MXPA06010554A - Pyrazolo`4,3-d! pyrimidines - Google Patents

Abstract

This inventionrelates to compounds of formula (I).

Description

NEW DRUGS Field of I? Invention The present invention relates to a series of novel 5,7-diaminopyrazolo [4,3-c /] pyrimidines which are type 5 inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase or 3 ', 5'-guanosine monophosphate ( cGMP) (hereinafter referred to as PDE-5 inhibitors) which are useful in the treatment of hypertension and other disorders, to processes for their preparation, to intermediates used in their preparation, to compositions containing them are uses of said compounds and compositions. . i) Hypertension The prevalence of hypertension in developed countries is approximately 20% in the adult population, reaching approximately 60-70% in those over 60 years of age. Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal dysfunction. Despite a large number of drugs available in various pharmacological categories, the need for effective treatment of hypertension is still not satisfied. ii) PDE5 inhibitors Vascular endothelial cells secrete nitric oxide (NO). This acts on the vascular smooth muscle cells and leads to the activation of guanylate cyclase and the accumulation of cyclic guanosine monophosphate (cGMP). The cGMP accumulator causes muscle relaxation and blood vessels to dilate, leading to a reduction in blood pressure. The cGMP is inactivated by hydrolysis to 5'-guanosine monophosphate (GMP) by a cGMP specific phosphodiesterase. An important cGMP phosphodiesterase has been identified as phosphodiesterase type 5 (PDE5). PDE5 inhibitors reduce the rate of hydrolysis of cGMP and thus potentiate the actions of nitric oxide.

Background of the Invention PDE5 inhibitors have been described in various chemical classes, including: pyrazolo [4,3-d] pyrimidin-7-ones (eg, published international patent applications WO 93/06104, WO 98/49166, WO 99/54333, WO 00/24745, WO 01/27112 and WO 01/27113); pyrazolo [3,4-d] pyrimidin-4-ones (for example, published international patent application WO 93/07149); pyrazolo [4,3-c (] pyrimidines (for example, published international patent application WO 01/18004); quinazolin-4-ohas (for example, published international patent application WO 93/12095); pyrido [3,2 -d] pyrimidin-4-ones (for example, published international patent application WO 94/05661); purin-6-ones (for example, published international patent application WO 94/00453); hexahydropyrazine [2 ', : 6,1] pyrid [3,4-b] yl-1, 4-diones (for example, published international patent application WO 95/19978) and imidazo [5,1-f] [1,2, 4] triazin-onas (for example, published international patent application WO 99/24433) WO 02/00660 describes pyrazolo [4,3-d | pyrimidines with an inhibitory effect of PDE5, which can be used to treat disorders of the cardiovascular system WO 01/18004 discloses pyrazolo [4,3-d] pyrimidines with an inhibitory effect of PDE-5 There is still a demand for new PDE5 inhibitors, in particular with pharmacokinetic properties and improved macodynamics.

The compounds provided herein are potent PDE5 inhibitors having an improved in vitro selectivity or a prolonged half-life in vivo.

Detailed Description of the Invention According to a first aspect, the present invention provides compounds of formula (I) -X (i) wherein R1 is a cyclic group selected from RA, RB, Rc and RD, each of which is optionally substituted with one or more R7 groups; R2 is hydrogen or d-C2 alkyl; each of R3 and R4 is independently dd alkyl, C2-d alkenyl, alkynyl dd or C3-C10 cycloalkyl, each of which is optionally subsituted with one or more R8 groups, or RE, which is optionally substituted with one or more R9 groups, or hydrogen; or -NR3R4 form RF, which is optionally substituted with one or more R10 groups; R5 is -YNR15R16; R6, which may be attached at N1 or N2, is alkyl dd, haloalkyl dd, C2-C2 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with alkoxy dd, (cycloalkyl d-djmethoxy, haloalkoxy dd or a selected cyclic group of RJ, R ?, RL and RM, or R6 is RN, C3-C7 cycloalkyl or C3-C7 halocycloalkyl, each of which is optionally substituted with CrC6 alkoxy or haloalkoxy d-d, or R6 is hydrogen; R7 is halo, alkyl d-d, haloalkyl d-d, C2-C6 alkenyl, C2-d alkynyl, C3-C3 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R12, CONR12R13 or CN; R8 is halo, phenyl, (C6-alkoxy) phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R12, CONR12R13, CN, C3-C6 cycloalkyl , RG or RH, of which the latter two are optionally substituted with one or more R9 groups; R9 is alkyl d-d, haloalkyl d-d or CO2R12; R10 is halo, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R13, CONR12R13, CN, oxo, Crd alkyl or haloalkyl dd, of which the latter two are optionally subsituted with R11; R11 is phenyl, NR12R13 or NR12CO2R14; each of R12 and R13 is independently hydrogen, d-d alkyl or haloalkyl d-d; R 14 is d-d alkyl or CrC 6 haloalkyl; R15 is selected from R17, R17C (O) and R18SO2, and R16 is selected from hydrogen, alkyl dd optionally substituted with one or more groups R19, haloalkyl CrC6 and cycloalkyl C3-C10 optionally substituted with one or more groups R20, or -NR15R16 it constitutes a saturated ring of 3 to 8 members which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from R21, R22 and (CrC6 alkoxy) alkyl d-d; R17 is hydrogen or R18; R18 is selected from optionally substituted CrCß alkyl with one or more R19, haloalkyl-d and C3-C10 cycloalkyl groups optionally substituted with one or more R20 groups; R19 is selected from R21, -NR23R24, -CO2R25, -CONR26R27, R28 and optionally substituted phenyl with R29; R20 is selected from R21, R22 and oxo; R21 is oxo, hydroxy, d-d alkoxy, (haloalkyl d-Ce) oxy, or (d-C7 cycloalkyl) oxyR22 is d-d alkyl or CrCβ haloalkyl; each of R23 and R24 is independently selected from hydrogen and alkyl d-d; or -NR23R24 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R25 is hydrogen or alkyl d-d; each of R26 and R27 is independently selected from hydrogen and alkyl d-d; or -NR26R27 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R28 is a saturated, unsaturated or aromatic heterocycle with up to 10 carbon atoms, at least one of which is selected from nitrogen, oxygen and sulfur; R29 is selected from halo, R21 and R22, each of RA and RJ is independently a C3-C10 cycloalkyl group or cycloalkenyl dC-, each of which may be monocyclic or, where there is an appropriate number of ring atoms, polycyclic and which may be condensed with (a) a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur, or (b) a heteroalicyclic ring of 5, 6 or 7 members containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; each of RB and R? is independently a phenyl or naphthyl group, each of which may be fused with t (a) a C5-C7 cycloalkyl ring or C5-C7 cycloalkenyl ring, (b) a 5-, 6- or 7-membered heteroalicyclic ring conjoining up to three selected heteroatoms of nitrogen, oxygen and sulfur, or (c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; each of Rc, RL and RN is independently a monocyclic saturated or partially unsaturated ring system or, when there is an appropriate number of unsaturated polycyclic ring atoms containing from 3 to 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur, said ring may be condensed with a C5-C cycloalkyl or C5-C cycloalkenyl group or a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three Selected heteroatoms of nitrogen, oxygen and sulfur; each of RD and RM is independently a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur, said ring may further be fused with (a) a second 5 or 6 membered heleroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; (b) a C5-C cycloalkyl ring or C5-C cycloalkenyl ring; (c) a 5, 6 or 7 membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; or (d) a benzene ring; each of RE, RF and RG is independently a monocyclic, safed ring system or, when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from niógeno, oxygen and sulfur; and Y is a covalent, alkylenyl d-d or cycloalkullenyl d-C7 bond; one of its laulomers or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tauíomer. As used herein, alkylenyl denotes an alkyl- / t7, A7-diyl unit in which m and n are equal or different, such as methylene (-CH2-), ethylene (-CH2CH2-) and propane- 1,2-diyl (-CH (CH3) CH2-), As used herein, cycloalkylenyl denotes a cycloalkyl-m, n-diyl unit, wherein m and n are the same or different, such as cyclopropane- 1,1-diyl and cydohexane-1,4-diyl. Unless indicated otherwise, an alkyl or alkoxy group may be linear or branched and contain from 1 to 8 carbon atoms, preferably from 1 to 6 and in particular from 1 to 4 carbon atoms. Examples of alkyl include methyl, efyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxy include methoxy, ethoxy, iopropoxy and p-butoxy. Unless indicated otherwise, an alkenyl or alkynyl group may be linear or branched and contain from 2 to 8, preferably from 2 to 6 and in particular 2 to 4 carbon atoms and can contain up to 3 double or triple bonds that can be conjugated. Examples of alkenyl and alkynyl include vinyl, allyl, butadienyl and propargyl. Unless indicated otherwise, a cycloalkyl or cycloalkoxy group may contain from 3 to 10 carbon atoms, may be monocyclic or, when there is an appropriate number of ring atoms, polycyclic. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.

Unless otherwise indicated, a cycloalkenyl group may contain from 3 to 10 ring atoms, may be monocyclic or, when there is an appropriate number of ring atoms, polycyclic and may contain 3 double bonds. Examples of cycloalkenyl groups are cyclopentenyl and cyclohexenyl. Aryl includes phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, a heteroalicyclic group contains from 3 to 10 ring atoms, which may be up to four of which heteroatoms such as nitrogen, oxygen and sulfur, and may be saturated or partially saturated. Examples of heteroalicyclyl groups are oxiranyl, azetidinyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, midazolinilo, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl. Unless indicated otherwise, a heteroaryl group contains from 3 to 10 ring atoms, up to 4 of which heteroatoms such as nitrogen, oxygen and sulfur may be. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolium, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, triazinyl. In addition, the term heteroaryl includes fused heteroaryl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, qulnolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and insoindolyl. Halo refers to fluoro, chlorine, bromine or iodine. Haloalkyl includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, such as 2-bromoethyl, 2,2,2-trifluorophyl, chlorodifluoromethyl and trichloromethyl. Haloalkoxy includes monohaloalkoxy, polyalkaloxyl and perhaloalkoxy, such as 2-bromoethoxy, 2,2,2-fluorifethoxy, chlorodifluoromethoxy and trichloromethoxy. Halocycloalkyl includes monohalocycloalkyl, polyhalocycloalkyl and perhalocycloalkyl. Unless indicated otherwise, the term "substituted" means substituted with one or more defined groups. In the case that the groups can be selected from a series of alternative groups, the selected groups can be equal or different. In some embodiments, R21 is hydroxy, d-alkoxy, (haloalkyl) Crd) oxy or (C3-C) cycloalkyl) oxy. In a preferred embodiment, R1 is RA, which is optionally substituted with one or more R7 groups; and RA is a cycloalkyl d-do group, which may be monocyclic or, when there is an appropriate number of ring atoms, polycyclic, which may be fused with (a) a monocyclic aromatic ring selected from a benzene ring and a heteroaromatic ring of 5 or 6 members containing up to three heteroatoms selected from niógeno, oxygen and sulfur, or (b) a 5, 6 or 7 membered ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur. Preferably, RA is a monocyclic C3-C8 cycloalkyl group. More preferably, RA is a monocyclic C5-C cycloalkyl group. Most preferred, RA is cyclopentyl or cyclohexyl. In another preferred embodiment, R1 is RB which is optionally substituted with one or more R7 groups. Preferably, RB is phenyl. In another preferred modality, R1 is Rc, which is optionally substituted with one or more R7 groups. Preferably, Rc is a monocyclic saturated or partially unsaturated ring system containing from 3 to 8 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur. More preferably, Rc is a monocyclic saturated or partially unsaturated ring system that confers 5 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur. More preferably, R c is a monocyclic saturated ring system containing from 5 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur.

In another preferred embodiment, R1 is RD, which is optionally substituted with one or more R7 groups. Preferably, RD is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur. More preferably, RD is a 5-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur and optionally up to two additional nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1, 2 or 3 carbon atoms. nitrogen. More preferably RD is furanyl, thienyl, pyrrolyl, pyrazolyl, midazolyl, isoxazolyl, oxazolyl, isotlazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl. Most preferably, RD is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl. Preferably, R7 is halo, d-alkyl, haloalkyl d-d, OR12 or CON12N13. More preferably, R7 is halo, d-d alkyl, d-d alkoxy, hydroxy or CONH (d-d alkyl). Most preferably, R7 is fluoro, mephyl, ethyl, hydroxy, methoxy, propoxy or CONHMe. Preferably, R2 is hydrogen or methyl. More preferably, R2 is hydrogen.

Preferably, R3 is hydrogen, alkyl dd, which is optionally substituted with one or more groups R8, or RE, which is optionally substituted with one or more groups R9 and wherein RE is a monocyclic saturated ring system or, where an appropriate number of ring atoms, polycyclic containing from 3 to 7 ring atoms, of which at least one is a heteroalome selected from nitrogen, oxygen and sulfur. More preferably, R3 is hydrogen, d-d alkyl which is optionally substituted with one or more R8 or RE groups, which is optionally substituted with one or more R9 groups; and wherein RE is a monocyclic saturated ring system containing from 3 to 7 carbon atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur. In a preferred embodiment, R3 is RE that is optionally substituted with one or more R9 groups and wherein RE is a monocyclic saturated ring system containing from 3 to 7 ring atoms containing a nitrogen atom. More preferably, RE is azetidinyl, pyrrolidinyl or piperidinyl. In another preferred embodiment, R3 is alkyl d-d which is optionally substituted with one or more R8 groups and wherein R8 is halo, phenyl, (C6-alkoxy) phenyl, OR12, NR12R13, NR12CO2R14, CO2R12, CONR12R13, RG or RH, of which the last two are optionally substituted with one or more R9 groups.

More preferably, R8 is hydroxy, methoxy, methoxyphenyl, NH2, NHMe, NMe2, NHCO2Bu, NMeCO ^ Bu, CO2H, 'CONHMe, RG or RH, of which the latter two are optionally substituted with one or more R9 groups. In a preferred embodiment, R8 is RG, which is optionally substituted with one or more R9 groups and wherein RG is a monocyclic saturated ring system containing from 3 to 7 ring atoms, of which at least one is a heteroalome selected from niógeno, oxygen and sulfur. More preferably, RG is a monocyclic saturated ring system containing from 3 to 7 ring atoms containing a nitrogen atom and optionally an oxygen atom. Most preferably, RG is pyrrolidinyl, piperidinyl or morpholinyl. In another preferred embodiment, R8 is RH, which is optionally substituted with one or more R9 groups and wherein RH is a 5- or 6-membered heteroaromatic ring containing up to two nitrogen atoms. More preferably, RH is pyrazolyl. Preferably, R9 is methyl or COz'Bu. In another preferred embodiment, R3 is hydrogen or alkyl dd which is optionally substituted with one or more groups R8, or R3 is azetidinyl, pyrrolidinyl or piperidinyl, each of which is optionally substituted with one or more groups R9, wherein R8 is hldroxy, methoxy, methoxyphenyl, NH2, NHMe, NMe2, NHCO ^ BU, NMeCO ^ Bu, CO2H, CONHMe, pyrrolidinyl, piperidinyl, morpholinyl or pyrazolyl, of which the last four are optionally substituted with one or more R9 groups and in which R9 is methyl or CO2lBu. In a preferred embodiment, R4 is hydrogen, d-alkyl, haloalkyl d-d, C2-C6 alkenyl or C2-C6 alkynyl. More preferably, R 4 is hydrogen, d-d alkyl or haloalkyl d-d. Most preferably, R4 is hydrogen, methyl or ethyl. In another preferred embodiment, -NR3R4 forms RF, which is optionally substituted with one or more R10 groups and in which RF is a monocyclic saturated ring system or, where there is an appropriate number of ring atoms, polycyclic ring containing 3 to 10 ring atoms containing at least one nitrogen atom and optionally another atom selected from oxygen and sulfur. More preferably, RF is a monocyclic saturated ring system or, when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms containing one or two nitrogen atoms and optionally another atom selected from oxygen and sulfur . Most preferably, RF is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 3-azabicyclo [3.1.0] hex-3-yl, homopiperazinyl, 2,5-diazabicyclo [4.3.0] non-2-yl, 3,8-diazabicyclo [3.2.1] oct-3-lo, 3,8-diazabicyclo [3.2.1] oct-8-yl, 2,5-diazabicyclo [2.2.1] hept-2-yl, 1 , 4-diazabicyclo [4.3.0] non-4-yl and 1,4-dlazabicyclo [3.2.2] non4-yl. Preferably, R10 is halo, OR12, NR12R13, NR12CO2R14, CO2R13, oxo, d-alkyl or Cr-haloalkyl, of which the latter two are optionally substituted with R11. More preferably, R10 is halo, mephyl, ethyl, isopropyl, hydroxy, methoxy, NH2, NHMe, NMe2, NHCO2tBu, CO2H, CO2tBu, oxo, benzyl, -CH2NH2"-CH2NHMe, CH2NMe2 or -CH2NMeCO2lBu. In a preferred embodiment, R5 is -Y-NR15R16 and Y is CrC6 alkylenyl. More preferably, Y is methylene (-CH2-). In another preferred embodiment, R5 is -Y-NR15R16, R15 is R17C (O) or R18SO2-, and R16 is hydrogen or alkyl d-d. In another preferred embodiment, R5 is -Y-NR15R16, R15 is R17, and R16 is hydrogen or alkyl d-d. In another preferred embodiment, R17 is R8 and R18 is alkyl d-d optionally substituted with a group R19. In another preferred embodiment, R5 is -Y-NR15R16 wherein -NR 5R16 comprises a saturated ring of from 3 to 8 members which may optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from R21, R22 and (alkoxy d-djalkyl Crd. More preferably, -NR15R16 constitutes a saturated 5 or 6 membered ring which may optionally include an additional nitrogen atom and which may be optionally subsituted with a group selected from R21, R22 and (alkoxy dd) CrC6 alkyl Preferably, R21 is alkoxy dd and R22 is alkyl dd Preferably, R6 is located at N1 to give the compound of formula (IA): In an alternate embodiment of the present invention, R6 may be located at N2 to give the compound of formula (IB): Preferably, R6 is alkyl d-d or haloalkyl d-d, each of which is optionally substituted with alkoxyl d-d, haloalkoxy d-d or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; RJ is a C3-C7 monocyclic cycloalkyl group; each of RL and RN is independently a saturated or partially unsaturated monocyclic ring system which confers 4 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; and RM is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nihorogen, oxygen and sulfur. More preferably, R6 is d-C alkyl or haloalkyl d-d, each of which is optionally substituted with d-C4 alkoxy, haloalkoxy d-d or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; RJ is cyclopropyl or cyclobutyl; each of RL and RN is independently a monocyclic, safed ring system containing 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; and RM is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur. More preferably, R6 is CrC alkyl or haloalkyl-d, each of which is optionally substituted with d-alkoxy or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; RJ is cyclopropyl or cyclobutyl; each of RL and RN is independently a monocyclic saturated ring system containing 5 or 6 ring atoms containing a heteroatom selected from nitrogen, oxygen and sulfur; and RM is a 5- or 6-membered heteroaromatic ring containing a nitrogen atom. More preferably, R6 is d-C alkyl or haloalkyl d-d, each of which is optionally substituted with d-d alkoxy, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl or pyridinyl, or R6 is hydrogen or tetrahydropyranyl. Most preferably, R6 is hydrogen, methyl, ethyl, isopropyl, isobutyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, 2,2,2-trifluoroethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, tetrahydropyranyl or pyridinylmethyl. Preferred embodiments of the compounds of formula (I) are those that incorporate two or more of the above preferences. In some embodiments, the compounds of formula (I) are as follows: R1 is a cyclic group selected from RA, RB, Rc and RD, each of which is optionally substituted with one or more R7 groups; R2 is hydrogen or alkyl d-d; R3 is hydrogen, alkyl d-d, which is optionally subsituted with one or more R8 groups, or RE, which is optionally substituted with one or more R9 groups; R4 is hydrogen, d-d alkyl or haloalkyl d-d, or -NR3R4 form RF, which is optionally substituted with one or more R10 groups; R5 is -Y-NR15R16; R6 is alkyl d-d or haloalkyl d-C4, each of which is optionally substituted with d-alkoxy, haloalkoxy d-d or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; R7 is halo, alkyl-d, haloC6 CrC6, C2-C6 alkenyl, C2-C alqu alkynyl, C3-C10 cycloalkyl, d-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13 , NR12CO2R14, C (O) R12, CO2R12, CONR12R13 or CN; R8 is halo, phenyl, (CrC6 alkoxy) phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R12, CONR12R13, CN, C3-C6 cycloalkyl, RG or RH, of which the latter two are optionally substituted with one or more R9 groups; R9 is CrC6 alkyl, haloalkyl -d or CO2R12; R10 is halo, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R13, CONR12R13, CN, oxo, alkyl d-d or haloalkyl d-d, of which the latter two are optionally substituted with R11; R11 is phenyl, NR12R13 or NR12CO2R14; each of R 12 and R 13 is independently hydrogen, C 1 -C 6 alkyl or haloalkyl d-d; R 14 is C C β alkyl or C C β haloalkyl; R15 is selected from R17, R17C (O) and R18SO2, and R16 is selected from hydrogen, alkyl -d optionally substituted with one or more groups R19, haloalkyl dd and cycloalkyo C3-C10 optionally substituted with one or more R20 groups, or - NR15R16 constitutes a 3- to 8-membered saturated ring which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur; and which may be optionally substituted with one or more groups selected from R21, R22 and (CrCß alkoxy) Crd alkyl; R17 is hydrogen or R18; R18 is selected from d-d alkyl optionally substituted with one or more R19, haloalkyl- and C3-C10 cycloalkyl groups optionally substituted with one or more R20 groups; R19 is selected from R21, -NR23R24, -CO2R25, -CONR26R27, R28 and phenyl optionally substituted with R29; R20 is selected from R21, R22 and oxo; R21 is hydroxy, d-alkoxy, (CrC14alkyl or (cycloalkyl) haloalkyl C3-C7) oxy; R22 is alkyl d-d or haloalkyl d-d; each of R23 and R24 is independently selected from hydrogen and CrCβ alkyl; or -NR23R24 constitutes an azetidine, pyrroiidine, piperidine or morpholine ring; R25 is hydrogen or Crd alkyl; each of R26 and R27 is independently selected from hydrogen and CrCß 'alkyl, or -NR26R27 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R28 is a saturated, unsaturated or aromatic heterocycle with up to 10 ring atoms, at least one of which is selected from nitrogen, oxygen and sulfur; R29 is selected from halo, R21 and R22, RA is a monocyclic C3-C8 cycloalkyl group; RB is phenolic; Rc is a monocyclic or partially unsaturated saturated ring system containing from 3 to 8 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RD is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur; RE is a monocyclic saturated ring system containing from 3 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RF is a monocyclic saturated ring system, or when there is an appropriate number of polycyclic ring atoms containing from 3 to 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RJ is cyclopropylo or cyclobutyl; each of RL and R is independently a monocyclic saturated ring system containing 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; R? is a phenyl or naphthyl group, each of which may be fused with (a) a C5-C cycloalkyl ring or a C5-C7 cycloalkenyl ring, (b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three selected heteroatoms of nitrogen, oxygen and sulfur, or (c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; RG is a monocyclic saturated ring system or, when there is an appropriate number of polycyclic ring atoms, which confers from 3 to 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered aromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur; RM is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nilrogen, oxygen and sulfur; and Y is Ci-Cβ alkylenyl. In other embodiments, the compounds of formula (I) are as follows: R1 is a cyclic group selected from RA, RB, Rc and RD, each of which is optionally substituted with one or more R7 groups; R2 is hydrogen or alkyl d-d; R3 is hydrogen, alkyl-d, which is optionally substituted with one or more groups R8, or RE, which is optionally substituted with one or more R9 groups; R 4 is hydrogen, CrCβ alkyl or CrCβ haloalkyl, or -NR 3 R 4 form RF, which is optionally substituted with one or more R 10 groups; R5 is -Y-NR15R16; Rd is d-d alkyl or CrC4 haloalkyl, each of which is optionally substituted with d-alkoxy, haloalkoxy d-d or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; R7 is halo, alkyl d-d, haloalkyl CrC6, OR12 or CONR12R13; R8 is halo, phenyl, (CrC6 alkoxy) phenyl, OR12, NR12R13, NR 2CO2R14, CO2R12, CONR12R13, RG or RH, of which the latter two are optionally substituted with one or more R9 groups; R9 is alkyl d-d, haloalkyl d-d or CO2R12; R10 is halo, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenol, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R13, CONR12R13, CN, oxo, alkyl d-d or haloalkyl d-Cß, of which the latter two are optionally substituted with R11; R11 is phenyl, NR12R13 or NR12CO2R14; each of R12 and R13 is independently hydrogen, d-d alkyl or Crd haloalkyl; R 14 is CrCß alkyl or haloalkyl d-d; R15 is selected from R17, R17C (O) and R8SO2, and R16 is selected from hydrogen, alkyl dd optionally substituted with one or more groups R19, haloalkyl dd and C3-C10 cycloalkyl optionally substituted with one or more R20 groups, or - NR15R16 constitutes a saturated ring of 3 to 8 members which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur; and which may be optionally substituted with one or more groups selected from R21, R22 and (Crd alkoxy) alkyl-d; R17 is hydrogen or R18; R18 is selected from optionally substituted d-d alkyl with one or more R9 groups, haloalkyl d-d and C3-C10 cycloalkyl optionally substituted with one or more R20 groups; R19 is selected from R21, -NR23R24, -CO2R25, -CONR26R27, R28 and phenyl optionally substituted with R29; R20 is selected from R21, R22 and oxo; R21 is hydroxy, d-Cß alkoxy, (haloalkyl CrCß) oxy or (cycloalkyl) C3-C7) oxy; R22 is CrCß alkyl or CrCß haloalkyl; each of R23 and R24 is independently selected from hydrogen and CrCβ alkyl; or -NR23R24 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R25 is hydrogen or CrCß alkyl; each of R26 and R27 is independently selected from hydrogen and alkyl d-d; or -NR26R27 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R28 is a saturated, unsaturated or aromatic heterocycle with up to 10 ring atoms, at least one of which is selected from nitrogen, oxygen and sulfur; R29 is selected from halo, R21 and R22, R? is a monocyclic C5-C cycloalkyl group; RB is phenyl; Rc is a monocyclic saturated ring system containing to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RD is a 5-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur and optionally up to two more nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1, 2 or 3 nitrogen atoms; RE is a monocyclic saturated ring system containing from 3 to 7 ring atoms which contains a nitrogen atom; RF is a monocyclic saturated ring system, or when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms containing at least one nitrogen atom and optionally another atom selected from oxygen and sulfur; RG is a monocyclic saturated ring system containing 3 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered heteroaromatic ring containing up to two nitrogen atoms; RJ is cyclopropyl or cyclobutyl; each of RL and RN is independently a monocyclic saturated ring system containing 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; R? is a phenyl or naphthyl group, each of which may be fused to (a) a C5-C7 cycloalkyl ring or C5-C cycloalkenyl ring, (b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three selected heteroatoms of nitrogen, oxygen and sulfur; or (c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; RM is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur; and Y is -CH2-; Preferably, R1 is a cyclic group selected from RA, RB, R and R, each of which is optionally substituted with one or more R7 groups; R2 is hydrogen or CrC2 alkyl; R3 is hydrogen, d-C alkyl, which is optionally substituted with one or more groups R8, or RE, which is optionally substituted with one or more R9 groups; R 4 is hydrogen, d-d alkyl or haloalkyl d-d; or -NR3R4 form RF, which is optionally substituted with one or more R10 groups; R5 is -Y-NR15R16; R6 is alkyl d-d or haloalkyl CrC, each of which is optionally substituted with alkoxy d-d, haloalkoxy d-d or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; R7 is halo, C-C-alkyl, d-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, C3-C10-halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13 , NR12CO2R14, C (O) R12, CO2R12, CONR 2R13 or CN; R8 is halo, phenyl, (CrC6 alkoxy) phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R12, CONR12R13, CN, RG or RH, the last two of which are optionally substituted with one or more R9 groups; R9 is CrC6 alkyl, d-C6 haloalkyl or CO2R12; R10 is halo, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R13, CONR12R13, CN, oxo, C6 alkyl or C6 haloalkyl, the last two of which are optionally substituted with R11; R11 is phenyl, NR12R13 or NR12CO2R14; each of R 12 and R 13 is independently hydrogen, C C β alkyl or haloalkyl d-d; R14 is CrC6 alkyl or haloalkyl d-d; R15 is hydrogen or CrC3 alkyl; R16 is tetrazol-5-yl, 5-trifluoromethyl-1,2-4-triazole-3-yl or 2,5-dihydro-5-oxo-1, 2,4-oxadiazol-3-yl; RA is a monocyclic d-d cycloalkyl group; RB is phenyl; Rc is a monocyclic or partially unsaturated saturated ring system containing from 3 to 8 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RD is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nihorogen, oxygen and sulfur; RE is a monocyclic saturated ring system containing from 3 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; each of RF and RG is independently a monocyclic saturated ring system, or when there is an appropriate number of polycyclic ring atoms containing from 3 to 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered aromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur; RJ is cyclopropyl or cyclobutyl; each of RL and RN is independently a monocyclic saturated ring system containing 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; R is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur; and Y is alkylene d-d. More preferably, R1 is a cyclic group selected from RA, RB, Rc and RD, each of which is optionally substituted with one or more R7 groups; R2 is hydrogen or d-C2 alkyl; R3 is hydrogen, alkyl-d, which is optionally substituted with one or more groups R8, or RE, which is optionally substituted with one or more R9 groups; R 4 is hydrogen, d- or haloalkyl d-d; or -NR3R4 form RF, which is optionally substituted with one or more groups R10; R5 is -Y-NR15R16; R6 is Crd alkyl or haloalkyl d-d, each of which is optionally substituted with d-alkoxy, haloalkoxy d-d or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; R7 is halo, alkyl d-d, haloalkyl CrC6, OR12 or CONR12R13; R8 is halo, phenyl, (C? -Cβ) alkoxy phenyl, OR12, NR12R13, NR12CO2R14, CO2R12, CONR12R13, RG or RH, the last two of which are optionally substituted with one or more R9 groups; R9 is alkyl d-d, haloalkyl d-d or CO2R12; R10 is halo, cycloalkyl dCyclohexacycloalkyl C3-C10, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R13,. CONR12R13, CN, oxo, alkyl d-d or haloalkyl d-d, the last two of which are optionally substituted with R11; , - R11 is phenyl, NR12R13 or NR12CO2R14; each of R12 and R13 is independently hydrogen, d-d alkyl or haloalkyl d-d; R 14 is CrCß alkyl or haloalkyl d-d; R15 is hydrogen; RA is a monocyclic d-C cycloalkyl group; RB is phenyl; Rc is a monocyclic saturated ring system containing from 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RD is a 5-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur and optionally up to two more nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1, 2 or 3 nitrogen atoms; RE is a monocyclic saline ring system which confers 3 to 7 ring atoms containing a nitrogen atom; RF is a monocyclic saturated ring system, or when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms which confers at least one nickel atom and optionally another atom selected from oxygen and sulfur; RG is a monocyclic saturated ring system that contains from 3 to 7 ring backs, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered aromatic ring containing up to two nitrogen atoms; each of RL and RN is independently a monocyclic saturated ring system containing 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RM is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulfur; and Y is methylene. In some embodiments, R2 in the compounds of formula (IA) is hydrogen, and the structure of the compounds corresponds to formula (IA-1): wherein R1 is a cyclic group selected from RB and RD, each of which is optionally substituted with one or more R7 groups; RB is phenyl; RD is a 6-membered heteroaromatic ring that includes 1, 2 or 3 nitrogen atoms; R7 is halo, d-d alkyl, d-d alkoxy, hydroxy or CONH (d-C3 alkyl); R3 is hydrogen, alkyl d-d, which is optionally. substituted with one or more R8 groups, or R3 is azetidinyl, pyrrolidinyl or piperidinyl, each of which is optionally substituted with one or more R9 groups; and R 4 is hydrogen, d-d alkyl or haloalkyl d-d; or -NR3R4 form RF, which is optionally substituted with one or more R10 groups; R8 is hydroxy, methoxy, methoxyphenyl, NH2, NHMe, NMe2, NHCO ^ Bu, NMeCO2lBu, CO2H, CONHMe, plrrolidinyl, piperidinyl, morpholinyl or pyrazolyl, the last four of which are optionally substituted with one or more R9 groups; R9 is methyl or CO2 * Bu; RF is a monocyclic saturated ring system or, when there is an appropriate number of ring atoms, polycyclic which confers from 3 to 10 ring atoms which confers one or two nitrogen atoms and optionally another atom selected from oxygen and sulfur; R10 is halo, mephyl, ethyl, isopropyl, hydroxy, methoxy, NH2, NHMe, NMe2, NHCO2tBu, CO2H, CO ^ Bu, oxo, benzyl, -CH2NH2, -CH2NHMe, CH2NMe2 or -CH2NMeCO2tBu; R5 is -Y-NR15R16; Y is C C β alkylenyl, R 15 is selected from R 17, R 17 C (O) and R 18 SO 2, and R 18 is selected from hydrogen, alkyl d- optionally substituted with one or more R 19 groups, CrC 9 haloalkyl and C 3 -C 10 cycloalkyl optionally substituted with one or more R20 groups, or -NR15R16 constitutes a 3- to 8-membered saturated ring which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from R21, R22 Y (CrCß alkoxy) alkyl -d; R 17 is hydrogen or R 8; R18 is selected from CrCß alkyl optionally substituted with one or more R19 groups, CrCß haloalkyl and C3-C10 cycloalkyl optionally substituted with one or more R20 groups; R19 is selected from R21, -NR22R24, -CO2R25, -CONR26R27, R28 and phenyl optionally substituted with R29; R20 is selected from R21, R22 and oxo; R21 is oxo, hydroxy, d-alkoxy, (CrC6 haloalkyl) oxy or (d-C7 cycloalkyl) oxy; R22 is alkyl d-d or haloalkyl CrC6; each of R23 and R24 is independently selected from hydrogen and alkyl d-d; or -NR23R24 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R25 is hydrogen or CrCß alkyl; each of R26 and R27 is independently selected from hydrogen and CrCβ alkyl; or -NR26R27 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R28 is a saturated, unsaturated or aromatic heterocycle having up to 10 ring atoms, at least one of which is selected from nitrogen, oxygen and sulfur; R29 is selected from halo, R21 and R22, R6 is d-C4 alkyl or haloalkyl dd, each of which is optionally substituted with alkoxl dd, haloalcoxl Crd or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; RJ is cyclopropyl or cyclobutyl; each of RL and RN is independently a monocyclic saturated ring system containing 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; Y RM is a 5- or 6-membered heteroaromatic ring that confers a heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the structure of the compounds of formula (LA-1) corresponds to formulas (LA-2) and (LA-3): In some embodiments, the compounds of formula (LA-2) and (I | MA-3) are as follows: R1 is phenyl, pyridinyl or pyrimidinyl, each optionally substituted with one or more R7 groups; R7 is halo or alkyl CrCs; R3 is hydrogen or alkyl substituted with one or more groups R8, and R4 is hydrogen or CrCß alkyl, or - NR3R4 piperazinyl form optionally substituted with one or more groups R10; R8 is hydroxy or methoxy; R10 is methyl; And it's metlleno; R15 is selected from R17, R17C (O) and R18SO2, and R16 is selected from hydrogen, CrCß alkyl optionally substituted with one or more R19 groups, haloalkyl dd and C3-C10 cycloalkyl optionally substituted with one or more R20 groups, or -NR15R16 it constitutes a saturated ring of 5 to 7 members which may optionally include one or more additional heleroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from R21, R22 and (alkoxy d-C6) alkyl CrCß; R17 is hydrogen or R18; R18 is selected from CrCß alkyl optionally substituted with one or more R19 groups, CrCß haloalkyl and C3-C10 cycloalkyl optionally substituted with one or more R groups; R19 is selected from R21 and -NR23R24; R20 is selected from R21, R22 and oxo; R21 is oxo, hydroxy and CrCβ alkoxy; R22 is alkyl d-d or haloalkyl d-d; and each of R23 and R24 is independently selected from hydrogen and alkyl d-d. In some embodiments, the compounds of formula (Ia-2) and (Ia-3) are as follows: R 1 is phenyl, pyridinyl or pyrimidinyl, each optionally substituted with one or more R 7 groups; R7 is halo or alkyl d-d; R3 is hydrogen or alkyl substituted with one or more R8 groups, and R4 is hydrogen or d-d alkyl, or -NR3R4 piperazinyl form optionally substituted with one or more R10 groups; R8 is hydroxy or methoxy; R10 is methyl; And it's methylene; R15 is selected from R17, R17C (O) and R18SO2, and R16 is selected from hydrogen, dd alkyl, C-C halo haloalkyl and d-do cycloalkyl optionally substituted with one or more hydroxy groups, or -NR15R16 constitutes a saturated ring of 5 to 7 members which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from alkyl C Cβ, oxo, hydroxy and (d-d-alkyloxy d-d-alkyl; R 17 is hydrogen or R 18; > R is selected from alkyl d-d optionally substituted with one or more groups R19, haloalkyl d-d and cycloalkyl d-do optionally substituted with one or more hydroxy groups; R19 is selected from hydroxy and -NR23R24; and each of R23 and R24 is independently selected from hydrogen and CrCß alkyl. In some embodiments, the structure of the compounds of formula (LA-1) corresponds to one of the following formulas: (C- | -C6 alkoxy) C-] - C6 alkyl, (C- | -C6 alkoxy) C- \ - CQ alkyl, (C- | -C6 alkoxy) C- \ - CQ alkyl, (C alco-Cg alkoxy) C C-Cß alkyl, (alkoxy C "| -Ce) alkyl C-i-C ?, CrCß) alkyl C- -CQ, C- | -C6 In the formulas (A1-5) to (A1-136) above, R7 and R10 represent one or more substituents R7 or R10, respectively. In some embodiments, the structure of the compounds of formula (LA-2) corresponds to the formula (LA-4) wherein R1 is a cyclic group RD that is optionally substituted with one or more alkyl groups d-d; each of R3 and R4 is independently hydrogen or d-d alkyl optionally substituted with a group selected from OH and OCH3; R15 is selected from R17, R17C (O) and R18SO2, and R16 is selected from hydrogen and alkyl dd, or -NR15R16 constitutes a saturated 5 or 6 membered ring which may optionally include one or more additional heteroatoms selected from nitrogen and oxygen, and which may optionally be substituted with a group selected from methyl, methoxy and methoxymethyl; R17 is selected from d-d alkyl optionally substituted with a group selected from hydroxy, methoxy and dimethylamino; R18 is selected from alkyl d-d optionally substituted with a group selected from hydroxy, methoxy and dimethylamino; and RD is a 6-membered heteroaromatic ring containing one or two nitrogen atoms; one of its tautomers or a pharmaceutically acceptable salt, solvate or polymorph of said compound or tautomer. In the compounds of formula (LA-4): R1 is preferably a cyclic group RA, which is optionally substituted with a methyl group. RA is preferably a pyridyl, pyrimidinyl or pyrazinyl group. Preferably, R3 is alkyl d-d optionally substituted with a group selected from OH and OCH3 and R4 is hydrogen or C1-C3 alkyl. R3 is more preferably me yyl or ethyl optionally substituted at the 2-position with a group selected from OH and OCH3. R4 is more preferably hydrogen or methyl. In a preferred embodiment, R15 is selected from R17, R17C (O) and R18SO2 and R16 is selected from hydrogen and alkyl d-d. In a more preferred embodiment, R15 is R7 and R17 is alkyl d-d or 2-methoxyielyl. In another more preferred embodiment, R15 is R17C (O) and R17 is selected from methyl, efil, hydroxymethyl and dlmethylaminomethyl. In another more preferred embodiment, R15 is R18SO2 and R18 is mephyl. In another preferred embodiment -NR15R16 constitutes a 5 or 6 membered saturated ring which may optionally include an additional heteroatom selected from nitrogen and oxygen, and which may optionally be susliluted with a group selected from methyl, methoxy and methoxymethyl. More preferably, -NR15R16 constitutes a pyrrolidine, morpholine or piperazine ring optionally substituted with a group selected from methyl, methoxy and methoxymethyl. In a modality, preferred compounds are the compounds of Examples 1 to 107. In another embodiment, preferred compounds are: 2-d-methylamino- / V- [5-dimethylamino-1 - (2-ethoxy-6-yl) -7- (4 -methylpyridin-2-ylamino) -1 / V-pyrazolo [4,3-cflpyrimidin-3-methylmethyl] acetamide,? / - [5-d-methylamino-1- (2- ethoxyethyl) -7- (4-methylpyridin-2-ylamine) -1 / - / - pyrrazolo [4,3-c-pyrimidin-3-ylmethyl] -mefanosulfonamide,? / - [5-dimethylamino-1- (2-ethoxy-ethyl) -7- (4-methylpyridn-2-ylamino) -1H-pyrazolo [4,3-d] pyrim Din-3-methoxy] hydroxy acetamide, / V- [5-diethylmethyl-1- (2-ethoxyethyl) -7- (4-methylpyridin-2-ylam No) -1H-pyrazolo [4,3-cdp-rimidin-3-methylmethyl] acetamide,? / - [1- (2-ethoxy) -5-ethyl-7- (4- methylpyridin-2-ylamino) -1H-pyrazolo [4,3-d] pyrimidin-3-methy1] acetamide,? / - [5-dlmethylamino-1- (2-eloxethyl) -7- (4-methylpyridin-2-ylamine) -1H-pyrazolo [4,3-GQpyrmidin-3-ylmethyl] propionamide, / V- [1- (2- ethoxyethyl) -5-ethylamino-7- (4-methylpyridin-2-ylamino) -1-pyrazolo [4,3-c-pyrimidin-3-ylmethyl] namide,? / - [1- (2-ethoxyethyl) -5-ethylamino-7- (4-methylpyridin-2-ylamino) -1H- p¡razolo [4,3-] pyrimidn-3-! lmethyl] -? / - methylacetamide, 1- (2-ethoxyethyl) -? / 5,? / -dmethyl-3 - [(4-methylpipezin-1-l) methyl-? / 7- (4-methylpyridin-2-yl) -1 W-pyrrazolo [4,3-c-pyrimidin-5,7-d-amine, 1 - (2-ethoxyethyl) - / V5,? / 5-d.methyl-3 - [(4-morpholino) methyl- / V7- (4-meiylpyridin-2-yl) -1H-pyrazolo [4,3-c] pyrimidine-5 , 7-d-amines, and 1- (2-eloxy-yl) -3- (ethylaminometyl) -? / 5,? / 5-dimelyl- / V7- (4-methylpyridin-2-yl) -1W-p Razolo [4,3-c (pyrimidin-5-J-diamine and its tautomers and pharmaceutically acceptable salts, solvates and polymorphs of said compounds or tautomers. The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts and bases thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate salts, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicoininate, nitrate, orolate, oxalate, palmitate, pamoate, phosphate / phosphate acid / diacid phosphate, saccharate, stearate , succinate, tartrate, tosylate and trifluoroacetate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, Usin, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wlley-VCH, Weinheim, Germany (2002)). A pharmaceutically acceptable salt of a compound of formula (I) can be prepared easily by mixing solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt can be precipitated in solution and can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in both unsolvated and solvated forms. The term 'solvate' is used in this specification to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is used when said solvent is water. Included within the scope of the invention are complexes such as clairaviruses, drug-host inclusion complexes in which, in contrast to the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or non-ionized.

