MXPA01010086A - Adamantane derivatives - Google Patents

Abstract

The invention provides compounds of general formula (I) in which m, A, R1 and Ar have the meanings defined in the specification;a process for their preparation;pharmaceutical compositions containing them;a process for preparing the pharmaceutical compositions;and their use in therapy.

Description

ADAMANTAN DERIVATIVES Field of the Invention The present invention relates to adamantane derivatives, to a process for their preparation, to pharmaceutical compositions containing them, to a process for preparing pharmaceutical compositions, and to their use in therapy.

BACKGROUND OF THE INVENTION Adamantane derivatives are already known in the art, for example, from WO 95/04720 for use as gastrin receptor ligands and cholecystokinin, from Chem. Abs. (1977), Volume 86, No. 13 (86: 89560d) for use as analgesics, and US-A-3 464 998 as antibiotics. The P2X receptor (previously known as the P2Z receptor), which is an inlet ion channel for the ligand, is present on a variety of cell types, which are widely known to be involved in the inflammatory / immune process specifically, macrophages, breast or breast cells and lymphocytes (T and B). The activation of the P2X7 receptor by the extracellular nucleotides, in particular the Ref.133223 adenosine triphosphate, leads to the release of interleukin-lß (IL-lß) and the formation of giant cells (macrophages / microglial cells), to degranulation (cells of the breast or breast) and proliferation (cells T), apoptosis and diffusion of L-selectin (lymphocytes). The P2X7 receptors are also located on the cells that present the antigen (.APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells. It may be desirable to manufacture effective compounds such as P2X receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the etiologies of which the P2X7 receptor may play a role. According to the present invention, there is thus provided a compound of the general formula (I) wherein m represents 1, 2 or 3, preferably 1 or 2; each R1 independently represents a hydrogen or halogen atom (for example fluorine, chlorine, bromine or iodine), preferably a hydrogen atom; A represents C (0) NH or, preferably, NHC (O); Ar represents a group X represents a bond, an oxygen atom or a CO group, (CH2)? - 6 / CH =, (CH2)? - 6Of 0 (CH2) a-6.0, (CH2) 2.60, 0 (CH2) 2-30 (CH2)? -3, CR '(OH), (CH2)? -3? (CH2)? -3 (CH2) a_30 (CH2) 2_30, NR5, (CH2 -6NR5, NR5 (CH2)! - 6, (CH2) 1-3NR5 (CH2) 1_3, 0 (CH2) 2.6NR5, 0 (CH2) 2.3NR5 (CH2) 1.3, (CE2) 1-2m5 (CH2) 2-30, NR5 (CH2) 2-60, NR5 (CH2) 2_30 (CH2) i_3, CONR5, NR5CO, S (0) n, S (0) nCH2, CH2S (0 ) n, S02NR5 or NR5S02, n is 0, 1 or 2; R 'represents a hydrogen atom or an alkyl group with Cj-Cβ, preferably methyl; one of R2 and R3 represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from (i) C6-C6 alkenyl optionally substituted by at least one of C3-C6 cycloalkyl, (ii) cycloalkyl with C3 -C8, (iii) alkyloxy with Ci-Cβ optionally substituted by at least one of cycloalkyl with C3-C6, and (iv) cycloalkyloxy with C3-C8, each of these groups is optionally substituted by one or more fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen atom; either R4 represents a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more substituents selected independently from the fluorine, hydroxyl, carboxyl, cyano, C?-C6 alkyl, hydroxyalkyl with d-Ce, -NR6R7, - (CH2) rNR6R7 and -C0NR6R7, or R4 represents a saturated 3 to 8-substituted carbocyclic ring system by one or more substituents independently selected from -NR6R7, - (CH2) rNR6R7 and -C0NRDR7, the ring system is optionally further substituted by one or more substituents independently selected from the fluorine, hydroxyl and alkyl atoms with C? C6, r is 1, 2, 3, 4, 5, or 6; R represents a hydrogen atom or an alkyl group with Ci-Cβ or a cycloalkyl group with C-C8; R6 and R7 each independently represent a hydrogen atom or an alkyl group with C? -C6, hydroxyalkyl with C2-C6 or cycloalkyl with C3-C8, or R and R7 together with the nitrogen atom to which they are attached forms a saturated heterocyclic ring of 3 to 8 elements; with the proviso that (a) when A represents C (0) NH and R4 represents a saturated aliphatic heterocyclic ring system of 3 to 8 elements containing a nitrogen atom, then X is different from a bond, and b) when A represents C (0) NH and X represents a group (CH2)? _ 6 or 0 (CH2)? _ 6, then R4 does not represent an unsubstituted imidazolyl group, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl, and (c ) when A represents NHC (O) and R4 represents an unsubstituted saturated aliphatic heterocyclic ring system of 3 to 8 elements, which contains a nitrogen atom, then X is different from a bond, and (d) when A represents NHC ( O) and X represents 0 (CH2) x_6, NH (CH2)? - 6 or SCH2, then R4 does not represent a group Unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl, and (e) when A represents NHC (O) and X represents O (CH2) 2_3NH (CH2) 2, then R4 does not represent an imidazolyl group; or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl portion in a substituent group may be linear or branched. Examples of alkyl groups / groups containing up to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. When one of R2 and R3 represents an alkyl with C? -C6 / C? -C6 alkyloxy optionally substituted by at least one cycloalkyl with C3-C6, it is to be understood that one or both of the alkyl and cycloalkyl portions may be substituted optionally by the fluorine atoms. Relative to R4, a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom may be a monocyclic or bicyclic ring system. Also in relation to R4, a saturated carbocyclic ring system of 3 to 8 elements can be a monocyclic or bicyclic ring system. When R ° or R7 represent a C2-C6 hydroxyalkyl in the substituent NR6R7, - (CH2) rNR6R7 or -CONR6R7, it will be appreciated that the hydroxyl group will not be bonded to the same carbon atom as the nitrono atom. When Rd and R7 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 3 to 8 elements, the ring obtained is monocyclic. Preferably X represents a bond, an oxygen atom or a group CO, (CH)? -6, CH =, 0 (CH2)? _6, 0 (CH2) 2-60, 0 (CH2) 2-3? (CH2 1-3f CR '(OH), NR5, (CHz -eNR5, CONR5, S (0) "OS (0) nCH2. One of R2 and R3 represents a halogen (for example fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl, or a group selected from (i) alkoyl with C? -C6, preferably C? ~ C alkyl, optionally substituted by at least one (eg 1, 2 or 3) cycloalkyls with C3- C6 (ie cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (ii) cycloalkyl with C3-C8 (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, (iii) alkyloxy with C? -C6, preferably alkyloxy with C? -C4, optionally substituted by at least one (for example 1, 2 or 3) cycloalkyls with C3-C6 (ie cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and (iv) cycloalkyloxy with C3-C8, (for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy) or cyclohexyloxy), each of these groups is optionally substituted by one or more (for example 1, 2, 3 or 4) fluorine atoms, and the other of R2 and RJ represents a hydrogen or halogen atom (for example fluorine, chlorine, bromine or iodine).

Preferably, one of R2 and R3 represents a halogen atom or a nitro group, amino or alkyl with d-Ce (especially methyl or ethyl) and the other of R2 and R3 represents a hydrogen atom. R4 may represent a system of 'saturated heterocyclic ring or unsaturated aliphatic 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more (for example 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, alkyl with C 6 alkyl, preferably alkyl Cx-C4 alkyl, hydroxyalkyl d-C6, preferably hydroxyalkyl C -C4,? - NR6R7, - (CH2) rNR6R7 and -C0NR6R7. The system of saturated aliphatic heterocyclic ring or unsaturated 3 to 9 elements in the group R4 may be a monocyclic ring system such as pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), 4-piperiden-3-yl, piperazinyl (eg 1-piperazinyl), homopiperazinyl, or a bicyclic ring system such as Alternatively, R4 may represent a 3- to 8-member saturated carbocyclic ring system substituted by one or more substituents (eg, 1, 2 or 3) independently selected from NR6R7, - (CH2) rNR6R7 or -CONR6R7, the ring system is optionally further substituted by one or more (for example 1, 2, 3 or 4) substituents independently selected from the fluorine, hydroxyl and alkyl atoms with C? -C6, preferably alkyl with C1-C4. The saturated carbocyclic ring of 3 to 8 elements in the group R4 is preferably a monocyclic ring system such as a cyclopentyl or cyclohexyl ring. Specific examples of the R4 groups include: When X represents a bond or a group CO, (CH2)? - 6/0 (CH2) 2.6, 0 (CH2) 2.30 (CH2) 2-3 / (CH2)! -30 (CH2) 2_3, NR- (CH2) 2-6, (CH2h-3NR5 (CH2) 2-3, 0 (CH2) 2-3NR5 (CH2) 2_3, NR5 (CH2) 2.30 (CH2) 2-3, NR5CO, S02 or NR5S02, R4 preferably represents a group: R'R When X represents an oxygen or sulfur atom or a group CH =, (CH2)? - 60, 0CH2, 0 (CH2) 2-6 ?, 0 (CH2) 2_3OCH2, CR '(OH), (CH2)? - 3OCH2 (CH2) 1.30 (CH2) 2-3 ?, NR5, (CH2) a-6NR5, NR5CH2, (CH2)? - 3NR5CH2 0 (CH2) 2_3NR5CH2, (CH2) X.3NR5 (CH2) 2_30, NR5 (CH2) 2-60, NR5 (CH2) 2.3OCH2 / CONR5, SO, S (0) nCH2, CH2S (0) not S02NR5, R4 preferably represents a group: R represents a hydrogen atom, or an alkyl group with C? -C6, preferably alkyl with C? -C4 (for example methyl, ethyl, propyl, butyl, pentyl or hexyl) or cycloalkyl with C3-C8, preferably cycloalkyl with C3 -C6 (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). R6 and R7 each independently represent a hydrogen atom, or an alkyl group with 'C? -C6, preferably alkyl with C1-C4 (for example methyl, ethyl, propyl, butyl, pentyl or hexyl), hydroxyalkyl with C2-C6 , or cycloalkyl with C3-C8, preferably cycloalkyl with C3 ~ C (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R6 and R7 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 3 to 8 elements, preferably from 3 to 6 elements, such as a pyrrolidinyl or piperidinyl ring. Preferred compounds of the invention include: 2-Nitro-3-piperazin-1-yl-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-amino-3-piperazin-1-yl -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, 2-chloro-3-piperazin-1-yl-N- (tricyclo [3.3.1.13" 7] dec-1-ylmethyl) -benzamide, 2-chloro-5-piperazin-1-yl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (hexahydro-lH- 1,4-diazepin-1-yl) -N- (tricyclo [3.3.1.13"'] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- (4-amino-1-piperidinyl) -2-chloro -N- (tricyclo [3.3.1.l3-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (+/-) -5- (3-amino-l-pyrrolidinyl) -2-chloro- N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.13-7] dec- 1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [(hexahydro-lH-1,4-diazepin-1-yl) methyl] -N- (tricyclo [3.3.1. L3-7] dec -l-ylmethyl) -benzamide, 5- [(4-amino-1-piperidinyl) methyl] -2-c hydrochloride salt parrot-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- [(3-amino-l-pyrrolidinyl) methyl] -2-chloro-N- (tricyclo [ 3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1. l3-7] dec-l-ylmethyl) -benzamide, hydrochloride salt of (R) -2-chloro-5- (2-pyrrolidinylmethoxy) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl] ) -benzamide, hydrochloride salt of (S) -2-chloro-5- (2-pyrrolidinyl ethoxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (3-piperidinylmethoxy) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, cis-5- [(4-aminociclohexyl) oxy] hydrochloride salt] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, 2-methyl-5- (1-piperazinylmethyl) -N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide hydrochloride salt, hydrochloride salt of 2-chloro-5- (1-piperazinylmethyl) -N- (2-tricyclo [3.3.1.13'7] dec-1-ylethyl) -benzamide, hydrochloride salt of (+/-) -2-chloro-5- (3-pyrrolidinyloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (+/-) -2-chloro-5- (3-piperidinyloxy) -N- (tricyclo [3.3 .1.13'7] dec-1-ylmethyl) -benzamide, trans-5- [(4-aminocyclohexyl) oxy] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide , cis- (+/-) -5- [(3-aminociclopentyl) oxy] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the ( S, S) -2-chloro-5- (2,5-diazabicyclo [2.2.1] hept-2-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, salt of 2-chloro-5- (2-methyl-1-piperazinyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of (+/-) -2-chloro-5- (3-pyrrolidinyl) -N- (tricyclo [ 3.3.1.13'7] dec-1-methyl) -benzamide, (+/-) -5- (3-amino-1-piperidinyl) -2-chloro-N- (tricyclo [3.3. l.l3'7] dec-l-ylmethyl) -benzamide, (+/-) -2-chloro-5- (3-piperidinylamino) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, 2-chloro-5- [hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, salt of N- [2-methyl-5- (4-piperidinyloxy) phenyl] -tricyclo [3.3.1.13'7] decan-1-acetamide hydrochloride, N- [2-chloro-5- (4-hydrochloride -piperidinyloxy) phenyl] -trichyclo [3.3.1.13'7] decan-1-acetamide, dihydrochloride salt of 2-chloro-5- [(4-piperidinylamino) methyl] -N- (tricyclo [3.3.1.13,7 ] dec-1-ylmethyl) -benzamide, 5 - [[[4- (aminomethyl) cyclohexyl] amino] methyl] -2-chloro-N- (tricyclo [3.3.1.13,7] dec-1 dihydrochloride salt -ylmethyl) -benzamide, hydrochloride salt of 5 - [[(4-aocyclohexyl) amino] methyl] -2-chloro-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, 5- [(L-azabicyclo [2.2.2] oct-3-ylamino) methyl] -2-chloro-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the N- [4- (3-aminopyrrolid in-l-yl) -2-methylphenyl] -2- (tricyclo [3.3.1.13"7] dec-1-yl) -acetamide, dihydrochloride salt of N- (2-methyl-4-piperazin-1- ilphenyl) -2- (tricyclo [3.3.1.13"7] dec-1-yl) -acetamide, hydrochloride salt of cis-4- (3-amino-cyclopepyltyloxy) -2-chloro-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (4-piperidinyloxy) -N- (tricyclo [3.3.1.13-7] dec-1- ylmethyl) -benzamide, (+/-) -2-chloro-4- (pyrrolidin-3-yloxy) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the 2-chloro-4- (piperidin-3-yloxy) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (4-piperazine) l-il) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (3-pyrrolidinylamino) -N- (tricyclo [3.3.1.13 -7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (hexahydro-1H-1,4-diazepin-1-yl) -N- (tricyclo [3.3.1.1 °] ] dec-1-ylmethyl) -benzamide, hydrochloride salt of the (+ ) -5- [(3-amino-1-piperidini1) methyl] -2-chloro-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro- 5- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5 - (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylmethyl) -N- (tricyclo [3.3.1.13-7] déc-1-ylmethyl) -benzamide, hydrochloride salt of 2 - chloro-5- (3,7-diazabicyclo [3.3. l] non-3-ylmethyl) -N- (tricyclo [3.3.1. l3'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of trans-2-chloro-5- [[8- (methylamino ) -3-azabicyclo [3.2.1] oct-3-yl] methyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of cis-2-chloro- 5- [(hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl) methyl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the -chloro-5- (4-piperidinylidenemethyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, salt of 2-chloro-5- (4-piperidinylmethyl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of 2-chloro-5- (4 -hydroxy-piperidin-4-yl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (1, 2, 3, 6-tetrahydro) -pyridin-4-yl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-ethyl-5-piperazin-1-ylmethyl-N- (tricyclo [ 3.3.1.13"7] dec-1-ylmethyl) -benzamide, 2-chloro-5- (piperidin-4-ylsulfanyl) -N- (tricyclo [3.3.1.13" 7] dec-1-ylmethyl hydrochloride salt) -benzamide, 2-chloro-5- (piperidin-4-ylsulfinyl) -N- (tricyclo [3.3.1.13"7] dec-l-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (piperidin) -4-ylsulfonyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (piperidin-4-ylmethylsulfanyl) -N- (tricyclo [ 3.3.1 .I3"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (piperidin-4-ylmethanesulfonyl) -N- (tricyclo [3.3.1.13-7] dec-1 -ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (piperazin-1-carbonyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the 2-chloro-5- ([1,4] diazepane-1-carbonyl) -N- (tricyclo [3.3.1. l3"7] dec-l-ylmethyl) -benzamide, hydrochloride salt of 4-chloro-N1- (piperidin-4-yl-) -N2- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -isophthalamide, salt of 2-chloro-5- (hydroxy-4-piperidinylmethyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of the (+) - 2-Chloro-5- (hydroxy-3-piperidinylmethyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-bromo-5-piperazin-1-ylmethyl -N- (tricyclo [3.3.1. I3'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (1-piperazinyl) ethyl] -N- (tricyclo [ 3.3.1.13"7] dec-l-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (2, 5-diazabicyclo [2.2.1] hept-2-yl) ethyl] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- [2- (4-amino-1-piperidinyl) ethyl] -2-chloro-N- ( tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, dihydrochloride salt of 2-chloro-5- [2- (3-piperidinylamino) ethyl] -N- (tricyclo [3.3.1.1J-7] ] dec-1-ylmethyl) -benzamide , hydrochloride salt of 5- [2- (3-amino-1-piperidinyl) ethyl] -2-chloro-N- (tricyclo [3.3.1. 13"7] dec-1-ylmethyl) -benzamide, 2-chloro-5- [2- (3-pyrrolidinylamino) ethyl] -N- (tricyclo [3.3.1.13'7] dec-1- dihydrochloride salt ylmethyl) -benzamide, hydrochloride salt of 5- [2- [(3R) -3-aminopyrrolidinyl] ethyl] -2-chloro-N- (tricyclo [3.3.1. Io-7] dec-1-ylmethyl) -benzamide, 2-chloro-5- [2- [2- (hydroxymethyl) -1-piperazinyl] ethyl] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide hydrochloride salt , hydrochloride salt of 2-chloro-5- (hexahydro-1H-1,4-diazepin-1-yl) -N- (2-tricyclo [3.3.1.13-7] dec-1-ylethyl) -benzamide, hydrochloride salt of (+/-) -5- (3-amino-1-pyrrolidinyl) -2-chloro-N- (2-tricyclo [3.3.1.13"7] dec-1-ylethyl) -benzamide, salt of 2-chloro-5- (4-piperidinylcarbonyl) -N- (tricyclo [3.3.1. I3'7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of 2-chloro-5- [ 1-hydroxy-1- (4-piperidinyl) ethyl] -N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- ( 1-piperazinyl) ethoxy) -N- (tricyclo [3.3. 1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (4-piperidinium) ethoxy) -N- (tricyclo [3.3.1.13"7] dec-1- ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (4-piperidinyloxy) ethoxy) -N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide, salt of 2-chloro-5- [2- [2- (1-piperazinyl) ethoxy] ethoxy] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide hydrochloride, 2-chloro-5 - [(5,6-dihydro-l (4H) -pyrimidinyl) methyl] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [[4- [(2-hydroxyethyl) amino] -l-piperidinyl] methyl] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, 2-chloro-5- [[4- hydroxy-4- [[(1-methylethyl) amino] methyl] -1-piperidinylmethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, 2-chloro-5- [(1, 2, 3, 6-tetrahydro-3-pyridinyl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt , acetate salt of 2-chloro-5- (3-piperidinylmethyl) -N- (tricyclo [3.3.1.1J "7] dec-1-ylmethyl) -benzamide, 2-bromo-5- [[4- [ (2-hydroxyethyl) amino] -1-piperidinylmethyl] -N- (tricyclo [3.3.1.13 * 7J dec-1-ylmethyl) -benzamide, and 2-chloro-5- [(E) -3-piperidinylidenemethyl J-N - (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide.

The present invention further provides a process for the preparation of a compound of the formula (I) as defined above, which comprises: (i) when X represents a CH2 group, R4 represents a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more substituents independently selected from the fluorine, hydroxyl, carboxyl, cyano, alkyl with Ca C6, hydroxyalkyl with C? -C6, -NR6R7, - (CH2) rNR6R7 and -C0NR6R7 and R4 is attached or bonded to X by means of a nitrogen atom, by reacting a compound of the general formula wherein one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group -Ci ^ L1 in which L1 represents a leaving group (for example a halogen atom) and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of the general formula R4'-H (III) in the presence of a base (for example diisopropylethylamine), wherein R4 'represents a saturated aliphatic heterocyclic ring system or unsaturated from 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more substituents independently selected from the fluorine, hydroxyl, carboxyl, cyano, alkyl atoms with Ci-C6, hydroxyalkyl with Ca-C6, -NRéR7, - (CH2) rNR6R7 or -CONR6R7 and wherein R6 and R7 are as defined in formula (I); or (ii) when X represents an oxygen atom or a group 0 (CH2 -é, 0 (CH2) 2-60, 0 (CH2) 2-30 (CH2 -3, 0 (CH2) 2-6NR5 or 0 (CH2 ) 2-3NR5 (CH2)? _3, by reacting a compound of the general formula wherein one of R12 and R13 represents a hydrogen atom and the other of R12 and R13 represents a hydroxyl group and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of the formula general R4-Y-OH (V) wherein Y represents a bond or a group (CH2)? _6.0 (CH2) 2_6, NR5 (CH2) 2.6 or (CH2) 1_3NR5 (CH2) 2-3 and R4 is as defined in formula (I), in the presence of 1,1- (azodicarbonyl) dipiperidine and tributylphosphine (under the conditions of the Mitsunobu reaction: Tetrahedron Lett. (1993), 34, 1639); or (iii) when X represents a bond, an oxygen atom or a group 0 (CH2 -6, 0 (CH2) 2-60, 0 (CH2) 2-30 (CH2) a_3, NR5, NR5 (CH2 -6, NR5 (CH2) 2-60 OR NR5 (CH2) 2.30 (CH2)! -3 and A is NHC (O), reacting a compound of the general formula wherein one of R 14 and R 15 represents a group -X'-R 4 and the other of R 14 and R 15 represents a hydrogen atom, X 'represents a bond, an oxygen atom or a group 0 (CH 2)? - 6, 0 (CH2) 2-60, 0 (CH2) 2-3? (CH2)? - 3, NR5, NR5 (CH2)? - 6, NR5 (CH2) 2.60 OR NR5 (CH2) 2_30 (CH2) i_3, L2 represents a leaving group (for example a leaving group of hydroxyl or chloride) and R2, RJ, R4 and R5 are as defined in formula (I), with a compound of the general formula wherein m and R1 are as defined in formula (I), optionally in the presence of a coupling agent (for example 1,1 '-carbonyldiimidazole); or (iv) when X represents a bond, an oxygen atom or a group 0 (CH2h-6, 0 (CH2) 2_60, O (CH2) 2.30 (CH2)? _3, NR5, NR5 (CH2 -6, NR5 (CH2 ) 2-o0 or NR5 (CH2) 2_30 (CH2) 1-3 and A is C (0) NH, reacting a compound of the general formula wherein R2 and R3 are as defined in formula (I) and R14 and R15 are as defined in formula (VI) in (iii) above, with a compound of the general formula wherein m and R1 are as defined in formula (I), in the presence of a base (for example diisopropylamine); or (v) when X represents a bond or a group NR5, NR5 (CH2)? - 6, .NR5 (CH2) 2-6? or NR5 (CH2) 2.30 (CH2)? -3, reacting a compound of the general formula where one of R16 and R17 represents a leaving group, L3, such as a halogen atom and the other of Rld and R17 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of the general formula R - Z (XI) wherein Z represents a hydrogen atom or a group NHR5, (CH2)? -6? HR5, 0 (CH2) 2_6? HR5 or a group (CH2)! _30 (CH2) 2.3? HR5 and R4 and R5 are as defined in formula (I), optionally in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BI? AP) and a base (e.g., cesium carbonate); or (vi) when X represents a CH20 group, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (V) as defined in (ii) above wherein Y represents a linkage, in the presence of a base (e.g., sodium hydride) or in the presence of a metal salt (e.g., silver trifluoromethanesulfonate); or (vii) when X represents a group CH2? R5, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (XI) as defined in (v) above wherein Z represents a group? HR5: or (viii) when X represents a group CH20 (CH2)? -3 or CH20 (CH2) 2_30, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (V) as defined in (ii) above wherein Y represents a group (CH2)? _ 3 or 0 (CH2) 2_3, in the presence of a base (for example sodium hydride) or in the presence of a metal salt (for example silver trifluoromethanesulfonate); or (ix) when X represents a CH2NR5CH2 group, CH2NR5 (CH2) 2_30, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (XI) as defined in (v) above wherein Z represents a group CH2NHR5 or 0 (CH2) 2_3NHR5; or (x) when X represents a group CH2 and R4 represents an unsubstituted saturated aliphatic heterocyclic ring system of 4 to 6 elements containing a nitrogen atom, reacting a compound of the formula (II) as defined in (i) above, with a compound of the general formula (xp) where s and t independently represent 1 or 2; or (xi) when X represents a group CO, CONR5, NR5CO, S02, NR5S02 or S02NR5 and A is NHC (O), reacting a compound of the general formula wherein one of R18 and R19 represent a group -X "-R4 and the other of R1 and R19 represents a hydrogen atom, X" represents a group CO, CONR5, NR5CO, S02, NR5S02 or S02NR5, L4 represents a group leaving (for example a leaving group of hydroxyl or chloride) and R2, R3, R4 and R5 are as defined in formula (I), with a compound of formula (VII) as defined in (iii) above, optionally in the presence of a binding agent (for example 1,1'-carbonyldiimidazole); or (xii) when X represents a group CO, CONR5, NR5CO, S02, NR5S02 or S02NR5 and A is C (0) NH, reacting a compound of the general formula wherein R2 and R3 are as defined in formula (I) and R18 and R19 are as defined in formula (XIII) in (xi) above, with a compound of formula (IX) as defined in (iv) ) above, in the presence of a base (for example diisopropylamine); or (xiii) when X represents a sulfur atom, reacting a compound of the formula (X) as defined in (v) above, with an organolithium reagent such as n-butyllithium (for example at -70 ° C) ) and then with a compound of the general formula R4-S-SOz-Tol (XV) wherein Tol represents a tolyl group (4-methylphenyl) and R4 is as defined in formula (I); or (xiv) when X represents a CHOH or a CH2 group, reacting a compound of the formula (X) as defined in (v) above, with an organolithium reagent (for example methyl lithium / t-butyl lithium or n-butyl lithium at -70 ° C) and then with a compound of the general formula R4-CHO (XVI) in where R 4 is as defined in formula (I), optionally followed by a reduction reaction, for example with methyloxalyl chloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or (xv) when X represents a bond, reacting a compound of the formula (X) as defined in (v) above, with an organo-lithium reagent such as n-butyllithium (for example at -70 ° C) ) and then with a compound of the general formula R4 = 0 (XVII) wherein R4 is as defined in formula (I), optionally followed by a reduction reaction, for example with methyloxalyl chloride and triethylamine followed by hydride tributyltin in the presence of azobisisobutyronitrile; (xvi) when X represents an SO group, oxidize a corresponding compound of the formula (I) in which X represents a sulfur atom (using for example, as the oxidizing agent, the 3-chloroperoxybenzoic acid or the potassium peroxymonosulfate ( sold commercially under the trademark "OXONE")); or (xvii) when X represents a SCH2 group, reacting a compound of the formula (X) as defined in (v) above, with an organolithium reagent (for example methyl lithium and / or t-butyl lithium at -70 ° C) and then with a compound of the general formula wherein R is as defined in formula (I); or (xviii) when X represents a group S0CH2 or S02CH2, oxidize a corresponding compound of the formula (I) in which X represents an SCH2 group (using for example, as the oxidizing agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulfate) (sold commercially under the trademark "OXONE")); or (xix) when X represents a CH = group, reacting a compound of the formula (II) as defined in (i) above with trimethyl phosphite and then with a compound of the formula (XVII) as defined in (cf. xv) above in the presence of a base (for example lithium diisopropylamide); or (xx) when X represents a group (CH2)? _ 6, reacting a compound of the general formula wherein one of R20 and R21 represent a group of CHO or a group of (CH2)! 5CH0 and the other of R20 and R21 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in the formula (I), with a compound of the general formula (XX), R-H, wherein R 4 is as defined in formula (I), in the presence of a reducing agent (for example sodium triacetoxyborohydride, in a suitable solvent such as dichloroethane); or (xxi) when X represents a group (CH2)? -eNR5, (CH2)? -3NR5 (CH2) 1-3 or (CH2) 1-3NR5 (CH2) 2-3 ?, reacting a compound of the formula ( XIX) as defined in (xx) above, with a compound of the general formula (XXI), R4-Z ', wherein Z' represents a group NHR5, (CH2)! -3NHR5, 0 (CH2) 2.3NHR5 and R4 and R5 are as defined in formula (I), in the presence of a reducing agent (for example sodium triacetoxyborohydride, in a suitable solvent such as dichloroethane); or (xxii) when X represents a group O (CH2)? -30 (CH2) x_3 or (CH2)? _30 (CH2) 2.30, reacting a compound of the formula (XIX) as defined in (xx) above in which one of R20 and R21 represents a CHO group or a group (CH2)! _ 2CH0 and the other of R20 and R21 represents a hydrogen atom, with a reducing agent (such as as sodium borohydride), followed by the reaction with a compound of the general formula (XXII), R4-E, wherein E represents a group (CH2)? -3L5 or 0 (CH2) 2_3L5, L5 is a leaving group (such as a halogen atom or a sulfonate ester group, for example p-toluenesulfonate) and R 4 is as defined in formula (I), in the presence of a base (such as sodium hydride); or (xxiii) when X represents a group (CH2)? -6, reacting a compound of the formula (II) as defined in (i) above with trimethylphosphite and then with a compound of the formula (XVI) as defined (xiv) above, a compound of the formula (XVII) as defined in (xv) above or with a compound of the general formula (XVIA), R "1 (CH2)? _4CHO in which R4 is as defined in the formula (I), in the presence of a base (for example lithium diisopropylamide), followed by a reduction reaction (for example, with hydrogen and a platinum oxide catalyst); or (xxiv) when X represents a group (CH2) 2-60, reacting a compound of the general formula wherein one of R22 and R23 represents a group (CH2) 2-6L6 and the other of R20 and R21 represents a hydrogen atom, L6 represents a leaving group (for example a halogen atom or a sulfonate ester group such as p-toluenesulfonate) and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of formula (V) as defined in (ii) above in which Y represents a bond; or (xxv) when X represents a group CR '(OH) in which R' is an alkyl group with C? -C6, oxidizing a corresponding compound of the formula (I) in which X represents CH (OH) (per example using oxalyl chloride oxidant / dimethyl sulfoxide), followed by reaction with an alkyl lithium reagent with C? -C6; or (xxvi) when X represents a CH2S group, reacting a compound of the formula (II) as defined in (i) above with a compound of the general formula (XXIV), R4-SH, wherein R4 is as defined in the formula (I), in the presence of a base (for example sodium hydride); or (xxvii) when X represents a CH2SO or CH2S02 group, oxidizing a corresponding compound of the formula (I) in which X represents a CH2S group (for example using, as the oxidizing agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulfate) (sold commercially under the trademark "OXONE")); or (xx'viii) when X represents a group CH2 and R4 represents a 3-piperidinyl or 2-piperazinyl group, reacting a compound of the formula (ii) as defined in (i) above with a reagent formed by combining the pyridine or the pyrazine with an aluminum hydride reagent (for example lithium aluminum hydride), followed by a reduction reaction (for example with hydrogen and a platinum catalyst); or (xxix) when X represents a group CH = and R4 represents a 3-piperidinyl group, reacting a compound of the general formula (XXV) wherein one of R24 and R25 represents an aldehyde group -CHO, and the other of R24 and R25 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with 2, 3, 4, 5-tetrahydropyridine (Bull, Chem. Soc., Jpn 1983, 56, 3199), followed by a reduction reaction (for example with sodium borohydride in a protic solvent such as methanol); or (xxx) when X represents a bond, NR5 or NR5 (CH2)? _6 and R4 represents a piperidyl or piperazinyl group bonded to carbon, reducing a compound of the general formula wherein one of R26 and R27 represents a group of pyridyl, pyrazinyl, NR5-pyridyl, NR5-pyrazinyl, NR5 (CH2)? -6-pyridyl or NR5 (CH2)? -6-pyrazinyl and the other of R26 and R27 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), with a source of hydrogen and a hydrogenation catalyst (such as platinum oxide); or (xxxi) when X represents 'a group CH20 (' CH2)? i3 or CH20 (CH2) 2-3O and A is NHC (O), reacting a compound of the general formula wherein one of R 8 and R 29 represents a group -X '' '- R 4 and the other of R and R represents a hydrogen atom, X' '' represents a group CH 20 (CH 2)? - 3 or CH 20 (CH 2) 2-3O, L7 represents a leaving group (for example a leaving group of hydroxyl or chloride) and R1, R3 and R4 are as defined in formula (I), with a compound of formula (VII) as defined in (iii) above, optionally in the presence of a coupling agent (for example 1,1'-carbonyldiimidazole); or (xxxii) when X represents a group CH20 (CH2)? _ 3 or CH20 (CH2) 2-30 and A is C (0) NH, reacting a compound of the general formula wherein R2 and R are as defined in formula (I) and R28 and R29 are as defined in formula (XXVII) in (xxxi) above, with a compound of formula (IX) as defined in (iv) ) above, in the presence of a base (for example diisopropylamine); and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii ), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), (xxiv), (xxv), (xxvi), (xxvii), (xxviii), (xxix), (xxx), (xxxi) or (xxxii) converting the compound of the formula (i) to an additional compound of the formula (I) and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of the formula (I). The processes of the invention can be conveniently carried out in a solvent, for example an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dioxane, xylene or dimethylformamide, at a temperature, for example in the range from 0 to 200 ° C. , preferably in the range from 0 to 150 ° C. The compounds of the formula (II) in which A is NHC (O) can be prepared by reacting a compound of the general formula wherein L10 represents a leaving group (for example a leaving group of hydroxide or chloride) and R2, R3, R10 and R11 are as defined in formula (II), with a compound of formula (VII) as defined above , optionally in the presence of a binding agent (for example 1,1 '-carbonyldiimidazole). The compounds of the formula (XXX) in which one of R 10 and R 11 represents a hydrogen atom and the other of R 10 and R 11 represents a group -CH 2 L and L 1 represents a bromine atom can be prepared by reacting a compound of the formula general wherein one of R30 and R31 represents a hydrogen atom and the other of R30 and R31 represents a methyl group and R2 and R3 are as defined in formula (I), with N-bromosuccinimide and azobisisobutyronitrile or dibenzoyl peroxide catalytic, followed optionally by chlorination with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride. The compounds of the formula (II) in which A is C (0) NH and L1 represents, for example, a bromine atom, can be prepared by reacting a compound of the general formula wherein R2 and R3 are as defined in formula (I) and Rj0 and R31 are as defined in formula (XXXI) above, with a compound of formula (IX) as defined above, in the presence of a base (for example diisopropylethylamine), followed by the reaction with N-bromosuccinimide and azobisisobutyronitrile or catalytic dibenzoyl peroxide. The compounds of the formula (IV) in which A is NHC (O) can be prepared in a manner analogous to the compounds of the formula (II) in which A is NHC (O), using instead of the intermediate of the formula (XXX), an intermediate compound of the general formula wherein L11 represents a leaving group (for example a leaving group of hydroxyl or chloride) and R2, R3, R12 and R13 are as defined in formula (IV). The compounds of the formula (IV) in which A is C (0) NH can be prepared by reacting a compound of the general formula wherein R2, R3, R12 and R13 are as defined in the formula (IV), with a compound of the formula (IX) as defined above, optionally in the presence of a base (for example diisopropylethylamine).

