrated to 1972 Daltons and collects diode array data for the 190 nm to 600 nm range.

HPLC means high performance liquid chromatography. The HPLC conditions used were:

Conditions 1: Rainin Dynamax column, 8 µ ODS, 24 x 300 mm, column temperature 40 ° C, flow rate 45 ml / min. elution with methanol: water (70:30), UV detection of product at 246 nm.

• · · ·

Conditions 2: Rainin Dynamax ™ column, 5 µ ODS, 21.6 x 250 mm, column temperature 40 ° C, flow rate 5 ml / min, eluting with acetonitrile: water (50:50), UV detection of product at 246 nm. Conditions 3: Rainin Dynamax ™ column, 8 µ ODS, 41 x 250 mm, column temperature 40 ° C, flow rate 45 ml / min. elution with acetonitrile: 0.1 M aqueous ammonium acetate (50:50), UV detection of the product at 235 nm.

Conditions 4: Phenomenex Magellan ™ column, 5 µC ^ silica, 21 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min. gradient elution with acetonitrile: 0.1 M aqueous ammonium acetate (30:70 to 95: 5 over 10 minutes), UV detection of the product at 220 nm.

Conditions 5: Phenomenex Magellan ™ column, 5 µ ODS, 21.2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min. gradient elution with acetonitrile: 0.1 M aqueous ammonium acetate (5:95 to 95: 5 over 20 minutes), UV detection of the product at 215 nm. Conditions 6: Phenomenex Magellan ™ column, 5 μ silica, 4.6 x 150 mm, column temperature 40 ° C, flow rate 1 ml / min. elution with a gradient of acetonitrile: 0.1 M aqueous heptanesulfonic acid (10:90 to 90:10 over 30 minutes),

UV detection of the product at 220 nm.

Conditions 7: Phenomenex Magellan ™ column, 5 µ silica silica, 21.2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min. elution with a gradient of acetonitrile: 0.05 M aqueous ammonium acetate (50:50 in 15 min and then 50:50 to 90:10 in 5 min), UV detection of the product at 220 nm.

Conditions 8: Phenomenex Magellan ™ column, 5 µ silica silica, 21.2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min. gradient elution with acetonitrile: 0.1 M aqueous ammonium acetate (15:85 to 85: 15), UV detection of the product at 220 nm. Conditions 9: Phenomenex Magellan ™ column, 5 µ ODS, 10 x 150 mm, column temperature 40 ° C, flow rate 5 ml / min. gradient elution with acetonitrile: 0.1 M aqueous ammonium acetate (5:95 to 30:70 over 5 minutes and then 30:70 over another 20 minutes), UV detection of the product at 225 nm.

Conditions 10: Phenomenex Magellan ™ column, 5 µC ₁₈ silica, 21.2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min. gradient elution acetonitrile: 0.1 M aqueous ammonium acetate (5:95 to 40:60 for 5 minutes and then 40:60 for another 25 minutes to 95: 5 over 10 minutes), UV detection of the product at 210 nm .

Conditions 11: Phenomenex Magellan ™ column, 5 µ ODS, 10 x 150 mm, column temperature 40 ° C, flow rate 5 ml / min. elution with acetonitrile: water gradient (5:95 to 55:45 in 5 minutes), UV detection of the product at 210 nm.

The free bases of azabicyclic compounds may be obtained from the hydrochloride or acetal salts, for example, as follows. The salt (0.3 mol) was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate solution (20 ml). The basic mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20ml)

The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the free base.

SPE column refers to a solid phase extraction column. This can be purchased from Varian (Mega Bond Elut® or Isolute ™).

NB "Examples 1-144 are compounds which are in accordance with the present invention but with different R ⁴ groups and are described in International Patent Application WO 00/39089, which is incorporated herein by reference in its entirety.

• · ttt

Additional examples of compounds in the table below may be prepared by the AK methods described below and in the details of the experiments following the table.

Method A

Alkylation

Alkylation of an amine of formula VIII or a salt thereof, with R ⁴ Lg, wherein Lg is a suitable leaving group such as halogen, triflate, mesylate, etc. in the presence of a base, optionally in the presence of a catalyst, in a polar solvent between 0 and 150 ° C .

Preferably, the alkylation is carried out with R ⁴ Lg (small excess), where Lg is Cl or Br, with an excess of a base (2.0-4.0 eq.) Such as K ₂ CO ₃ , NaHCO ₃ or a tertiary amine such as triethylamine or Huning base, in a polar solvent such as THF, DMF or MeCN at a temperature between 40 and 120 ° C, optionally in the presence of a catalyst such as NaI or KI for 2-24 hours.

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

R4Lg

SO ^ e

Conditions: Amino salt (1.0 eq), RX (1.1 eq), NaHCO ₃ (2-4 eq), DMF, NaI (catalyst), 40

Method B

Reductive amination

The corresponding aldehyde R ^{4 and} CHO is reacted 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 as the catalyst). The reaction is often carried out in the presence of acetic acid at 0-100 ° C in THF, MeOH, DCM or DCE (1,2-dichloroethane) for 2-24 hours.

Preferably, the amino salt is reacted with an organic base (1-3 eq.) Such as triethylamine or Huning base, and then with an aldehyde (1-1.5 eq.), Followed by sodium triacetoxyborohydride (1-2.0 eq.). ), in dichloromethane or DCE, at room temperature for 2-24 hours, see RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparatons, Second Edition, (1999) pp. 835-842, and references cited therein and Abdel-Magid et al, J. Org. Chem., 1996, 61, 3849.

Conditions: Amino salt · (1.0 eq), RCHO (1-1.5 eq), Et ₃ N (13 eq), Na (OAc) ₃ BH (1-2 eq), DCM, room temperature .

Method C ····

Reduction of the amide of formula XXXI

The carbonyl amide can be reduced with a suitable reducing agent, for example lithium aluminum hydride or borane, in an ethereal solvent such as THF at 0-100 ° C to give 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 aluminum hydride (1.0-3 eq.) At 0 ° C-room temperature, in THF, for 1-24 hours, for example:

Method D

Oxidation

The aldehydes used in Method B can be prepared using suitable oxidizing 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 the Dess-Martin Periodinane reagent (Desset · (J. Org. Chem., 1983, 48, 4155-4156).

oxidant oxidant .R

OH

H

Method E

The acid / amino salt reaction gives the amide of formula XXXI

When using acid chloride + amine in a suitable solvent or acid activated with a suitable reagent, optionally in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) pp.1941-1949, and references cited therein. Preferably, the carboxylic acid (0.9-1.1 eq.), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. HCl (1-1.5 eq.) And 1-hydroxybenzotriazole (1.0 eq.) Are stirred in DMF or DCM at room temperature for 5-15 minutes and then the amino salt (1 eq.) And base ( NaHCO ₃ or organic base, Et ₃ N or Hunig's base (2-4 eq)), the reaction takes 2-24 hours at room temperature.

For example:

.and

SO ₂ Me

Method F

Formation of urea

Aniline can be converted to urea using potassium cyanate (excess) in an acidic aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432. See reaction type:

NH 3 k ⁺ O '- = N> 1N HCl, RT, 0.1-10 hr

Method G

Conversion of ester to alcohol

Esters can be converted to the corresponding alcohol using the appropriate reducing agent, see Larrock " Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) pp.1117-1120, and references cited therein. Suitable reducing agents include diisobutylaluminum hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and 1 lithium aluminum hydride (LiAlH4, see Brown, Org Reactions, 1951, 6, 469), see reaction type

O'

R1

OH

Method H

Conversion of acid to alcohol

It will be appreciated that the alcohols used in Method D may be prepared from the corresponding acid using a suitable reducing agent; , see Larrock in "Comprehensive Organic Transformatons-A. Guide to Functional Group

Preparations, Second Edition, (1999) pp.1114-1116, and references cited therein. A preferred reducing agent is borane (BH3 (12 eq.), J. Org. Chem., 1973, 38, 2786), or LiAlH4 (1-4 eq.), In an ether solvent such as THF, 0-80 ° C , for 1-24 hours.

OH

Method 1

Conversion of alcohol to halide

It will be appreciated that the R ⁴ Lg used in Method A can be prepared from the corresponding alcohol R ^{4 and} OH.

Direct methods for preparing alkyl halides and alkyl sulfonates from their alcohols are described in RC Larrock in Comprehensive Organic Transformations-A. Guide to Functional Group Preparations, Second Edition, (1999) p.689700, and references cited therein.

Method J

Conversion of benzyl halides to benzyloxy alcohols.

benzyloxy alcohols may be prepared by refluxing the corresponding benzyl halides with sodium or sodium hydride and polymethylene glycol in xylene. J. Am. Chem. Soc., 1951, 3159-3162, see reactions of the type:

• · · ·

X = halogen

Method K

Conversion of acetals to benzyl alcohols

The acetals are treated with a suitable reducing agent in the presence of a Lewis acid or an organic acid to form benzyl alcohols.

Representative examples are given in Organic preparationsand procedures, Int., 1991, 23.4, 427-431, ZrCl ₄ / LiAlH ₄ ; J. Org. Chem. 1987, 52, 2594.