For a review of such complexes, see J. Pharm Sci, 64 (8), 1269-1288 of Haleblian (August 1975). Hereinafter all references to the compounds of formula (I) include references to the salts, solvates and complexes thereof and to solvates and complexes of their salts. The compounds of the invention include compounds of formula (I) as defined herein above, polymorphs, prodrugs, and isomers thereof (including optical, geometric, and tautomeric isomers) as defined herein below and the isotope-labeled compounds of formula (I) ). As discussed, the invention includes all polymorphs of the compounds of formula (I) that have been defined hereinbefore. Also within the scope of the invention are the so-called "prodrugs" of the compounds of formula (I). Thus, certain derivatives of the compounds of formula (I) which may have little or no pharmacological activity by themselves may, when administered in the interior or on the body, become the compounds of formula (I) having the desired activity , for example, by hydrolytic cleavage. Said derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found at 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and in 'Bioreversible Carriers in Drug Design ', Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Assoclation). Prodrugs according to the invention can, for example, be produced by replacing the appropriate functionalities present in the compounds of formula (I) with certain residues known to those skilled in the art as "pro-resins" as described, for example. , in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples of prodrugs according to the invention include: (i) when the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example replacement of hydrogen with (Ci-C8) alkyl; (ii) when the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of hydrogen with alkanoymethyl (CrCß); and (ili) when the compound of formula (I) confers a primary or secondary amino functionality (-NH2 or -NHR where R? H), an amide thereof, for example, replacement of one or both hydrogens with alkanoyl (C1-) C10). Other examples of the replacement groups according to the above examples and examples of other types of prodrugs can be found in the aforementioned references. Finally, certain compounds of formula (I) can themselves act as prodrugs of other compounds of formula (I). The compounds of formula (I) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans isomers (or Z / E) are possible. When the compound contains, for example, a keto or oxime group or an aromatic residue, it may produce an omeutomeric ("tautomeric") solution. From this it follows that an individual compound may have more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and taufomeric forms of the compounds of formula (I), including compounds that show more than one isomeric type, and mixtures of one or more thereof. Also included are acid addition salts or bases in which the counterion is optically active, for example, D-lactate, or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional chrystallisation and one or both of the diastereoisomers can be converted to the corresponding enantiomer (s) by means well known to those skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can be obtained in an enantiomerically enriched form using chromaeography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% isopropanol, typically 2 to 20%, and 0 to 5% of an alkylamine; typically 0.1% diethylamine. The concentration of the eluate produces the enriched mixture. The stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York; 1994).

The present invention includes all pharmaceutically acceptable isotope-labeled compounds of formula (I) in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or number Massive usually found in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chloro, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen such as 13N and 15N, oxygen such as 15O, 17O and 18O, phosphorus such as 32P and sulfur such as 35S. Certain compounds labeled with isotopes of formula (I), for example, those incorporating a radioactive isotope, are useful in distribution studies in drug tissues and / or substrates. The radioactive isotopes tritium, ie 3H, and carbon-14, ie 14C, are particularly useful for this purpose in view of their easy incorporation and simple means of detection. Substitution with heavier isotopes such as deuterium, ie 2H, may provide certain therapeutic advantages that result from increased metabolic stability, for example, increased half-life in vivo or decreased dosing requirements, and therefore It can be preferred in some circumstances. Substitution with positron emitting isotopes, such as 1C, 18F, 15O, and 13N, may be useful in post-emission emission tomography (PET) studies to examine the occupation of substrate receptors. The isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the examples and accompanying preparations using appropriate isotope-labeled reactants in place of the reactants not previously marked employees. The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example D2O, d6-acetyone, d6-DMSO. The compounds of the invention proposed for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, in the form of plugs, powders, or solid films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radiofrequency drying can be used for this purpose. The present invention provides pharmaceutical compositions comprising compounds of formula (I), or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a pharmaceutically acceptable diluent or carrier. The present invention also provides pharmaceutical compositions comprising compounds of formula (I), or pharmaceutically acceptable salts, solvates or polymorphs thereof, and a second pharmaceutically active agent selected from aspirin, angiotensin receptor antagonists 11 (such as losartan, candesartan, telmisartan , valsartan, irbesartan and eprosartan), calcium channel blockers (such as amlodipine), beta-blockers (ie, beta-adrenergic receptor antagonists such as sotalol, propranolol, imolol, atenolol, carvedilol and metoprolol), CU 027, CCR5 receptor antagonists, imidazoles, sGCa (soluble guanylate cyclase activators) antihypertensive agents, diuretics (such as hydrochlorothiazide, urside, chlorothiazide, chlorthalidone and amiloride), alpha adrenergic antagonists (such as doxazosin), ACE inhibitors (converting enzyme of angiotensin) (such as quinapril, enalapril, ramipril and lisinopril), Aldosterone receptor aniagonyses (such as eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (such as insulin), sulfonylureas (such as glyburide, glipizide and glimeplide), glitazones (such as rosiglltazone and pioglitazone) and metformin), hypocholesterolemic agents (such as atorvastatin, pravastatin, lovastatin, simvastatin, clofibrate and rosuvastatin) and alpha-2-delta ligands (such as as gabapentin, pregabalin, [(1 R, 5R, 6S) -6- (aminomethyl) b [clo] 3.2 (2) hept-6-yl] acetic acid, 3- (1-aminonomethyl) -cyclohexylmethyl) -4H- [1, 2,4] oxadiazol-5-one, C- [1- (1 H-tetrazol-5-ylmethyl) -cycloheptyl] -methylamine, (3S, 4S) - ( 1-aminomethyl-3,4-di-methyl-cyclopentyl) -acetic acid, (1 a, 3a, 5a) - (3-amino-methyl-bicyclo [3.2.0] hept-3-1) ) -acetic, (3S, 5R) -3-aminomethyl-5-methyl-o-alanic acid, (3S, 5R) -3-amlno-5-methyl-heptane-1-acetic acid, (3S, 5R) -3- acid amino-5-methyl-nonanoic and (3S, 5R) -3-amino-5-methyl-octanolcocid). The compounds of formula (I) are inhibitors of PDE5. Accordingly, in a further aspect of the present invention there is provided the use of a compound of formula (I), or a tautomer, salt or solvate thereof, as a pharmaceutical agent, and particularly as a therapeutic agent for the treatment of a pathological state in which it is known, or it can be shown that the inhibition of PDE5, produces a beneficial effect. The term "treatment" includes palliative, curative and prophylactic treatment. The pathological states suitable for treatment with the compounds of the invention include hyper-tension (including essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabes, hypertension associated with atherosclerosis and renovascular hyper-tension), congestive heart failure, angina (including stable angina, unstable and variants (Prinzmetal)), stroke, coronary artery disease, congestive heart failure, conditions of reduction of blood vessel permeability, (such as post-percutaneous coronary angioplasty), peripheral vascular disease, atherosclerosis, induced tolerance for children, tolerance to nitrates, diabetes, impaired glucose tolerance, metabolic syndrome, obesity, sexual dysfunction (including male erectile dysfunction, impotence, female sexual arousal disorder, clitoral dysfunction, desire sex female hypoacillus, female sexual pain disorder, female sexual orgasmic dysfunction and sexual dysfunction due to spinal cord injury), premature delivery, preeclampsia, dysmenorrhea, polycystic ovary syndrome, benign prostatic hyperplasia, obstruction of bladder outlet, incontinence, chronic obstructive pulmonary disease, acute respiratory failure, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, bowel motility disorders, (including irritable bowel syndrome), Kawasaki syndrome, multiple sclerosis, Alzheimer's disease, psoriasis, necrosis cutaneous, scarring, fibrosis, pain (particularly neuropathic pain), cancer, metastasis, baldness, nutcracker esophagus (symptomatic peristalsis), anal fissure and hemorrhoids. The present invention provides methods for the treatment of a disorder or disease state in which it is known or can be shown that the inhibition of PDE5 produces a beneficial effect, in a mammal, by administering to said mammal a therapeutically effective amount of a compound of formula (I), or one of its pharmaceutically acceptable salts, solvates or polymorphs. The present invention also provides methods of treating the disease states listed above in a mammal by administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof.