The compounds of the formula (VI) can be prepared by reacting a compound of the general formula wherein Rj2 represents a hydrogen atom or an alkyl group with C? -C6, one of R33 and R34 represents a leaving group, L12, such as a halogen atom (for example bromine or iodine) or a trifluoromethanesulfonate group and the other of R33 and R34 represents a hydrogen atom, and R2 and R3 are as defined in formula (VI), with a compound of the general formula H-R'-R4 (XXXVI) f wherein X 'and R4 they are as defined in formula (VI), in the presence of a palladium catalyst (for example palladium acetate), a phosphine ligand (for example BINAP) and a base (for example cesium carbonate) (1996 J. Am. Chem. Soc., 7215-6; 1997 J. Am. Chem. Soc., 3395), followed by a hydrolysis reaction (e.g. with sodium hydroxide) and optionally a chlorination reaction (e.g. oxalyl chloride and catalytic dimethylformamide or thionyl chloride). The compounds of the formula (VIII) can be conveniently prepared by reacting a compound of the formula (VI) in which L2 represents a hydroxyl group with diphenylphosphoryl azide in the presence of a base such as triethylamine. The compounds of the formula (X) in which A is NHC (O) can be prepared in a manner analogous to the compounds of the formula (II) in which A is NHC (O), using instead of the intermediate of the formula (XXX), an intermediate compound of the general formula (xxxvp) wherein L13 represents a leaving group (for example a leaving group of hydroxyl or chloride) and R2, R3, R16 and R: 7 are as defined in formula (X).

The compounds of the formula (X) in which A is C (0) NH can be prepared in a manner analogous to the compounds of the formula (IV) in which A is C (0) NH, using instead of the intermediate of the formula (XXXIV), an intermediate of the General Formula (xxxvpi) wherein R2, R3, R1 and R are as defined in the formula (X) • The compounds of the formula (XII) can be prepared as described in Syn. Lett. (1998) 379-380. The compounds of the formula (XIII) in which R "represents a group CO, CONR5, S02 or S02NR5 can be prepared by reacting a compound of the general formula wherein one of R35 and R36 represents a group COL14 or S02L14 and the other of R25 and R26 represents a hydrogen atom, L14 represents a leaving group (for example a halogen atom), Rj7 represents a hydrogen atom or a group of alkyl with C? -C6, and R2 and R3 are as defined in formula (XIII), with a compound of formula (XXXVI) in which X 'represents a bond or a group NR5, in the presence of a base such as diisopropylethylamine and catalytic dimethylaminopyridine, followed by a hydrolysis reaction (for example sodium hydroxide) and, optionally, a chlorination reaction (for example with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride). The compounds of the formula (XIII) in which X "represents a group NR5C0 or NR ^ SO? they can be prepared by reacting a compound of the general formula wherein one of Rj8 and R39 represents a group NHR5 and the other of R38 and R39 represents a hydrogen atom, R37 is as defined for the compound (XXXIX), and R2 and R3 are as defined in the formula (XIII) , with a compound of the general formula (XLI), R4-J, where J represents a group COCÍ or S02C1 and R4 is as defined in the formula (I), in the presence of a base such as diisopropylethylamine. The compounds of the formula (XIV) can be conveniently prepared by reacting a compound of the formula (XIII) in which L4 represents a hydroxyl group with diphenylphosphoryl azide in the presence of a base such as triethylamine. The compounds of the formula (XIX) in which one of R20 and R21 represents one group (CH2 -5CHO and the other of R20 and R'1 represents a hydrogen atom can be prepared by oxidizing a compound of the general formula (XDD wherein one of R40 and R41 represents one (CH2) 2 -OH group and the other of R40 and R41 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I) , using as the oxidizing agent, for example, the Dess Martin Periodinano reagent The compounds of the formula (XLII) in which one of R40 and R41 represents one group (CH2) 2OH and the other of R40 and R41 represents a Hydrogen atom can be prepared from a compound of the general formula (X) as defined above, an organolithium reagent such as methyl-lithium (at -70 ° C) followed by n-butyllithium (a- 70 ° C), and then the treatment with ethylene oxide The compounds of the formula (XLII) in which one of R40 and R41 represents a group (CH2) 3_6OH and the other of R40 and R41 represents a hydrogen atom can be prepared by reacting a compound of the general formula (X) as defined above with a compound of the general formula ^ r. .- .: Su.Sn '., Rt ** - *, 3 (. Ip) in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), followed by reduction for example, with hydrogen and a platinum oxide catalyst. The compounds of the formula (XIX) in which one of R20 and R21 represents a CHO group and the other of R20 and R21 represents a hydrogen atom (which are equivalent to the compounds of the formula (XXV)) can be prepared from a compound of the general formula (X) as defined above, with an organolithium reagent such as methyl-lithium (at -70 ° C) followed by n-butyllithium (at -70 ° C) and then with dimethylformamide. The compounds of the formula (XXIII) in which LD represents an iodine atom or the p-toluenesulfonyloxy group can be prepared by reacting a compound of the formula (XLII) as defined above with iodine / triphenylphosphin / imidazole or with a chloride of sulfonyl such as p-toluenesulfonyl chloride, in the presence of a base such as diisopropylethylamine. The compounds of the formula (XXVI) in which one of R26 and R'7 represents a pyridyl or pyrazinyl group and the other of R '? and R27 represents a hydrogen atom, can be prepared from a compound of the formula (X) as defined above by the reaction with a pyridyl or pyrazinyl boronic acid in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0).

The compounds of the formula (XXVI) in which one of R2 ° and R27 represents a group of NR5-pyridyl, NR5-pyrazinyl, NR5- (CH2)? _6-pyridyl or NR-- (CH2)? _6-pyrazinyl and the other of R2 ° and R27 represents a hydrogen atom can be prepared from a compound of the formula (X) as defined above by the reaction with a compound of NHR5 pyridyl, NHR5 pyrazinyl, NHR5 (CH2): - 5-pyridyl or NHR "(CH2) 1-5-pyrazinyl, in the presence of a palladium catalyst (for example paiadium acetate), a phosphine ligand (for example BINAP) and a base (for example cesium carbonate) The compounds of formulas (III), (V), (VII), (IX), (XI), (XV), (XVI), (XVIA), (XVII), (XVIII), (XX), (XXI), (XXII), (XXIV), (XXVII), (XXVIII), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII) ), (XXXIX), (XL), (XLI), (XLII) and (XLIII) can either be commercially available, be well known in literary literature or can be easily prepared using known techniques. The compounds of the formula (I) can be converted to additional compounds of the formula (I) using standard procedures. For example, compounds of the formula (I) in which one of R "and R ° represent a nitro group can be converted into the compounds of the formula (I) in which one of R2 and RJ represents an amino group by reduction using iron powder and ammonium chloride in ethanol / water under reflux conditions The latter compounds can be converted in turn into the compounds of the formula (I) in which one of R2 and R3 represents a halogen atom , for example chlorine, by nitrogenation (for example with sodium nitrite) and the reaction with copper chloride The compounds of the formula (I) in which R ° and R7 represent a hydrogen atom can be converted to the compounds of the formula (I) in which R ° or R 'represent an alkyl with CI-CO, hydroxyalkyl with C2-C6, cycloalkyl with C3-Ce or a heterocyclic ring saturated with 3 to 8 elements by standard chemical methods. by those experts in the art that in the p Methods of the present invention certain functional groups such as the hydroxyl or amino groups in the starting reagents or intermediates may need to be protected by protecting groups. Accordingly, the preparation of the compounds of the formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of the functional groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 2 / a. Edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991). The compounds of formula (I) above can be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate. , methanesulfonate or p-toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt. Certain compounds of the formula (I) are capable of existing in the stereoisomeric forms. It will be understood therefore that the invention encompasses all geometric and optical isomers of the compounds of the formula (I) and mixtures thereof including the racemates. Tauteromers and mixtures thereof also form an aspect of the present invention. The compounds of the present invention are advantageous in that they possess a pharmacological activity. They are therefore indicated as pharmaceutical substances for use in the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hypersensitivity of the respiratory tract, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastasis of malignant cells, myoblastic leukemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injuries, ischemic disease of the heart, stroke and varicose veins. Accordingly, the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore for use in therapy. In another aspect, the invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted accordingly. The invention further provides a method for effecting immunosuppression (for example in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of the formula (I) , or a pharmaceutically acceptable salt or solvate thereof, as defined herein above, to a patient. The invention also provides a method of treating an obstructive airway disease (eg, asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of the formula (I), or a salt or solvate thereof pharmaceutically acceptable, as defined hereinbefore, to a patient. For the therapeutic uses mentioned above, the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dose of the compound of the formula (I) / salt / solvate (active ingredient) can be in the range from 0.001 mg / kg to 30 mg / kg. The compounds of the formula (I) and the pharmaceutically acceptable salts and solvates thereof can be used per se but will generally be administered in the form of a pharmaceutical composition in which the compound of the formula (I) / salt / solvate (active ingredient) is in association with a pharmaceutically acceptable auxiliary, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight (percent by weight), more preferably from 0.10 to 70% by weight, of the active ingredient, and, from 1 to 99.95% by weight, more preferably from 30 to 99.90% by weight, of a pharmaceutically acceptable auxiliary, diluent or carrier, all percentages by weight are based on the total composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore in association with a pharmaceutically acceptable auxiliary, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined herein above with an auxiliary, diluent or carrier. pharmaceutically acceptable The pharmaceutical composition of the invention can be administered topically (for example to the lungs and / or the respiratory tract or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, for example by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. The present invention will now be further explained by reference to the following illustrative examples.

Example 1 2-Nitro-3-piperazin-l-yl-N- (tricyclo [3.3.1. L3 7] dec-l-ylmethyl) -benzamide i? . a) 3-Chloro-2-nitro-N- (tricyclo [3.3.1. l3-7] dec-l-ylmethyl) -benzamide To a suspension of 3-chloro-2-nitrobenzoic acid (2.68 g) in dichloromethane (10 ml) at 0 ° C is added oxalyl chloride (3 ml) in dimethylformamide (1 drop). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 1 hour, then concentrated under reduced pressure to give a solid. The solid is dissolved in dichloromethane (10 ml) and cooled to 0 ° C. A solution of 1-adamantanemethylamine (2.19 g) and N, N-diisopropylethylamine (11 ml) in dichloromethane (10 ml) is added in portions and the resulting solution is allowed to stir at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture is poured into water and the organic phase is separated and washed with 2N hydrochloric acid, 10% aqueous sodium hydroxide and saturated brine. The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure and the resulting solid is recrystallized from iso-propanol to give the subtitle compound as a solid (3.52 g).

MS (APCI + ve) 349 (M + H) * NMR: H (DMSO-d €) d 8.74 (H, t); 7.89 (ÍH, m); 7.75-7.69 (2H, m); 2.91 (2H, d), 1.93 (3H, sa); 1.64 (6H, dd); 1.47 (6H, d) b) 3- (4-. {1, 1-dimethylethyl} -oxycarbonyl] -piperazin-1-yl) -2-nitro-N- (tricyclo [3.3.1.13"7-Jdec-1-ylmethyl) -benzamide A mixture of 3-chloro-2-nitro-N- (tricyclo [3.3. I. 1 J "7] dec-1-ylmethyl) -benzamide (2.80 g, Example la) and tert-butyl ester of piperazin-1 acid -carboxylic, (7.47 g) in dry dimethyl sulfoxide (10 ml) is heated to 120 ° C under a nitrogen atmosphere for 24 hours. The cooled reaction mixture is diluted with water and extracted three times with ethyl acetate. The combined extracts are washed with water, dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give a solid. Purification by chromatography on silica gel eluting with iso-hexane / ethyl acetate (2: 1) gave the subtitle compound as a solid (3.8 g).

MS (APCI + ve) 499 (M + H) * NMR: H (DMS0-d6) d 8.55 (H, t); 7.62-7.59 (2H, m); 7.43 (ÍH, dd); 3.38 (4H, ta); 2.90-2.84 (6H,), 1.93 (3H, sa); 1.63 (6H, dd); 1.47 (6H, d); 1.41 (9H, s) c) 2-Nitro-3-piperazin-l-yl-N- (tricyclo [3.3.1. l37] dec-l-ylmethyl) -benzamide A solution of 3- (4-. {1,1-dimethylethyl} oxycarbonyl] -piperazin-1-yl) -2-nitro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) ) -benzamide (0.58 g, Example Ib) and hydrochloric acid (6.4 ml, 4N in dioxane) in tetrahydrofuran (20 ml) is stirred at room temperature under a nitrogen atmosphere for 18 h. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in water, made basic with solid sodium bicarbonate and extracted with dichloromethane three times. The combined organic extracts are dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure to give a solid. Purification by chromatography on silica gel, eluting with 10% methanol in dichloromethane afforded the title compound as a solid (0.165 g).

MS (APCI + ve) 399 (M + H) * NMR: H (DMSO-dβ) d 8.52 (H, t); 7.59 (ÍH, t); 7.51 (ÍH, d); 7. 35 (ÍH, d), 2.88 (2H, d); 2.81 (4H, m); 2.37 (4H, m); 1.93 (3H, sa); 1.67 (3H, d); 1.60 (3H, d); 1.60 (3H, d); 1.47 (6H, s) Example 2 2-amino-3-piperazin-1-yl-N- (tricyclo [3.3.1.1.17] dec-1-ylmethyl) -benzamide dihydrochloride salt a) 2-Amino-3- (4-. {1, 1-dimethylethyl} oxycarbonyl] -piperazin-1-yl) -N- (tricyclo [3.3.1. I37Jdec-1-ylmethyl) -benzamide) A suspension of 3- (4-. {1,1-dimethylethyl} oxycarbonyl] -piperazin-1-yl) -2-nitro-N- (tricyclo [3.3.1.1"'"'] dec-1 -ylmethyl) -benzamide (3.8 g, Example Ib), iron powder (2.13 g) and ammonium chloride (2.04 g) in ethanol / water 2: 1 (90 ml) was heated to reflux, under a nitrogen atmosphere, for 2 hours. The cold reaction mixture is filtered and the filtrate partitioned between water and ethyl acetate. The organic layer is separated and washed with water twice additionally, dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure to give a residue. Purification of the residue by chromatography on silica gel, eluting with 20% ethyl acetate in iso-hexane, afforded the subtitle compound as a solid (2.27 g).

MS (APCI + ve) 469 (M + H) + b) Hydrochloride salt of 2-amino-3-piperazin-1-yl-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide Prepared as described in Example lc) using 2-amino-3- (4-. {1,1-dimethyl-ethyl-loxycarbonyl] -piperazin-1-yl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide (0.2 g, Example 2a) and hydrochloric acid (5 ml, 4N in dioxane). The reaction mixture is concentrated under reduced pressure to give a solid which when triturated with diethyl ether gave the title compound as a solid (0.2 g).

MS (APCI + ve) 369 (M-2HC1T NMR XH (DMSO-d6) d 9.16 (2H, sa); 8.14 (HH, t); 7.37 (HH, d); 7. 07 (ÍH, d); 6.64 (1H, t); 3.27 (4H, sa); 2.98 (4H, sa); 2. 95 (2H, d); 1.93 (3H, sa); 1.67 (3H, d); 1.59 (3H, d); 1. 48 (6H, s).

Example 3 2-Chloro-3-piperazin-1-yl-N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide a) 2-Chloro-3- (4. {1, 1-dimethylethyl} oxycarbonyl-1-piperazin-1-yl) -N- (tricyclo [3.3.1. 13'7] dec-1-ylmethyl) -benzamide To a solution of 2-amino-3- (4-. {1,1-dimethylethylloxycarbonyl] -piperazin-1-yl) -N- (tricyclo [3.3.1.1J *] dec-1-ylmethyl) - Benzamide (Ig, Example 2a) in tetrahydrofuran (23 ml) were added 1M aqueous hydrochloric acid (2.78 ml) and water (10 ml). The solution is cooled to 0 ° C and sodium nitrite (1.91 g) is added in portions, while maintaining the internal temperature below 5 ° C. After stirring at 0-5 ° C for 0.5 hours, a pre-cooled suspension of copper (I) chloride (10.58 g) and copper (II) chloride in water (20 ml) is added in portions to the colored suspension. dim yellow The mixture is stirred at 0 ° C for 0.5 h then at room temperature for 0.5 h. The reaction mixture is poured into a mixture of water and dichloromethane and ammonia / water 1/1: 0.88 is added until the aqueous phase is homogeneous. The layers were separated and the aqueous phase was extracted twice additionally with dichloromethane. The combined organic extracts were washed with ammonia / water 1/1: 0.88 until the aqueous phase was colorless, they were dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oil. Purification by chromatography on silica gel, eluting with 20-35% ethyl acetate / iso-hexane gave the substituent compound as a solid (0.45 g).

MS (APCI + ve) 388 (M-BOC) t NMR: H (DMSO-dβ) d 8.27 (ΔH, t); 7.32 (ÍH, t); 7.19 (ÍH, d); 7.04 (ÍH, d); 3.48 (4H,); 2.93-2.91 (6H, m); 1.94 (3H, sa); 1.64 (3H, d); 1.59 (3H, d); 1.52 (6H, s); 1.43 (9H, s). b) 2-Chloro-3-piperazin-1-yl-N- (tricyclo [3.3.1. I37] des-1-ylmethyl) -benzamide To a solution of 2-chloro-3- (4-. {1, 1-dimethylethyl loxycarbonyl] -piperazin-1-yl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) - Benzamide (0.45 g, Example 3a) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml). After stirring at room temperature under a nitrogen atmosphere the reaction mixture is concentrated under reduced pressure to give a gum. The gum is partitioned between water and dichloromethane and made basic with solid sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice additionally with dichloromethane. The combined organic extracts were washed twice with water, saturated brine then dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a foam. The foam was purified by normal phase HPLC (0-20% ethanol / dichloromethane) and chromatography on silica gel, eluting with 10% methanol in dichloromethane, to give the title compound as a foam (0.05 g). MS (APCI + ve) 388/90 (M + H) * NMR XH (DMSO-d6) d 8.24 (1H, t); 7.31 (ÍH, t); 7.15 (ÍH, d); 7.00 (ÍH, d); 2.96-2.87 (10H, m); 1.93 (3H, sa); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, s).

Example 4 2-Chloro-5-piperazin-1-yl-N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide a) 2-Chloro-5-nitro-N- (tricyclo [3.3.1.137Jdec-1-ylmethyl) -benzamide) To a solution of 2-chloro-5-nitrobenzoic acid (1.22 g) in N, N-dimethylformamide (1.5 ml) is added carbonyldiimidazole (1.0 g). The resulting reaction mixture is stirred for 2.5 h and then 1-adamantane-methylamine (1.0 g) is added. After 14 hours the reaction mixture is partitioned between ethyl acetate and water and the organic layer is separated, washed with water and brine and then dried over sodium sulfate (Na2SO4). The organic layer is concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 3-10% methanol in dichloromethane) to give the subtitle compound as a yellow solid (1.7 g).

MS (APCI + ve) 348/350 (M + H) + NMR: H (DMSO-d6) d 8.53 (OH, d), 8.2 (OH, dd), 7.6 (OH, d), 6.2 (OH, SA ), 3.2 (2H, d), 2.0 (3H, sa), 1.8 (12H, m) b) 5-Amino-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide A solution of the nitro compound of Example 4a, (0.50 g) and ammonium chloride (0.5 g) is dissolved in 50% aqueous ethanol. Iron powder (0.5 g) is added and the mixture is stirred at reflux temperature for 3 hours before being cooled and the solids removed by filtration. The mother liquors were treated with a 10% sodium hydroxide solution and the product was extracted into ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate (Na 2 SO 3) and concentrated to give a residue which was purified by silica gel chromatography to give the title compound as a white solid (0.4 g) .

MS (APCI + ve) 319/21 (M + H) * H NMR (DMSO-d6) d 8.14 (1H, t); 7.03 (ÍH, dd); 6.56 (2H, m); 5.36 (2H, s); 2.89 (2H, d); 1.95 (3H, s); 1.7 (12H, m) c) 2-Chloro-5-piperazin-1-yl-N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide To a solution of the 5-amino-2-chloro-N- (tricyclo [3.3.1.1"''] dec-1-ylmethyl) -benzamide (1.00 g, Example 4b) in xylene (20 ml) is added the salt of the bis- (2-chloroethyl) amine hydrochloride (0.620 g) The mixture is heated at 150 ° C for 12 hours (a dark solution is obtained) The cold solution is washed with 2M HCl, the aqueous layer is washed with ethyl acetate, then it is made basic with sodium bicarbonate and extracted twice with dichloromethane, the organic layer is dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure to give a foam. on silica gel (0-10% ethanol / dichloromethane), to give the title compound as a white solid (0.90 g).

MS (APCI + ve) 388/90 (M + H) * NMR? (DMSO-de) d 8.22 (ÍH, t); 7.22 (ÍH, d); 6.96 (ÍH, dd); 6.84 (ÍH, d); 3.50-3.20 (7H,); 3.00-2.90 (2H, t); 2.91 (2H, d); 1.94 (3H, sa); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, s).

