MXPA02012878A

MXPA02012878A - 3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity.

Info

Publication number: MXPA02012878A
Application number: MXPA02012878A
Authority: MX
Inventors: David Morris Gethin
Original assignee: Pfizer
Priority date: 2000-06-23
Filing date: 2001-06-07
Publication date: 2003-05-14
Also published as: EA005117B1; TNSN01094A1; ZA200210278B; EP1292574A1; NZ523141A; WO2001098267A8; JP2004512263A; GB0015562D0; NO20026168L; BG107329A; WO2001098267A1; AR028969A1; HRP20020998A2; CZ20023967A3; EA200201269A1; PA8519401A1; UA73176C2; PL365956A1; YU91802A; HUP0301228A2

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

DERIVATIVES OF 3-AZABICICLO (3.1.0) HEXANO THAT HAVE AFFINITY WITH OPIOID RECEPTORS DESCRIPTIVE MEMORY This invention relates to pharmaceutically useful compounds, in particular to compounds that bind opioid receptors (eg, mu, kappa and delta opioid receptors). Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opioid receptors, for example irritable bowel syndrome, constipation, nausea, vomiting and pruritic dermatosis, such as allergic dermatitis and atopy in animals and humans. . Compounds that bind opioid receptors have also been indicated for the treatment of eating disorders, opioid overdoses, depression, tobacco and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and brain trauma. There is a particular need for an improved treatment of the itch. Itching, or pruritus, is a common dermatological symptom that can lead to considerable discomfort in both animals and humans. Pruritus is often associated with inflammatory skin diseases that may be caused by hypersensitivity reactions, including reactions against insect bites, such as mosquito bites, and against environmental allergens, such as dust mites. domestic or pollen, bacterial or fungal infections of the skin, or ectoparasitic infections. Existing treatments that have been used in the treatment of pruritus include the use of corticosteroids and antihistamines. However, it is known that both treatments have undesired side effects. Other therapies that have been used include the use of dietary supplements of essential fatty acids, although these have the disadvantages of being slow to act and offering only limited efficacy against allergic dermatitis. A series of emollients such as petrolatum, glycerin and lanolin are also employed, but with limited success. Thus, there is a continued need for alternative and / or improved pruritus treatments. Certain compounds based on 4-arypiperidines are described among others in the European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. In addition, the international patent application WO 95/15327 describes azabicycloalkane derivatives useful as neuroleptic agents. The international patent application WO00 / 39089, filed before the priority date of the present application, but published after it, is hereby incorporated by reference in its entirety, and discloses azabicycloalkanes of similar structure to that described below in the present, with different R4 groups. According to the invention, a compound of formula I is provided, (0) q (i) wherein the "Ar" ring represents a phenyl optionally fused with benzene or a 5- or 6-membered heteroaryl ring; R1, when taken alone, is H, halogen, N02, NH2, NY2WY1, Het1, AD, C02R7, C (0) R8, C (= NOH) R8, or OE, Y2 is H, C? -6 alkyl, C6-alkenyl (each of the alkyl and alkenyl is optionally substituted with aryl, aryloxy or Het1), W is S02, CO, C (0) 0, P (Y1) = 0, P (Y1) = S, Y1 is C-MO alkyl (optionally substituted with one or more substituents independently selected from halogen, OH, Ci-4 alkoxy, C-γ-6 alkanoyloxy, CONH2, Ci-β alkoxy, NH2, aryl, mono- or dialkyl (Ci-4) amino, C3-8 cycloalkyl, phthalimidyl, Het1, aryl (optionally substituted with one or more substituents independently selected from C- [alpha] 4 alkyl, haloalkyl CM and halogen), NH2, N (C [alpha] -6) alkyl or NH (C- | 6 alkyl), Het1 is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally heteroaryl condensed with benzene or with pyridyl), optionally substituted with one or more substituents independently selected from C? -6 alkyl, C6-6 alkoxy, C3-6 cycloalkyl. haloalkoxy C -? - 6, haloalkyl C -? - 6, halocycloalkyl C3-6, = 0, OH, halogen, N02, SiR19aR19bR19c, CONR20aR20b, NR20aR20b, SR21a, NR21bS02R22a, NR21cC (0) OR22b, NR21dCOR22b and alkoxy (d. 6) carbonyl, and if an S atom is present in a ring, it may be present as part of a group -S-, S (0) - or -S (02) -, and the ring carbon atoms may be present. present as part of a carbonyl residue; R19a, R19b, R19c each independently represent C1-6 alkyl or aryl, R20a and R20b independently represent H, C6-6 alkyl, aryl, alkyl (C-? -4) phenyl, each of said alkyl, aryl and alkylphenyl is optionally substituted with one or more C1-4 alkyl, C1-4 alkoxy, OH, N02, NH2 and / or halogen, or R20a and R20b may be taken together with the N atom to which they are attached to form a ring of 4 to 6 members optionally substituted with one or more substituents independently selected from one or more C1-4 alkyl, C1-4 alkoxy, OH, = 0, N02, NH2 and / or halogen, p2ia, b, c and d represent each independently H , alkyl C? -6, aryl or alkyl (C? -4) phenyl, each of said alkyl, aryl and alkylphenyl being optionally substituted with one or more C1-4 alkyl, C1-4 alkoxy, OH, N02, halogen, NH2, R22a, b and c each independently represent Ci-β alkyl, aryl or C 1 -4 alkyl phenyl, each of said alkyl, aryl and alkylphenyl optionally substituted with one or more C? -4 alkyl, C-? - alkoxy, OH, N02, halogen, NH2, A is alkylene C? 4 > C2-4 alkenylene or C2-4 alkynylene, each being optionally substituted with one or more C - --4 alkyl, C1.4 alkoxy, halogen and / or OH, D is H, OH, CN, NR25R26, CONR25R26, NHR27 , C02R28, COR29, C (= NOH) R29, or AD is CN, NR25R26, CONR25R26, where R25 and R26 are each independently H, C1-3 alkyl, Cß-a cycloalkyl, aryl, alkyl (C? -) phenyl ( each of said C1-3 alkyl, Css cycloalkyl, aryl and C1-4 alkyl phenyl is optionally substituted with one or more N02, halogen, C1.4 alkyl and / or C1-4 alkoxy (each of these latter alkyl C1.4 and C1-4 alkoxy is optionally substituted with one or more halogens), or R25 and R26 are taken together with the N atom to which they are attached and can form a 4- to 7-membered heterocyclic ring optionally incorporating one or further additional heteroatoms selected from N, O and S, and said ring is optionally substituted with one or more C 1-4 alkyl, OH, = 0, N 0 2, NH 2 and / or halogen, R 27 is COR 30, C 0 R 32 A, S 02R31b, R28 and R29 are each independently H, C? -6 alkyl, cycloalkyl 03.3, aryl or alkyl (C-) phenyl, each of said C1-6 alkyl, C3-8 cycloalkyl, aryl and alkyl (C? 4) phenyl is optionally substituted with one or more N02, halogen, C1-4alkyl, C4-4alkoxy (each of the latter C4alkyl and C4alkoxy is optionally substituted with one or more halogens), R30 is H, C-alkyl ? -4, C3-8 cycloalkyl, C1-4 alkoxy, C3-8 cycloalkyloxy, aryl, aryloxy, alkyl (C1.4) phenyl, phenylalkoxy (C -? - 4), (each of said C1.4 alkyl, C3-8 cycloalkium, C1.4 alkoxy, C3-8 cycloalkyloxy, aryl, aryloxy, alkyl (C1-4) phenyl and (C1-4) phenylalkoxy is optionally substituted with one or more N02, halogen, C? -4 alkyl, C1-4 alkoxy (the latter alkyl and alkoxy are optionally substituted with one or more halogens)), R31a and R31b are each independently C1-4alkyl, Cs-cycloalkyl, aryl or (C 1-4) alkyl phenyl, each of which is optionally substituted with one or more N 0 2, halogen, C 1-4 alkyl, d-4 alkoxy, each of these latter being alkyl and alkoxy optionally substituted with one or more halogens, E is H, CONR32R33, CSNR32R33, COR34, COsR34, COCH (R343) NH2, R35, CH = COsR353, CHR ^ COsR353, CH = OCOaR350, CHR ^ OCOaR350, COCR36 = CR37NH2, COCHR36CHR37NH2, or POIOR38 ^, R32 and R33 are each independently H, C3-10 alkyl alkenyl, C3-7 cycloalkyl (optionally substituted with C1-4 alkyl), phenyl (optionally substituted with (X) n ), C-MO alkyl (optionally substituted with C 4-7 cycloalkyl (optionally substituted with C 1-4 alkyl) or phenyl optionally substituted with (X) n), or R32 and R33 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising additional heteroatoms selected from N, O and S, said heterocycle being optionally substituted with C 1-4 alkyl, optionally substituted with one or more halogens, R 34 is H, C 4-7 cycloalkyl (optionally substituted with one or more C? - alkyl), phenyl (optionally substituted with (X) n, alkanoyl (Ci ^ oxy, NR32R33, CONR32R33 and / or OH), or C? -6 alkyl (optionally substituted with one or more halogen, C4-7 cycloalkyl (optionally substituted with one or more C? - alkyl), or phenyl (optionally substituted with (X) n, alkanoyl NR32R33, CONR32R33 and / or OH)), R343 is H, Ci-β alkyl (optionally substituted with one or more halogens, C4-7 cycloalkyl (optionally substituted with one or more C1-4 alkyl), or phenyl (optionally substituted with (X) n, alkanoyl CONR ^ R33 and / or OH)), C4-7 cycloalkyl (optionally substituted with one or more C1.4 alkyl), phenyl (optionally substituted with (X) n, (C1) alkoxy) oxy, NR32R33, CONR32R33 and / or OH) or an amino acid substituent of natural origin, R35 is C4.7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl (optionally substituted with one ornas (X) n, alkanoyl (C1-), NHR32, CON (R32) 2 and / or OH), alkyl C ? -6 (optionally substituted with C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, or phenyl (optionally substituted with one or more (X) n, C1-4 alkanoyl, NHR32, CON (R32) 2 and / or OH)), alkoxy (C? -4) C? -4 alkyl, phenyl (C1-4 alkyl) C14 alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, R35a, b.cyd are independently capped ..H, C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl optionally substituted with one or more (X) non-C1-6 alkyl (optionally substituted with cycloalkyl 04-7 optionally substituted with one or more C1.4 alkyl, or phenyl optionally substituted with one or more (X) n), R3β and R37 each independently represent H, alkyl (C3-6) alkenyl, C4-7 cycloalkyl, phenyl optionally substituted with one or more (X) n, or Ci-β alkyl, (optionally substituted with C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, or phenyl optionally substituted with one or more (X) n), R38 is C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl optionally substituted with one or more (X) n, or Ci-β alkyl (optionally substituted with C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, or phenyl optionally substituted with one or more (X) n), R2 when taken alone is H or halogen; or R1 and R2, when attached to adjacent carbon atoms, may be taken together with the carbon atoms to which they are attached, and may represent Het1a; Het1a is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably a 5 to 7 membered heterocyclic ring) optionally condensed with benzene) and said group is optionally substituted with one or more substituents independently selected from OH, 0 =, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C? -4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy groups optionally substituted with one or more C 3-6 cycloalkyl, arylalkyl (C 1-6), the optionally substituted aryl group being with one or more halogen, C - - - 4 alkyl, C - - - 4 haloalkyl, C 1-4 alkoxy and C - haloalkoxy, the latter being C - alkyl, C - halo - 4 haloalkyl, C - - alkoxy and haloalkoxy C? - optionally substituted with one or more NR23R24, NR23S (0) nR24, NR23C (0) m, R24, and if an S atom is present in a ring, it may be present as part of a -S- group, S (O) - or -S (02) -, said R23 and R24 when taken alone independently represent H, C1-4 alkyl or C1-4 haloalkyl, or R23 and R24 may be taken together with the N atom at which are joined to form a 4- to 6-membered heterocyclic ring optionally comprising one or more additional heteroatoms selected from N, O or S, and said heterocyclic ring being optionally substituted with one or more halogen groups, C1-4alkyl, haloalkyl C1 -4, C1-4 alkoxy and / or C1-4 haloalkoxy, R3 is H, CN, halogen, C6-6 alkoxy, (C6-6) alkoxycarbonyl, C2.6 alkanoyl, (C2-6) alkanoyl oxy , C3-8 cycloalkyl, (C3-s) oxy cycloalkyl, C4.9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13, NY2WY \ C1-6 alkyl, C2-? 0 alkenyl, C2-10 alkynyl (each of said alkyl, alkenyl and alkynyl groups is optionally substituted with one or more CN, halogen, OH, C6-6 alkoxy, alkoxy (d-6) carbonyl, C2-6 alkyloxycarbonyloxy, C6-6 alkanoyl, C6-6 alkanoyloxy, C3-8 cycloalkyl , cycloalkyl (C. ß) oxy, C4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13 and / or NY2Y1), R4 is C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl. each of said groups is linked to the N atom through a sp3 carbon, and said group is substituted with one or more substituents selected from: C2-6 alkoxy [substituted with one or more groups selected from OH, NR25R26, CONR25R26, halogen, alkoxy d-β, C2.4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl), C02CH2 (aryl1), C02CH2heteroaryl1), S (0) n (alkyl d-6), S (0) n (aryl1), S (O) n (heteroaryl), S02NR25R26 and cycloalkyl1], S (O) n (Ci alkyl) -β) [optionally substituted with one or more groups selected from OH, NR25R26, CONR25R26, halogen, C ?S alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, heteroaryl, aryl, COCH 2 CN, CO (heteroaryl), CO ( aryl1), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl), C02CH2 (aryl1), C02CH2 (hetearyl1), S (0) n (alkyl d-e), S (0) n (aryl1), S (0) n (heteroaryl1), S02NR25R26 and cycloalkyl1)], aryl2, C02CH2 (heteroaryl), C02CH2 (aryl1), cycloalkyl1, CO (heteroaryl), CO (aryl1), OCO (aryl1), OCO (heteroaryl), OCO (C6-6 alkyl), OCOCH2CN, C02 (heteroaryl), C02 (aryl1), COCH2 (heteroaryl), S (0) narilo1, S (0) nCH2aryl1, S (0) n (heteroaryl), S (0) pCH2 (heteroaryl) 1, NHS02aryl1, NHS02 (C6-alkyl), NHS02 (heteroaryl), NHS02CH2 (heteroaryl), NHS02CH2 (aryl1), NHCOaryl1, NHCO (Cm alkyl), NHCONHaryl1, NHCONH (C1-6alkyl) NHCOheteroaryl1, NHCONHheteroaryl1, NHC02aryl1) NHC02 (C1-6alkyl), NHC02 (heteroaryl1), Aryl oxy, Heteroaryl1 oxy, alkyxycarbonyl d-β substituted with C6-6alkyl, aryl, alkoxy d-ß, CH2 (aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, C2-6 alkanoyl substituted with C6-6 alkyl, aryl, C1.6 alkoxy, CH2 (aryl1), haloalkyl C1-4, halogen, OH , CN or NR25R26, C2.6 alkanoyloxy substituted with C? -6 alkyl, aryl, C1-6 alkoxy, CH2 (aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, cycloalkyl oxy, CO-cycloalkyl1, heterocycle substituted with one or more substituents selected from alkyl d-6 (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (C 1-6 alkyl), S02NR25R26, S02 (C? -6 alkyl), C02 (alkyl) Ci-β), CH2C02 (C6-alkyl), OCH2C02 C6-6 alkyl), aryl, heterocyclyl, aryloxy, ariI (CH2) oxy, aryl (CH2), CN and C3-7 cycloalkyl, heterocyclyloxy substituted with one or more substituents selected from C1-6 alkyl (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (d-β alkyl), S02NR25R26, S02 (C1-6 alkyl), C02 (C1-6 alkyl), CH2C02 (alkyl d-6), OCH2C02 (d-β alkyl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN and C3.7 cycloalkyl, wherein aryl1 is phenyl optionally fused to a C5-7 carbocyclic ring. said group being optionally substituted with one or more substituents selected from d-β alkyl (optionally substituted with OH, CN or halogen), haloalkoxy d-6, OH, = 0, NY2WY1, halogen, C?-6 alkoxy, CONR25R26, CH2CONR25R26 , NR25R26. NHCONR25R26, CO (C 1-6 alkyl), Caryl, COheteroaryl, S02NR25R26, S (0) n (C? -6 alkyl), S (0) n (aryl), S (0) n (heteroaryl), C02 (alkyl) d-6), C02 (aryl), C02 (heteroaryl), C02H, (CH2) 1-4C02 (C1-6 alkyl), (CH2) 1-4C02H, (CH2) 1.4C02 (aryl), (CH2)? -4C02 (heteroaryl), O (CH2) 1-4C02 (alkyl d-6), 0 (CH2) 1-4C02H, 0 (CH2)? -4C02 (aryl), 0 (CH2)? -4C02 (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH2oxi, aryl (CH2), CN, O (CHs ^ CONR ^ R26 and C3-7 cycloalkyl) aryl2 is phenyl optionally fused with a C5-7 carbocyclic ring, said group being substituted with one or more substituents selected from C 1-6 alkyl (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (alkyl d-6), COaryl, COheteroaryl, S02NR25R26, S (0) n (C? -6 alkyl), S (0) n (aryl), S (0) n (heteroaryl), C02 (C? -6 alkyl), C02 (aryl), C02 (heteroaryl), C02H, (CH2) 1 ^ C02 (C? -6 alkyl) ), (CH2) 1 ^ C02H, (CH2) ^ C02 (aryl), (CH2)? - 4C02 (heteroaryl), 0 (CH2) i.4C02 (alkyl d.6), 0 (CH2) 1-4C02H, O (CH2)? - 4C02 (aryl) , 0 (CH2)? - 4C02 (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN, O (CH ^ CONR ^ R26 and C3-7 cycloalkyl. heteroaryl is heteroaryl optionally fused with a C5-7 carbocyclic ring, said group being optionally substituted with one or more substituents selected from C? -6 alkyl (optionally substituted with OH, CN or halogen), haloalkoxy d-b, OH, = 0 , NY2WY1, halogen, C? -6 alkoxy, CONR25R26, CH2CONR 5R26, NR25R26, NHCONR25R26, CO (C? -6 alkyl), Caryl, COheteroaryl, S02NR25R26, S (0) n (alkyl d-6), S (0) ) n (aryl), S (0) n (heteroaryl), C02 (alkyl d-6), C02 (aryl), C02 (heteroaryl), C02H, (CH2) 1-4C02 (alkyl d-6), (CH2) ) 1-4C02H, (CH2)? - 4C02 (aryl), (CH2)? - 4C02 (heteroaryl), 0 (CH2) 1.4C02 (alkyl d-6), 0 (CH2) 1-4C02H, 0 (CH2) 1-4C02 (aryl), 0 (CH2)? - 4C02 (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN, O (CH2)? - 4CONR25R26 and C3- cycloalkyl. Cycloalkyl1 is a C3-10 carbocyclic system with one or two rings and is substituted with d-β alkyl. aryl, C1-6 alkoxy, CH2 (aryl1), C4-4 haloalkyl, halogen, OH, CN or NR25R26, with the proviso that there are no N-R4 groups in which there is a heteroatom attached to another heteroatom by a carbon SP3. Z is a direct bond, a CO or S (0) n group, B is (CH2) P, R12 and R13 each independently represent H or C? -4 alkyl, or R12 and R13 may be taken together with the N atom. to which they are united to form a heterocycle of 4 to 7 members that optionally comprises an additional hetero moiety selected from NR16, O and / or S, and which is optionally substituted with one or more C1.4 alkyl, R14 and R15 each independently represent H, C-? -10 alkyl, C3-10 alkenyl , C3-10 alkynyl, cycloalkyl 03.3, aryl or heteroaryl, or R14 and R15 can be taken together with the N atom to which they are attached to form a 4- to 7-membered heterocycle optionally comprising an additional hetero moiety selected from NR16, O and / or S, and which is optionally substituted with one or more C1-4 alkyl, R16 is H, Ci.e alkyl, C8 cycloalkyl, (C6-6 alkylene) (C3.8 cycloalkyl) or -β) aryl, R5 and R8 when taken separately are each independently H, alkyl d-6, R5 and R8 can be taken together with the carbon atoms to which they are attached to form a cycloalkyl ring Cß-s, R6, R7, R9 and R10 when taken separately are H, R5 and R6 or R7 can be taken together with the volumes of carbon they are attached to form a C3.8 cycloalkyl ring, X is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or haloalkoxy C-, m is 1 or 2; n is 0, 1 or 2; p is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; q is 0 or 1; "amino acid substituent of natural origin" means the substituent a which occurs in any of the following natural amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid , glutamic acid, asparagine, glutamine, lysine, arginine or proline; "heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if an S atom is present in the ring, it may be present as part of a group -S-, S (O) - or -S (0) 2-, and which may be linked to the rest of the compound through any available atom (s); "heterocycle" is a group containing 1, 2 or 3 rings, and containing up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms; "aryl", including the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate an additional carbocyclic ring fused to said phenyl ring and which may be attached to the rest of the compound through any available atom (s) (examples of said groups include naphthyl, indanyl, etc.); the groups "alkyl", "alkenyl" and "alkynyl" may be linear or branched if the number of carbon atoms permits; the "cycloalkyl" groups can be polycyclic if the number of carbon atoms allows it; or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof. When a condensed heterocyclic group is present, it may be attached to the rest of the compound through any available atom (s). The "haloalkyl", "haloalkoxy" groups and the like may contain more than one halogen atom, and for example may be perhalogenated. Certain compounds of the invention may exist in one or more geometric and / or stereoisomeric forms. The present invention includes all said individual isomers and the salts and prodrugs thereof. Certain compounds of the present invention may exist in more than one tautomeric form. Analogously, certain compounds of the invention may have ionic dipolar forms. It will be understood that the invention encompasses all said tautomers, dipolar ions and their derivatives. The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts and the base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulfate, acid sulfate, nitrate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate salts , citrate, gluconate, succinate, benzoate, methanesulfonate, benzenesulfonate and p-toluenesulfonate. Suitable base salts are formed from bases that form non-toxic salts and are Examples are the aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review of suitable salts 10 see Berge et al., J. Pharm. Sci-, 66, 1-19 (1977). Those skilled in the art will note that certain protected derivatives of compounds of formula (I), which can be prepared prior to the final deprotection step, may not possess pharmacological activity as such, but may, in certain cases, be transformed after administration to the or in the body, for example by metabolism, to form compounds of formula (I) that are pharmacologically active. Said derivatives are included in the term "prodrug". Those skilled in the art will further observe that certain residues known to those skilled in the art as "prorrests", for example as those described in "Design of Prodrugs" by H. Bundgaard (Elsevier) 1985, can be placed on suitable functionalities, when said Functionalities are present in compounds of formula (I), to also form a "prodrug". In addition, certain compounds of formula I can act as prodrugs of other compounds of formula I. All protected derivatives, and prodrugs, of the compounds of formula I are included in the scope of the invention. Preferably the "Ar" ring represents phenyl or pyridyl. It is most preferred that the "Ar" ring represents a group of formula: Preferably, when R1 is taken alone it is OH, CN, halogen, N02, NH2, NY2WY1 or Het1. More preferably, when R1 is taken alone it is OH, CN, I, Cl, NH2, N02, heteroaryl optionally condensed with benzene, NHS02Y \ NHCOY1 or NHC02Y1. Even more preferably, when R1 is taken alone it is OH, CN, I, Cl, NH2, N02, 1, 2,3-triazolyl, 1,4-triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzoimidazol-2 ilo, NHS02Calkyl -6), NHS02 (C1-6alkyl substituted with methoxy, CONH2, OH, C02 (C2-6alkyl), phthalimido, NH2 or halogen), NHS02NH2, NHS02NH (C1-6alkyl), NHS02N (alkyl d-6) 2, NHS02Het1a, NHCO (C1-6 alkyl) or NHCO; (alkyl d-6). Even more preferably, R1 is OH, NHS02CH3, NHS02C2H5, NHS02 (n-C3H7), NHS02 (i-C3H7), NHS02 (n-C4H7), NHS02NH (i-C3H7), NHS02 (N-methylimidazol-4-yl) , NHS02 (CH2) 2OCH3, NHS02 (CH2) OH, 1, 2,4-triazolyl or imidazol-2-yl. It is most preferred that R1 is OH, NHS02CH3, NHS02C2H5 or imidazol-2-yl. Preferably, when R2 is taken alone it is H.