In some embodiments, the present invention provides methods of treating essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis and renovascular hypertension in a mammal by administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof. In some embodiments, the present invention provides methods of treating diabetes in a mammal by administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof. The present invention provides methods of treating the disease states listed above in a mammal by administering to said mammal a therapeutically effective substance of a compound of formula. (I), or one of its pharmaceutically acceptable salts, solvates or polymorphs and a second pharmaceutically active agent selected from aspirin, angiotensin II receptor antagonists (such as losarían, candesartan, telmisartan, valsartan, irbesartan and eprosartan), channel blockers of calcium (such as amlodipine), beta-blockade (ie, antagonists of the bela-adrenergic receptor such as sotalol, propranolol, timolol, atenolol, carvedilol and metoprolol), CI1027, CCR5 receptor antagonists, imidazolines, sGCa (soluble guarnase cyclase activators), antihypertensive agents, diuretics (such as hydrochlorothiazide) , torsemide, chlorothiazide, chlorthalidone, and amiloride), alpha-adrenergic antagonists (such as doxazosin), ACE inhibitors (such as quinapril, enalapril, ramipril, and lisinopril), aldosterone receptor antagonists (such as eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (such as insulin, sulfonylureas (such as glyburide, glipizide and glimepiride), glitazones (such as rosiglitazone and pioglitazone) and metformin), hypocholesterolemic agents (such as atorvastatin, pravastatin, lovastatin, simvastatin, clofibrate and rosuvastatin) and alpha-2-delta ligands (such as g abapentin, pregabalin, [(1R, 5R, 6S) -6- (amnomethyl) bicyclo [3.2.0] hept-6-yl] acetic acid, 3- (1-ammonomethyl-cyclohexyl) l) -4H- [1, 2,4] oxadiazol-5-one, C- [1- (1 H-tetrazol-5-methyl-1-cycloheptyl] -methalamine, (3S, 4S) - (1-aminomethyl-3,4-dylmethyl-cyclopenic) -acetic acid, (1, 3a, 5a) - (3-amino-methyl-bicyclo) [3.2.0] hept-3-yl) -acetic, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-hepanic acid, acid ( 3S, 5R) -3-amino-5-methyl-nonanoic acid and (3S, 5R) -3-amino-5-methyl-octanico acid). The present invention provides uses of compounds of formula (I), or their pharmaceutically acceptable salts, solvates or polymorphs, in the preparation of a medicament for the treatment of a disease or disease state in which it is known, or it can be shown that the PDE5 inhibition, produces a beneficial effect. In another aspect, the present invention provides the use of a compound of formula (I), or one of its tautomers, salts or solvates, for the manufacture of a medicament for the treatment of hypertension (including essential hypertension, pulmonary hypertension, secondary hypertension, systolic hypertension isolated, hypertension associated with diabetes, hypertension associated with atherosclerosis and renovascular hypertension), congestive heart failure, angina (including stable angina, unstable angina and variants (Prinzmetal)), stroke, coronary artery disease, congestive heart failure, conditions of reduced permeability of blood vessels, (such as post-percutaneous coronary angioplasty), peripheral vascular disease, atherosclerosis, tolerance induced by nitrates, tolerance to nitrates, diabetes, impaired glucose tolerance, metabolic syndrome, obesity, sexual dysfunction (including male erectile disorder, impotence , translucency of exci female sexual arousal, clitoral dysfunction, female hypoactive sexual desire disorder, female sexual pain disorder, female sexual orgasmic dysfunction and sexual dysfunction due to spinal cord injury), preterm delivery, preeclampsia, dysmenorrhea, polycystic ovary syndrome, prostatic hyperplasia benign, obstruction of bladder outlet, incontinence, chronic obstructive pulmonary disease, acute respiratory failure, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, bowel motility disorders, (including irritable bowel syndrome), Kawasaki syndrome, multiple sclerosis, Alzheimer's disease, psoriasis, skin necrosis, scarring, fibrosis, pain (particularly neuropathic pain), cancer, metastasis, baldness, nutcracker esophagus (symptomatic peristalsis), anal fissure and hemorrhoids. In some embodiments, the present invention provides uses of compounds of formula (I) or their pharmaceutically acceptable salts, solvates or polymorphs in the preparation of a medicament for the treatment of essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension. associated with diabetes, hypertension associated with atherosclerosis and renovascular hypertension. In some embodiments, the present invention provides uses of compounds of formula (I) or their pharmaceutically acceptable salts, solvates or polymorphs in the preparation of a medicament for the treatment of diabetes. The compounds of the present invention can be used alone or in combination with other therapeutic agents. When used in combination with another therapeutic agent, the administration of the two agents can be simulataneous or sequential. Simultaneous administration includes administration of a single dose form comprising both agents and administration of the two agents in separate dosage forms at substantially the same time. Sequential administration includes the administration of the two agents according to different guidelines as long as there is an overlap in the periods during which the treatment is provided. Suitable agents with which the compounds of formula (I) can be administered in combination include aspirin, angiotensin II receptor antagonists (such as losarían, candesartan, telmisartan, valsartan, irbesartan and eprosartan), calcium channel blockers (such as amlodipine), beta-blockers (ie, beta-adrenergic receptor antagonists such as sotalol, propranolol, timolol, atenolol, carvedilol and metoprolol), CI1027, CCR5 receptor antagonists, midazolines, sGCa (soluble guanylate cyclase activators) agents antihypertensives, diuretics (such as hydrochlorothiazide, torsemide, chlorothiazide, chlorthalidone, and amiloride), alpha-adrenergic antagonists (such as doxazosin), ACE inhibitors (such as quinapril, enalapril, ramipril, and lisinopril), aldosterone receptor antagonists (such as eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (such as insulin, sulfonylureas (such as glyburide, glipizide and glimepiride), glitazones (such as rosiglitazone and pioglitazone) and metformin), agents hypocholesterolemic (such as atorvastatin, pravastatin, lovastatin, simvaslatin, clofibrate and rosuvastatin) and alpha-2-delta ligands (such as gabapentin, pregabalin, acid [(1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2. 0] hept-6-yl] acetic acid, 3- (1-ammonityl-cyclohexylmethyl) -4 H- [1, 2,4] oxadiazol-5-one, C- [1- (1 H -tetrazol-5-ylmethyl) -cycloheptyl] -methylamine, (3S, 4S) - (1-aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid, acid (1 a, 3a, 5a) - (3 -amino-methyl-bicyclo [3.2.0] hepf-3-yl) -acetic acid (3S, 5R) -3-aminomethyl-5-methyl-octane-3-amino (3S, 5R) -3-amino acid -5-methyl-heptanoic, (3S, 5R) -3-amino-5-methyl-nonanoic acid and (3S, 5R) -3-amino-5-methyl-octanoic acid). The compounds of formula (I) can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered in the form of a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the release of the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th edition (Mack Publishing Company, 1995). The compounds of the invention can be administered orally. Oral administration may involve ingestion, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, dragees (including liquid-filled ones), chewing gums, multi- and nanoparticles, gels, solid solution, liposome, films (including mucoadhesive), ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from an envelope. The compounds of the invention can also be used in rapidly dissolving, rapid disintegrating dosage forms such as those described in Expert Opinion in Therapeuíic Patents, H (6), 981-986 by Liang and Chen, (2001). For dosage forms of tablets, depending on the dose, the drug can constitute up to between 1 and 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5 to 20% by weight of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and calcium phosphate dibasic dihydrate. The tablets may also optionally comprise surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present the surfactants may comprise from 0.2 wt% to 5 wt% of the tablet, and the glidants may comprise from 0.2% to 1 wt% of the tablet. In general, the tablets also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium oxide with sodium lauryl sulfate. Lubricants in general comprise 0.25% by weight a % by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% > by weight of diluent, from about 2% by weight to about 10% by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant. Blends of the tablets can be prepared directly by compression or by a cylinder to form the tablets. Alternatively, mixtures of tablets or portions of mixtures may be granulated by wet, dry, or melt, coagulated in the molten state or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; they may even be encapsulated. Tablet formulations are described in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N. Y., N. Y., 1980 (ISBN 0-8247-6918-X). Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and coated and osmotic particles are found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gums to achieve controlled release is described in WO 00/35298. The compounds of the invention can also be administered directly into the blood stream, into the muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, iníratecal, intraventricular, intraurethral, intraestemal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle), needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably up to a pH of 3 to 9), but, for some applications, may be more adequately formulated as a sterile non-aqueous solution or as a dry form that will be used together with a suitable vehicle tel as pyrogen-free sterile water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be carried out easily using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula I used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus the compounds of the invention can be formulated in the form of solid, semi-solid or fixotropic liquid for administration as an implanted slow release form which provides the modified release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-coglycolic) acid microspheres (PGLA). The compounds of the invention can also be administered topically to the skin or mucosa., that is, by dermal or transdermal route. The formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, extemporaneous application powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).Other means of topical administration include distribution by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry mixture with lactose, or as a particle of mixed components, example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressure vessel, pump, sprayer, atomizer (preferably an atomizer using the hydrohydrodynamic to produce a fine mist), or nebulizer , with or without the use of a suitable propellant, such as 1,1,1,2-terylfluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressure vessel, pump, sprayer, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent to disperse, solubilize or extending the release of the active ingredient, a propellant (s) as a solvent (s) and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Before use in a dry powder or suspension formulation, the product drug is micronized to a suitable size to be distributed by inhalation (typically less than 5 microns). This can be achieved by any suitable crushing process, such as spiral injection grinding, fluid bed injection grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (made, for example, of gelatin or HPMC), blister packs and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose. or starch and a behavior modifier such as / -leucine, mannitol, or magnesium spheroid. The lacíosa can be anhydrous or be in the form of monohydrate, preferably the last one. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a fine mist may contain from 1 μg to 10 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin, or sodium saccharin, can be added to those formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, poly (DL-lactic-coglycolic acid) (PGLA). Modified release formulations include, delayed, sustained, pulsed, controlled, directed and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that distributes a measured quantity. The units according to the invention are typically arranged to deliver a metered dose or "discharge" containing from 1 μg to 20 mg of the compound of formula (I). The overall daily dose will typically be in the range of 1 μg to 80 mg that can be administered in a single dose or, more usually, in the form of divided doses throughout the day. The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. The compounds of the invention can also be administered directly to the eye or ear, typically in the form of droplets of a suspension or micronized solution in sterile isotonic saline with adjusted pH. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crosslinked poly (acrylic acid), polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a hydrocarbyl derivative may be incorporated together with a preservative such as benzalkonium chloride. heteropolysaccharide polymer, for example, gelan gum. Said formulations can also be administered by ontophoresis. Formulations for ocular / otic administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed or programmed release. The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the previously mentioned modes of administration. For example, it is found that the drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Complexes can be used, both inclusion and non-inclusion. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. The most commonly used for these purposes are the alpha, beta and gamma cyclodextrins, examples of which can be found in international patent applications numbers WO / 91/11172, WO 94/02518 and WO 98/55148. Insofar as it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions can be conveniently combined, at least one of which confers a compound according to the invention, in the form of a kit suitable for the co-administration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which confers a compound of formula ... according to the invention, and means for separately keeping said compositions, such as a container , divided bottle or divided aluminum foil pack. An example of such a kit is the blister-type container used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for assessing the doses of compositions separated from each other. To help therapeutic compliance, the kit typically comprises instructions for administration and may be provided with what is termed a reminder. For administration to human patients, the total daily dose of the compounds of the invention typically varies in the range of 0.1 mg to 500 mg, depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 0.1 mg to 500 mg, while an intravenous dose may require only 0.01 mg to 50 mg. The total daily dose can be administered in individual or divided doses. These dosages are based on an average human subject who weighs approximately 65 kg to 70 kg. The doctor can easily determine doses for subjects whose weight is outside this range, such as children and the elderly. The compounds of the invention can be prepared in a known manner in a variety of ways. In the following reaction schemes and hereafter, unless otherwise indicated R1 to R18 are as defined in the first aspect. These methods form additional aspects of the invention. a) Compounds of formula (Ic), ie compounds of formula (I) wherein R15 is R17C (O) can be prepared by acylation of the corresponding compounds of formula (Id), wherein R15 is hydrogen, as illustrated in scheme 1.

Scheme 1 The compound of formula (Id) is treated with 1-2 equivalents of a tel acylating agent such as an acyl chloride R17C (O) CI or an anhydride (R17C (O)) 2O in a suitable solvent in the presence of an amine base tertiary such as triethylamine, N-ethyldiisopropylamine or pyridine. Suitable solvents include dichloromethane and dimethylformamide. Preferably, the compound of formula (Id) is treated with about 1.3 equivalents of acyl chloride and about 1.3 equivalents of triethylamine in dichloromethane for 18 hours. Alternatively, a mixture of the compound of formula (Id) and an acid R17COOH in a suitable solvent is treated with a condensing agent, optionally in the presence of 1-hydroxybenzoyriazole (HOBT) (or 1-hydroxy-7-azabenzotriazole (HOAT)). ) and a tertiary amine base such as triethylamine, N-ethyldiisopropylamine or 4- (dimethylamino) pyridine, at a temperature of 0 ° C at the boiling temperature of the solvent. Suitable solvents include acetonitrile, dichloromethane, dimethylformamide, ethyl acetate, N-methylpyrrolidinone, tetrahydrofuran and mixtures thereof. Suitable condensation agents include: 1,1'-carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodimide (DCC) and 1- (3-dimethylaminopropyl) -1-ethylcarbodiimide (WSCDI); uronium salts such as O- (benzotriazol-1-yl) -1,1, 3,3-tetramethyluronium hexafluorophosphate (HBTU) and O- (7-azabenzotriazol-1-yl) -1, 1, 3 hexafluorophosphate, 3-tetramethyluronium (HATU); phosphonium salts such as 1-benzotriazolyloxy-tris (d, meth) amino phosphonium hexafluorophosphate (BOP) and 1-benzotriazolyloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP); diphenylphosphine chloride (Dpp-CI) and bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl).

Preferably, an equimolar solution of the compound of formula (Id) and the acid in dichloromethane is treated with about 1.1 equivalents of HATU and about 1.5 equivalents of N-ethyldiisopropylamine at room temperature for 18 hours. It will be appreciated that any functional group in R1, R3, R4, R16 and R17 and, in particular any primary or secondary amine group, may need protection in order to allow this reaction to proceed satisfactorily. In this case, a later stage of deprotection will be necessary. b) Compounds of formula (IE), ie, compounds of formula (I) wherein R15 is R18SO2 can be prepared by sulfonylating the corresponding compounds of formula (Id), as illustrated in Scheme 2. Scheme 2 The compound of formula (Id) is treated with 1-2 equivalents of a sulfonyl chloride R18SO2CI in a suitable solvent in the presence of a tertiary amine base such as triethylamine, N-ethyldiisopropylamine or pyridine. Suitable solvents include dichloromethane and dimethylformamide. Preferably, the compound of formula (Id) is treated with about 1.1 equivalents of sulfonyl chloride and about 1.5 equivalents of N-ethyldiisopropylamine in dichloromethane for 18 hours. Again, any functional group in R1, R3, R4, R16 and R17 and, in particular any primary or secondary amine group, may need protection. c) Compounds of formula (I) can be prepared, ie, compounds of formula (I) wherein R15 is R17, by working up the R5A substituent on C3 of a precursor of formula (II) as illustrated in Scheme 3 .

Scheme 3 When at least one of R16 and R17 is hydrogen, such that the amine function of R5 is a primary or secondary amine, the group R5A may be the same as R5 with the amine protected by a protecting group such as a phenylbutyloxycarbonyl group (BOC), fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Z, sometimes referred to as Cbz). In such cases, the transformation of Scheme 1 is an appropriate deprotection step for the protecting group used, such as treatment with acid (for example, HCl in dioxane or trifluoroacetic acid in dichloromethane) for the removal of a BOC group., treatment with a base (such as piperidine) for the removal of a Fmoc group or catalytic hydrogenolysis for the removal of a Z group. Other protected functional groups can be deprotected in the same step or, if orthogonal protecting groups are chosen, deprotection It can be in several stages. When none of R 5 and R 17 is hydrogen, such that the amine function of R 5 is a tertiary amine, a protecting group can not be used. Scheme 3 also provides for the preparation of the amine group of R5 in one or more steps from the functional group which is most suitable for the reaction conditions necessary for the preparation of the compounds of formula (II). Examples of the reactions, which include substitution reactions, mine reduction reactions and transposition reactions, are illustrated in Schemes 3A to 3J, where Ra, Rb, Rc and Rd are hydrogen, alkyl, cycloalkyl or aryl groups .

Substitution Reactions Primary, secondary and tertiary amines can be prepared by reacting an alkylating agent with ammonia, a primary or secondary amine, respectively, as illustrated in Scheme 3A, where LG is a halogen atom such as a chlorine, bromine or iodine atom, or a sulfonate group such as methanesulfonate, toluenesulfonate for trifluoromethanesulfonate group.

Scheme 3A In Scheme 3B a variation of this reaction is illustrated. In this case, the alkylating agent is an epoxide.

Scheme 3B The utility of these reactions is sometimes limited by the propensity of the product amine to react with the alkylating agent, resulting in a complex mixture. This problem can be solved by using an amine equivalent that gives a product that can not react anymore. Scheme 3C illustrates the use of an alkali metal azide or phthalimide as an amine equivalent.

Scheme 3C Imine reduction reactions Compounds containing a carbon-nitrogen double bond are susceptible to reduction to give the corresponding amine. Scheme 3D illustrates the reductive amination of an aldehyde or ketone, in which a mine species is generated as a reactive intermediate. 3D scheme This process is applied generally to the synthesis of secondary and tertiary amines. It is less suited to the synthesis of primary amines (ie, when Ra and Rb are both hydrogen). In this case, an easier route to take to practice is the use of hydroxylamine, as illustrated in Scheme 3E.

Scheme 3E The carbon-nitrogen triple bond of the nitriles can also be reduced to provide primary amines, as illustrated in Scheme 3F. The nitrile can be obtained by the reaction of an alkali metal cyanide with an appropriate alkylating agent.

Scheme 3F Amide Reduction Reactions Compounds containing an amide functional group can be reduced to the corresponding amines using reactants such as lithium aluminum hydride as illustrated in Scheme 3G. The amides can be prepared generally from the corresponding acids and amines. 3G scheme The carbamate esters are reduced analogously to the corresponding N-methyl amines.

Transposition reactions A series of well-known reactions involving transposition reactions are useful for the preparation of amines. An example, illustrated in Scheme 3H, is the Curtius reaction, in which a carboxylic acid is converted to a corresponding acyl azide and then to an acyl niirane which is transposed to an isocyanate. The hydrolysis gives the amine.

Scheme 3H The transposition of Lossen provides an equivalent process in which acyl nitrene is generated from a hydroxamic acid. The Schmidt reaction and the Hofmann reaction are other equivalent procedures. The Beckmann transposition, illustrated in Scheme 3J, provides secondary amines from oximes.

Scheme 3J The intermediate nitrile ion can be reduced in situ to provide the amine directly, or it can be activated with water to provide an amide that can be reduced to the amine in a separate step. Preferred methods for introducing the -NR16R17 group are the displacement reaction of Scheme 3A and the reductive amination of Scheme 3D. Particularly preferred variants are illustrated in Schemes 3K and 3L (where -W- is a covalent bond or an alkylenyl group such that -W-CH2- forms -Y-).

Scheme 3K Scheme 3L (HB) In view of the above description, it will be appreciated that R5A can be, for example, -W-CO2H, -Y-CO2H, -W-CO2RA, -Y-CO2RA, -W-CHO, -W-CN , -Y-OH, -Y-LG or -Y-NHPG, in which -W- is a covalent bond or an alkylenyl group such that -W-CH2- forms -Y-, RA is a methyl, ethyl group, fer-butyl or benzyl, LG is a labile group as defined above, PG is an amine protecting group and Y is as defined for general formula (I). Of these, less reactive groups such as -W-CO2RA, -Y-CO2RA, -W-CN, -Y-OH and -Y-NHPG are more likely to be compatible with the conditions required in the general synthesis sequence. The -Y-CI and -W-CHO groups present in the compounds of formulas (IIA) and (IIB) are unlikely to be compatible with the conditions required to make the compounds. However, both groups are easily prepared from more robust groups such as -W-CO2RA. These transformations are described in more detail in parts o) to z) below. It will be further appreciated that the preparation of the amine group of R5 does not necessarily need to be the last step of the synthesis cycle, but can be carried out at any point during the route with which the amine (optionally in protected form) is compatible. with the subsequent chemical transformations. In particular, it has been found that it may be advantageous to make R5 before introducing the -NR3R4 group as described in part d) below. When the amine group of R5 is made at an early stage of synthesis it may be necessary to use a suitable protecting group in order to maintain it through subsequent manipulations. d) Compounds of formula (II) can be prepared from the monochlorides of formula (III) by reaction with NHR3R4 as illustrated in Scheme 4.

Scheme 4 (III) (II) A solution of the monochloride (III) and the amine HNR3R4 in a suitable dipolar aprotic solvent are stirred at elevated temperature for 1 to 24 hours. Suitable solvents include dimeti! sulfoxide, dimethylformamide and N-methylpyrrolidinone. An excess of tertiary amine such as N-ethyldiisopropylamine, N-methylmorpholine or triethylamine may optionally be included. Sometimes it is necessary to carry out the reaction under high pressure in a closed vessel, in particular when the amine HNR3R4 or the solvent is volatile. Preferably, the monochloride is treated with 1 to 5 equivalents of the amine HNR3R4 and optionally 3 to 5 equivalents of N-ethyldiisopropylamine in dimethyl sulfoxide or N-methylpyrrolidinone at 100-125 ° C for 12 to 18 hours in a hermetically sealed container.

It will be appreciated that any functional group in HNR3R4 and, in particular any primary or secondary amine group, may need to be protected in order to allow this reaction to proceed successfully. In such a case, a subsequent deprotection reaction as described in part c) will be necessary. The protecting group can be selected such that it can be removed at the same time as the protecting group of the amine in R5 (when said protective group is present). As an alternative, it may be preferable to provide a sequential removal of the protecting groups. e) Compounds of formula (III) can be prepared from the corresponding dichlorides of formula (IV) by reaction with HNR1R2 as illustrated in Scheme 5.

Scheme 5 (IV) (lll) A solution of the dichloride (IV), the amine HNR1R2 and an excess of a tertiary amine such as N-ethyldiisopropylamine, N-methylmorpholine or triethylamine in a suitable dipolar aprotic solvent are stirred at room or high temperature for 1 to 24 hours. Suitable solvents include dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidinone. It will be appreciated that any functional group in HNR1R2 and, in particular any primary or secondary amine group, may need to be progged in order to allow this reaction to proceed successfully. Preferably, the monochloride is treated with 2 to 5 equivalents of the amine HNR1R2 and optionally 2 to equivalents of N-ethyldiisopropylamine in dimethyl sulfoxide or a mixture of dimethyl sulfoxide and N-methylpyrrolidinone at 30-90 ° C for 1 to 18 hours. Alternatively, a solution of the amine HNR1R2 in a suitable solvent is treated with butyl lithium or sodium hexamethyldisilazide and the dichloride is added to the resulting solution. Suitable solvents include tetrahydrofuran and dioxane. As described in part d), the reactive functional groups in HNR1R2 may need to be protected for this reaction to give a satisfactory result. When R5A is an ester group such as -CO2CH3 directly attached to the pyrazolopyrimidine core, the reaction of the compounds of formula (IV) with less reactive amines HNR1R2 can give a low yield. In such cases, it is sometimes advantageous to use an alternative strategy, as described later in part z). f) Compounds of formula (IV) can be prepared from the corresponding pyrazolopyrimidinediones of formula (V) as illustrated in Scheme 6.

(V) (IV) Dione was added with a large excess of an appropriate chlorinating reagent such as phosphorus oxychloride (POCI3) or phenylphosphoryl dichloride (PhP (O) CI2) in the presence of a tertiary amine such as N-ethyldiisopropylamine, N-methylmorpholine, triethylamine or N, N-dimethylaniline or tetraethylammonium chloride at elevated temperature for 8 to 48 hours. Dimamerylformamide can optionally be added as a catalyst. The reaction can be carried out in the presence of a solvent. When a solvent is used, then suitable solvents include acetonitrile and propionitrile. Preferably, the diona is treated with 10 to 30 equivalents of POCI3 and 3 equivalents of N-ethyldiisopropylamine or 3 to 5 equivalents of teraethylammonium chloride in acetonitrile or propionitrile at reflux for 18 hours. g) Compounds of formula (V) can be prepared from the corresponding aminoamides of formula (VI) as illustrated in Scheme 7.

Scheme 7 (VI) (V) A solution of the pyrazolecarboxamide (VI) and phosgene or one of its equivalents, such as carbonyl, is stirred at an ambient temperature to the boiling temperature of the solvent, optionally at elevated pressure for 2 to 18 hours. diimidazole, trichloromethyl chloroformate or bis (trichloromethyl) carbonate, in a dipolar aprotic solvent. Preferably, a solution of the dione and 1 to 2 equivalents of carbonyl diimidazole in dimethylformamide are stirred at 70 ° C to 90 ° C for 18 hours. h) Compounds of formula (VI) can be prepared from the corresponding nitroamides of formula. (Vll) as illustrated in Scheme 8.

(VII) (VI) The reduction of the nitro group can be achieved, for example, by hydrogenation by transfer or catalytic or by a metal reduction with solution. For transfer hydrogenation, the nitro compound is reacted with a suitable hydrogen donor, such as ammonium formate or cyclohexene, in a polar solvent, such as tetrahydrofuran, methanol or ethanol, in the presence of a transition metal or salt catalyst. of transition metal, such as palladium or palladium (II) hydroxide, optionally at elevated temperature and pressure. For the catalytic hydrogenation, a solution of the nitro compound in a polar solvent, such as tetrahydrofuran, methanol or ethanol, is stirred under a hydrogen atmosphere in the presence of an ion transitional or transition metal salt catalyst, such as palladium or Palladium hydroxide (II), optionally at elevated pressure. The catalyst may be in solution (homogeneous catalysis) or in suspension (heterogeneous catalysis). For the metal reduction with solution, the nitro compound is treated with a suitable reactive metal such as zinc or tin, in the presence of an acid such as acetic acid or hydrochloric acid. Other reducing agents such as tin chloride (ll) can be used.

) Compounds of formula (Vll) can be prepared from the corresponding nitroacids of formula (VIII) as illustrated in Scheme 9.

Scheme 9 (VIII) (IX) (Vil) The acid (VIII) is converted to the corresponding acid chloride (IX) by treatment with oxalyl chloride and dimethylformamide in a suitable solvent such as dichloromethane or thionyl chloride. A solution of the acid chloride in a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane with gaseous ammonia or aqueous ammonia is then treated to provide the amide of formula (Vll). j) Compounds of formula (VIII) can be prepared from the corresponding acids of formula (X) as illustrated in Scheme 10.

Scheme 10 (X) (VIII) The nitration of pyrazoles is well known. The compounds of formula (X) are treated with nitric acid or a mixture of nitric acid and sulfuric acid to provide the compounds of formula (VIII). k) Certain compounds of formula (X) are commercially available. Compounds of formula (X) that are not commercial articles can be prepared through the corresponding methyl esters (XI) as illustrated in Schemes 11 to 13.

Scheme 11 The procedure illustrated in Scheme 9 is the synthesis of Knorr pyrazoles. A 1,3-diketone of formula (Xll) is reacted with hydrazine to give a pyrazole of formula (XIA), or with a substituted hydrazine R6A-NHNH2, wherein R6A is any group according to R6 except hydrogen, for give a pyrazole of formula (XIB). Pyrazoles of formula (XIB) can also be prepared by N-alkylation of the corresponding pyrazoles of formula (XIA). The pyrazole of formula (XIA) is treated with a base such as an alkali metal carbonate or bicarbonate, for example, potassium carbonate or cesium carbonate, or a tertiary amine, for example triethylamine, dipropylethylamine or pyridine, and chloride (R6A-CI), bromide (R6A-Br), iodide (R6A-I), mesylate (R6A- OSO2CH3) or tosylate (R6A-OSO2Tol) in a suitable solvent at a temperature of -70 ° C to 100 ° C. Some solvents include alcohols such as methanol, ethanol, isopropanol and butanol, ethers such as tetrahydrofuran and dioxane, dimethylformamide and acetonitrile. When the reaction gives a mixture of alkylated products in N1 and N2, these can be separated using conventional techniques. The methyl esters (XIA) and (XIB) are hydrolyzed to provide the corresponding acids of formula (XA) and (XB) by treatment with an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a solvent suitable. Suitable solvents include lower alcohols such as methanol and ethanol and mixtures of water and dioxane or tetrahydrofuran. Compounds of formula (Xll) can be prepared from the corresponding methyl ketones of formula (Xlll) using a cross Claisen condensation as illustrated in Scheme 12.

Scheme 12 A methyl ketone of formula (Xlll) is reacted with dimethyloxane in a suitable solvent in the presence of a suitable base. Suitable solvents include ethers, such as tetrahydrofuran. Suitable bases include sodium hydrate, potassium t-butoxide and lithium diisopropylamide. Alternatively, unless R5A includes a reactive functional group, sodium methoxide can be used as the base and methanol as the solvent.

Scheme 13 + (X | B) R5 ^ 2 (XV) The procedure illustrated in Scheme 13 is the synthesis of Pechmann pyrazoles. A diazo compound and an acetylene are combined to produce a pyrazole of formula (XIA). When R5A is distinct from -COOCH3 two variants of the procedure can be considered. An acetylene of formula (XIV) can be combined with methyl diazoacetate, or a diazo compound of formula (XV) can be combined with methyl propiolate. The product of the initial reaction (XIA) can be N-alkylated as described above to give the pyrazoles of formula (XIB).

I) A particularly useful series of compounds are those in which R5A is -CO2CH3. Its elaboration is illustrated in Scheme 14.

Scheme 14 (VIIIA) Dimethyl 4-nitropyrazole-3,5-dicarboxylate is easily prepared according to the process described in published international patent application WO 00/24745 (see preparation 2, page 48) and can be N-alkylated in accordance with procedures described in part k) above. Because the two nitrogen atoms of the pyrazole are equivalent, a single alkylation product is obtained. Selective hydrolysis of the diester with one equivalent of alkali metal hydroxide according to the procedure of Chambers et al. (J. Org. Chem. 50, 4736-4738, 1985) cleaves the ester adjacent to the substituted nitrogen, yielding the monoacids of formula (VIIIA), ie, compounds of formula (HIV) wherein R5A is -CO2CH3 and R6A it is attached to the nitrogen atom adjacent to the free carboxylic acid group. m) In some embodiments of the compounds of formula (I), the R6 group may not be compatible with the synthesis procedures described above. An alternative in these circumstances is to introduce the R6 group at a later stage, as illustrated in Scheme 15.

Scheme 15 A compound of formula (llc) may be alkylated, ie, a compound of formula (II) wherein R6 is hydrogen, using the procedures described in part k) above. The reaction will generally give a mixture of the N1-alkylated compound (llD) and the N2-isomer (llE). These can be separated and purified by conventional methods. The use of more reactive alkylating agents tends to promote alkylation at the N2 position. It will be appreciated that the alkylation reaction to introduce R6A could be carried out in other steps in the synthesis sequence. n) Compounds of formula (I) can be prepared in which Y is a covalent bond by the processes described in parts c) to f) above, starting from compounds of formula (VA), ie, compounds of formula (V) in which R5A is -NR16R17, provided that any functional group incompatible is adequately protected. The required compounds of formula (VA) can be prepared from the corresponding compounds of formula (VB), ie, compounds of formula (V) in which R5A is hydrogen, following the procedure illustrated in Scheme 16.

(VB) (V) The pyrazolopyrimidinedione of formula (VB) can be brominated by treatment with bromine. Treatment with an amine HNR15R16 leads to the introduction of the amino group at the C3 position. The compound of formula (VB) can be treated with chlorine to give the 3-chloropyrazolopyrimidinedione which reacts in an analogous manner to provide the compound of formula (VA). The compounds of formula (VA) can be prepared from methyl pyrazole-3-carboxylate by N-alkylation (when R6 is other than hydrogen) as described in part k) above, followed by elaboration as described in parts j), i), h) and g). As indicated above in part c), the compounds of formula (II) and (III) wherein R5A is -W-CO2H, -Y-CO2H, -W-CO2RA, -Y-CO2RA, -W- CHO, -W-CN, -Y-OH or -Y-LG are particularly useful precursors for compounds in which the amine group has been prepared in R5. It may be necessary or convenient to introduce some of these groups by manipulation of a more accessible starting material. Interconversions of these common functional groups are well known in the art. Some representative manipulations are described below. It will be appreciated that the described synthetic transformations can also be used in the preparation of precursor compounds such as the pyrazoles of formula (XI). o) Esters of formula (IIIA) can be interconverged in which -V- represents either -W- or -Y-, ie, compounds of formula (III) in which R5A is -V-CO2RA, and the corresponding acids of formula (IIIb), ie, compounds of formula (III) wherein R5A is -V-CO2H, as illustrated in Schemes * 17A and * 17B.

Scheme 17A (IIIA) (IIIB) When RA is methyl or ethyl, the conversion can be conveniently carried out by treating the compound of formula (IIIA) with an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent at a temperature of about 10. ° C at the boiling temperature of the solvent. Suitable solvents include water, methanol, ethanol and mixtures of water with methanol, ethanol, tetrahydrofuran and dioxane. When RA is fer-butyl, the conversion can be carried out by treating the compound of formula (IIIA) with an ial acid such as hydrogen chloride or trifluoroacetic acid in a suitable solvent at a temperature of 0 ° C at ambient temperature. Suitable solvents include dioxane and dichloromethane. When RA is benzyl, the conversion can be conveniently carried out by treating the compound of formula (IIIA) with an alkali metal hydroxide as described above, or by hydrogenolysis using molecular hydrogen or a suitable hydrogen donor such as ammonium formate in the presence of a catalyst of a transition metal or transition metal salt such as palladium on carbon, in a suitable solvent such as methanol.

Scheme 17B HO2 (IIIB) (IHA) The version can be conveniently carried out by treating a mixture of the acid of the formula (IIIb) and an alcohol RA-OH in a suitable solvent with a condensation agent such as a carbodiimide, for example, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl). ) -N'-ethylcarbodiimide, optionally in the presence of 4-dimethylaminopyridine, at a temperature of 0 ° C at the boiling point of the solvent. Suitable solvents include dichloromean and dimethylformamide. Alternatively, the acid of formula (IIIb) can be converted to the corresponding acid chloride using thionyl chloride or oxalyl chloride and then treated with the alcohol RA-OH. p) Compounds of formula (IIIc), ie, compounds of formula (IIIA) wherein V is CH2 can be prepared from the corresponding compounds of formula (III), ie, compounds of formula (IIIb) in the that V is a covalent bond, by a method of homologation of a carbon such as the Arndt-Eistert reaction illustrated in Scheme 18.