Example 5 2-chloro-5- (hexahydro-lH-l, 4-diazepin-1-yl) -N- (tricyclo [3.3.1. L3'7] 'dec-l-ylmethyl) -benzamide hydrochloride salt a) 4- [4- (Chloro-3- (ethoxycarbonyl) phenyl Jhexahydro-lH-1,4-diazepine-1-carboxylic acid ester 1-, 1-dimethylethyl) A mixture of the 5-bromo-2-chloro-benzoic acid ethyl ester (0.50 g), 1, 1-dimethylethyl hexahydro-lH-1, -diazepine-l-carboxylic acid ester (0.46 g), cesium carbonate ( 0.86 g), palladium (II) acetate (8.5 mg) and (R) -BINAP (35 mg) in toluene (3 ml) is heated at 100 ° C for 14 h in a pressure vessel filled with nitrogen. The cooled reaction mixture is poured into water and extracted (3 times) with ethyl acetate. The combined organic extracts are washed with a saturated sodium chloride solution and then dried over magnesium sulfate. Evaporation under reduced pressure gave an oil which was purified by chromatography on silica gel, eluting with 20% ethyl acetate in iso-hexane to give the subtitle compound as an oil (0.21 g).

EM (APCI + ve) 282/284 (M + BOC) + b) 4- (3-carboxy-4-chlorophenyl) hexahydro-1H-1,4-diazepine-1-carboxylic acid ester 1, 1-dimethylethyl A suspension of 4- [4-chloro-3- (ethoxycarbonyl) phenyl] hexahydro-lH-1,4-diazepine-1-carboxylic acid ester (Example 5a, 0.21 g), hydroxide monohydrate of lithium (1.05 ml of a 3M solution in water) in ethanol / water 1: 1 (7 ml) was stirred at room temperature for 14 hours. Additional lithium hydroxide monohydrate (0.55 ml of the 3M solution in water) was added followed by tetrahydrofuran (1 ml). The resulting solution is stirred for 4 hours at room temperature then poured into water and extracted with diethyl ether. The aqueous phase is separated, acidified with 2M hydrochloric acid and then extracted with dichloromethane three times. The combined dichloromethane layers were dried over magnesium sulfate and evaporated under reduced pressure to give the subtitled compound as a glass.

EM (APCI + ve) 298/300 (M-cBu) + c) Hexahydro-4- [4-methyl-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] -phenyl] lH-1,4 acid, 1-dimethylethyl ester -diazepin-l-carboxyl A solution of 1, 1-dimethylethyl acid ester 4- (3-carboxy-4-chlorophenyl) hexahydro-lH-1,4-diazepine-l-carboxylic acid (Example 5b, 0.10 g) and N, N'-carbonyldiimidazole (0.045 g) in dimethylformamide (3 ml) is stirred at room temperature for 2 hours. The 1-adamantanemethylamine (0.050 ml) is then added and stirring is continued for 14 hours. The reaction mixture is poured into water and extracted with ethyl acetate three times. The ethyl acetate layers are combined and washed with 2M hydrochloric acid, 10% aqueous sodium hydroxide and brine, then dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel, eluting with 20-30% ethyl acetate in isohexane, gave the subtitle product as a gum which crystallized during rest.

MS (APCI + ve) 502/504 (M + H) d) Chlorohydrate salt of 2-chloro-5- (hexahydro-1H-1,4-diazepin-1-yl) -N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benza The 1,1-dimethylethyl ester of hexahydro-4- [4-methyl-3- [[(tricyclo [3.3.1.13"7] dec-1-yl ethyl) amino] carbonyl] phenyl] -1H-1, 4 Diazepin-1-carboxylic acid (from Example 5c) is dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) is added.After stirring at room temperature for 14 hours, the mixture is evaporated to 2/3 parts of the original volume under reduced pressure Diethyl ether was added gradually and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuo to give the title compound as a solid (0.027 g) .

MS (APCI + ve) 402/404 (M + H) * NMR: H (DMSO-de) d 9.11 (2H, br.s); 8.18 (1H, t); 7.24 (ÍH, d) 6.81 (ÍH, dd); 6.71 (ÍH, d); 3.71 (2H, t); 3.50 (2H, t) 3.19 (2H, sa); 2.93 (2H, sa); 2.92 (2H, d); 2.08 (2H, m) 1.94 (3H, sa); 1.67 (3H, d); 1.59 (3H, sa); 1.52 (6H, s) Example 6 Hydrochloride salt of 5- (4-amino-1-piperidinyl) -2-chloro-N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide a) 2-Chloro-5- [4- [[(1,1-dimethylethoxy) carbonyl-amino] -1-piperidinyl] -benzoic acid ethyl ester Prepared as described in Example 5a) using the 5-bromo-2-chloro-benzoic acid ethyl ester (0.50 g), 1,4-piperidinyl-carbamic acid 1,1-dimethyl ester (0.46 g), cesium carbonate (0.36 g), palladium (II) acetate (8.5 mg) and (R) -BINAP (35 mg) and toluene (3 ml) to give the subtitle compound as an oil (0.17 g).

MS (APCI + ve) 383/385 (M + H) + b) 2-Chloro-5- [4- [[(1,1-dimethylethoxy) carbonyl Jamino] -1-piperidinyl J -benzoic acid Prepared as described in Example 5b) using 2-chloro-5- [4- [[(1,1-dimethylethoxy) carbonyl] amino] -1-piperidini] -benzoic acid ethyl ester (Example 6a, 0.17 g) ), lithium hydroxide monohydrate (0.88 ml of a 3M solution in water), ethanol / water 1: 1 (7 ml) and tetrahydrofuran (1 ml) to give the subtitle compound as a solid (0.14 g).

MS (APCI + ve) 354/356 (M + H) * c) [1- [4-Chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] f-ethyl J -4-piperidinyl J ester 1, 1-dimethylethyl -carbamic Prepared as described in Example 5c) using 2-chloro-5- [4- [[(1,1-dimethylethoxy) carbonyl] amino] -1-piperidinyl] -benzoic acid (Example 6b, 0.065 g), N , N '-carbonyldiimidazole (0.030 g), 1-adamantanemethylamine (0.032 ml) and dimethylformamide (3 ml) to give the subtitled compound as a solid.

EM (APCI + ve) 501/503 (M + H) + d) Hydrochloride salt of 5- (4-amino-1-piperidinyl) -2-chloro-N- (tricyclo [3.3.1.13"7Jdec-1-ylmethyl) -benzamide) Prepared as described in example 5d) above using the l, l-[4-chloro-3- [[(tricyclo [3.3.1.13-7] dec-1-ylmethyl) amino] carbonyl ester 1, 1-dimethylethyl. ] phenyl] -4-piperidinyl] -carbamic acid (Example 6c), hydrochloric acid (0.5 ml of a 4N solution in dioxane) and methanol (10 ml). The mixture is refluxed for 15 minutes to complement the reaction. After evaporation to two thirds of the original volume, a solid was recrystallized during rest which was collected by filtration and dried in vacuo to give the title compound as a solid (0.025 g).

MS (APCI + ve) 402/404 (M + HC1) * NMR: H (DMSO-de) d 8.23 (1H, t); 8.11 (ÍH, sa); 7.28 (ÍH, d); 7. 03 (ÍH, dd); 6.94 (ÍH, s); 3.74 (2H, d); 3.20 (ÍH, m); 2. 91 (2H, d); 2.83 (2H, t); 1.98 (2H, sa); 1.94 (3H, sa); 1.69-1.58 (8H, m); 1.52 (6H, s) Example 7 Hydrochloride salt of (+/-) -5- (3-amino-l-pyrrolidinyl) -2-chloro-N- (tricyclo [3.3.1. L 7 Jdec-l-ylmethyl) -benzamide a) Ethyl ester of (+/-) -2-Chloro-5- [3- [[(1,1-dimethylethoxy) carbonylJamino] -l-pyrrolidinyl] -benzoic acid ester Prepared as described in Example 5a) using 5-bromo-2-chloro-benzoic acid ethyl ester (0.50 g), 1-dimethylethyl 3-pyrrolidinyl-carbamic acid ester (0.42 g), cesium carbonate (0.86 gj, palladium (II) acetate (21 mg) and (R) -BINAP (88 mg) and toluene (3 ml) to give the subtitle compound as an oil (0.25 g).

EM (APCI + ve) 311/313 (M-BOC) + b) Acid (+/-) -2-Chloro-5- [3- [[(1,1-dimethylethoxy) carbonyl] -amino] -l-pyrrolidinyl] -benzoic acid Prepared as described in Example 5b) using the ethyl ester of the acid (+/-) -2-Chloro-5- [3- [[(1,1-dimethylethoxy) carbonyl] amino] -l-pyrrolidinyl] -benzoic acid (Example 7a, 0.25 g), lithium hydroxide monohydrate (1.36 ml of a 3M solution in water), ethanol / water 1: 1 (7 ml) and tetrahydrofuran (1 ml) to give the subtitle compound as a solid ( 0.23 g).

EM (APCI + ve) 284/286 (M-BOC) * c) 1,1-dimethylethyl ester of (+/-) - [1- [4-chloro-3- [[(tricyclo [3.3.1. I37] dec-1-ylmethyl) aminoj carbonyl] phenyl J-3 acid -pyrrolidinyl] -carbamic Prepared as described in Example 5c) using the acid (+/-) -2-chloro-5- [3- [[(1,1-dimethylethoxy) carbonyl] amino] -l-pyrrolidinyl] -benzoic acid (Example 7b) , 0.070 g), N, N'-carbonyldiimidazole (0.033 g), 1-adamantanemethylamine (0.036 g) and dimethylformamide (3 ml) to give the subtitled compound as a gum.

MS (.APCI + ve) 487/489 (M + H) + d) Salt of the hydrochloride of (+/-) -5- (3-amino-l-pyrrolidinyl) -2-chloro-N- (tricyclo [3.3.1. l3"7] dec-l-ylmethyl) -benzamide Prepared as described in example 5d) above using the 1,1-dimethylethyl ester of (+/-) - [l- [4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1] -ylmethyl) amino] carbonyl] phenyl] -3-pyrrolidinyl] -carbamic acid (Example 7c), hydrochloric acid (0.5 ml of a 4N solution in dioxane) and methanol (5 ml). Evaporation under reduced pressure gave a solid during trituration with diethyl ether. Recrystallization from ethanol / diethyl ether gave the title compound as a solid (0.030 g).

MS (APCI + ve) 388/390 (M + H) + NMR: H (DMSO-de) d 8.24 (3H, br s); 3.20 (ÍH, t); 7.25 (ÍH, d); 6. 61 (ÍH, dd); 6.51 (ÍH, d); 3.94 (ÍH, m); 3.55-3.32 (2H, m); 3.29 (2H,); 2.92 (2H, d); 2.37-2.27 (ÍH, m); 2.13-2.05; iH, m); 1 . 94 (3H, sa); 1 . 68 (3H, d); 1 . 59 (3H, d); 1 . 52; 6H, s) Example 8 Salt of 2-chloro-5-piperazin-l-ylmethyl-N- (tricyclo [3.3.1.1 i 3. "7] dec-l-ylmethyl) -benzamide hydrochloride a) 5-Bromomethyl-2-chloro-benzoic acid To a stirred solution of 2-chloro-5-methyl-benzoic acid (25 g) in chloroform (500 ml) at 50 ° C is added N-bromosuccinimide (27.40 g). The vessel is purged with nitrogen and azobisisobutyronitrile (0.10 g) is added in one portion. The solution is refluxed for 1 hour. Additional azobisisobutyronitrile (0.10 g) is added and the mixture is heated an additional 3 hours. The solution is concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ethereal solution is washed with 2N aqueous hydrochloric acid solution followed by brine then dried over magnesium sulfate. The solution is concentrated to a volume of 150 ml then diluted with isohexane. After the additional partial concentration crystallization was started. The mixture is allowed to stand in an ice bath for 1 hour. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitle compound (17 g). b) 5-Bromomethyl-2-chloro-N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide To a stirred solution of 5-bromomethyl-2-chloro-benzoic acid (Example 8a, 12.4 g) in dichloromethane (250 ml) and dimethylformamide (0.12 ml) at 0 ° C is added oxalyl chloride (8.7 ml). The cooling bath was removed and the solution allowed to warm to room temperature. Once the gas evolution has ceased, the solution is concentrated in vacuo. The residue is redissolved in dichloromethane (300 ml), cooled to 0 ° C and treated with diisopropylethylamine (12.4 ml) and adamantylmethylamine (7.54 ml). After 15 minutes at 0 ° C the solution is poured into diethyl ether (1 liter) and washed with 1 N aqueous hydrochloric acid followed by brine. The organics were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white powder (19 g).

MS (APCI + ve) 396/398 (M + H) +. RMN: H (DMSO-d6) d 8.39 (H, t); 7.50-7.40 (2H, m); 4.74 (2H, s); 2.92 (2H, d); 2.50 (3H, s); 1.94 (3H, sa); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, s). c) 2-Chloro-5- (4- [. {1,1-dimethylethyl} oxycarbonyl] -piperazin-1-yl) methyl-N- (tricyclo [3.3.1.137] dec-1-ylmethyl) ) -benzamide, A mixture of 5-bromomethyl-2-chloro-N- (tricyclo [3.3.1.1J "'] dec-1-ylmethyl) -benzamide (Example 8b, 0. 130 g), 1-tert-butyloxycarbonylpiperazine (0.074 g) and diisopropylethylamine (6.3 ml) in dimethylformamide (3 ml) is heated at 60 ° C for 3 hours. The mixture is diluted with water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The organic layer is dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The crude material was purified on silica gel eluting with dichloromethane / ethanol (0-20% gradient) to give the title compound as a white foam (0.112 g).

MS (APCI + ve) MW 502/504 (M + H) + NMR: H (DMSO-dí) d 8.28 (ΔH, t); 7.40 (ÍH, d); 7.32 (ÍH, dd); 7.29 (ÍH, d); 3.74 (2H, s); 3.28 (4H, t); 2.90 (2H, d); 2.31 (4H, t); 1.92 (3H, sa); 1.70-1.50 (6H, m); 1.59 (6H, d); 1.37 (9H, s). d) Hydrochloride salt of 2-chloro-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, 2-Chloro-5- (4- [ { 1, 1-dimethylethylloxycarbonyl] -piperazin-1-yl) ethyl-N- (tricyclo [3.3.1.1J "'] dec-1-ylmethyl) -benzamide (Example 8c, 0.080 g) is dissolved in methanol (3 ml), 4N HCl in dioxane (1 ml) is added and the mixture is stirred at room temperature for 1.5 hours.The solvent is removed under vacuum and the resulting solid triturate with ether to give the title compound as a white powder (0.062 g).

MS (APCI + ve) MW 402/404 (M + H) * NMR '? E (DMSO-de) d 8.30 (H, t); 7.63 (2H, sa); 7.55 (ÍH, d); 4.33 (ÍH, sa); 4.05 (4H, m); 3.50-3.00 (4H, m); 3.50-3.40 (1H, m); 2.92 (2H, d); 1.92 (3H, sa); 1.70-1.50 (6H, m); 1.57 (6H, sa).

In accordance with the procedure described in Example 8, the following compounds were prepared.

Example 9 Salt of 2-chloro-5- [(hexahydro-1H-1,4-diazepin-1-yl) -N- (tricyclo [3.3.1. L3"7] dec-1-ylmethyl) -benzamide hydrochloride MS (APCI + ve) MW 416/418 (M + H) "NMR"? (DMSO-de) d 11.62 (sa, ÍH), 9.57 (sa, ÍH); 9.30 (sa, ÍH); 8.34 (ÍH, t); 7.80-7.60 (2H, m); 7.59 (ÍH, d); 4.50-4.30 (sa, 2H); 3.80-3.00 (m, 8H); 2.94 (2H, d); 2.25-2.10 (m, 2H), 1.94 (3H, sa); 1.66 (3H, d); 1.58 (3H, d); 1.54 (6H, s).

Example 10 - [(4-amino-1-piperidinyl) methyl] -2-chloro-N- (tricyclo [3.3.1.137Jdec-l-ylmethyl] -benzamide hydrochloride salt] MS (APCI + ve) MW 416/418 (M + H) * NMR: H (DMSO-de) d 8.35 (1H, t); 8.30 (2H, sa); 7.66 (1H, d); 7.65 (ÍH, s); 7.59 (ÍH, d); 4.28 (d, 2H); 3.65-3.18 (m, 4H); 3.10-2.90 (ÍH, m); 2.95 (2H, d); 2.15-2.05 (2H, m); 2.05-1.90 (ÍH,); 1.94 (3H, sa); 1.68 (3H, d); 1.61 (3H, d); 1.54 (6H, s).

Example 11 - [(3-Amino-l-pyrrolidinyl) methyl-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-methylmethyl) -benzamide hydrochloride salt MS (APCI + ve) MW 402/404 (M + H) t NMR I (DMSO-de) d 8.56 (H, SA); 8.42 (2H, sa); 8.35 (ÍH, t); 7.66 (2H, sa); 7.59 (1H, d); 4.60-4.40 (m, 2H); 4.20-3.00 (, 5H); 2.94 (2H, d); 2.35-1.95 (, 2H); 1.95 (3H, sa); 1.68 (3H, d); 1.61 (3H, d); 1.54 (6H, s).

Example 12 2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1. L3"7] dec-l-ylmethyl) -benzamide hydrochloride salt a) 2-Chloro-5-hydroxy-N- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide To a solution of 2-chloro-5-hydroxybenzoic acid (3.12 g) in N, N-dimethylformamide (50 ml) is added 1,1'-carbonyldiimidazole (3.0 g). The resulting reaction mixture is stirred for 2.5 hours and then 1-adamantanemethylamine (3.0 g) is added. Stirring is continued for 14 hours. The reaction mixture is partitioned between ethyl acetate and water and the organic layer is separated, washed with water and brine and then dried over sodium sulfate (Na 2 SO 4). The organic layer is concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 3-10% methanol in dichloromethane) to give the subtitle compound as a white solid (0.15 g).

MS (APCI + ve) 319/321 (M + H) *. RMN: H (DMSO-de) d 9.85 (H, s), 8.25 (H, t), 7.24 (H, d), 6.76-6.82 (2H, m), 2.90 (2H, d), 1.93 (3H, s), 1.67 (3H, d), 1.57 (3H, d), 1.51 (6H, s) b) Hydrochloride salt of 2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1. 13"7] dec-1-methylmethyl) -benzamide To a solution of 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide (0.20 g, Example I2a), 1-dimethylethyl ester of 4-hydroxy-1-piperidinecarboxylic acid (0.19 g) and tributylphosne (0.23 ml) in dry tetrahydrofuran (6 ml) is added 1 - [[(1-piperidinylcarbonyl) azo] carbonyl ] -piperidine (0.24 g). The orange solution is heated to 60 ° C under a nitrogen atmosphere for 2 hours. At this point ester 1 is added, 4-hydroxy-1-piperidinecarboxylic acid 1-dimethylethyl (0.19 g), tributylphosphine (0.23 ml) and 1- [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g). Heating is continued and the procedure described above is repeated until the reaction complements as judged by LC / MS. The cooled reaction mixture is diluted with diethyl ether then filtered. The filtrate is concentrated and purified by normal phase HPLC (0.2% methanol / dichloromethane) followed by chromatography on silica gel (0-2% methanol / dichloromethane) to give the t-butyloxycarbonyl compound (BOC) -protected as a foam. colorless The foam is dissolved in methanol (5 ml) and 4N hydrochloric acid in dioxane (0.25 ml) is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LC / MS. Evaporation of the solvent followed by trituration with diethyl ether gave the title compound as a colorless solid (0.15 g).

MS (APCI + ve) 417/419 (M + H) * NMR: H (DMSO-de) d 8.65 (2H, br.s); 8.30 (ÍH, t); 7.39 (ÍH, d); 7.07 (ÍH, dd); 6.99 (ÍH, d); 4.72-4.67 (ÍH, m); 3.21 (2H, ma); 3.07 (2H, ma); 2.92 (2H, d); 2.12-2.07 (2H, m); 1.94 (3H, sa); 1.88-1.30 (2H, m); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, s) Example 13 Salt of the hydrochloride of (R) -2-chloro-5- (2-pyrrolidinylmethoxy) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide JO Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1"" 7] dec-1-ylmethyl) -benzamide (0.20 g, Example 12a), N-tBOC- D-prolinol (0.19 g) and tributylphosphine (0.23 ml), dry tetrahydrofuran (6 ml) and 1- [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) to obtain the butyloxycarbonyl compound (BOC) - protected, followed by treatment with 4N hydrochloric acid in dioxane (0.4 ml) and methanol (5 ml) to give the title compound as a colorless solid (0.14 g).

MS (APCI + ve) 403/405 (M + H) + XH NMR (CD3OD) d 8.45 (1H, ta); 7.46 (ÍH, d); 7.14-7.10 (2H, m); 4.41 (ÍH, dd); 4.18 (ÍH, t); 4.10-4.04 (ÍH, m); 3.41 (2H, t); 3.10 (2H, m); 2.36-2.28 (ÍH, m); 2.25-2.08 (2H, d); 2.03 (3H, s); 2.00-1.90 (ÍH, m); 1.83 (3H,); 1.74 (3H, d); 1.68 (6H, s) Example 14 Hydrochloride salt of (S) -2-chloro-5- (2-pyrrolidinylmethoxy) -N- (tricyclo [3.3.1.137] dec-l-ylmethyl) -benzamide Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1J-7] dec-1-methyl) -benzamide (0.20 g- Example 12a), N-tBOC- L-prolinol (0.19 g) and tributylphosphine (0.23 ml), dry tetrahydrofuran (6 ml) and 1- [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) to obtain the t-butyloxycarbonyl compound (BOC) ) -protected, followed by treatment with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a colorless solid (0.07 g).

MS (APCI + ve) 403/405 (M + H) * NMR; H (CD3OD) d 8.45 (1H, ta); 7.46 (ÍH, d); 7.14-7.10 (2H, m); 4.41 (ÍH, dd); 4.18 (ÍH, t); 4.10-4.04 (ÍH, m); 3.41 (2H, t); 3.10 (2H, m); 2.36-2.28 (ÍH,); 2.25-2.08 (2H, d); 2.03 (3H, s); 2.00-1.90 (ÍH, m); 1.83 (3H, m); 1.74 (3H, d); 1.68 (6H, s) Example 15 Salt of 2-chloro-5- (3-piperidinylmethoxy) -N- (tricyclo [3.3.1. 13'7] dec-1-ylmethyl) -benzamide hydrochloride, .HC: Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.13"7] dec-1-ethyl) -benzamide (0.20 g- Example 12a), 3- piperidinmethanol (0.20 g) and tributylphosphine (0.23 ml), dry tetrahydrofuran (6 'ml)' and 1- [[(1-piperidincarbonyl) azo] carbonyl] -piperidine (0.24 g) to obtain the t-butyloxycarbonyl compound (BOC) ) -protected This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a colorless solid (0.09 g).

MS (APCI + ve) 417/19 (M + H) "NMR-IE (DMSO-d6) d 8.34 (2H, sa); 8.29 (1H, t); 7.38 (1H, d); 7. 01 (ÍH, dd); 6.93 (ÍH, d); 3.99-3.95 (ÍH, m); 3.91-3.87 (ÍH,); 3.34 (ÍH, m); 3.23 (ÍH, da); 2.92 (2H, d); 2.82-2.71 (2H, m); 2.22 (1H, m); 1.94 (3H, s); 1.82 (2H, d); 1. 72-1.66 (4H, m); 1.59 (3H, d); 1.52 (6H, s); 1.39-1.32 (ÍH, m) Example 16 Salt of cis-5- [(4-aminocyclohexyl) oxy] -2-chloro-N- (tricyclo [3.3.1. 13'7] dec-l-ylmethyl) -benzamide hydrochloride Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1J ''] dec-1-ethyl) -benzamide (0.20 g, Example 12a), trans-4- amino-cyclohexanol (0.20 g) and tributylphosphine (0.23 ml), dry tetrahydrofuran (6 ml) and 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) to obtain the t-butyloxycarbonyl compound (BOC) ) -protected. This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a colorless solid (0.065 g). MS (APCI + ve) 417/19 BP 417 X H NMR (DMSO-de) d 8.30 (H, t); 7.97 (3H, sa); 7.38 (ÍH, d); 7. 02 (ÍH, dd); 6.92 (1H, d); 4.62 (ÍH, sa); 3.11 (ÍH, sa); 2. 92 (2H, d); 1.94 (5H, s); 1.76-1.58 (12H,); 1.52 (6H, s).

Example 17 2-Methyl-5- (1-piperazinylmethyl) -N- (tricyclo [3.3.1. I37Jdec-1-ylmethyl) -benzamide hydrochloride salt, To a solution of 2-bromo-5- (4- [ { 1, 1-dimethylethyl] oxycarbonyl] -piperazin-1-yl) methyl-N- (tricyclo [3.3.1. Io-7] dec- 1-ylmethyl) -benzamide (0.20 g, Example 65b) and tetrakis (triphenylphosphine) palladium (0) (2 mg) in dry toluene (6 ml) is added trimethyltin (0.2 ml). The solution is heated to 130 ° C in a sealed tube for 18 hours. The cooled reaction mixture is evaporated and the residue is treated with 10% KF solution in acetone and stirred for 45 minutes. The mixture is concentrated and chromatographed on silica gel (isohexane then 60% ethyl acetate / 40% isohexane) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless oil. The oil is dissolved in methanol (2 ml) and 4N hydrochloric acid in dioxane is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LC / MS. Evaporation of the solvent followed by trituration with diethyl ether gave the title compound as a colorless solid (0.03 g).

MS (APCI + ve) 382 (M + H) * 1N-NMR (CD3OD) d 7.61 (1H, s); 7.55 (ÍH, d); 7.39 (ÍH, d); 4.45 (2H, s); 3.67-3.46 (8H, ma); 3.08 (2H, s); 2.45 (3H, s); 1.99 (3H, s); 1.78 (3H, d); 1.71 (3H, d); 1.62 (6H, s).

Example 18 Salt of 2-chloro-5- (1-piperazinmethyl) -N- (2- (tricyclo [3.3.1.13'7] dec-1-ylethyl) -benzamide hydrochloride a) 5- (Bromomethyl) -2-chloro-N- (2-tricyclo [3.3.1.13'7] dec-1-ylethyl) -benzamide To a solution of 2-chloro-5- (bromomethyl) -benzoic acid (1.0 g) in dichloromethane (25 ml) at 0 ° C is added dimethylformamide (0.05 ml) followed by oxalyl chloride (0.52 ml). The reaction is allowed to warm to room temperature and is stirred for 30 minutes. The volatiles were removed under vacuum and the residue dried under high vacuum. The acyl chloride is dissolved in dichloromethane (20 ml) and added to a solution of the hydrochloride salt of 2-adamantanemethylamine (0.95 g) in dichloromethane (20 ml) and diisopropylamine (2 ml) at 0 ° C. The reaction is allowed to warm to room temperature and is stirred for 2 hours. The organic substances are washed with water (20 ml) then with a saturated aqueous ammonium chloride solution and the organic layer is dried over magnesium sulfate and then filtered. The filtrate is concentrated under reduced pressure to a solid. The crude material was recrystallized from dichloromethane / hexane to give the subtitle compound as a white solid (1.3 g). b) 4- [[4-Chloro-3- [[(2-tricyclo [3.3.1.13,7Jdec-1-ylethyl) aminoJ carbonyl] phenylmethyl] -1-piperazinecarboxylic acid 1, 1-dimethylethyl ester A mixture of 5- (bromomethyl) -2-chloro-N- (2-tricyclo [3.3.1.1J'7] dec-1-ylethyl) -benzamide (Example 18a, 0.35g), 1-tert-butyloxycarbonylpiperazine (0.213 g) ), potassium carbonate (0.20 g) and potassium iodide (10 g) in acetone (5 ml) is heated at 60 ° C for 2 hours. The acetone is removed under vacuum, the residue is taken up in dichloromethane and the solid is removed by filtration. The crude material was purified on silica gel eluting with dichloromethane / ethanol (0-10% gradient) to give the subtitle compound as a white foam (0.333 g).

MS (APCI + ve) MW 516/518 (M + H) + X H NMR (CDCl 3) d 7.63 (δH, sa); 7.34 (2H, sa); 6.09 (ÍH, sa); 3.60-3.30 (8H, m); 2.50-2.30 (4H, sa); 1.97 (3H, sa); 1.72 (3H, d); 1.68 (3H, d); 1.56 (6H, sa); 1.44 (9H, 's); .50-1.35 (2H, m); c) Hydrochloride salt of 2-chloro-5- (1-piperazinylmethyl) -N- (2-tricyclo [3.3.1. l3'7] dec-1-ylethyl) -benzamide 1,4-[[4-Chloro-3- [[(2-tricyclo [3.3.1.13,7] dec-1-ylethyl) amino] carbonyl] -phenyl] methyl ester 1, 1-dimethylethyl] -1- piperazinecarboxylic acid (Example 18, 0.270 g) is dissolved in methanol (3 ml), 4N HCl in dioxane (2 ml) and the mixture is stirred for 14 hours at room temperature. The solvent is removed under vacuum and the resulting solid is triturated with ether to give the title compound as a white powder (0.207 g).