R1 and R2 when taken together with the carbon atoms to which they are attached are preferably a heteroaryl ring fused with 5-7 membered benzene, optionally substituted with C? -4 alquiloalkyl or C? --haloalkyl. More preferably, R1 and R2 when taken together with the carbon atoms to which they are attached are a member heteroaryl moiety optionally substituted with d-4 alkyl or C-α-4 haloalkyl. Even more preferably, R1 and R2 when taken together with the carbon atoms to which they are attached are an imidazole group optionally substituted in 2 with CF3. Preferably X is Cl. Preferably n is 0. Preferably q is 0. Preferably R3 is H, CN, C? -6 alkyl (optionally substituted with one or more halogen, OH, d-6-alkoxy, (C? -6) alkoxy) carbonyl, C2-6 alkanoyl, (C2-6) alkanoyl, oxy (C2-6) alkyloxycarbonyloxy, NR12R13, CONR12R13 and / or NY2WY1). More preferably, R3 is H, CH3, C2H5, i-C3H7, n-C3H7 or CH2OCH3. It is most preferred that R3 is CH3. Preferably, R 4 is C-MO alkyl optionally substituted with one or more substituents selected from: C2-6 alkoxy [substituted with one or more groups selected from OH, NR25R26, CONR25R26, halogen, d6 alkoxy, C2.4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl1) ), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl), C02CH2 (aryl1), C02CH2 (heteroaryl1), S (0) n (C6-6 alkyl), S (0) n (aryl1), S (0) n (heteroaryl1), S02NR25R26 and cycloalkyl1], S (0) n (d-β alkyl) [optionally substituted with one or more groups selected from OH, NR25R26, CONR25R26, halogen, d6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl1), C02 (heteroaryl), COCH2 (aryl1), COCH2 ( heteroaryl), C02CH2 (aryl1), C02CH2 (heteroaryl), S (0) n (alkyl d-6), S (0) n (aryl1), S (0) n (heteroaryl), S02NR25R26 and cycloalkyl1], aryl2, C02CH2 heteroaryl), C02CH2 (aryl1), cycloalkyl1, CO (heteroaryl), CO (aryl1), OCO (aryl1), OCO (heteroaryl), OCO (alkyl d.6), OCOCH2CN, C02 (heteroaryl), C02 (aryl1), COCH2 (heteroaryl), S (0) narilo1, S (0) nCH2aryl1, S (0) n (heteroaryl), S (0) nCH2 (heteroaryl) 1, NHS02aryl1, NHS02 (alkylo-6), NHS02 (heteroaryl), NHS02CH2 (heteroaryl), NHS02CH2 (aryl1), NHCOaril1, NHCO (alkyl d.6), NHCONHaril1, NHCONH (C6-alkyl) NHCOheteroaryl1, NHCONHheteroaryl1, NHC02 (aryl1) NHC02 (C6-6 alkyl), NHC02 (heteroaryl), Aril2oxi, Heteroaryl1 oxy, alkoxycarbonyl d-6, substituted with C?-6 alkyl, aryl, d-β alkoxy, CH 2 (aryl 1), haloalkyl d.4, halogen, OH, CN or NR 25 R 26, C 2-6 alkanoyl substituted with d-β alkyl, aryl , C 2-6 alkoxy, CH 2 (aryl 1), haloalkyl d-4, halogen, OH, CN or NR 25 R 26, C 2-6 alkanoyloxy substituted with d 6 alkyl, aryl, d-β alkoxy, CH 2 (aryl 1), haloalkyl d-4, halogen, OH, CN or NR25R26, cycloalkyl-oxy, CO-cycloalkyl, heterocycle substituted with one or more substituents selected from alkyl d-6 (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (C? -6 alkyl), S02NR25R26, S02 (C1-6 alkyl), C02 (alkyl) C? -6), CH2C02 (C? -6 alkyl), OCH2C02 (alkyl d-6), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN and C3-7 cycloalkyl, heterocyclyloxy substituted with one or more substituents selected from C 1-6 alkyl (substituted with OH), CONR 25 R 26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (alkyl d-6), S02NR25R26, S02 (C? -6 alkyl), C02 (d-6 alkyl), CH2C02 (C? -6 alkyl), OCH2C0 (C1-? Alkyl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2) , CN and C3-7 cycloalkyl, More preferably, R4 is C1-10 alkyl substituted with cycloalkyl1. Even more preferably, R4 is C2-4 alkyl substituted with cycloalkyl1.

Still more preferably, R4 is propyl substituted with cycloalkyl1. More preferably still R4 is propyl substituted with a C3-? 0 carbocyclic system with one or two rings and which is substituted with OH. Even more preferably, R 4 is propyl substituted with (cyclohexyl substituted with OH). It is most preferred that R4 is (l-hydroxycyclohexyl) prop-3-yl. Another preferred group of compounds are those in which R4 takes the values specified in Examples 145-203 below. Preferably, R5, R6, R7, R8, R9 and R10 are each taken separately and are H. A preferred group of substances is one in which the ring "Ar", R \ R2, R3, R4, R5, R6 , R7, R8, R9, R10, q and (X) n have the values detailed in the following examples. The invention also provides synthetic processes for the production of compounds and salts of the invention, which are described below and in the examples and preparations. The skilled artisan will note that the compounds of the invention could be prepared by methods other than those described herein, by adaptation of the methods described herein and / or adaptation of methods known in the art, for example the technique described herein, or using conventional textbooks such as "Comprehensive Organic Transformations- A Guide to Functional Group Transformations ", RC Larock, VCH (1989 or later editions)," Advanced Organic Chemistry - Reactions, Mechanisms and Structure ", J. March, Wiley-lnterscience (3rd edition or later)," Organic Synthesis - The Disconnection Approach ", S. Warren (Wiley), (1982 or later editions), "Designing Organic Synthesis", S. Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis", R.K. Mackie and D.M. Smith (Longman), (1982 or later editions), etc., and the references of the present as a guide. It will be understood that the synthetic transformation methods set forth herein are merely illustrative and that they can be carried out in various different sequences so that the desired compounds can be efficiently configured. The skilled chemist will exercise his judgment and his abilities regarding the most efficient sequence of synthesis reactions of a given target compound. For example, the substituents a and / or the chemical transformations can be added with intermediates different from those indicated below in conjunction with a particular reaction. This will depend, among others, on factors such as the nature of the other functional groups present in the particular substrate, the availability of the key intermediates and the protective group strategy (if any) to adopt. Obviously, the type of chemistry involved it will influence the choice of the reagent used in the aforementioned synthetic steps, the need and the type of protecting groups that are used and in the sequence to carry out the synthesis. The methods may be adapted as appropriate for the reactants, reagents and other parameters of the reaction in a manner that will be apparent to the skilled person with reference to conventional textbooks and the examples provided hereunder. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during the synthesis of a compound of the invention. This can be done by conventional methods, for example as those described in "Protective Groups in Organic Synthesis" of T.W. Greene and P.G.M. Wuts, John Wiley & Sons Ine (1999), and references in it. Functional groups that may be desirable to protect include oxo, hydroxy, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (for example ethylene ketals) and dithynes. Suitable protecting groups for hydroxy include trialkylisilyl and diarylalkysilyl groups (for example tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C 1-6 alkyl benzyl esters.