Scheme 18 (IIP) (IIP) The carboxylic acid is converted to the reactive intermediate such as the acid chloride (by reaction with oxalyl chloride) or a mixed anhydride (by reaction with isobutyl chloroformate). The intermediate is reacted with diazomethane to provide α-diazoketone. This is treated with silver oxide in the presence of RA-OH to give the homologated ester of formula (IIIc). q) Compounds of formula (IIIE), ie, compounds of formula (IIIb) wherein V is CH2, can be prepared from the corresponding nitriles of formula (III) by the procedure illustrated in Scheme 19 Scheme 19 (IHF) (IHE) The nitrile group can be hydrolyzed, for example, by treatment with aqueous mineral acids, such as hydrochloric acid. r) Compounds of formula (III) can be prepared from the corresponding chlorides of formula (III) by the process illustrated in Scheme 20.

Scheme 20 The chloride is treated with a metal cyanide, such as sodium cyanide or potassium cyanide in a suitable solvent, such as dimethyl sulfoxide, dimethylformamide or ethanol. s) Compounds of formula (III) can be prepared from the corresponding alcohols of formula (IIIH) by the method illustrated in Scheme 21.

Scheme 21 The alcohol was added with a mixture of pyridylphosphine and N-chlorosuccinimide or tetrachloromethylene or with thionyl chloride. i) Compounds of formula (IIIH) can be prepared from the corresponding esters of formula (III), ie, compounds according to formula (IIIA) in which V is a covalent bond or from the corresponding acids of formula (lllD) by the procedure outlined in Scheme 22.

Scheme 22 The acids of the formula (III) and the esters of the formula (III) can be reduced to the alcohols of the formula (IIIH) by treatment with lithium aluminum hydride in a suitable solvent at a temperature of 0 ° C at the boiling point. of the solvent. Suitable solvents include ethers such as tetrahydrofuran. The acids can also be reduced by treatment with isobutyl chloroformate and a tertiary amine base to provide a mixed anhydride, followed by reaction with sodium borohydride.

The esters can also be reduced by treatment with diisobutylaluminum hydride or lithium borohydride. u) Compounds of formula (III), ie, compounds of formula (IIIA) wherein V is CH2CH2 can be prepared from the corresponding acrylate ester of formula (III) by the procedure illustrated in Scheme 23.

Scheme 23 Reduction of the carbon-carbon double bond of (IIL) to give compounds of formula (III) can be carried out by catalytic hydrogenation using molecular hydrogen in the presence of a transition metal catalyst such as palladium, platinum or nickel. When RA is benzyl, the conditions can be chosen such that only the double bond is reduced or the reduction is carried out by hydrogenolytic cleavage of the ester to the carboxylic acid.

The acrylates of formula (Iti) can also be treated with alkyl copper reactants to give analogs of the compounds of formula (III) in which the alkyl substituent is introduced into the carbon atom adjacent to the pyrazole pyrimidine ring system, or with a sulfonium ylide or an equivalent carbene to give a 2- (pyrazolopyrimidinyl) -cyclopropane-1-carboxylate derivative. v) Compounds of formula (III) can be prepared from the corresponding aldehydes of formula (III) by the procedure illustrated in Scheme 24.

Scheme 24 The aldehyde of formula (IIIM) can be converted to the acrylate ester of formula (III) by reaction with a phosphorus reactant following the protocols of the Wittig, Horner or Wadsworth-Homer-Emmons reactions.

The reactant is prepared by treating a triphenylphosphonium salt Ph3P + CH2CO2RAX (Wittig), a phosphine oxide Ph2P (O) CH2CO2RA (Horner) or a phosphonate (EtO) 2P (O) CH2CO2RA (WadsworIh-Horner-Emmons) with such a base such as lithium lithium, a lithium dialkylamide or an alkali metal alkoxide, in a suitable solvent such as tetrahydrofuran. The process is not limited to the preparation of unsubstituted acrylate esters in a. The use of an alkyl-substituted phosphorus reactant such as Ph3P + CH (R) CO2RA.X "or the equivalent phosphine oxide or phosphonate, wherein R is alkyl, gives access to the corresponding a-alkyl acrylate derivative. conversion of the aldehydes of formula (IIIM) to acrylate esters of formula (III) can also be carried out by reaction with a malonate derivative following the Knoevenagel condensation procedure. w) Compounds of formula (IIIM) can be prepared from the esters of formula (III) or, more preferably, from the corresponding alcohols of formula (IIIH) by the procedures illustrated in Scheme 25.

Scheme 25 (IIP) Reduction of the formula esters (111) can be achieved using diisobutylaluminum hydride (DIBAL) in a suitable solvent at a temperature of less than 0 ° C, preferably less than -60 ° C. Suitable solvents include hydrocarbon compounds such as pentane, hexane and toluene, ethers such as tetrahydrofuran and mixtures thereof. Oxidation of the alcohols of formula (IIIH) can be achieved using a chromium (VI) reactant such as pyridinium chlorochromate, a hypervalent iodine reactant such as Dess-Martin periodinane or a combination of tetra-n-propylammonium perruthenate. and N-methylmorpholine N-oxide in a suitable solvent at a temperature of 0 ° C at ambient temperature. Suitable solvents include dichloromethane. x) The aldehydes of formula (\\ M) can be converted to esters of formula (lllc) as illustrated in Scheme 26.

Scheme 26 The aldehyde is treated with methyl methyl mercaptyl sulfoxide (CH3SCH2S (O) CH3) and triton B in tetrahydrofuran to give the intermediate (HIN) which is treated with the appropriate alcohol RAOH and acetyl chloride to provide the ester of formula (IIIc). This procedure is particularly useful when RA is methyl. y) The compounds of formula (III) can also be prepared from the corresponding chlorides of formula (III) by the process illustrated in Scheme 27.

Scheme 27 The chloride of formula (lllG) is reacted with dialkyl malonate (RAO2C) 2CH2 and a base in a suitable solvent. Typically, the base is an alkali metal alkoxide such as sodium ethoxide or potassium terebutoxide and the solvent is an alcohol such as ethanol or an ether such as tetrahydrofuran. Preferably, the base and the solvent are chosen such that the ransesification with the malonation reactant and the intermediate (IIIo) is minimized. For example, when the reactant is diethyl malonate the base is preferably sodium ethoxide and the solvent is ethanol. The intermediate (IIIo) is then decarboxylated to give the product (III?). This can be achieved by selective hydrolysis using one equivalent of an alkali metal hydroxide such as sodium hydroxide, followed by acidification, or by any other method known in the art. The procedure is not limited to symmetrical malonates. For example, the use of fer-butyl mephyl malonate would give an intermediate (IIIo) in which RA is methyl and the other is fer-butyl. By choosing the appropriate conditions, the decarboxylation could then be controlled to give a product (III?) In which RA was fer-butyl or me yl. The procedure can be extended to substituted malonates (RAO2C) 2CHR, wherein R is an alkyl group. This gives access to compounds analogous to (III) in which the R group is a substituent on the carbon atom adjacent to the RAO2C group. These compounds can also be prepared by alkylating the intermediate (IIIo) with R-Br or R-1 in the presence of an alkali metal alkoxide base. z) As mentioned in part e) above, the reaction of compounds of formula (IVA), ie, compounds of formula (IV) in which R5A is -CO2RA, with weakly nucleophilic amines HNR1R2 does not sometimes give good yield . An alternative route is illustrated in Schemes 28A and 28B.

Scheme 28A The esters of formula (IVA) can be reduced to alcohols of formula (IVa) according to the procedures described in part t) above. A preferred procedure is reduction with diisobutylaluminum hydride at a temperature of -20 ° C to 0 ° C. The primary alcohol is then protected to give compounds of formula (IVC), in which PG is an alcohol protecting group. A preferred protecting group is a trialkylsilyl group, in particular a ferc-butyldimethylsilyl group. The compounds of formula (IVo) are then reacted with an amine HNR1R2 according to the procedures described in part e) above to give compounds of formula (IIIp).

Scheme 28B The compounds of formula (111) can be deprotected to provide the primary alcohols of formula (IIIH) using appropriate conditions. When PG is a trialkylsilyl group, it can be referred by treatment with a fluoride salt, such as tetrabufilamonium fluoride, or with hydrochloric acid. The alcohols of formula (IIIH) can then be modified as described above. For example, the group -NR3R4 can be introduced according to the procedures described in part d) above to provide compounds of formula (llF). The primary alcohol can then be oxidized as described in part w) above to provide the aldehydes of formula (IIG). A preferred oxidizing agent is perodynamic Dess-Martin. Finally, if carboxylic acids are desired, the aldehydes of formula (IIG) can be oxidized to provide the acids of formula (IIH). Suitable oxidizing agents include potassium permanganate, Jones reactant and sodium chlorite. A preferred process is to treat the aldehydes with sodium chlorite, sodium dihydrogen phosphate and 2-methyl-2-butene in fer-butanol at room temperature for about 1 hour. The compounds of formula (LA-4) can also be prepared by the following Schemes 29 to 41. aa) Compounds of formula (IA), ie, compounds of formula (Ia-4) in which R15 is R17C (O) can be prepared by acylation of the corresponding compounds of formula (II), as illustrated in the Scheme 29 Scheme 29 The compound of formula (II) is treated with 1-2 equivalents of an acylating agent such as an acyl chloride R17C (O) CI or an anhydride (R17C (O)) 2O in a suitable solvent in the presence of an amine base tertiary such as triethylamine, N-ethyldiisopropylamine or pyridine. Suitable solvents include dichloromethane and dimethylformamide. Preferably, the compound of formula (II) is treated with about 1.3 equivalents of acyl chloride and about 1.3 equivalents of triethylamine in dichloromethane for about 18 hours. Alternatively, a mixture of the compound of formula (II) and an acid R17COOH in a suitable solvent is treated with a condensing agent, optionally in the presence of 1-hydroxybenzotriazole (HOBT) (or 1-hydroxy-7-azabenzotriazole (HOAT )) and a tertiary amine base such as triethylamine, N-ethyldiisopropylamine or 4- (dimethylamino) pyridine at a temperature of 0 ° C at the boiling point of the solvent. Suitable solvents include acetonitrile, dichloromethane, dimethylformamide, ethyl acetate, N-methylpyrrolidinone, tetrahydrofuran, and mixtures thereof. Suitable condensation agents include 1,1 '-carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) -1-ethylcarbodimide (WSCDI); uronium salts such as O- (benzotripazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate (HBTU); phosphonium salts such as 1-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and 1-benzotriazole xylitol (pyrrolidinone) phosphonium hexafluorophosphate (PyBOP); Diphenylphosphinic chloride (Dpp-CI) and bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl).

Preferably, an equimolar solution of the compound of formula (ID) and the acid in dichloromethane is treated with about 1.1 equivalents of HATU and about 1.5 equivalents of N-ethyldiisopropylamine at room temperature for 18 hours. bb) Compounds of formula (Ib), ie, compounds of formula (LA-4) in which R15 is R18SO2 can be prepared by sulfonylating the corresponding compounds of formula (II), as illustrated in Scheme 30.

Scheme 30 The compound of formula (II) is treated with 1-2 equivalents of a sulfonyl chloride R18SO2CI in a suitable solvent in the presence of a tertiary amine base such as triethylamine, N-ethyldiisopropylamine or pyridine. Suitable solvents include dichloromean and dimethylformamide. Preferably, the compound of formula (II) is treated with about 1.1 equivalents of sulfonyl chloride and about 1.5 equivalents of N-ethyldiisopropylamine in dichloromethane for about 18 hours. ce) Compounds of formula (Ic), ie, compounds of formula (LA-4) in which R15 is R17, and compounds of formula (II) can be prepared by reductive amination of an aldehyde of formula (III) with a amine HNR16R17 or R16NH2, respectively, as illustrated in Scheme 31.

Scheme 31 A solution of the amine and the aldehyde in a suitable solvent is treated with a reducing agent such as sodium cyanoborohydride (NaBH3CN) or sodium tri (acetoxy) borohydride (Na (AcOs) BH), optionally in the presence of acetic acid, at an hour. from 0 ° C to the boiling temperature of the solvent, for 1 hour to 24 hours. Suitable solvents include alcohols, in particular meianol and ethanol. This process is also suitable for the preparation of compounds of formula (I) in which -NR 15 R 16 constitutes a saturated ring. The appropriate amine HNR15R16 is used in place of the amine HNR16R17. dd) Compounds of formula (1) and compounds of formula (II) may also be prepared by reaction of a chloride or bromide of formula (IV), wherein X is a leaving group such as Cl, Br or CHsSO 2 O ", with an amine HNR16R17 or R16NH2, respectively, as illustrated in Scheme 32.

Scheme 32 A solution of the amine and the compound of formula (IV) in a suitable solvent, opdonally in the presence of a base such as the like, is stirred at a temperature of 0 ° C at the boiling point of the solvent for 1 hour to 24 hours. a tertiary amine (e.g., N-ethyldiisopropylamine) or an alkali metal carbonate (e.g., potassium carbonate). Suitable solvents include tetrahydrofuran, dimethylformamide and dimethyl sulfoxide. Preferably, the leaving group X is Br or Cl, and more preferably is Cl. This process is also suitable for the preparation of compounds of formula (I) in which -NR 15 R 16 constitutes a saturated ring. The appropriate amine HNR15R16 is used in place of the amine HNR 6R17. ee) Compounds of formula (III) can be prepared from the esters of formula (V), either directly or, more preferably, through the corresponding alcohols of formula (VI) by the procedures illustrated in Scheme 33.

Scheme 33 (SAW) Reduction of the esters of formula (V) to the aldehydes of formula (III) can be achieved using diisobutylaluminum hydride (DIBAL) in a suitable solvent at a temperature of less than 0 ° C, preferably less than -60 ° C. Suitable solvents include hydrocarbon compounds such as penan, hexane and toluene, such as tetrahydrofuran and mixtures thereof. The use of DIBAL in excess or higher temperatures generally results in the production of the alcohols of formula (VI). These alcohols can also be produced using other reducing agents such as lithium aluminum hydride or lithium borohydride. Oxidation of the alcohols of formula (VI) can be achieved using a chromium (VI) reactant such as pyridinium chlorochromate, a hypervalent chlorine reactant such as Dess-Martin periodinane or a combination of tetra-n-propylammonium perruthenate. and N-methylmorpholine N-oxide in a suitable solvent at a temperature of 0 ° C to room temperature. Suitable solvents include dichloromethane. The use of Dess-Martin periodinane is preferred. ff) Compounds of formula (IV) can be prepared from the corresponding acids of formula (VI) by the procedure illustrated in Scheme 34.

Scheme 34 Compounds of formula (IV) can be prepared in which X is Cl treating the alcohol (VI) with a mixture of triphenylphosphine and N-chlorosuccinimide or tetrachloromethane, or with thionyl chloride. Suitable solvents include dichloromethane and tetrahydrofuran. Analogous compounds in which X is Br can be prepared by reaction with a mixture of triphenylphosphine and N-bromosuccinimide, bromine or tetrabromomethane. Compounds of formula (IV) in which X is an alkyl sulfonate, such as CH 3 SO 2 O-, can be prepared by treating the alcohol with the corresponding alkylsulfonyl chloride in the presence of a tertiary amine base. gg) Compounds of formula (V) can be prepared from the corresponding monochlorides of formula (Vll) by reaction with HNR2R3 as illustrated in Scheme 35.

Scheme 35 A solution of the monochloride (VI) and the amine HNR3R4 in a suitable dipolar aprotic solvent is stirred at elevated temperature for 1 to 24 hours. Suitable solvents include dimethyl sulfoxide, dimethylformamide and N-methylpyrrolidinone. An excess of tertiary amine such as N-ethyldiisopropylamine, N-methylmorpholine and N-methylpyrrolidinone may optionally be included. Sometimes it is necessary to carry out the reaction under high pressure in a hermetically sealed container, in particular when the amine HNR3R4 or the solvent is volatile. Preferably, the monochloride is treated with 1-5 equivalents of the amine HNR3R4 and optionally 3-5 equivalents of N-ethyldiusopropylamine in dimethyl sulfoxide or N-methylpyrrolidinone at 100-125 ° C for 12-18 hours in a hermetically sealed container. hh) Compounds of formula (Vll) can be prepared from the dichloride of formula (VIII) by reaction with R 1 NH 2 as illustrated in Scheme 36.

Scheme 36 A solution of the dichloride (HIV), the amine R1NH2 and an excess of a tertiary amine such as N-ethyldiisopropylamine, N-methylmorpholine or triefylamine in a suitable dipolar aprotic solvent are stirred at room or high temperature for 1 to 24 hours. Suitable solvents include dimethylsulfoxide, dimethylformamide and N-methylpyrrolidinone. Preferably, the monochloride is treated with 2 to 5 equivalents of the amine R1NH2 and optionally 2 to 5 equivalents of N-ethyldiisopropylamine in dimethyl sulfoxide or a mixture of dimethylsulfoxide and N-methylpyrrolidinone at 30-90 ° C for 1 to 18 hours . Alternatively, a solution of the amine R1NH2 in a suitable solvent is treated with butyl lithium or sodium hexamethyldisilazide at low temperature and the dichloride is added to the resulting solution. Suitable solvents include tetrahydrofuran and dioxane. With less reactive amines R1NH2, this reaction may have a low yield. In such cases, it is often advantageous to use an alternative strategy, as described in part I) below. The preparation of the dichloride of formula (HIV) is described by way of example. ii) In a variation of the above strategy, the compounds of formulas (I) and (ll) can be prepared from monochlorides of formulas (IXA) and (IXB), respectively, as illustrated in Scheme 37.

Scheme 37 The transformation is carried out as described in part gg) above. jj) The compounds of formulas (IXA) and (IX8) can be prepared from the corresponding aldehydes of formula (X) or the alkylating agents of formula (XI) by the procedures illustrated in Schemes 38A and 38B (in which X has the same meaning as defined in part dd) above), respectively.

Scheme 38a (X) (IXA) RA = R15 (IXB) RA = H The transformation is carried out as described in part c) above. Scheme 38B The transformation is carried out as described in part dd) above. kk) The compounds of formula (X) and (XI) can be prepared from the esters of formula (Vll) as illustrated in Scheme 39.

Scheme 39 The aldehydes of formula (X) can be prepared by limited reduction of the ester group or indirectly through the alcohols of formula (Xll) using the procedures described in part ee) above. The compounds of formula (XI) can be prepared from the alcohols of formula (Xll) using the procedures described in part ff) above.

II) As mentioned in part hh) above, the reaction of the compounds of formula (VIII) with weakly nucleophilic amines R1NH2 sometimes gives low yields. An alternative route is illustrated in Scheme 40.

Scheme 40 The reduction of the ester of formula (Vll) is described in detail in the Examples. The primary alcohol (Xlll) is then protected to give compounds of formula (XIV) in which PG is an alcohol protecting group. A preferred protecting group is a trialkylsilyl group, in particular a ferc-butyldimethylsilyl group. The compounds of formula (XIV) are then reacted with an amine R1NH2 according to the procedure described in part hh) above to give compounds of formula (XV). Finally, the compounds of formula (XV) are deprotected to provide the primary alcohols of formula (Xll) using appropriate conditions. When PG is a trialkylsilyl group, it can be removed by treatment with a fluoride salt, such as tetrabutylammonium fluoride or with hydrochloric acid. The alcohols of the formula (Xll) can also be prepared as described in parts kk), jj) and ii) above. mm) In another variation, the alcohols of formula (Xll) can be made following the route illustrated in Scheme 41.

Scheme 41 The group -NR3R4 can be introduced according to the procedures described in part gg) above to provide compounds of formula (XVI). The primary alcohol group can then be oxidized as described in part ee) above to provide the aldehydes of formula (III) or derivatized as described in part ff) above to provide the compounds of formula (IV). The following compounds form additional aspects of the present invention. A compound of formula (IIA) wherein R1, R2, R3, R4, R6 and Y are as defined above in the description of the compounds of formula (I). Preferably, R6 is linked at N1. Preferably Y is -CH2-. A compound of formula (IIB) wherein R > 1, D R2, D R3, R D4, and, D R6 are as defined above in the description about the compounds of formula (I) and W is as defined above, for example, in Schemes 3J and 3L and in the description that accompanies these examples. Preferably, R6 is linked at N1. Preferably, W is a covalent bond. A compound of formula (XVI) wherein R1, R2, R5 and R6 are as defined above in the description about the compounds of formula (I). Preferably, R6 is linked at N1. A compound of formula (III) wherein R1, R3 and R4 are as defined above in the description about the compounds of formula (LA-4).

A compound of formula (IV) wherein R1, R3 and R4 are as defined above in the description about the compounds of formula (LA-4) and X is Cl, Br or CH3SO2O-. A compound of formula (XIA) wherein R1, R15 and R16 are as defined above in the description of the compounds of formula (LA-4). A compound of formula (XIB) wherein R1 and R16 are as defined above in the description of the compounds of formula (LA-4).

The invention is further illustrated by the following non-limiting examples. The melting points were determined in a Gallenkamp melting point apparatus using glass capillary tubes and are uncorrected. Unless otherwise indicated, all reactions were carried out in a nitrogen atmosphere, using commercially available anhydrous solvents. 'Ammonia 0.88' refers to commercially available aqueous ammonia solution of approximately 0.88 specific gravity. Thin-layer chromatography was performed on pre-coated silica gel plates with Merck glass backing (60 F254), and column chromatography on silica gel was carried out using silica gel 40-63 μm (silica gel). Merck silica 60). The ion exchange chromatography was performed using the specified ion exchange resin that had previously been washed with deionized water. The proton NMR spectra were measured on a Varian Inova 300, Varian Inova 400, or Varian Mercury 400 spectrometer in the specified solvents. In the NMR spectra, only the non-interchangeable protons that appear differentiated from the solvent peaks are indicated. Low-resolution mass spectra were recorded either in a Fisons Trio 1000, using positive ionization by thermoforzing, or a Finnígan Navigator, using positive or negative ionization by elecrofoiling. The high resolution mass spectra were recorded in a Bruker Apex II FT-MS using positive ionization by electrospray. The combustion analyzes were carried out by Exeter Analytical UK. Ltd., Uxbridge, Middlesex. Optical rotations were determined at 25 ° C using a Perkin Elmer 341 polarimeter using the solvents and concentrations specified. Compounds of the examples designated as optical isomers (+) or (-) are assigned based on the sign of optical rotation when determined in a suitable solvent.

Abbreviations, definitions v glossary AcOH acetic acid Amberlyst® 15 Ion exchange resin, available from Aldrich Chemical Company APCl chemical ionization at atmospheric pressure Arbocel ™ Filtering agent, from J. Rettenmaier &; Sohne, Germany atm Pressure in atmospheres (1 atm = 760 Torr = 101.3 kPa) Biotage ™ Chromatography performed using Flash 75 silica gel cartridge, from Biotage, UK BOC ferc-butoxycarbonyl at width c Concentration used for rotation measurements optics in g per 100 ml (1 mg / ml is c 0.10) cat Catalytic CBz benzyloxycarbonyl CDl N, N'-carbonyldiimidazole d doublet DCC N, N'-dicyclohexylcarbodiimide DCM dichloromethane dd doublet doublet DEAD diethyl azodicarboxylate Degusa® 101 palladium at 10% by weight on activated carbon, Degussa type E101 available from Aldrich Chemical Company 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1 H) -one Dess-Martin periodinane Column supplied by Phenomenex - manufactured by Nomura HPLC Develosil Chemical Co. composed of particles of Combi silica - RP C30 spherical (size 3 μm or 5 μm) having a chemically bonded surface of C30 chains. These particles are filled into stainless steel columns with dimensions of 2 cm in internal diameter and 25 cm in length DIAD diisopropyl azodicarboxylate DIBAL diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide Dowex® ion exchange resin, from Aldrich Chemical Company Enantiomeric excess Et3N triethylamine EtOAc Ethyl acetate EtOH Ethanol HOAT 1 -hydroxy-7-azabenzonitrile HOBT 1-Hydroxybenzotriazole hydrate HRMS high resolution mass spectrometry (positive ionization scan by electrospray) Hünig base N-ethyldiisopropylamine Hyflo ™ Hyflo supercel®, from Aldrich Chemical Company KHMDS bis (trimethylsilyl) amide potassium liq liquid LRMS low resolution mass spectroscopy (positive ionization scan by electrospray or thermospray) LRMS (ES ") low resolution mass spectroscopy (scanning of negative ionization by ele ctropulverization) m multiplet m / z peak mass spectrum gel MCI ™ high porosity polymer, CHP20P 75 - 150 μm, from Mitsubishi Chemical Corporation MeOH methanol reactive 2-chloro-1-methylpyridinium iodide Mukaiyama NaHMDS bis (trimethylsilyl) amide of sodium NMM N-methylmorpholine NMO N-oxide of 4-methylmorpholine NMP 1 -methyl-2-pyrrolidinone Column of hplc Supplied by Phenomenex. Composed by Luna C18 of spherical silica particles (size 5 μm or 10 μm) Phenomenex that have a chemically bonded surface of C18 chains. These particles are filled into a stainless steel column with dimensions of 2.1 cm in internal diameter and 25 cm in length, psi pounds per square inch (1 psi = 6.9 kPa) PyBOP ® benzotrazole-1-iloxitris hexafluorophosphate ( pyrrolidino) phosphonium PyBrOP ® bromo-tris-pyrrolidino-phosphonium hexafluorophosphate c quatrain Rf retention factor on TLC s singlet Sep-Pak® reverse phase C18 silica gel cartridge, Waters Corporation t triplet TBDMS-CI eerc-butyldimethylchlorosilane TFA acid trifluoroacetic THF tetrahydrofuran TLC Thin layer chromatography TMS-CI chlorotrimethylsilane WSCDI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; Chemical shift The following examples illustrate the preparation of the compounds of the formula (I) Preparation 1- 1 - (2-Ethoxyethyl) -4-nitro-1 H-pyrazole-3,5-d-dimethylcarboxylate Potassium carbonate (1.32 g, 9.57 mmol) and 2-ethoxyethyl bromide (1.18 mL, 9.57 mmol) were added to a solution of 4-nitro-1-pyrazol-3,5-dicarboxylate. of dimethyl (EP 1241170, page 50, preparation 10) (2 g, 9.57 mmol) in N, N-dimethylformamide (35 ml) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 ml) and water (100 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with pentane: ethyl acetate 100: 0 to 70:30 in 10% increments yielding the title product, 1.63 g. 1 H-NMR (CDCl 3, 400 MHz) d: 1.07 (t, 3 H), 3.41 (m, 2 H), 3.73 (t, 2 H), 3.89 (s, 3 H), 3.94 (s, 3H), 4.76 (t, 2H). MS APCI + m / z 302 [MH] +.

Preparation 2 1- (2-Ethoxyethyl) -4-nylro-1 / -pyrazole-3,5-d-carboxylic acid 3-methyl ester The diester from Preparation 1 (1.63 g, 5.4 mmol) was added to a solution of potassium hydroxide (300 mg, 5.9 mmol) in methanol (20 mL) and the reaction mixture was stirred at room temperature. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (100 ml) and washed with ether. The aqueous phase was acidified with 2M hydrochloric acid and extracted with dichloromethane (3 x 100 ml). The organic phases were combined, dried over magnesium sulfate and concentrated in vacuo to give the title product, 1.34 g. 1 H NMR (CD 3 OD, 400 MHz) d: 1.07 (t, 3 H), 3.47 (m, 2 H), 3.80 (t, 2 H), 3.88 (s, 3 H), 4.77 (t, 2H). MS APCI + m / z 288 [MH] +.

Preparation 3 5-Carbamoyl-1- (2-ethoxyetiO-4-nitro-1-pyrazole-3-carboxylic acid methyl) Oxalyl chloride (15.7 ml, 190 mmol) was added uniformly to a solution of the carboxylic acid from preparation 2 (17.1 g, 59.5 mmol) in dichloromethane (300 ml). N, N-dimethylformamide (46 μL, 6 mmol) was then added and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo and the residue subjected to azeotropic desylation with dichloromethane (3 x 200 ml). The product was dissolved in tetrahydrofuran (300 ml), the solution was cooled in ice, treated with 0.88 ammonia (200 ml) and stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (200 ml) and ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the crude product which was triturated in ether to give the title product, 8.2 g. 1 H NMR (DMSO-d 6, 400 MHz) d: 1.03 (t, 3H), 3.38 (m, 2H), 3.70 (t, 2H), 3.86 (s, 3H), 4 , 36 (t, 2H), 8.30 (m, 1H), 8.46 (m, 1H). MS APCI + m / z 287 [MH] +.