Zn (BH ₄ ) 2 / Me ₃ SiCl; and Organic preparationsand procedures, Int., 1985, 17 (1), 11-16, NaBH ₄ / TFA. See reaction type:

R · ry

HO .O

TYPES OF RESPONSE

AC

Example

Precursor (s)

Type of reaction

- _(CH2) nO _(CH2) nR examples

N- (3- {6-ethyl-3- [2- (2-hydroxy-ethoxy) -ethyl] -3-azabicyclo [3.1.0] hex-6-yl} -phenyl) -methanesulfonamide

Method A

Alkylation

146

N- [3- (3- {2- [2- (dimethylamino) ethoxy] ethyl} -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl] methanesulfonamide

Method B Reductive amination

Oxidation Method D

147

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

148

149

HIM

Method B Reductive amination o

Method D Oxidation

77- (3- {6-ethyl-3- [2- (2-pyridinylmethoxy) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

77- (3- {6-ethyl-3- [2- (2,2,2-trifluoroethoxy) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Method B

Amide reduction

Method E

150

(N- (3- {6-ethyl-3- [2- (2-propynyloxy) ethyl) -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Method B

Method D

151

N - (3- {3- [2- (allyloxy) ethyl] 6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Method B

153

# - (3- {6-ethyl-3- [2- (2-methoxyethoxy) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

O'

Method D

Methods B and D

154 ° (fj oo N- (3- {3- [2- (cyclohexylmethoxy) ethyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide Methods C and E - (CH ₂ ) _n O (CH ₂ ) "Ar examples 155 N- [3- (3- {2 - [(4- H (chlorobenzyl) ethoxy] ethyl} - (ΓΎ%) 6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} -phenyl] -methane- n sulfonamide Methods B and D - 156 (V- [3- (6-ethyl-3- {2 - [(4- gk -methoxybenzyl) oxy] ethyl} -3-azabicyclo [3.1.0] hex-6-yl) phenyl] methanesulfonamide Methods Ba D St.xí ° ' All other examples of (CH ₂ ) _n O (CH ₂ ) _n Ar can be prepared in two steps from benzyl alcohol or benzyl chloride For a general procedure, see, Am. Chem. Soc., 1951,3162 J 3159- Aryl substituents (aryl and aryloxy examples):

157

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

Methods B and D

158

2- {4- [2- (6-ethyl-6- {3 [(methylsulfonyl) amino] phenyl} -3-azabicyclo [3.1.0] hex-3-yl) ethoxy] phenyl} acetamide

Method A

159

N- (3- {3- [2 - [(4-aminophenoxy) -ethyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} -phenyl) methanesulfonamide

Methods C and Di

L__________ »

160

N- {3- [3- (2- {4 [(aminocarbonyl) amino] phenoxy} ethyl) -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

Method F

161

N- (3- {3- [3- (4-acetyl-phenyl) -propyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} -phenyl] -methanesulfonamide

UK-156607

Method A

162

4- [2- (6-ethyl-6- {3 - [(methylsulfonyl) amino] phenyl} -3-azabicyclo [3.1.0] hex-3-yl) ethoxy] benzenesulfonamide cv

Method A

163

N - [3- (6-ethyl-3- {2- [4 (methylsulfonyl) phenoxy] ethyl} -3-aza-bicyclo [3.1.0] hex-6-yl} phenyl] methanesulfonamide

HIM

'A' * oo

Methods C and E

164

methyl 4- [2- (6-ethyl-6- {3 [(methylsulfonyl) amino] phenyl} -3-aza-bicyclo [3.1.0] hex-3-yl) -ethoxy] benzoate

Methods B and D ethyl- {2- [2- (6-ethyl-6- {3 - [(methylsulfonyl) amino] phenyl} -3-azabicyclo [3.1.0] hex-3-yl) -ethoxy] -phenyl } acetate

Method A

166

methyl {4- [2- (6-ethyl-6- {3 - [(methylsulfonyl) amino] phenyl} -3-aza-bicyclo [3.1.0] hex-3-yl) -ethoxy] -phenoxy} acetate

Methods B and D

167

N- [3- (6-ethyl-3- {2- [4 (hydroxymethyl) phenoxy] ethyl} -3-azabicyclo [3.1.0] hex-6-yl} phenyl] methanesulfonamide

HIM

OH

Methods B and D or the reduction of Example 19-Method G

168

N - (3- {3- [2 - ([1,1'-biphenyl] 4-yloxy) ethyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl] methanesulfonamide

Methods B and D • ·

169

N- [3- (3- {2- [4- (4,5-dihydrol, 3-oxazol-2-yl) phenoxy] ethyl} -6-ethyl-3-azabicyclo [3.1.0] hex-6- yl) phenyl] methanesulfonic acid d

Methods B and D

170

N- (3- {6-ethyl-3- [2- (4-phenoxy-phenoxy) -ethyl] -3-azabicyclo [3.1.0] hex-6-yl) -phenyl] -methanesulfonamide

HIM

Methods B and D

171

N- (3- {3- [2-benzyloxy) benzyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Commercial aldehyde

Method B

172

ΊΟ

N - (3- {3- [2- (4-Benzyl-phenoxy) -ethyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} -phenyl) -methanesulfonamide

OH

Methods C and E

173

N- {3- [3- (4-cyanobenzyl) -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

Commercial aldehyde Method D

174

N - (3- {3- [2- (4-cyclopropylphenoxy) ethyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

UK-419966

Substituents of basic alkyl / alkenyl / alkynyl chains:

• · · · · ·

175

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

Method A

176

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

Method A o

177

N- {3- [6-ethyl-3- (3-oxo-3-phenylpropyl) -3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

Method A

178

N- (3- {3- [3- (2,3-dihydrol / 7-inden-5-yl) -3-propyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Method A • * • ··········

179 Η r ς UJ ° o .'X \ | ÁxOyV O 2- (6-ethyl-6- {3 - [(methylsulfonyl) amino] phenyl} -3-azabicyclo [3.1.0] hex-3-yl) ethylbenzoate Method A i 80 2- (6-ethyl-6- {3- Híi Ί X ' [(methylsulfonyl) amino] phenyl} -3-azabicyclo- 0 IIJ 0 ° [3.1.0] hex-3-yl) ethyl cyanoacetate Method A ^υ Ά, 0 181 2- (6-ethyl-6- {3 - [(methylsulfonyl) amino] phenyl} -3-azabicyclo- [3.1.0] hex-3-yl) ethyl 1,5- • X yj oo dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4- Method A HE carboxylate 0 0

182

N- (3- {3 - [(4- tert -butylcyclohexyl) methyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6yl} phenyl) methanesulfonamide

183

184

Methods C and E

N - (3- {6-ethyl-3 - [(4-methoxycyclohexyl) methyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

N - (3- {3 - [(2-benzylcyclohexyl) methyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

/

O

Methods C and E

CK .OH

Methods C and E

185

N- {3- [6-ethyl-3- (octahydro-1 H -inden-2-ylmethyl) -3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

Methods C and E

186

187

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

N- (3- {6-ethyl-3- [2 (phenylsulfonyl) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

HIM

Methods C and E ⁰ R / P

HIM

Method C and E

188

N- (3- {6-ethyl-3- [2 (ethylsulfonyl) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Methods B and D

189

(benzylsulfonyl) ethyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Method A

190

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

_______

191

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

H

0 °

Method A

Cl

192

193

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

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

Ν '

Η

Methods Β and D

Method A and *

194

N.

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

Methods B and D

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

196

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

HIM

Methods B and D

197

N- (3- {6-ethyl-3- [2- (phenylsulfonyl) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Methods C and E

77- (3- {6-ethyl-3- [2- (2-pyridinylsulfanyl) ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

Methods C and E

Example 199:

N- (3- {3- [3- (4-acetylphenyl) propyl] -6-ethyl-3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide and formic acid salt

cr

To a solution of the trifluoroacetic acid salt of N- [3- (6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) -phenyl] -methanesulfonamide (106 mg, 0.27 mmol) in 2 N, N-dimethylformamide (4 mL) was added. sodium bicarbonate (90 mg, 1.1 mmol), 1- [4- (3-chloropropyl) phenyljethanone (58 mg, 0.29 mmol) and sodium iodide (catalyst) were added and the reaction mixture was heated at 7 ° C for 20 hours. After cooling, the solvent was removed in vacuo to give a crude residue. This was then purified by silica gel column chromatography (14 g) eluting with ethyl acetate: hexane (75:25) and then with undiluted ethyl acetate. Pooling and evaporation of the appropriate fractions yielded a partially purified product. This was further purified by preparative HPLC condition 1) to afford the formate formate of the title compound (16 mg, 12%) as a yellow oil.

¹ H-NMR (300 Hz, CDCl ₃ , formic acid): 0.85 (t, 3H), 1.70 (q, 2H), 2.05 (quintet, 2H),

2.15 (s, 2H), 4H), 2.95 (s, 7.10 (m, 2H),

2.55 (s, 3H), 2.70 (t, 2H), 2.80-2.85 (m, 3H), 3.70-3.80 (m, 2H), 7.00 (d, 1H), 7.057.20-7.28 (m, 3H), 7.90 (d, 2H), 8.40 (s,

1H).

MS (Electrospray): M / Z (MH) 439; C25H32N2O3S-H requires 439.2

Example 200:

N- (3- {3- [2-benzyloxy) benzyl] -6-ethyl-3-aza-bicyclo [3.1. (Hex-6-yl} phenyl) methanesulfonamide

To a solution of 2-benzyloxybenzaldehyde (27 mg, 0.13 mmol) in dichloromethane (5 mL) at room temperature was added N- [3- (6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl] ] trifluoroacetic acid methanesulfonamide salt (50 mg, 0.13 mmol) and triethylamine (0.05 mL, 0.38 mmol). The reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (40.8 g, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water (5 mL) 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 dried under a stream of nitrogen. The residue was purified by column chromatography using a Sep-Pak ™ column packed with silica gel (10 g) eluting with hexane: ethyl acetate (100: 1, 1: 1, 1: 3, 1: 6, 1: 9 and 1: 100) to give the title compound. Compound (28 mg, 46%) as an oil.

¹ H-NMR (300 Hz, CDCl ₃ ): 0.85 (t, 3H), 2.80 (s, 2H), 2.002.10 (m, 2H), 2.85 (d, 2H), 3, Δ0 (s, 3H), 3.10-3.20 (dd, 2H), 3.80 (s, 2H), 5.10 (s, 2H), 6.90-7.05 (m, 3H) 7.10 (m, 2H); 7.20-7.30 (m, 3H); 7.40-7.50 (m, 6H).

MS (Electrospray): M / Z (M + H) 477; C28H32N2O3S + H requires 477.

Example 201:

N - {3- [3- (4-Cyanobenzyl) -6-ethyl-3-α-bicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

The title compound was prepared in the same manner as in Example 167 using the trifluoroacetic acid N- [3- (6-ethyl-3-aza-bicyclo [3.1.0] hex-6-yl) -phenyl] -methanesulfonamide salt (100 mg, 0, 25 mmol) and 4-cyanobenzaldehyde (33 mg, 0.25 mmol) as starting material, the product was purified using preparative HPLC (condition 3) to give the title compound (28 mg, 28%) as an off-white solid.