In the following procedures, unless otherwise indicated, the substituents are as defined above with reference to the compounds of formula (I). The invention provides a process for the preparation of compounds of formula I as defined above, or a pharmaceutically or veterinarily acceptable derivative thereof comprising; (a) for compounds of formula I wherein q is 0 and R represents NY2WY1, reacting a compound of formula II, »With a compound of formula III, Z1-WY1 III in which Z1 is a suitable leaving group, such as halogen or Y1S020-; (b) for compounds of formula I wherein q is 0 and R6 and R7 represent both H, the reduction of a compound of formula IV, IV using a suitable reducing agent; (c) for compounds of formula I wherein q is 0 and R9 and R10 represent both H, the reduction of a compound of formula V, using a suitable reducing agent; (d) for compounds of formula I wherein q is 0 and R1 and R2 are bonded to adjacent carbon atoms and taken together with the carbon atoms to which they are attached representing Het1a, in which Ret1a represents an imidazole unit , the reaction of a corresponding compound of formula VI, VI with a compound of formula VII, RyC02H VII in which Ry represents H or any of the optional substituents on Het1a (as defined above), preferably H, alkyl d-4 or haloalkyl C? -4; (e) wherein q is 0, reacting a compound of formula VIII, VIII with a compound of formula IX, R4Lg IX where Lg is a leaving group; (f) for compounds of formula I wherein q is 0 and R, R, R9 and R10 are all H, the reduction of a compound of formula X, with a suitable reducing agent; (g) for compounds of formula I wherein q is 0 and R1 represents OH, reacting a compound of formula II wherein Y2 is H, as defined above, with fluoroboric acid and isoamyl nitrite; (h) for compounds of formula I wherein q is 0 and R 1 represents Cl, 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 copper (I) chloride in the presence of concentrated acid; (i) for compounds of formula I wherein q is 1, 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 reduction of a corresponding compound of formula XXXI, XXXI in which R4aCH2 takes the same meaning as R4 as defined above; or (k) for compounds of formula (I) wherein q is 0, the reductive amination reaction of the amine of formula VIII above with an aldehyde of formula R4a-CHO, wherein R4aCH2 takes the same meaning as R4 as it was previously defined, and when desired or necessary, to convert the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa. In process (a), the reaction can be carried out at between 0 ° C and room temperature in the presence of a suitable base (for example pyridine) and an appropriate organic solvent (for example dichloromethane). The compounds of formula II can be prepared by reduction of the corresponding compound of formula XI or formula Xll, XI Xll in the presence of a suitable reducing agent, such as lithium aluminum hydride. The reaction can be carried out at between room temperature and reflux temperature in the presence of a suitable solvent (e.g. tetrahydrofuran).

The compounds of formulas XI and Xll can be prepared by reduction of the corresponding compounds -N02 under conditions which are well known to those skilled in the art (for example using Raney H2 / Ni or in the presence of CaCl2 and iron powder, in the presence of a suitable solvent system (eg EtOH, EtOAc and / or water)). The skilled artisan will observe that, in preparing a compound of formula II, wherein Y2 is H, from the corresponding compound -N02, the two reduction steps indicated above may be carried out in the same step or sequentially in any order.

Said corresponding compounds -N02 can be prepared by reaction of a compound of formula Xll or of formula XIV, as appropriate, wherein L1 represents a suitable leaving group [such as halo (for example chloro or bromo)], L2 represents a suitable leaving group (such as C3-alkoxy) and R3 is as defined above, with a compound of formula XV, R4NH2 XV The reaction can be carried out at between room temperature and reflux temperature in the presence of a suitable base (for example NaHCOa) and in an appropriate organic solvent (for example dimethylformamide), or at a higher temperature (for example between 50 Y 200 ° C, preferably between 100 and 160 ° C of temperature) in the presence of the pure compound of formula XV. The compounds of formulas XIII and XIV can be prepared according to conventional techniques. For example, the compounds of formulas XIII and XIV can be prepared by reacting the corresponding compound of formulas XVI or XVII, XVI XVII with a compound of formulas XVIII or XIX, respectively, N2CHR5OL2 XVIII N2CHR8COL2 XIX where L2 is as defined above. The reaction can be carried out at room temperature in the presence of a suitable catalyst [for example Rh2 (OAc) 4] and an appropriate non-protic organic solvent (for example dichloromethane).

The compounds of formula XVI and formula XVII are available or can be prepared using known techniques. The compounds of formula XVI and formula XVII can be prepared, for example, from the corresponding compounds of formula XX, XX for example performing a Wittig reaction using an appropriate supplier of the nucleophilic group R02C-CR5H "or R02C-CR8H" (representing R lower alkyl (eg C1-3)), as appropriate, under conditions which are well known to those skilled in the art. The group - C02R of The resulting compound can be converted to an appropriate CH2L1 group using conventional techniques (e.g., reduction of the ester to the primary alcohol and conversion of the latter to an alkyl halide) under conditions that are well known to those skilled in the art. In processes (b) and (c), suitable reducing groups include lithium aluminum hydride. The reaction can be carried out between room temperature and reflux temperature in the presence of a suitable solvent (for example tetrahydrofuran).

The compounds of formula II can be prepared by reduction of the corresponding compound of formula XXX, XXX by analogy with the procedural steps indicated above. The compounds of formulas IV and V can be prepared respectively from compounds of formulas XXI and XXII, XXI XXII wherein L3 represents a group that is capable of undergoing functional group transformations (e.g., cyano) using conventional functional group conversion or substitution techniques.

For example: (1) Compounds of formulas IV and V wherein R 1 represents 1,4-triazol-3-yl can be prepared by reaction of an appropriate compound of formulas XXI or XXII, wherein L3 represents -CN , with HCl (gas) in the presence of an appropriate lower alkyl alcohol (for example ethanol), for example at 0 ° C to room temperature, followed by reaction of the resulting intermediate with formic acid hydrazide (for example at reflux temperature, with or without the presence of a suitable organic solvent (for example methanol), followed, if necessary, by removing the solvent and heating the resulting residue at a high temperature (for example at about 150 ° C)). (2) Compounds of formulas IV and V in which R1 represents imidazol-2-yl can be prepared by reaction of an appropriate compound of formulas XXI or XXII, wherein L3 represents -CN, with HCl (gas) in the presence of an appropriate lower alkyl alcohol (for example ethanol), for example at between 0 ° C and room temperature, followed by reaction of the resulting intermediate with aminoacetaldehyde dialkylacetal (for example dimethylacetal) (for example at reflux temperature or approximately, in the presence of an appropriate solvent, such as methanol). (3) The compounds of formulas IV and V in which R1 represents 1, 2,3-triazol-5-yl can be prepared by reaction of an appropriate compound of formulas XXI or XXII, wherein L3 represents -CN, with diazomethane, or a; protected derivative (for example trialkylisilyl) of this, by example at between 0 ° C and room temperature in the presence of a suitable base (for example n-BuLi) and, optionally, an appropriate organic solvent (for example THF), followed by removal of the protecting group when necessary. (4) The compounds of formulas IV and V in which R 1 represents benzoimidazol-2-yl can be prepared by reaction of an appropriate compound of formulas XXI or XXII, in which L3 represents C = NH (OEt), with 1, 2 -diaminobenzene. The reaction can be carried out in a solvent such as methanol, at an elevated temperature (such as the reflux temperature of the solvent). The preparations 81, etc. They provide additional details. The compounds of formulas IV and V in which R1 represents Het1 can also be prepared from compounds of formulas XI and Xll respectively according to the following scheme: where Het1 is defined above. Additional details can be found in preparations 67, 68, etc. in WO00 / 39089, incorporated herein by reference in its entirety. The compounds of formulas XXI and XXII can be prepared analogously to the methods described herein, for example those described hereinabove for the preparation of compounds of formula II. Other compounds of formulas (IV) and (V) can be prepared by analogy with the methods described herein (for example by analogy with the processes described hereinabove for the preparation of compounds of formulas XI and Xll (and especially the corresponding one compound -N02)). In process (d), the reaction can be carried out by heating under reflux, with or without the presence of an appropriate organic solvent. The compounds of formula VI can be prepared using known techniques. For example, the compounds of formula VI can be prepared by nitration (in the 4-position) of a corresponding 3-aminobenzene compound (a compound of formula II), the latter compound being able to be activated by the conversion of the 3-amino group to a group 3 -amido, followed by hydrolysis of the amide and reduction of the 4-nitrobenzene compound. All these reactions can be performed using techniques that are familiar to the experts, and are illustrated in the 45-48 preparations, etc. then. In process (e), suitable leaving groups that Lg may represent include halogen, such as bromine, or a sulfonate group such as tosylate, mesylate or triflate. The reaction can be carried out in a polar solvent which does not adversely affect the reaction, at a suitable temperature, for example 0-150 ° C, in the presence of a base. A catalyst such as sodium iodide can optionally be added. Preferred choices are a slight excess of R4-Lg, where Lg = Cl or Br, an excess of base (2.0-4.0 eq.) Such as K2C03, NaHC03, or a tertiary amine such as triethylamine or Hunigs base, in a polar solvent such as THF, DMF or MeCN, at between 40 and 120 ° C of temperature, optionally in the presence of a catalyst such as Nal or Kl, for 2-24 hours, see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", VCH, (1989), p. 397, and the references cited therein. The compounds of formula VIII can be prepared from compounds of formula XXV, XXV in which Pg represents a suitable protecting group. Suitable protecting groups include allyl, which can be removed using a palladium (0) and N, N-dimethylbarbituric acid (see preparation 53, etc.) continuation). The compounds of formula XXV can be prepared using methods analogous to those described herein for the preparation of compounds of formula I. In process (f), the appropriate reducing agents They include lithium aluminum hydride. The reaction can be carried out in a solvent which does not adversely affect the reaction (for example tetrahydrofuran) at an elevated temperature (for example the reflux temperature of the solvent). The compounds of formula X can be prepared by reaction of a compound of formula XXVI with a compound of formula XXVII in the presence of an oxidizing agent. The right oxidizing agents They include manganese dioxide. The reaction can be carried out in a solvent that does not adversely affect the reaction (eg dioxane) to an elevated temperature such as the reflux temperature of the solvent (for example, see preparation 77, and WO00 / 39089). The Intermediates XXIXa are isolatable using suitable conditions (for example, see Preparation 58, WO00 / 39089).

XXVI XXVII XXlXa XXIX The compounds of formula XXVI can be prepared from compounds of formula XXVIII, by reaction of the corresponding ketone with hydrazine monohydrate, using known techniques (as described in preparation 76, etc., WO00 / 39089). Process (f) is particularly useful when Ar represents a heteroaryl ring optionally fused with 5 or 6 membered benzene. A similar methodology can be used to obtain compounds of formula II: the precursor nitro compound can be prepared from a compound of formula XX, as defined above, using the steps described above (see for example, Preparations 57-61, WO00 / 39089). In process (g), the reaction can be carried out in a solvent which does not adversely affect the reaction (for example ethanol), first below room temperature and then at elevated temperature (Examples 79, etc., WO00 / 39089, provide additional details). In process (h), suitable acids include dilute aqueous hydrochloric acid and concentrated hydrochloric acid, respectively. The reaction can be carried out at about room temperature, ending at elevated temperature (for example at 90 ° C). Example 51 in WO00 / 39089 provides additional details. In process (j), the compound of formula XXXI can be prepared by acylation of the compound of formula VIII as defined above, with an acylating agent of formula R ^ CO-Lg, where Lg is a suitable leaving group as defined above with respect to (e), and includes halogen (alkyl, haloalkyl or aryl) sulfonate, OCOR43 (ie an acid anhydride) ) and similar, well known by those who practice the technique. See for example the conditions used for preparation 47. The coupling can optionally be carried out in the presence of a catalyst, for example DMAP, in a suitable solvent; see R.C. Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations ", second edition (1999), page 1941-1949, and the references cited therein Preferably, the carboxylic acid (0.9-1.1-eq.), The HCl of 1- (3-dimethylaminopropyl) - are stirred. 3-ethylcarbodiimide (1-1.5 eq.) And 1-hydroxybenzotriazole (1.0 eq.) In DMF or DCM at room temperature for 5-15 minutes and then the amine salt (1 eq.) And the base (NaHCO3) are added. or organic base, Et3N or Hunigs base (2-4 eq.)), the reaction taking place at room temperature for 2-24 hours The amide bond can be reduced with a suitable reducing agent, for example lithium aluminum hydride or borane, in an ether solvent, such as THF, at 0-100 ° C temperature to generate the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", VCH (1989), page 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-ambient temperature. in THF for 1-24 hours. In process (k) the appropriate aldehyde is reacted with an amine, optionally present as acid addition salt, in the presence of a suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd catalysts , Pt or Ni). The reaction is suitably carried out in the presence of acetic acid at 0-100 ° C temperature in THF, methanol, DCM (dichloromethane), or DCE (1,2-dichloroethane), for a suitable time such as 1-24 hours. Preferably the amine salt, such as the acid salt trifluoroacetic (TFA), treated with an organic base (1-3 molar equivalents), such as triethylamine or Hunig's base, and then the aldehyde (1-1.5 molar equivalents), followed by sodium triacetoxyborohydride (1-2.0 molar 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), p. 835-842, and references cited therein, and Abdel-Magid et al., J. Org. Chem., 1996, 61, 3849. The aldehydes used in this process can be prepared from the corresponding alcohols using suitable oxidizing agents; see R.C. Larrock; "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition (1999), p. 1234-1236 and 1238-1247 and the references cited therein. Preferred oxidants are tetrapropylammonium perruthenate (Ley, et al., Synthesis, 1994, 639-666), Swem oxidation and related procedures (Tidweil, Organic Reactions, 1990, 39, 297-572), and Peryodinan reagent from Dess. Martin (Dess et al., J. Org. Chem., 1983, 48, 4155-4156). Various functional group interconversions can be carried out in compounds of formula (I), or in intermediates thereof, by providing different compounds of formula (I) or intermediates. Some of these are indicated below.