MS (APCI + ve) MW 416/418 (M + H) * KM. lE (CD.OD) d 7.69 (ÍH, s); 7.66 (ÍH, d); 7.60 (ÍH, d); 4.86 (2H, s); 3.70-3.50 (8H, m); 3.50-3.35 (2H,); 1.98 (3H, sa); 1.73 (3H, d); 1.70 (3H, d); 1.62 (6H, sa); 1.50-1.35 (2H, m).

Example 19 Hydrochloride salt of (+/-) -2-chloro-5- (3-pyrrilidinyloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) - 'benzamide Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide (0.155 g, Example 12a), tributylphosphine (0.23 ml) ), (+/-) - 3-hydroxy-1-pyrrolidinecarboxylic acid 1-dimethylethyl ester (0.19 g), 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) and dry tetrahydrofuran (10 ml) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless foam. This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a colorless solid (0.075 g). MS (APCI + ve) 389/391 (M + H) * NMR: H (CD3OD) d 8.42 (1H, ta); 7.42 (ÍH, d); 7.09-7.03 (2H, m) '; 5.23 (ÍH, ma); 3.59-3.41 (4H, m); 3.07 (2H, d); 2.36-2.30 (2H, m); 1.99 (3H, sa); 1.79 (3H, d); 1.70 (3H, d); 1.63 (6H, d) Example 20 Hydrochloride salt of the (+/-) -2-chloro-5- (3-piperidinyloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, Prepared as described in Example 12b using the (+/-) -2-chloro-5-hydroxy-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.15 g, Example 12a) , triphenylphosphine (2 x 0.18 ml), 1,1-dimethylethyl ester of 3-hydroxy-1-piperidinecarboxylic acid (2 x 0.14 g), 1- [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (2 x 0.18 g) and dry tetrahydrofuran (6 ml) to give the t-butyloxycarbonyl compound (BOC) -protected as a 'colorless foam'. This compound was treated with 4N hydrochloric acid in dioxane (0.25 ml) and methanol (5 ml) to give the title compound as a colorless foam (0.042 g).

MS (APCI + ve) 403/405 (M + H) * 1 L NMR (CD3OD) d 8.42 (1H, t); 7.41 (ÍH, d); 7.14-7.10 (2H, m); 4. 82 (1H, ma); 3.51-3.39 (ÍH, m); 3.38 (2H, m); 3.20-3.17 (ÍH, m); 3.06 (2H, d); 2.10-2.04 (2H, m); 2.00 (3H, sa); 1.94- 1.89 (ÍH, m); 1.84-1.68 (7H, d); 1.64 (6H, d) Example 21 Trans-5- [(4-aminocyclohexyl) oxy] -2-chloro-N- (tricyclo- [3.3. 1.13'7] dec-l-ylmethyl) -beñzamide Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide (0.15 g, Example 12a), tributylphosphine (3 x 0.18 ml), cis- (4-hydroxycyclohexyl) -carbamic acid 1, 1-dimethylethyl ester (3 x 0.15 g), 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (3 x 0.18 g) and dry tetrahydrofuran (6 ml) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless foam. This mixture was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (3 ml) to give the title compound as a colorless foam (0.080 g). MS (APCI + ve) 417/419 (M + H) * NMR * H (CD30D) d 8.38 (1H, t); 7.34 (ÍH; d); 6.98 (ÍH, dd); 6. 96 (ÍH, d); 4.30 (ÍH,); 3.17 (ÍH, m); 3.04 (2H / d); 2.22 (2H, ma); 2.09 (2H, m); 1.98 (3H, sa); 1.77 (3H, d); 1.68 (3H, d); 1.62 (6H, s); 1.55 (4H, m) Example 22 Cis- (+/-) -5- [(3-Aminocyclopentyl) oxy] -2-chloro-N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.1J'7] dec-1-ylmethyl) -benzamide (0.20 g, Example 12a), tributylphosphine (0.24 ml ), 1,3-, 1-dimethylethyl ester of trans- (+/-) - (3-hydroxycyclopentyl) -carbamic acid (0.19 g), 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) and dry tetrahydrofuran (3 ml) to give the t-butyloxycarbonyl (BOC) -protected compound as a colorless foam.

This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a colorless foam (0.15 g).

MS (APCI + ve) 403/405 (M + H) * NMR: H (CD3OD) d 7.36 (1H, d); 7.02-6.98 (2H, m); 4.94-4.90 (ÍH, m); 3.75-3.68 (ÍH, m); 3.04 (2H, s); 2.55 (ÍH, m); 2.24-2.17 (ÍH, m); 2.09-2.03 (2H, m); 1.98-1.86 (5H, m); 1.76 (3H, d); 1.68 (3H, d); 1.62 (6H, d) Example 23 Salt of hydrochloride of (S, S) -2-chloro-5- (2,5-diazabicyclo [2.2.1Jhept-2-yl] -N- (tricyclo [3.3.1. L3'7] dec-l- ilmetil) -benza gone a) 5-Bromo-2-chloro-N- (tricyclo [3.3.1.13:7Jdec-1-methylmethyl) -benzamide Prepared as in the Example from 5-bromo-2-chlorobenzoic acid (7.17 g), oxalyl chloride (5.3 ml), dichloromethane (150 ml), dimethylformamide (0.05 ml), diisopropylethylamine (6 ml) and adamantylmethylamine ( 5 ml) to give the subtitle compound as white, colorless needles (7.3 g).

EM (APCI + ve) 382/384 (M-H) + b) Hydrochloride salt of (S, S) -2-chloro-5- (2,5-diazabicyclo [2.2.1 Jhept-2-il) -N- (tricyclo [3.3.1.13'7] dec-1 -ylmethyl) -benzamide A mixture of 5-bromo-2-chloro-N- (tricicls' [3.3.1.13,7] dec-1-ylmethyl) -benzamide (1.70 g, Example 23a), 1, 1-dimethylethyl ester of acid 2, 5-diazabicyclo [2.2.1] heptan-2-carboxylic acid (1.06 g), cesium carbonate (2.20 g), (R) - (+) -2, 2'-bis (diphenylphosphino) -1, 1'-biphenyl ((R) - (+) - BINAP, 0.20 g), and palladium (II) acetate (0.050 g) in dry toluene (10 ml) is heated at 100 ° C under nitrogen for 24 hours. The cold reaction mixture is filtered, the residue is washed with ethyl acetate. The filtrate is washed with water and brine, dried (MgSO 4) and evaporated under reduced pressure to give an orange oil. The oil is purified by chromatography on silica gel, eluting with 0.5% methanol / dichloromethane to give the protected t-butyloxycarbonyl compound (BOC) as a colorless foam. The foam is dissolved in methanol (20 ml) and 4N hydrochloric acid in dioxane (2.5 ml) is added. The solution is stirred at room temperature until the reaction complements (LCMS). The solution is then evaporated under reduced pressure and the residue triturated with diethyl ether to give the title compound as a white off-color solid (0.92 g).

MS (APCI + ve) 400/402 (M-HCD * NMR 'LE (CD3OD) d 8.32 (1H, t); 7.30 (1H, d); 6.77-3.70 (2H, m); 4. 69 (ÍH, s); 4.50 (ÍH, s); 3.73 (ÍH, dd); 3.67 (2H, d); 3.06 (2H, d); 2.30 (1H, da); 2.06 (ÍH, da); 1.99 (3H, sa); 1.78 (3H, d); 1.70 (3H, d); 1.64 (6H, s); 1.55 (4H,). The peak or point of methanol masks another "H.

Example 24 2-Chloro-5- (2-methyl-1-piperazinyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt 14 Prepared as described in Example 23 above from 5-bromo-2-chloro-N- (tricyclo [3.3.1.l3'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 23a), 3-methyl-1-piperazinecarboxylic acid 1, 1-dimethylethyl ester (0.20 g), cesium carbonate (0.36 g), (R) - (+) -2, 2-bis (diphenylphosphino) -1,1 '-bubfyl ((R) - (+) - BINAP, 0.036 g), palladium (II) acetate (0.009 g) and toluene dry (10 ml) to give the t-butyloxycarbonyl compound (BOC) -protected. This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a solid (0.025 g). MS (APCI + ve) 402/404 (M + HC1) * 1 E NMR (CD3OD) d 8.40 (1H, t); 7.37 (ÍH, d); 7.11 (ÍH, dd); 7.07 (ÍH, d); 4.00-3.96 (ÍH, m); 3.43-3.39 (3H, m); 3.28-3.19 (3H, m); 3.06 (2H, d); 1.98 (3H, sa); 1.77 (3H, d); 1.70 (3H, d); 1.63 (6H, s); 1.10 (3H, d). fifteen Example 25 Hydrochloride salt of (+/-) -2-chloro-5- (3-pyrrolidinylamino) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared as described in Example 23 above from 5-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 23a), ester 1 , 3-amino-1-pyrrolidinecarboxylic acid 1-dimethylethyl (0.18 g), cesium carbonate (0.36 g), (R) -BINAP (0.036 g), anhydrous toluene (3 ml) and palladium (II) acetate (0.009 g); The mixture is heated for 14 h in a pressure vessel with a rapid flow of nitrogen. Additional (R) -BINAP (0.036 g) and palladium (II) acetate (0.009 g) are added and heating is continued for an additional 24 hours. The cold reaction mixture is poured into water and extracted with ethyl acetate three times. The organic fractions were combined and washed with water then with brine, and dried (MgSO4). Evaporation under reduced pressure gave an oil which was purified by normal phase HPLC (0-5% methanol / dichloromethane) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless foam. The foam is dissolved in methanol (5 ml) and 4N hydrochloric acid in dioxane (0.5 ml) is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LCMS. Evaporation followed by trituration with diethyl ether and methanol gave the title compound as a solid / colorless white foam (0.040 g).

MS (APCI + ve) 388/390 (M-HC1) * NMR XH (CD3OD) d 8.20 (H, ta); 7.12 (ÍH, d); 6.63-6.60 (2H, m); 4.76-4.08 (ÍH, m); 3.43-3.38 (2H, m); 3.35-3.28 (ÍH, m); 3.25 (ÍH, m); 2.94 (2H, s); 2.31-2.22 (ÍH, m); 2.01-1.94 (ÍH, m); 1.89 (3H, sa); 1.67 (3H, d); 1.60 (3H, d); 1.53 (6H, s) Example 26 (+/-) -5- (3-Ami o-1-piperidinyl) -2-chloro-N- (tricyclo [3.3.1.13,] dec-l-ylmethyl) -benzamide Prepared as described in Example 23 above from 5-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.20 g, Example 23a), 1-dimethylethyl ester of 3-piperidinylcarbamic acid (0.12 g), cesium carbonate (0.24 g), (R) - (+) - 2, 2'-bis (diphenylphosphino) -1, 1 '-bubfin ((R) - (+) - BINAP, 0.024 g), palladium (II) acetate (0.006 g) and dry toluene (3 ml) to give the t-butoxycarbonyl compound (BOC) -protected. The t-butoxycarbonyl (BOC) -protected compound was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane). After stirring at room temperature for 24 h the mixture is evaporated and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous phase acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated under reduced pressure to give a gum. Purification by chromatography on silica gel, eluting with 4-10% methanol in dichloromethane / aqueous ammonia afforded the title compound as a solid (0.036 g).

MS (APCI + ve) 402/404 (M + H) + NMR? E (CD3OD) d 7.25 (1H, d); 7.00 (ÍH, dd); 6.96 (ÍH, d); 3. 59 (ÍH, dd); 3.48-3.45 (ÍH, m); 3.04 (2H, d); 2.91-2.85 (ÍH, m); 2.82-2.75 (ÍH, m); 2.58 (1H, dd); 1.98-1.93 (4H, m); 1.85-1.75 (3H, d); 1.70-1.62 (10H, d); 1.34-1.25 (ÍH, d).

Example 27 (+/-) -2-chloro-5- (3-piperidinylamino) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared as described in Example 23 above from 5-bromo-2-chloro-N- (tricyclo [3.3.1.l3,7] dec-1-ylmethyl) -benzamide (0.30 g, Example 23a), 1-dimethylethyl ester of 3-amino-1-piperidinecarboxylic acid (0.19 g), cesium carbonate (0.36 g), (R) - (+) -2, 2'-bis (diphenylphosphino) -1, 1'-biphenyl ((R) - (+) - BINAP, 0.036 g), palladium (II) acetate (0.008 g) and dry toluene (3 ml) to give the t-butyloxycarbonyl compound (BOC) -protected. This compound was treated with methanol (5 ml) and hydrochloric acid (0.5 ml of a 4 M solution in dioxane) followed by a working procedure with an acid / base. Purification by chromatography on silica gel, eluting with 4-10% methanol in dichloromethane / aqueous ammonia afforded the title compound as a solid (0.008 g).

MS (APCI + ve) 402/404 (M + H) + XH NMR (CD3OD) d 7.14 (1H, d); 6.68-6.65 (2H, m); 3.47-3.40 (ÍH, m); 3.25 (ÍH, m); 3.05-3.02 (3H, m); 2.72-2.65 (ÍH, m); 2.52-2.47 (ÍH, m); 2.08-2.04 (ÍH, m); 1.97 (3H, sa); 1.89-1.82 (ÍH, m); 1.77 (3H, d); 1.70-1.62 (10H, d); 1.50-1.40 (ÍH, m).

Example 28 2-Chloro-5- [hexahydropyrrolo [3,4-c] pyrrole-2 (lH) -yl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared as described in Example 23 above from 5-bromo-2-chloro-N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide (0.15 g, Example 23a), hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -carboxylic acid ester (0.17 g), cesium carbonate (0.33 g), (R) - (+) - 1, 1-dimethylethyl ester 2, 2'-bis (diphenylphosphino) -1, 1'-biphenyl ((R) - (+) - BINAP, 0.018 g), palladium (II) acetate (0.004 g) and dry toluene (2 ml) to give the t-butyloxycarbonyl compound (BOC) -protected. This compound was treated with methanol (5 ml) and hydrochloric acid (0.5 ml of a 4 M solution in dioxane) followed by work or elaboration with an acid / base. Trituration of the residue with dichloromethane afforded the title compound as a solid (0.020 g).

MS (APCI + ve) 414/416 (M + H) + XR-NMR (CD3OD) d 8.17 (1H, t); 7.20 (ÍH, d); 6.63 (ÍH, dd); 6.54 (ÍH, d); 3.36 (2H, m); 3.02 (2H, dd); 2.95-2.90 (4H, m); 2.80 (2H, m); 2.60 (2H, dd); 1.94 (3H, sa); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, d).

Example 29 Salt of N- [2-methyl-5- (4-piperidinyloxy) phenyl] -trichloride hydrochloride [3.3.1. 13'7] decan-l-acetamide, Prepared as described in Example 12b using the N- (5-hydroxy-2-methylphenyl) -tricyclo [3.3.1.13'7] decan-1-acetamide (0.51 g, Example 12, WO 99/29660), tributylphosphine ( 0.64 ml), 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.65 g), 4-hydroxy-1-piperidinecarboxylic acid 1, 1-dimethylethyl ester (0.52 g) and dry tetrahydrofuran (10 ml) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless solid. This compound was treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound as a colorless solid (0.13 g). f MS (APCI + ve) 383 (M-HC1) * XR NMR (CD3OD) d 7.19 (1H, d); 7.12 (ÍH, d); 6.83 (ÍH, dd); 4. 71-4.66 (ÍH, m); 3.46-3.40 (2H, m); 3.28-3.22 (2H,); 2. 25 (3H, s); 2.21 (ÍH, s); 2.21-2.14 (2H, m); 2.11-2.04 (5H, m); 1.84-1.73 (12H, m).

Example 30 N- [2-chloro-5- (4-piperidinyloxy) phenyl] - (tricyclo [3.3.1.13'7] decan-1-acetamide hydrochloride salt .HCl Prepared as described in Example 12b using N- (2-chloro-5-hydroxyphenyl) - (tricyclo [3.3.1.13'7] decan-1-acetamide (0.25 g, Example 28, WO 99/29660), tributylphosphine (0.29 ml), 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.30 g), ester 1, 1-dimethylethyl 4-hydroxy-1-piperidinecarboxylic acid (0.24 g) and dry tetrahydrofuran (10 ml) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless solid. This compound was treated with 4N hydrochloric acid in dioxane (1 ml) and methanol (20 ml) to give the title compound as a colorless solid. (0.08 g).

MS (APCI + ve) 375/377 (M-HC1) * X H NMR (CD3OD) d 7.55 (1H, d); 7.41 (ÍH, d); 6.88 (ÍH, dd); 4.76-4.70 (ÍH, m); 3.48-3.39 (2H, m); 3.30-3.22 (2H, m); 2.25 (2H, s); 2.22-2.16 (2H, m); 2.14-2.03 (2H, m); 1.84-1.72 (12H, m).

Example 31 Salt of 2-chloro-5- [(4-piperidinylamino) methyl] -N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide dihydrochloride a) 2-Chloro-5- ormil-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide A solution of the 5-bromo-2-chloro-N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide (3.25 g, Example 23a) in anhydrous tetrahydrofuran (150 ml) is cooled to -78. ° C under a nitrogen atmosphere. A solution of methyl-lithium (1.4 M in diethyl ether, 6.1 ml) is added for 2 minutes. The mixture is stirred at -78 ° C for 10 minutes, then a solution of tert-butyl-lithium is added dropwise. (1.7 M in pentane, 10.0 ml). The mixture is stirred at -78 ° C for an additional 10 minutes, then dimethylformamide (1.0 ml) is added. The resulting solution is stirred at -78 ° C for 30 minutes, the temperature is reduced with a saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the subtitle compound as a solid (2.76 g).

MS (APCI + ve) 332 (M + H) + X H NMR (DMSO-de) d 10.04 (H, s); 8.49 (ÍH, t); 7.96-7.91 (2H, m); 7.74 (ÍH, d); 2.96 (2H, d), 1.95 (3H, s); 1.64 (6H, AB); 1.53 (6H, d). b) 4- [4-Chloro-3- [(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenyl] -methyl] mino] -1- piperidinecarboxylic 2-Chloro-5-formyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.270 g, Example 31a) and the 1,1-dimethylethyl ester of 3-amino-1 -pyrrolidinecarboxylic (0.325 g, Journal of Medicinal Chemistry, 1998, 41 (22), 4273-4278) are dissolved in 1,2-dichloroethane (30 ml) under a nitrogen atmosphere. Sodium triacetoxyborohydride (0.24 g) is added and the mixture is stirred for 14 hours at room temperature. Water and dichloromethane are added and the layers are distributed. The organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by HPLC eluting with a gradient of 0-10% ethanol in dichloromethane, then by chromatography on silica gel eluting with ethyl acetate: isohexane (1: 1) then ethyl acetate: ethanol (98: 2) to give the subtitle compound as a colorless oil (0.158 g).

MS (APCI + ve) 516 (M + H) + c) 2-Chloro-5- [(4-piperidinylamino) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide dihydrochloride salt Prepared from 4- [[[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenyl] ethyl] amino acid, 1-dimethylethyl ester] -1-piperidinecarboxylic acid (0.158 g, Example 31b), methanol (3 ml) and a solution of 4N hydrochloric acid in dioxane (2 ml). The solvents were removed under reduced pressure and the residue was triturated with ethyl acetate, iso-hexane and diethyl ether to give the title compound as a white solid (0.126 g).

MS (APCI + ve) 416 (M + H-2HC1) * NMR XH (CD3OD) d 8.47 (1H, t); 7.62-7.56 (3H, m), 4.33 (2H, s); 3.58-3.55 (3H, m); 3.12 (2H, t); 3.07 (2H, d); 2.44 (2H, d); 2.03-1.92 (5H, m); 1.73 (6H, c); 1.63 (6H, d).

Example 32 - [[[4- (Aminomethyl) cyclohexyl] amino] methyl] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide dichloride. a) [[4 - [[[[4-chloro-3 - [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenylmethyl] amino] cyclohexyl] -1] -dimethylethyl ester] me il] -carbamic Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide (0.30 g, 31a), the 1 - (1-dimethylethyl) -carbamic acid ester (0.207 g, WO 97/32882), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml) The residue is purified by chromatography on silica gel eluting with ethyl acetate: isohexane (1: 1) then ethyl acetate: ethanol (9: 1) to give the subtitle compound as a colorless oil (0.26 g).

MS (APCI + ve) 544 (M + H) + b) 5 - [[[4- (Aminomethyl) cyclohexyl] -Jamino-methyl] -2-chloro-N- (tricyclo [3.3.1.13,7Jdec-l-ylmethyl] -benzamide) dihydrochloride Prepared from [[4- [[[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenylmethyl] amino acid, 1-dimethylethyl ester] cyclohexyl] methyl] -1-carbamic acid (0.26 g, Example 32a), methanol (5 ml) and a solution of 4N hydrochloric acid in dioxane (2 ml). The solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.191 g).

MS (APCI + ve) 444 (M + H-2HCD * H NMR (CD3OD) d 7.60-7.58 (3H, m), 4.29 (2H, s); 3.28-3.12 (H, m); 3.09 (2H, s) ), 2.84 (2H, d), 2.31 (2H, da), 2.00 (5H, ba), 1.75 (6H, c), 1.65 (6H, d), 1.71-1.65 (HI, m), 1.63-1.44 ( 2H, m); 1.31-1.12 (2H, m).

Example 33 - [[(4-aminocyclohexyl) amino] methyl] -2-chloro-N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide dihydrochloride salt a) 1, 1-dimethylethyl ester of [4- [[[4-chloro-3 - [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl aminoJ carbonyl] phenyl] methylJa ino] ciciohexyl] -1 -carbá ico Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 31a), 1-dimethylethyl ester of (4-aminocyclohexyl) -carbamic acid (0.194 g, Journal of Organic Chemistry, 1996, 61 (25), 8811-8818), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane ( 10 ml). The residue is purified by chromatography on silica gel eluting with ethyl acetate: iso-hexane (1: 1) then ethyl acetate: ethanol (95: 5) to give the subtitle compound as a colorless oil (0.24 g).

MS (APCI + ve) 530 (M + H) + b) 5- [[(4-aminocyclohexyl) -aminojmethyl] -2-chloro-N- (tricyclo [3.3.1. 13'7] dec-1-ylmethyl) -benzamide dihydrochloride salt Prepared from [4- [[[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenylmethyl] amino] cydohexyl acid, 1-dimethylethyl ester ] -1-carbamic acid (0.26 g, Example 33a), methanol (5 ml) and 4N hydrochloric acid solution in dioxane (1 ml). The solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.190 g).

MS (APCI + ve) 430 (M + H-2HC1) * aH NMR (CD3OD) d 7.61-7.59 (3H, m), 4.30 (2H, s); 3.28-3.11 (2H, m); 3.08 (2H, s); 2.40-2.32 (2H, m); 2.21-2.17 (2H, m); 2.00 (3H, s); 1.74 (6H, c); 1.64 (6H, d); 1.63-1.48 (4H, m).

Example 34 - [(1-Azabicyclo [2.2.2] oct-3-ylamino) methyl] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 31a), 1-azabicyclo [2.2.2] octan-3-amine dihydrochloride salt (0.18 g), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue is purified by chromatography on silica gel eluting with ethyl acetate: iso-hexane (1: 1) followed by ethyl acetate: ethanol (95: 5). Re-purification by chromatography on silica gel eluting with dichloromethane: methanol (95: 5) then (9: 1) gave the title compound as a white gum (0.013 g).

MS (APCI + ve) 442 (M + H) + XH NMR (CDC13) d 7.68 (1H, d); 7.39 (ÍH, d); 7.31 (ÍH, dd); 6.41 (ÍH, t); 3.75 (2H, s); 3.42-3.31 (2H, m); 3.25-3.09 (6H, m); 2.94 (ÍH, d); 2.38-2.23 (2H, m); 2.22-2.14 (ÍH, m); 2.01 (3H, s); 1.92-1.82 (2H, m); 1.69 (6H, c); 1.59 (6H, d).

Example 35 N- [4- (3-aminopyrrolidin-1-yl) -2-methylphenyl J -2- (tricyclo [3.3.1.13'7] dec-1-yl) acetamide dihydrochloride salt a) [1- (3-Methyl-nitrophenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester 4-Fluoro-2-methyl-1-nitrobenzene (1 g), pyrrolidin-3-ylcarbamic acid tert-butyl ester (1.2 g), potassium carbonate (1.79 g) and dimethyl sulfoxide (10 ml) are heated together at 80 ° C under nitrogen for 15 hours. The mixture is then cooled, diluted with ethyl acetate (200 ml), washed with 2N aqueous hydrochloric acid (200 ml), dried (MgSO 4) and then concentrated. Purification of the residue by chromatography on silica gel (eluting with 20% ethyl acetate in isohexane) gave the subtitle compound (1744 g). • 4 * NMR lE (DMSO-d6) d 8.03-8.00 (ÍH, d), 7.28-7.21 (ÍH, d amp.), 6.51-6.47 (2H, m), 4.20-4.12 (ÍH, m amp.) , 3.61-3.16 (4H, m), 2.56 (3H, s), 2.20-2.08 (HH, m), 1.98-1.85 (HH, m), 1.39 (9H, s). b) [1- (4-Amino-3-methylphenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester [1- (3-Methyl-4-nitrophenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester (1.744 g, Example 35a), iron powder (1.52 g), ammonium chloride (1.45 g) ), ethanol (50 ml) and water (50 ml) were refluxed together under nitrogen for 2 hours. The mixture is cooled and the iron is removed by filtration. Water (200 ml) is added to the residue and the product is extracted with ethyl acetate (3 x 200 ml), dried (MgSO 4), and concentrated to give the subtitle compound (1.56 g).

XH NMR (CDC13) d 6.65 (H, s'amp.), 6.38 (2 H, m amp.), 4.80 (H, m), 4.33 (2 H, m amp.), 3.60-2.80 (5 H, m), 2.31 - 2.17 (4H, m), 1.92-1.82 (ÍH, m), 1.45 (9H, s amp.). c) Tert-butyl acid ester. { l- [4- (2- (tricyclo [3.3.1.13'7] dec-l-yl) acetylamino) -3-methylphenyl] -pyrrolidin-3-yl} -carbamic To a solution of adamantan-1-yl-acetic acid (0.46 g) in dichloromethane (10 ml) at 0 ° C is added dimethylformamide (0.1 ml) followed by oxalyl chloride (2.50 ml). The reaction is allowed to warm to room temperature and is stirred for 30 minutes. The volatiles are removed under vacuum and the residue is dried under high vacuum. The residue is dissolved in dichloromethane (10 ml) and added to a solution of [1- (4-amino-3-methylphenyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester (0.70 g, Example 35b ) in dichloromethane (10 ml) and triethylamine (0.8 ml) at 0 ° C. The reaction is allowed to warm to room temperature and is stirred for 3 hours. The solution is washed with 2N aqueous hydrochloric acid (20 ml), then with brine (20 ml) and the organic layer is dried over magnesium sulfate then filtered. The filtrate is concentrated under reduced pressure. The crude material is purified by chromatography on silica gel (eluting with 1% methanol in dichloromethane) to give the subtitle compound (1.1 g).

MS (APCI + ve) MW 468 (M + H) * NMR tE (DMSO-d6) d 8.86 (OH, s); 7.01-6.98 (ÍH, d); 7.18-7.14 (ÍH, d amp.); 6.33-6.27 (3H, m); 4.15-4.04 (ÍH, m); 3.42-3.15 (3H, m); 3.00-2.97 (ÍH,); 2.12 (3H, s); 2.00 (2H, s); 1.99-1.80 (5H, m); 1.70-1.61 (12H, m); 1.39 (9H, s). d) N- [4- (3-aminopyrrolidin-1-yl) -2-methylphenyl] -2- (tricyclo [3.3.1.13'7] dec-1-yl) acetamide dihydrochloride salt The tert-butyl ester of acid. { 1- [4- (2-tricyclo [3.3.1.13,7] dec-1-yl) acetylamino) -3-methylphenyl] -pyrrolidin-3-yl} -carbamic (0.20 g, Example 35c) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to 2/3 parts of the original volume under reduced pressure. The diethyl ether was added gradually to the solution and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuo to give the title compound as a solid (0.15 g).