Preparation 4 methyl 4-amino-5-carbamoyl-1- (2-ethoxyethyl) -1f / -pyrazol-3-carboxylate Palladium hydroxide (II) on carbon (1 g) was added to a solution of the nitro compound of preparation 3 (8.2 g, 28.6 mmol) in methanol (300 ml). Ammonium formate (8.8 g, 0.14 mol) was added in several portions to the reaction mixture for 20 minutes and the reaction mixture was stirred at reflux for 2 hours. The reaction was cooled to room temperature and filtered to remove the catalyst. The filtrate was concentrated in vacuo and subjected to azeotropic distillation with toluene to yield the title product, 7.3 g. 1 H NMR (DMSO-d 6, 400 MHz) d: 1.04 (t, 3H), 3.32 (m, 2H), 3.66 (t, 2H), 3.78 (s, 3H), 4 , 49 (t, 2H), 5.12 (m, 2H), 7.50 (m, 2H). MS APCI + m / z 257 [MHf.

Preparation 5 1-f2-Ethoxyethyl) -5.7-dioxo-4.5.6.7-tetrahydro-1H-pyrazolor4.3-dlpyrimidine-3-carboxylic acid methyl ester N, N'-Carbonyldiimidazole (5.54 g, 34.2 mmol) was added to a solution of the amide of Preparation 4 (7.3 g, 28.5 mmol) in N, N-dimethylformamide (250 mL). and the reaction mixture was stirred at ambient temperature for 1 hour and then at 90 ° C for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was sonicated in acetone (200 ml), the solid separated by filtration and dried under vacuum to yield the title product, 5.3 g. 1 H-NMR (DMSO-d 6, 400 MHz) d: 0.99 (t, 3 H), 3.37 (m, 2 H), 3.77 (t, 2 H), 3.82 (s, 3 H), 4 , 64 (t, 2H). MS ES-m / z 281 [M-H] ".

Preparation 6 5.7-Dichloro-1- (2-ethoxyethyl) -1 H-pyrrazolor-4,3-o-pyrimidine-3-carboxylic acid methyl Phosphorus oxychloride (6.5 ml, 70 ml) and tatraethylammonium chloride (3.47 g, 21 mmol) were added to a solution of the dione of preparation 5 (1.97 g, 7 mmol) in propionitrile (28). ml) and the reaction mixture was heated to reflux for 4 hours. More phosphorus oxychloride (2.5 mL, 26.9 mmol) was added and the reaction mixture was then stirred at reflux for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between dichloromethane (300 ml) and water (50 ml). The organic extracts were separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate.pentene 0: 100 to 25:75 to yield the title product, 1.98 g. 1 H-NMR (CDCl 3, 400 MHz) d: 1.03 (t, 3 H), 3.40 (m, 2 H), 3.87 (t, 2 H), 4.06 (s, 3 H), 4.98 (t, 2H). MS APCI + m / z 319 [MH] +.

Preparation 7 5-Chloro-1- (2-ethoxy-ethyl) -7- (4-methylpyridin-2-ylamino) -1H-pyrazolof4,3-c / lpyrimidine-3-carboxylic acid methyl 2-Amino-4-methylpyridine (1.34 g, 12.4 mmol) was added to a solution of the dichlor compound of Preparation 6 (1.98 g, 6.2 mmol) in dimethyl sulfoxide (10 mL) and the reaction was stirred at 35 ° C for 5 hours. The reaction mixture was partitioned between dichloromethane (300 ml) and water (500 ml).

The organic extracts were separated, washed with water (3 x 100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with dichloromethane: acetonitrile 98: 2. The appropriate fractions were concentrated in vacuo, triturated with ether (50 ml), filtered and the solid dried to give the title product, 1.2 g. 1 H NMR (CDCl 3, 400 MHz) d: 1, 06 (t, 3 H), 2.49 (s, 3 H), 3.62 (m, 2 H), 4.00 (t, 2 H), 4.06 (s, 3H), 5.05 (m, 2H), 6.98 (m, 1H), 8.16 (m, 1H), 8.50 (m, 1 H). MS APCI + m / z 391 [MH] +.

Preparation 8 5-Chloro-1- (2-ethoxyethyl) -7- (5-methylpyridin-2-ylamino) -1H-pyrazolof4.3-cf pyrimidine-3-carboxylic acid methyl The title product was prepared by a procedure similar to that described for preparation 7 using the dichloro compound of preparation 6 and 2-amino-5-methylpyridine. 1 H NMR (DMSO-d 6, 400 MHz) d: 1.01 (t, 3H), 2.26 (s, 3H), 3.52 (m, 2H), 3.88 (m, 5H), 4 , 96 (m, 2H), 7.76 (m, 1H), 8.03 (m, 1H), 8.20 (m, 1 H). MS APCI + m / z 391 [MH] +.

Preparation 9 r5.7-Dichloro-1- (2-eioxy-yl) -1 / - / - pyrazolor4.3-Qlpirimidin-3-ipmetanol The dichloro compound from Preparation 6 (2.4 g, 7.52 mmol) was dissolved in tetrahydrofuran (60 mL) and the reaction mixture was cooled to -78 ° C. A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (37.6 ml, 37.6 mmol) was added dropwise over 10 minutes and the reaction mixture was stirred at -78 ° C for 10 minutes and then at -10 ° C. C last 1 hour.

The reaction mixture was cooled to -78 ° C, quenched with ammonium chloride solution (25 ml) and allowed to return to room temperature. The reaction mixture was diluted with dichloromethane (200 ml) and water (100 ml) and the solution was filtered through Arbocel®, washing through dichloromethane (3 x 100 ml).

The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: mephanol 99: 1 to yield the title product, 1.67 g. NMR of H (CDCl 3, 400 MHz) d: 1.08 (t, 3H), 3.42 (m, 2H), 3.80 (m, 2H), 4.90 (m, 2H), 5.10 (s, 2H). MS APCI + m / z 291 [MH] +.

Preparation 10 3- (ferc-Butyldimethylsilyloxymethyl) -5,7-dichloro-1- (2-ethoxyethyl) -1H-pyrazolo [4,3-olpyrimidine] The alcohol of preparation 9 (1.32 g, 4.53 mmol) was dissolved in dichloromene (25 ml) and the solution was treated with imidazole (339 mg, 4.98 mmol) and then ferd-butyldimethylsilyl chloride (750 mg). mg, 4.98 mmol). The reaction mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (200 ml) and washed with 10% polybasic carbonate solution. (100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 99: 1 dichloromethane: methanol to yield the title product, 1.56 g. 1 H NMR (CDCl 3, 400 MHz) d: 0.00 (s, 6H), 0J8 (s, 9H), 0.93 (t, 3H), 3.29 (c, 2H), 3.71 (t, 2H), 4.72 (m, 2H), 4.94 (s, 2H). MS APCI + m / z 405 [MHf.

Preparation 11? / - r3-ferc-Butylmethylsilyloxymethyl) -5-chloro-1- (2-ethoxy-1-yl) -1-p -razolor4.3-Qlp¡rim¡din-7-il pi rimdin-4-ilam Pyrimidin-4-ylamine (1.10 g, 11.55 mmol) was dissolved in tetrahydrofuran (30 ml) and the solution was labeled with sodium hexamethyldisilazide. (2.12 g, 11.55 mmol) and stirred at room temperature for 20 minutes.

The solution was treated with a solution of the dichlor compound of preparation 10 (1.56 g, 3.85 mmol) in tetrahydrofuran (10 ml) and the reaction mixture was stirred for 90 min. At room temperature. The reaction mixture was quenched with ammonium chloride solution (100 ml) and extracted with dichloromethane (200 I). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol 97: 3, yielding the title product, 830 mg. 1 H-NMR (CDCl 3, 400 MHz) d: 0.00 (s, 6H), 0.77 (s, 9H), 1.08 (t, 3H), 3.54 (c, 2H), 3.80 (m, 2H), 4.63 (m, 2H), 4.90 (s, 2H), 8.33 (d, 1H), 8.51 (d, 1H) , 8.77 (s, 1H). MS APCI + m / z 464 [MH] +.

Preparation 12? / - r3-ferc-Butyldimethylmethoxymethyl) -5-chloro-1- (2-ethoxyethep-1 / - / - pyrololo [4.3-olpyr midin-7-pyrazin-4-amlamine The title compound was prepared by a procedure similar to that described for preparation 11 using the dichlor compound of preparation 10 and aminopyrazine. 1 H NMR (CDCl 3, 400 MHz) d: 0.18 (s, 6 H), 0.93 (s, 9 H), 1, 21 (t, 3 H), 3.65 (m, 2 H), 3.97 (m, 2H), 4.80 (m, 2H), 5.06 (m, 2H), 8.30 (m, 2H), 9.77 (m, 1 H), 10.17 (m, 1H) ).

Preparation 13 5-Chloro-1- (2-ethoxyethyl) -7 - (, pyrimidin-4-ylamino) -1H-pyrrazolor4.3-jpyrimidin-3-ipmephanol The protected alcohol from Preparation 11 (2.0 g, 1.76 mmol) was dissolved in tetrahydrofuran (40 ml) and the solution treated with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (8.63 ml, 8%). 63 mmol). The reaction mixture was stirred for 90 minutes at room temperature and then treated with additional solution of tetrabutylammonium fluoride in tetrahydrofuran (4.32 ml, 4.32 mmol) and stirred for another hour. The reaction mixture was diluted with water (50 ml) and the aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane.methanol 99: 1 to 95: 5, yielding the title product, 1.25 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.26 (t, 3 H), 3.70 (c, 2 H), 3.97 (m, 2 H), 4.76 (m, 2 H), 5.10 (s, 2H), 8.51 (d, 1 H), 8.72 (d, 1H), 8.99 (s, 1H). MS APCI + m / z 350 [MH] +.

Preparation 14 r5-Chloro-1- (2-ethoxyethyl) -7- (pyrazin-2-ylamino) -1H-p -razolor4.3-Gf) pyrimidip-3-p-methanol The title compound was prepared by a procedure similar to that described for preparation 13 using the protected alcohol from preparation 12. 1 H NMR (CDCl 3, 400 MHz) d: 1.22 (l, 3 H), 3.66 (m, 2H) 3.98 (m, 2H), 4.80 (m, 2H), 5.08 (s, 2H), 8.34 (m, 2H), 9.80 (m, 1H), 10.22 (m, 1H).

Preparation 15 f5-Chloro-1- (2-ethoxyethyl) -7- (methylpyridin-2-ylamino) -1H-pyrazolor4.3-jpyrimidin-3-ipmetanol The ester of Preparation 7 (1.89 g, 4.84 mmol) in tetrahydrofuran (450 mL) was suspended and the reaction mixture was cooled to -78 ° C. Diisobutylaluminum hydride (39 ml, 1M solution in toluene, 39 mmol) was added and the reaction mixture was allowed to warm to -5 ° C. The reaction mixture was stirred at -5 ° C for 15 minutes before re-cooling to -78 ° C and quenching with aqueous ammonium chloride solution (10 ml). The reaction mixture was allowed to warm to room temperature and partitioned between dichloromethane (200 ml) and water (200 ml). The mixture was filtered through Arbocel® and the organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was triturated with ethyl acetate and the solid was removed by filtration to give the title product. 1 H-NMR (CDCl 3, 400 MHz) d: 1.11 (t, 3 H), 2.46 (s, 3 H), 3.61 (m, 2 H), 3.94 (m, 2H), 4.86 (m, 2H), 5.07 (m, 2H), 6.96 (m, 1H), 8.19 (m, 1 H), 8.48 (m, 1 H). MS APCI + m / z 363 [MH] +.

Preparation 16 r5-Chloro-1- (2-ethoxyethyl) -7- (5-methylpyridin-2-ylamino) -1H-pyrazolof4.3-o-pyrimidin-3-inmethanol The title compound was prepared by a procedure similar to that described for preparation 15 using the ester of preparation 8. 1 H NMR (CD3OD, 400 MHz) d: 1.12 (t, 3H), 2.34 ( s, 3H), 3.61 (c, 2H), 3.89 (m, 2H), 4.69 (m, 2H), 4.77 (s, 2H), 7.63 (d, 1 H) , 8.15 (s, 1H), 8.36 (d, 1H).

Preparation 17 r5-Chloro-1- (2-ethoxyethyl) -7- (4-methypyridin-2-ylammon) -1-pyrazoloyl-4-c-pyridin-3 -carbaldehyde The alcohol from preparation 15 (90 mg, 0.25 mmol) was dissolved in dichloromethane (15.5 ml) and the solution was cooled to 0 ° C and treated with 1,1,1-triacetoxy-1,1. -dihydro-1,2-benzodoxol-3 (1H) -one (111 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 2 hours and then treated with saturated sodium thiosulfate solution (13 ml), sodium hydrogen carbonate solution (13 ml) and ether (13 ml). The mixture was allowed to stand for 15 minutes before being extracted into dichloromethane (3 x 100 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 98: 2, yielding the title product, 53 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.10 (m, 3 H), 2.40 (s, 3 H), 3.62 (m, 2 H), 3.99 (t, 2 H), 4.85 (m, 2H), 6.90 (d, 1H), 8.20 (d, 1H), 8.40 (m, 1H), 10.35 (m, 1H).

Preparation 18 N-f5-Chloro-1- (2-ethoxyethyl) -3-methlaminomethyl-1 / - / - pyrazolo [4,3- Gpp-rimidin-7-n-4-methylpyridin-2-ylamine The aldehyde from preparation 17 (53 mg, 0.15 mmol) was dissolved in dichloromethane (2 ml) and the solution was treated with methylamine hydrochloride (11 mg, 0.17 mmol) and triethylamine (22 μl, 0.17 g). mmol). The mixture was stirred at room temperature for 30 minutes and then treated with more methylamine hydrochloride (11 mg, 0.17 mmol) and triethylamine (22 μL, 0.17 mmol) and stirred for another 30 minutes. Sodium Iriacetoxyborohydride (48 mg, 0.22 mmol) was added to the mixture and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between sodium hydrogencarbonate solution (100 ml) and dichloromethane (100 ml). The aqueous extract was extracted with dichloromethane (3 x 10 ml) and the organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia 0.88 95: 5: 0 to 90: 10: 1, yielding the title product, 19 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.10 (t, 3 H), 2.37 (s, 3 H), 2.72 (s, 3 H), 3.58 (c, 2H), 3.90 (t, 2H), 4.38 (s, 2H), 4.85 (t, 2H), 6.81 (s, 1H), 8.10 (d, 1 H) ), 8,30 (d, 1H). MS APCI + m / z 376 [MH] +.

Preparation 19? / - r3-Bromomethyl-5-chloro-1- (2-ethoxyethylp-1f-p -razolo [4.3-cpp! R¡m¡d¡n-7-il] -4-met.lp R¡d¡n-2-amine The alcohol of preparation 15 (560 mg, 1.54 mmol) was dissolved in dichloromethane (15 ml) and the solution was treated with tetrabromoethane (614 mg, 1.85 mmol) and cooled to 0 ° C in a water bath. ice. The mixture was treated dropwise with a solution of triphenylphosphine (567 mg, 2.16 mmol) in dichloromethane (5 ml) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting dichloromethane: methanol 100: 0 to 98: 2, yielding the title product, 457 mg. 1 H-NMR (CDCl 3, 400 MHz) d: 1.13 (t, 3 H), 2.49 (s, 3 H), 3.63 (c, 2 H), 3.94 (t, 2 H), 4.81 (s, 2H), 4.98 (t, 2H), 6.95 (s, 1 H), 8.18 (d, 1H), 8.50 (d, 1 H). MS ES + m / z 425 [MH] +.

Preparation 20? / - r3-Bromomethyl-5-chloro-1 - (2-ethoxyethyl) -1 / - / - pyrazolol4.3- cf1p¡r¡mid¡n-7-il-hieraz¡n-2- sheet The title compound was prepared by a procedure similar to that described for Preparation 19 using the alcohol in Preparation 14. 1 H NMR (CDCl 3, 400 MHz) d: 1.12 (t, 3 H), 3.64 ( c, 2H), 3.94 (t, 2H), 4.81 (s, 2H), 4.98 (t, 2H), 6.95 (s, 1H), 8.16 (d, 1H), 8.46 (d, 1H).

Preparation 21? / - r5-Chloro-3- (d.-ethalaminomethyl) -1- (2-ethoxyethyl) -1-p.-cyclo-4-cyclinimide-7-pyrimidine-4-ylamine The alcohol from Preparation 13 (446 mg, 1.28 mmol) was dissolved in dichloromethane (30 mL) and the solution was treated with teirabromomethane (507 mg, 1.53 mmol) and triphenylphosphine (401 mg, 1.53 mmol). . The reaction mixture was stirred at room temperature for 2 hours, additional tetrabromomethane (85 mg, 0.26 mmol) and triphenylphosphine (67 mg, 0.26 mmol) were added and the reaction mixture was stirred for another 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 80:20 pentane: ethyl acetate. The crude product was further purified by column chromatography on silica gel one more time, eluting with toluene: diethylamine 95: 5, yielding the title product, 196 mg. NMR from H (CDCl 3, 400 MHz) d: 1.19 (t, 3 H), 1, 14 (t, 6 H), 2.99 (m, 4 H), 3.67 (c, 2 H), 3.96 (t, 2H), 4.57 (s, 2H), 4.79 (t, 2H), 8.41 (d, 1H), 8.67 (d, 1H), 8.99 (s, H). MS ES + m / z 405 [MH] + P repair 22? / - r5-Chloro-3- (chloromethin-1 - (2-ethoxyethylene-1 Hp -razolor4.3-c-pyrimid) -7-il1-4-methyl-pyridin-2-amide The alcohol of preparation 15 (1.80 g, 5.00 mmol) was dissolved in dichloromethane (15 ml) and the solution was treated with thionyl chloride (150 ml, 17 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo, the residue was subjected to azeotropic distillation and then dried under vacuum. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 95: 5, yielding the title product, 980 mg. 1 H NMR (CDCl 3, 400 MHz) d: 0.92 (t, 3 H), 2.63 (s, 3 H), 3.58 (m, 2 H), 3.91 (m, 2 H), 4.81 (s, 2H), 5.20 (m, 2H), 7.14 (m, 1H), 8.16 (m, 1H), 8.97 (m, 1H). MS APCI + m / z 381 [MH] +.

Preparation 23? / - 3-Azidomethyl-5-chloro-1- (2-ethoxyethyl) -1H-pyrrazoloi4.3- | pyrimidn-7-ip-4-methylpyridin-2- sheet The chlorine compound of Preparation 22 (700 mg, 1.80 mmol) was dissolved in N, N-dimethyl formamide (10 mL) and the solution treated with sodium azide (129 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 1 hour and then allowed to stand at room temperature for another 18 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in water (100 ml) and washed with ether (4 x 20 ml). The ether washings were combined, washed with water (20 ml), dried over magnesium sulfate and concentrated in vacuo to give the title product, 600 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.20 (t, 3 H), 2.40 (s, 3 H), 3.60 (c, 2 H), 3.95 (t, 2 H), 4.70 (s, 2H), 4.80 (m, 2H), 6.90 (s, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.00 (s, 1H) . MS APCI + m / z 388 [MH] +.

Preparation 24? / - r3-Aminomethyl-5-chloro-1- (2-ethoxyethyl) -1- -pyrazolor4.3- pyrimidin-7-yl-4-methylpyridin-2-ylamine The azide of Preparation 23 (130 mg, 0.34 mmol) was dissolved in tetrahydrofuran (5 mL) and the solution treated with triphenylphosphine (92 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (5 ml) and stirred for another 18 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in brine and extracted with dichloromelan. The dichloromethane phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonium hydroxide 95: 5: 0.5, yielding the title product, 70 mg. 1 H NMR (CDCl 3, 400 MHz) d:, 23 (t, 3 H), 2.45 (s, 3 H), 3.65 (c, 2 H), 3.95 (t, 2 H), 4.20 ( s, 2H), 4.78 (t, 2H), 6.82 (s, 1H), 8.18 (m, 1H), 8.30 (m, 1H). MS APCI + m / z 362 [MH] +.

Preparation 25? / - r5-Chloro-1 - (2-ethoxyethyl) -7- (4-methylpyridin-2-ylamino) -1H-pyrazolor4,3-lp-r -midin-3-methylmethanesulfonamide The amine from Preparation 24 (150 mg, 0.40 mmol) was dissolved in dichloromethane (5 mL) and the solution was extracted with N-ethyldiisopropylamine (108 μL, 0.62 mmol) and methanesulfonyl chloride (34 μL, 44 mmol). The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: mefanol 100: 0 to 98: 2, yielding the title product, 110 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.10 (t, 3 H), 2.40 (s, 3 H), 3.00 (s, 3 H), 3.60 (c, 2H), 3.90 (t, 2H), 4.50 (s, 2H), 4.70 (t, 2H), 6.90 (d, 1H), 8.15 (d, 1H) 8.40 (s, 1H). MS APCI + m / z 438 [M-H] -.

Preparation 26 / V-r5-Chloro-1 - (2-ethoxyethyl) -7- (4-methylpyridin-2-ylamino) -1H-pyrazoloyl-4-olpyrimidin-3-ylmetiphidroxyacetamida The amine from Preparation 24 (50 mg, 0.14 mmol) was dissolved in dichloromethane (15 mL) and the solution was treated with glycolic acid (11 mg, 0.14 mmol), N-ethyldiisopropylamine (36 μL, 0, 21 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (57 mg, 0.15 mmol). The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (20 ml), washed with water (10 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane.-methanol 98: 2, yielding the title product, 50 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.20 (t, 3 H), 2.40 (s, 3 H), 3.60 (m, 2 H), 3.90 (t, 2H), 4.20 (s, 2H), 4.75 (m, 2H), 4.80 (d, 2H), 6.85 (m, 1H), 7.60 (m, 1 H) ), 8.20 (m, 1H), 8.30 (m, 1H), 10.10 (m, 1H). MS APCI + m / z 420 [MH] +.

Preparation 27 / V-r5-Chloro-1-f2-ethoxy-ethin-7- (4-methyl-pyridin-2-ylamino) -1H-pyrazolor-4,3-dpyrimidin-3-ylmethip-2- (dimethylamino) acetamide The title product was prepared by a procedure similar to that described for preparation 26 using N, N-dimethylaminoacetic acid and the amine of preparation 24. The crude product was purified by column chromatography on silica gel. eluting with dichloromethane: methanol: ammonium hydroxide 98: 2: 0.5. 1 H NMR (CDCl 3, 400 MHz) d:: 1.20 (t, 3 H), 2.39 (s, 6 H), 2.40 (s, 3 H), 3.10 (s, 2 H), 3, 60 (c, 2H), 3.90 (t, 2H), 4.75 (m, 2H), 4.80 (d, 2H), 6.85 (m, 1H), 7.90 (m, 1H ), 8.20 (m, 1H), 8.35 (m, 1H), 10.00 (m, 1H). MS APCI + m / z 447 [MH] +.

Preparation 28? / - r5-Chloro-1-f2-ethoxyethin-7- (4-methylpyridin-2-ylammon) -1H-pyrazolo [4,3-d] pyrimidin-3-pyridin; lmethyl] acetamide The amine from Preparation 24 (70 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL) and the solution was halided with acetyl chloride (16 μL, 0.23 mmol) and N-ethyldiisopropylamine (40 μL, 0.degree. , 23 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was suspended in methanol and treated dropwise with dichloromethane until all the solid was in solution. The solution was treated with 2M sodium hydroxide solution (500 μl) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and the residue was suspended in water (5 ml) and washed with dichloromethane (3 x 10 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 98: 2, yielding the title product, 50 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.18 (t, 3 H), 2.20 (s, 3 H), 2.40 (s, 3 H), 3.65 (c, 2H), 3.95 (t, 2H), 4.75 (m, 2H), 4.80 (t, 2H), 6.50 (m, 1H), 6.85 (m, 1H) , 8.20 (m, 1H), 8.30 (s, 1H), 10.00 (s, 1H). MS APCI + m / z 404 [MH] +.

Preparation 29? / - r5-Chloro-1 - (2-ethoxy-ethyl) -7- (4-methylpyridin-2-ylamino) -1H p¡razoloí4.3-d | pyrimidine- 3-methylmethionamide The title product was prepared by a procedure similar to that described for preparation 28 using propionyl chloride and the amine of preparation 24. 1 H NMR (CDCl 3, 400 MHz) d: 1.20 (t, 6H), 2.30 (m, 2H), 2.40 (s, 3H), 3.60 (c, 2H), 3.90 (t, 2H), 4.75 (t, 2H), 4.80 (d , 2H), 6.60 (m, 1H), 6.90 (d, 1H), 8.20 (d, 1H), 8.30 (s, 1H), 10.10 (s, 1H). MS ES + m / z 418 [MH] +.

Preparation 30? / - r5-Chloro-1- (2-ethoxyethyl) -7-f4-methylpyridin-2-ylammon) -1H-pyrazolof4.3-QlPyridin-3-methylmethyl? methylacetamide The title product was prepared by a procedure similar to that described for preparation 28 using the amine of preparation 18 and acetyl chloride. 1 H-NMR (CDCl 3, 400 MHz) d: Rotamers 1, 20 (t, 3 H), 2.15 (m, 1 H), 2.40 (s, 2 H), 2.45 (s, 3 H), 3, 05, 3.15 (2x, 3H), 3.65 (c, 2H), 4.70 (t, 2H), 4.80 (m, 3H), 4.90 (s, 1H), 6.85 (t, 1 H), 8.20 (m, 1H), 8.30 (s, 1H), 10.00 (s, 1 H). MS ES + m / z 418 [MHf.

Preparation 31 / V-r5-Chloro-3-chloromethyl-1- (2-ethoxyethyl) -1H-pyrazolof4,3-cfypyridin-7-inpyrimidin-4-ylamine The alcohol from Preparation 13 (1.35 g, 3.86 mmol) was dissolved in dichloromethane (10 mL) and the solution was treated dropwise with thionyl chloride (1.13 mL, 15.44 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was subjected to azeotropic distillation with toluene, yielding the title product, 1.44 g. 1 H NMR (CD 3 OD, 400 MHz) d: 1, 24 (t, 3 H), 3.72 (c, 2 H), 4.00 (t, 2 H), 4.90 (t, 2 H), 4.99 (s, 2H), 8.68 (m, 1H), 8.86 (m, 1H), 9.22 (m, 1 H). MS APCI + m / z 368 [MH] +.

Preparation 32? / - r5-Chloro-1- (2-ethoxyethyl) -3-methylaminomethyl-1-pyrazolor4.3-lp¡r¡m¡d¡n-7-n-pyrimidin-4-ylamine The chlorine compound from Preparation 31 (770 mg, 2.09 mmol) and N-ethyldisopropylamine (400 μL, 2.30 mmol) was dissolved in N, N-dimethylformamide (10 mL) and the solution was treated with a solution 35% methylamine in ethanol (6 ml, 42.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia 0.88 95: 5: 0 to 95: 5: 0.5 to 90: 10: 1, yielding the title product, 560 mg . NMR of H (CD3OD, 400 MHz) d: 1.17 (t, 3H), 2.52 (s, 3H), 3.65 (c, 2H), 3.95 (t, 2H), 4.13 (s, 2H), 4.87 (m, 2H), 8.36 (dd, 1 H), 8.65 (d, 1H), 8.84 (s, 1H).

MS APCI + m / z 363 [MHf.

Preparation 33 / V-5-Chloro-1 - (2-eloxyethyl) -3-methylaminomethyl-1 H-pyrazolo [4,3-cflp] rm-dn-7-n N-2-lalam To the 1-methyl-2-pyrrolidinone (1 ml) was added the bromine compound from preparation 20 (109 mg, 0.26 mmol) and a 33% solution of methylamine in ethanol (490 μl, 5.2 mmol) and the reaction mixture was heated to 35 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give the title product. MS APCI + m / z 363 [MHf.

Preparation 34 / V-f5- Chloro-1- (2-ethoxyethyl) -7-('p-rimidin-4-y-lamino) -1 H -pyrazolor4.3-c / 1-p -midin-3-methylmetin -? / - methylacetamide The amine of preparation 32 (530 mg, 1.45 mmol) and N-ethyldiisopropylamine (280 μl, 1.59 mmol) were dissolved in dichloromethane (15 ml) and the solution was treated with chloride of acetyl (114 μl, 1.59 mmol). The reaction mixture was stirred at ambient temperature for 45 min. And then concentrated in vacuo. The residue was dissolved in methanol (15 ml), treated with 2M sodium hydroxide solution (5 ml) and allowed to stand at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 96: 4, yielding the title product, 495 mg. 1 H NMR (CD 3 OD, 400 MHz) d: Rotamers 1, 20 (t, 3 H), 2.16, 2.38 (2x, 3 H), 2.99, 3.18 (2x, 3 H), 3.67 (m, 2H), 3.95 (c, 2H), 4.75-4.91 (m, 4H), 8.43 (d, 1 H), 8.67 (dd, 1 H), 8, 86 (s, 1 H). MS APCI + m / z 405 [MHf.

