EP1809632A2

EP1809632A2 - Pyrazolo[4,3-d]pyrimidine derivatives useful as pde-5 inhibitors

Info

Publication number: EP1809632A2
Application number: EP05800579A
Authority: EP
Inventors: Brad Alan Pfizer Global R&D ACKER; Robert Owen Pfizer Global R&D HUGHES; Eric John Pfizer Global R&D JACOBSEN; Hwang-Fun Pfizer Global R&D LU; Thomas Edward Pfizer Global R&D ROGERS; Michael Brent Pfizer Global R&D TOLLEFSON; John Keith Pfizer Global R&D WALKER
Original assignee: Pharmacia and Upjohn Co LLC
Current assignee: Pharmacia and Upjohn Co LLC
Priority date: 2004-10-28
Filing date: 2005-10-17
Publication date: 2007-07-25
Also published as: JP2008517994A; CA2585557A1; WO2006046135A2; CA2585557C; WO2006046135A3

Abstract

This invention relates to compounds of formula (I) wherein R1, R2, R3, R4, R5 and R5 and R6 are as described herein,which are cyclic guanylate monophosphate (cGMP)-specific phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) that are useful in the treatment of hypertension and other disorders, to processes for their preparation, intermediates used in their preparation, to compositions containing them and the uses of said compounds and compositions.

Description

Novel Pharmaceuticals

The present invention relates to a series of novel 5,7-diaminopyrazolo[4,3-c(] pyrimidines, which are cyclic guanylate monophosphate (cGMP)-specific phosphodiesterase type 5 inhibitors (hereinafter referred to as PDE-5 inhibitors) that are useful in the treatment of hypertension and other disorders, to processes for their preparation, intermediates used in their preparation, to compositions containing them and the uses of said compounds and compositions.

i) Hypertension

The prevalence of hypertension in developed countries is about 20% of the adult population, rising to about 60-70% of those aged 60 or more. Hypertension is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. Despite the large number of drugs available in various pharmacological categories, the need for an effective treatment of hypertension is still not satisfied.

ii) PDE5 inhibitors

Vascular endothelial cells secrete nitric oxide (NO). This acts on vascular smooth muscle cells and leads to the activation of guanylate cyclase and the accumulation of cyclic guanosine monophosphate (cGMP). The accumulation of cGMP causes the muscles to relax and the blood vessels to dilate, leading to a reduction in blood pressure. The cGMP is inactivated by hydrolysis to guanosine 5'-monophosphate (GMP) by a cGMP-specific phosphodiesterase. One important cGMP-phosphodiesterase has been identified as Phosphodiesterase type 5 (PDE5). Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP and so potentiate the actions of nitric oxide.

Inhibitors of PDE-5 have been reported in several chemical classes, including: pyrazolo[4,3-αflpyrimidin-7- ones (e.g. 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-c(|pyrimidin-4-ones (e.g. published international patent application WO 93/07149); pyrazolo[4,3-c(]pyrimidines (e.g. published international patent application WO 01/18004); quinazolin-4-ones (e.g. published international patent application WO 93/12095); pyrido[3,2-φyrimidin-4-ones (e.g. published international patent application WO 94/05661); purin-6-ones (e.g. published international patent application WO 94/00453); hexahydro- pyrazino[2',1':6,1]pyrido[3,4-b]indole-1 ,4-diones (e.g. published international application WO 95/19978) and imidazo[5,1-/][1 ,2,4]triazin-ones (e.g. published international application WO 99/24433).

There remains a demand for new PDE5 inhibitors, particularly with improved pharmacokinetic and pharmacodynamic properties. The compounds provided herein are potent inhibitors of PDE5 that have improved selectivity in vitro and/or an extended half-life in vivo.

WO 02/00660 and WO 01/18004 disclose pyrazolo[4,3-φyrimidines with a PDE-5 inhibiting effect, which can be used for treating disorders of the cardiovascular system.

According to a first aspect, the present invention provides compounds of formula (I) wherein

R¹ is a cyclic group selected from R^A, R^B, R^c and R^D, each of which is optionally substituted with one or more R⁷ groups;

R² is hydrogen or C₁-C₂ alkyl;

R³ and R⁴ are each independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl or C₃-C₁₀ cycloalkyl, each of which is optionally substituted with one or more R⁸ groups, or R^E, which is optionally substituted with one or more R⁹ groups, or hydrogen;

or -NR³R⁴ forms R^F, which is optionally substituted with one or more R¹⁰ groups;

R⁵ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₇ cycloalkyl, each of which is optionally substituted by one or more groups selected from hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃- C₇ cycloalkyl and C₃-C₇ cycloalkoxy, or hydrogen;