¹ H-NMR (300 Hz, CDCl ₃ ): 0.85 (t, 3H), 1.80 (s, 2H), 2.05 (q, 2H), 2.80 (d, 2H), 3, Δ (s, 3H), 3.10 (d, 2H), 3.70 (s,

2H), 7.00-7.20 (m, 3H), 7.20 (m, 1H), 7.40 (d, 2H), 7.60 (d, 2H)

MS (Electrospray): M / Z (M + H) 396; C22H25N3O2S-H requires 396

Example 202

N- (3- {3- [2- (4-cyclopropylphenoxy) ethyl-6-ethyl] -3-azabicyclo [3.1.0] hex-6-yl} phenyl) methanesulfonamide

H

TFA sul

H

Cl

H

O

N

To a solution of trifluoroacetic acid salt with N- [3- (6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl] methanesulfonamide (75 mg, 0.19 mmol) in Ν, Ν-dimethylformamide (3 mL) sodium bicarbonate (64 mg, 0.8 mmol), 1- (2-chloro-ethoxy) -4-cyclopropylbenzene (41 mg, 0.21 mmol) and sodium iodide (3 mg, catalytic) were added and the reaction mixture was heated at 60 ° C for 20 hours. After cooling, the solvent was removed in vacuo to give a crude residue. This was then purified by preparative HPLC (condition 2) to give the salt of the title compound with formic acid (4 mg, 5%) as a brown resin.

¹ H-NMR (300 Hz, CDCl ₃ , formic acid salts): 0.55 -0.60 (m, 2H), 0.80-0.95 (m, 5H), 1.80-1 90 (m, 3H), 2.25 (bs, 2H), 2.95 (s, 3H), 3.15 (d, 2H), 3.45 (t, 2H), 3.80-3, 90 (m, 2H), 4.20 (t, 2H), 6.90 (d, 2H), 7.00 (d, 2H), 7.05-7.15 (t, 2H), 7.20 (s, 1H), 7.30 (t, 1H).

MS (Electrospray): M / Z (MH) 439; C25H32N2O3S-H requires 439.2

Example 203:

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

To a mixture of trans-2-phenylcyclopropylcarboxaldehyde (ref. J. Org. Chem., 1992, 57, 1526) (30 mg, 0.2 mmol) and trifluoroacetic acid salt with N - [3- (6-ethyl-3-azabicyclo) [3.1.0] hex-6-yl) phenyl] methanesulfonamide (50 mg, 0.13 mmol) in dry 1,2-dichloroethane was added Hunig's base (0.02 mL, 0.12 mmol). The mixture was sonicated for 3 min, then stirred for 30 min and sodium triacetoxyborohydride (50 mg, 0.25 mmol) was added. The mixture was stirred for 72 hours and was then diluted with ethyl acetate (50 mL) and partitioned with saturated sodium bicarbonate (2 x 25 mL). The organic layer was washed with brine (2 x 20 mL), dried over sodium sulfate anhydride, filtered, and the solvent was evaporated under reduced pressure to give a tan oil.

¹ H-NMR (300 Hz, CDCl ₃ ): 0.70-0.90 (m, 3H), 0.97 (m, 1H),

1.24 (m, 1H), 1.72 (m, 1H), 1.76-1.79 (m, 2H), 1.9-2.05 (m, 2H), 2.45 (dd, 1H), 2.60 (dd, 1H), 2.84-2.95 (m, 2H), 2.99 (s, 3H), 3.02-3.08 (m, 2H), 6.98 -7.3 (m, 9H).

MS (Electrospray): M / Z (M + H) 411; C ₂₄ H ₃₀ SO ₂ N ₂₊ H requires 411

Preparations

Preparations 1 to 148 of International Published Patent Application WO 00/39089 are incorporated herein by reference in their entirety and hence the numbering.

Preparation 149 1- [4- (3-Chloropropyl) phenyl] ethanone

Aluminum chloride (15.0 g, 11 mol) and acetyl chloride (16.0 g, 0.20 mol) were dissolved in dichloromethane (50 mL) at room temperature. This mixture was then added dropwise to a solution of 1-chloro-3-phenylpropanone (15.5, g, 0.10 mol) in dichloromethane (25 mL) at room temperature over 15 minutes. The mixture was stirred for 1 hour and then poured carefully on ice. The aqueous layer was extracted with dichloromethane (450 mL). The organic layer was washed with brine and dried (MgSO ₄ ) and concentrated in vacuo to give the title compound (19.2 g, 98%) as an oil.

1 H-NMR (300 Hz, CDCl ₃ ): 2.10 (quintet, 2H), 2.60 (s, 3H),

2.85 (t, 2H), 3.55 (t, 2H), 7.30 (d, 2H), 7.90 (d, 2H).

MS (thermospray): M / Z [+ ₄ ] ⁺ 214; ChHi ₃ C 10 + NH ₄ requires 214.1

Preparation 150

1- (2-Chloroethoxy) -4-cyclopropylbenzene

HIM

Cl

4-Cyclopropylphenol) 6.75 g, 50.3 mmol, reference: Horror et al., Org. Prep. Proceed, Int. 1992, 24 (6): 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 nitrogen atmosphere at reflux for 30 min. hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (1000 mL). The organic phase was washed with water (3 x 250 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo.

The resulting crude material was purified by silica gel column chromatography eluting with hexane: dichloromethane (4: 1) and then hexane: dichloromethane (3: 1) to afford the title compound (8.7 g, 88%) as a solid.

Melting point: 47-48 ° C 1 H-NMR (300 Hz, CDCl ₃ ): 0.60-0.70 (m, 2H), 0.85-0.95 (m, 2H), 1.80-1 95 (m, 1H); 3.81 (t, 2H); 4.21 (t, 2H); 6.82 (d, 1H);

2H), 7.02 (d, 2H)

MS (thermospray): M / Z (M) 196; C _for Hi ₃ OC1 requires 196.1

Preparation 151 1-Allyl-1H-pyrrole-2,5-dione (see J. Org. Chem., 1997, 62,

2652)

To a solution of maleic 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 1 hour. clock. 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 mixture was heated to a warm 80 ° C. 1,1,1,3,3,3-Hexamethyldisilazane (242 g, 1.5 mol) in toluene was added dropwise over 1 hour and the mixture was stirred at 80 ° C for another 4 hours. The mixture was cooled to room temperature and then poured into 1N HCl (4000 mL). The two layers were separated and the organic layer was washed with water (2000 mL), saturated bicarbonate (2000 mL), and brine (2000 mL). The organic phase was then concentrated in vacuo to give the title compound (74 g, 54%) as a solid.

¹ H-NMR (300 Hz, CDCl ₃ ): 4.05 (d, 2H), 5.05-5.15 (m, 2H),

5.60-5.80 (m, 1H); 6.65 (2H, s)

Preparation

1- (3-Nitrophenyl) -1-propanone hydrazone

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 to 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 (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give an orange oil. This residue was crystallized from diisopropyl ether at -20 ° C to give the title compound ( 110 g, 61%) as a yellow crystalline solid.

Melting point. 32 ° C ^X H-NMR (300 MHz, CDC1 _3): 1.20 (t, 3H), 2.70 (q, 2H), 5.65 (limit s, 2H), 7.50 (t, 1H ), 7.95 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H).

MS (electrospray): M / Z [m H] ⁺ 194; C9HUN3O2 + H requires 194.1.

Preparation

3-Allyl-6-ethyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione

To a stirred solution of 1- (3-nitrophenyl) propanone hydrazone (84.7 g, 439 mmol) in 1,4-dioxane (1000 mL) was quickly added manganese dioxide (CMD-1 type from Sumitromo, 175 g, 2.01). mol) and a saturated solution of potassium hydroxide in ethanol (40 ml) at room temperature. The mixture was stirred at room temperature for 18 minutes, during which time the reaction temperature rose from 19 ° C to 25 ° C. Stirring was then stopped and the mixture was allowed to settle. The mixture was then filtered through a Celite® filter dropwise, directly into a solution of 1-allyl-1H-pyrrole-2,5-dione (57.3 g, 418 mmol) in 1,4-dioxane (200 mL). The filter packed with Celite® was washed with 1,4-dioxane (100 mL) to ensure complete addition of the reactants.

After stirring at room temperature for 1 hour, the mixture was heated to reflux for 20 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was crystallized from diisopropyl ether (1000 mL) at 0 ° C to give the title compound (83 g, 66%) as an off-white crystalline solid.

Melting point: 128-129 ° C ¹ H-NMR (300 Hz, CDCl ₃ ): 0.90 (t, 3H), 1.80 (q, 2H), 2.80 (s, 2H), 4.05 (d, 2H), 5.20 (d, 1H), 5.30 (d, 1H), 5.75-5.85 (m, 1H), 7.55 (t, 1H), 7.70 (d, 1H); dd, 1H), 8.20 (dd, 1H), 8.25 (s, 1H).

Preparation

3-Allyl-6- (3-aminophenyl) -6-ethyl-3-azabicyclo [3.1.0] hexane-2,4-dione

-> · o

o • ·

To a stirred suspension of 3-allyl-6-ethyl-6- (nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (93 g, 310 mmol) and iron powder (151 g, 2.70 mol) in ethanol (6.75 L) calcium chloride (16.7 g, 0.15 mol) in water (1.2 L) was added. The mixture was heated to reflux for 3 hours and then cooled to room temperature before filtration 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 (MgSO ₄ ), filtered and concentrated in vacuo to give a pale yellow solid (81 g). This material was crystallized from ethyl acetate and hexane (1: 1; 6 mL / g) at room temperature to afford the title compound (54 g, 65%) as a light yellow solid.

¹ H-NMR (300 Hz, CDCl ₃ ): 0.90 (t, 3H), 1.75 (q, 2H), 2.75 (s,

2H), 3.95 (broad s, 2H), 4.05 (d, 2H) , 5.35 (d, 1H), 5.75 5.85 (m, 1H), 6.65 (d, 1 H), 6, 70 (with, 1H), 6.75 (d, 1 H), 7.10 (t, 1H). Preparation 155

3- (3-Allyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) aniline

To a solution of lithium aluminum hydride (1 M, solution in THF; mL, 400 mmol) in tetrahydrofuran (400 mL) under nitrogen

400

3-allyl-6- (3-aminophenyl) -6-ethyl-3-azabicyclo [3.1.0] hexane-2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 mL) was added at -15 ° C. ) through a dropping funnel within 0.5 hour. The mixture was then allowed to slowly warm to room temperature over 1 hour. The mixture was heated at 50 ° C for 3 hours and then cooled to 5 ° C. Water (400 mL) was then carefully added to the cooled (5 ° C) reaction mixture. The solid was filtered through a pad of Celite®, washed with ethyl acetate (400 mL). The filtrate was dried (MgSO 4), filtered and concentrated in vacuo to yield

the title compound (38.1 g, 96%) in the form of gold oil. ¹ H-NMR (300 Hz, CDCl ₃ ): 0.85 (t, 3H), 1.80-1.95 (m, 4H); 2.85-3.00 (m, 4H); 3.15 (d, 2H), 3.60 (broad s, 2H), 5.10 (d, 1H), 5.20 (d, 1H), 5.80 -5, 95 (m, 1H); 6.50 (d, 1H); 6.60 (s, 1 H), 6.65 (d, 1 H), 7.05 (t, 1 H).