MS (APCI + ve) 368 (M + H) + NMR * H (DMSO-e) d 8.92 (1H, s); 8.21 (2H, s amp.); 7.07-7.04 (ÍH, d); 6.41-6.35 (2H,); 3.91 (ÍH, m amp.); 3.50-3.39 (2H, m); 3.29-3.20 (2H, m); 2.37-2.27 (2H, m); 2.14 (3H, s); 2.02 (2H, s); 1.94 (3H, s); 1.70-1.58 (12H, m).

Example 36 N- (2-methyl-4-piperazin-l-ylphenyl) -2- (tricyclo [3.3.1.13,7] dec-l-yl) acetamide dihydrochloride salt a) 4- (3-Methyl-4-nitrophenyl) piperazine-l-carboxylic acid tert-butyl ester The 4-fluoro-2-methyl-1-nitrobenzene (2 g), the tert-butyl ester of piperazine-1-carboxylic acid (4.8 g), potassium carbonate (3.57 g) and dimethyl sulfoxide (20 ml) are heat together at 80 ° C under nitrogen for 15 hours. The mixture is then cooled, diluted with ethyl acetate (200 ml), washed with 2N aqueous hydrochloric acid (200 ml), dried (MgSO), and concentrated to give the subtitle compound (4.10 g).

MS (APCI + ve) 321 (M) + XH-NMR (DMSO-de) d 8.02-7.98 (ÍH, d), 6.89-6.86 (2H, m), 3.45 (8H, s), 2.55 (3H, s) , 1.42 (9H, s). b) 4- (4-Amino-3-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester 4- (3-Methyl-4-nitrophenyl) piperazine-l-carboxylic acid tert-butyl ester (2 g, Example 36a), iron powder (1.74 g), ammonium chloride (1.67 g), ethanol (50 g) ml) and water (50 ml) are refluxed together under nitrogen for 2 hours. The mixture is cooled and the iron is removed by filtration. Water (200 ml) is added to the residue and the product is extracted into ethyl acetate (3 x 200 ml), dried (MgSO 4), and concentrated to give the subtitle compound (1.22 g).

XH-NMR (DMSO-de) d 6.62-6.52 (3H, m), 4.38 (2H, s), 3.41 (4H, s amp.), 2.83 (4H, s amp.), 2.02 (3H, s), 1.41 (9H, s). c) 4- [4- (2- (Tricyclo [3.3.1.13'7] dec-1-yl) acetylamino) -3-methylphenyl-1-piperazine-1-carboxylic acid tert-butyl ester To a solution of adamantan-1-yl-acetic acid (0.40 g) in dichloromethane (10 ml) at 0 ° C is added dimethylformamide (0.1 ml) followed by oxalyl chloride (2.00 ml). The reaction is allowed to warm to room temperature and is stirred for 30 minutes. The volatiles were removed under vacuum and the residue dried under high vacuum. The residue is dissolved in dichloromethane (10 ml) and added to a solution of 4- (4-amino-3-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester (0.60 g, Example 36b) in dichloromethane (10 ml). ml) and triethylamine (0.7 ml) at 0 ° C. The reaction is allowed to warm to room temperature and is stirred for 3 hours. The solution is washed with 2N aqueous hydrochloric acid (20 ml), then with brine (20 ml) and the organic layer is dried over magnesium sulfate then filtered. The filtrate is concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (eluting with 1% methanol in dichloromethane) to give the subtitle compound (0.42 g).

MS (APCI + ve) MW 468 (M + H) + X H NMR (DMSO-d 6) d 8.96 (ΔI, s); 7.14-7.11 (ÍH, d); 6.79-6.72 (2H, m); 3.47-3.40 (4H, m); 3.20-3.00 (4H, m); 2.14 (3H, s); 2.03 (2H, s); 1.94 (3H, s amp.); 1.70-1.56 (12H,); 1.42 (9H, s). d) N- (2-methyl-4-piperazin-1-ylphenyl) -2- (tricyclo [3.3.1.13'7] dec-1-yl) acetamide dihydrochloride salt 4- [4- (2- (Tricyclo [3.3.1.13'7] dec-1-yl) acetylamino) -3-methylphenyl] -piperazine-1-carboxylic acid tert -butyl ester (0.05 g, Example 36c) Dissolve in methanol (2 ml) and add hydrochloric acid (0.5 ml of a 4N solution in dioxane). After stirring at room temperature for 14 h, the mixture is evaporated to 2/3 parts of the original volume under reduced pressure. The diethyl ether was gradually added to the solution and the resulting precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to give the title compound as a solid (0.043 g).

MS (APCI + ve) 368 (M + H) + X H NMR (DMSO-de) d 9.01 (3H, s amp.); 7.18-7.15 (ÍH, d); 6.84-6.82 (ÍH, d); 6.79-6.76 (ÍH, dd); 3.31-3.29 (4H, m); 3.28-3.16 (4H, m); 2.16 (3H, s); 2.04 (2H, s); 1.94 (3H, s amp.); 1.69-1.58 (12H, m).

Example 37 Salt of cis-4- (3-amino-cyclopentyloxy) -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylme) -benzamide hydrochloride a) 2-Chloro-4-hydroxy-N- (tricyclo [3.3.1. l3,7] dec-l-ylmethyl) -benzamide To a solution of 2-chloro-4-hydroxybenzoic acid (3.30 g) in dimethylformamide (20 ml) was added 1,1'-carbonyldiimidazole (3.30 g). The reaction mixture is stirred for 2.5 hours and then the 1-adamantanemethylamine (3.4 ml) is added. After 14 h the reaction mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid and the organic layer is separated, washed with water and then with brine and dried (MgSO4). The organic layer is concentrated under reduced pressure to give a residue which is purified by chromatography on silica gel (eluting with 10-70% ethyl acetate in dichloromethane) to give a white solid which was triturated with ethyl acetate give the subtitle compound as a white solid (3.6 g).

MS (APCI + ve) 320/322 (M + H) + NMR * H (DMSO-de) d 10.12 (H, s), 8.10-8.06 (H, t), 7.27-7.24 (H, d), 6.81. (ÍH, d), 6.77-6.73 (ÍH, dd), 2.91-2.88 (2H, d), 1.93 (3H, s amp.), 1.69-1.56 (6H, c amp.), 1.50 (6H, s amp .). b) Cis-4- (3-amino-cyclopentyloxy) -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt To a solution of 2-chloro-4-hydroxy-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.20 g, Example 37a), the tert-butyl ester of trans- ( 3-hydroxycyclopentyl) -carbamic acid (0.19 g) and tributylphosphine (0.23 ml) in dry tetrahydrofuran (6 ml) is added 1- [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g). The orange solution is heated to 60 ° C under a nitrogen atmosphere for 2 hours. Tert-butyl ester of trans- (3-hydroxycyclopentyl) -carbamic acid (0.19 g), tributylphosphine (0.23 ml) and additional 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) are added. Heating is continued and the procedure described above was repeated until the reaction was judged to be complete as assessed by LC / MS. The cold reaction mixture is diluted with diethyl ether then filtered. The filtrate is concentrated and purified by chromatography on silica gel (25-33% ethyl acetate / hexane) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless foam. The foam is dissolved in methanol (5 ml) and 4N hydrochloric acid in dioxane (0.25 ml) is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LC / MS. Evaporation of the solvent followed by trituration with diethyl ether gave the title compound as a colorless solid (0.24 g).

MS (APCI + ve) 403/405 (M + H) + X H NMR (DMSO-de) d 8.18 (1H, t); 7.96 (2H, s amp.); 7.37-7.34 (ÍH, d); 7.05 (ÍH, m); 6.97-6.94 (ÍH, m); 4.87 (ÍH, m amp.); 3. "72-3.40 (2H, m), 2.93-2.90 (2H, d), 2.04-1.51 (19H, m), 1.22 (2H, m).

Example 38 Salt of 2-chloro-4- (4-piperidinyloxy) -N- (tricyclo [3.3.1. L3,7Jdec-l-ylmethyl) -benzamide hydrochloride To a solution of 2-chloro-4-hydroxy-N- (tricyclo [3.3.1. L3,7] dec-1-ylmethyl) -benzamide) 0.20 g, Example 37a), 1,1-dimethylethyl ester of acid 4-hydroxy-1-piperidinecarboxylic acid (0.19 g) and tributylphosphine (0.25 ml) in dry tetrahydrofuran (6 ml) is added 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g). The orange solution is heated to 50 ° C under a nitrogen atmosphere for 2 hours. The 1,1-dimethylethyl ester of 4-hydroxy-1-piperidinecarboxylic acid (0.19 g), tributylphosphine (0.25 ml) and additional 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g) are added. Heating is continued and the procedure described above was repeated until the reaction complements as judged by LC / MS. The cold reaction mixture is diluted with diethyl ether then filtered. The filtrate is concentrated and purified by chromatography on silica gel (3: 1 isohexane / ethyl acetate) to give the t-butyloxycarbonyl compound (BOC) -protected as a colorless foam. The foam is dissolved in methanol (10 ml) and 4N hydrochloric acid in dioxane (10 ml) is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LC / MS. Evaporation of the solvent followed by trituration with diethyl ether gave the title compound as a colorless solid (0.165 g).

MS (APCI + ve) 403 (M + H) + XR-NMR (DMSO-d6) 8 8.80 (2H, br.s); 8.21-8.16 (ÍH, t); 7.37-7.34 (ÍH, d); 7.16 (ÍH, m); 7.03-6.99 (ÍH, m); 4.80-4.68 (ÍH, m); 3.25-3.18 (2H, m); 3.17-3.01 (2H, m); 2.93-2.90 (2H, d); 2.17-2.02 (2H, m); 1.93 (3H, sa); 1.87-1.73 (2H, m); 1.69-1.57 (6H, AB); 1.51 (6H, s) Example 39 (+/-) -2-Chloro-4- (pyrrolidin-3-yloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared as described in Example 38 from 2-chloro-4-hydroxy-N- (tricyclo [3.3.1.l3,7] dec-1-ylmethyl) -benzamide (0.20 g, Example 37a), ester (+/-) -3-hydroxy-l-pyrrolidinecarboxylic acid 1,1-dimethylethyl (0.18 g), tributylphosphine (0.25 ml), dry tetrahydrofuran (6 ml) and 1 - [[(1-piperidinylcarbonyl) azo] carbonyl ] -piperidine (0.24 g) to obtain the t-butyloxycarbonyl compound (BOC) -protected. This compound was treated with 4N hydrochloric acid in dioxane (10 ml) and methanol (10 ml) to give the title compound as a colorless solid (0.165 g).

MS (APCI + ve) 389 (M + H) + X H NMR (DMSO-de) d 8.19-8.15 (H, t); 7.35-7.32 (ÍH, d); 6.99 (ÍH,); 6.93 -6.90 (ÍH, m); 4.94-4.89 (ÍH, m); 3.24 (ÍH, s); 3.08-3.02 (ÍH, dd); 2.92-2.90 (2H, d); 2.88-2.72 (3H, m); 2.08-1.98 (ÍH, m); 1.93 (3H, s); 1.76-1.57 (7H, m); 1.51 (6H, s).

Example 40 Salt of 2-chloro-4- (piperidin-3-yloxy) -N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide hydrochloride To a solution of 2-chloro-4-hydroxy-N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide (0.20 g, Example 37a), the tert-butyl ester of 3-hydroxy acid -piperidine-1-carboxylic acid (0.189 g) and tributylphosphine (0.23 ml) in dry tetrahydrofuran (6 ml) is added 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g). The orange solution is heated to 60 ° C under a nitrogen atmosphere for 2 hours. They are added tert-butyl ester of 3-hydroxy-piperidin-l-carboxylic acid (0.19 g), tributylphosphine (0.23 ml) and additional 1 - [[(1-piperidinylcarbonyl) azo] carbonyl] -piperidine (0.24 g). Heating is continued and the procedure described above was repeated until the reaction complements as judged by LC / MS. The cooled reaction mixture is diluted with diethyl ether then filtered. The filtrate is concentrated and purified by chromatography on silica gel (25% ethyl acetate: iso-hexane) followed by normal phase CIAR (0-1% ethanol in dichloromethane) to give the t-butyloxycarbonyl compound ( BOC) -protected as a colorless foam. The foam is dissolved in methanol (5 ml) and 4N hydrochloric acid in dioxane (0.25 ml) is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LC / MS. Evaporation of the solvent followed by trituration with diethyl ether gave the title compound as a colorless solid (0.006 g).

MS (APCI + ve) 403/405 (M + H) + XH NMR (DMSO-de) d 8.84 (2H, s amp.), 8.21 (H, t); 7.38 (ÍH, d); 7.18 (1H, d); 7.05 (ÍH, dd); 4.82 (ÍH, s amp.); 3.24 (ÍH, d); 3.20 (ÍH, dd); 3.06 (2H, s amp.); 2.92 (2H, d); 1.94-1.51 (19H, m).

Example 41 Chlorohydrate salt of 2-chloro-4- (4-piperazin-1-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide a) 4-Bromo-2-chloro-N- (tricyclo [3.3.1. l3,7] dec-l-ylmethyl) -benzamide To a suspension of 4-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0 ° C is added oxalyl chloride (3.7 ml) and dimethylformamide (5 drops). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 1 hour, then concentrated under reduced pressure to give a solid. The solid is dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N, N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution is allowed to stir at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture is diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium acid sulfate and saturated brine. The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure to give the subtitle compound as a solid (4.28 g).

MS (APCI + ve) 382/384 (M + H) * NMR XH (DMSO-de) d 8.39-8.34 (H, t); 7.78 (ÍH, m); 7.62-7.59 (ÍH, m); 7.37-7.34 (ÍH, d), 2.94-2.92 (2H, d); 1.94 (3H, s amp.); 1.69-1.57 (6H, AB amp.); 1.52 (6H, s). b) Hydrochloride salt of 2-chloro-4- (4-piperazin-1-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide To a suspension of the 4-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 41a, 0.30 g), piperazine-1, 1-dimethylethyl ester 1-carboxylic acid (0.18 g), cesium carbonate (0.36 g) and (R) -BINAP (0.036 g) in anhydrous toluene (3 ml) is added palladium (II) acetate (0.009 g) and the mixture is heated to 100 ° C for 14 hours in a pressure vessel with rapid flow of nitrogen. The cooled reaction mixture is evaporated under reduced pressure to give an oil which is purified by chromatography on silica gel (2: 1 / isohexane: ethyl acetate) to give the t-butyloxycarbonyl (BOC) -protected compound as a colorless foam. The foam is dissolved in methanol (15 ml) and 4N hydrochloric acid in dioxane (15 ml) is added. The solution is stirred at room temperature under a nitrogen atmosphere until the reaction complements as judged by LC / MS. Evaporation followed by trituration with diethyl ether and methanol afforded the title compound as a colorless white solid / foam (0.161 g).

MS (APCI + ve) 388/390 (M + H) * NMR: H (DMSO-d6) d 8.98 (2H, br.s); 8.11-8.07 (ÍH, t); 7.33-7.31 (ÍH, d); 7.05 (ÍH, m); 6.99-6.95 (ÍH, m); 3.46-3.43 (4H, m); 3.20 (4H, sa); 1.94 (3H, sa); 1.69-1.57 (6H, AB a); 1.51 (6H, sa).

Example 42 Salt of 2-chloro-4- (3-pyrrolidinylamino) -N- (tricyclo [3.3.1.13'7] dec-l-ylmethyl) -benzamide hydrochloride Prepared according to the method described in Example 41b from 4-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.25 g, Example 41a), 3-amino-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester (0.182 g, Journal of Medicinal Chemistry, 1998, 41 (22), 4273-4278), cesium carbonate (0.347 g), (R) - (+) -2, 2'-bis (diphenylphosphino) -1,1'-biphenyl (0.036 g), palladium (II) acetate (0.009 g) and anhydrous toluene (3 ml) ). The residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The product is dissolved in methanol and stirred at room temperature for 3 hours in the presence of a solution of 4N hydrochloric acid in dioxane (2 ml). The solution is concentrated under reduced pressure and triturated with diethyl ether to give the title compound as a white powder (0.057 g).

MS (APCI + ve) 388 (M + H-HC1) + XH NMR (CD3OD) d 7.33 (1H, d); 6.71 (ÍH, d); 6.63 (ÍH, dd); 4.27-4.21 (ÍH, m); 3.57-3.40 (3H, m); 3.23 (ÍH, dd); 3.05 (2H, s); 2.43-2.33 (ÍH,); 2.33-2.01 (ÍH, m); 1.99 (3H, sa); 1.73 (6H, c); 1.62 (6H, d).

Example 43 Salt of 2-chloro-4- (hexahydro-lH-1,4-diazepin-1-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride .HCl Prepared according to the method described in Example 41b from 4-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.25 g, Example 41a ), hexahydro-lH-1,4-diazepine-1-carboxylic acid 1-dimethylethyl ester (0.182 g), cesium carbonate (0.347 g), (R) - (+) -2, 2'-bis (diphenylphosphino) -1,1'-biphenyl (0.036 g), palladium (II) acetate (0.009 g) and anhydrous toluene (3 ml). The residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The product is dissolved in methanol and stirred at room temperature for 3 h in the presence of a solution of 4N hydrochloric acid in dioxane (2 ml). The solution is concentrated under reduced pressure and triturated with diethyl ether to give the title compound as a white powder (0.17 g).

MS (APCI + ve) 402 (M + H-HCD * NMR XH (DMSO-de) d 7.41 (ΔH, d), 6.88 (ΔH, d), 6.81 (ΔH, dd), 3.83 (2H, t); 3.63 (2H, t), 3.40 (2H, t), 3.30 (2H, t), 3.06 (2H, s), 2.24-2.16 (2H, m), 1.99 (3H, sa), 1.74 (6H, c); 1.63 (6H, d).

In accordance with the procedure described in Example 8, the following compounds were prepared: Example 44 Hydrochloride salt of (+) - 5 - [(3-amino-1-piperidinyl) methyl] -2-chloro-N- (tricyclo [3.3.1. L, 7] dec-1-ylmethyl) -benzamide MS (APCI + ve) MW 416/418 (M + H) + X H NMR (DC30D) d 7.70 (SS, br); 7.67 (ÍH, dd); 7.60 (ÍH, d); 4. 49 (ÍH, d); 4.45 (ÍH, d); 3.73-3.58 (2H, m); 3.57-3.45 (ÍH, m); 3.14-2.95 (4H,); 2.25-2.04 (2H,); 1.98 (4H, sa); 1.76 (3H, d); 1.73-1.58 (ÍH, m); 1.63 (6H, sa).

Example 45 Salt of 2-chloro-5- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -N- (tricyclo [3.3.1. L3'7] dec-1-ylmethyl) -benzamide hydrochloride MS (APCI + ve) MW 414/416 (M + H) + XH NMR (CD30D) d 7.74 (ÍH, d); 7.72 (ÍH, dd); 7.60 (ÍH, d) 4.70-4.55 (3H, m); 4.45 (ÍH, d); 4.00 (ÍH, d); 3.73 (1H, d) 3.60-3.50 (2H, m); 3.07 (2H, s); 2.71 (ÍH, d); 2.27 (ÍH, d) 1.98 (3H, sa); 1.77 (3H, d); 1.69 (3H, d); 1.63 (6H, sa).

Example 46 Salt of 2-chloro-5- (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylmethyl) -N- hydrochloride (tricyclo [3.3.1. L3,7] dec-1- ilmetil) -benzamide MS (APCI + ve) 442/446 (M + H) * NMR XH (CD30D) d 7.60-7.40 (3H, m); 4.25-4.00 (2H, m); 3.70-3.40 (2H, m); 3.46 (4H, m); 3.07 (2H, s); 3.15-2.90 (2H, m); 2.80-2.50 (2H, m); 2.00 (3H, sa); 1.78 (3H, d); 1.71 (3H, d); 1.63 (6H, sa).

Example 47 Salt of 2-chloro-5- (3,7-diazabicyclo [3.3.1] non-3-ylmethyl-n- (tricyclo [3.3.1. I37] dec-1-ylmethyl) -benzamide hydrochloride MS (APCI + ve) MW 442/444 (M + H) + 1N NMR (CD3OD) d 7.91 (1H, s); 7.78 (ÍH, d); 7.56 (ÍH, d); 7.46 (ÍH, sa); 4.44 (2H, sa); 3.65-3.28 (8H, m); 3.08 (2H, sa); 2.48 (2H, sa); 2.05-1.90 (5H, m); 1.77 (3H, d); 1.71 (3H, d); 1.64 (6H, sa).

Example 48 Hydrochloride salt of trans-2-chloro-5- [[8- (methylamino) -3-azabicyclo [3.2.1] oct-3-yl] methyl] -N- (tricyclo [3.3.1.13'7] dec -1-ylmethyl) -benzamide MS (APCI + ve) MW 456/458 (M + H) + XH NMR (CD30D) d 7.79 (1H, d); 7.77 (ÍH, dd); 7.58 (ÍH, d); 4. 71 (2H, sa); 3.80 (2H, d); 3.40 (ÍH, t); 3.25 (2H, dd); 3.07 (2H, s); 2.86 (3H, s); 2.70 (2H, sa); 2.10-1.90 (7H, m); 1.77 (3H, d); 1.70 (3H, d); 1.63 (6H, sa).

Example 49 Salt of cis-2-chloro-5- [(hexahydropyrrolo [3,4-c] pyrrole-2 (IH) -yl) methyl] -N- (tricyclo [3.3.1.13'7] hydrochloride] dec-l- ilmetil) -benzamide MS (.APCl + ve) 428/430 (M + H) + 1 E NMR (DMSO-de) d 8.00 (1H, t); 7.65 (ÍH, s); 7.63 (ÍH, d); 7.52 (ÍH, d); 4.34 (2H, sa); 3.60-3.05 (10H, m); 2.97 (2H, d); 1.95 (3H, sa); 1.70 (3H, d); 1.63 (3H, d); 1.57 (6H, s).

Example 50 Salt of 2-chloro-5- (4-piperidinylidenemethyl) N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride a) [[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenyl] -methyl] -phonic acid dimethyl ester The 5-bromomethyl-2-chloro-N- (tricyclo [3.3.1. L3,7] dec-1-ylmethyl) -benzamide (5.70 g, Example 8b) in 100 ml of trimethylphosphite is refluxed for 15 hours. The solvent is removed by azeotropic distillation with toluene under high vacuum to give the subtitle compound as a yellow solid.

MS (APCI + ve) 426/428 (M + H) * NMR: H (DMSO-de) d 8.34 (1H, t); 7.42 (ÍH, d); 7.35-7.27 (2H, m); 3.63 (3H, s); 3.58 (3H, s); 3.42 (2H, d); 2.92 (2H, d); 1.94 (3H, sa); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, sa). »• b) 4- [[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenyl] -methylene] -1-dimethylethyl ester -piperidinecarboxylic To a solution of [[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] -phenyl] ethyl] phosphonic acid dimethyl ester (2.50 g, Example 50a) in tetrahydrofuran (50 ml) at -78 ° C a solution of the lithium diisopropylamide (7.30 ml, 2M in tetrahydrofuran) is added. The reaction is allowed to warm to room temperature and is stirred for 15 minutes. The N-t-butoxycarbonylpiperidin-4-one (1.52 g) in tetrahydrofuran (5 ml) is then added and the mixture is stirred for 24 hours. The reaction is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine and dried over magnesium sulfate. The crude material is purified on silica gel (0 to 5% methanol in dichloromethane) to give the subtitle compound as a white foam.

MS (APCI + ve) MW 443/445 (M + H) * X H NMR (DMSO-de) d 7.52 (1H, d); 7.34 (ÍH, d); 7.16 (ÍH, dd); 6.30 (ÍH, s); 6.25 (t, ÍH); 3.48 (2H, t); 3.40 (2H, t); 3.40 (2H, t); 3.18 (2H, d); 2.42 (t, 2H); 2.32 (t, 2H); 2.05 (3H, sa); 1.73 (3H, d); 1.64 (d, 3H); 1.59 (6H, s); 1.47 (9H, sa). c) Chlorohydrate salt of 2-chloro-5- (4-piperidinylidenemethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide A solution of acid 1, 1-dimethylethyl ester 4- [[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] -carbonyl] phenyl] -methylene] -1-piperidinecarboxylic acid (0.10 g, Example 50b) in methanol (3 ml) is treated with a 4N solution of hydrochloric acid in dioxane (1 ml) and stirred for 14 h at room temperature. The reaction mixture is concentrated under vacuum and the residue is recrystallized from isopropanol / ether to give the title compound as a white solid (0.071 g).

MS (APCI + ve) MW 399/401 (M + H) * NMR: H (DMS0-d6) d 7.52 (1H, d); 7.34 (ÍH, d); 7.16 (ÍH, dd); 6.30 (ÍH, s); 6.25 (t, ÍH); 3.48 (2H, t); 3.40 (2H, t); 3.40 (2H, t); 3.18 (2H, d); 2.42 (t, 2H); 2.32 (t, 2H); 2.05 (3H, sa); 1.73 (3H, d); 1.64 (d, 3H); 1.59 (6H, s); 1.47 (9H, sa).

Example 51 2-chloro-5- (4-piperidinylmethyl) -N- (tricyclo [3.3.1.13'7] dec-l-ylmethyl) -benzamide hydrochloride salt To a solution of the hydrochloride salt of 2-chloro-5- (4-piperidinylidenemethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.10 g, Example 50c) in ethanol (10 ml) is added platinum oxide (2 mg). The vessel is placed under 3 bars of hydrogen pressure for 3 hours. The catalyst is removed by filtration through a pad of celite, washed with ethanol and the solution is concentrated under vacuum. The crude material is recrystallized from iso-propanol to give a white solid. The protected t-butoxycarbonyl compound is dissolved in methanol (10 ml) and treated with a solution of 4N HCl in dioxane (2 ml). The reaction is stirred for 14 hours at room temperature, the volatiles are removed under vacuum and the residue is recrystallized from isopropanol / ether to give the hydrochloride salt as a white powder (0.065 g).

MS (APCI + ve) MW 402/404 (M + H) + X H NMR (CD3OD) d 8.38 (ΔI, t); 7.38 (ÍH, d); 7.30-7.20 (2H, m); 3. 35 (2H, d); 3.05 (2H, d); 2.92 (2H, td); 2.63 (2H, d); 1.98 (3H, sa); 1.95-1.80 (ÍH, m); 1.85 (2H, d); 1.77 (3H, d); 1.68 (3H, d), 1.62 (6H, s); 1.40 (2H, c).

Example 52 2-Chloro-5- (4-hydroxy-piperidin-4-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt To a solution of the 5-bromo-2-chloro-N- (tricyclo [3.3.1.1.17'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 23a) in anhydrous tetrahydrofuran (10 ml) ) at -78 ° C a solution of n-butyllithium in hexanes (2.5 M, 0.72 ml) is added dropwise. After 10 minutes, a solution of t-butyloxycarbonyl-4-piperidone (0.21 g) in tetrahydrofuran (2 ml) is added. The solution is stirred an additional 20 minutes, then treated with a saturated aqueous ammonium chloride solution. The mixture is allowed to warm to room temperature then partitioned between ethyl acetate and a saturated aqueous ammonium chloride solution. The organic extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica (ethyl acetate: isohexane / gradient 1: 4 to 1: 2) to give the protected t-butoxycarbonyl product (0.153 g). This was dissolved in methanol (4 ml) and treated for 14 hours with 4N HCl in dioxane (1 ml). The solution is partially concentrated in vacuo and the product is precipitated with diethyl ether. The solution is filtered and the white solid is washed with diethyl ether to give the title compound (0.091 g).

MS (APCI + ve) MW 403 (M + H) * NMR: H (CD3OD) d 8.43 (MH, m amp.); 7.59 (ÍH, m); 7.55 (ÍH, d); 7. 49 (lHm d); 3.52-3.30 (4H, m); 3.09 (2H, d); 2.23 (2H, m); 2. 04-1.88 (5H, m); 1.95-1.80 (ÍH, m); 1.84-1.66 (6H,); 1.65 (6H, d).

Example 53 Salt of 2-chloro-5- (1,2,3,6-tetrahydro-pyridin-4-yl) -N- (tricyclo [3.3.1. L3'7] dec-l-ylmethyl) -benzamide hydrochloride A solution of the hydrochloride salt of 2-chloro-5- (4-hydroxy-piperidin-4-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.25 g, Example 52) in concentrated hydrochloric acid (10 ml) is heated at 100 ° C for 5 hours. The solution is allowed to cool slowly. Colorless crystals are separated. These were removed by filtration, washed with diethyl ether then with acetonitrile and dried to give the title compound (0.031 g).