Preparation 35? / - f5-Chloro-1 - (2-ethoxylll) -7- (4-methylpyridin-2-ylamino) -1 Hp -razolof4.3- / lpirimin-3-ilmet P -? / - fer-butyl methylcarbamate The amine of preparation 18 (157 mg, 0.42 mmol) was dissolved in dichloromethane (10 ml) and the solution was treated with di-fer-butyl dicarbonate (129 mg 0.59 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo to give the title product, 200 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.10 (t, 3 H), 1.52 (s, 9 H), 2.42 (s, 3 H), 2.96 (s, 3 H), 3.60 (c, 2H), 3.94 (t, 2H), 4.75 (s, 2H), 4.82 (t, 2H), 7.00 (d, 1H), 8.18 (m, 1 H) ), 8.36 (m, 1 H). MS APCI + m / z 476 [MHf.

Preparation 36 f5-Dimethylamino-1- (2-ethoxyethyl) -7- (4-methylpyridin-2-ylamino) -1H-pyrazolo [4.3-olpyrimidin-3-ynmethenol The chlorine compound of Preparation 15 (780 mg, 2.15 mmol) and N-ethyldiisopropylamine (1.125 mL, 6.46 mmol) were dissolved in dimethyl sulfoxide (6 mL) and the mixture was treated with a solution of sodium chloride. , 6M dimethiamine in ethanol (1.15 ml, 6.46 mmol) and heated to 120 ° C for 18 hours in a sealed container. The reaction mixture was partitioned between dichloromethane (100 ml) and water (100 ml) and the organic phase was separated and washed with water (3 x 200 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 98: 2. The product was triturated with ether, yielding the title product, 230 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.07 (t, 3 H), 2.38 (s, 3 H), 3.20 (s, 6 H), 3.60 (c, 2 H), 3.85 (t, 2H), 4.65 (t, 2H), 4.80 (s, 2H), 6.90 (d, 1H), 8.12 (d, 1H), 8.39 (s, 1H) . MS APCI + m / z 372 [MHf.

Preparation 37 f5-Dimethylamino-1- (2-ethoxy-yl) -7- (5-methylpyridin-2-ylamino) -1H-pyrazolo [4.3-d1-pyrimidin-3-yl-methanol] The title compound was prepared by a procedure similar to that described for preparation 36 using the chlorine compound of preparation 16. 1 H NMR (CD3OD 400 MHz) d: 1.12 (t, 3H), 2.33 (s, 3H), 3.20 (s, 6H), 3.59 (c, 2H), 3.85 (m, 2H), 4.71 (m, 2H), 4.81 (s, 2H) , 7.62 (d, 1 H), 8.13 (s, 1 H), 8.38 (d, 1H). MS APCI + m / z 372 [MHf. Preparation 38 [5-D-methylamino-1- (2-ethoxyethyl) -7- (pyridn-4-ylamino) -1-p -razolof4,3- / pyr Md-3-methanol The title compound was prepared by a procedure similar to that described for preparation 36 using the chlorine compound of preparation 1. 1 H NMR (CD3OD 400 MHz) d: 1.21 (t, 3H), 3.30 (s, 6H), 3.66 (c, 2H), 3.92 (t, 2H), 4.69 (t, 2H), 4.83 (s, 2H), 8.39 (d, 1H) , 8.58 (d, 1H), 8.79 (s, 1H). MS APCI + m / z 359 [MHf.

Preparation 39 5-D-methylammon-1- (2-ethoxyethyl) -7- (4-methylpyridn-2-ylamine) -1H-pyrazolof4.3-c / [ pirimdin-3-carbaldehyde The alcohol from Preparation 36 (330 mg, 0.89 mmol) was dissolved in dichloromethane (15.5 L) and the solution was cooled to 0 ° C and boiled with 1,1,1-triacetoxy-1, 1- dihydro-1,2-benziodoxol-3 (1H) -one (394 mg0.93 mmol). The reaction mixture was stirred at room temperature for 2 hours and then treated with saturated sodium thiosulfate solution (13 ml), sodium hydrogencarbonate solution (13 ml) and ether (13 ml). The mixture was allowed to stand for 15 minutes before being extracted in dichloromelane (3 x 100 ml). The organic exiphats were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 98: 2, yielding the title product, 300 mg. 1 H NMR (CDCl 3 400 MHz) d: 1.10 (m, 3H), 2.40 (s, 3H), 3.30 (s, 6H), 3.62 (m, 2H), 3.99 ( t, 2H), 4.85 (m, 2H), 6.90 (d, 1H), 8.20 (d, 1H), 8.40 (m, 1H), 10.35 (s, 1 H) . MS APCI + m / z 370 [MHf Preparation 40 5-Dimethyl-1- (2-ethoxyethylp-7- (5-methylpyridn-2-ylamino) -1H-pyrazolof4, 3-Qlpirimidin-3-carbaldehyde The title product was prepared by a procedure similar to that described for preparation 39 using the alcohol of preparation 37. 1 H NMR (CD3OD, 400 MHz) d: 1.11 (t, 3H), 2.34 ( s, 3H), 3.24 (s, 6H), 3.61 (c, 2H), 3.97 (m, 2H), 4.80 (m, 2H), 7.63 (d, 1H), 8.13 (s, 1H), 8.31 (d, 1H), .10 (s, 1H). MS APCI + m / z 370 [MH] +.

Preparation 41 5-Dimethylamino-1 - (2-ethoxyethyl) -7- (pyrimidin-4-ylamino) -1 H-pyrrazolo [4.3-d1-pyrimidine-3-carbaldehyde The title product was prepared by a procedure similar to that described for preparation 39 using the alcohol of preparation 38. 1 H NMR (CD3OD, 400 MHz) d: 1, 21 (t, 3H), 3.25 ( s, 6H), 3.62 (c, 2H), 4.00 (t, 2H), 4.83 (t, 2H), 8.35 (d, 1H), 8.59 (d, 1H), 8.82 (s, 1 H). MS APCI + m / z 357 [MHf.

Preparation 42 4- [5-Dimethylamino-1- (2-ethoxyethyl) -7- (4-methylpyridin-2-ylamino) -1-pyrazolo [4,3-d1-pyrimidin-3-ylmethylpiperazine-1 - ferric butyl carboxylate The aldehyde from Preparation 39 (75 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL) and the solution was treated with sodium triacetoxyborohydride (52 mg, 0.24 mmol) and piperazin-1-ferric acid ester. -carboxylic acid (45 mg, 0.24 mmol). The reaction mixture was stirred in a ReactiVial ™ for 2 hours at room temperature and then treated with saturated sodium bicarbonate solution (8 ml). The mixture was extracted into dichloromethane (3 x 15 ml) and the organic extracts were combined and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting dichloromethane: methanol 100: 0 to 97.5: 2.5, yielding the title product, 80 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.10 (t, 3 H), 1.42 (s, 9 H), 2.38 (s, 3 H), 2.59 (m, 4 H), 3.20 (s, 6H), 3.40 (m, 4H), 3.58 (c, 2H), 3.80 (s, 2H), 3.81 (t, 2H), 4.65 (m, 2H) , 4.85 (d, 1 H), 6.88 (d, 1H), 8.10 (d, 1 H), 8.40 (s, 1H). MS APCI + m / z 538 [MHf.

Preparation 43 (3) -3-Methoxypyrrolidin-1-ferro-butylcarboxylate (3) -3-Hydroxy-pyrrolidin-1-carboxylic acid (12.5 g, 66.70 mmol) was dissolved in tetrahydrofuran (334 mL) and the reaction mixture was cooled to 0 ° C in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20 g, 73.3 mmol) and stirred until it returned to room temperature. The reaction mixture was then treated with methyl iodide (14.5 g, 100.0 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 ml) and concentrated in vacuo until only the aqueous phase remained. The aqueous solution was extracted with ethyl acetate (750 ml), the organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to give the title product, as a brown oil, 12.48 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H).

Preparation 44 (3S) -3-Methoxypyrrolidin-1-ferro-butylcarboxylate The title product was prepared by a procedure similar to that described for preparation 43 using (3S) -3-hydroxy-pyrrolidine-1-carboxylic acid-tert-butyl ester. 1 H NMR (CDCl 3, 400 MHz) d: 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H).

Preparation 45 (3f?) - 3-methoxypyrrolidine hydrochloride Hydrogen chloride gas was bubbled into an ice-cold solution of the compound of preparation 43 (6.02 g, 30.0 mmol) in dichloromethane (30 ml) and the reaction was allowed to warm to room temperature and stirred for 48 hours . The solution was concentrated under reduced pressure and the residue was triturated with water. The resulting crystals were separated by filtration and dried in vacuo to provide the title compound. 1 H NMR (400 MHz CD3OD) d: 2.06 (m, 1H), 2.20 (m, 1H), 3.26-3.42 (m, 7H), 4.17 (m, 1H).

Preparation 46 (3S) -3-methoxypyrrolidine hydrochloride H3C- -O The title compound was obtained from the compound of preparation 44, following a procedure similar to that described in Preparation 45. 1 H NMR (CD3OD 400 MHz) d: 2.14 (m, 1H) , 2.20 (m, 1H), 3.24-3.44 (m, 7H), 4.18 (m, 1H).

Example 1 2-Dimethylamino -? / - f5-dimethylamino-1- (2-ethoxyethyl) -7- (4-methylpyridin-2-amyl) -1H-pyrazolo [4.3-Qlpyrmidin- 3-ilmetipacetemide The chlorine compound from Preparation 27 (50 mg, 0.11 mmol) was dissolved in dimethyl sulfoxide (2 mL) and the solution was brought up with N-ethyldiisopropylamine (22 μL, 0.12 mmol) and a 33% solution. of dimethylamine in ethanol (160 μl, 1.10 mmol). The reaction mixture was heated to 100 ° C in a ReactiVial ™ for 18 hours and then partitioned between water (20 ml) and ethyl acetate (20 ml) and the aqueous phase was washed with ethyl acetate (2 x 20 ml ). The organic extracts were combined, washed with water (10 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting dichloromethane: methanol: ammonium hydroxide 98: 2: 0.5, yielding the title product, 32 mg. 1 H NMR (400 MHz CD3OD) d: 1.10 (t, 3H), 2.30 (s, 6H), 2.40 (s, 3H), 3.00 (s, 2H), 3.25 ( s, 6H), 3.60 (c, 2H), 3.90 (t, 2H), 4.70 (m, 4H), 6.90 (d, 1H), 8.10 (d, 1 H) 8.40 (s, 1 H). MS APCI + m / z 456 [MHf.

Examples 2 to 15 The following compounds, of the general formula shown below, were prepared by a procedure similar to that described for Example 1 using the appropriate chlorine compound of the preparations 18, 25, 26, 28, 29 and 30 , and the appropriate HNR3R4 amine.

N ° -NR3R4 Data Examples 3, 5, 8, 11 and 15 used a 2M solution of ethylamine in methanol as the source of the amine HNR3R4 Examples 2, 4, 6, 99, 12 and 13 used 33% solutions of dimethylamine in ethanol as a source of the amine HNR3R4 Examples 7, 10 and 14 used 2M solutions of methylamine in methanol as the source of the amine HNR3R4 Example 16? / - [5-Dimethylamino-1- (2-ethoxyethyl) -7- (pyrimidin-4-ylamino) -1H-pyrazolor4.3-Qlpyrimidin-3-ylmethyl-A / -methylacetamide The title product was prepared by a procedure similar to that described for Example 1 using the chlorine compound of preparation 34 and a 33% solution of dimethylamine in ethanol. 1 H NMR (CD3OD, 400MHz) d: Rotamers 1, 22 (t, 3H), 2.15, 2.47 (2xs, 3H), 2.97, 3.16 (2xs, 3H), 3.21 ( s, 3H), 3.22 (s, 3H), 3.65 (c, 2H), 3.90 (m, 2H), 4.68 (m, 2H), 4.77, 4.84 (2x) , 2H), 8.37 (d, 1 H), 8.56 (d, 1 H), 8.78 (d, 1 H). MS APCI + m / z 414 [MH] +.

Example 17 1- (2-Ethoxyethyl) -? / 5.N5-dimethyl-3-methylammonium-7 / 7- (pyrazin-2-yl) -1AY-p¡razolo [4.3-c] hydrochloride /] pyrimidine-5J-diamine The mixture was heated at 120 ° C for 18 hours in a ReacliVial ™ to a mixture of the chloride from Preparation 33 (109 mg, 0.3 mmol), dimethylamine (33% in ethanol, 0.27 mL, 1.5 mmol) and N , N-diisopropylethylamine (0.26 ml, 1.5 mmol) in 1-methyl-2-pyrrolidinone (1 ml). The cooled mixture was evaporated in vacuo and (the residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonium hydroxide (98: 2: 0.2) as eluent) The product was dissolved in dichloromethane, chloride of 2M hydrogen and ether (0.037 ml, 0.074 mmol) added and the solution was evaporated in vacuo to give the title compound, 23 mg 1 H NMR (CD3OD, 400MHz) d: 1.20 (t, 3H), 2, 62 (s, 3H), 3.23 (s, 6H), 3.66 (c, 2H), 3.92 (t, 2H), 4.19 (s, 2H), 4.73 (t, 2H), 7.04 (s, 1 H), 8.24 (d, 1H) ), 8.38 (d, 1H). MS APCI + m / z 372 [MHf.

Example 18 Hydrochloride of l - ^ - ethoxyethyl -? / ^ / V ^ dimethyl-Sf ^ -methylpiperazin-1-yl) met? P -? / 7- (4-methy1pyridin-2-yl) -1 - pyrazolo [4.3-Gflp¡rimidin-5,7-diamine The aldehyde from Preparation 39 (75 mg, 0.2 mmol), sodium triacetoxyborohydride (52 mg, 0.24 mmol) and 1-methylpiperazine (73 mg, 0.73 mmol) were dissolved in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 2 hours and then treated with sodium bicarbonate solution (8 ml) and extracted with dichloromean (3 x 15 ml). The organic extracts were combined, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane.metanol 100: 0 to 90:10. The product was treated with 2M hydrogen chloride in ether (0.1 ml), the mixture was concentrated and the product was dried in vacuo to give the title compound as a yellow crystalline solid, 29.6 mg. 1H NMR (D2O, 400MHz) d: 0.80 (t, 3H), 2.30 (s, 3H), 2.50 (broad m, 2H), 2.72 (s, 3H), 3.00 (m broad, 4H), 3.06 (s, 6H), 3.38 (m, 4H), 3.80 (m, 4H), 4.75 (t, 2H), 7.00 (d, 1 H), 7.55 (s, 1 H), 7.84 (d, 1 H). MS APCI + m / z 454 [MHf.

Examples 19 to 27 The following compounds, of the general formula shown below, were prepared by a procedure similar to that described for Example 18 using the appropriate amine HNR 5R16 and the appropriate aldehyde of preparations 39 and 40. (m, 2.94 2H), (m, MS (s, 3H), 5H), APCI + 2.10 (m, (m, 7.99 (d, (s, 6H), (m, • Example 21 - The product of preparation 46 was used as amine HNR15R16. • Example 22 - The product of preparation 45 was used as amine HNR15R16.

Examples 28 to 31 The bromine compound of preparation 19 (76 mg, 0.18 mmol) was dissolved in 1-methyl-2-pyrrolidinone (150 μl) and the solution was treated with the appropriate amine HNR15R16 (1.78 mmol). The reaction mixture was stirred at 60 ° C for 2 hours and then concentrated to reduce the volume in vacuo. A 33% solution of dimethylamine (0.18 mmol) in ethanol was added and the reaction mixture was sealed in ReactiVial ™ and heated to 120 ° C for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (1 ml) and saturated sodium bicarbonate solution (1 ml). The organic phase was separated and purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia 0.88 100: 0: 0 to 90: 10: 1. The residues were treated with 2 M hydrogen chloride in ether (30 μl) and the mixtures were evaporated in vacuo to give the title compounds.

• Example 28 - A 33% solution of dimethylamine in ethanol was used as the source of the amine HNR15R16. Example 31 - A 2M solution of ethylamine in methanol was used as the source of the amine HNR15R16.

Example 32 1- (2-Ethoxyethyl) -3- (ethylaminomethyl) -? / 5./V5-dmethyl-? / 7- (pyrimidin-4-yl) -1 / - / - pyrazolo [ 4.3-c 1-pyrimidine-5,7-diamine The aldehyde from the preparation was dissolved in dichloromethane (2 ml). 41 (50 mg, 0.14 mmol) and the solution was treated with ethylamine hydrochloride (13 mg, 0.15 mmol), sodium triacetoxyborohydride (45 mg, 0.21 mmol) and ithylamine (20 μl, 0.15 mmol) . The reaction mixture was stirred at room temperature for 30 minutes and then treated with more ethylamine hydrochloride (13 mg, 0.15 mmol) and ithylamine (20 μl, 0.15 mmol) and stirred for another minutes. The mixture was then treated with a 2M solution of ethylamine in ethanol (160 μl) and tetrahydrofuran (1 ml) and stirred at room temperature for 1 hour. The reaction mixture was partitioned between saturated sodium hydrogencarbonate solution (20 ml) and dichloromethane (20 ml) and the aqueous phase was extracted with dichloromethane (20 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia 90: 10: 1, yielding the title product, 29 mg. 1 H NMR (CD3OD, 400MHz) d: 1, 18 (m, 6H), 2.78 (c, 2H), 3.23 (s, 6H), 3.63 (c, 2H), 3.90 ( m, 2H), 4.69 (m, 2H), 4.85 (s, 2H), 8.40 (m, 1 H), 8.56 (d, 1H), 8.79 (s, 1 H) ). MS APCI + m / z 386 [MHf.

Example 33 1- (2-Ethoxyethyl) -3-f (2-meioxyethylamino) methyn-? / 5? 5 -dmethyl-? / 7- pyridin-4-yl- 1H-pyrololor4,3-c / lpirimidin-5,7-diamnam The title product was prepared by a procedure similar to that described in Example 32 using 2-methoxyethylamine and the aldehyde of preparation 41. 1 H NMR (CD3OD, 400 MHz) d: 1.20 (t, 3H), 2.90 (t, 2H), 3.23 (s, 6H), 3.34 (s, 3H), 3.55 (m, 2H), 3.63 (c, 2H), 3.91 (m , 2H), 4.09 (s, 2H), 4.68 (m, 2H), 8.38 (m, 1H), 8.58 (d, 1H), 8.79 (s, 1H). MS APCI + m / z 416 [MH] +.

EXAMPLE 34 3- (Diamethanol) -1- (2-ethoxyethylene) - 5/5-d-methyl-? 4-in- 1 - p¡razolor4.3-o1pir¡m¡d¡n-5,7-d¡am¡na The chlorine compound of preparation 21 (60 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (2 ml) and the solution was treated with N-ethyldiisopropylamine (129 μl, 0.74 mmol) and a 33% solution. of dimethylamine in ethanol (133 μl, 0.74 mmol). The reaction mixture was sealed in a ReactiVial ™ and heated to 120 ° C for 18 hours. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate (x3). The organic extracts were combined and washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 95: 5 to 90:10, yielding the title product, 29 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.24 (t, 6H), 1.42 (t, 3H), 2.86 (c, 2H), 3.22 (s, 6H), 3.65 (c, 2H), 3.92 (t, 2H), 4.25 (s, 4H), 4.68 (t, 2H), 8.32 (d, 1H), 8.58 (d, 1 H) ), 8.86 (s, 1 H). MS ES + m / z 414 [MHf Example 35 1 - (2-Ethoxyethyl) -5,? / -dimethyl-3- (methylaminomethyl) -? / 7- (pyrimidin-4-yl) -1 / - / - pyrazoloyl-4,3-cppirimidin-5,7- hydrochloride diamine The chlorine compound from Preparation 32 (32 mg, 0.09 mmol) was added to a mixture of a 33% solution of dimethylamine in ethanol (60 μL, 0.45 mmol) and N-ethyldiisopropylamine (80 μL, 0.degree. , 45 mmol) in 1-methyl-2-pyrrolidinone (1 ml). The reaction mixture was heated to 120 ° C for 18 hours in a ReactiVial ™ and then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 90: 10: 1 ammonia. The crude product was dissolved in dichloromethane and treated with 2M hydrogen chloride in ether and then concentrated in vacuo to give the title product, 9 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.21 (t, 3 H), 2.63 (s, 3 H), 3.24 (s, 6 H), 3.64 (c, 2 H), 3.92 (m, 2H), 4.21 (s, 2H), 4.73 (m, 2H), 8.36 (s, 1H), 8.58 (d, 1H), 8.81 (s, 1H) MS APCI + m / z 372 [MHf.

Example 36 2- Hydrochloride. { [1- (2-ethoxyethyl) -3- (methylaminomethyl) -7- (4-methylpyridin-2-ylamino) -1H-pyrazolo [4.3-c | pyrimidin-5-inmethylamino > ethanol The BOC-protected amine from Preparation 35 (66.5 mg, 0.14 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and the solution was treated with 2- (mephilamino) ethylene (56 μL, 0.70 μm). mmol) and N-ethyldiisopropylamine (120 μl, 0.70 mmol). The reaction mixture was treated in a ReactiVial ™ and heated to 120 ° C for 18 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and the solution was treated with trifluoroacetic acid (1 ml) and stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and the residue was partitioned between dichloromethane (10 ml) and saturated sodium bicarbonate solution (10 ml). The organic phase was separated and purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 0 to 97: 3. The crude product was dissolved in dichloromethane, treated with 2M hydrogen chloride in ether (100 μl) and concentrated in vacuo to give the title product, 30 mg. 1 H NMR (D 2 O, 400 MHz) d: 0.85 (t, 3 H), 2.37 (s, 3 H), 2.65 (s, 3 H), 3.14 (s, 3 H), 3.42 (c, 2H), 3.72 (m, 2H), 3.78 (m, 2H), 3.85 (t, 2H), 4.40 (s, 2H), 4.80 (t, 2H) , 7.08 (d, 1H), 7.48 (s, 1H), 7.95 (d, 1H). MS APCI + m / z 415 [MH] +.

EXAMPLE 37 1- (2-Ethoxyethyl-β-5- (2-methoxyethyl) -? - 5-methyl-3- (methylamnomethyl) -? / 7- (4-methylpyridinyl) hydrochloride 2-l) -1H-pyrazolo [4,3-lpyrimidin-5J-diamine] The title compound was prepared by a procedure similar to that described for example 36 using N- (2-methoxyethyl) methylamine and the BOC-protected amine of preparation 35. H-NMR (D2O, 400MHz) d: 0, 85 (t, 3H), 2.37 (s, 3H), 2.65 (s, 3H), 3.14 (s, 3H), 3.22 (s, 3H), 3.44 (c, 2H) ), 3.65 (t, 2H), 3.78 (t, 2H), 3.87 (t, 2H), 4.40 (s, 2H), 4.82 (t, 2H), 7.10 (d, 1H), 7.49 (s, 1H), 7.95 (d, 1H). MS APCI + m / z 429 [MHf.

Example 38 2-ri- (2-Ethoxyethyl) -3- (methylaminomethyl) -7- (4-methylpyridin-2-ylamino) -1H-pyrrazol 4.3-o1p Rimidin-5-amyl-ethanol The title compound was prepared by a procedure similar to that described for example 36 using ethanolamine and the protected amine of preparation 35. 1 H NMR (D 2 O, 400 MHz) d: 0.80 (t, 3H), 2 , 35 (s, 3H), 2.62 (s, 3H), 3.40 (m, 4H), 3.65 (m, 2H), 3.82 (t, 2H), 4.33 (s, 2H), 4.78 (t, 2H), 7.05 (d, 1H), 7.42 (s, 1 H), 7.95 (d, 1 H). MS APCI + m / z 402 [MHf.

Example 39? / - r 5 -D.methyllamino-1- (2-ethoxyethyl) -7- (4-methylpyridn-2-ylamino) -1 - / - pyrazolo [ 4.3- / lp¡rim¡din-3-lmetin -? / - prop¡lacetam¡da The product of Example 24 (30 mg, 0.07 mmol) was added to a solution of triethylamine (10 μ, 0.09 mmol) in dichloromethane (1 ml) and the mixture was treated with acetyl chloride (8 μl, 0.degree. , 09 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo.

The residue was dissolved in meianol (2 ml) and washed with 2M sodium hydroxide solution (10 ml) and water (10 ml). The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulfate and purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonium hydroxide 98: 2: 0.2, providing the title product, 10 mg. 1 H NMR (CDCl 3, 400 MHz) d: 0.90 (t, 3 H), 1.15 (t, 3 H), 1.65 (m, 2 H), 2.19 (s, 3 H), 2.42 (s, 3H), 3.32 (s, 6H), 3.59 (c, 2H), 3.85 (t, 2H), 4.59 (s, 2H), 4.79 (s, 2H), 4.82 (t, 2H), 6.95 (d, 1H), 7.75 (s, 1H), 8.27 (d, 1H), 10.60 (s, 1H) .

MS APCI + m / z 455 [MHf.

EXAMPLE 40 Hydrochloride of 1 - (2-ethoxyethyl) -? / 5? 5 -d / metl-? / 7- (4-methylpyridn-2-1) 3 - (piperazin-1-methylmethyl) -1H-p¡razolof4,3-dlpyrimidin-5,7-d-amines The protected amine of Preparation 42 (80 mg, 0.15 mmol) in 10% solution of trifluoroacetic acid in dichloromethane (5 mL) was dissolved and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane.methanol 100: 0 to 90:10. The crude product was treated with 2M hydrogen chloride in ether (100 μl) and concentrated in vacuo to give the title product, 33 mg. 1 H-NMR (D 2 O, 400 MHz) d: 0.70 (t, 3 H), 1.80 (s, 3 H), 2.50 (m, 4 H), 2.70 (m, 6 H), 2.80 (m, 4H), 3.30 (c, 2H), 3.55 (s, 2H), 3.65 (m, 2H), 4.30 (m, 2H), 6.65 (m, 1 H), 7.80 (m, 2H). MS APCI + m / z 440 [MHf.

Example 41 5-Piperazin-1-yl-3- (p-piperazin-1-ylmethyl) -? / - pyrimidin-4-yl-1- [2- (2,2,2-trifluoroethoxypetin-1H-pyrazolor trifluoroacetate) -cppirimidin-7-amin Methyl sulfoxide (1 ml) was mixed in a reaction vial with 5-chloro-3- (chloromethyl) -? / - pyrimidin-4-yl-1- [2- (2,2,2-trifluoro-epoxy) ethyl. ] -1H-pyrazolo [4,3-d] pyrimidin-7-amine (100 mg, 0.24 mmol), 1-boc-piperazine (250 mg, 1.18 mmol) and N, N-diisopropylethylamine (150 mg 1.18 mmol). The reaction mixture was stirred 1.5 hours at room temperature and then heated to 110 ° C for 18 hours. The reaction mixture was purified on reverse phase HPLC to give the compound protected with BOC (160 mg). The BOC protected compound was treated with trifluoroacetic acid (6 ml) at room temperature for 30 minutes. The reaction mixture was purified by reverse phase HPLC and lyophilized to give 5-piperazin-1-yl-3- (piperazin-1-methyl) - / V-pyrimidin-4-yl-1-trifluoroacetate. [2- (2,2,2-Trifluoroethoxy) eyl] -1 H -pyrazolo [4,3-d] pyrimidin-7-amine (58 mg). 1 H NMR (400 MHz, (CD3) 2 SO) d: 9.13 (broad s, 1H), 8.90 (m, 1H), 8.71 (m, 2H), 8.69 (m, 1H) , 7.90 (m, 1 H), 4.80 (t, 2H, J = 5.0 Hz), 4.66 (s, 2H), 3.89 (m, 8H), 3.47 (m , 4H), 3.36 (m, 4H), 3.16 (m, 4H). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.55 (t, 3F, J = 9.2 Hz). Calculated Exact Mass: M + H 522.2660, found: 522.2635.