The anilines can be converted to a urea using potassium cyanate (excess) in an aqueous acidic solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432. Esters can be converted to the corresponding alcohols using a suitable reducing agent, see Larock, "Comprehensive Organic Transformations - A Guide to Functional Group Preparations," second edition (1999), p. 1117-1120 and the references cited therein. Suitable reducing agents include diisobutylaluminum hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminum hydride (LiAIH4, see Brown, Org Reactions, 1951, 6, 469), ie a reaction of the type Alcohols can be prepared from a corresponding acid using a suitable reducing agent, see R.C. Larock, "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", second edition. (1999), p. 1114-1116. Preferably, the reducing agent is borane (BH3 (1-2 eq.), J. Org. Chem., 1973, 38, 2786) or LiAIH4 (1-4 eq.), In an ether solvent, such as THF, a 0-80 ° C temperature, for 1-24 hours, that is, a reaction of the type: Direct procedures for preparing alkyl halides and allyl sulfonates from their alcohols are described in R.C. Larrock, "Comprehensive Organic Transformations- A Guide to Functional Group Preparations," second edition (1999), p. 689-700, and the references cited therein. The benzylacetals can be treated with a suitable reducing agent in the presence of a Lewis acid or an organic acid to provide benzyloxy alcohols. For representative examples, see Organic Preparations and Procedures, Int., 1991, 23, 4, 427-431, ZrC ^ LiAIH ^ J. Org. Chem., 1987, 52, 2594, Zn (BH4) 2 / Me3SiCI; and Organic Preparations and Procedures, Int., 1985, 17 (1), 11-16, NaBHf / TFA. That is, a reaction of the type: It will be apparent to those skilled in the art that the compounds of formula I can be converted to other compounds of formula I using known techniques. For example, the compounds of formula I in the that Y1 represents alkoxycarbonyl can be converted into compounds in which Y1 represents alkyl substituted with OH, by reduction using LiAIH4 (example 57 provides further details). Similarly, intermediates can be interconverted using known techniques (see for example preparation 85). Intermediates such as those of formulas III, XV, XVIII, XIX, XX, VII, XXVI, XXVII and XXVIII, and derivatives thereof, when not commercially available or not described below, can be obtained by analogy with the methods described herein, or by conventional synthetic procedures, according to conventional techniques, from readily available starting materials using appropriate reagents and reaction conditions. The invention further provides the intermediates of formulas II, IV, V, VI, X, Xa, XI, Xll, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX and XXXI as defined above. When desired or necessary, the compound of formula (I) can be converted to a pharmaceutically acceptable salt thereof, conveniently by the combined mixing of solutions of a compound of formula (I) and the desired acid or base, as appropriate. appropriate. The salt may precipitate from the solution and be collected by filtration, or may be collected by other means, such as by evaporation of the solvent. Both types of salt can also be formed or interconverted using 10 ion exchange resin techniques.

The compounds of the invention can be purified by conventional methods, for example the separation of diastereomers can be carried out by conventional techniques, for example by fractional crystallization, chromatography or HPLC of a stereoisomeric mixture of a compound of formula (I) or a salt thereof. A single enantiomer of a compound of formula (I) can also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC, of the corresponding racemate using a suitable chiral support, or by fractional crystallization of the diastereoisomeric salts by reaction of the corresponding racemate with a suitable optically active base or acid. The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. Therefore they are indicated as pharmaceutical products and, in particular, for use as animal medicines. According to another aspect of the invention, the compounds of the invention are provided for use as medicaments, limes such as pharmaceuticals and animal medicaments, such as for the treatment of diseases and conditions mediated by opiates. In the term "treatment", this term includes both therapeutic (curative) and prophylactic treatment. In particular, the substances of the invention have been found useful in the treatment of diseases and conditions modulated by opiate receptors, such as irritable bowel syndrome, constipation, nausea, vomiting, pruritus, eating disorders, opioid overdose, depression, tobacco and alcohol addiction, sexual dysfunction, shock, stroke, spinal injury and / or brain trauma, and of the conditions characterized by having pruritus as a symptom. Thus, according to another aspect of the invention, there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease modulated by an opioid receptor. Further provided is the use of compounds of the invention in the manufacture of a medicament for the treatment of irritable bowel syndrome, constipation, nausea, vomiting, pruritus, eating disorders, opioid overdose, depression, addiction to tobacco and alcohol, sexual dysfunction , shock, apoplexy, spinal damage and / or brain trauma, and of the conditions characterized by having itching as a symptom. The compounds of the invention are therefore expected 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 can be cited include contact dermatitis, psoriasis, eczema and insect bites. Thus, the invention provides a method of treatment or prevention of a disease modulated by an opioid receptor. There is further provided a method of treating irritable bowel syndrome, constipation, nausea, vomiting, pruritus, disorders food, opioid overdose, depression, tobacco and alcohol addiction, sexual dysfunction, shock, stroke, spinal injury and / or brain trauma, or of a medical condition characterized by pruritus as a symptom in an animal (eg a mammal), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment. The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic or inorganic acid or base addition salt, in a form of pharmaceutically acceptable dosage. Depending on the disorder and the patient to be treated, as well as the route of administration, the compositions may be administered at various doses (see below). Although it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient and a compound of the invention. The vehicle, diluent or excipient can be selected taking into account the intended route of administration and conventional pharmaceutical and / or veterinary practice. The pharmaceutical compositions comprising the compounds of the invention may contain from 0.1% by weight to 90.0% by weight of the active ingredient.

The methods by which the compounds can be administered for veterinary use include oral administration in capsules, boluses, tablets or potions, topical administration as ointment, pouring, spraying, bathing, spraying, lathering, shampooing, of collar or powder, or, alternatively, can be administered by injection (for example subcutaneous, intramuscular or intravenous), or as an implant. Said formulations can be prepared in a conventional manner according to standard veterinary practice. The formulations will vary with respect to the weight of active component contained therein depending on the species of animal being treated, the severity and type of infection and the animal's body weight. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg. In any case, the veterinary practitioner, or the expert, will be able to determine the actual dosage that will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are examples of the average case; there may, of course, be individual cases where larger or smaller dosage intervals are necessary, and these are within the scope of this invention.

For veterinary use, the compounds of the invention are particularly valuable for the treatment of pruritus in domestic animals such as cats and dogs and in horses. As an alternative for treatment in animals, the compounds can be administered with the animal feed, and for this purpose a food additive or premix can be prepared to mix it with the normal animal feed. For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Said compositions include tablets, capsules and conventional ointment preparations which are formulated according to standard pharmaceutical practice. The compounds of the invention can be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of the disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be considered as limiting) include antiparasitics, for example fipronil, lufenuron, imidacloprid, avermectins (e.g., abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, for example chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, for example fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, for example enroflaxacin, marbofloxacin, ampicillin, amoxicillin; anti-inflammatory, for example prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, for example gamma-linoleic acid, and emollients. Therefore, the invention further provides a product containing a compound of the invention and one or more compounds selected from the above list as a combined preparation for simultus, separate or sequential use in the treatment of diseases modulated by opioid receptors. The skilled person will also appreciate that the compounds of the invention can be taken as a single dose based on "as needed" (ie, as needed or desired). Thus, according to another aspect of the invention, a pharmaceutical or veterinary formulation is provided which includes a compound of the invention mixed with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. The compounds of the invention may also have the advantage that, in the treatment of human and / or animal patients, they may be more effective, less toxic, have a broader spectrum of activity, be more potent, produce fewer side effects, be more easily absorbed or have other useful pharmacological properties than the compounds known in the prior art. The biological activities of the compounds of the present invention were determined by the following test procedure.

Biological assay It has been found that the compounds of the present invention exhibit activity in three selective opioid receptor binding assays for mu, kappa and delta opioid receptors in dog brain. The tests were carried out by the following procedure. Beagles bred in the laboratory were used as a source of dog brain tissue. The animals were sacrificed, their brains were removed and the cerebellum was discarded. The remaining brain tissue was sectioned into small pieces of approximately 3 g in weight and homogenized in 50 mM Tris buffer, pH 7.4 at 4 ° C temperature using a Kinematica Polytron ™ tissue homogenizer. The resulting homogenate was centrifuged at 48,400 x g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 37 ° C temperature for 10 minutes. The centrifugation, resuspension and incubation steps were repeated two more times, and the final precipitate was resuspended in Tris buffer and stored at -80 ° C. The membrmaterial prepared in this way can be stored up to four weeks before use. For the mu, kappa and delta assays, increasing concentrations of the experimental compound were combined (5 x 10-12 to 10"5 M), Tris buffer and 3H ligand (mu = [D-Ala2, N-Me-Phe4, Gly-ol5 ] -enkephalin, DAMGO; kappa = U-69.593; delta = enkephalin, [D-pen25] DPDPE) in polystyrene tubes. The reaction was started by adding the tissue, and the mixture was incubated at room temperature for 90 minutes. The reaction was finished by rapid filtration using a Brandel Cell Harvester ™ through Betaplate ™ GF / A fiberglass filters pre-soaked in 50 mM Tris buffer, pH 7.4, 0.1% polyethylenimine. The filters were then washed three times with 0.5 ml of ice-cold Tris pH 7.4 buffer. For the mu and delta assays, the washed filters were placed in bags and Starscint ™ scintillation agent was added. For the kappa assay, the Meltilex ™ B / HS scintillation solid was used. The bags containing the filters and the scintillation agent were heat sealed and counted with a beta Betaplate ™ 1204 counter. Duplicate samples were used for each experimental compound and the generated data were analyzed using IC5o analysis software in Graphpad Prism. The Ki values were calculated using Graphpad Prism according to the following formula: Ki = IC50 ñ + [ligand 3H] / KD where IC50 is the concentration at which 50% of the 3H ligand is displaced by the test compound and KD is the dissociation constant for the 3H ligand at the receptor site.

Biological activity The Ki values of certain compounds of the present invention were determined in the opiode receptor binding assays, and they were found to have Ki values of 4,000 nM or less for the μ receptor.

It is believed that the procedures used in the following examples produce compounds with the relative stereochemistry. shown below, and said compounds are preferred: wherein R1"4 and (X) n are as defined above The invention is illustrated with the following examples and preparations in which the following abbreviations may be used: APCI = chemical ionization at atmospheric pressure DMF = dimethylformamide DMSO = dimethisulfoxide d (in relation to time) = day d (in relation to NMR) = doublet ES (in relation to EM) = electrospray EtOAC = ethyl acetate EtOH = ethanol h = hour MeOH = methanol min = minute EM = mass spectrum n-BuOH = n-butanol ODS = octadecylsilyl THF = tetrahydrofuran TSP = thermospray. The melting points were determined using a Gallenkamp melting point apparatus and are not corrected. Nuclear magnetic resonance spectral data refer to 1H and were obtained using a Varian Unity 300 or 400 spectrometer, with observed chemical shifts (d) consistent with the proposed structures. The mass spectral (MS) data were obtained in a Fisons Instruments Trio 1000 or a Fisons Instruments Trio 1000 APCI, or an EM Finnigan Navigator, or an LC Micromass Platform spectrometer. The calculated and observed ions indicated refer to the lower mass isotopic composition. Ambient temperature means 20 to 25 ° C. The mass spectrometer that is used as a detector in the HPLC-EM analytical system is a Micromass VG Platform II, running on Masslinx / Openlynx software. The system can work with positive or negative ions with electrospray or APCI probes and is calibrated at 1972 Dalton, collecting data from rows of complete diodes from 190 nm to 600 nm. HPLC means high performance liquid chromatography. The HPLC conditions used were: Condition 1: Rainin Dynamax ™ column, ODS 8 μm, 24 x 300 mm, column temperature 40 ° C, flow rate 45 ml / min, eluting with methanol: water (70:30), UV detection of the product at 246 nm. Condition 2: Rainin Dynamax ™ column, ODS 5 μm, 21.6 x 250 mm, column temperature 40 ° C, flow rate 5 ml / min, eluting with acetonitrile: water (50:50), UV detection of the product at 246 nm. Condition 3: Rainin Dynamax ™ column, ODS 8 μm, 41 x 250 mm. column temperature 40 ° C, flow rate 45 ml / min, eluting with acetonitrile: aqueous buffer of 0.1 M ammonium acetate (50:50), UV detection of the product at 235 nm. Condition 4: Phenomenex Magellan ™ column, silica C-is 5 μm, 21. 2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min, eluting with a gradient of acetonitrile: aqueous buffer of 0.1 M ammonium acetate (30:70 to 95: 5 for 10 minutes), UV detection of the product at 220 nm. Condition 5: Phenomenex Magellan ™ column, ODS 5 μm, 21.2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min, eluting with a gradient of acetonitrile: aqueous buffer of 0.1 M ammonium acetate (5: 95 to 95: 5 for 20 minutes), UV detection of the product at 215 nm. Condition 6: Phenomenex Magellan ™ column, Cía 5 μm silica, 4.6 x 150 mm, column temperature 40 ° C, flow rate 1 ml / min, eluting with a gradient of acetonitrile: aqueous heptanesulfonic acid 0.1 M (10:90 to 90:10 for 30 minutes), UV detection of the product at 220 nm. Condition 7: Phenomenex Magellan ™ column, silica d8 5 μm, 21. 2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min, eluting with a gradient of acetonitrile: aqueous buffer of 0.05 M ammonium acetate (50:50 for 15 minutes, then 50:50 to 90 : 10 for 5 minutes), UV detection of the product at 220 nm. Condition 8: Phenomenex Magelle ™ column, 5 μm silica, 21. 2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min, eluting with a gradient of aoetonitrile: aqueous buffer of 0.1 M ammonium acetate (15:85 to 85:15), UV detection of the product at 220 nm. Condition 9: Phenomenex Magellan ™ column, ODS 5 μm, 10 x 150 mm, column temperature 40 ° C, flow rate 5 ml / min, eluting with a gradient of acetonitrile: aqueous buffer of 0.1 M ammonium acetate (5:95 to 30:70 for 5 minutes, then 30:70 for 20 minutes more), UV detection of the product at 225 nm. Condition 10: Phenomenex Magellan ™ column, silica ds 5 μm, 21.2 x 150 mm, column temperature 40 ° C, flow rate 20 ml / min, eluting with a gradient of acetonitrile.-aqueous buffer of 0.1 M ammonium acetate ( 5:95 to 40:60 for 5 minutes, then 40:60 for 25 minutes more), UV detection of the product at 210 nm. Condition 11: Phenomenex Magellan ™ column, ODS 5 μm, 10 x 150 mm, column temperature 40 ° C, flow rate 5 ml / min, eluting with a gradient of acetonitrile: water (5:95 to 55:45 for 5 minutes), UV detection of the product at 210 nm. The free base form of the azabicycles could be obtained from the hydrochloride or acetate salts, for example in the following manner: the salt (0.3 mmol) was dissolved in dichloromethane (20 ml) and washed with an acidic acid carbonate solution. sodium (20 ml). The basic mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were dried (Na 2 S 4) and concentrated in vacuo to give the free base. SPE cartridge represents a solid phase extraction cartridge. These can be obtained commercially from Varian (Mega Bond Elut®) or Isolute ™. NB: The "examples" numbered 1-144 are compounds related to the present invention, but with different R4 groups, and are described as such in the international patent application No. WO00 / 39089, incorporated herein by reference in its entirety . A number of additional examples, such as those in the tables below, can be prepared by the A-K procedures described below and with the experimental details according to the table.

Procedure A Alkylation Alkylation of the amine of formula VIII or of a salt thereof with R 4 Lg, where Lg is a suitable leaving group, such as a halogen, triflate, mesylate, etc., in the presence of a base, optionally in the presence of a catalyst, in a polar solvent between 0 and 150 ° C of temperature. Preferably with R4Lg (slight excess), where Lg = Cl or Br, an excess of base (2.0-4.0 eq.), Such as K2C03, NaHCO3, or a tertiary amine such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF or MeCN, at between 40 and 120 ° C of temperature, optionally in the presence of a catalyst such as Nal or Kl, for 2-24 hours, see RC Larrock in "Comprehensive Organic Transformations- A Guide to Functional Group Preparations", VCH (1989), p. 397, and the references cited therein, For example: Lg = Bró Cl Conditions: amine salt (1.0 eq.), RX (1.1 eq.), NaHCO3 (2-4.0 eq.), DMF, Nal (cat.), 40-120 ° C temperature.