MS (APCI + ve) MW 385 (M + H) * NMR XH (CD3OD) d 8.44 (ΔI, m, amp.); 7.55-7.45 (3H, m); 6.23 (ÍH, m); 3.85 (2H, m); 3.47 (2H, t); 3.07 (2H, d); 2.79 (2H, m); 1.98 (3H, m); 1.77 (3H, m); 1.69 (3H, m); 1.63 (6H, s amp.).

Example 54 2-ethyl-5-piperazin-l-ylmethyl-N- (tricyclo [3.3.1.13'7] dec-l-ylmethyl) -benzamide hydrochloride salt 2-Bromo-5- (4- [. {1,1-dimethylethyloxycarbonyl] -piperazin-1-yl) methyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (example 65b, 0.89 g) is dissolved in dry tetrahydrofuran. Sodium hydride (60% dispersion, 0.07 g) is added and the mixture is stirred at room temperature for 5 minutes. The mixture is cooled to -70 ° C under a nitrogen atmosphere and t-butyllithium (1.9 ml, 1.7 M solution) is added. After 5 minutes, ethyl iodide (0.5 ml) is added and the mixture is stirred at -70 ° C for 30 minutes. The aqueous ammonium chloride solution was added and the product was extracted with diethyl ether, dried (MgSOj) and concentrated in vacuo. Chromatography on silica gave the t-butyloxycarbonyl compound (BOC) -protected as a foam. This is redissolved in methanol (5 ml) and 4N HCl in dioxane is added. (1 ml). The mixture is stirred at room temperature for 14 h. The solution is partially concentrated under vacuum and the product is precipitated with diethyl ether. The resulting solid is filtered and washed with ether to give the title compound as a white powder (0.040 g).

X H NMR (DMSO) d 9.59 (2H, s, amp.); 8.15 (ÍH, t); 7.58 (2H, s, amp.); 7.35 (ÍH, d), 4.37 (2H; s, amp.); 3.49 (m); 3.25 (2H, m, amp.); 2.95 (2H, d); 2.72 (2H, c); 1.94 (3H, s, amp.); 1.69-1.59 (6H, m); 1.52 (6H, s); 1165 (3H, t).

Example 55 Salt of 2-chloro-5- (piperidin-4-ylsulfanyl) N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide hydrochloride a) 4- (Toluene-4-sulfonylsulfanyl) -piperidine-1-carboxylic acid tert-butyl ester The tert-butyl ester of 4-iodo-piperidine-1-carboxylic acid (1.3 g) and potassium toluene-4-thiosulfonate (1.0 g) were combined in ethanol (10 ml) with cis-dicyclohexane 18-crown-6 ( 10 mg) and heated under reflux for 12 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and water, the organic layer separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluting with iso-hexane / ethyl acetate 4: 1 to 7: 3), to give the subtitle compound as an oil (0.65 g).

MS (APCI + ve) 315 (M + H-tBu) + XH NMR (CDC13) d 7.80-7.85 (2H, m), 7.30-7.40 (2H, m), 3.95-4.10 (H, m), 3.75- 3.85 (lH, 'm), 3.40-3.50 (1 / 2H, m), 3.10- 3.20 (1 / 2H, m), 2.95-3.05 (HH, m), 2.80-2.90 (HH, m), 2.64 ( 3H, s), 1.90-2.10 (2H, m), 1.50-1.70 (2H, m), 1.43 and 1.45 (9H, s pair). b) 2-Chloro-5- (4- [ { 1, 1-dimethylethyl} oxycarbonyl-Jpiperidin-4-ylsulfanyl) -N- (tricyclo [3.3.1.13'7-Jdec-1-ylmethyl) -benzamide) To a solution of 5-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 23a) in anhydrous tetrahydrofuran (10 ml) at -78 ° C a solution of n-butyllithium in hexanes (2.5 M, 0.72 ml) is added dropwise. After 10 minutes a solution of the 4- (toluene-4-sulfonyl-sulfanyl) -piperidine-1-carboxylic acid tert-butyl ester (0.38 g, Example 55a) in tetrahydrofuran (7 ml) is added. After an additional 1 hour at -78 ° C the reaction mixture is warmed to room temperature and the temperature is reduced by the addition of [72]. water (5 ml). The reaction mixture is diluted with ethyl acetate and washed twice with saturated aqueous sodium carbonate solution, then with brine and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure to give a residue which is purified by chromatography on silica gel (eluting with 0-5% ethanol in dichloromethane) to give the subtitle compound (0.20 g).

EM (APCI + ve) 419/21 (M + H-BOC) * c) Hydrochloride salt of 2-chloro-5- (piperidin-4-ylsulfanyl) -N- (tricyclo [3.3.1.13'7Jdec-1-ylmethyl) -benzamide) 2-Chloro-5- (4- [. {1,1-dimethylethyl} oxycarbonyl] -piperidin-4-ylsulfanyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) - Benzamide (0.20 g, Example 55b) is dissolved in methanol (15 ml) and the hydrochloric acid (1.0 ml of a 4N solution in dioxane) is added. After stirring at room temperature for 14 hours, the reaction mixture is basified with a saturated sodium hydrogen carbonate solution and extracted twice with dichloromethane. The organic layer is concentrated under reduced pressure to give a residue which is purified by chromatography on silica gel (eluting with 0-100% methanol in dichloromethane).

The residue is dissolved in dichloromethane (5 ml) and hydrochloric acid (IN in diethyl ether, 2 ml) is added. Evaporation to dryness gave the title compound as the hydrochloride salt (0.050 g).

MS (APCI + ve) 419/21 (M + H) * NMR XH (DMSO-de) d 8.75 (2H, d amp.), 8.38 (H, t), 7.48 (2H, s), 7.37 (H, s), 3.50-3.60 (ÍH, m), 3.30 (2H, d amp.), 2.92-3.05 (4H, m), 2.06 (2H, d amp.), 1.94 (3H, s), 1.57-1.75 ( 8H, m), 1.52 (6H, s).

Example 56 2-chloro-5- (piperidin-4-ylsulfinyl) -N- (tricyclo [3.3.1.13'7Jdec-1-ylmethyl) -benzamide) The m-chloroperoxybenzoic acid (166 mg) is added to a solution of 2-chloro-5- (piperidin-4-ylsulfanyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide ( 0.35 g, Example 55c) in dichloromethane (5 ml). After 2 hours calcium hydroxide (0.20 g) was added and 30 minutes later the salts were removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which is purified by chromatography on silica gel (eluting with 0-25% ethanol in dichloromethane). The residue is dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) is added. After stirring at room temperature for 14 hours, the solution is concentrated under reduced pressure and triturated with diethyl ether to give the title compound as the hydrochloride salt (0.030 g).

MS (APCI + ve) 435/37 (M + H) + X H NMR (DMSO-de) d 8.88 (ΔH, s amp.), 8.47 (2H, t amp.), 7.76 (ΔH, d), 7.67 ( ÍH, dd), 7.61 (ÍH, d), 3.30-3.40 (2H, m), 3.13 (ÍH, t), 2.98 (2H, d), 2.80-2.90 (2H,), 2.15 (ÍH, d), 1.95 (3H, m), 1.50-1.85 (15H, m).

Example 57 2-chloro-5- (piperidin-4-ylsulfonyl) N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt The m-chloroperoxybenzoic acid (0.30 g) was added to a solution of 2-chloro-5- (piperidin-4-ylsulfinyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.30 g) in dichloromethane (10 ml). After 2 hours calcium hydroxide (170 mg) is added and 30 minutes later the salts are removed by filtration. The filtrate is concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel (eluting with 0-2% ethanol in dichloromethane). The residue is dissolved in methanol (5 ml) and hydrochloric acid (0.25 ml of a 4N solution in dioxane) is added. After stirring at room temperature for 14 hours, the solution was [76 concentrate under reduced pressure and triturate with diethyl ether to give the title compound (0.03 g).

MS (APCI + ve) 451/53 (M + H) + XH-NMR (DMSO-de) d 8.89 (OH, SA), 8.57 (OH, T), 8.50 (OH, SA), 7.87 (2H, ABC) , 7.75 (ÍH, d), 3.71 (ÍH, d), 3.40 (2H, d), 3.00 (2H, d), 2.80-2.90 (2H, m), 1.95-2.05 (5H, m), 1.50-1.90 (14H, m).

Example 58 2-Chloro-5- (piperidin-4-ylmethylsulinyl) -N- (tricyclo [3.3.1. L3'7] dec-l-ylme) -benzamide hydrochloride salt a) 2-Chloro-5- (4- [ { 1, 1-dimethylethyl} oxycarbonyl] piperidin-4-ylmethylsulfanyl) -N- (tricyclo [3.3.1. 13'7] dec-1-ylmethyl) ) -benzamide The trifluoroacetic acid anhydride (2 ml) is added to a solution of 2-chloro-5-methylsulfinyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.53 g, Example 58a, WO 99/29661) in dichloromethane (10 ml) and heated under reflux for 1.5 hours, cooled and concentrated. The resulting residue is dissolved in methanol (30 ml), allowed to stand for 1 hour, then concentrated. The resulting residue is dissolved in acetone (10 ml) and potassium carbonate (0.60 g) and tert-butyl ester of 4-iodomethyl-piperidine-l-carboxylic acid (0.94 g) are added. The reaction mixture is heated under reflux for 3 hours, cooled and concentrated. The resulting residue is dissolved in ethyl acetate, washed twice with a 10% w / w KHS0 solution, twice with a saturated sodium hydrogen carbonate solution, once with brine and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel (eluting with 0-2% ethanol in dichloromethane) to give the subtitle compound (0.46 g).

MS (APCI + ve) 433/35 (M + H-BOC) * XH NMR (DMSO-de) d 7.61 (ΔH, d), 7.25-7.31 (2H, m), 6.27 (ΔI, ta), 4.09 ( 2H, da), 3.17 (2H, d), 2.86 (2H, d), 2.66 (2H, t), 2.01 (3H, s), 1.60-1.90 (15H, m), 1.45 (9H, s), 1.18 (2H, dc). b) Hydrochloride salt of 2-chloro-5- (piperidin-4-ylmethylsulfanyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Hydrochloric acid (4N in dioxane, 0.5 ml) is added to a solution of 2-chloro-5- (4- [. {1,1-dimethylethyl loxycarbonyl] piperidin-4-ylmethylsulfanyl) -N- (tricyclo [3.3 1.1.17] dec-1-ylmethyl) -benzamide (0.235 g, Example 58a) in methanol (10 ml). After 24 h the reaction mixture is concentrated, then triturated with ether to give the title compound (0.20 g).

MS (APCI + ve) 433/35 (M + H) * NMR XH (DMSO-de) d 8.76 (OH, SA), 8.48 (OH, SA), 8.35 (OH, T), 7.40 (2H, ABC) , 7.28 (ÍH, d), 3.24 (2H, d), 3.00 (2H, d), 2.92 (2H, d), 2.84 (2H, c), 1.94 (5H, sa), 1.75-1.82 (ÍH, m ), 1.65 (6H, c), 1.52 (6H, s), 1.40 (2H, c).

Example 59 2-chloro-5- (piperidin-4-ylmethanesulfonyl) -N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide hydrochloride salt M-chloroperoxybenzoic acid (0.19 g) is added to a solution of 2-chloro-5- (4- [. {1, 1-dimethylethyl} oxycarbonyl} piperidin-4-ylmethylsulfanyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.165 g, Example 58a) in chloroform (10 ml). After 5 hours calcium hydroxide (120 mg) is added and 30 minutes later the salts are removed by filtration. The reaction mixture is concentrated, then dissolved in methanol (10 ml) and hydrochloric acid (1.0 ml of a 4N solution in dioxane) is added. After stirring at room temperature for 14 hours, concentration under reduced pressure afforded the title compound (0.075 g).

MS (APCI + ve) 465/67 (M + H) + H-NMR (DMSO-de) d 8.70 (OH, SA), 8.55 (OH, T), 8.48 (OH, SA), 7.95 (OH, DD) , 7.88 (HH, d), 7.82 (HH, d), 3.47 (2H, d), 3.21 (2H, d), 2.97 (2H, d); 2.89 (2H, d), 2.10-2.25 (HH,), 1.95 (5H, sa), 1.40-1.80 (14H, m).

Example 60 Salt of 2-chloro-5- (piperazine-1-carbonyl) N- (tricyclo [3.3.1. L3,7] dec-l-ylmethyl) -benzamide hydrochloride a) 4-chloro-N- (tricyclo [3.3.1.13,7] dec-l-ylmethyl) -isophthalic acid N-Butyllithium (3 mL, 2M hexanes) is added at -78 ° C to a solution of 5-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) - Benzamide (1.0 g, Example 23a) in tetrahydrofuran (20 ml). After 10 minutes, the reaction mixture is decanted over dry solid carbon dioxide and allowed to warm to room temperature. The reaction mixture is acidified with concentrated hydrochloric acid and extracted with ether. The organic substances are separated, dried over magnesium sulfate and concentrated under reduced pressure to give a residue which is purified by chromatography on silica gel (eluting with iso-hexane / ethyl acetate 3: 1 to 1: 1 + 1% AcOH, to give the subtitle compound as a solid (0.45 g).

MS (APCI + ve) 348/350 (M + H) * NMR XH (DMSO-de) d 13.33 (H, s), 8.44 (H, t), 7.94 (H, d,), 7.87 (H, d) , 7.63 (ÍH, d), 2.95 (2H, d), 1.95 (3H, s), 1.63 (6H, c), 1.53 (6H, s). b) Salt of 2-chloro-5- (piperazin-1-carbonyl) -N- (tricyclo [3.3.1. l3,7] dec-l-ylmethyl) -benzamide hydrochloride The ethyldiisopropylamine (0.3 ml) is added at room temperature to a solution of 4-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -isophthalic acid (0.15 g, Example 60a), the tert-butyl ester of piperazine-1-carboxylic acid (0.16 g) and PyBrOP (0.40 g) in N-methylpyrrolidinone (10 ml). After 5 hours the reaction mixture is diluted with ethyl acetate and washed twice with water, twice with a 10% KHS04 solution, twice with a saturated NaHCO3 solution and once with brine, then Dry over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (eluting with ethanol (0-5%) in dichloromethane), then redissolved in methanol (10 ml) and treated with hydrochloric acid (4N dioxane, 1 ml). After 48 hours the reaction mixture is concentrated under reduced pressure and recrystallized from iso-hexane / propan-2-ol to give the title compound as a solid (0.10 g).

MS (APCI + ve) 416/18 (M + H) * NMR XH (DMSO-de) d 9.18 (H, t), 8.42 (H, t), 7.59 (H, d), 7.47-7.52 (2H, m), 3.50-3.90 (4H, sa), 3.05-3.25 (4H, sa), 2.94 (2H, d), 1.95 (3H, s), 1.63 (6H, c), 1.52 (6H, s).

The following examples were made in an analogous way: Example 61 Salt of 2-chloro-5- ([1,4] diazepane-carbonyl) -N- (tricyclo [3.3.1.13'7] dec-1-methylmethyl) -benzamide hydrochloride MS (APCI + ve) 430/432 (M + H) * H NMR (DMSO-de) d 9.10 (2H, sa), 8.06 (H, S), 7.53 (H, D), 7.45-7.48 (2H, m), 3.78 (2H, sa), 3.54 (2H, sa), 3.20-3.25 (4H, m), 2.97 (2H, d), 2.00 (2H, m), 1.95 (3H, s), 1.65 (6H , c), 1.55 (6H, s).

Example 62 Hydrochloride salt of 4-chloro-N-l- (piperidin-4-yl) -N2- (tricyclo [3.3.1.13'7] dec-l-ylmethyl) -isophthalamide MS (APCI + ve) 435/37 (M + H) + XH NMR (DMSO-de) d 8.66-8.76 (3H, m), 8.42 (H, t), 7.89-7.93 (2H, m), 7.60 (HH, d), 4.01-4.09 (HH, m), 3.29 (2H, d), 2.95-3.05 (4H, m), 1.95 (5H, sa), 1.47-1.82 (14H , m).

Example 63 2-Chloro-5- (hydroxy-4-piperidinylmethyl) -N- (tricyclo [3.3.1. 13'7] dec-1-ylmethyl) -benzamide hydrochloride salt a) 2-Chloro-5- [4- [[. { 1,1-dimethylethyl} oxycarbonyl] -piperidinyl] -hydroxymethyl] -N- (tricyclo [3.3.1. I3,7] dec-1-ylmethyl) -benzamide To a solution of the 5-bromo-2-chloro-N- (tricyclo [3.3.1.l3,7] dec-1-ylmethyl) -benzamide (1.5 g, Example 23a) in anhydrous tetrahydrofuran (50 ml) under a nitrogen atmosphere at -78 ° C a solution of n-butyllithium (2.5 M in hexanes) is added dropwise3.4 ml). The mixture is stirred for 10 minutes at -78 ° C, then a solution of 4-formyl-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (1.09 g, Journal of Medicinal Chemistry, 1999, 42 (12) is added dropwise. ), 2180-2190) in anhydrous tetrahydrofuran (10 ml). The reaction mixture is stirred at -78 ° C for 30 minutes, then the temperature is reduced with a saturated aqueous ammonium chloride solution (100 ml). The product is extracted twice with ethyl acetate (2x100 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel eluting with iso-hexane: ethyl acetate / (2: 1) then (1: 2), then further purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the subtitled compound as a white foam (0.61 g).

MS (APCI + ve) 517 (M + H) + X H NMR (DMSO-de) d 8.28 (H, t); 7.40 (1H, d); 7.33-7.27 (2H,); 5.33 (ÍH, d); 4.34 (ÍH, t); 3.93 (3H, sa); 2.93 (2H, d); 2. 61 (2H, sa); 1.94 (3H, sa); 1.63 (6H, c); 1.53 (6H, d); 1.37 (9H, s); 1.34-1.23 (2H, m); 1.09 (2H, dt). b) Hydrochloride salt of 2-chloro-5- (hydroxy-4-piperidinylmethyl) -N- (tricyclo [3.3.1. l3,7] dec-l-ylmethyl) -benzamide A solution of 2-chloro-5- [4- [[. { 1, 1-dimethylethyl loxycarbonyl] piperidinyl] -hydroxymethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.10 g, Example 63a) in methanol (3 ml) is treated with a solution of 4N hydrochloric acid in dioxane (1 ml). After 14 hours the solvents are removed under reduced pressure and the residue is triturated with diethyl ether to give the title compound as a white powder (0.062 g).

MS (APCI + ve) 417 (M + H-HCl) * WW lE (DMSO-de) d 8.70 (H, SA); 8.29 (2H, ta); 7.44 (ÍH, d); 7.33 (2H, dt); 5.53 (ÍH, d); 4.40 (ÍH, t); 3.23 (2H, sa); 2.93 (2H, da); 2.76 (2H, da); 1.94 (3H, sa); 1.77-1.36 (ÍH, m); 1.53 (6H, s).

Example 64 Hydrochloride salt of (+) -2-chloro-5- (hydroxy-3-piperidinylmethyl) -N- (tricyclo [3.3.1.13'7Jdec-1-ylmethyl) -benzamide Prepared by a route analogous to Example 63 using 3-formyl-1-piperidinecarboxylic acid 1-dimethylethyl ester.

MS (APCI + ve) MW 417/419 (M + H) + XH NMR (CD30D) d 8.41 (ÍH, t); 7.46 (ÍH, d); 7.41 (ÍH, d); 7.39 (ÍH, s); 4.65 (0.5H, d); 4.50 (0.5H, d); 3.74 (0.5H, td); 3.66 (ÍH, c); 3.57 (0.5H, t); 3.44 (0.5H, da); 3.18 (0.5H, da); 3.06 (2H, d); 2.86 (2H, cd); 2.10-1.87 (m, 2H); 1.98 (3H, sa); 1.77 (3H, d); 1.68 (3H, da); 1.63 (6H, s), 1.60-1.50 (m, ÍH); 1.50- 1.36 (m, ÍH).

Example 65 Hydrochloride salt of 2-bromo-5-piperazin-l-ylmethyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide a) 2-Bromo-5-bromomethyl-N- (tricyclo [3.3.1. l3,7] dec-l-ylmethyl) -benzamide To a solution of 2-bromo-5-bromomethyl-benzoic acid (6.1 g) in dichloromethane (100 ml) at 0 ° C is added dimethylformamide (0.2 ml) followed by oxalyl chloride (3 ml). The reaction is stirred at room temperature for 0.5 hour and concentrated under vacuum. The acyl chloride is redissolved in dichloromethane (100 ml) and diisopropylethylamine (6 ml) is added followed by adamantanmethylamine (3.5 ml) at 0 ° C. The mixture is stirred at 0 ° C for 10 minutes, then partitioned between diethyl ether and 1 N aqueous hydrochloric acid. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by recrystallization from dichloromethane / ethyl acetate / i-hexane to give the title compound as a white solid (6.5 g) (the sample contained some of the corresponding benzyl chloride). b) 2-Bromo-5- (4- [ { 1, 1-dimethylethyl.}. oxycarbonyl] -piperazin-1-yl) -N- (tricyclo [3.3.1.13,7] dec-l-ylmethyl) -benzamide A mixture of 2-bromo-5-bromomethyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 65a, 5.0 g), 1-tert-butyloxycarbonylpiperazine (2.3 g), potassium carbonate (3.2 g), potassium iodide (0.30 g) and acetone (75 ml) is refluxed in the dark for 14 hours. The mixture is concentrated in vacuo, partitioned between ethyl acetate and water, then washed with brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo. Recrystallization from ethyl acetate: isohexane gave the subtitle compound as a colorless solid (4.7 g).

MS (APCI + ve) pm 546 (M + H) * c) Hydrochloride salt of 2-bromo-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1. 13'7] dec-1- ilmetil) -benzamide 2-Bromo-5- (4- [. {1,1-dimethylethylloxycarbonyl] -piperazin-1-yl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 65b, 0.40 g) is dissolved in methanol (15 ml), and 4N HCl in dioxane (3 ml) is added. The mixture is stirred at room temperature for 14 hours. The solvent is removed under vacuum and the resulting solid is triturated with ether to give the title compound as a white powder (0.23 g).

MS (APCI + ve) MW 447 (M + H) * NMR XH (DMSO-de) d 9.53 (1H, s, amp.); 8.31 (ÍH, t); 7.72 (ÍH, d); 7.60 (ÍH, m); 4.33 (ÍH, m); 3.50-3.00 (4H, m); 3.50-3.40 (ÍH,); 2.94 (2H, d); 1.94 (3H, sa); 1.71-1.58 (6H, m); 1.54 (6H, sa).

Example 66 2-chloro-5- [2- (l-piperazinyl) ethylj N- (tricyclo [3.3.l.l3,7] dec-l-ylmethyl) -benzamide hydrochloride salt A) 2-Chloro-5- (2-hydroxyethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide A solution of the 5-bromo-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (3.0 g, Example 23a) in anhydrous tetrahydrofuran (100 ml) is cooled to -78. ° C under a nitrogen atmosphere. A solution of methyl lithium (1.4M in diethyl ether, 4.9 ml) was added over 2 minutes. The mixture is stirred at -78 ° C for 10 minutes, then a solution of tert-butyllithium (1.7 M in pentane, 9.3 ml) is added dropwise. The mixture is stirred at -78 ° C for an additional 10 minutes, then the ethylene oxide (1.0 ml) is added. The resulting solution is stirred at -78 ° C for 30 minutes, then warmed to 0 ° C and stirred for another 6 h. The temperature is reduced to the reaction mixture with a saturated aqueous ammonium chloride solution (70 ml) and extracted with ethyl acetate (3 × 100 ml). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel eluting with dichloromethane: ethanol (98: 2) to give the title compound as a faint yellow solid (0.89 g).

MS (APCI + ve) 348 (M + H) * NMR XH (DMSO-d6) d 8.27 (H, t), 7.36 (H, d); 7.28-7.23 (2H, m); 4.65 (ÍH, t); 3.60 (2H, c); 2.92 (2H, d); 2.73 (2H, t); 1. 94 (3H, sa); 1.63 (6H, c); 1.52 (6H, d). b) 2-Chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1. l3'7] dec-l-ylmethyl) -benzamide To a solution of 2-chloro-5- (2-hydroxyethyl) -N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide (1.07 g, Example 66a) in anhydrous dichloromethane (20 ml) is added the Dess-Martin periodinane reagent (1.95 g) and the mixture is stirred at room temperature for 1 hour. Sodium thiosulfate (3.43 g) is dissolved in an aqueous sodium bicarbonate solution (28 ml) and added to the reaction mixture. Then diethyl ether is added and the mixture is stirred for 10 minutes. The layers are partitioned and the organic layer is washed with water then with brine. The organic extracts are then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the subtitle compound as a white solid (1.06 g).

MS (APCI + ve) 346 (M + H) + X H NMR (DMSO-de) d 9.69 (1H, s); 8.32 (ÍH, t); 7.45 (ÍH, d); 7.30-7.24 (2H, m); 3.84 (2H, s); 2.92 (2H, d); 1.94 (3H, sa); 1.63 (6H, c); 1.52 (6H, d). c) 2-Chloro-5- [2- (1-piperazinyl) ethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt To a solution of 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.101 g, Example 66b) in anhydrous 1,2-dichloroethane (5 ml) is added 1-piperazinecarboxylic acid 1, 1-dimethylethyl ester (0.108 g) then sodium triacetoxyborohydride (0.086 g).

The reaction mixture is stirred for 14 hours at room temperature. Water (10 ml) and dichloromethane (10 ml) are added and the layers are partitioned. The organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then by chromatography on silica gel eluting with ethyl acetate. The white powder obtained was dissolved in methanol (5 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture is stirred for 14 hours at room temperature. The solvents were then removed under reduced pressure and the product obtained is triturated with diethyl ether to give the title compound as a white powder (0.047 g).

MS (APCI + ve) 416 (M + H) + XH NMR (CD3OD) d 8.42 (ΔI, t); 7.46 (ÍH, d); 7.41-7.38 (2H,); 3.63-3.49 (8H,); 3.48-3.45 (2H, m); 3.19-3.14 (2H, m); 3.06 (2H, s), 1.99 (3H, sa); 1.73 (6H, c); 1.63 (6H, d).

Example 67 2-chloro-5- [2- (2,5-diazabicyclo [2.2.1] hept-2-yl) ethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl hydrochloride salt ) -benzamide Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), 1,1-dimethylethyl ester of 2,5-diazabicyclo [2.2. l] heptan-2-carboxylic acid (0.108 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After the working procedure, the residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture is stirred for 14 hours at room temperature. The solvents were then removed under reduced pressure and the obtained product was triturated with diethyl ether to give the title compound as a white powder (0.067 g).

MS (APCI + ve) 428 (M + H) * NMR XH (CD3OD) d 7.49-7.40 (3H, m); 4.64 (2H, d); 3.92 (2H, d); 3.77-3.48 (4H, m); 3.18 (2H, t); 3.08 (2H, s); 2.61 (ÍH, da); 2.28 (ÍH, da), 2.00 (3H, sa); 1.75 (6H, c); 1.64 (6H, d).

Example 68 - [2- (4-Amino-l-piperidinyl) ethyl J-2-chloro-N- (tricyclo [3.3.1.13,7] dec-l-ylmethyl) -benzamide hydrochloride salt Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), 1,4-piperidinylcarbamic acid 1,1-dimethyl ethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g), and 1,2-dichloroethane (2 ml). After the working procedure, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. The solvents were then removed under reduced pressure q and the product obtained was triturated with diethyl ether to give the title compound as a white powder (0.065 g).

MS (APCI + ve) 430 (M + H) + XH NMR (CD3OD) d 8.43 (1H, t); 7.49-7.38 (3H, m); 3.78 (2H, da); 3.64-3.42 (2H, m); 3.41-3.35 (2H, m); 3.23-3.14 (3H, m); 3. 08 (2H, s); 2.33-2.29 (2H,); 2.13-2.04 (2H, m); 2.00 (3H, sa); 1.75 (6H, c); 1.64 (6H, d).

Example 69 Salt of 2-chloro-5- [2- (3-piperidinylamino) ethyl] -N- (tricyclo [3.3.1. L, 7] dec-l-ylmethyl) -benzamide dihydrochloride Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), 1-l-dimethylethyl ester of 3-amino-1-piperidinecarboxylic acid (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After the working procedure, the residue is purified by CIAR eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained is dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) is added. The mixture is stirred for 14 hours at room temperature. The solvents were then removed under reduced pressure and the product obtained is triturated with diethyl ether to give the title compound as a white powder (0.065 g).

MS (APCI + ve) 430 (M + H) * NMR XH (CD3OD) d 7.49-7.46 (1H, 'm); 7.42-7.38 (2H, m); 3.76 (ÍH, da), 3.64-3.54 (ÍH, m); 3.44-3.34 (3H, m); 3.19-2.98 (4H, m); 3.08 (2H, s); 2.34 (ÍH, da); 2.18-2.12 (ÍH, m); 2.00 (3H, sa); 1.89-1.78 (2H, m); 1 ^ 74 (6H, c); 1.64 (6H, d).