EXAMPLE 42 5-f (3R) -3-methyl-piperazin-1 -n-3- (morpholip-4-methyl-1-trifluoroacetate) -? / - pyrimidn-4-yl-1 - [2- (2,2,2-trifluoroethoxy) etip-1 - / - p -razolor4,3-c | pyrimidin-7-amine Ephapa 1: Preparation of 5-Chloro-3- (morpholin-4-ylmethyl) - / V-pyrimidin-4-yl-1- [2- (2,2,2-trifluoroethoxy) ethyl trifluoroacetate] -1 V-pyrazolo [4,3-d] pyrimidin-7-amine Methyl sulfoxide (2 ml) was mixed in a reaction vial with 5-chloro-3- (chloromethyl) -? / - pyrimid-4-1-l- [2- (2, 2,2-Trifluoroethoxy) etl] -1H-pyrazolo [4,3-c-pyrimidin-7-amine (300 mg, 0.7 mmol), morpholine (185 mg, 2.1 mmol) and N , N-diisopropylethylamine (270 mg, 2.1 mmol). The reaction mixture was stirred 18 hours at room temperature and then purified on reverse phase HPLC and lyophilized giving 5-chloro-3- (morpholin-4-methylmethyl) -? / - pyrimidin-4-yl trifluoroacetate. -1- [2- (2,2,2-Trifluoroethoxy) ethyl] -1H-pyrrazolo [4,3-c (l-pyrimidin-7-amine (350 mg). 1 H NMR (400 MHz, (CD3) 2SO) d: 9.15 (m, 1 H), 8.77 (m, 1H), 8.06 (m, 1 H), 4.91 (t, 2H, J = 4.8 Hz), 4.70 (s, 2H), 3.80 (m, 6H), 3.60 (m, 2H), 3.42 (m, 2H), 3.18 (m, 2H). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.69 (t, 3F, J = 9.78 Hz). Calculated Exact Mass: M + H 473.1423, found: 473.1437.

Step 2: Preparation of 5 - [(3R) -3-methyl-piperazin-1-yl] -3- (morpholin-4-ylmethyl) - / V-pyrimidin-4-yl-1- trifluoroacetate [2- (2,2,2-trifluoroethoxy) etl] -1H-pyrazolo [4,3-c jpyrimidin-7-amine] Methyl sulfoxide (1.0 ml) was mixed in a reaction vial of 5-chloro-3- (morpholin-4-ylmethyl) -? / - pyrimidin-4-yl-1- [2- (2-trifluoroacetate. , 2,2-trifluoroethoxy) ethyl] -1W-pyrrazolo [4,3-c / pyrimidin-7-amine (150 mg, 0.2 mmol), (R) - (-) - 2 -methylpiperazine (86 mg, 0.85 mmol) and N, N-diisopropylethylamine (140 mg, 1.0 mmol). The reaction mixture was heated at 110 ° C for 18 hours. The reaction was cooled to room temperature and brought to acidic conditions by the addition of trifluoroacetic acid. The crude reaction mixture was purified on reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) and lyophilized giving 5 - [(3R) -3-methylpiperazine-1-trifluoroacetate. -yl] -3- (morform-4-ylmethyl) -? / - pyrimidin-4-yl-1- [2- (2,2,2-trifluoroethoxy) elyl] -1H-pyrazolo [4, 3-c0pyrimidine-7-amine (143 mg). 1 H NMR (400 MHz, (CD3) 2 SO) d: 9.16 (s, 1H), 9.03 (m, 1H), 8.71 (m, 2H), 7.91 (m, 1H), 4.80 (t, 2H, J = 5.2 Hz), 4.59 (s, 2H), 4.53 (m, 2H), 3.87 (m, 6H) ), 3.62 (m, 2H), 3.28 (m, 9H), 1, 23 (d, 3H, J = 6.6 Hz). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.53 (t, 3F, J = 9.6 Hz). Calculated Exact Mass: M + H 537.2656, found: 537.2647.

Example 43 Trifluoroacety of 3- (morpholin-4-methyl) -5-p-piperazin-1-yl -? / - pyrimidn-4-yl-1-r2- (2.2.2-trifluoroethoxy) ¡) Et1l1-1H-pyrazolo [4.3-o1pyrimidin-7-amine Example 43 was prepared by a procedure similar to that descr in Example 42 using piperazine in place of (R) - (-) - 2-methylpiperazine in Step 2. 1 H NMR (400 MHz, (CD3) 2SO) d: 8.84 (broad s, 3H), 8.60 (m, 1H), 7.86 (m, 1H), 4.82 (t, 2H, J = 4.9 Hz), 4.53 (s) s, 2H), 4.03-3.88 (m, 10H), 3.6 (m, 2H), 3.4 (m, 2H), 3.17 (m, 6H). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.56 (t, 3F, J = 9.0 Hz). Calculated Exact Mass: M + H 523.2500, found: 523.2475.

Example 44? / 5-ethyl-? / -methyl-? / -pyrimidin-4-yl-3- (thiomorpholin-4-ylmethyl-1-f2- (2.2.2-trifluoroethoxy) trifluoroacetate) 1H-p¡razolor4.3-cppirimid¡n-5.7-d¡amina Example 44 was prepared by a procedure similar to that descr in Example 42 using thiomorpholine in Step 1 and N-ethyl-N-methylamine in place of (R) - (-) - 2-methylpiperazine in Step 2. 1 H NMR (400 MHz, (CD3) 2 SO) d: 8.83 (broad s, 1H), 8.61 (m, 1H), 7.99 (m, 1H), 4.79 (m, 2H), 4.52 (s, 2H), 4.04-3.94 (m, 4H), 3.64 (m, 2H), 3.47 (m, 4H) ), 3.10 (s, 3H), 2.89 (m, 4H), 1.10 (t, 3H, J = 6.98 Hz). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.53 (t, 3F, J = 9.0 Hz). Calculated Exact Mass: M + H 512.2162, found: 512.2154.

EXAMPLE 45 5 - [(3R) -3-Methylpiperazin-1-p-3- (p.per.din-1-ylmethyl) -? / - pyrimid-4-trifluoroacetate l-1- [2- (2,2,2-trifluoro-eoxy) etl1-1 -pyrazolo [4,3-Qlp¡r¡m¡d¡n-7-amine Example 45 was prepared by a procedure similar to that descr in Example 42 using piperidine in place of morpholine. 1 H NMR (400 MHz, (CD3) 2SO) d: 9.90 (broad s, 1H), 9.13 (m, 1H), 8.83 (m, 2H), 8.63 (m, 1H) , 7.86 (m, 1H), 4.84 (t, 2H, J = 4.9 Hz), 4.51 (m, 4H), 4.05-3.94 (m, 4H), 3, 48-3.24 (m, 5H), 3.09-3.03 (m, 2H), 2.93-2.91 (m, 2H), 1.80-1, 77 (m, 2H), 1.64-1.62 (m, 3H), 1.30-1.25 (m, 4H). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.57 (t, 3F, J = 9.2 Hz). Calculated Exact Mass: M + H 535.2864, found: 535.2827.

Example 46 5 - [(3R) -3-Methylpiperazin-1 -p -? / - pyrimidn-4-yl-3- (t-morpholin-4-methyl-1-r2-) trifluoroacetate (2.2.2-trifluoroethoxytin-1 / - / - pyrazolo [4.3-o-pyrimidn-7-amine] Example 46 was prepared by a procedure similar to that descr in Example 42 using thiomorpholine in place of morpholine in step 1. 1 H NMR (400 MHz, (CD3) 2 SO) d: 9.10 (m, 1H) , 8.86 (m, 1H), 8.79 (m, 1H), 8.63 (m, 1H), 7.86 (m, 1H), 4.84 (m, 2H), 4.53 (m, 1H), m, 4H), 4.05-3.94 (m, 4H), 3.75 (m, 2H), 3.40-2.9 (m, 11H), 1.26 (d, 3H, J = 6.45 Hz). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.53 (t, 3F, J = 9.2 Hz). Calculated Exact Mass: M + H 553.2428, found: 553.2410.

Example 47 5 - [(3R) -3-Methylpiperazin-1-n-3-f (4-methy1p-piperazin-1-yl) methyn-? / -pyrifluoroacetate [0102] 4-yn-4-yl-1-f2- (2,2,2-trifluoroethoxy) etin-1-pyrazolo [4,3-c] pyrimidin-7-amine Example 47 was prepared by a procedure similar to that descr in example 42 using 1-methylpiperazine in place of morpholine in step 1. 1 H NMR (400 MHz, (CD3) 2 SO) d: 9.06 (m, 1H), 8.85 (m, 1H), 8.76 (m, 1H), 8.61 (m, 1 H), 7.86 (m, 1H), 4.76 (t, 2H, J = 4.8 Hz), 4.50 (m, 2H), 4.03-3, 91 (m, 6H), 3.40-2.99 (m, 10H), 2.73 (s, 3H), 2.48-2.50 (m, 3H), 1.25 (d, 3H, J = 6.4 Hz). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.53 (t, 3F, J = 9.2 Hz). Dough Exact Calculated: M + H 550.2973, found: 550.2976.

EXAMPLE 48 Trifluoroacetate of 3-r (dimethylammon) methyl- / V5.? / 5-diethyl-? / 7-pyrimidn-1-f2- (2.2.2) -trifluoroethoxy) etp-1 / - / - pyrazolo [4.3-cppirimidin-5,7-diamine Example 48 was prepared by a procedure similar to that descr in Example 41 using N, N-diethylamine in place of 1-Boc-piperazine in step 1 and N, N-diethylamine in place of (R) -methylpiperazine in step 2. NMR of 1H (400 MHz, (CD3) 2SO) d: 9.66 (m, 1H), 9.10 (m, 1H), 8.71 (m, 1H), 7.90 (m , 1H), 4.76 (t, 2H, J = 5.0 Hz), 4.51 (m, 2H), 3.94-3.87 (m, 4H), 3.60-3.55 ( m, 4H), 3.10-3.08 (m, 4H), 1.30 (t, 6H), 1.12 (t, 6H, J = 7.0 Hz). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.53 (t, 3F, J = 9.6 Hz). Calculated Exact Mass: M + H 496.2755, found: 496.2750.

Example 49 3-f Trifluoroacetate (1,1-dioxidothiomorpholin-4-pmethin-5 - [(3R) -3-methyl-piperazin-1-in-γ-pyrimidin-4-yl-1-r2- (2.2.2- trifluoroethoxy) etip-1H-pyrazolof4,3-lPyrimidin-7-amine Example 49 was prepared by a procedure similar to that described in Example 42 using 1,1-thiomorpholine dioxide in place of morpholine in step 1. 1 H NMR (400 MHz, (CD3) 2SO) d: 9.00 (m, 1H), 8.85 (broad s, 1H), 8.68 (m, 1H), 8.61 (m, 1 H) ), 7.86 (m, 1H), 4.77 (t, 2H, J = 4.8 Hz), 4.51 (m, 2H), 4.09 (s, 2H), 4.0 (c , 2H, J = 9.3 Hz), 3.92 (t, 2H, J = 4.8 Hz), 3.40-3.00 (m, 13H), 1.25 (d, 3H, J = 6.8Hz). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.53 (t, 3F, J = 9.0 Hz). Calculated Exact Mass: M + H 585.2326, found: 585.2322.

EXAMPLE 50 1- (2- (2.2.2-Trifluoroethoxyethi) -3 - ((2.2.2-trifluoroethylamino) methyl) -5- (piperazin-1-p- / V) trifluoroacetate - (pyrimid-4-yl) -1 H-pyrrazolo-4,3-dlpyrimidin-7-amine Step 1: Preparation of 1- (2- (2,2,2-trifluoroethoxy) ethyl) -3 - ((2,2,2-trifluoroethylamino) methy1) -5-chloro -? / - (pyrim Din-4-yl) -1 H -pyrazolo [4,3-c] pyrimidin-7-amine They were mixed in dimethyl sulfoxide (10 ml) in a reaction vial 5-chloro-3- (chloromethyl) -? / - pyridin-4-yl-1- (2- (2,2, 2-trifluoroethoxy) ethyl) -1H-pyrazolo [4,3- /] pyrimidin-7-amine (610 mg, 1.5 mmol), trifluoroethylamine hydrochloride (390 mg, 2.9 mmol) and N, N-diisopropylethylamine (410 mg, 3.2 mmol) together with tetraethylammonium bromide (1 mg) and tetraethylammonium iodide. The reaction mixture was stirred for two days at room temperature and a second canity of triethylamine hydrochloride (390 mg, 2.9 mmol) and N, N-diisopropylethylamine (410 mg, 3.2 mmol) was added and allowed to elapse. the reaction for another two days. The reaction mixture was partitioned between ethyl acetate (70 ml) and water (2 x 25 ml) and the organic phase was dried (Na2SO) and concentrated to an oil which solidified on standing. This intermediate was used without further purification. MS ES + [MHf m / z (relative intensity): 485.1 (100), 486.1 (10), 487.1 (20). Step 2. Dimethyl sulfoxide (3.0 ml) in a reaction vial was mixed with 1- (2- (2,2,2-trifluoroethoxy) ethyl) -3 - ((2,2,2-trifluoroethylamino) methyl) ) -5-chloro -? / - (pyrimidin-4-yl) -1H-pyrazolo [4,3-irmmidn-7-amine (213 mg, 0.41 mmol) prepared in the Step 1 and piperazine (152 mg, 1.8 mmol). The reaction mixture was heated at 120 ° C for 10 hours. The reaction was cooled to room temperature and brought to acidic conditions by adding trifluoroacetic acid. The crude reaction mixture was purified by reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) and lyophilized to give the title compound as a dark yellow solid (70 mg). 1 H NMR (400 MHz, (CD3) 2 SO) d: 10.4 (broad s, 1 H), 8.87 (s, s 2 H), 8.61 (m, 1 H), 7.88 (m, 1 H), 4.77 (t, 2H, J = 4.9 Hz), 4.19 (s, 2H), 3.99 (m, 2H), 3.90 (m, 6H), 3.6 (m, 2H), 3.19 (broad s, 4H). 19 F NMR (400 MHz, (CD3) 2SO) d: -73.57 (t, 3F, J = 9.64 Hz), -74.88 (s). MS ES + [MHf m / z (relative intensity): 535.2 (100), 536.2 (25). Examples 51-107 can be prepared by selecting suitable reactants and following the guidelines of Schemes 1-41 and Examples 1-50.

Example 51? / 5-Ethyl -? / 5-methyl-3- (piperazin-1-methylmethyl) -? / 7-pyrimidin-4-yl-1-r2- (2.2.2- trifluoroethoxy) etn-1 - pyrrazolo [4.3-c / lpyrimidine-5.7-diamine Example 52 5 - [(3R) -3-Methylpiperazin-1-p-3- (piperazin-1-methylmethyl) -? - pyrimide-4-yl-1-r2- (2.2. 2-trifluoroethoxy) etill-1H-pyrazolor4.3-QlPyrimin-7-amine Example 53 5-r (3S) -3-Metyl-piperazin-1-n-3- (piperazin-1-ylmei-p -? / - pyrimidin-4-yl-1-f2- (2,2,2-trifluoroethoxy) etill-1 / - / - pyrazolor4.3-Qlp¡r¡m¡d¡n-7-am¡na Example 54? / - (4-Fluorophenyl) -5-p-piperazin-1-yl-3- (piperazin-1-ylmethyl) -1- [2- (2,2,2-trifluoroethoxy) ethyl ] -1H-p¡razolo [4.3-lpyrimidin-7-amine] EXAMPLE 55 1- (2-Ethoxyethyl) -5-piperazin-1-yl-3- (piperazin-1-ylmetip- / V-pyrimidin-4-yl-1 H -pyrazolo [4.3 -d1-pyrimidine-7-amine EXAMPLE 56 1- (2-Ethoxyethyl) -? / 5-et.l -? / 5-methyl-3- (morpholin-4-ylmethyl) - / V7-pyridine -4- l-1H-pyrazolo [4,3-cflpyrimidin-5J-diamine Example 57? / 5-Ethyl -? / 5-methyl-3- (piperidin-1-methylmethyl) / V7-pyrimidin-4-yl-1-r2- (2.2. 2-Trifluoroethoxy) ein-1H-pyrazolof4,3-cflpyrimidin-5,7-d-amines Example 58 5-Piperazin-1-yl-3- (piperidin-1-methylmethyl) -? / - pyrimidin-4-yl-1-r2- (2.2.2-trifluoroethoxy) et N-1 - / - p¡razolo [4.3-cflpyrimidin-7-amine Example 59? / - (4-Methylpyridn-2-n-5-p-piperazin-1-1-3 - ('piperidn-1-methyl) - 1-r2- (2,2,2-trifluoroethoxy) eyl1-1H-pyrrazolor4.3-cflpyrimidin-7-amine EXAMPLE 60 1- (2-Ethoxyethyl) -5-piperazin-1-yl-3- (piperidin-1-ylmethyl) -? - pyrimidin-4-yl -1H-pyrazolor4.3-d-pyrimidimam-7-amine Example 61 5-Piperazin-1-yl -? / - pyrimidin-4-yl-3- (pyrrolidin-1 -ImetiD-l -f2- (2,2,2-tr? -fluoroethoxy) etin-1 - / - pyrazolo [4.3-QlPyrmidn-7-amine EXAMPLE 62 1- (f5-Piperazin-1-yl-7- (p, r, m, d, n-4-ylamino) -1- [2- (2.2.2-trifluoroethoxy) et1n-1H-p¡razolo [4.3-c lpir¡m¡d¡n-3-l) methyl) piper¡d¡n-4-ol EXAMPLE 63 3- (R-Ethyl (methylamino) methyl) -5-p yperazin-1-yl -? / - pyrimidin-4-yl-1-y2- (2,2,2-trifluoroethoxy) etin-1H-pyrazolo [ 4.3-d] pyrimidin-7-amine Example 64 3-. { [(3S) -3-Methylpiperazin-1-yl-1-methyl] -5-piperazin-1-yl- / V-pyrimid-4-yl-1- [2- (2.2.2- trifluoroethoxy) etn-1A-p¡razolof4,3-Qlpir¡mdin-7-amine EXAMPLE 65 3- (f (3R) -3-Met.lp.perazin-1-pmethyl) -5-p-piperazin-1-yl -? / - pyrimidn -4-il-1-r2- (2.2.2-trifluoroethoxy) etin-1H-pyrazolo [4.3-cppirimidin-7-amine EXAMPLE 66 3-r (1,1-D-oxothio-morpholin-4-yl) met.p-1- (2-ethoxyethyl) -5-p-piperazin-1-yl -? -pyrimidin-4-l-1H-pyrazolof4.3-Qlp-rimidin-7-amine Example 67 3 - [(3,5-Dimethyl-piperazin-1-yl) -methin-5-p-piperazin-1-yl -? / - pyrimide-4-yl-1-f2- (2.2.2-trifluoroethoxy) etin-1-p -razolor4,3-olpyrimid-7-amine Example 68 1- (2- (2.2.2-Trifluoroethoxy) etn-3 - ((2-methylpiperidin-1-yl) methyl) -5- (p-piperazin-1-yl) ) -? / - (p¡rim¡d¡n-4-il) -1 / - / - p¡razolo [4.3-olp¡rim¡din-7-am¡na EXAMPLE 69 3- (f2.2.2-Trifluoroethylamino) methyl) -1- (2-ethoxyetin-5- (p-piperazin-1 -n-? / - (p. -4-ip-1H-pyrazolof4.3-dlpyrimidin-7-amine Example 70 1 - (2-Ethoxyethyl) -3 - ((3,3-dimethyl-piperazin-1-l) methyl) -5- (piperazin-1 -iO-? / - (p. Midin-4-yl) -1 -pyrazolo [4,3-c-pyrimidin-7-amine] Example 71 5 - [(3S) -3-Methylpiperazin-1-yn-3- (piperidin-1-ylmethyl) -? / - pyrimidin-4-yl-1-f2- (2.2.2-trifluoroethoxy) etn-1H-pyrazolor4.3-olPyrimidin-7-amine Example 72 5- (3,3-Dimethyl-piperazin-1-yl) -3- (piperidin-1-ylmethyl) - / V-pyrimidin-4-yl-1-r2- (2.2.2-trifluoroethoxytitip-1H- p.razolor4.3-olPÍrim¡din-7-amina Example 73 1- (2-Eloxielil) -5-r (3R) -3-mell-piperazin-1-in-3- (piperidin-1-methylmethyl) - (pyrimidine) -4-yl) -1H-pyrazolof4.3-cflpyrimidn-7-amine Example 74 1 - (2-Ethoxyethyl) -5-r (3S) -3-methy1p-piperazin-1 -p-3- (piperidin-1-methylmethin-? / - (pyrimidin-4-yl) -1 - / - p -razolor4,3-o1pyrimidin-7-amine EXAMPLE 75 d-CS.S-Dimeylylpiperazin-1-iD-1-ethoxy-pi-S-1-piperidin-1-ylmethin-β-pyrimidin-4-yl-1H-pyrazolo [4.3-cppirimidin-7-amine Example 76 5-. { f (3R) -3-Met.lpiperazin-1-n- / V- (4-methylpyridin-2-yl) -3- (piperidin-1-ylmethyl) -1-f2- (2.2.2) -trifluoroethoxy) etp-1-pyrazolof4.3-olPyrimidin-7-amine Example 77 5-fr (3S) -3-Met.lpiperazin-1 -n -? / - (4-methy1pyridin-2-yl) -3- (piperidin-1-methyl) L) -1-f2- (2.2.2-trifluoroethoxy) etp-1 - / - pyrazolof4,3-cfjpyrmidn-7-amine EXAMPLE 78 1- (2-Ethoxyethyl) -5-f (3R) -3-methylpiperazin-1-in-γ / - (4-methy1-pyridin-2-in-3- ( piperidin-1-ylmethyl) -1H-pyrazolo [4,3-cflpyrimidin-7-amine] Example 79 1- (2-Ethoxyethyl) -5-r (3S) -3-methylpiperazin-1 -n -? / - (4-methylpyridyl) 2-n-3- (piperdin-1-methyl) -1 - prazolo [4.3-cf] pyrimidin-7-amine EXAMPLE 80 1- (2-Ethoxyethyl) - / V- (4-methylpyridn-2-yl) -5-piperazin-1-yl-3- (piperidin-1- ilmethyl) -1 H-pyrrazolo [4.3-cppimitrim-7-amine EXAMPLE 81 1- (2-Ethoxyethyl- / V5-etl) -? / 5-methyl-? / 7- (4-methylpyridin-2-in-3- (piperidin-1 - ilmethyl) -1 H-pyrazolof4,3-c? pyrimidine-5,7-diamine Example 82 N- (4-Fluorophenol) -5-f (3R) -3-methylpiperazin-1-n-3- (p-per-d-n-1-methyl) -1 - [2- (2,2,2-trifluoroethoxy) etn-1 - p -razolor4.3-dlpyridin-7-amine Example 83 N- (4-Fluorophenyl) -5-piperazin-1-yl-3- (p -peridin-1-ylmethyl) -1-r2- (2.2.2-trifluoroethoxy) ethyl] -1- pyrazolof4,3-dlpyridin-7-amine EXAMPLE 84 N- (4-Fluorophenol) -5-r ('3S) -3-methylpiperazin-1-p-3- (p -peridin-1-ylmethyl) -1-f2 - (2.2.2-trifluoroethoxy) et1ll-1 - p¡razolo [4.3-c lpirimdin-7-amine EXAMPLE 85 1- (2-Ethoxyethyl) -N- (4-fluorophenyl) -5-r (3R) -3-methy1p-piperazin-1-p-3- (p-peridin) -1-methylmethyl) -1 / - p -razolo [4.3-c / lp] rimidin-7-amine Example 86 1 - (2-Ethoxyethyl) -N- (4-fluorophen-D-5-p-piperazin-1-yl-3- (piperidin-1-lmethip-1H-pyrazolor4,3-c 1p) rimin-7-amine Example 87 1- (2-Ethoxyethyl) -N- (4-fluorophenyl) -5-r (3S) -3-methylpiperazin-1-n-3- (piperidin-1- lmethyl) -1 Hp¡razolof4.3-c / lpyrmidin-7-amine EXAMPLE 88 1- (2-Ethoxy-yl) -N- (4-fluorophenin-5-r (3S) -3-methylpiperazin-1-p-3- (piperidin-1-methylmethi-1 - / - pyrazoloF4,3-Gpp¡r¡m¡din-7-amine EXAMPLE 89 3- (Azepan-1-ylmethyl) -1 - (2-ethoxyethyl) -5-piperazin-1-yl -? - pyrimidin-4-yl-1H-pyrazolor4.3 -olpyrimidine-7-amine EXAMPLE 90 3 - [(2,6-Dimethylpiperidin-1-ipmetn-1- (2-ethoxyethyl) -5-piperazin-1-yl- / V-pyrimidin-4-yl-1 / -pyrazolo [4.3-o-pyrimidin] -7-amine EXAMPLE 91 3-f (3,3-Dimethylpiperidin-1-iD-methyl-l - (2-ethoxyethyl) -5-piperazin-1-yl -? / - pyrimid-4-yl-1-p -razolof4, 3-d] pyrimidin-7-amine Example 92 3 - ((Cyclohexylammon) methyl) -1- (2-ethoxyethyl) -5- (piperazin-1-yl) -? / - (pyrimidn-4-! l) -1 / - / - pyrazolo [4.3-QlPÍrim¡din-7-amine EXAMPLE 93 4 - ((1- (2-Ethoxyethyl) -5 - (, piperazin-1-yl) -7- (pyrimidn-4-ylamino) -1 - p¡razolo [4,3-olPyr¡m¡din-3-yl) methylamino) cyclohexanol Example 94 (1r.4r) -4 - ((1- (2-Ethoxy-1-yl) -5- (piperazin-1-yl) -7- (pyrimidin-4-ylamino) - H- pyrazolor4.3-Gppirimidin-3-yl) methylamino) cyclohexanol Example 95 3 - ((Cyclopentylamino) methyO-1- (2-ethoxythiO-5- (piperazin-1-yl) -? / - (pyrimidin-4-yl) -1H-pyrazolof4.3-cf1pyridin- 7-amine Example 96 3- (Y Cyclopropylamino) methyl) -1- (2-ethoxyethyl) -5- (piperazin-1-yl) -? / - (pyrimidin-4-yl) -1 H-p razolo [4,3-cpp¡r¡mid¡n-7-amine] EXAMPLE 97 3 - ((ferc-Butyllamine) methyl) -1- (2-ethoxy-loyl-5- (piperazin-1-yl) -? / - (pyrimidin-4-yl) -1 / - / - pyrazolo [4.3-cpprimidin-7-amine EXAMPLE 98 1 - (2-Ethoxyethyl) -5- (piperazin-1 -yl) -3 - (? Piper-dine-1-yl) methyl) -? / - (pyridin--yl) -1 / - pyrazolo [4,3-Qlpyrimidin-7-amine] Example 99 1- (2-Ethoxyethyl) -? / - phenyl-5- (piperazin-1-ip-3 - ((piperidin-1-ylmethyl) -1H-pyrazolo [4,3-ol-pyrimidin-7-amine] Example 100 1- (2-Ethoxyethyl) -? / - (, 6-methylpyridin-2-yl) -5- (piperazin-1-yl) -3 - ((pperidin -1-iDmetiD-1 H-pyrazolo [4.3-cflPirimidin-7-amine Example 101 5-r (3R) -3-methylpiperazin-1 -n -? / - (4-methylpyridin-2-yl) -3- (morpholin-4-ylmet-p-1-) r2- (2.2.2-trifluoroethoxy) etp-1Ay-pyrazolo [4.3-Qlpyrimidin-7-amine Example 102 / V5-et¡l-? 5 -methyl- 3- (morpholin-4-methyl) -7/pyrimidin-4-l1-r2-(2.2.2-trifluoroeloxi)etl '| -1 / - / - pyrazolof4.3-cppirmidin-5.7-diamine Example 103? / 5-ethyl-? / 5-methyl) -? / 7- (4-methylpyridin-2-yl) -3- (morpholin-4-ylmethyl) -1-r2- (2.2.2-tr! fluoroethoxypep-1 - p -razolof4.3-Qf] pyrimidn-5-diamine Example 104? / 5-ethyl- / V7- (4-fluorophenin -? / 5-methyl-3- (morpholin-4-ylmethyl) -1-r2- (2.2.2-trifluoroethoxy) etill -1 / - pirazolo [4.3-Qlp¡rim¡d¡n-5.7-d¡am¡na EXAMPLE 105 1- (2-ethoxy-ethyl) -5-r (3R) -3-methyl-piperazin-1-yn-3- (morpholin-4-ylmethyl-pyrim) Din-4-l-1H-pyrrazolo [4,3-tflpyrimidin-7-amine] Example 106 1- (2-ethoxyethanol-5-R3R) -3-methylene piperazin-1-nN- (4-methylpyridine-2-n-3) - (morpholin-4-methylmet) -1H-pyrazolo [4,3-dlpyridin-7-amino] EXAMPLE 107 1- (2-Ethoxyethyl VN- (4-fluorophenyl) 5 - [(3RV3-methylpiperazin-1-in-3- (morpholin-4-ylmelll) -1H-pyrrazolo [4.3-Qlpyrim D-n-7-amine Test The compounds of the invention are inhibitors of the phosphodiesterase type 5 specific for 3 ', 5'-guanosine monophosphate (cGMP) (inhibitors of PDE-5). Preferred compounds suitable for use according to the present invention are potent and selective inhibitors of PDE-5. PDE inhibitory activities in vitro against phosphodiesterases of 3 ', 5'-cyclic guanosine monophosphate (cGMP) and 3', 5'-cyclic adenosine monophosphate (cAMP) can be determined by measuring their Cl50 values ( concentration of compound necessary for 50% inhibition of enzymatic activity). The required PDE enzymes can be isolated from a variety of sources, including human cavernous body, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by a modification of the method of Thompson, W.J., et. to the. Biochemistry 18 (23), 5228-5237, 1979, as described by Ballard S.A. ef al., J. Urology 159 (6), 2164-2171, 1998. In particular, cAMP cGMP and PDE-3 specific PDE-5 inhibited by cGMP can be obtained from human cavernous body tissue, human platelets or platelets of rabbit; PDE-2 stimulated by cGMP was obtained from the human corpus cavernosum; calcium / calmodulin-dependent PDE-1 (Ca / CAM) of human cardiac ventricle; the human skeletal muscle cAMP specific PDE-4 and the bovine retina photoreceptor PDE-6. Phosphodiesterases 7-11 can be generated from whole human recombinant clones transfected into SF9 cells. The assays can be performed using a modification of the "batch" procedure of Thompson, W.J. and Appleman, M.M .; Biochemistry 10 (2), 311-316, 1971, essentially as described by Ballard S.A. et al., J. Urology 159 (6), 2164-2171, 1998 or using a scintillation proximity assay for the direct detection of AMP / GMP labeled with [3 H] using a modification of the protocol described by Amersham foot with the code of product TRKQ 7090/7100. In summary, for the scintillation proximity assay, the effect of the PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying concentrations of inhibitor and low substrate (cGMP or cAMP in a 3: 1 ratio of non-labeled a [3H] labeled at a concentration of ~ 1/3 Km or less) such that CI5o = K1. The final assay volume was completed to 100 μl with assay buffer [20 mM Tris-HCl, pH 7.4, 5 mM MgCl 2, 1 mg / ml bovine serum albumin]. Reactions were initiated with enzyme, incubated for 30-60 min at 30 ° C, providing a substrate renewal < 30% and were terminated with 50 μl of yttrium silicate microspheres SPA (containing 3 mM of the unlabeled cyclic nucleoides respecific for PDE9 and 11). The plates were resealed and shaken for 20 min, after which the microspheres were allowed to settle for 30 min in the dark and then counted in a TopCount plate reader (Packard, Meriden, CT). The radioactivity units were converted to% activity of an uninhibited control (100%), plotted against the inhibitor concentration, and Cl50 values were obtained using the Microsoft Excel extension "Fit Curve" (curve fitting). ).