Procedure B Reductive amination Treatment of an appropriate aldehyde R4aCHO with an amine of formula VIII in the presence of u? suitable reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride or catalytic hydrogenation with Pd, Pt or Ni catalysts). The reaction is often carried out in the presence of acetic acid at 0-100 ° C en.THF, MeOH, DCM or DCE (1,2-dichloroethane), for 1-24 hours. Preferably, the amine salt is treated with an organic base (1-3 eq.), Such as triethylamine or Hunigs base, and then with 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 R.C. Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", second edition (1999), p. 835-842, and references cited therein, and Abdel-Magid et al., J. Org. Chem., 1996, 61, 3849.

For example: Conditions: Amine salt (1.0 eq.), RCHO (1-1.5 eq.), Et3N (1-3 eq.), Na (OAc) 3BH (1-2 eq.), DCM, T amb.

Procedure C Amide Reduction of Formula XXXI Carbonylamide can be reduced with a suitable reducing agent, for example lithium aluminum hydride or borane, in an ether solvent, such as THF, at 0-100 ° C temperature, to generate the desired tertiary amine , see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", second edition (1999), p. 432-434, and the references cited therein. Preferably, the amide (1.0 eq.) Is treated with lithium aluminum hydride (1.0-3 eq.) At 0 ° C-T amb., In THF for 1-24 hours.

Procedure D } Oxidation The aldehydes used in process B can be prepared using suitable oxidizing agents; see R.C. Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", second edition (1999), p. 1234-1246 and 1238-1247, and the references cited therein. Preferred oxidants are tetrapropylammonium perruthenate (Ley, et al., Synthesis, 1994, 639-666), Swem oxidation and related procedures (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin periododyne reagent (Dess et al., J. Org. Chem., 1983, 48, 4155-4156).

Procedure E Acid / amine salt coupling to provide amides of formula XXXI Using an acid + amine chloride in a suitable solvent or activated acid by a suitable agent, optionally in the presence of a catalyst, for example DMAP, in a suitable solvent; see R.C. Larrock in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations", second edition (1999), p. 1941-1949, and the references cited therein. Preferably, the carboxylic acid (0.9-1.1 eq.), The HCl of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1-1.5 eq.) And 1-hydroxybenzotriazole (1.0 eq.) In DMF or DCM are stirred a T amb, for 5-15 minutes and then add the amine salt (1 eq.), And the base (NaHCOß or organic base, Et3N or Hunigs base (2-4 eq)), bringing the reaction of 2 to 24 hours.

For example: Procedure F Urea formation Anilines can be converted to a urea using potassium cyanide (in excess) in an aqueous acidic solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432, ie a reaction of the kind: Procedure G Ester to an alcohol Esters can be converted to the corresponding alcohol using a suitable reducing agent, 'see Larock, "Comprehensive Organic Transformations- A Guide to Functional Group Preparations," Second edition (1999), p. 1117-1120, and the references cited therein. Suitable reducing agents include diisobutylaluminum hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminum hydride (LiAIH, see Brown, Org Reactions, 1951, 6, 469), ie a reaction of the type : Procedure H Acid to alcohol It will be noted that the alcohols used in process D can be prepared from the corresponding acid using a suitable reducing agent; see Larock, "Comprehensive Organic Transformations-A Guide to Functional Group Preparations," second edition (1999), p. 1114-1116. Preferably, the reducing agent is borane (BH3 (1-2 eq.), J. Orgr. Chem., 1973, 38, 2786) or LiAIH (1-4 eq.), In an ether solvent, such as THF, -80 ° C temperature, for 1-24 hours.

R Y H - R4a \ / 0H or Process Alcohol to halide It will be noted that the R 4, Lg used in process A can be prepared from the corresponding alcohol R 4aOH. Direct procedures for preparing alkyl halides and alkyl sulfonates from their alcohols are described in R.C. Larock, "Comprehensive Organic Transformations- A Guide to Functional Group Preparations," second edition (1999), p. 689-700, and the references cited therein.

Procedure J Benzyl halides to benzyloxyalcohols The benzyloxyalcohols can be prepared by refluxing the appropriate benzyl halide with sodium or sodium hydride and a polymethylene glycol in xylene, see J. Am. Chem. Soc, 1951, 3159-3162, ie a reaction of the type: X = halide Procedure K Acétals to benzyloxyalcohols Acétals can be treated with a suitable reducing agent in the presence of a Lewis acid or organic, providing the benzyloxyalcohols. For representative examples see Organic Preparations and Procedures, Int., 1991, 23, 4, 427-431, ZrCU / LiAl ^; J. "Org. Chem., 1987, 52, 2594, Zn (BH4) 2 / Me3SiCI; and Organic Preparations and Procedures, Int., 1985, 17 (1) 11-16, NaBH4 TFA, ie a reaction of the type : HO rv O Procedure D 151 N- (3- { 3- [2- (allyloxy) ethyl] - H 6 -ethyl-3-azabicyclo-J [3.1.0] hex-6-yl.}. -phenyl) - Process B methanesulfonamide Procedure D 153 N- (3-. {6-ethyl-3- [2- (2-methoxyethoxy) -ethyl] -3-azabicyclo- [3.1.0] hex- Procedure B and D 6 -yl.}. -phenyl ) - methanesulfonamide EXAMPLE 199 N- (3- (3-r3- (4-ACETYLPHENYL) PROPYL1-6-ETHYL-3-AZABICICL1-3.1.01HEX-6-IDFENIL) METANOSULPHONAMIDE AND SAL FORMATE To a solution of the trifluoroacetic acid salt of N- [3- (6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenylmethanesulfonamide (106 mg, 0.27 mmol) in N, N-dimethylformamide was added (4 ml), sodium hydrogen carbonate (90 mg, 1.1 mmol), 1- [4- (3-chloropropyl) phenyl] ethanone (58 mg, 0.29 mmol) and sodium iodide (catalytic) and the reaction mixture at 70 ° C temperature during 20 hours. After cooling, the solvent was removed in vacuo to give a crude residue. This was purified by chromatography on a silica column (14 g), eluting with ethyl acetate: hexane (75:25) and then with pure ethyl acetate. The combination and evaporation of the appropriate fractions gave the partially purified product. This material was further purified by preparative HPLC (condition 1) to provide the formate salt of the title compound (16 mg, 12%) as a yellow oil. 1 H-NMR (300 MHz, CDCl 3, data for formate salt): 0.85 (t, 3H), 1.70 (q, 2H), 2.05 (quintuplet, 2H), 2.15 (s, 2H), 2.55 (s, 3H), 2.70 (t, 2H), 2.80-2.85 (m, 4H), 2.95 (s) , 3H), 3.70-3.80 (m, 2H), 7.00 (d, 1 H), 7.05-7.10 (m, 2H), 7.20-7.28 (m, 3H), 7.90 (d, 2H), 8.40 (s, 1 H). MS (electrospray): m / z (M-H) 439; (C25H32N203S - H requires 439.2.

EXAMPLE 200 N- (3- (3-r2- (BENCILOXI) BENCIL1-6-ETHYL-3-AZABICICLO-r3.1.01HEX-6- IL1FENILMETANOSULFONAMIDA To a solution of 2-benzyloxybenzaldehyde (27 mg, 0.13 mmol) in dichloromethane (5 ml) at room temperature, the trifluoroacetic acid salt of N- [3- (6-ethyl-3-azabicyclo [3.1.0] was added. hex-6-yl) phenyl] methanesulfonamide (50 mg, 0.13 mmol) and triethylamine (0.05 ml, 0.38 mmol). The reaction was allowed to stir at room temperature for 2 hours. At that point, sodium triacetoxyborohydride (40.8 mg, 0.19 mmol) was added and the reaction was allowed to stir 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 tube filter (hydrophobic polytetrafluoroethylene membrane). The organic layer was dried in a stream of nitrogen. The residue was purified by column chromatography using a Sep-Pak ™ cartridge packed with silica gel (10 g), eluting with hexane: ethyl acetate (100: 0, 1: 1, 1: 3, 1: 6, 1: 9 and 0: 100) to afford the title compound (28 mg, 46%) as an oil. 1 H-NMR (300 MHz, CDCl 3): 0.85 (t, 3H), 2.80 (s, 2H), 2.00-2.10 (m, 2H), 2.85 (d, 2H), 3.00 (s, 3H), 3.10-3.20. (dd, 2H), 3.80 (s, 2H), 5.10 (s, 2H), 6.90-7.05 (m, 3H), 7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.40-7.50 (m , 6H). MS (electrospray): m / z (M + H) 477; C2sH32N2? 3S + H requires 477.

EXAMPLE 201 N- (3-r3- (4-CYANOBENCIL) -6-ETHYL-3-AZABICICL -3.1.01HEX-6- IL1FENIDMETANOSULFONAMIDE The above compound was prepared by a procedure similar to that of Example 167, using the trifluoroacetic acid salt of N- [3- (6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl] methanesulfonamide (100 mg, 0.25 mmol) and 4-cyanobenzaldehyde (33 mg, 0.25 mmol) as starting materials. The product was purified using preparative HPLC (condition 3) to afford the title compound (28 mg, 28%) as an off-white solid. 1 H-NMR (300 MHz, CDCl 3): 0.85 (t, 3 H), 1.80 (s, 2 H), 2.05 (q, 2 H), 2.80 (d, 2 H), 3.00 (s, 3 H), 3.10 (d, 2 H) ), 3.70 (s, 2H), 7.00-7.20 (m, 3H), 7.20 (m, 1H), 7.40 (d, 2H), 7.6020 (d, 2H). MS (electrospray): m / z (M + H) 396; C22H25N302S-H requires 396.

EXAMPLE 202 N- (3- (3-r2-r4-CICLOPROPYLPHENOXY) ETIL1-6-ETHYL-3-AZABICICLCL3.1.01HEX-6-IL) PHENYL) METHANOSULPHONAMIDE To a solution of the trifluoroacetic acid salt of N- [3- (6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl] methanesulfonamide (75 mg, 0.19 mmol) in N were added. , N-dimethylformamide (3 ml), sodium hydrogen carbonate (64 mg, 0.8 mmol), 1- (2-chloroethoxy) -4-cyclopropylbenzene (41 mg, 0.21 mmol) and sodium iodide (3 mg, catalytic) and the reaction mixture was heated at 60 ° C for 20 hours. After cooling, the solvent was removed in vacuo to give a crude residue. This was purified by preparative HPLC (condition 2), affording the formate salt of the title compound (4 mg, 5%) as a brown gum. 1 H-NMR (300 MHz, CDCl 3, data for formate salt): 0.55-0.60 (m, 2H), 0.80-0.95 (m, 5H), 1.80-1.90 (m, 3H), 2.25 (sa, 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, 1 H), 7.30 (t, 1 H). MS (electrospray): m / z (M-H) 439; C25H32N203S - H requires 439.2.

EXAMPLE 203 N- (3-f6-ETHYL-3-r (2-PHENYLCYCLOPROPYL) METHYL1-3-AZABICICL3.1.01HEX-6-IL) PHENYL) METHANOSULPHONAMIDE It was added to a mixture of trans-2-phenylcyclopropylcarboxaldehyde (ref: J. Org. Chem., 1992, 57, 1526) (30 mg, 0.2 mmol) and the trifluoroacetic acid salt of N- [3- (6 -ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl-methanesulfonamide (50 mg, 0.13 mmol) in dry 1,2-dichloroethane, base of Hunigs (0.02 ml, 0.12 mmol). The mixture was sonicated for 3 minutes and then stirred for an additional 30 minutes followed by the addition of sodium triacetoxyborohydride (50 mg, 0.25 mmol). After stirring for 72 hours, the reaction was 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 anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give a yellow / brown oil. This oil was dissolved in the minimum amount of dichloromethane and purified using a 6 g Biotage ™ cartridge, eluting with a gradient of ethyl acetate: hexane (30:70) to ethyl acetate (100%), affording the title compound. title (32 mg, 62%) in the form of an oil. 1 H-NMR (300 MHz, CDCl 3): 0.78-0.90 (m, 3H), 0.97 (m, 1 H), 1.24 (m, 1 H), 1.72 (m, 1 H), 1.76-1.79 (m, 2H). ), 1.90-2.05 (m, 2H), 2.45 (dd, 1H), 2.60 (dd, 1H), 2.84-2.95 (m, 2H), 2.99 (s, 3H), 3.02-3.08 (m, 2H), 6.89-7.3 (m, 9H). MS (electrospray): m / z (M + H) 411; C24H30SO2N2 + H requires 411.

PREPARATIONS NB: Preparations 1 to 148 of the International Patent Application Publication No. WO00 / 39089 are hereby incorporated by reference in their entirety, and the same numbering is hereby appended.

PREPARATION 149 1-r4- (3-Chloropropyl) phenyletanone Aluminum chloride (15.0 g, 0.11 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-phenylpropane (15.5 g, 0.10 mol) in dichloromethane (25 ml) at room temperature for 15 minutes. The mixture was stirred for 1 hour and then poured carefully onto ice. The aqueous layer was extracted with dichloromethane (450 ml). The organic layers were washed with water and brine, then dried (MgSO 4) and concentrated in vacuo to give the title compound (19.2 g, 98%) as an oil. 1 H-NMR (300 MHz, CDCl 3): 2.10 (quint., 2H), 2.60 (s, 3H), 2.85 (t, 2H), 3.55 (t, 2H), 7.30 (d, 2H), 7.90 (d, 2H). MS (thermospray): m / z [M + NH4] + 214; CnH13CIO + NH4 requires 214.1.

PREPARATION 150 1- (2-Chloroethoxyfl-4-cyclopropylbenzene) 4-Cyclopropylphenol (6.75 g, 50.3 mmol, reference: Horrom et al, Org. Prep. Proceed Int.Cl., 1992, 24 (6), 696-698), 2-chloroethyl p-toluenesulfonate (17.71 g) were stirred together. , 75.5 mmol) and potassium carbonate (10.4 g, 75.4 mmol) in anhydrous acetonitrile (500 ml) under nitrogen at reflux for 30 hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (1000 ml). The organic layers were washed with water (3 x 250 ml), dried (MgSO), filtered and concentrated in vacuo. This crude material was purified by chromatography on a silica column, eluting with hexane: dichloromethane (4: 1) and then with hexane: dichloromethane (3: 1), affording the title compound (8.7 g, 88%) as a solid. P.f .: 47-48 ° C. 1 H-NMR (300 MHz, CDCl 3): 0.60-0.70 (m, 2H), 0.85-0.95 (m, 2H), 1.80-1.95 (m, 1 H), 3.81 (t, 2H), 4.21 (t, 2H) ), 6.82 (d, 2H), 7.02 (d, 2H). MS (thermospray) m / z (M) 196; C11H13OCI requires 196.1.

PREPARATION 151 1-AIH-1H-pyrrole-2,5-dione (see J. Orq. Chem .. 1997, 62. 2652) To a solution of maleic anhydride (98 g, 1.00 mmol) in dry toluene (3000 ml) at room temperature under nitrogen, a solution of allylamine (57.1 g, 1.00 mmol) in toluene (1000 ml) was added dropwise. for 1 hour. The mixture was stirred at room temperature for 20 hours and then zinc chloride (136.3 g, 1.00 mol) was added and the reaction was heated to 80 ° C. Then 1, 1, 1, 3,3, 3-hexamethyldisilazane (242 g, 1.5 mmol) in toluene (1000 ml) was added dropwise over 1 hour and the mixture was stirred at 80 ° C temperature 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 sodium bicarbonate (2000 ml) and brine (2000 ml). The organic layers were concentrated in vacuo to give the title compound (74 g, 54%) as a solid. 1 H-NMR (300 MHz, CDCl 3); 4.05 (d, 2H), 5.00-5.15 (m, 2H), 5. 60-5.80 (m, 1 H), 6.65 (2H, s).