MS (AP ⁺ ) M / Z [MH] ^< + &^gt;243; C ₁₆ H ₂ N ₂ + H requires 243.2.

Preparation 156

N- [3- (3-Allyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) aniline

To a solution of 3- (3-allyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) aniline (41 g, 169 mmol) and triethylamine (34 g, 337 mmol) in dichloromethane (750 mL) at - Methylsulfonyl chloride (23.7 g, 206 mmol) was added dropwise at 40 ° C via a dropping funnel. The reaction mixture was then allowed to warm slowly to room temperature over two hours and then stirred at room temperature for 20 hours. Then, the organic solution was 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 resin.

¹ H-NMR (300 Hz, CDCl ₃ ): 0.85 (t, 3H), 1.85 (s, 2H), 1.95 (q, 2H), 2.80-3.20 (m, 9H) ), 5.10-5.25 (m, 2H), 5.80-5.95 (m,

1H), 7.00-7.40 (m, 4H).

Preparation 157

N- [3- (6-Ethyl-3-ayabicyclo [3.1.0] hex-6-yl) phenyl] methanesulfonamide

To a degassed solution of N- [3- (3-allyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl] methylsulfonamide (5-4.0 g, 169 mmol) and 1,3- Dimethylbarbituric acid (80.0 g, 512 mmol) in dichloromethane (500 mL) under a nitrogen atmosphere was added tetrakis (triphenylphosphine) palladium (0) (2.0 g, 1.73 mmol). The mixture was heated to reflux for 8 hours and then stirred at room temperature for 20 hours. The organic solution was then extracted with 2 M HCl (2 x 100 mL) and water (1000 mL). The combined aqueous layers were then washed with dichloromethane (4 x 100 mL) and freeze dried to give a crude solid. This material was purified by preparative HPLC (condition 4) to give the title compound salt of trifluoroacetic acid (25.2 g, 53%) as a gray solid.

¹ H-NMR (300 Hz, CD ₃ OD): 0.90 (t, 3H), 1.65 (q, 2H), 2.30-2.40 (m, 2H), 2.90 (s, 3H), 3.25-3.35 (m, 2H), 3.70-3.80 (m,

2H), 7.10-7.15 (m, 2H), 7.20 (s, 1H), 7.30 (t, 1H).

MS (AP ⁺ ): M / Z [MH] ^< + &^gt;281; C ₁₄ H ₂₀ N ₂ O ₂ S + H requires 281.1

Preparation 158:

3-Benzyl-6-methyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione

To a solution of 1- (3-nitrophenyl) -1-ethanone hydrazone (100 g, 0.56 mol) in dioxane (1 L) was added MnO ₂ (350 g, 2.3 mol) and the reaction mixture was stirred at room temperature for 30 minutes. The slurry was then filtered through celite and the celite filter was washed with dioxane (200 mL). The filtrate was returned to the flask and N-benzylmaleimide (110 g) was added portionwise over 20 minutes. The reaction mixture was stirred at room temperature for 4 hours and then heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated in methanol (500 mL) and the product isolated by filtration as a white crystalline solid (56%).

¹ H-NMR (CDCl ₃ ): 1.31 (s, 3H), 1.55 (s, 3H), 2.80 (s, 2H),

4.63 (s, 2H), 7.28-7.34 (m, 3H), 7.43-, 7.45 (d, 2H), 7.52-7.56 (t, 1H), 7 63-7.65 (d, 1 H), 8.13-8.16 (d, 1 H), 8.17 (s, 1 H).

MS (APCI): M / Z [MH < ⁺ >]337.5; + H requires 337.3

Preparation 159:

6- (3-Aminophenyl) -3-benzyl-6-methyl-3-azabicyclo [3.1.0] hexane-2,4-dione

To a slurry of 3-benzyl-6-methyl- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (30 g, 89 mmol) in ethyl acetate (600 mL) was added 5% Pt / C (1.5 g, 5 wt%). The mixture was hydrogenated at 4 atm, (= 60 psi) / room temperature for 18 hours. The slurry was filtered through arbacel and the resulting solution was evaporated in vacuo to give the product as a white crystalline solid (24 g, 88%).

¹ H-NMR (CDCl ₃ ): 1.26 (s, 3H), 2.74 (s, 2H), 3.7 (2H, bs),

4.60 (s, 2H), 6.56-6.58 (d, 1H), 6.60 (s, 1H), 6.65-6.67 (d, 1H), 7.07-7.11 ( t, 1H), 7.26-7.33 (m, 3H), 7.42-7.44 (m, 2H).

MS (APCI): M / Z [MH < ⁺ >]307.5; + H requires 307.4

Preparation 160:

N- {3- [3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

To a solution of 6- (3-aminophenyl) -3-benzyl-6-methyl-3-azabicyclo [3.1.0] hexane-2,4-dione (24.7 g, 78 mmol) in ethyl acetate (480 mL) was added pyridine ( 9.5 mL, 118 mmol) and then methanesulfonyl chloride (9.1 mL, 118 mmol) was added slowly. The reaction mixture was stirred for 2.5 hours. The reaction mixture was washed sequentially with 1 M HCl solution and water (120 mL). The ethyl acetate was dried over MgSO ₄ and evaporated in vacuo to yield the product as an orange solid (30 g, 99%).

¹ H-NMR (CDCl ₃ ) d: 1.27 (s, 3H), 2.77 (s, 2H), 3.02 (s, 3H),

4.61 (s, 2H); 7.08-7.14 (m, 3H); 7.26-7.32 (m, 4H); 7.41-7.42 (d, 2H).

MS (APCI): M / Z [MH < ⁺ >]385.7; + H requires 385.5 ♦ ♦ · ·

Preparation 161:

N- {3- [B-Benzyl-5-methyl-1-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

To a solution of N- {3- [3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide (150 g, 391 mmol) under nitrogen atmosphere was added sodium borohydride (31 g, 820 mmol). The reaction mixture was cooled to less than 10 ° C and BF ₃₀ O ₂ (138.6 mL, 1094 mmol) was added dropwise at less than 10 ° C. The reaction mixture was then allowed to warm to room temperature over 2 hours and then heated to reflux for an additional 8.5 hours. The reaction mixture was cooled to between 0 ° C and 5 ° C and an aqueous solution of piperazine (198.5 g, 2304 mmol in 1.26 L of water) was added. The reaction mixture was then heated to reflux for 18 hours. The THF was removed in vacuo, ethyl acetate (900 mL) was added and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (450 mL). The organic phases were combined and washed with water (750 mL). Then they were dried over MgSO ₄ and evaporated in vacuo to give the product as a white crystalline solid (129 g, 93%).

¹ H-NMR (CDCl ₃ ) d: 2.62 (s, 3H), 2.80-2.83 (d, 2H), 2.99 (s, 3H), 3.03-3.07 (d 2H, 3.68 (s, 2H), 7.01-7.02 (s, 1H), 7.06-7.08 (m, 2H), 7.22-7.26 (m, 3H) 7.30-7.32 (m, 3H).

MS (APCI): M / Z [MH ^+] 357.5; + H requires 357.5

Preparation 162

N- (3- [6-Methyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl] methanesulfonamide

To a solution of {- {3-benzyl- [6-methyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide (20 g, 56 mmol) in methanol was added ammonium formate (10.61 g) (168 mmol) and the reaction mixture was stirred for 5 minutes. 10% Pd / C (8 g) was added and the resulting mixture was heated to reflux for 16 hours. The reaction mixture was then allowed to cool and the catalyst was removed by filtration through celite. The solvent was removed in vacuo to yield a pale yellow oil which solidified on standing (15.2 g, 85%).

¹ H-NMR (CDCl ₃ ) d: 1.27 (s, 3H), 1.85-1.88 (d, 2H), 2.93 (s, 3H), 3.07-3.10 (d (2H), 3.39-3.44 (d, 2H), 6.92-6.97 (m,

2H), 7.06 (s, 1H), 7.20-7.23 (m, 1H).

MS (APCI): M / Z [MH < ⁺ >] 267.4; + H requires 267.3

Preparation 163

3-Benzyl-6-ethyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione

To a solution of 1- (3-nitrophenyl) -1-propanone hydrazone (42.1 g, 217 mmol) in dioxane (630 mL) was added MnO ₂ (126 g, 1440 mmol) and the reaction mixture was stirred at room temperature for 20 minutes. The slurry was filtered through celite, and the celite was washed with dioxane (200 mL). The filtrate was returned to the flask and N-benzylmaleimide (44.9 g, 239 mmol) was added portionwise over 20 minutes. The reaction mixture was stirred at room temperature for 60 hours and then heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was heated to reflux in methanol (1200 mL) for 3 hours and then cooled to room temperature. The product was isolated by filtration as a white crystalline solid (42.4 g, 56%) ¹ H-NMR (CDCl ₃ ) d: 0.69-0.73 (t, 3H), 1.47-1.49 (q, 2H)

2.78 (s, 2H), 4.64 (s, 2H), 7.3-7.32 (m, 2H), 7.43-7.44 (d, 1H), 7.52-7, 55 (t, 1H); 7.62-7.65 (d, 2H); 8.17-8.18 (m,

3H).

MS (APCI): M / Z [MH < ⁺ >]351.5; + H requires 351.3

Preparation 164:

6- (3-Aminophenyl) -3-benzyl-6-ethyl-3-azabicyclo [3.1.0] hexane-2,4-dione

To a slurry of 3-benzyl-6-ethyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione in ethyl acetate (850 mL) was added 5% Pt / C (2.1 g, 5% by weight). The mixture was hydrogenated at 60 psi / room temperature for 18 hours. The mixture was filtered through arbacel and the resulting solution was evaporated in vacuo to yield the product as a white crystalline solid (34.1 g, 89%).

NMR (CDC1 3) d: 0.70-0.74 (t, 3H) 1.41-1.47 (q. 2H), 2.73 (with, 2H), 3, 66 (bs, 2H) 4.61 (s, 2H), 6,55- 6, 57 (d, 1 H), 6, 60 (with, 1H), 6.66-6.68 (d, 1 H), 7.07-7.10 (t, 1H), 7.28- 7.32 (m, 3H), 7.41-7.43 (d 2H).