Example 70 Hydrochloride salt of 5- [2- (3-amino-1-piperidinyl) ethyl] 2-chloro-N- (tricyclo [3.3.1.13'7] des-1-ylmethyl) -benzamide Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13, J dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), 3-piperidinyl-carbamic acid 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After the working procedure, the residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then by HPLC eluting with a gradient of 0-2% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture is stirred for 14 hours at room temperature. The solvents were then removed under reduced pressure and the product obtained is triturated with diethyl ether to give the title compound as a white powder (0.032 g).

MS (APCI + ve) 430 (M + H) + XH NMR (DC3OD) d 7.49-7.46 (HH, m); 7.42-7.39 (2H, m); 3.80-3.67 (3H, m); 3.46 (2H, t); 3.19 (2H, s); 3.08 (2H, s); 3.09-3.04 (ÍH, m); 2.14 (ÍH, ta); 2.00 (3H, sa); 1.74 (6H, c); 1.77-1.68 (2H, m); 1.64 (6H, d).

Example 71 Salt of 2-chloro-5- [2- (3-pyrrolidinylamino) ethyl] -N- (tricyclo [3.3.1.13'7Jdec-1-ylmethyl) -benzamide dihydrochloride] Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), 1-dimethylethyl 3-amino-1-pyrrolidinecarboxylic acid ester (0.101 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After the working procedure the residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The dim orange powder obtained is dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, lml) is added. The mixture is stirred for 14 h at room temperature. The solvents were removed under reduced pressure and the product obtained was triturated with diethyl ether to give the title compound as a faint orange powder (0.033 g).

MS (APCI + ve) 416 (M + H) + XH NMR (DMSO-ds) d 7.46-7.39 (3H, m); 4.12 (ÍH, sa); 3.78-3.71 (ÍH, m); 3.69-3.57 (2H, m); 3 ^ 43-3.32 (4H, m); 3.13 (2H, ta); 3.06 (2H, s); 2.62-2.51 (ÍH, m); 2.38-2.29 (ÍH, m); 1.98 (3H, s); 1.73 (6H, c); 1.63 (6H, s).

Example 72 - [2- [(3R) -3-aminopyrrolidinyl] ethyl] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), (3R) -pyrrolidinyl-carbamic acid 1,1-dimethylethyl ester (0.101 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After the working procedure, the residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained is dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) is added. The mixture is stirred for 14 hours at room temperature. The solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to give the title compound as a white powder (0.060 g).

MS (APCI + ve) 416 (M + H) * XH NMR (CD3OD) d 7.49-7.41 (3H, m); 4.86 (ÍH, sa); 4.05-3.80 (2H, m); 3.58 (4H, sa); 3.17 (2H, t); 3.08 (2H, s); 2.66 (ÍH, sa); 2.28 (ÍH, sa); 2.00 (3H, s); 1.74 (6H, c); 1.64 (6H, s).

Example 73 Salt of 2-chloro-5- [2- [2- (hydroxymethyl) -1-piperazinyl] ethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride Prepared according to the method described in Example 66c from 2-chloro-5- (2-oxoethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.094 g, Example 66b), 3- (hydroxymethyl) -1-piperazinecarboxylic acid 1,1-dimethylethyl ester (0.117 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After the working procedure, the residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then chromatography eluting with ethyl acetate then with ethyl acetate: ethanol (95: 5). The white powder obtained is dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture is stirred for 14 hours at room temperature. The solvents were then removed under reduced pressure and the product obtained is triturated with diethyl ether to give the title compound as a white powder (0.016 g).

MS (APCI + ve) 446 (M + H) + X H NMR (CD3OD) d 8.43 (ΔI, t); 7.48-7.40 (3H, m); 4.14 (ÍH, da); 3.93 (ÍH, da); 3.81-3.76 (2H, m); 3.74-3.58 (5H, m); 3.57-3.45 (2H, m); 3.28-3.19 (ÍH, m); 3.17-3.11 (ÍH, m); 3.07 (2H, s); 1.99 (3H, sa); 1.73 (6H, c); 1.64 (6H, s).

Example 74 Salt of 2-chloro-5- (hexahydro-1H-1,4-diazepin-1-yl) -N- (2-tricyclo [3.3.1. L3,] dec-1-ylethyl) -benzamide hydrochloride a) 4- [4-chloro-3- [[(2-tricyclo [3.3.1.13'7] dec-1-ylethyl) amino] carbonyl] phenyl] -hexahydro-lH-1-1-dimethylethyl ester , 4-diazepin-1-carboxylic acid A solution of acid 1, 1-dimethylethyl ester 4- (3-carboxy-4-chlorophenyl) hexahydro-lH-1,4-diazepine-l-carboxylic acid (0.075 g, Example 5b) and 1,1 '-carbonyldiimidazole (0.034 g) in dimethylformamide (3 ml) is stirred at room temperature for 2.5 hours. Then the hydrochloride salt of the tricycle [3.3.1.13'7] decan-1-ethanamide (0.045 g) and N, N-diisopropylethylamine (0.037 ml) are added and stirring is continued for 14 hours. The reaction mixture is poured into water and extracted with ethyl acetate three times. The ethyl acetate layers were combined and washed with 2M hydrochloric acid, 10% aqueous sodium hydroxide and slam, then dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with 20% ethyl acetate in iso-hexane gave the subtitle compound as a yellow oil (0.053 g).

EM (APCI + ve) 460/462 (M-'Bu) " b) Hydrochloride salt of 2-chloro-5- (hexahydro-1H-1,4-diazepin-1-yl) -N- (2-tricyclo [3.3.1. l3'7] dec-1-ylethyl) -benzamide The 1,4-chloro-3- [[(2-tricyclo [3.3.1.13'7] dec-1-ylethyl) amino] carbonyl] phenyl] -hexahydro-lH-1 acid ester, 1,1-dimethylethyl ester 4-diazepin-1-carboxylic acid (0.053 g, Example 74a) is dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4M solution in dioxane) is added. After stirring at room temperature for 14 h, the mixture is evaporated to 3/4 parts of the original volume under reduced pressure. The diethyl ether is gradually added to the solution and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuo to give the title compound as a creamy solid (0.017 g).

MS (APCI + ve) 416/418 (M-HC1) * X H NMR (DMSO-de) d 9.07 (2H, sa); 8.18 (ÍH, t); 7.22 (ÍH, d); 6.80 (ÍH, dd); 6.71 (ÍH, d); 3.70 (2H, m); 3.50 (2H, t); 3.25-3.17 (4H, m); 3.07 (2H, m); 2.09-2.06 (2H,); 1.93 (3H, sa); 1.68 (3H, d); 1.61 (3H, d); 1.51 (6H, s); 1.34-1.28 (2H, m).

Example 75 Hydrochloride salt of the (+/-) -5- (3-amino-l-pyrrolidinyl) -2-chloro-N- (2-tricyclo [3.3.1.13'7] dec-l-ylethyl) -benzamide Prepared as described in Example 74 above using the acid (+/-) -2-chloro-5- [3- [[(1,1-dimethylethoxy) carbonyl] amino] -l-pyrrolidinyl] -benzoic acid (0.090 g ), 1,1 '-carbonyldiimidazole (0.043 g), hydrochloride salt of the tricycle [3.3.1.13'7] decan-1-ethanamine (0.057 g), N, N-diisopropylethylamine (0.046 ml) and dimethylformamide (3 ml) ). This compound is treated with 4N hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to give the title compound (0.025 g).

MS (APCI + ve) 402/404 (M-HC1) * NMR XH (DMSO-de) d 8.24 (3H, sa); 8.18 (ÍH, t); 7.24 (ÍH, d); 6.60 (ÍH, dd); 6.49 (ÍH, d); 3.93 (ÍH, m); 3.54-3.37 (2H,); 3.31-3.17 (4H, m); 2.37-2.28 (ÍH, m); 2.07 (ÍH, m); 1.93 (3H, sa); 1.68 (3H, d); 1.61 (3H, d); 1.51 (6H, s); 1.34-1.28 (2H, m).

Example 76 Salt of 2-chloro-5- (4-piperidinylcarbonyl) N- (tricyclo [3.3.1.17'7] dec-1-methylmethyl) -benzamide hydrochloride a) 4- [4-Chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] benzoyl] -1-piperidinecarboxylic acid 1,1-dimethylethyl ester To dimethyl sulfoxide (0.155 ml) in anhydrous dichloromethane (11 ml) at -78 ° C oxalyl chloride (0.086 ml) is added and the mixture is stirred for 5 minutes at -78 ° C. A solution of 4- [[4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] -carbonyl] phenyl] -hydroxymethyl] -1-dimethylethyl ester -piperidinecarboxylic acid (0.47 g, Example 64) in anhydrous dichloromethane (3 ml) is added dropwise and the mixture is stirred for 15 minutes at -78 ° C. Then triethylamine (0.633 ml) is added and the solution is warmed to room temperature. After 45 minutes, at room temperature. After 45 minutes at room temperature, the reaction mixture is poured into water and the layers are separated. The organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the subtitle compound as a foam (0.31 g).

MS (APCI + ve) 15 (M + H) + XH NMR (DMSO-d6) d 8.46 (ΔI, t); 8.06-8.01 (ÍH, m); 7.95-7.92 (ÍH, m); 7.70-7.65 (ÍH, m); 3.97 (2H, da); 3.72-3.61 (ÍH, m); 2.97 (2H, t); 2.92 (2H, sa); 1.96 (3H, sa); 1.77 (2H, d); 1.65 (6H, c); 1.55 (6H, s); 1.41 (9H, s); 1.48-1.33 (2H, m). b) Hydrochloride salt of 2-chloro-5- (4-piperidincarbonyl) -N- (tricyclo [3.3.1. l3'7] dec-l-ylmethyl) -benzamide A solution of acid 1, 1-dimethylethyl ester 4- [4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] -carbonyl-benzoyl] -1-piperidinecarboxylic acid (0.07 g, Example 76a) in methanol (3 ml) is treated with a solution of 4N hydrochloric acid in dioxane (1 ml). After 14 hours the solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.025 g).

MS (APCI + ve) 415 (M + H-HCD * NMR XH (DMSO-de) d 8.90 (H, S), 8.64 (H, S), 8.46 (H, T), 8.03 (H, D); 7.95 (ÍH, s), 7.69 (ÍH, d), 3.81 (ÍH, t), 3.24-3.18 (2H,), 3.09-2.99 (2H, m), 2.96 (2H, d), 2.01 (2H, dd ), 1.95 (3H, s), 1.79 (2H, t), 1.64 (6H, c), 1.45 (6H, s).

Example 77 2-Chloro-5- [1-hydroxy-1- (4-piperidinyl) ethyl] -N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide hydrochloride salt .He has a) 4- [1- [4-Chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenyl] -1-hydroxyethyl] 1,1-dimethylethyl ester -1-piperidinecarboxylic To the methyl magnesium bromide (3M solution in diethyl ether, 0.225 ml) in anhydrous diethyl ether (7 ml) under a nitrogen atmosphere is slowly added the 1,1-dimethylethyl ester of the 4- [4-chloro-3- [] acid. [(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] -carbonyl] benzoyl] -1-piperidinecarboxylic acid (0.23 g, Example 76a) in anhydrous diethyl ether (7 ml). The reaction mixture is stirred for 14 hours at room temperature, then poured onto crushed ice. A solution of 10% aqueous potassium hydrogen sulfate is added maintaining the pH of the solution > 4. The layers were separated, and the aqueous layer was extracted with ethyl acetate (4 x 25 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in methanol (3 ml) and hydrochloric acid (4N solution in dioxane, 2 ml) and stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product (0.11 g) is redissolved in dichloromethane (3 ml). Triethylamine (0.066 ml) is added followed by di-tert-butyl dicarbonate (0.055 g) and the reaction mixture is stirred for 1 hour at room temperature. Water is added and the layers were distributed. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane, then by RPHPLC eluting with a gradient of 75-5% aqueous 0.1% ammonium acetate in acetonitrile to give the subtitle compound as a white foam (0.06 g).

MS (APCI + ve) 431 (M + H-BOC) + b) Salt of 2-chloro-5- [1-hydroxy-1- (4-piperidinyl) ethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride To a solution of 4- [l- [4-chloro-3- [[(tricyclo [3.3.1.13'7] dec-1-ylmethyl) amino] carbonyl] phenyl] -1- dimethylethyl ester hydroxyethyl] -1-piperidinecarboxylic acid (0.07 g, Example 77a) in methanol (3 ml) is added a solution of 4N hydrochloric acid in dioxane (1 ml). After 14 hours the solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.038 g).

MS (APCI + ve) 431 (M + H-HCl) * X H NMR (DMSO-de) d 8.78 (OH, sa); 8.28 (ÍH, t); 7.44-7.40 (3H, m); 5.21 (ÍH, s); 3.25 (ÍH, d); 3.16 (ÍH, d); 2.98-2.89 (2H, m); 2.79-2.67 (2H, m); 1.94 (3H, sa); 1.84-1.75 (2H, m); 1.63 (6H, c); 1.53 (6H, s); 1.42 (3H, s); 1.53-1.31 (3H, m).

Example 78 2-chloro-5- [2- (1-piperazinyl) ethoxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt Prepared as described in Example 12b using the 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.13'7] dec-1-methyl) -benzamide (Example 12a) and the 1,1-dimethylethyl ester of the 4- (2-hydroxyethyl) -1-piperazinecarboxylic acid.

MS (APCI + ve) 432 (M + H) * NMR XH (CD3OD) d 8.40 (1H, t); 7.41 (ÍH, d); 7.14-7.06 (2H,); 4.45 (2H, t); 3.76-3.58 (10H, m); 3.07-3.03 (2H, m); 1.98 (3H, s); 1.77 (3H, d); 1.69 (3H, d); 1.62 (6H, s).

Example 79 Salt of 2-chloro-5- [2- (-piperidinyl) ethoxy) -N- (tricyclo [3.3.1.13'7] dec-l-iimethyl) -benzamide hydrochloride Prepared as described in Example 12b using the 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.13'7] dec-1-methyl) -benzamide (Example 12a) and the 1,1-dimethylethyl ester of the 4- (2-hydroxyethyl) -1-piperazinecarboxylic acid.

MS (APCI + ve) 431 (M + H) * H NMR (DMSO-de) d 8.75 (OH, s amp.); 8.49 (ÍH, s amp.); 8.27 (ÍH, t); 7.37 (ÍH, d); 6.99 (ÍH, dd); 6.91 (ÍH, d); 4.03 (2H, t); 3.22 (2H, d); 2.92 (2H, d); 2.82 (2H, t); 1.94 (3H, s); 1.82 (2H, d); 1.79-1.70 (ÍH, m); 1.69-1.64 (5H, m); 1.59 (3H, d); 1.53 (6H, s); 1.43-1.30 (2H, m).

Example 80 2-chloro-5- [2- (4-piperidinyloxy) ethoxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1. 13'7] dec-1-methyl) -benzamide (Example 12a) and ester 1, 1- 4- (2-hydroxyethoxy) -1-pyridinecarboxylic acid dimethylethyl.

MS (APCI + ve) 447 (M + H) X H NMR (CD 3 OD) d 8.39 (ΔI, ta); 7.38-7.33 (ÍH, m); 7.06-6.98 (2H, m); 4.22-4.16 (2H, m); 3.88-3.82 (2H, m); 3.80-3.71 (ÍH, m); 3.36-3.24 (2H, m); 3.16-3.04 (4H, m); 1.99 (3H, s); 2.08-1.86 (4H, m); 1.78 (3H, d); 1.69 (3H, d); 1.62 (6H, s).

Example 81 2-Chloro-5- [2- [2- (1-piperazinyl) ethoxy] ethoxy] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt Prepared as described in Example 12b using 2-chloro-5-hydroxy-N- (tricyclo [3.3.1.] 3.7] dec-1-methyl) -benzamide (0.20 g, Example 12a) and ester 1 , 4- [2- (2-Hydroxyethoxy) ethyl] -1-piperazinecarboxylic acid 1-dimethylethyl ester (0.26 g).

MS (APCI + ve) 476 (M + H) * NMR XH (CD3OD) d 7.7 (1H, dd); 7.04-7.01 (2H, m); 4.25-4.18 (2H, m); 3.94 (2H, t); 3.91-3.87 (2H, m); 3.80-3.43 (10H, m); 3.06 (2H, s); 1.99 (3H, s); 1.75 (3H, d); 1.67 (3H, d); 1.62 (6H, s).

Example 82 2 - . 2-Chloro-5- [(5,6-dihydro-l (4H) -pyrimidinyl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared according to the method described in Example 8 from 5-bromomethyl-2-chloro-N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide (Example 8b), and 1, 4, 5, 6-tetrahydro-pyridine .

MS (APCI + ve) 400/402 (M + H) * NMR XH (CDCl 3) d 7.84 (1H, s); 7.60 (ÍH, d); 7.43 (ÍH, d), 7.29 (ÍH, dd); 6.51 (ÍH, t); 4.39 (2H, s); 3.40-3.10 (3H, m); 3.17 (2H, d), 3.14 (ÍH, t); 2.01 (3H, s); 1.91 (c, 2H); 1.74 (3H, d); 1.64 (3H, d); 1.59 (6H, sa).

Example 83 2-Chloro-5- [[4- [(2-hydroxyethyl) amino] -l-piperidinyl] methyl] -N- (tricyclo- [3.3.1.13'7] des-1-ylmethyl) hydrochloride salt - benzamide a) 2-Chloro-5- [(4-oxo-l-piperidinyl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide Prepared according to the method described in Example 8c from 5-bromomethyl-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 8b) and 4-piperidinone .

EM (APCI + ve) 456/458 (M + H) * b) Salt of 2-chloro-5- [[4- [(2-hydroxyethyl) amino] -1-piperidinylmethyl] -N- (tricyclo [3.3.1.13,7] dec-1-ylmethyl) -benzamide hydrochloride To a solution of 2-chloro-5- [(4-oxo-l-piperidinyl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.150 g, Example 83a) in methanol (3 ml) at room temperature ethanolamine (0.11 ml) and sodium cyanoborohydride (0.068 g) are added. The pH is adjusted to 6 by adding a 4N solution of hydrogen chloride in dioxane and the reaction is stirred for 48 hours. The reaction is acidified with concentrated hydrochloric acid until the evolution of the gas has ceased. The precipitate is removed by filtration and the filtrate is concentrated under vacuum. The residue is partitioned between ethyl acetate and water. The aqueous layer is basified with 5% aqueous sodium hydroxide and extracted with dichloromethane. The organics were washed with brine and dried over magnesium sulfate. The crude material was purified on silica gel (5% 7N ammonia in methanol / 95% dichloromethane) to give a white foam which was dissolved in ether / methanol and treated with a 4N solution of hydrogen chloride in dioxane to give the give the title compound (0.135 g).

MS (APCI + ve) 460/462 (M + H) * NMR XH (CD3OD) d 8.47 (1H, t); 7.67 (ÍH, d); 7.64 (ÍH, dd), 7. 60 (ÍH, d), 4.39 (2H, s); 3.81 (2H, t); 3.62 (2H, da); 3.52 (ÍH, t); 3.23-3.10 (4H, m); 3.09 (2H, d); 2.39 (2H, d); 2.07 (2H, c), 1.99 (s, 3H); 1.77 (3H, d), 1.70 (3H, d), 1.64 (6H, d).

Example 84 2-Chloro-5- [[4-hydroxy-4 - [[(1-methylethyl) aminojmethyl] -1-piperidinyl] methyl] -N- (tricyclo [3.3.1.13'7 dec-1-ylmethyl] -benzamide] a) 2-Chloro-5- (l-oxa-6-azaspiro [2,5] oct-6-ylmethyl) -N- (tricyclo [3.3.1. l3,7Jdec-l-ylmethyl) -benzamide) To the dimethyl sulfoxide (2 ml) is added sodium hydride (0.033 g, 60% in oil) at room temperature. The mixture is stirred for 5 minutes at this temperature and a solution of trimethylsulfoxonium iodide (0.178 g) in dimethyl sulfoxide (2 ml) is added. After 30 minutes, 2-chloro-5- [(4-oxo-l-piperidinyl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.28 g, Example 83a) in dimethyl sulfoxide (2 ml) and the reaction is stirred at room temperature for 3 hours before the temperature is reduced with ice / water (20 ml). The mixture is extracted three times with ethyl acetate, the combined organic layers are washed with brine and dried over magnesium sulfate. The crude material is purified on silica gel eluting with ethyl acetate to give the subtitle compound as a white foam (0.25 g).

MS (APCI + ve) 429/431 (M + H) * NMR XH (CDC13) d 7.68 (1H, s); 7.40-7.30 (2H, m); 6.27 (ÍH, t); 3. 54 (2H, s); 3.18 (2H, d); 2.70-2.50 (6H, m); 2.00 (s, 3H); 1. 90-1.75 (2H, m); 1.74 (3H, d); 1.66 (3H, d); 1.59 (6H, sa); 1. 80-1.50 (m, 2H). b) 2-Chloro-5 - [[4-hydroxy-4- [[(1-methylethyl) aminojmethyl] -1-piperidinyl] methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide In a sealed tube, 2-chloro-5- (1-oxa-azaspiro [2.5] oct-6-ylmethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 84a, 0.15 g) was dissolved in a mixture of ethanol (4 ml) and 'di-isopropylamine (1 ml) and heated at 65 ° C for 14 hours. The volatiles are removed under vacuum and the residue is purified on silica gel (5% 7N ammonia in methanol / 95% dichloromethane) to give the title compound as a white solid (0.115 g).

MS (APCI + ve) 488/490 (M + H) + XH NMR (CD3OD) d 7.45-7.35 (3H, m); 3.55 (2H, s), 3.06 (2H, s), 2.76 (ÍH, c); 2.70-2.55 (2H, m); 2.54 (2H, s), 2.50-2.35 (2H, m); 1.99 (s, 3H); 1.77 (3H, d); 1.70 (3H, d); 1.63 (10H, sa); 1.07 (m, 2H).

Example 85 Salt of 2-chloro-5- [(1, 2, 3, 6-tetrahydro-3-pyridinyl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride To the pyridine (6 ml) at 0 ° C, lithium aluminum hydride (0.24 g) is added in portions. The mixture is alloto warm to room temperature and is stirred for 24 hours.

Lithium iodide (0.220 g) and pyridine (1 ml) are added and the reaction is stirred for an additional 1 hour. Add 5-bromomethyl-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.30 g, Example 8b) in dry pyridine (2 ml) to the solution at the temperature ambient. After 2 hours the mixture is reduced to 0 ° C with a cold 15% aqueous solution of acetic acid, stirred for one hour and concentrated under vacuum. The residue is taken up in IN sodium hydroxide, extracted with dichloromethane and the organic layers are dried over magnesium sulfate. The crude material is purified on silica gel (2 to 10% 7N ammonia in methanol / dichloromethane) then treated with a 4N solution of hydrogen chloride in dioxane and methanol to give the title compound (0.20 g).

MS (APCI + ve) 339/401 (M + H) + XH NMR (CD30D) d 8.42 (ΔI, t); 7.43 (ÍH, dd); 7.32 (ÍH, dd); 7.30 (d; ÍH); 5.89 (ÍH, d); 5.80 (ÍH, d), 3.64 (2H, s); 3.40-3.30 (ÍH, m); 3.06 (4H, d), 1.99 (s, 3H); 1.78 (3H, d); 1.68 (3H, d); 1.63 (6H, d).

Example 86 Salt of 2-chloro-5- (3-piperidinylmethyl) -N- (tricyclo [3.3.1.13,7] dec-l-ylmethyl) -benzamide acetate a) Salt of 2-chloro-5- (3-piperidinylmethyl) -N- (tricyclo [3.3.1.13,7] dec-l-ylmethyl) -benzamide acetate Pyridine (12 ml) at 0 ° C is added in portions lithium aluminum hydride (0.46 g). The mixture is alloto warm to room temperature and is stirred for 24 hours. Lithium iodide (0.44 g) and pyridine (5 ml) are added and the reaction is stirred for an additional 1 hour. The solution is cooled to -10 ° C and 5-bromomethyl-2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 8b, 0.5 g) in dry pyridine is added. (5 ml). After 1 hour, the mixture is reduced to -10 degrees with cold water, then with sodium hydroxide IN. The solution is stirred for 1 hour then concentrated under vacuum. The residue is taken up in water, extracted with dichloromethane and the organic layers are dried over magnesium sulfate. The crude material is purified on silica gel (ethyl acetate: i-hexane / 4: 1) to give the subtitle compound as a white foam (0.355 g). b) Acetate salt of 2-chloro-5- (3-piperidinylmethyl) -N- (tricyclo [3.3.1.13'7Jdec-l-ylmethyl) -benzamide) 2-Chloro-5- (3-pyridinylmethyl) -N- (tricyclo- [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.10 g, Example 86a) is dissolved in methanol and treated with a solution 4N hydrogen chloride in dioxane. The hydrochloride salt is isolated and hydrogenated in ethanol over platinum oxide following the procedure described in Example 51 to give the title compound as an acetate salt after purification by reverse phase HPLC (0.1% ammonium acetate). 0.1% aqueous / acetonitrile) (0.053 g).

MS (APCI + ve) 401/403 (M + H) + XH NMR (CD3OD) d 7.42 (ΔH, d), 7.31-7.25 (2H, m); 3.38-3.28 (ÍH, m); 3.28-3.18 (ÍH, 2m); 3.07 (2H, s); 2.86 (ÍH, dt); 2.72-2.61 (ÍH, m); 2.65 (ÍH, d), 2.13-2.05 (ÍH, m); 2.01 (3H, s), 1.94 (3H, s), 1.90-1.85 (H, m); 1.85-1.60 (2H, m); 1.80 (3H, d); 1.71 (3H, d), 1.64 (6H, d); 1.29 (ÍH, cd).

Example 87 2-Bromo-5- [[4- [(2-hydroxyethyl) amino] -l-piperidinyl] methyl] -N- (tricyclo [3.3.1.13'7Jdec-1-ylmethyl) -benzamide] Prepared according to the procedures described in Examples 83a and 83b from 2-bromo-5-bromomethyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (Example 65a), -piperidone and ethanolamine.

MS (APCI + ve) MW 505/506 (M + H) * NMR XH (CDC13) d 7.53 (1H, d); 7.52 (ÍH, d); 7.26 (ÍH, dd); 6. 05 (ÍH, t); 3.65 (2H, t); 3.46 (2H, s), 3.17 (2H, d); 2.82 (2H, t); 2.60-2.45 (ÍH, m); 2.20-1.95 (7H,); 1.95-1.82 (2H, da); 1.75 (3H, d); 1.66 (3H, d); 1.61 (6H, d); 1.50-1.35 (2H, cd).

Example 88 2-Chloro-5- [(E) -3-piperidinylidenemethyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benza a) 2-Chloro-5- [(E) - (5,6-dihydro-3 (4H) -3-piperidinylidene) -methyl-N- (tricyclo- [3.3.1.13'7] dec-1-ylmethyl) -benzamide The 2-chloro-5-formyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.152 g, Example 31a) and the trimer of 2,3,4,5-tetrahydropyridine (Org. Synth., 1977, Vol. 56, 118-122, 0.038 g) are dissolved in methanol (3 ml) and heated at reflux for 4 hours. The mixture is evaporated under reduced pressure then purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the subtitle compound as a white foam (0.046 g).

MS (APCI + ve) 397 (M + H) + X H NMR (CD3OD) d 7.98 (1H, s); 7.51 (3H, s); 6.83 (ÍH, s); 3.66-3.62 (2H, m); 3.07 (2H, s), 2.78-2.73 (2H, m); 1.99 (3H, sa); 1.73 (6H, c); 1.77-1.69 (2H,); 1.64 (6H, s). b) 2-chloro-5- [(E) -3-piperidinylidenemethyl] -N- (tricyclo- [3.3.1.13'7] dec-1-ylmethyl) -benzamide Sodium borohydride (0.009 g) in methanol (0.5 ml) is added to a solution of 2-chloro-5- [(E) - (5,6-dihydro-3 (4H) -pyridinylidene) methyl] -N- ( tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide (0.046 g, Example 88a) in methanol (1.5 ml). The reaction mixture is stirred for 4 hours under a nitrogen atmosphere at room temperature. Concentrated hydrochloric acid (0.01 ml) is added and the mixture is evaporated under reduced pressure. An aqueous solution of sodium hydroxide (2M, 2 ml) is added to re-basify the residue followed by water (10 ml) and dichloromethane (10 ml).