PREPARATION 152 1- (3-NitropheniD-1-Propanone Hydrazone It was added slowly to a solution of 3-nitropropiophenone (168 g, 0.93 mol) in ethanol (830 ml) at room temperature, hydrazine monohydrate (96.8 g, 1.93 mol) by means of a tap 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 (Na2SO4), filtered and concentrated in vacuo to give an orange oil. This reside was crystallized with diisopropyl ether at -20 ° C temperature to afford the title compound (110 g, 61%) as a yellow crystalline solid. P.f .: 32 ° C. 1 H-NMR (300 MHz, CDCl 3): 1.20 (t, 3 H), 2.70 (q, 2 H), 5.65 (s a, 2H), 7.50 (t, 1H), 7.95 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H). MS (electrospray) m / z [MH +] 194; 09HnN302 + H requires 194.1.

PREPARATION 153 3-AIII-6-ethyl-6- (3-nitrophenip-3-azabicyclo3.1.01hexane-2,4-dione It was added rapidly to a stirred solution of hydrazone of 1- (3-nitrophenyl) -1-propanone (84.7 g, 439 mmol) in 1,4-dioxane (1000 ml), manganese dioxide (purity CMD-1 from Sumitomo, 175 g, 2.01 mol), followed by a saturated ethanolic solution of potassium hydroxide (40 ml) at room temperature, the mixture was stirred at room temperature for 18 minutes, and during this period the temperature of the reaction had risen to 19 ° C at 25 ° C. The stirring was then stopped and the mixture was allowed to settle in. This mixture was filtered dropwise through a layer of Celite®, directly into a solution of 1-allyl-1H-pyrrole-2, 5-dione (57.3 g, 418 mmol) in 1,4-dioxane (200 ml) The Celite® layer was washed with 1,4-dioxane (100 ml) to ensure complete addition of the reactants. at room temperature for one hour, the mixture was heated to reflux for 20 hours.The mixture was cooled to room temperature and the solvent was removed in vacuo. or. the residue with diisopropyl ether (1000 ml) at 0 ° C temperature was then crystallized to give the title compound (83 g, 66%) as a white crystalline solid.

P.f .: 128-129 ° C. 1 H-NMR (300 MHz, CDCl 3): 0.90 (t, 3 H), 1.80 (q, 2 H), 2.80 (s, H), 4.05 (d, 2 H), 5.20 (d, 1 H), 5.30 (d, 1 H), 5.75-5.85 (m, 1 H), 7.55 (t, 1 H), .70 (dd, 1 H), 8.20 (dd, 1 H), 8.25 (s, 1 H).

PREPARATION 154 3-Allyl-6- (3-aminophenip-6-ethyl-3-azabicyclo3.1.01hexane-2,4-dione It was added to a stirred suspension of 3-allyl-6-ethyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (93 g, 310 mmol) and iron powder ( 151 g, 2.70 mmol) in ethanol (6.75 I), calcium chloride (16.7 g, 0.15 mol) in water (1.2 I). The mixture was refluxed for 3 hours and then cooled to room temperature, before filtering through Celite®. The filtrate was concentrated in vacuo to give a wet solid. This material was dissolved in dichloromethane (500 ml) and the two layers were separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid (81 g). This material was crystallized with ethyl acetate and hexane (1: 1, 6 ml per gram) at room temperature, affording the title compound (54 g, 65%) as a yellow crystalline solid. 1 H-NMR (300 MHz, CDCl 3): 0.90 (t, 3 H), 1.75 (q, 2 H), 2.75 (s, 2 H), 3.95 (br s, 2 H), 4.05 (d, 2 H), 5.25 (d, 1 H), 5.35 (d, 1 H), 5.75-5.85 (m, 1 H), 6.65 (d, 1 H), 6.70 (s, 1 H), 6.75 (d, 1 H), 7.10 (t, 1) H) PREPARATION 155 3- (3-Allyl-6-ethyl-3-azabicyclo3.1.01hex-6-yl) aniline It was added to a solution of lithium aluminum hydride (solution 1 M in THF; 400 mL, 400 mmol) in tetrahydrofuran (400 mL) under nitrogen at -15 ° C temperature, 3-allyl-6- (3- (aminophenyl) -6-ethyl-3-azabicyclo [3.1.0] hexane -2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 ml) by means of a tap funnel for 0.5 hours The mixture was allowed to warm slowly to room temperature for 1 hour. The mixture was heated to 50 ° C. The mixture was then cooled to 5 [deg.] C. Water (400 ml) was then carefully added to the cooled reaction mixture (at 5 [deg.] C.). through a layer of Celite®, washing with ethyl acetate (400 ml). The filtrate was dried (NgSO4), filtered and concentrated in vacuo to provide the title compound (38.1 g, 96%) as a golden oil. 1 H NMR (300 MHZ, CDCl 3): 0.85 (t, 3H), 1.80-1.95 (m, 4H), 2.85-3.00 (m, 4H), 3.15 (d, 2H), 3.60 (sa, 2H), 5.10 (d, 1H), 5.20 (d, 1 H), 5.80-5.95 (m, 1 H), 6.50 (d, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 7.05 (t, 1H) ) MS (AP +) m / z [MH +] 243; H requires 243.2.

PREPARATION 156 N-r3- (3-Allyl-6-ethyl-3-azabicyclo3.1.01hex-6-ipfenill-methanesulfonamide It was added dropwise 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 -40 ° C temperature, methanesulfonyl chloride (23.7 g, 206 mmol) by means of a tap funnel. The reaction mixture was slowly allowed to warm to room temperature for 2 hours and then stirred at room temperature for 20 hours. The organic layers were washed with water (4 x 500 ml), dried (MgSO 4), they were filtered and concentrated in vacuo to give the title compound (59.0 g) as a crude gum. 1 H NMR (300 MHz, 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, 1 H), 7.00-7.40 (m, 4H).

PREPARATION 157 N-l "3- (6-Ethyl-3-azabicyclo [3.1.01hex-6-iDfeni1 l methane-sulfonamide It was added to a degassed solution of N- [3- (3-allyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl) phenyl] methanesulfonamide (54.0 g, 169 mmol) and acid 1, 3 dimethylbarbituric acid (80.0 g, 512 mmol) in dichloromethane (500 ml) under nitrogen, 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 phases were then extracted with 2 M HCl (2 x 100 ml) and water (100 ml). The combined aqueous layers were then washed with dichloromethane (4 x 100 ml) and lyophilized to give a crude solid. This material was purified by HPLC Preparation (condition 4), affording the trifluoroacetic acid salt of the title compound (25.2 g, 53%) as a gray solid. 1 H-NMR (300 MHz, CD3OD): 0.90 (t, 3 H), 1.65 (q, 2 H), 2.30-2.40 (m, 2 H), 2.90 (s, 3 H), 3.25-3.35 (m, 2 H), 3.70 -3.80 (m, 2H), 7.10-7.15 (m, 2H), 7.20 (s, 1 H), 7.30 (t, 1H). MS (AP +) m / z [MH] + 281; C? 4H20N2O2S + H requires 281, 1.

PREPARATION 158 3-Benzyl-6-methyl-6- (3-nitrophenip-3-azabyl) r3.1.01-hexane-2,4-dione To a solution of hydrazone of 1- (3-nitrophenyl) -1-ethanone (100 g, 0.56 mol) in dioxane (1 I), MNOi (350 g, 2.3 mol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The suspension was filtered through Celite and the Celite layer was washed with dioxane (200 ml). The filtrate was returned to a vessel and N-benzylmaleimide (110 g) was added in portions over a period of 20 minutes. The reaction mixture was stirred at room temperature for 4 hours, before heating 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 was isolated by filtration as a white crystalline solid (56%).

NMR (CDCl 3) d: 1.31 (s, 3H), 1.55 (s, 3H), 2.80 (s, 2H), 4.63 (s, 2H), 7.28-7.34 (m, 3H), 7.43-7.45 (d, 2H) ), 7.52-7.56 (t, 1 H), 7.63-7.65 (d, 1 H), 8.13-8.16 (d, 1H), 8.17 (s, 1 H) EM (APCI): m / z [MH +] 337.4 + H requires 337.3.

PREPARATION 159 6- (3-Aminophenyl-3-benzyl-6-methyl-3-azabicyclo-r3.1.01-hexane-2,4-dione It was added to a suspension of 3-benzyl-6-methyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (30 g, 89 mmol) in ethyl acetate (600 ml), 5% Pt / C (1.5 g, 5% by weight). The mixture was hydrogenated at 4 atm (= 414 kPa) / room temperature for 18 hours. The suspension was filtered through Arbocel and the resulting solution was evaporated in vacuo to give the product as a white crystalline solid (24 g, 88%). NMR (CDCl 3) d: 1.26 (s, 3H), 2.74 (s, 2H), 3.7 (2H, s a), 4.60 (s, 2H), 6.56-6.58 (d, 1 H), 6.60 (s, 1H), 6.65-6.67 (d, 1 H), 7.07-7.11 (t, 1 H), 7.26-7.33 (m, 3H), 7.42 -7.44 (m, 2H). MS (APCI): m / z [MH +] + H requires 307.4.

PREPARATION 160 N-Í3- r3-Benzyl-6-methyl-2,4-dioxo-3-azabicichlor3.1.01hex-6- ipfeniD methanesulfonamide It was added to a solution of 6- (3-aminophenyl) -3-benzyl-6-methyl-3-azabicyclo [3.1.0] hexane-2,4-dione (24 g, 78 mmol) in ethyl acetate (480 ml), pyridine (9.5 ml, 118 mmol), followed by the slow addition of methanesulfonyl chloride (9.1 ml, 118 mmo |). The reaction was stirred at room temperature for 2.5 hours. The reaction mixture was sequentially washed with a 1 M solution of HCl (120 ml) and water (120 ml). The ethyl acetate was dried over MgSO 4 and evaporated in vacuo to give the product as an orange solid (30 g, 99%). 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-Benzyl-6-methyl-3-azabicyclo r3.1.01 hex-6-ill phenyl) - methanesulfonamide It was added 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, sodium borohydride (31 g, 820 mmol). It cooled reaction mixture at < 10 ° C temperature and BF3.OEt2 (138.6 ml, 1094 mmol) was added dropwise, maintaining the temperature at < 10 ° C. The reaction mixture was allowed to warm to room temperature for 2 hours before heating to reflux for an additional 8.5 hours. The reaction mixture was cooled to between 0 ° C and 5 ° C, and an aqueous piperazine solution (198.5 g, 2304 mmol in 1.26 l of water) was added. The reaction mixture was then heated to reflux for a period of 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). The organic phases were dried over MgSO4 and evaporated in vacuo to give the product as a white crystalline solid (129 g, 93%). 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) , 1 H), 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-r6-Methyl-3-azabicyclo r3.1.01hex-6-ipphenyl) methanesulfonamide It was added to a solution of N- (3-benzyl-6-methyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl] methanesulfonic acid (20 g, 56 mmol) in methanol, ammonium formate (10.6 g, 168 mmol) and the reaction was stirred for 5 hours. minutes 10% Pd / C (8 g) was added and the resulting mixture was heated to reflux for 16 hours. The mixture was allowed to cool and the catalyst was removed by filtration through Celite. The solvent was removed in vacuo to give the product as a pale yellow oil, which solidified on standing (15.2 g, 85%). 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, 1 H), 7.20-7.23 (m, 1 H). MS (APCI): m / z [MH +] 267.4 + H requires 267.3.

PREPARATION 163 3-Benzyl-6-ethyl-6-.3-nitrophenyl) -3-azabicyclo3.1.01hexane-2,4-dione To a solution of hydrazone of 1- (3-nitrophenyl) -1-propanone (42.1 g, 0.217 mol) in dioxane (630 ml), Mn02 (126 g, 1440 mmol) was added and the reaction mixture was stirred at room temperature. environment for 20 minutes. The suspension was filtered through Celite and the Celite layer was washed with dioxane (200 ml). The filtrate was returned to a vessel and N-benzylmaleimide (44.9 g, 239 mmol) was added in portions over a period of 20 minutes. The reaction mixture was stirred at room temperature for 60 hours before heating 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 in the form of a white crystalline solid (42.2 g, 56%). NMR (CDCI3) d: 0.69-0.73 (t, 3H), 1.47-1.49 (q, 2H), 2.78 (s, 2H), 4.64 (s, 2H), 7.3-7.32 (m, 2H), 7.43-7.44 (d, 1 H), 7.52-7.55 (t, 1 H), 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-Aminopheni-3-benzyl-6-ethyl-3-azabicyclo3.1.01hexane-2,3-dione It was added to a suspension of 3-benzyl-6-ethyl-6- (3-nitrophenyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (42.1 g, 120 mmol) in ethyl acetate (850 ml), 5% Pt / C (2.1 g, 5% by weight). The mixture was hydrogenated at 414 kPa / room temperature for 18 hours. The suspension was filtered through Arbocel and the resulting solution was evaporated in vacuo to give the product as a white crystalline solid (34.1 g, 89%). NMR (CDCl 3) d: 0.70-0.74 (t, 3H), 1.41-1.47 (q, 2H), 2.73 (s, 2H), 3.68 (sa, 2H), 4.61 (s, 2H), 6.55-6.57 (d , 1 H), 6.60 (s, 1 H), 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-f3-r3-Benzyl-6-ethyl-2,4-d »oxo-3-azabicyclo3.1.01hex-6-illphenD methanesulfonamide It was added 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). , pyridine (9.5 ml, 118 mmol), followed by the slow addition of methanesulfonyl chloride (9.1 ml, 118 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was sequentially washed with a 1 M solution of HCl (250 ml) and water (120 ml). The dichloromethane was dried over MgSO4 and evaporated in vacuo to give the product as a pink waxy 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-Benzyl-6-ethyl-3-azabicyclo T3.1.01hex-6-ipphenyl) -methanesulfonamide It was added 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) under nitrogen, sodium borohydride (7.46 g, 201 mmol).

The reaction mixture was cooled to < 10 ° C temperature and BF3.OEt2 (38.1 ml, 268 mmol) was added dropwise, keeping the temperature at <10 ° C. The reaction mixture was allowed to warm to room temperature for 2 hours before heating to reflux for an additional 12 hours. The reaction mixture was cooled to between 0 ° C and 5 ° C, and an aqueous piperazine solution (48.7 g, 565 mmol in 320 ml of water) was added. The reaction mixture was then heated to reflux for a period of 18 hours. The 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 x 400 ml). The organic phases were dried over MgSO 4 and evaporated in vacuo to give 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), 2.06-2.12 (q, 2H), 2.79-2.81 (d, 2H), 2.99 (s, 3H), 3.06 -3.08 (d, 2H), 3.67 (s, 2H), 7.01-7.03 (d, 1 H), 7.08-7.10 (d, 2H), 7.22-7.26 (m, 3H), 7.30-7.32 (m, 3H) ). MS (APCI): m / z [MH +] 371.3 + H requires 371.5.