MS (APCI): M / Z [MH < ⁺ >] 321.4; + H requires 321.4 • *

Preparation 165:

N- {3- [3-Benzyl-6-ethyl-2,4-dioxo-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

To a solution of 6- (3-aminophenyl) -3-benzyl-6-ethyl-3-azabicyclo [3.1.0] hexane-2,4-dione (31.5 g, 98 mmol) in dichloromethane (250 mL) was added pyridine (9.5 mL, 118 mmol) and then methanesulfonyl chloride (9.1 mL, 118 mmol) was added slowly. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed sequentially with 1M HCl solution (250 mL) and water (120 mL). Dichloromethane was dried over MgSO ₄ and evaporated in vacuo to yield the product as a waxy pink solid (38.2 g, 98%).

NMR (CDCl ₃ ) d: 0.68-0.72 (t, 3H), 1.42-1.47 (q, 2H), 2.75 (s, 2H), 3.02 (s, 3H) 4.62 (s, 2H); 7.13-7.18 (m, 3H); 7.29-7.42 (m, 4H); 7.41-7.43 (d 2H).

MS (APCI): M / Z [MH ⁺ ] 399.6; + H requires 399.5

Preparation 166:

N- {3- [3-Benzyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

To a solution of N- {3- [3-Benzyl-6-ethyl-2,4-dioxo-3-azabicyclo [3.1.0] hex-6-yl] phenyl] methanesulfonamide (38.2 g, 95 mmol) in THF (200 mL) mL) sodium borohydride (7.46 g, 201 mmol) was added under nitrogen. The reaction mixture was cooled to less than 10 ° C and BF ₃₀ O 2 (38.1 mL 268 mmol) was added dropwise, maintaining the temperature below 10 ° C. The reaction mixture was allowed to warm to room temperature over 2 hours and was then heated to reflux for an additional 12 hours. The reaction mixture was cooled to between 0 and 5 ° C and an aqueous solution of piperazine (48.7 mg, 565 mmol in 320 mL water) was added. The reaction mixture was then heated to reflux for 18 hours. THF was removed in vacuo, ethyl acetate (200 mL) was added and the phases were separated. The aqueous phase was extracted with a second portion of ethyl acetate (200 mL ·). The organic phases were combined and washed with 3 separate portions of water (3-400 mL). Then they were dried over MgSO 4 and evaporated in vacuo to yield the product as a white crystalline solid (33.5 g, 94%).

NMR (CDCl ₃ ) d: 0.84-0.88 (t, 3H), 1.76-1.77 (d, 2H), 2.062.12 (g, 2H), 2.79-2.81 ( d, 2H), 2.99 (s, 3H), 3.06-3.08 (d, 2H), 3.67 (s, 2H), 7.01-7.03 (d, 1H), 7 10-7.10 (d, 2H); 7.22-7.26 (m, 3H); 7.30-7.32 (m 3H).

MS (APCI): M / Z [MH ⁺ ] 371.3; + H requires 371.5

Preparation 167:

N- {3- [6-Ethyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide

To a solution of N- {3-benzyl- [6-ethyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl] methanesulfonamide (500 mg, 1.34 mmol) in methanol (30 mL) was added ammonium formate ( 255 mg, 4.05 mmol) and the reaction mixture was stirred for 5 minutes. 10% Pd / C (200 mg) was added and the resulting mixture was heated to reflux for 2 hours. The mixture was then allowed to cool and the catalyst was removed by filtration through celite. The solvent was removed in vacuo to yield the product as a pale yellow oil which solidified on standing (15.2 g, 85%).

NMR (CDCl 3) d: 0.80-0.84 (t, 3H), 1.64-1.69 (q, 3H), 1.8299

1.86 (d, 2H), 2.98 (s, 3H), 3.12-3.18 (d, 2H), 3.21-3.26 (d, 2H), 7.01-7, Δ (d, 1H), 7.10-7.14 (m, 2H), 7.25-7.28 (m,

1H).

MS (APCI): M / Z [MH ⁺ ] 281.7; + H requires 281.4

100 ALIGN!

Other compounds useful for the synthesis of compounds of formula I with various R ⁴ groups are available from the starting materials listed in the table below and by their routine derivatization or analogous synthesis.

R⁴ substituents Example of commercial

Claims (34)