In Vitro Assays Method A: Scintillation Proximity Assay of the Inhibition of PDE-5 - Human Platelets The assay measures the inhibition of the activity of the human PDE5 enzyme on human platelets of a test compound in an in vitro assay that uses PDE5 isolated from human platelets. The enzyme PDE5 can be isolated from platelets basically by a modification of the procedure of Thompson, WJ ef al .; Biochemistry 18 (23), 5228-5237, 1979, as described by Ballard SA et al .; J. Urology 159 (6), 2164-2171, 1998. PDE5 catalyzes the hydrolysis of [3 H] cGMP at 5 'nucleotide [3 H] GMP. [3H] GMP binds to yttrium silicate SPA microspheres and is detected by scintillation counting. In summary, for the scintillation proximity assay, the effect of a test compound was investigated by assaying a fixed amount of enzyme in the presence of varying concentrations of test compounds and substrate depletion, (cGMP or cAMP in a 3: 1 ratio). marked with [3H] at a concentration equal to or less than about 1/3 Km) such that CI5o = K1. The inhibition of the activity of the enzyme is calculated with respect to the total activity of PDE5 of non-inhibited controls.

PDE5 Clgn Assay: 96-well microtiter plate format Reactive Buffer A: 20 mM Tris-HCl, 25 mM MgCl, pH 7.4 Buffer B: 2 mg / ml BSA in Buffer A (enzyme buffer) cGMP Substrate : Final concentration of 500 nM in the test. The amount of substrate labeled with 3 H added depends on the specific activity of [3 H] cGMP, and this is diluted with a 10 mM stock solution of cold cGMP in Buffer A for a final subsitiate concentration of 500 nM in the assay. PDE Enzyme: Prepared in Buffer B. The dilution factor is determined by the activity of the enzyme. SPA microspheres: Suspension 20 mg / ml prepared in dH2O.

Positive control Negative control Standard / test compound 2 μl of 100% DMSO 2 μl of 100% DMSO 2 μl of standard / test compound 25 μl of Buffer A 25 μl of Buffer A 25 μl of Buffer A 25 μl of Enzyme 25 μl of Buffer B 25 μl of Enzyme 50 μl of Substrate 50 μl of Substrate 50 μl of Substrate 50 μl of SPA to stop 50 μl of SPA to stop 50 μl of SPA to stop Template stocks and test compounds are prepared at 5 mM in 100% DMSO. The compounds are serially diluted in separate dilution plates using a logarithmic 10-point dilution format. 2 μl of the compound dilutions are added in duplicate to the wells of the assay plate. 2 μl of 100% DMSO is added to the designated control wells. 25 μl of Buffer A is added to all wells. 25 μl of Buffer B are added to the negative control wells and 25 μl of enzyme is added to the rest of the wells. 50 μl of substrate is added to each well. The plates are sealed and incubated for 60 minutes on a plate agitator at 30 ° C. To stop the reaction, 50 μl of SPA microspheres are added. The plates are sealed again and stirred for 15 minutes to allow the microspheres to bind to the product GMP. The microspheres are allowed to settle for 30 minutes and then read on an NXT TopCount. The data is analyzed with the ECADA application. In this analysis, the% inhibition is calculated (Average maximum value - Compound value) / (Average maximum value - Average minimum value) x 100. The CI5o are determined from the sigmoidal dose-response curves of the activity of the enzyme versus the concentration of compound.

Procedure B: Scintillation Proximity Assay (SPA) of the PDE-5 human platelet nhibition This procedure is a modified protocol of the Method A. The assay measures the inhibition of the activity of the PDE5 enzyme in human platelets by a test compound in an in vitro assay using PDE5 isolated from human platelets. PDE5 catalyzes the hydrolysis of [3 H] cGMP at 5 'nucleotide [3 H] GMP. [3H] GMP binds to yttrium silicate SPA microspheres and is detected by scintillation counting. The inhibition of the activity of the enzyme is calculated with respect to the total activity of PDE5 of non-inhibited controls. PDE5 Clgn assay: 96-well microtiter plate format Reactive Buffer A: 20 mM Tris-HCl, 5 mM MgCl 2, pH 7.4 Buffer B: 2 mg / ml BSA in Buffer A (enzyme buffer) Substrate cGMP: Final concentration of 50 nM in the assay. The amount of substrate labeled with 3H added depends on the specific activity of [3H] cGMP, and this is diluted in Buffer A. Enzyme PDE: Prepared in Buffer B. The dilution factor is determined by the activity of the enzyme. SPA microspheres: Suspension 4 mg / ml prepared in dH2O.

Positive control Negative control Standard / test compound 3 μl of 100% DMSO 3 μl of 100% DMSO 3 μl of standard / test compound 27 μl of Buffer A 27 μl of Buffer A 27 μl of Buffer A 30 μl of Enzyme 30 μl of Buffer B 30 μl of Enzyme 30 μl of Substrate 30 μl of Substrate 30 μl of Substrate 30 μl of SPA for 30 μl of SPA for 30 μl of SPA to stop stopping stop Standard stock solutions and test compounds are prepared at 2 mM in 100% DMSO. The compounds are serially diluted in separate dilution plates using an 8-point logarithmic dilution format such that the starting concentration in the assay is 2 μM for an initial IC50 screen. 27 μl of Buffer A is added to the wells of the test plates. From the dilution plates, 30 μl of diluted compounds are administered in duplicate or 3 μl of 100% DMSO is added (for positive and negative controls). 30 μl of enzyme is added. For negative control wells, Buffer B is substituted for the enzyme. 30 μ of labeled substrate are added to all wells. After incubating for 60 minutes at room temperature, the reaction is stopped with the addition of 30 μl of the trio silicate microspheres. These microspheres are dense and require a consitant agitation while they are added to the plate. The plates are sealed and shaken on a plate shaker for fifteen minutes to allow the microspheres to bind to the product GMP. After allowing the microspheres to settle for 30 min., The plates are read in a NXT TopCouní and the dalos are analyzed in the Bioassay Solver application. The percentage inhibition values are calculated using the 0% and 100% conirol averages of each plate. The estimates of the 4 parameters of the logistic sigmoidal dose-response model are then calculated using the percentage inhibition values weighted for each plate for each compound. These estimates are used to calculate the concentration that corresponds to a 50% inhibition.

Ex Vivo Assays Procedure C: Aortic Ring Test This protocol describes the procedure for measuring the direct relaxation of rat aortic rings exposed to test compounds. In this assay, compounds that inhibit PDE5 cause a relaxation of the aorta rings by enhancing the cGMP signal evoked by a stable exogenous NO donor, DETA-NO. As an index of power, an EC50 is calculated, with confidence intervals of 95%, for the relaxation evoked by the compound. Male Sprague-Dawley rates (250-350 g) are smothered by CO2 gas and their thoracic aorta is carefully cut and placed in Krebs buffer. The aortas are then dissected carefully free of connective tissue and divided into 8 sections, each with 3-4 mm in length. The aorta rings are suspended between parallel stainless steel wires in a 15 ml bath with a water bath (37 ° C) under a resting tension of 1 g. The voltage is measured using voltage cuvette transducers and recorded using a Ponemah tissue platform system.

Each preparation is left to equilibrate for at least 60 minutes before the drug trial. During this time, the tissues are also incubated with 200 μM L-NMMA and the incubation media are changed every 15-20 minutes (L-NMMA is added after each wash to maintain the final concentration at 200 μM in each tissue bath ). After the balancing period, the basal stresses for each tissue are recorded. The vasoconstrictor response to phenylephrine (1 μM) is evaluated and when the response to phenylephrine reaches a maximum, the vascular reactivity is then assessed by stimulation of acetylcholine (1 μM). After another washing period, a second baseline is recorded, the vasoconstrictor noradrenaline (25 nM) is added to each bath and the tissues are incubated for a period of time (approximately 15 min.) To achieve a stable tone. An exogenous stable NO generator is supplied using the stable NO donor, DETA-NO. The concentration of DETA-NO. it is valued (cumulatively in semilogarithmic increments) to achieve approximately a 5-15% relaxation of the previous constriction evoked by norepinephrine. Cumulative concentration-response curves are constructed in a single ring, typically using 5 doses / ring and leaving 15 minutes between each addition.

Method D: Aortic Ring Test The protocol of Procedure C can be modified to provide an alternative pro-cell to generate aortic ring data. For the modified pro-group, the endothelium is first removed by gently rubbing the vessel lumen between the fingers before preparing the rings (unprotected rings). The resting tension is adjusted to 2 grams and the vasoconstrictor response is titrated at a maximum concentration of phenylephrine (1 μM), followed (after the washing period) by two additional exposures to 300 nM of phenylephrine. The concentration-response ratio to noradrenaline is constructed in each tissue over a concentration range of 0.1 to 300 nM. After another washing period, the tissues are restricted to a CEgo concentration of noradrenaline to test the compounds.

In Vivo Assays Procedure E: C? Lex ™ Assay The conscious precannulated spontaneous hypertensive rat (SHR) model is used to evaluate the efficacy of test compounds and other antihypertensive agents in reducing systemic blood pressure. An automatic blood sampler system is incorporated in this model (ABS). The Culex ™ ABS system consists of a laptop, four conirol units and meiabolic cages. This system allows obtaining multiple blood samples from a single rat without causing unwanted stress to the animal. In addition, the system allows obtaining urine samples that can potentially be used for biomarker identification. Through this technique, conventional efficacy and pharmacokinetic studies are carried out in simultaneously unaware SHR rats to accelerate the rate of screening or selection of compounds and define the relationship between the concentration of free drug in plasma or potential biomarker (s) ( es) and the pharmacological effect (reduction of the mean arterial blood pressure). Surgery of the bilateral jugular veins and cannulations of the right carotid artery undergo SHR rats of 14 weeks with a weight of approximately 300 g. After recovery from surgery, the animals are placed in Culex ™ cages and attached to a movement-sensitive arm with a sensor that controls the movement of the cage as the animal moves to prevent the catheters from bending. Connections are made between the right jugular catheter and the sterile flexible Culex ™ tube for blood sampling, or the left jugular catheter and the flexible long tube for drug delivery, or the catheter in the right carotid artery and the prolonged tube that is connected to a pressure transducer to control the blood pressure. To maintain the patency or light of the catheters, the right jugular cannula is maintained by the "tend" function of the Culex ™ that injects 20 μl of heparin saline solution (10 units / ml) every 12 minutes or between each preparation. sample, and the left jugular cannula is filled with heparin saline (20 units / ml). The permeability or light of the right carotid cannula is maintained by slow infusion of heparin saline solution either directly into the prolonged flexible tube when blood pressure is not recorded or through the pressure transducer during blood pressure control. The animals are allowed to acclimate for at least 2 hours before they are used for the evaluation of any compound. The animals receive three test compounds over a study period of 5 days with 30-40 hours of washout period between two consecutive test compounds.

All test compounds are administered intravenously or by gavage. Blood sampling protocols (sampling time and volume) are programmed using the Culex ™ program. The total amount of blood drawn from each animal will not exceed 750 μl / 24 hours and 10 ml / kg in two weeks. The systolic blood pressure is recorded by a pressure transducer through a data acquisition system (PONEMAH) for 6-24 hours based on the experimental pro-code. The mean arterial blood pressure (main endpoint) is analyzed to assess the efficacy of the compounds. Blood samples will be analyzed to measure plasma drug concentration and assess potential biomarkers.

Procedure F: Implantation of radio transmitters and subsequent determination of blood pressure by telemetry in Hypertensive Rats Spontaneously (SHR) Hypertensive Rats are spontaneously anesthetized with isoflurane gas through an anesthesia machine that is calibrated to administer isoflurane at a range of percentages when the Oxygen passes through the internal chambers of the machine. The animals are placed in an induction chamber and 4-5% isoflurane is administered to reach a surgical plane of anesthesia. They are maintained at 1-2% during the surgical procedure by means of a nasal cone with isoflurane administered through a small isoflurane anesthesia device on the operating table. After administering anesthesia, transmitting rats are implanted using aseptic procedures with commercially available sterile radiotelemetry units (Data Sciences, International, Roseville, MN 55113-1136). Before surgery, the surgical fields are shaved, rubbed with Dial ™ brand antimicrobial solution (containing 4% chlorhexidine glyconate and 4% isopropyl alcohol) followed by the application of a spray solution of iodine (10%). ). A laparotomy of 2.5 to 3.0 cm is performed and the radiotelemetry units are implanted in the abdomen, with the tip of the catheter inserted in the abdominal aorta. Baby Weitlaner retractors are used to retain the soft tissue. A 1 cm section of the abdominal aorta is partially dissected and said section is immobilized crosswise, punctured with a 21 gauge needle and the tip of the transmitting catheter is inserted into the vessel and secured by a suture with anchored silk 4.0 to the adjacent psoas muscle. The body of the transmitter is then inserted into the abdominal cavity and secured simultaneously to the abdominal muscle wall while closing with resorbable suture. It is administered in and around the suture line subcutaneously (s.c.) marcaine followed by a topical application of iodine, respectively after closure. All rats receive a postoperative injection of buprenorphine at 0.05 mg / kg, s.c. before returning to the state of consciousness. A typical dose volume for a 0.300 kg rat will be 0.050 ml. The raias must recover fully from their operative anesthesia before the administration of buprenorphine. They then receive the same dose once a day for two consecutive days, unless the animal demonstrates that it suffers from compromising postoperative pain. After surgery, the rabies are returned to their cages and individually housed in solid-bottom cages with a paper bed. A period of no less than 7 days is allowed for recovery before beginning experimental procedures. It has been observed that rats are typically hypertensive for several days after surgery and return to "normotensive" levels approximately on the seventh day after surgery. These are fed with conventional diet for rats and water ad libitum during the whole time of the experiment. The test compounds are administered intragastrically (i.e.) by gastric tube, using a 2-inch and a half-inch stainless steel gastric needle with a rounded end. For the single daily dosage, the final volume is 3.33 ml / kg, i.g. The vehicles in which the test compounds are administered will vary depending on the solubility of the compound, however, the first choice is methylcellulose (0.5%) in water. Blood pressure data will be obtained using the data acquisition program of Data Sciences International. Blood pressure samples are recorded at intervals of 1.5-3 minutes for a duration of 5 seconds 24 hours a day throughout the study. These data are processed by the Data Science data analysis program in averages of desired time intervals. The rest of the data reduction takes place in Microsoft Excel ™ spreadsheets.

Procedure G: SHR Rat This experimental protocol is designed to determine the reduction of blood pressure by the test compounds. The spontaneously hypertensive rat (SHR) is cannulated in the jugular vein and the carotid artery; one for the administration of compound and one for direct measurement of blood pressure, respectively. The animals are fully aware after the surgery and all the experimentation takes place within one working day. The reduction of blood pressure is the main parameter to evaluate. However, systolic and diastolic blood pressure and heart rate will also be recorded. The rats are dosed in a scaled and cumulative manner to observe the responses after that dosing schedule. This parficular procedure will also allow to track more than one compound or several doses of a compound in a day using the same animals.

Procedures Anesthesia: Rats are anesthetized with 5% isoflurane until it takes effect. The incision sites are shaved and prepared aseptically for surgery. The rats are then transferred to the surgical site with a calenic bed, supplemented soflurane and kept at 37 ° C and isoflurane throughout the surgical procedure. Surgery: Arterial and venous cannulas are implanted in the jugular vein and the carotid artery, respectively. The cannulas are tunneled subcutaneously on the dorsum and neck where they exit percutaneously. Stainless steel staples are used to close the incision site. The cannulas run through a spring-loaded device to an oscillating device by which the cannulas are protected from the movements of the animal during the experiment. Recovery: The rats are placed in an opaque polycarbonate cage instrumented with a counterbalanced arm that supports the weight of the fixation and oscillation apparatus. A paper bed material is used to cover the floor of the cage. The rats are allowed to recover from surgery at this point and receive 2 ml of volume at the beginning during their recovery phase. No food is provided to the animals. The timeline shown in Figure 1 shows the experimental time period used for this test period. All the compounds of the invention have an activity against PDE-5 less than 10,000 nM. The IC50 values found using Procedure A for compounds 1-40 are listed in the following table. The IC50 values found using Procedure B for compounds 41-50 are also listed in the following table.

Claims (20)

1. A compound of formula (I) wherein R1 is a cyclic group selected from RA, RB, Rc and RD, each of which is optionally substituted with one or more R7 groups; R 2 is hydrogen or C 1 -C 2 alkyl; each of R3 and R4 is independently Ci-Cs alkyl, C2-Cs alkenyl, C2-Cd alkynyl or C3-C10 cycloalkyl, each of which is optionally substituted with one or more R8 groups, or RE, which is optionally substituted with one or more R9 groups, or hydrogen; or -NR3R4 form RF, which is optionally substituted with one or more groups R10; R5 is -YNR15R16; R6, which may be attached at N1 or N2, is Ci-Cß alkyl, Ci-Cß haloalkyl, C2-C al alkenyl or C2-C6 alkynyl, each of which is optionally substituted with C-pCβ alkoxy, (C3- cycloalkyl) C6) methoxy, haloalkoxy C? -C6 or a cyclic group selected from RJ, R ?, RL and RM, or R6 is RN, C3-C7 cycloalkyl or C3-C7 halocycloalkyl, each of which is optionally substituted with C1-C2-alkoxy -Cβ or haloalkoxy C? -C6, or R6 is hydrogen; R7 is halo, C6-C6 alkyl, CrC6 haloalkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR2R13, NR12C ( O) R13, NR12CO2R14, C (O) R12, CO2R12, CONR12R13 or CN; R8 is halo, phenyl, (C6-C6 alkoxy) phenol, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR12CO2R14, C (O) R12, CO2R12, CONR12R13, CN, cycloalkyl C3-C6, RG or RH, of which the latter two are optionally substituted with one or more R9 groups; R9 is C? -C6 alkyl, C6 haloalkyl or CO2R12; R10 is halo, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, phenyl, OR12, OC (O) R12, NO2, NR12R13, NR12C (O) R13, NR2CO2R14, C (O) R12, CO2R13, CONR12R13, CN, oxo, C? -C6 alkyl or C? -C6 haloalkyl, of which the latter two are optionally substituted with R11; R11 is phenyl, NR12R13 or NR12CO2R14; each of R 12 and R 13 is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 14 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R15 is selected from R17, R17C (O) and R18SO2, and R16 is selected from hydrogen, Ci-Cß alkyl optionally substituted with one or more R19 groups, CrC6 haloalkyl and C3-C10 cycloalkyl optionally substituted with one or more R20 groups, or -NR15R16 constitutes a 3 to 8 membered saturated ring which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from R2, R22 and (C6-C6 alkoxy) C6-C6 alkyl; R17 is hydrogen or R18; R18 is selected from C-i-Cß alkyl optionally substituted with one or more R19 groups, C-t-Cß haloalkyl and C3-C10 cycloalkyl optionally substituted with one or more R20 groups; R 9 is selected from R21, -NR23R24, -CO2R25, -CONR26R27, R28 and phenyl optionally substituted with R29; R20 is selected from R21, R22 and oxo; R21 is oxo, hydroxy, C-C-alkoxy, (C-C-haloxy haloalkyl, or (C3-C cycloalkyl) oxy; R22 is C? -C6 alkyl or Ci-C? Haloalkyl; each of R23 and R24 is independently selected from hydrogen and C-? -C6 alkyl; or -NR23R24 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R25 is hydrogen or d-Cß alkyl; each of R26 and R27 is independently selected from hydrogen and C-? -C6 alkyl; or -NR26R27 constitutes an azetidine, pyrrolidine, piperidine or morpholine ring; R28 is a saturated, unsaturated or aromatic heterocycle with up to 10 carbon atoms, at least one of which is selected from nitrogen, oxygen and sulfur; R29 is selected from halo, R21 and R22, each of RA and RJ is independently a C3-C10 cycloalkyl or C3-C10 cycloalkenyl group, each of which may be monocyclic or, when there is an appropriate number of ring atoms, polycyclic and which may be condensed with (a) a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur, or (b) a heteroalicyclic 5-ring. , 6 or 7 members containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; each of RB and R? is independently a phenyl or naphthyl group, each of which may be fused with (a) a Cs-C cycloalkyl ring or a C5-C7 cycloalkenyl ring, (b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; or (c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; each of Rc, RL and R is independently a monocyclic saturated or partially unsaturated ring system or, when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms, of which at least one is a selected nitrogen, oxygen and sulfur heteroatom, said ring may be fused with a C5-C7 cycloalkyl or Cs-C7 cycloalkenyl group or a monocyclic aromatic ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; each of RD and RM is independently a 5- or 6-membered heteroaromatic ring containing up to three hepheno-atoms selected from nitrogen, oxygen and sulfur, which ring can also be fused with (a) a second 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; (b) a C-C7 cycloalkyl ring or Cs-C cycloalkenyl ring; (c) a 5, 6 or 7 membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulfur; or (d) a benzene ring; each of RE, RF and RG is independently a monocyclic saturated ring system or, when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur; and Y is a covalent bond, C 1 -C 7 alkylenyl or C 3 -C 7 cycloalkylenenyl; one of its tautomers or a pharmaceutically acceptable salt, solvate or polymorph of said compound or fautomer.
2. 2. - A compound according to claim 1, wherein R1 is RB, which is optionally substituted with one or more R7 groups.
3. 3. - A compound according to claim 1, wherein R1 is RD, which is optionally substituted with one or more R7 groups.
4. 4. - A compound according to claim 1, wherein R7 is halo, C? -C6 alkyl, C? -C6 haloalkyl, OR12 or CNR12R13.
5. 5. - A compound according to claim 1, wherein R2 is hydrogen.
6. 6. - A compound according to claim 1, wherein R3 is hydrogen, Ci-Cß alkyl, which is optionally substituted with one or more R8 groups, or RE, which is optionally substituted with one or more R9 group; and wherein RE is a monocyclic saturated ring system, or when there is an appropriate number of polycyclic ring atoms containing from 3 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur.
7. 7. - A compound according to claim 1, wherein R 4 is hydrogen, C C β alkyl, C α -C 6 haloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.
8. 8. - A compound according to claim 1, wherein -NR3R4 forms RF, which is optionally substituted with one or more R10 groups, and wherein RF is a monocyclic sacral ring system, or when there is an appropriate number of ring atoms , polycyclic containing from 3 to 7 ring atoms containing at least one nitrogen atom and optionally another atom selected from oxygen and sulfur.
9. 9. - A compound according to claim 1, wherein Y is Ci-Cß alkenyl.
10. 10. - A compound according to claim 1, wherein R15 is R17C (O) or R1dSO2 and R16 is hydrogen or CrC6 alkyl.
11. 11. - A compound according to claim 1, wherein R is R17 and R16 is hydrogen or C6 alkyl.
12. 12. - A compound according to claim 1, wherein - NR15R16 constitutes a saturated ring of 3 to 8 members which may optionally include one or more additional heteroatoms selected from nitrogen, oxygen and sulfur, and which may be optionally substituted with one or more groups selected from R21, R22 and (C6-C6 alkoxy) C-Cß alkyl.
13. 13. - A compound according to claim 1, wherein R6 is located at N1.
14. 14. - A compound according to claim 1, wherein R6 is CrC6 alkyl or C-Cß haloalkyl, each of which is optionally substituted with C-i-Cß alkoxy, C-i-Cß haloalkoxy or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; RJ is a monocyclic C3-C7 cycloalkyl group; each of RL and RN is independently a saturated or partially unsaturated monocyclic ring system containing from 4 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; and RM is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur.
15. 15. - A compound according to claim 1, wherein R3 is hydrogen, CrC4 alkyl, which is optionally substituted with one or more R8 groups, or RE, which is optionally substituted with one or more R9 groups; R 4 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or -NR3R4 form RF, which is optionally substituted with one or more groups R10; R6 is C? -C alkyl or CC haloalkyl, each of which is optionally substituted with C? C4 alkoxy, C? -C haloalkoxy or a cyclic group selected from RJ, RL and RM, or R6 is RN or hydrogen; RA is a monocyclic C3-C8 cycloalkyl group; RB is phenyl; Rc is a monocyclic saturated or partially unsaturated ring system containing 3 to 8 ring atoms, at least of which "one is a heteroatom selected from nitrogen, oxygen and sulfur; RD is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur; RE is a monocyclic saturated ring system containing from 3 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur, RF is a monocyclic saturated ring system or, when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 atoms of ring, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur, RJ is cyclopropyl or cyclobutyl, each of RL and R is independently a monocyclic saturated ring system containing 5 or 6 ring atoms, which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RM is a 5- or 6-membered heteroaromatic ring containing a heteroatom as selected nitrogen, oxygen and sulfur; and Y is C? -C6 alkylenyl.
16. 16. - A compound according to claim 15, wherein R1 is a cyclic group selected from RA, RB, Rc and RD, each of which is optionally substituted with one or more R7 groups; R7 is halo, CrC6 alkyl, haloalkyl C Ce, OR12 or CONR12R13; R8 is halo, phenyl (C6-C6 alkoxy) phenyl, OR12, NR12R13, NR12CO2R14, CO2R12, CONR12R13, RG or RH, the last two of which are optionally substituted with one or more R9 groups; RA is a monocyclic C5-C7 cycloalkyl group; RB is phenyl; Rc is a monocyclic saturated ring system containing from 5 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RD is a 5-membered heteroaromatic ring containing a hetero-atom selected from nitrogen, oxygen and sulfur and optionally up to two additional nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1, 2 or 3 nitrogen atoms; RE is a monocyclic saturated ring system containing from 3 to 7 ring atoms containing a nitrogen atom; RF is a monocyclic saturated ring system or, when there is an appropriate number of ring atoms, polycyclic containing from 3 to 10 ring atoms containing at least one nitrogen atom and optionally another atom selected from oxygen and sulfur; RG is a monocyclic saturated ring system containing from 3 to 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulfur; RH is a 5- or 6-membered heteroaromatic ring containing up to two nitrogen atoms; and Y is -CH2-.
17. 17. - A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable diluent or carrier.
18. 18. A method of treating a disorder or pathological condition in which it is known, or can be shown, that inhibition of PDE5 produces a beneficial effect in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula ( I) according to claim 1, or one of its pharmaceutically acceptable salts, solvates or polymorphs.
19. 19. - A method according to claim 18, wherein the disorder or pathological condition is diabetes.
20. 20. - A method according to claim 18, wherein the disorder or condition is hypertension.