PREPARATION 167 N- (3-r6-Ethyl-3-azabicyclo3.1.01 hex-6-ill phenylmethanesulfonamide It was added to a solution of N-. { 3-benzyl-6-ethyl-3-azabicyclo [3.1.0] hex-6-yl] phenyl} methanesulfonamide (500 g, 1.34 mmol) in methanol (30 ml), ammonium formate (255 mg, 4.05 mmol) and the reaction 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 allowed to cool and the catalyst was removed by filtration through Celite. The solvent was removed in vacuo to give the product as a pale yellow oil, which solidified on standing (15.2 g, 85%). RMM (CDCI3) d: 0.80-0.84 (t, 3H), 1.64-1.69 (q, 3H), 1.82-1.86 (d, 2H), 2.98 (s, 3H), 3.12-3.18 (d, 2H), 3.21 -3.26 (d, 2H), 7.01-7.06 (d, 1 H), 7.10-7.14 (m, 2H), 7.26-7.28 (m, 1 H). MS (APCI): m / z [MH +] 281.7 + H requires 281.4. Other building block materials useful in the synthesis of compounds of formula (I) with various different R4 groups are available from the sources indicated in the following table, and the routine derivation thereof or analogous syntheses.

Having described the invention as above, the content of the following claims is declared as property:

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A substance that is a compound of formula I, O) wherein the "Ar" ring represents a phenyl optionally fused with benzene or a 5- or 6-membered heteroaryl ring; R1, when taken alone, is H, halogen, N02, NH2, NY2WY1, Het1, AD, C02R7, C (0) R8, C (= NOH) R8, or OE, Y2 is H, alkyl d * alkenyl C3. 6 (each of the alkyl and alkenyl is optionally substituted with aryl, aryloxy or Het1), W is S02, CO, C (0) 0, P (Y1) = 0, P (Y1) = S, Y1 is CMO alkyl (optionally substituted with one or more substituents independently selected from halogen, OH, C 1-4 alkoxy, C 1-6 alkanoyloxy, CONH 2, C 1-6 alkoxycarbonyl, NH 2, aryl, mono- or dialkyl (domino, C 3-8 cycloalkyl, phthalimidyl , Het1, aryl (optionally substituted with one or more substituents independently selected from d-alkyl, C1-4 haloalkyl and halogen), NH2, N (C? -6 alkyl) 2? NH (C? -6 alkyl), Het1 is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (preferably a heteroaryl group, optionally heteroaryl fused with benzene or with pyridyl), optionally substituted with one or more substituents independently selected from alkyl d -β, C-6 alkoxy, C 3-6 cycloalkyl, haloalkoxy d-6, haloalkyl C? -6, haiocycloalkyl C 3-6, = 0, OH, halogen, N02, sRi9aRi9bRi90 > CONR20aR20b, NR20aR20b, SR21a, NR ^ SOsR223, NR21cC (0) OR22b, NR21dCOR22b and (C6-6) alkoxycarbonyl, and if an S atom is present in a ring, it may be present as part of a group -S- , S (O) - or -S (02) -, and the ring carbon atoms may be present as part of a carbonyl moiety; R19a, R19b, R19c each independently represent d-6 alkyl or aryl, R20a and R20b independently represent H, C6-6 alkyl, aryl, C1-4 alkyl phenyl, each of said alkyl, aryl and alkylphenyl is optionally substituted with one or more alkyl d-4, alkoxy d-4, OH, N02, NH2 and / or halogen, or R20a and R20b may be taken together with the N atom to which they are attached to form a ring of 4 to 6 members optionally substituted with one or more substituents independently selected from one or more C- alkyl, C 1-4 alkoxy, OH, = 0, N02, NH2 and / or halogen, R21a 'b- c and d each independently represent H, alkyl d-β , aryl or alkyl each of said alkyl, aryl and alkylphenyl being optionally substituted with one or more C 1-4 alkyl, C 1-4 alkoxy, OH, N 0 2, halogen, NH 2, R 223 'and c each independently represent C 1-6 alkyl, aryl or alkyl ( C1-4) phenyl, each one of said alkyl, aryl and alkylphenyl optionally substituted with one or more C ?- alkyl, d-4 alkoxy, OH, NO 2, halogen, NH 2, A is C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, each optionally substituted with one or more C1-4 alkyl, C1-4 alkoxy, halogen and / or OH, D is H, OH, CN, NR25R26, CONR25R26, NHR27, C02R28, COR29, C (= NOH) R29, or AD is CN, NR25R26, CONR25R26, where R25 and R26 are each independently H, C1-3 alkyl, C3-8 cycloalkyl. aryl, alkyl (C 4 -4) phenyl (each of said C 1-3 alkyl, C 3-8 cycloalkyl, aryl and C 1-4 alkyl) phenyl is optionally substituted with one or more N 0 2, halogen, C 1-4 alkyl and or C 4 -4 alkoxy (each of these latter d 4 alkyl and C 1-4 alkoxy is optionally substituted with one or more halogens), or R 25 and R 26 are taken together with the N atom to which they are attached and can forming a 4- to 7-membered heterocyclic ring optionally incorporating one or more additional heteroatoms selected from N, O and S, and said ring is optionally substituted with one or more C 1-4 alkyl, OH, = 0, N02, NH2 and / or halogen, R27 is COR30, C02R31a, S02R31b, R28 and R29 are each independently H, C1-6 alkyl, C3-8 cycloalkyl, aryl or (C? -4) alkyl phenyl, each said C? ) C3-8 cycloalkyl, aryl and alkyl is optionally substituted with one or more N02, halogen, alkyl d ^, C? -4 alkoxy (each of these latter C- and a-oxyloxy CM is optionally substituted with one or more halogens), R30 is H, C1-4 alkyl , C3-8 cycloalkyl, C1-4 alkoxy, C3.8 cycloalkyloxy, aryl, aryloxy, C1-4 alkyl phenyl, phenylalkoxy (d4), (each of said G- alkyl, C3-8 cycloalkyl, alkoxy d-4, C3-8 cycloalkyloxy, aryl, aryloxy, alkyl (d-4) phenyl and phenylalkoxy (d-4) is optionally substituted with one or more N02, halogen, C1-4 alkyl, d-4 alkoxy (the latter alkyl and alkoxy are optionally substituted with one or more halogens)), R31a and R31b are each independently C? -4 alkyl, C3-8 cycloalkyl, aryl or alkyl (d-4) phenyl, each of which is optionally substituted with one or more N02, halogen, d-4 alkyl, C1 alkoxy -4, each of these latter being alkyl and alkoxy optionally substituted by one or more halogens, E is H, CONR ^ R33, CSNR32R33, COR34, C02R34, COCH (R343) NH2, R35, CH2C02R35a, CHR35bC02R35a, CH2OC02R35c, CHR35dOC02R35c, COCR36 = CR37NH2, COCHR36CHR37NH2, or PO (OR38) 2, R32 and R33 are each independently H, C3-10 alkyl, alkenyl, C3-7 cycloalkyl (optionally substituted with C? -4 alkyl), phenyl (optionally substituted with (X) p), C 1-10 alkyl (optionally substituted with C 4-7 cycloalkyl (optionally substituted with d 4 alkyl) or phenyl option ally substituted with (X) n), or R32 and R33 can be taken together with the N atom to which they are attached and can form a 5- to 8-membered heterocycle optionally comprising additional heteroatoms selected from N, O and S, being said heterocycle optionally substituted with C 1-4 alkyl, optionally substituted with one or more halogens, R 34 is H, C 4-7 cycloalkyl (optionally substituted with one or more C 1-4 alkyl), phenyl (optionally substituted with (X) n, alkanoyl (C? .4) oxy, NR ^ R33, CONR32R33 and / or OH), or C1-6 alkyl (optionally substituted with one or more halogen, C4-7 cycloalkyl (optionally substituted with one or more C1-4 alkyl), or phenyl (optionally substituted with (X) n, alkanoyl (d-4) oxy, NR32R33, CONR32R33 and / or OH), R343 is H, alkyl d-6 (optionally substituted with one or more halogen, C4-7 cycloalkyl (optionally substituted with one or more C1-4 alkyl), or phenyl (optionally substituted with (X) n, alkanoyl (d-4) oxy, NR32R33, CONR ^ R33 and / or OH), C4-7 cycloalkyl (optionally substituted with one or more alkyl C1.4), phenyl (optionally substituted with (X) n, (C1-4) alkanoyloxy, NR32R33, CONR32R33 and / or OH) or an amino acid substituent of natural origin, R35 is C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl (optionally substituted with one ornas (X) n, alkanoyl (C? -4), NHR32, CON (R32) 2 and / or OH), d-6 alkyl (optionally substituted with cycloalkyl C. optionally substituted with one or more C? - alkyl, or phenyl (optionally substituted with one or more (X) n, alkanoyl d-, NHR32, CON (R32) 2 and / or OH), alkoxy (C? .4) C? -4 alkyl, phenyl (C? - alkyl) oxyalkyl d-4, tetrahydropyranyl, tetrahydrofuranyl or, cinnamyl or trimethylsilyl, 35a'b ° and d are each independently H, cycloalkyl d-7 optionally substituted with one or more C? -4 alkyl, phenyl optionally substituted with one or more (X) non-C1-6 alkyl (optionally substituted with C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, or phenyl optionally substituted with one or more (X) n), R36 and R37 each independently represent H, C3-6 alkenyl, C4 cycloalkyl -7, 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 C 1-4 alkyl, or phenyl optionally substituted with one or more (X ) n), R38 is C4.7 cycloalkyl optionally substituted with one or more alkyl d-4, phenyl optionally substituted with one or more (X) n, or C? -6 alkyl (optionally substituted with C4.7 cycloalkyl optionally substituted with one or more alkyl d-, or phenyl optionally substituted with one or more (X ) n), R2 when taken alone is H or halogen; or R1 and R2, when attached to adjacent carbon atoms, may be taken together with the carbon atoms to which they are attached, and may represent Het1a; Ret1a is a heterocyclic group containing up to 4 heteroatoms selected from N, O and S, which may comprise up to 3 rings (and is preferably a 5- to 7-membered heterocyclic ring optionally condensed with benzene) and said group is optionally substituted with one or more substituents independently selected from OH, 0 =, halogen, C1.4 alkyl, C1-4 haloalkyl, C1 alkoxy. and C 1-4 haloalkoxy, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy groups optionally substituted with one or more C 3-6 cycloalkyl, arylalkyl (C 1-6), being the aryl group optionally substituted by one or more halogen, C 1-4 alkyl, C? -4 haloalkyl, d-4 alkoxy and C 1-4 haloalkoxy, the latter being C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C? -4 halo haloalkoxy optionally substituted with one or more NR23R24, NR23S (0) nR24, NR23C (0) m, R24, and if an S atom is present in a ring, it may be present as part of a -S group -, S (O) - or -S (02) -, said R23 and R24 when taken alone independently represent H, C1-4 alkyl or C1-4 haloalkyl, or R23 and R24 may be taken together with the N atom at which are joined to form a 4- to 6-membered heterocyclic ring comprising optionally one or more additional heteroatoms selected from N, O or S, and said heterocyclic ring being optionally substituted by one or more halogen groups, C1.4alkyl, haloalkyl C-? 4, C1-4alkoxy and / or haloalkoxy C1-? 4, R3 is H, CN, halogen, C6-6 alkoxy, (C- | 6) alkoxycarbonyl, C2.6 alkanoyl, (C2.6) alkanoyloxy, C3-8 cycloalkyl, (C3-8) cycloalkyl oxy, C-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13, NY2WY1, C? -6 alkyl, C2-10 alkenyl C2-? 0 alkynyl (each of said alkyl, alkenyl and alkynyl groups is optionally substituted with one or more CN, halogen, OH, alkoxy CIT, alkoxy (d-6) carbonyl, alkyl (C2-6) oxycarbonyloxy, alkanoyl C-? -6, alkanoyl (C? -6) oxy, cycloalkyl C3.8 , (C3-8) cycloalkyl oxy, C4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13 and / or NY2Y1), R4 is CMO alkyl, C3-10 alkenyl or C3-10 alkynyl, each of these groups is linked to N atom through a sp3 carbon, and said group is substituted with one or more substituents selected from: C2-6 alkoxy [substituted with one or more groups selected from OH, NR25R26, CONR25R26, halogen, C1-6 alkoxy, alkynyl C2.4, C2.4 alkenyl. heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl), C02CH2 (aryl), C02CH2 heteroaryl1), S (0) n (alkyl d-β ), S (O) "(aryl1), S (O) n (heteroaryl1), S02NR25R26 and cycloalkyl1], S (O) n (C6-6 alkyl) [optionally substituted with one or more groups selected from OH, NR25R26 , CONR25R26, halogen, C1.6 alkoxy, C2.4 alkynyl, C2.4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl1), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl) , C02CH2 (aryl1), C02CH2 (heterariio1), S (0) n (alkyl d-6), S (0) n (aryl1), S (0) n (heteroaryl), S02NR25R26 and cycloalkyl1)], aryl2, C02CH2 ( heteroaryl), C02CH2 (aryl1), cycloalkyl1, CO (heteroaryl), CO (aryl1), OCO (aryl1), OCO (heteroaryl), OCO (C6-6 alkyl), OCOCH2CN, C02 (heteroaryl), C02 (aryl1) , COCH2 (heteroaryl1), S (0) narilo1, S (0) nCH2aryl1, S (0) n (heteroaryl1), S (0) pCH2 (heteroaryl) 1, NHS02aryl \ NHS02 (alkynylC6), NHS02 (heteroaryl), NHS02CH2 (heteroaryl), NHS02CH2 (ary1), NHCOaryl1, NHCO (alkyl d-6), NHCONHaryl1, NHCONH (alkyl d.6) NHCOheteroaryl1, NHCONHheteroaryl1, NHC02aryl1) NHC02 (alkyl d-6), NHC02 (heteroaryl), Aryloxy, Heteroaryl1 oxy, C1-6 alkoxycarbonyl substituted with alkyl C? -6, aryl, C? -6 alkoxy, CH2 (aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, C2.6 alkanoyl substituted with C? -6 alkyl, aryl, C? -6 alkoxy , CH2 (aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, C2.6 alkanoyloxy substituted with C6-6 alkyl, aryl, C6-6 alkoxy, CH2 (aryl1), haloaikyl d-4, halogen , OH, CN or NR25R26, cycloalkyl-oxy, CO-cycloalkyl, heterocycle substituted with one or more substituents selected from C1-6 alkyl (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (C1-6 alkyl), S02NR25R26, S02 ( alkyl d-6), C02 (alkyl d-6), CH2C02 (alkyl d-6), OCH2C02 alkyl Ci-6), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN and cycloalkyl C3 -7, heterocyclyloxy substituted with one or more substituents sele of alkyl d-β (substituted with OH), CONR25R26, CH2CONR 5R26, NR 5R26, NHCONR25R26, CO (C6-alkyl), S02NR25R26, S02 (C6-alkyl), C02 (C6-alkyl) , CH2C02 (alkyl d-β), OCH2C02 (C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN and C3.7 cycloalkyl, wherein aryl1 is phenyl optionally fused to a Cs-7 carbocyclic ring, said group being optionally substituted with one or more substituents selected from C1-6alkyl (optionally substituted with OH, CN or halogen), haloalkoxy Ci-6, OH, = 0, NY2WY1, halogen, C6-6 alkoxy, CONR25R26, CH2CONR25R26, NR25R26. NHCONR25R26, CO (C? 6 alkyl), Caryl, COheteroaryl, S02NR25R26, S (0) n (alkyl d-6), S (0) n (aryl), S (0) n (heteroaryl), C02 (C? -6 alkyl), C02 (aryl), C02 (heteroaryl), C02H, (CH2) 1.4C02 (C? -6 alkyl), (CH2)? - 4C02H, (CH2)? - 4C02 (aryl ), (CH2) 1.4C02 (heteroaryl), O (CH2) 1.4C02 (alkyld-6), 0 (CH2)? - 4C02H, 0 (CH2) 1.4C02 (aryl), 0 (CH2) -4C02 (heteroaryl) ), aryl, heterocyclyl, aryloxy, aryl (CH2oxi, aryl (CH2), CN, O (CH2) 1.4CONR25R26 and C3 cycloalkyl aryl2 is phenyl optionally fused with a C5 carbocyclic ring, said group being substituted with one or more substituents selected from alkyl d-β (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (alkyl d-6), COaryl, COheteroaryl, S02NR25R26, S (0) n (C6-6 alkyl), S ( 0) n (aryl), S (0) n (heteroaryl), C02 (alkyl d-6), C02 (aryl), C02 (heteroaryl), C02H, (CH2) ^ C02 (alkyl d-6), (CH) ^ CO ^, (CH2) 1-4C02 (aryl), (CH2) L C02 (heteroaryl), 0 (CH2)? -4C02 (alkyl d-6), 0 (CH2) 1-4C02H, O (CH2)? -4C02 (aryl), 0 (CH2)? - 4C02 (heteroaryl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN, O (CH2) CONR25R26 and cycloalkyl or C3-7. heteroaryl is heteroaryl optionally fused to a C5.7 carbocyclic ring, said group being optionally substituted with one or more substituents selected from alkyl C -? - 6 (optionally substituted by OH, CN or halogen), haloalkoxy C? -6, OH, = 0, NY2WY1, halogen, C? -6 alkoxy, CONR 5R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (alkyl d-6), COaryl, COheteroaryl, S02NR25R26, S (0) n (C6-alkyl), S (0) n (aryl), S (0) n (heteroaryl), C02 (alkyl d-6) ), C02 (aryl), C02 (heteroaryl), C02H, (CH2) .4C02 (C6-alkyl), (CH2) 1.4C02H, (CH2) 1-4C02 (aryl), (CH2) 1.4C02 (heteroaryl) ), 0 (CH2) 1.4C02 (alkyl d-6), 0 (CH2) 1.4C02H, 0 (CH2) 1.4C02 (aryl), 0 (CH2)? -4C02 (heteroaryl), aryl, heterocyclyl, aryloxy , aryl (CH2) oxy, aryl (CH2), CN, O (CH2)? - 4CONR25R26 and C3.7 cycloalkyl. cycloalkyl1 is a C3-10 carbocyclic system with one or two rings and is substituted with alkyl d-β, aryl, C 1-6 alkoxy, CH 2 (aryl 1), haloalkyl C 1-4, halogen, OH, CN or NR 25 R 26, with the condition that there are no N-R4 groups in which there is a heteroatom attached to another heteroatom by an SP3 carbon. Z is a direct bond, a CO or S (0) n group, B is (CH2) P, R12 and R3 each independently represent H or C1-4 alkyl, or R12 and R13 may be taken together with the N atom. to which they are attached to form a 4- to 7-membered heterocycle optionally comprising an additional hetero moiety selected from NR16, O and / or S, and which is optionally substituted with one or more C1-4 alkyl, R14 and R15 each represent independently H, C-MO alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-8 cycloalkyl, aryl or heteroaryl, or R 14 and R 5 can be taken together with the N atom to which they are attached to form a heterocycle of 4. to 7 members optionally comprising an additional hetero moiety selected from NR16, O and / or S, and which is optionally substituted by one or more C1-4 alkyl, R16 is H, Ci.e alkyl, C3-8 cycloalkyl, (Ci-β alkylene) (C3-8 cycloalkyl) or ( alkylene d-6) aryl, R5 and R8 when taken separately are each independently H, C6-6 alkyl, R5 and R8 can be taken together with the carbon atoms to which they are attached to form a C3-8 cycloalkyl ring , R6, R7, R9 and R10 when taken separately are H, R5 and R6 or R7 can be taken together with the carbon atoms to which they are attached to form a C3.8 cycloalkyl ring, X is halogen, C1-4 alkyl , C1.4 alkoxy, C1-4 haloalkyl or C1-4 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; "amino acid substituent of natural origin" means the substituent a which occurs in any of the following natural amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid , glutamic acid, asparagine, glutamine, lysine, arginine or proline; "heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from N, O and S, and if an S atom is present in the ring, it may be present as part of a group -S-, S (0) - or -S (0) 2-, and which may be linked to the rest of the compound through any available atom (s); "heterocycle" is a group containing 1, 2 or 3 rings, and containing up to 4 ring heteroatoms selected from N, O and S and up to 18 ring carbon atoms; "aryl", including the definitions of "aryloxy", etc., means a group comprising a phenyl ring and which may incorporate an additional carbocyclic ring condensed with said phenyl ring and which can be attached to the rest of the compound through any available atom (s) (examples of said groups include naphthyl, indanyl, etc.); the groups "alkyl", "alkenyl" and "alkynyl" may be linear or branched if the number of carbon atoms permits; the "cycloalkyl" groups can be polycyclic if the number of carbon atoms allows it; or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof. 2. The substance according to claim 1, further characterized in that the "Ar" ring represents phenyl or pyridyl. 3. The substance according to any of the preceding claims, further characterized because R1 when taken alone is OH, CN, halogen, N02, NH2, NY2WY1 or Het1. 4. The substance according to any of the preceding claims, further characterized in that R2 when taken alone is H. 5. The substance according to claim 1 or 2, further characterized in that R1 and R2 are taken together with the carbon atoms to which they are attached and represent a 5- to 7-membered heteroaryl ring optionally condensed with benzene, optionally substituted with C 1-4 alkyl or C 1-4 haloalkyl. 6. The substance according to any of the preceding claims, further characterized in that X is Cl. 7. - The substance according to any of the preceding claims, further characterized in that n is 0 and q is 0. 8. The substance according to any of the preceding claims, further characterized in that R3 is H, CN or C? -6 alkyl (optionally substituted with one or more halogen, OH, alkoxy Ci- 6) alkoxy (C? -6) alkoxycarbonyl, C2.6 alkanoyl, alkanoyl (C2-6) alkyloxy, alkyl (C2.6) oxycarbonyloxy, NR12R13, CONR12R13 and / or NY2WY1). 9. The substance according to any of the preceding claims, further characterized in that R4 is C-MO alkyl substituted with one or more substituents selected from: C2-6 alkoxy [substituted with one or more groups selected from OH, NR25R26, CONR25R26 , halogen, d-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl), C02CH2 (aryl1), C02CH2heteroarilo1), S (0) n (alkyl), S (O) n (aryl1), S (O) n (heteroarilo1), S02NR25R26 and cicloalquilo1], S (O) "(alkyl Oi- e) [optionally substituted with one or more groups selected from OH, NR25R26, CONR25R26, halogen, C6-alkoxy, C2 alkynyl. , C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO (heteroaryl), CO (aryl1), C02 (heteroaryl), COCH2 (aryl1), COCH2 (heteroaryl), C02CH2 (aryl1), C02CH2 (heteroaryl1), S (0) ) n (alkyl), S (0) n (aryl1), S (0) n (heteroaryl), S02NR25R26 and cycloalkyl1)], aryl2, C02CH2 (heteroaryl), C02CH2 (aryl1), cycloalkyl1, CO (heteroaryl), CO (aryl1), OCO (aryl1), OCO (heteroaryl), OCO (C6-6 alkyl), OCOCH2CN, C02 (heteroaryl), C02 (aryl1), COCH2 (heteroaryl1), S (0) narile, S (0) nCH2aryl1, S (0) n (heteroaryl), S (0) nCH2 (heteroaryl) 1, NHS02aryl1, NHS02 (alkyld-6), NHS02 (heteroaryl), NHS02CH2 (heteroaryl), NHS02CH2 (ary1), NHCOaryl1, NHCO (alkyl d-6), NHCONHaryl1, NHCONH (alkyl d-6) NHCOheteroaryl1, NHCONHheteroaryl1, NHC02aryl1) NHC02 (alkyl d.6), NHC02 (heteroaryl), Aryloxy, Heteroaryl-oxi, C1-6 alkoxycarbonyl substituted with Ci-alkyl -ß, aryl, alkoxy Ci-e, CH2 (aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, C2.6 alkanoyl substituted with d-ß alkyl, aryl, C1-6 alkoxy, CH2 (aryl1) , C1-4 haloalkyl, halogen, OH, CN or NR25R26, C2-6 alkanoyloxy substituted with C-? 6 alkyl, aryl, C1-6 alkoxy, CH2 (aryl1), haloalkyl C? -4, halogen, OH, CN or NR25R26, cycloalkyl1 oxy, cycloalkyl1, heterocycle substituted with one or more substituents selected from C? -6 alkyl (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (C1-6alkyl), S02NR25R26, S02 (C-alkyl) ? -6), C02 (d.6 alkyl), CH2C02 (C1-6 alkyl), OCH2C02 C1-6) alkyl, aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN and cycloalkyl C3- 7, heterocycicyloxy substituted with one or more substituents selected from alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO (alkyl d-6), S02NR 5R26, S02 (alkyl d-6), C02 (alkyl Ci-ß), CH2C02 (alkyl C1- 6), OCH2C02 (Ci-β alkyl), aryl, heterocyclyl, aryloxy, aryl (CH2) oxy, aryl (CH2), CN and C3-7 cycloalkyl, 10. The substance according to any of the preceding claims, characterized in addition because R5, R6, R7, R8, R9 and R10 are each taken separately and are all H. 11. - The substance according to any of the preceding claims, further characterized in that the ring "Ar" represents a group of the formula: 12. - The substance according to any of the preceding claims, further characterized in that R3 is H, CH3 C2H5, i-C3H7, n-C3H7 or CH2OCH3. 13. The substance according to any preceding claim except claim 5, further characterized in that R1 is OH, CN, I, Cl, NH2, N02, optionally fused with benzene heteroaryl, NHS02Y1, NHCOY1 or NHC02Y1. 14. The substance according to any of the preceding claims, further characterized in that R4 is alkyl-10 substituted with cycloalkyl1. 15. The substance according to any of the preceding claims, except claims 3, 4 and 13, further characterized in that R and R2 are taken together with the carbon atoms to which they are attached and are a 5-membered heteroaryl moiety optionally substituted with C1-4 alkyl or C1-4 haloalkyl. 16. - The substance according to any of the preceding claims, further characterized in that R3 is CH3 or C2Hd. 17. The substance according to any of the preceding claims, except claims 5 and 15, further characterized in that R1 when taken alone is OH, CN, I, Cl, NH2, N02, 1, 2,3-triazolyl, 1, 2,4-triazolyl, imidazol-2-yl, pyridinium-2-yl, thien-2-yl, imidazol-4-yl, benzoimidazol-2-yl, NHS02 (alkyl d-β), NHS02 (alkyi C ? -6 substituted with methoxy, CONH2, OH, C02 (C2-6 alkyl., Phthalimido, NH; or halogen), NHS02NH2, NHS02NH (C? -6 alkyl), NHS02N (alkyl), NHS02Het1a, NHCO (alkyl 1-6) or NHC02 (alkyl d-6) 18. The substance according to claim 17, further characterized in that R1 is OH, NHS02CH3, NHS02C2H5, NHS02 (i-C3H7), NHS02 (n-C4H7) ), NHS02NH (i-C3H7), NHS02 (N-N-methylimidazol-4-yl), NHS02 (CH2) 2OCH3, NHS02 (CH2) OH, 1, 2,4-triazolyl or imidazol-2-yl. substance according to claim 18, further characterized in that R1 is OH, NHS02CH3, NHS02C2H5 or imidazol-2-yl 20.- The substance in accordance with claim 15, further characterized in that when R1 and R2 are taken together with the carbon atoms to which they are attached they are a midazole group optionally substituted in 2 with CF3. 21. - The substance according to any one of the preceding claims, further characterized in that R4 is C2.4 alkyl substituted with cycloalkyl1. 22. The substance according to any one of the preceding claims, further characterized in that R4 is propyl substituted with cycloalkyl1. 23. The substance according to any one of the preceding claims, further characterized in that R4 is propyl substituted with a C3-10 carbocyclic system with one or two rings, and is substituted with OH. 24. The substance according to any one of the preceding claims, further characterized in that R4 is propyl substituted with (cyclohexyl substituted with OH). 25. The substance according to any of the preceding claims, further characterized in that R4 is (1-hydroxycyclohexyl) prop-3-yl. 26. The substance according to claim 1, further characterized by having the following relative stereochemistry: 27. - The substance according to claim 1, further characterized in that it is selected from the compounds of the examples described herein, and. of the salts and prodrugs of these. 28. A pharmaceutical or veterinary composition comprising a substance of any one of the preceding claims, and a pharmaceutically or veterinarily acceptable vehicle. 29. The substance according to any of claims 1 to 26 for use in medicine. 30. The substance according to any of claims 1 to 26 for use as a medicament useful for the treatment of an opiate-mediated disease or condition. 31. The use of a substance according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of a disease or condition mediated by opioid receptors. 32. A process for the preparation of a substance according to claim 1, further characterized in that comprises: (a) for compounds of formula I wherein q is 0 and R1 represents reacting a compound of formula II, II with a compound of formula III, Z1-WY1 III wherein Z1 is a suitable leaving group, such as halogen or Y1S020-; (b) for compounds of formula I wherein q is 0 and R6 and R7 represent both H, the reduction of a compound of formula IV, IV using a suitable reducing agent; (c) for compounds of formula I wherein q is 0 and R9 and R10 represent both H, the reduction of a compound of formula V, using a suitable reducing agent; (d) for compounds of formula I wherein q is 0 and R1 and R2 are bonded to adjacent carbon atoms and taken together with the carbon atoms to which they are attached representing Het a, in which Ret1a represents a unit imidazole, the reaction of a corresponding compound of formula VI, VI with a compound of formula VII, RyC02H V1 in which Ry represents H or any of the optional substituents on Het1a (as defined above), preferably H, C1-4 alkyl or C1-4 haloalkyl; (e) wherein q is 0, reacting a compound of formula VIII, VIII with a compound of formula IX, R4Lg IX wherein Lg is a leaving group; (f) for compounds of formula I wherein q is 0 and R6, R7, R9 and R10 are all H, the reduction of a compound of formula X, with a suitable reducing agent; (g) for compounds of formula I wherein q is 0 and R1 represents OH, reacting a compound of formula II in the that Y2 is H, as defined above, with luoroboric acid and isoamyl nitrite; (h) for compounds of formula I wherein q is 0 and R 1 represents Cl, 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 copper (I) chloride in the presence of concentrated acid; (i) for compounds of formula I wherein q is 1, 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 reduction of a corresponding compound of formula XXXI, XXXI in which R ^ C ^ takes the same meaning as R4 as defined previously; or (k) for compounds of formula (I) wherein q is 0, the reductive amination reaction of the amine of formula VIII above with a aldehyde of formula R ^ -CHO, in which R4aCH2 takes the same meaning that R4 as defined above, and when desired or necessary, convert the resulting compound of formula I into a pharmaceutically or veterinarily acceptable derivative or vice versa. 33.- A compound of formula II, IV, V, VI, X, Xa, XI, Xll, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX or XXXI or a salt thereof, as described herein .