Claims Compounds of formula I wherein the ring "Ar" represents an optionally benzofused phenyl or a 5- or 6-membered heteroaryl ring; R ¹ , when alone, is H, halogen, NO ₂ , NH ₂ , NY ² WY ¹ , Het ^1, AD, CO ₂ R ^7, C (O) R ^8, C (= NOH) ^R8, or OE, Y ² is H, Ci-6 alkyl, C _3-6 alkenyl (each of which alkyl and alkenyl may be optionally substituted aryl, aryloxy or Het ^1), W is SO ₂ CO, C (O) O, P (Y ^X ) = O, Ρ (Υ ^Χ ) = 3, Y ¹ is C 1-10 alkyl (optionally substituted with one or more substituents independently selected from halogen, OH, C 4 alkoxy, C ₆ alkanoyloxy, CONH _2, C ₆ alkoxycarbonyl, _NH2, aryl, mono- or di (C ₄ alkyl) amino, C _3-8 cycloalkyl, phthalimidyl, ^{Het1), Het1,} aryl (optionally substituted by one or more substituents independently selected from the group consisting of C _3.4 alkyl, C ₄ haloalkyl and halogen), NH _2, N (C ₃ -6 alkyl) _2, alkyl NHfX) 109 • 4 · 444 4 44 « 44 * Het ¹ is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may consist of up to 3 rings (preferably a heteroaryl group, optionally a benzo- or pyrido-fused heteroaryl), optionally substituted with one or more substituents independently selected from Ci_6 alkyl, C ₆ alkoxy, C _3-6 cycloalkyl, C ₆ haloalkoxy, Ci_6 haloalkyl, C3-6 halogencykloakylu, = 0, OH, halogen, N0 _2, SiR ^19a R ^19b R ^{19c, 20a} CON R ^20b, NR ^20a R ^20b , SR ^21a , NR ^21b SO 2 R ^22a , NR ^21c C (O) OR ^22b , NR ^21d COR ^22d and C 1-6 alkoxycarbonyl and if the ring contains an S atom, this atom is present as part of -S-, S (O) - or -S (O ₂ ) -groups and carbon atoms in the ring may be present as part of a carbonyl group; R ^19a , R ^19b , R ^19c each independently represent C 1-6 alkyl or aryl; And R ² ° _{and R} 20b independently represent Η, C1-6 alkyl, aryl, (C1-4 alkyl) -phenyl, wherein each of the groups alkyl, aryl and alkylphenyl are optionally substituted by one or more groups selected from the group consisting of C ₄ alkyl, C 1-4 alkoxy, OH, NO ₂ , NH ₂ , and / or halogen, or R ^20a and R ^20b together with the N atom to which they are attached form a 4- to β-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of C 1-4 alkyl, C _1-4 alkoxy, OH, = O , NO ₂ NH ₂ and / or halogen, R ^21a , R ^21b , R ^21c and R ^21d each independently represent H, C 1-6 alkyl, aryl or C _1-4 alkylphenyl, wherein each of alkyl, aryl and alkylphenyl is optionally substituted with one or more substituents selected from the group consisting of C _1-4 alkyl, C _1-4 alkoxy, OH, NO ₂ , halogen, NH ₂ , 110 • * * · ··· · · · ··· ··· R ^22a , R ^22b and R ^22c each independently represent C 1-8 alkyl, aryl or C 1-4 alkylphenyl, each optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, C _1-4 alkoxy, OH, NO ₂ , halogen, NH ₂ , A is C 4 alkylene, C _2-4 akenylen, C ₂ _ ₄ akynylen, each of which is optionally substituted with one or more substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen and / or OH, , D is H, OH, CN, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , NHR ²⁷ , CO ₂ R ²⁸ , COR ²⁹ , C (= NOH) R ²⁹ or AD is CN, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , wherein R ²⁵ and R ²⁵ each independently represent H, C 1-3 alkyl, C3-8 cycloalkyl, aryl, C1-4 alkylphenyl (each of the groups C 1-3 alkyl, C ₃ _ ₈ cycloalkyl, aryl, C _x _ ₄ alkylphenyl optionally substituted by one or more groups selected from the group consisting of NO ₂ , halogen, C _1-4 alkyl and / or C 1-4 alkoxy, (each of the last C _1-4 alkyl and C _1-4 alkyl groups C 1-4 alkoxy is optionally substituted with one or more halogen atoms), or R 25 _and R 26 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from the group which is N, O and S and which is optionally substituted by one or more substituents from the group consisting of C 1-4 alkyl, OH, = O, NO ₂ , NH ₂ and / or halogen, R ^{2 7} is COR ³⁰ , CO2R ^31a , SO2R ^31b , 111 ··· ··· ··· ·· » R ²⁸ and R ²⁹ each independently represent H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl and C _1-4 alkylphenyl, wherein each of the C 1-6 alkyl, C _3-8 cycloalkyl, aryl, C _1-4 alkylphenyl is optionally substituted with one or more groups selected from the group consisting of NO ₂ , halogen, C ₄ _ ₄ alkyl, CX- ₄ alkoxy, (each of the last _four groups Cx_ alkyl and C 1-4 alkoxy optionally substituted by one or more halogen atoms), R ³⁰ is H, C _1-4 alkyl, C 3-8 cycloalkyl, C _1-4 alkoxy, C 3-8 cycloalkoxy, aryl, aryloxy, C _1-4 alkylphenyl, phenyl (C 1-4) alkoxy, (wherein each of the C _1-4 alkyl, C ₃ _ ₈ cycloalkyl, C 1-4 alkoxy, C _3-8 cycloalkoxy, aryl, aryloxy, C1-4 alkylphenyl and phenyl (Cx_ ₄₎ alkoxy optionally substituted with one or more substituents selected from the group consisting of N0 _2, halogen, C _1-4 alkyl or C _1-4 alkoxy (wherein the last alkyl and alkoxy are optionally substituted with one or more halogen atoms)). R ^31a and R ^31b each independently represent C _1-4 alkyl, C ₃ _ ₈ cycloalkyl, aryl or Cx_ ₄ alkylphenyl, each of which is optionally substituted by one or more substituents selected from the group consisting of N0 _2, halogen, Cx- _C4 alkyl or alkoxy Cx_ _4, wherein each of the last of the alkyl and alkoxy is optionally substituted with one or more halogen atoms. E is H, CONR ³² R ^33, CSNR ³² R ^33, COR ^34, CO 2 R ^34, COCH (R ^34a) NH 2, R ^35, CH2CO2R ^35a, CHR ^35b CO 2 R ^35a, CH2OCO2R ^35c, CHR ^35d OCO2R ^35c CoCr ³⁶ = CR ³⁷ NH2, COCHR ³⁶ CHR ³⁷ NH2 or PO (OR ³⁸ ) ₂ R ³² and R ³³ each independently represents H, C ₃ _x ₀ alkyl alkenyl, C 3-7 cycloalkyl (optionally substituted Cx_ ₄ alkyl), 112 phenyl (optionally substituted by (X) _n), C-io alkyl (optionally substituted by C4-7 cycloalkyl (optionally substituted 0χ- ₄ alkyl) or phenyl · optionally substituted by (X) _n), or R ³² and R ³³ together with the N atom to which they are attached may form a 5- to 8-membered heterocycle, optionally containing additional heteroatoms selected from N, O and S, which is optionally substituted with C _1-4 alkyl, which is optionally substituted one or more halogen atoms, R ³⁴ is H, C 4-7 cycloalkyl (optionally substituted with one or more C 1-4 alkyl) phenyl (optionally substituted with (X) n, C 1-4 alkanoyloxy, NR ³² R ³³ , CONR ³² R ³³ and / or OH) or C 1-7 Alkyl (optionally substituted with one or more substituents selected from the group consisting of halogen, C4-7 cycloalkyl (optionally substituted with one or more C 1-4 alkyl groups)) or phenyl (optionally substituted with one or more groups selected from the group consisting of (X) _n , C 1-4 alkanoyloxy, NR ³² R ³³ , CONR ³² R ³³ and / or OH), R ^34a is H, C 1-6 alkyl (optionally substituted with one or more substituents from the group consisting of halogen atoms, C 4-7 cycloacyl (optionally substituted with one or more C 1-4 alkyl) or phenyl (optionally substituted with (X) _n , C 1-4 alkanoyloxy, NR ³² R ³³ , CONR ³² R ³³ and / or OH)), _C4 _7 cycloalkyl (optionally substituted with one or more of C 1-4 alkyl), phenyl (optionally substituted by (X) _n, C 1-4 alkanoyloxy, NR ³² R ^33, CONR ³² R ³³ and / or OH) or a residue of naturally occurring amino acids, R ³⁵ is C ₄ -7 cycloalkyl, optionally substituted with one or 113 more C ₄ alkyl groups, phenyl (optionally substituted by one or more (X) _n, C ₄ alkanoyl, NHR ^32, CON (R ^{3 ')} 2 and / or OH), C g alkyl (optionally substituted C ₄ _7 cycloalkyl, which is optionally substituted by one or more C ₄ alkyl or phenyl (optionally substituted by one or more (X) _n, C _1-4 alkanoyl, NHR ³² , CON (R ³² ) ₂ and / or OH)), C _1-4 alkoxy (C _1-4 alkyl), phenyl (C _1-4 ) alkyloxy (C _1-4 ) alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, R ^35a , R ^35b , R ^35c and R ^35d each independently represent H, _C4 -7 cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of C ₄ alkyl, phenyl optionally substituted with one or more (X) _n or C 6 alkyl (optionally substituted C _4-7 cycloalkyl, which is optionally substituted with one or more C 1-4 alkyl or phenyl groups, optionally substituted with one or more (X) _n ), ₆ R3 and R37 each independently represents H, C ₃ _ ₆ alkyl alkenyl, C _4-7 cycloalkyl, phenyl optionally substituted with one or more (X) _n or C1-6 alkyl (optionally substituted _C4 -7 cycloalkyl, which is optionally substituted by one or more C ₄ alkyl or phenyl optionally substituted with one or more (X) _n), R ³⁸ is C ₄ -7 cycloalkyl optionally substituted by one or more C ₄ alkyl, phenyl optionally substituted with one or more (X) _n or C ₆ alkyl (optionally substituted C ₄ _ ₇ cycloalkyl which is optionally substituted with one or more C - ₄ alkyl or phenyl, optionally substituted with one or more (X) _n ), 114 R ² when independently represents H or halogen; or R ¹ and R ² , when attached to adjacent carbon atoms, may together with the carbon atom to which they are attached represent Het ^{1 a} ; Het ^1a is a heterocyclic group containing up to 4 heteroatoms selected from the group consisting of N, O and S, which may consist of up to 3 rings (and preferably represents a benzofused 5- to 7-membered heterocyclic ring) optionally substituted with one or more substituents independently selected from OH, = 0, halogen, C _x - ₄ alkyl, C ₄ haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy, which C 1-4 alkyl group, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy may be optionally substituted with one or more substituents selected from the group consisting of C 3-6 cycloalkyl, aryl (C _1-6 ) alkyl, wherein the aryl may be optionally substituted with one or more groups from the group consisting of halogen atom, C 1-4 alkyl, C _1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy, the last C _1-4 alkyl, C _x _ ₄ haloalkyl, C 1-4 alkoxy and C _x _4 haloalkoxy groups can be optionally substituted by one or more NR ²³ R ^24, NR ²³ S (0) n R ^24, NR ²³ C (0) m R ^24, and if an S atom present in the ring may be part of the groups -S-, S (O) -, -S (O ₂ ) -, wherein R ²³ and R ²⁴ , when independently represent, H, C 1-4 alkyl or C 1-4 haloalkyl, or R ²³ and R ²⁴ together with the N atom to which they