The layers were partitioned and the aqueous layer was further extracted with dichloromethane (2x10 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white powder (0.024 g).

MS (APCI + ve) 399 (M + H) * NMR XH (CD3OD) d 7.43 (ΔH, d), 7.29-7.26 (2H, m); 6.38 (ÍH, s); 3.45 (2H, s); 3.07 (2H, s), 2.96 (2H, t); 2.55 (2H, t); 2.00 (3H, sa); 1.75 (6H, c); 1.81-1.64 (2H, m); 1.64 (6H, s).

Pharmacological Analysis Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) are known to be P2X7 receptor agonists, effecting the formation of pores in the plasma membrane (Drug Development Research (1996), 37 (3), p.126). Accordingly, when the receptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of ethidium bromide bound to the intracellular DNA is observed. The increase in fluorescence can be used as a measure of the activation of the P2X7 receptor and therefore to quantify the effect of a compound on the P2X7 receptor. In this manner, each of the title compounds of Examples 1 to 88 was tested to verify antagonist activity at the P2X7 receptor. Accordingly, the test was performed on 96-well flat bottom microtiter plates, the wells are filled with 250 μl of the test solution comprising 200 μl of a THP cell suspension (2.5 x 10 6 cells / ml) which contains 10"M ethidium bromide, 25 μl of a high potassium buffer solution containing 10-5M of bbATP, and 25 μl of the high potassium buffer containing 3 x 10-5M of the test compound The plate was covered with a plastic sheet and incubated at 37 ° C for one hour.The plate is then read on a Perkin-Elmer fluorescent plate reader, excitation at 520 nm, emission at 595 nm, slot widths : Ex 15 nm, Em 20 nm For comparison purposes, bbATP (a P2X7 receptor agonist) and pyridoxal 5-phosphate (a P2X7 receptor agonist) were used separately in the test as controls. of the readings obtained, a pIC5o value was calculated for each test compound, this value is the negative logarithm of the test compound concentration necessary to reduce the bbATP agonist activity by 50%. Each of the compounds of Examples 1 to 88 demonstrated agonist activity, having a value of pIC5o > 4.50.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (16)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as a priority: 1. A compound of the general formula characterized in that m represents 1, 2 or 3; each Rx independently represents a hydrogen or halogen atom; A represents C (0) NH or NHC (O); Ar represents a group X represents a bond, an oxygen atom or a CO group, (CH2)? -6, CH =, (CH2) a-60, 0 (CH2)? -6, 0 (CH2) 2-60, 0 (CH2 ) 2-30 (CH2) 1.3, CR '(OH), (CHaJi-sOÍCHjJi-a, (CH2) 1-3O (CH2) 2-30, NR5, (CH2)? - 6NR5, NR5 (CH2) 1_6, (CH2)? - 3NR5 (CH2) 1.3, 0 (CH2) 2-6NR5, O (CH2) 2-3NR5 (CH2)? -3, (CH2) 1.3NR5 (CH2) 2-3 ?, NR5 (CH2) 2-60, NR5 (CH2) 2-30 (CH2) -3, CONR5, NR5CO, S (0) ", S (0) nCH2, CH2S (0) n, S02NR5 or NR5S02, n is 0, 1 or 2 R 'represents a hydrogen atom or an alkyl group with C? -C6, one of R2 and R3 represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from (i) alkenyl with substituted Ci-Ce optionally by at least one of cycloalkyl with C3-C6, (ii) cycloalkyl with C3-C8, (iii) alkyloxy with C? -C6 optionally substituted by at least one of cycloalkyl with C3-C6, and (iv) cycloalkyloxy with C3 -C8, each of these groups is optionally substituted by one or more fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen atom; where either R4 represents a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more substituents independently selected from the fluorine, hydroxyl, carboxyl, cyano, alkyl with C? -C6, hydroxyalkyl with C? -C6, -NR6R7, - (CH2) rNR6R7 and -CONR6R7, or R4 represents a saturated carbocyclic ring system of 3 to 8 elements substituted by one or more substituents independently selected from -NR6R7, - (CH2) rNR6R7 and -CONR6R7, the ring system is optionally further substituted by one or more substituents independently selected from the fluorine, hydroxyl and alkyl atoms with Ci Ce, r is 1, 2, 3, 4, 5, or 6; R5 represents a hydrogen atom or an alkyl group with C? -C6 or a cycloalkyl group with C3-C8; R6 and R7 each independently represent a hydrogen atom or an alkyl group with C? -C6, hydroxyalkyl with C2-C6 or cycloalkyl with C3-C8, or R6 and R7 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 3 to 8 elements; with the proviso that (a) when A represents C (0) NH and R4 represents a 3- to 8-membered saturated aliphatic heterocyclic ring system containing a nitrogen atom, then X is different from a bond, and b) when A represents C (0) NH and X represents a group (CH2)? -6 or then R4 does not represent an unsubstituted imidazolyl group, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl, and (c) when A represents NHC ( O) and R4 represents an unsubstituted saturated aliphatic heterocyclic ring system of 3 to 8 elements, which contains a nitrogen atom, then X is different from a bond, and (d) when A represents NHC (O) and X represents 0 (CH2)? -6, NH (CH2)? -e or SCH2, then R4 does not represent an unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl group, and (e) when A represents NHC (O) and X represents 0 ( CH2) 2.3NH (CH2) 2, then R4 does not represent an imidazolyl group; or a pharmaceutically acceptable salt or solvate thereof.
2. 2. A compound according to claim 1, characterized in that A represents NHC (O).
3. 3. A compound according to claim 1 or claim 2, characterized in that Ar represents a group .
4. A compound according to any of claims 1 to 3, characterized in that X represents a bond, an oxygen atom or a group CO, (CH 2)? - 6, CH =, 0 (CH 2)? - 6, 0 (CH2) 2-60, 0 (CH2) 2.30 (CH2) 1-3, CR '(OH), NR5, (CH2 _6NR5, CONR
5. 5, S (0) ", S (0) nCH2. compound according to any of claims 1 to 4, characterized in that R4 represents a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system it is optionally substituted by one or two substituents independently selected from hydroxyl, C 1 -C 6 alkyl, hydroxyalkyl with C 6 -C 6, -NR 6 R 7 and - (CH 2) rNR 6 R 7
6. 6. A compound according to any of claims 1 to 4 , characterized in that R4 represents a group selected from: R «R7 or ~
7. 7. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof according to claim 1, characterized in that it is: 2-nitro-3-piperazin-1-yl-N- (tricyclo [3.3.1.13 ' 7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-amino-3-piperazin-1-yl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, 2- chloro-3-piperazin-1-yl-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, 2-chloro-5-piperazin-1-yl-N- (tricyclo [3.3.1] l3-7] dec-l-ylmethyl) -benzamide, 2-chloro-5- (hexahydro-lH-1,4-diazepin-l-yl) -N- (tricyclo [3.3.1.13-7] hydrochloride salt ] dec-1-ylmethyl) -benzamide, 5- (4-amino-1-piperidinyl) -2-clsro-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide hydrochloride salt, hydrochloride salt of (+/-) -5- (3-amino-l-pyrrolidinyl) -2-chloro-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [ (hexahydro-lH-1,4-diazepin-1-yl) methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- [(4-amino- l-piperidinyl) methyl] -2-chloro-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- [(3-amino-l-pyrrolidinyl) methyl] - 2-chloro-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1.13 ' 7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (R) -2-chloro-5- (2-pyrrolidinylmethoxy) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) - benzamide, hydrochloride salt of the (S) -2-chloro-5- (2-pyrrolidinylmethoxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the 2- chloro-5- (3-piperidinylmethoxy) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, cis-5- [(4-aminociclohexyl) oxy] hydrochloride salt] -2- chloro-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-methyl-5- (1-piperazinylmethyl) -N- (tricyclo [3.3.1.1 3'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (1-piperazinylmethyl) -N- (2-tricyclo [3.3.1.13'7] dec-1-ylethyl) - benzamide, hydrochloride salt of the (+/-) -2-chloro-5- (3-pyrrolidinyloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the (+/-) -2-chloro-5- (3-piperidinyloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, trans-5- [(4-aminociclohexyl) oxy] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, cis- (+/-) -5- [(3-aminociclopentyl) oxy] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (S, S) -2-chloro-5- (2,5-diazabicyclo [2.2.1] hept-2- il) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (2-methyl-1-piperazinyl) -N- (tricyclo [3.3 .1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (+/-) -2-chloro-5- (3-pyrrolidinylamino) -N- (tricyclo [3.3.1.13'7] dec- 1-ylmethyl) -benzamide, (+/-) -5- (3-amino-1-piperidinyl) -2-chloro- N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, (+/-) -2-chloro-5- (3-piperidinylamino) -N- (tricyclo [3.3.1.13,7] dec -l-ylmethyl) -benzamide, 2-chloro-5- [hexahydropyrrolo [3,4-c] pyrrole-2 (ÍH) -yl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of N- [2-methyl-5- (4-piperidinyloxy) phenyl] -tricyclo [3.3.1.13'7] decan-1-acetamide, hydrochloride salt of N- [2-chloro] -5- (4-piperidinyloxy) phenyl] -tricyclo [3.3.1.13'7] decan-1-acetamide, dihydrochloride salt of 2-chloro-5- [(4-piperidinylamino) methyl] -N- (tricyclo [ 3.3.1.13'7] dec-1-ylmethyl) -benzamide, 5 - [[[4- (aminomethyl) cyclohexyl] amino] methyl] -2-chloro-N- (tricyclo [3.3.1.13 '] dihydrochloride salt 7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5 - [[(4-aminocyclohexyl) amino] methyl] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl] ) -benzamide, 5- [(1-azabicyclo [2.2.2] oct-3-ylamino) methyl] -2-chloro-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, salt of N- [4] hydrochloride - (3-aminopyrrolidin-1-yl) -2-methylphenyl] -2- (tricyclo [3.3.1.13-7] dec-1-yl) -acetamide, N- (2-methyl-4-piperazin-1-ylphenyl) -2- (tricyclo [3.3.1.13-7] dec-1-yl) -acetamide dihydrochloride salt, cis-4 hydrochloride salt - (3-amino-cyclopentyloxy) -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (4-piperidinyloxy) - N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, (+/-) -2-chloro-4- (pyrrolidin-3-yloxy) -N- (tricyclo [3.3.1.13'7 ] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (piperidin-3-yloxy) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, salt of 2-chloro-4- (4-piperazin-1-yl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of 2-chloro-4 - (3-pyrrolidinylamino) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-4- (hexahydro-lH-1,4-diazepin-1) -il) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (+) - 5 - [(3-amino-1-piperidinylmethyl) -2-chloro- N- (tricycle [3.3.1.13"7] dec -1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -N- (tricyclo [3.3.1.13'7] dec- 1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylmethyl) -N- (tricyclo [3.3.1. 13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (3,7-diazabicyclo [3.3.1] non-3-ylmethyl) -N- (tricyclo [3.3.1.13 '7] dec-1-ylmethyl) -benzamide, hydrochloride salt of trans-2-chloro-5- [[8- (methylamino) -3-azabicyclo [3.2. l] oct-3-yl] methyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of cis-2-chloro-5- [(hexahydropyrrolo [3, -c] pyrrole-2 (1H) -yl) methyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (4-piperidinylidenemethyl) ) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (4-piperidinylmethyl) -N- (tricyclo [3.3.1.13"7] dec -1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (4-hydroxy-piperidin-4-yl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide , salt of 2-chloro-5- (1, 2, 3, 6-tetrahydro-pyridin-4-yl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide hydrochloride, salt of 2-ethyl-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide hydrochloride, 2-chloro-5- (piperidin-4-hydrochloride salt -ylsulfanyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, 2-chloro-5- (piperidin-4-ylsulfinyl) -N- (tricyclo [3.3.1.13-7] dec -1-ylmethyl) -benzamide, salt d and 2-chloro-5- (piperidin-4-ylsulfonyl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of 2-chloro-5- ( piperidin-4-ylmethylsulfanyl) -N- (tricyclo [3.3.1. l3-7] dec-l-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (piperidin-4-ylmethanesulfonyl) -N- (tricyclo [3.3.1. I3"7] dec-1-ylmethyl] ) -benzamide, hydrochloride salt of 2-chloro-5- (piperazin-1-carbonyl) -N- (tricyclo [3.3.1.l3-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of the 2-chloro-5- ([1,4] diazepane-1-carbonyl) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 4-chloro-Nx- (piperidin-4-yl-) -N2- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -isophthalamide, salt of 2-chloro-5- (hydroxy-4-piperidinylmethyl) -N- hydrochloride ( tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of (+) -2-chloro-5- (hydroxy-3-piperidinylmethyl) -N- (tricyclo [3.3.1.13-7] ] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-bromo-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (1-piperazinyl) ethyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro ro-5- [2- (2, 5-diazabicyclo [2.2.1] hept-2-yl) ethyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- [2- (4-amino-1-piperidinyl) ethyl] -2-chloro-N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, dihydrochloride salt of the 2- chloro-5- [2- (3-piperidinylamino) ethyl] -N- (tricyclo [3.3.1.13'7] dec-l-ylmethyl) -benzamide, 5- [2- (3-amino-1-piperidinyl) ethyl] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide hydrochloride salt, dihydrochloride salt of 2-chloro-5- [2- (3-pyrrolidinylamino) ethyl] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 5- [2- [ (3R) -3-aminopyrrolidinyl] ethyl] -2-chloro-N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- [ 2- (Hydroxymethyl) -1-piperazinyl] ethyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- (hexahydro-1H-1) , 4-diazepin-1-yl) -N- (2-tricyclo [3.3.1.13-7] dec-1-ylethyl) -benzamide, ^^ £ M * ¡^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ salt of hydrochloride of (+/-) -5- (3-amino-l-pyrrolidinyl) -2-chloro-N- (2-tricyclo [3.3 .1.13-7] dec-1-ylethyl) -benzamide, hydrochloride salt of 2-chloro-5- (4-piperidinylcarbonyl) -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide salt of 2-chloro-5- [1-hydroxy-1- (4-piperidinyl) ethyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide hydrochloride, hydrochloride salt of 2-chloro-5- [2- (1-piperazinyl) ethoxy) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (4-piperidinyl) ethoxy) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- (4-piperidinyloxy) ethoxy) -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [2- [2- (1-piperazinyl) ethoxy] ethoxy] - N- (tricyclo [3.3.1. L3"7] dec-l-ylmethyl) -benzamide, 2-chloro-5- [(5,6-dihydro-l (4H) -pyrimidinyl) methyl] -N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide, chlorhi salt 2-chloro-5- [[4- [(2-hydroxyethyl) amino] -l-piperidinyl] methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide 2 -chloro-5- [[4-hydroxy-4- [[(1-methylethyl) aminojmethyl] -1-piperidinyl] methyl] -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, hydrochloride salt of 2-chloro-5- [(1, 2, 3, 6-tetrahydro-3-pyridinyl) methyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, acetate salt of 2-chloro-5- (3-piperidinylmethyl) -N- (tricyclo [3.3.1.13'7] dec-1-ylmethyl) -benzamide, 2-bromo-5- [[4- [(2 -hydroxyethyl) amino] -1-piperidini1] ethyl] -N- (tricyclo [3.3.1.13-7] dec-1-ylmethyl) -benzamide, or 2-chloro-5- [(E) -3-piperidinylidenemethyl] - N- (tricyclo [3.3.1.13"7] dec-1-ylmethyl) -benzamide.
8. 8. A process for the preparation of a compound of the formula (I) as defined in claim 1, characterized in that it comprises: (i) when X represents a CH2 group, R4 represents a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more substituents independently selected from the fluorine, hydroxyl, carboxyl, cyano, alkyl with C2 atoms. Ce, hydroxyalkyl with C? -C6 # -NR6R7, - (CH2) rNR6R7 and -CONR6R7 and R4 is attached or bonded to X by means of a nitrogen atom, by reacting a compound of the general formula wherein one of R10 and Rxx represents a hydrogen atom and the other of R10 and Rxx represents a group -CH2LX in which L1 represents a leaving group and m, A, Rx, R2 and R3 are as defined in the formula (I ), with a compound of the general formula R4'-H (III) in the presence of a base, wherein R4 'represents a saturated or unsaturated aliphatic heterocyclic ring system of 3 to 9 elements containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system is optionally substituted by one or more substituents independently selected from the fluorine, hydroxyl, carboxyl, cyano, alkyl with d-C6, hydroxyalkyl with d-C6, -NR6R7, - (CH2) rNR6R7 and -CONR6R7 and wherein R6 and R7 are as defined in formula (I); or (ii) when X represents an oxygen atom or a group OCHZhzh-e, 0 (CH2) 2-60, O (CH2) 2_30 (CH2)! -3, 0 (CH2) 2_6NR5 u 0 (CH2) 2_3NR5 (CH2)? -3, reacting a compound of the general formula wherein one of R12 and R13 represents a hydrogen atom and the other of R12 and R13 represents a hydroxyl group and m, A, Rx, R2 and R3 are as defined in formula (I), with a compound of the formula general R4-Y-OH (V) wherein Y represents a bond or a group (CH2)? -6 / 0 (CH2) 2-e / (CH2)? _ 3? (CH2) 2-3 NR5 (CH2) 2 -6 or (CH2) 1-3NR5 (CH2) 2_3 and R4 is as defined in formula (I), in the presence of 1,1- (azodicarbonyl) dipiperidine and tributylphosphine; or (iii) when X represents a bond, an oxygen atom or a group 0 (CH2)? -6.0 (CH2) 2_60, 0 (CH2) 2-30 (CH2) 1-3, NR5, NR5 (CH2) ? -e, NR5 (CH2) 2_60 or NR5 (CH2) 2_30 (CH2)? _3 and A is NHC (O), reacting a compound of the general formula wherein one of R 14 and R 15 represents a group -X'-R 4 and the other of R 14 and R 15 represents a hydrogen atom, X 'represents a bond, an oxygen atom or a group 0 (CH 2)? - 6, 0 (CH2) 2-eO, 0 (CE2) 2.30 (CE2) l.3, NR5, NR5 (CH2 -6, NR (CH2) 2.60 or NR5 (CH2) 2-30 (CH2) 1-3, L2 represents a leaving group and R2, R3, R4 and R5 are as defined in formula (I), with a compound of the general formula wherein m and R1 are as defined in formula (I), optionally in the presence of a binding agent; or (iv) when X represents a bond, an oxygen atom or a group 0 (CH2): -6.0 (CH2) 2_60, O (CH2) 2_30 (CH2) x-3, NR5, NR5 (CH2) 1-6, .NR5 (CH2) 2-60 or NR5 (CH2) 2-3O (CH2)! -3 and A is C (0) NH, reacting a compound of the general formula wherein R2 and R3 are as defined in formula (I) and R14 and R15 are as defined in formula (VI) in (iii) above, with a compound of the general formula where m and Rx are as defined in formula (I), in the presence of a base; or (v) when X represents a bond or a group NR5, NR5 (CH2) 1_6, NR5 (CH2) 2-60 or NR5 (CH2) 2_30 (CH2)? _3, reacting a compound of the general formula wherein one of R16 and R7 represents a leaving group, L3, and the other of R16 and R17 represents a hydrogen atom and m, A, Rx, R2 and R3 are as defined in formula (I), with a compound of the general formula R4-Z (XI) wherein Z represents a hydrogen atom or a group NHR5, (CH2) a_6NHR5, 0 (CH2) 2-6NHR5 or a group (CH2)! _30 (CH2) 2-3NHR5 and R4 and R5 are as defined in formula (I), optionally in the presence of a palladium catalyst, a phosphine ligand and a base; or (vi) when X represents a CH20 group, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (V) as defined in (ii) above wherein Y represents a bond, in the presence of a base or in the presence of a metal salt; or (vii) when X represents a CH2NR5 group, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (XI) as defined in (v) above wherein Z represents a NHR5 group: o (viii) when X represents a group CH20 (CH2)? -3 or CH20 (CH2) 2-30, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (V) as defined in (ii) above wherein Y represents a group ( CH2) X_3 or 0 (CH2) 2_3, in the presence of a base or in the presence of a metal salt; or (ix) when X represents a CH2NR5CH2 group, CH2NR5 (CH2) 2_30, reacting a compound of the formula (II) as defined in (i) above with a compound of the formula (XI) as defined in (v) above wherein Z represents a group CH2NHR5 or O (CH2) 2_3NHR5; or (x) when X represents a CH2 group and R4 represents an unsubstituted saturated aliphatic 4 to 6 element heterocyclic ring system containing a nitrogen atom, reacting a compound of the formula (II) as defined in (i) above, with a compound of the general formula wherein s and t independently represent 1 or 2; or (xi) when X represents a group CO, CONR5, NR5CO, S02, NR5S02 or S02NR5 and A is NHC (0), reacting a compound of the general formula wherein one of R18 and R19 represent a group -X "-R4 and the other of R18 and R19 represents a hydrogen atom, X" represents a group CO, CONR5, NR5C0, S02, NR5S02 or S02NR5, L4 represents a group of salient and R2, R3, R4 and R5 are as defined in formula (I), with a compound of formula (VII) as defined in (iii) above, optionally in the presence of a binding agent; or (xii) when X represents a group CO, CONR5, NR5CO, S02, NNRR55SS0022 oo SS0022NNRR55 yy AA eess C (0) NH, reacting a compound of the general formula wherein R2 and R3 are as defined in formula (I) and R18 and R19 are as defined in formula (XIII) in (xi) above, with a compound of formula (IX) as defined in (iv) ) earlier, in the presence of a base; or (xiii) when X represents a sulfur atom, reacting a compound of the formula (X) as defined in (v) above, with an organolithium reagent and then with a compound of the general formula R4-S-S02- Tol (XV) wherein Tol represents a tolyl group and R4 is as defined in formula (I); or (xiv) when X represents a CHOH or CH2 group, reacting a compound of the formula (X) as defined in (v) above, with an organolithium reagent and then with a compound of the general formula R4-CHO (XVI ) wherein R4 is as defined in formula (I), optionally followed by a reduction reaction; or (xv) when X represents a bond, reacting a compound of the formula (X) as defined in (v) above, with an organo-lithium reagent and then with a compound of the general formula R4 = O (xvii; wherein R4 is as defined in formula (1), optionally followed by a reduction reaction; (xvi) when X represents an SO group, oxidizing a corresponding compound of the formula (I) in which X represents a sulfur atom; or (xvii) when X represents a SCH2 group, reacting a compound of the formula (X) as defined in (v) above, with an organolithium reagent and then with a compound of the general formula wherein R is as defined in formula (I); or (xviii) when X represents a group SOCH2 or S02CH2, oxidizing a corresponding compound of the formula (I) in which X represents an SCH2 group; or (xix) when X represents a CH = group, reacting a compound of the formula (II) as defined in (i) above with trimethyl phosphite and then with a compound of the formula (XVII) as defined in (cf. xv) previous in the presence of a base; or (xx) when X represents a group (CH2)? _ 6, reacting a compound of the general formula wherein one of R20 and R2X represents a group of CHO or a group of (CH2) _5CHO and the other of R20 and R2X represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in the formula ( I), with a compound of the general formula (XX), R 4 -H, wherein R 4 is as defined in the formula (I), in the presence of a reducing agent; or (xxi) when X represents a group (CH2)? _ 6NR5, (CH2) 1-3NR5 (CH2) 1-3 or (CH2) 1_3NR5 (CH2) 2-30, reacting a compound of the formula (XIX) as was defined in (xx) above, with a compound of the general formula (XXI), R4-Z ', where Z' represents a group NHR5, (CH2)! _3NHR5, 0 (CH2) 2-3NHR5 and R4 and R5 they are as defined in formula (I), in the presence of a reducing agent; or (xxii) when X represents a group 0 (CH2)? _30 (CH2) a_3 or (CH2)? -30 (CH2) 2_30, reacting a compound of the formula (XIX) as defined in (xx) above in which one of R20 and R21 represent a CHO group or a group (CH2)! _ 2CHO and the other of R20 and R2X represents a hydrogen atom, with a reducing agent, followed by the reaction with a compound of the general formula (XXII), RE, where E represents a group (CH2)? 3L5 or 0 (CH2) 2_3L5, L5 is a leaving group and R4 is as defined in formula (I), in the presence of a base; or (xxiii) when X represents a group (CH2)? -6, reacting a compound of the formula (II) as defined in (i) above with trimethylphosphite and then with a compound of the formula (XVI) as defined ( xiv) above, a compound of the formula (XVII) as defined in (xv) above or with a compound of the general formula (XVIA), R4 (CH2)? -4CHO in which R4 is as defined in the formula (I), in the presence of a base, followed by a reduction reaction; or (xxiv) when X represents a group (CH2) 2-60, reacting a compound of the general formula wherein one of R22 and R23 represents a group (CH2) 2-eL6 and the other of R20 and R2X represents a hydrogen atom, L6 represents a leaving group and m, A, R1, R2 and R3 are as defined in the formula (I), with a compound of the formula (V) as defined in (ii) above in which Y represents a bond; or (xxv) when X represents a group CR '(OH) in which R' is an alkyl group with Ci-Cβ, oxidizing a corresponding compound of the formula (I) in which X represents CH (OH), followed by the reaction with an alkyl lithium reagent with C? -C6; or (xxvi) when X represents a CH2S group, reacting a compound of the formula (II) as defined in (i) above with a compound of the general formula (XXIV), R-SH, where R4 is as defined in the formula (I), in the presence of a base; or (xxvii) when X represents a CH2SO or CH2S02 group, oxidizing a corresponding compound of the formula (I) in which X represents a CH2S group; or (xxviii) when X represents a group CH2 and R4 represents a 3-piperidinyl or 2-piperazinyl group, reacting a compound of the formula (ii) as defined in (i) above with a reagent formed by combining pyridine or pyrazine with an aluminum hydride reagent, followed by a reduction reaction; or (xxix) when X represents a group CH = and R4 represents a 3-piperidinyl group, reacting a compound of the general formula wherein one of R24 and R25 represents a group of aldehyde -CHO, and the other of R24 and R25 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with the , 3, 4, 5-tetrahydropyridine, followed by a reduction reaction; or (xxx) when X represents a bond, NR or NR (CH2)? _ 6 and R4 represents a piperidyl or piperazinyl group bonded to carbon, reducing a compound of the general formula wherein one of R26 and R27 represents a group of pyridyl, pyrazinyl, NR5-pyridyl, NR5-pyrazinyl, NR5 (CH2)? -6-pyridyl or NR5 (CH2) ^ e-pyrazinyl and the other of R26 and R27 represents an atom of hydrogen, and m, A, R1, R2 and R3 are as defined in formula (I), with a hydrogen source and a hydrogenation catalyst; or (xxxi) when X represents a group CH20 (CH2)? -3 or CH20 (CH2) 2_30 and A is NHC (O), reacting a compound of the general formula wherein one of R28 and R29 represents a group -X '"- R4 and the other of R28 and R29 represents a hydrogen atom, X *" represents a group CH20 (CH2) 1_3 or CH20 (CH2) 2_30, L7 represents a leaving group and R2, R3 and R4 are as defined in formula (I), with a compound of formula (VII) as defined in (iii) above, optionally in the presence of a coupling agent; or (xxxii) when X represents a group CH20 (CH2)? _ 3 or CH20 (CH2) 2_30 and A is C (0) NH, reacting a compound of the general formula wherein R2 and R3 are as defined in formula (I) and R28 and R29 are as defined in formula (XXVII) in (xxxi) above, with a compound of formula (IX) as defined in (iv) above, in the presence of a base; and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), (xxiv), (xxv), (xxvi), (xxvii), (xxviii), (xxix), (xxx), (xxxi) or (xxxii) converting the compound of the formula (i) to a further compound of the formula (I) and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of the formula (I) ).
9. 9. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any of claims 1 to 7 in association with a pharmaceutically acceptable auxiliary, diluent or carrier. A process for the preparation of a pharmaceutical composition according to claim 9, characterized in that it comprises mixing a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any of claims 1 to 7 with a pharmaceutically acceptable auxiliary, diluent or carrier. 11. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any of claims 1 to 7, characterized in that it is used in therapy. 12. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any of claims 1 to 7 in the manufacture of a medicament for use in the treatment of arthritis. rheumatoid The use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any of claims 1 to 7 in the manufacture of a medicament for use in the treatment of a disease obstructive of the respiratory tract. 14. The use according to claim 13, wherein the obstructive airway disease is asthma or chronic obstructive pulmonary disease. A method of treating rheumatoid arthritis, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of the claims 1 to 7. 16. A method of treating an obstructive airway disease, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 7.