are attached may form a 4- to 6-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from N, O and S, wherein the heterocyclic ring is optionally ♦ * * * ** ** ** ** ** ** ** ** ** ** ** ** 115 substituted with one or more groups selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and / or C 1-4 haloalkoxy, R ³ is H, CN, halogen, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, _C2 -6 alkanoyl, C ₂ -6 alkanoyloxy, C _3-3 cycloalkyl, C 3-8 cycloalkoxy, C 4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR ¹² R ^13, CONR ¹² R ^13, NY ² WY ^1, C 1-6 alkyl, C ₂ -i ₀ alkenyl, C _2-10 alkynyl (wherein each of alkyl, alkenyl, and alkynyl is optionally substituted by one or more CN, halogen, OH, C _x 6 alkoxy, C1-6 alkoxycarbonyl, _C2 -6 alkoxycarbonyloxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, C _3-8 cycloalkyl, C ₃ -g cycloalkyloxy, C 4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocyclyl, NR ¹² R ¹³ , CONR ¹² R ¹³ and / or NZ ² WY ¹ ), R ⁴ is C 1-10 alkyl, C 3-10 alkenyl, C ₃ . ₁₀ alkynyl wherein each of these groups is linked to the N atom via an sp ³ carbon, wherein the group is substituted with one or more substituents selected from the group consisting of: _C2 _6 alkoxy [substituted by one or more radicals selected from the group consisting of OH, NR ²⁵ R ^26, CONR ²⁵ R ^26, halogen, C _alkoxy, C _2-4 alkynyl, _C2 -4 alkenyl, heteroaryl ^1, aryl ¹ , COCH ² CN, CO (heteroaryl ¹ ), CO (aryl ¹ ), CO 2 (heteroaryl ¹ ), COCH ₂ (aryl ¹ ), COCH ₂ (heteroaryl ¹ ), CO ₂ CH ₂ (aryl ¹ ), CO ₂ CH ₂ (heteroaryl ¹ ), S (O) _n (C 1-6 alkyl), S (O) _n (aryl ¹ ), S (O) _n (aryl ¹ ), S (O) n (heteroaryl ¹ ), SO ² NR ²⁵ R ²⁶ and cycloalkyl ¹ ], S (O) _n C _1-6 alkyl [optionally substituted with one or more groups selected from OH, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , halogen, Ci_6 alkoxy, _C2 -4 alkynyl, C ₂ _ ₄ alkenyl, heteroaryl, - ^1, aryl ^1, COCH2CN, CO ^{(heteroaryl1),} CO (aryl ^1), C02 (heteroaryl ^1), • · * 116 COCH? ^(Aryl1), COCH2 (heteroaryl ^1), ₂ CO2CH ^(aryl1), CO2CH2 ^{(heteroaryl1),} S (O) n (C _C6 alkyl), S (0) _n ^(aryl1), S ( O) n (heteroaryl ¹ ), SO ² NR ²⁵ R ²⁶ and cycloalkyl ¹ ], aryl ² , CO ₂ CH ₂ (heteroaryl ¹ ) CO ² CH ² -aryl ¹ ), cycloalkyl ¹ , CO (heteroaryl ¹ ), CO (aryl ¹ ) OCO (aryl ^x ) OC0 (heteroaryl ¹ ), 0C0 _{(Ci_6} alkyl) OCOCH ₂ CN CO ₂ (heteroaryl ¹ ), C0 ₂ (aryl ¹⁾ COCH ₂ (heteroaryl ¹ ), S (O) n (aryl ¹ ), S (O) _n CH ₂ (aryl ¹ ), S (0) n (heteroaryl ^1). S (O) _n CH ₂ (heteroaryl ¹ ), NHSO ₂ (aryl ¹ ), NHSO ₂ (C _1-6 alkyl), NHSO2 (heteroaryl ¹ ) NHSO ₂ CH ₂ (heteroaryl ¹ ), NHSO 2 CH 2 (aryl ¹ ), NHCO (aryl ¹ ) NHCO (C _1-6 alkyl), NHCONH (aryl ¹ ) NHCONH (C 1-6 alkyl), NHCO (heteroaryl ¹ ) NHCONH (heteroaryl ¹ ), NHCO ₂ (aryl ¹ ) 117 NHCCMC 1-6 alkyl), NHCO ₂ (heteroaryl ¹ ), aryl ² oxy, heteroaryl ¹ oxy, C 1-6 alkoxycarbonyl substituted with C 1-8 alkyl, aryl, C 1-6 alkoxy, C 1-4 Mar ¹ ), C 1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ^{2 S} , _C2 -6 alkanoyl substituted with C ₆ alkyl, aryl, C ₆ alkoxy, _CH2 ^(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ^2S, _C2 -s alkanoyloxy-substituted C ₆ alkyl, aryl, C 1-6 alkoxy, CH ₂ (aryl ¹ ), C _1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ²⁶ , cycloalkyloxy, COcycloalkyl ¹ , heterocyclyl substituted with one or more substituents selected from the group consisting of C 1-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , CH ₂ CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NHCONR ²⁵ R ²⁶ , CO (Ci_s alkyl), SO ₂ NR ²⁵ R ^26, SO ₂ (C _alkyl), CO ₂ (C _alkyl), C0 ₂ CH ₂ (C ₆ alkyl) OCH ₂ CO ₂ (C ₆ alkyl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C3-7 cycloalkyl, heterocyclyloxy substituted by one or more substituents selected from the group consisting of C _S alkyl (substituted by OH), CONR ²⁵ R ^26, CH ₂ CONR ²⁵ R ^26, NR ²⁵ R ^25, NHCONR ²⁵ R ^26, CO _{(Ci_6} alkyl), SO ₂ NR ²⁵ R ^{2 S,} SO ₂ {C ^ ₅ alkyl), C0 ₂ (Cx- _C6 alkyl), CO ₂ CH ₂ (C ₆ alkyl) OCH ₂ CO ₂ (C - ₅ alkyl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C3-7 cycloalkyl, wherein aryl ¹ is phenyl, optionally fused to a C _5-7 carbocyclic ring, wherein the group is optionally substituted with one or more substituents selected from the group consisting of: 118 is C 1-6 alkyl (optionally substituted with OH, CN or halogen), C 1-6 haloalkoxy, OH, = O, NY ² WY ¹ , halogen, C 1-6 alkoxy, CONR ²⁵ R ²⁵ , CH ₂ CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NHCONR ²⁵ R ²⁵ , CO (C _1-6 alkyl), COaryl, COheteroaryl, SO ₂ NR ²⁵ R ²⁶ , S (O) _n (C _1-6 alkyl), S (O) _n (aryl), S (O) _n (heteroaryl), CO ₂ (C 1-6 alkyl), CO ₂ (aryl), CO ₂ (heteroaryl), CO ₂ H, (CH ₂ ) _2-4 CO ₂ (C 1-6 alkyl), (CH ₂ ) i- ₄ CO ₂ H, (CH ₂ ) _1-4 CO ₂ (aryl), (CH ₂ ) _1-4 CO ₂ (heteroaryl), O (CH ₂ ) _1-4 CO ₂ (C _1-6 alkyl), O ( CH ₂ ) _1-4 CO ₂ H, O (CH ₂ ) _1-4 CO ₂ (aryl), O (CH ₂ ) _1-4 CO ₂ (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH ₂ ) oxy, aryl (CH ₂ ), CN, O (CH ₂ ) ₁₄ CONR ²⁵ R ²⁵ a _C3 _7 cycloalkyl. aryl ² is phenyl, optionally fused to a C 5-7 carbocyclic ring, which group is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , CH ² CONR ²⁵ R ²⁵ , NR ²⁵ R ^26, NHCONR ²⁵ R ^2s, CCUCi-alkyl), COaryl, COheteroaryl, SO 2 NR ²⁵ R ^26, s (O) n (C - _C6 alkyl), s (0) _n (aryl), s (0) _n ( heteroaryl), CO ₂ (C _1-6 alkyl), CO ₂ (aryl), CO ₂ (heteroaryl), CO ₂ H, (CH ₂ -C ₁ C ₂ -C ₆ alkyl), (CH ₂ ) _1-4 CO ₂ H, ( CH ₂ ) _1-4 CO ₂ (aryl), (CH ₂ ) _1-4 CO ₂ (heteroaryl), O (CH ₂ ) _1-4 CO ₂ (C 1-6 alkyl), O (CH ₂ ) _1-4 CO ₂ H , 0 (CH ₂₎ i ₄ CO ₂ (aryl), 0 (CH ₂₎ 4 _CO-2 (heteroaryl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN, O (CH ₂ ) _1-4 CONR ²⁵ R ²⁶ and C ₃ . ₇ cycloalkyl. heteroaryl ¹ is heteroaryl optionally fused to A C 5-7 carbocyclic ring, which group is optionally substituted with one or more substituents selected from the group consisting of C _1-6 alkyl (optionally substituted with OH, CN or halogen), C 1-6 haloalkoxy, OH, = 0, NY ² WY ¹ , halogen, C 1-6 alkoxy, CONR ²⁵ R ²⁶ , CH ² CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NHCONR ²⁵ R ²⁶ , CO (C 1-6 alkyl), COaryl, CO heteroaryl, SO ₂ NR ²⁵ R ²⁶ , «·« «· · 119 s (O) _n (C 1-6 alkyl), S (O) _n (aryl), S (O) _n (heteroaryl), CO ₂ (C 1-6 alkyl), CO ₂ (aryl), CO ₂ (heteroaryl), CO ₂ H, (CH ₂ ) 1-4 CO ₂ (C 1-6 alkyl), (CH ₂ ) _1-4 CO ₂ H, (CH ₂ ) _1-4 CO ₂ (aryl), (CH ₂ ) _1-4 CO ₂ (heteroaryl), 0 (CH ₂ ) _1-4 CO ₂ (C _1-6 alkyl), 0 (CH ₂ ) i - ₄ CO ₂ H, O (CH ₂ ) _1-4 CO ₂ (aryl), O (CH ₂ ) _1-4 CO ₂ (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH ₂ ) oxy, aryl (CH ₂ ) CN O (CH ₂ ) _1-4 CONR ²⁵ R ²⁶ and C 3-7 cycloalkyl, cycloalkyl ¹ is a C 3-10 carbocyclic system with one or two rings which is substituted with C _1-6 alkyl, aryl, C1-6 alkoxy, _CH2 (aryl ^1), C ₄ haloalkyl, halogen, OH, CN or NR ²⁵ R ²⁶ 'provided that it does not contain NR ⁴ groups in which the heteroatom is linked to another heteroatom by one sp 3 carbon, Z is a direct bond, CO or S (O) _n group, B is (CH _{2) p,} R ¹² and R ¹³ each independently represent H or C 1-4 alkyl, or R ¹² and R ¹³ together with the nitrogen atom to which they are attached may form a 4- to 7-membered heterocycle which optionally contains an additional hetero group selected from NR ¹⁶ , O and / or S and which is optionally substituted with one or more C _1-4 groups alkyl, R ¹⁴ and R ¹⁵ each independently represent H, C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C ₃ _ ₈ cycloalkyl, aryl or heteroaryl, • · 120 R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached may form a 4- to 7-membered heterocycle which optionally contains an additional hetero group selected from NR ^1c , O and / or S and which is optionally substituted with one or more C ₁ groups - ₄ alkyl, R ¹⁶ is H, Ci_6 alkyl, C ₃ _ ₈ cycloalkyl, (Ci-6 alkylene) (C ₃ - _B cycloalkyl) or (Ci-β alkylene) aryl, R ⁵ and R ⁸ when independently, each independently represent H, C 1-6 alkyl, R ⁵ and R ⁹ may together with the carbon atom to which they are attached form a C ₃ _ ₈ cycloalkyl ring, R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are independently H R ⁵ and ^R or R ⁷ may together with the carbon atom to which they are attached form C ₃ _G cycloalkyl ring, X is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy, m is 1 or 2; n is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; q is 0 or 1; "Naturally occurring amino acid residues are α-substituents that originate from any *" 121 of the following natural amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histiaine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid, aspargin, glutamine, lysine, arginine, proline; "Heteroaryl means an aromatic ring containing up to four heteroatoms selected from N, O, and S, and if an S atom is present in the ring, it may be present as part of the group -S-, S (O) -, -S (O) ₂ -, wherein the heteroaryl may be attached to the remainder of the compound via any suitable atom or atoms; "Heterocyclyl" is a group containing 1, 2 or 3 rings containing up to 4 ring heteroatoms selected from N, O and S and a maximum of 18 ring carbon atoms. "Aryl, including the meaning of the definition of" aryloxy, etc., means a phenyl ring-containing group which may further comprise another carbocyclic ring fused to said phenyl, wherein the aryl may be attached to the remainder of the compound via any suitable atom or atoms (e.g. naphthyl, indanyl, etc.) .); The groups "alkyl," alkenyl, "alkynyl may be linear or branched if the number of atoms allows; A "cycloalkyl" group may be polycyclic if the number of carbon atoms allows; or a pharmaceutically or veterinarily acceptable derivative thereof and a prodrug thereof. 122 A compound according to claim 1, wherein "Ar is phenyl or pyridyl. A compound according to any one of the preceding claims, wherein R ¹ , when alone, is OH, CN, halogen, NO ₂ , NH ₂ , NY ² WY ^x or Het ¹ . A compound according to any one of the preceding claims, wherein R ² , when alone, is H. A compound according to claim 1 or 2 wherein R ¹ and R ² together with the carbon atoms to which they are attached form an optionally benzofused, 5- to 7-membered heteroaryl ring optionally substituted with C _1-4 alkyl or C _1-4 haloalkyl. A compound according to any one of the preceding claims wherein X is Cl. A compound according to any one of the preceding claims wherein n is 0 and q is 0. A compound according to any one of the preceding claims wherein R ³ is H, CN or C 1-6 alkyl (optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkoxy. C 1-6 alkoxycarbonyl, _C2 -6 alkanoyl, C ₂ -6 alkanoyloxy, C ₂ - _to alkyloxycarbonyloxy, NR ¹² R ^13, CONR ¹² R ¹³ and / or NY-Y ^1). A compound according to any one of the preceding claims, wherein R ^q is C 1-10 alkyl substituted with one or more substituents selected from the group consisting of: • · 123 C ₂ -6 alkoxy [substituted by one or more radicals selected from the group consisting of OH, NR ²⁵ R ^26, CONR ²⁵ R ^26, halogen, Ci_6 alkoxy, C2-4 alkynyl, Ο2_4 alkenyl, ^{heteroaryl1, aryl1,} COCH2CN, CO (heteroaryl ¹⁾ COfaryl ^1), C02 (heteroaryl ^1), COCH2 ^(aryl1), COCH2 (heteroaryl ^1), ₂ CO2CH (aryl ¹⁾ CO ₂ CH ₂ (heteroaryl ¹ ), S (O) _n (C _1-6 alkyl), S (O) _n (aryl ¹ ), S (O) _n (heteroaryl ¹ ), SO ₂ NR ²⁵ R ²⁶ and cycloalkyl ¹ ], S (O) NC 1-6 alkyl [optionally substituted with one or more groups selected from OH, NR ²⁵ R ²⁶ , CONR ²⁵ R ²⁶ , halogen, Ci_6 alkoxy, _C2 -4 alkynyl, C ₂ _ ₄ alkenyl, heteroaryl \ ^aryl1, COCH2CN, CO ^{(heteroaryl1),} CO (aryl ^1), C02 (heteroaryl ¹⁾ COCH ₂ (aryl ¹ ), COCH ₂ (heteroaryl ¹ ), CO ₂ CH ₂ (aryl ¹ ), CO ₂ CH 2 (heteroaryl ¹ ), S (O) _n (C _1-6 alkyl), S (O) _n (aryl ¹ ), S (O) _n (heteroaryl ¹ ), SO ₂ NR ²⁵ R ²⁶ and cycloalkyl ¹ ], aryl ² , CO ₂ CH ₂ (heteroaryl ¹ ) CO ₂ CH ₂ (aryl ¹ ), cycloalkyl ¹ , CO (heteroaryl ¹ ), COIaryl ¹ ), OCOaryl ¹ ), OC0 (heteroaryl ¹ ), OC0 (C1-6 alkyl), OCOCHzCN, CO ₂ (heteroaryl ¹ ), C0 ₂ (aryl ¹⁾ COCH ₂ (heteroaryl ¹ ) S (O) _n (aryl ¹ ), S (O) _n CH ₂ (aryl ¹ ), S (0) _n (heteroaryl ^1). S (O) _r CH ₂ (heteroaryl ¹ ), 124 NHSO ₂ (aryl ¹ ), NHSO ₂ (C 1-6 alkyl), NHSO ₂ (heteroaryl ¹ ) NHSO ₂ CH ₂ (heteroaryl ¹ ), NHSO 2 CH 2 (aryl ¹ ), NHCO (aryl ¹ ), NHCO (C _alkyl), NHCONH (aryl ¹ ), NHCONH _{(Ci_6} alkyl) NHCO (heteroaryl ¹ ), NHCONH (heteroaryl ¹ ) NHCO ₂ (aryl ¹ ) NHCO 2 (ΟΙ-g alkyl), NHCO ₂ (heteroaryl ¹ ), aryl ² oxy, heteroaryl ^x oxy, C 1-6 alkoxycarbonyl substituted with C _1-6 alkyl, aryl, C 1-6 alkoxy, CH ₂ (aryl ¹ ), C 1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ²⁶ , C ₂₆ alkanoyl substituted with _{Ci_6} alkyl, aryl, C ₆ alkoxy, _CH2 (aryl ^1), C 1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ^26, C ₂ -6 alkanoyloxy-substituted C ₆ alkyl, aryl, C 1-6 alkoxy, CH ₂ (aryl ¹ ), C 1-4 haloalkyl, halogen, OH, CN or NR ²⁵ R ²⁵ , cycloalkyl ¹ oxy, Cycloalkyl ¹ , heterocyclyl substituted with one or more substituents selected from the group consisting of C _1-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , CH ₂ CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , NHCONR ²⁵ R ²⁶ , CO (C _1-6 alkyl), SO ₂ NR ²⁵ R ²⁶ , SO ₂ -C 1-6 alkyl), CO ₂ (C _1-6 alkyl), CH ₂ CO ₂ (C 1-6 alkyl), OCH ₂ CO ₂ (C _1-6 alkyl) ), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C _3-7 cycloalkyl 125 heterocyclyloxy substituted with one or more substituents selected from the group consisting of C _1-6 alkyl (substituted with OH), CONR ²⁵ R ²⁶ , CH ₂ CONR ²⁵ R ²⁶ , NR ²⁵ R ²⁶ , nhconr ²⁵ R ²⁶ , CO (C _1-6 alkyl), SO ₂ NR ²⁵ R ²⁶ , SO ₂ (C _1-6 alkyl), CO ₂ (C _1-6 alkyl), CH ₂ CO ₂ (C 1-6 alkyl), OCH ₂ CO ₂ ( _{Ci_6} alkyl), aryl, heterocyclyl, aryloxy, aryl _(CH2) oxy, aryl _(CH2), CN and C _{3rd 7} cycloalkyl, A compound according to any one of the preceding claims, wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , when alone, are all H. A compound according to any one of the preceding claims, wherein "Ar represents a group of the formula: R ² A compound according to any one of the preceding claims, wherein R ³ is H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , n C ₃ H ₇ or CH ₂ OCH ₃ . A compound according to any one of the preceding claims, with the exception of claim 5, wherein R ¹ is OH, CN, I, Cl, NH ₂ , NO ₂ , optionally benzofused heteroaryl, NHSO ₂ Y ¹ , NHCOY ¹ or NHCO ₂ Y ¹ . A compound according to any one of the preceding claims, wherein R ⁴ is C 1-10 alkyl substituted with cycloalkyl ¹ ' A compound according to any one of the preceding claims; 126 except for claims 3, 4 and 13 wherein R ¹ and R ² together with the carbon atoms to which they are attached form a 5-membered heteroaryl, optionally substituted with C _1-4 alkyl or C _1-4 haloalkyl. A compound according to any one of the preceding claims, wherein R ³ is CH 3 or C ₂ H 5. A compound according to any one of the preceding claims, with the exception of claims 5 and 15, wherein R ¹ when alone is OH, CN, I, Cl, NH ₂ , NO ₂ , 1,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO ₂ (C 1-6 alkyl), NHSO ₂ ( C _1-6 alkyl substituted by methoxy, CONH ₂ , OH, CO ₂ (C ₂ -6 alkyl), phthalimido, _NH2 or halogen), NHSO ₂ NH _2, NHSO ₂ NH (C - _C6 alkyl), NHSO ₂ N _(X C - _C6 alkyl) _2, NHSO ₂ Het _la , NHCO (C _1-6 alkyl) or NHCO ₂ (C _1-6 alkyl). A compound according to claim 17, wherein R ¹ is OH, NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ (nC ₃ H ₇ ), NHSO ₂ (iC ₃ H ₇ ), NHSO ₂ (nC ₄ H) ₇ ), NHSO ₂ NH (iC ₃ H ₇ ), NHSO ₂ (N-methylimidazol-4-yl), NHSO ₂ (CH ₂ ) ₂ OCH ₃ , NHSO ₂ (CH ₂ ) ₂ OH, 1,2,4-triazolyl or imidazol-2-yl. A compound according to claim 18 wherein R ¹ is OH, NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ or imidazol-2-yl. A compound according to claim 15, wherein R ¹ and R ² together with the carbon atoms to which they are attached form an imidazole group of an optionally 2-substituted CF ₃ 21. A compound according to any preceding claim, wherein R ⁴ represents C _2-4 alkyl, substituted cykloalkylenr. 127 A compound according to any one of the preceding claims, wherein R ⁴ is propyl substituted with cycloalkyl ¹ . A compound according to any one of the preceding claims, wherein R ⁴ is propyl substituted with a C 3-10 carbocyclic system with one or two rings which is substituted with OH. A compound according to any preceding claim, wherein R ⁴ is propyl substituted (cyclohexyl, substituted with OH). A compound according to any one of the preceding claims, wherein R ⁴ is (1-hydroxycyclohexyl) prop-3-yl. The compound of claim 1 having the following relative stereochemistry: A compound according to claim 1, which is selected from the compounds described in the Examples herein, salts and prodrugs thereof. A pharmaceutical or veterinary composition comprising a compound according to any one of the preceding claims, and 128 a pharmaceutically or veterinarily acceptable carrier. A compound according to any one of claims 1 to 26 for use in medicine. A compound according to any one of claims 1 to 26 for use as a medicament suitable for the treatment of opioid-mediated diseases or conditions. Use of a compound according to any one of claims 1 to 26 for the manufacture of a medicament suitable for the treatment of diseases or conditions mediated by opiate receptors. A method of treating conditions mediated by an opioid receptor or receptors comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 26. 33. A method for producing a compound according to claim 1 comprising: (a) for compounds of formula I wherein q is 0 and R ¹ is NY ² WY ¹ , reacting a compound of formula II with a compound of formula III, zMjy ¹ (III), 129 • · · · · · · · · · · · · · · · · · · · · · · «♦ ♦ ♦ ♦ ♦ ♦ ··· ··· ··· ··· ·· ·· wherein Z ¹ is a suitable leaving group, Y 2 C 2 O-; such as halogen or (b) for compounds of formula I wherein q is 0 and R ⁶ and R ⁷ both represent H, a reduction of the compound of formula IV, (IV), using a suitable reducing agent; (c) for compounds of formula I wherein q is 0 is H, reduction of a compound of formula V, and R ⁹ and R ¹⁰ both using a suitable reducing agent; (V), 130 (d) for compounds of formula I in which q is 0 and R ¹ and R ² are bonded to adjacent carbon atoms and together with the carbon atoms to which they are attached represent Het ^Ia in which Het ^Ia represents an imidazole group by reaction corresponding to a compound of formula VI, (VI), with a compound of formula VII, Rycote ₂ H (VII) wherein R ^y represents H or any of the possible substituents on Het ^la (as defined above), preferably H, Cl-4 alkyl or C _x - ₄ haloalkyl; with a compound of formula IX, 131 Ug R ⁴ (IX) wherein LG is a leaving group; (f) for compounds of formula I wherein q is 0 and R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are all H, by reduction of a compound of formula X, with a suitable reducing agent; (g) for compounds of formula I wherein q is 0 and R ¹ is OH, by reacting a compound of formula II as defined above, wherein Y ² is H, with fluoroboric acid and nitroisopentyl; (h) for compounds of formula I wherein q is 0 and R ¹ is Cl, by reacting a compound of formula II wherein Y ² is H as defined above with sodium nitrite in the presence of dilute acid, followed by reaction with cuprous chloride in the presence concentrated acids; (i) for compounds of formula I wherein q is 1, by reacting a compound of formula I wherein q is 0 with a suitable oxidizing agent such as aqueous hydrogen peroxide; or 132 (j) for compounds of formula 1 wherein q is 0, by reducing the corresponding compound of formula XXXI, wherein R ^{4 and} CH ₂ have the same meaning as R ⁴ as defined above, (k) for compounds of formula I wherein q is 0, by a reductive amination reaction of an amine of formula VIII as defined above with an aldehyde of formula R ^4a CHO, where R ^4a CH ₂ has the same meaning as R ⁴ as defined above, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically or veterinarily acceptable derivative or vice versa. 34. Compounds of formulas II, IV, V, VI, X, ^X, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, or XXXI, or a salt thereof as defined above.