R⁶, which may be attached at N¹ or N², is R^6A or hydrogen;

R^6A is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substituted by C₁-C₆ alkoxy, (C₃-C₆ cycloalkylJd-Ce alkoxy, C₁-C₆ haloalkoxy or a cyclic group selected from R^J, R^κ, R^L and R^M, or R^6A is R^N, C₃-C₇ cycloalkyl or C₃-C₇ halocycloalkyl, each of which is optionally substituted by C₁-C₆ alkoxy or C₁-C₆ haloalkoxy;

R⁷ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, oxo, phenyl, OR¹², OC(O)R¹², NO₂, NR¹²R¹³, NR¹²C(O)R¹³, NR¹²CO₂R¹⁴, C(O)R¹², CO₂R¹², CONR¹²R¹³ Or CN;

R⁸ is halo, phenyl, C₁-C₆ alkoxyphenyl, OR¹², OC(O)R¹², NO₂, NR¹²R¹³, NR¹²C(O)R¹³, NR¹²CO₂R¹⁴, C(O)R¹², CO₂R¹², CONR¹²R¹³, CN, C₃-C₆ cycloalkyl, R^G or R^H, the last two of which are optionally substituted with one or more R⁹ groups;

R⁹ is C₁-C₆ alkyl, C₁-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, C₁-C₆ alkyl or C₁-C₆ haloalkyl, the last two of which are optionally substituted by R¹¹;

R¹¹ is OH, phenyl, NR¹²R¹³ or NR¹²CO₂R¹⁴;

R¹² and R¹³ are each independently hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R¹⁴ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^A and R^J are each independently a C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkenyl group, each of which may be either monocyclic or, when there are an appropriate number of ring atoms, polycyclic and which may be fused to either

(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 sulphur, or

(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

R^B and R^κ are each independently a phenyl or naphthyl group, each of which may be fused to (a) a C₅-C₇ cycloalkyl or C₅-C₇ cycloalkenyl ring,

(b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur, or

(c) a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

R^c, R^L and R^N are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated or partly unsaturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur, which ring may be fused to a C₅-C₇ cycloalkyl or C₅-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 sulphur;

R^D and R^M are each independently a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur, which ring may further be fused to

(a) a second 5- or 6-membered heteroaromatic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur;

(b) C₅-C₇ cycloalkyl or C₅-C₇ cycloalkenyl ring;

(c) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur; or

(d) a benzene ring; R^E, R^F and R^G are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

and

R^H is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur;

a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

Unless otherwise indicated, an alkyl or alkoxy group may be straight or branched and contain 1 to 8 carbon atoms, preferably 1 to 6 and particularly 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxy include methoxy, ethoxy, isopropoxy and n-butoxy.

Unless otherwise indicated, an alkenyl or alkynyl group may be straight or branched and contain 2 to 8 carbon atoms, preferably 2 to 6 and particularly 2 to 4 carbon atoms and may contain up to 3 double or triple bonds which may be conjugated. Examples of alkenyl and alkynyl include vinyl, allyl, butadienyl and propargyl.

Unless otherwise indicated, a cycloalkyl or cycloalkoxy group may contain 3 to 10 ring-atoms, may be either monocyclic or, when there are 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 3 to 10 ring-atoms, may be either monocyclic or, when there are an appropriate number of ring atoms, polycyclic and may contain up to 3 double bonds. Examples of cycloalkenyl groups are cyclopentenyl and cyclohexenyl.

Aryl includes phenyl, naphthyl, anthracenyl and phenanthrenyl.

Unless otherwise indicated, a heteroalicyclyl group contains 3 to 10 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated or partially unsaturated. Examples of heteroalicyclyl groups are oxiranyl, azetidinyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl.

Unless otherwise indicated, a heteroaryl group contains 3 to 10 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, triazinyl. In addition, the term heteroaryl includes fused heteroaryl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.

For the avoidance of doubt, oxo-substituted heteroaromatic systems such as pyridinonyl, pyranonyl, imidazolonyl and the like are also considered to be heteroaryl groups.

Halo means fluoro, chloro, bromo or iodo.

Haloalkyl includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, such as 2-bromoethyl, 2,2,2- trifluoroethyl, chlorodifluoromethyl and trichloromethyl.

Haloalkoxy includes monohaloalkoxy, polyhaloalkoxy and perhaloalkoxy, such as 2-bromoethoxy, 2,2,2- trifluoroethoxy, chlorodifluoromethoxy and trichloromethoxy. Halocycloalkyl includes monohalocycloalkyl, polyhalocycloalkyl and perhalocycloalkyl.

Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

In one preferred embodiment, R¹ is R^A, which is optionally substituted with one or more R⁷ groups; and R^A is a C₃-C₁₀ cycloalkyl group, which may be either monocyclic or, when there are an appropriate number of ring atoms, polycyclic, which may be fused to either

(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 sulphur, or (b) a 5-, 6- or 7-membered heteroalicyclic ring containing up to three heteroatoms selected from nitrogen, oxygen and sulphur.

Preferably, R^Λ is a monocyclic C₃-C₈ cycloalkyl group.

More preferably, R^A is a monocyclic C₅-C₇ cycloalkyl group.

Most preferably, R^Λ is cyclopentyl or cyclohexyl.

In another preferred embodiment, R¹ is R^B, which is optionally substituted with one or more R⁷ groups.

Preferably, R^B is phenyl.

In another preferred embodiment, R¹ is R^c, which is optionally substituted with one or more R⁷ groups. -O-

Preferably, R^c is a monocyclic saturated or partly unsaturated ring system containing between 3 and 8 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.

More preferably, R^c is a monocyclic saturated or partly unsaturated ring system containing between 5 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.

More preferably, R^c is a monocyclic saturated ring system containing between 5 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.

Most preferably, R^c is piperidinyl.

In another preferred embodiment, R¹ is R^D, which is optionally substituted with one or more R⁷ groups.

Preferably, R^D is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur.

More preferably, R^D is a 5-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulphur and optionally up to two further nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1 , 2 or 3 nitrogen atoms.

More preferably R^D is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl.

Most preferably, R^D is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl.

Preferably, R⁷ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, oxo, OR¹² or CONR¹²R¹³.

More preferably, R⁷ is halo, C₁-C₃ alkyl, C_rC₃-haloalkyl, oxo, C₁-C₃ alkoxy, hydroxy or CONH(C₁-C₃ alkyl).

Most preferably, R⁷ is fluoro, methyl, ethyl, hydroxy, methoxy, propoxy, trifluoromethyl, oxo or CONHMe.

Preferably, R² is hydrogen or methyl.

More preferably, R² is hydrogen.

Preferably, R³ is hydrogen, C₁-C₆ alkyl, which is optionally substituted with one or more R⁸ groups, or R^E, which is optionally substituted with one or more R⁹ groups; and wherein R^E is a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur. More preferably, R³ is hydrogen, CrC₄ alkyl, which is optionally substituted with one or more R⁸ groups, or R^E, which is optionally substituted with one or more R⁹ groups; and wherein R^E is a monocyclic saturated ring system containing between 3 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.

In one preferred embodiment, R³ is R^E, which is optionally substituted with one or more R⁹ groups and wherein R^E is a monocyclic saturated ring system containing between 3 and 7 ring atoms containing one nitrogen atom.

More preferably, R^E is azetidinyl, pyrrolidinyl or piperidinyl.

In another preferred embodiment, R³ is C₁-C₄ alkyl, which is optionally substituted with one or more R⁸ groups and wherein R⁸ is halo, phenyl, C₁-C₆ alkoxyphenyl, OR¹², NR¹²R¹³, NR¹²CO₂R¹⁴, CO₂R¹², CONR¹²R¹³, R^G or R^H, the last two of which are optionally substituted with one or more R⁹ groups.

More preferably, R⁸ is hydroxy, methoxy, methoxyphenyl, NH₂, NHMe, NMe₂, NHCO₂ ¹Bu, NMeCO₂ ⁴Bu, CO₂H, CONHMe, R^G or R^H, the last two of which are optionally substituted with one or more R⁹ groups.

In one preferred embodiment, R⁸ is R^G, which is optionally substituted with one or more R⁹ groups and wherein R^G is a monocyclic saturated ring system containing between 3 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur.

More preferably, R^G is a monocyclic saturated ring system containing between 3 and 7 ring atoms containing one nitrogen atom and optionally one oxygen atom.

Most preferably, R^G is pyrrolidinyl, piperidinyl or morpholinyl.

In another preferred embodiment, R⁸ is R^H, which is optionally substituted with one or more R⁹ groups and wherein R^H is a 5- or 6-membered heteroaromatic ring containing up to two nitrogen atoms.

More preferably, R^H is pyrazolyl.

Preferably, R⁹ is methyl or CO₂ ¹Bu.

In another preferred embodiment, R³ is hydrogen or C₁-C₄ alkyl, 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, wherein

R⁸ is hydroxy, methoxy, methoxyphenyl, NH₂, NHMe, NMe₂, NHCO₂ ¹Bu, NMeCO₂ ¹Bu, CO₂H, CONHMe, pyrrolidinyl, piperidinyl, morpholinyl or pyrazolyl, the last four of which are optionally substituted with one or more R⁹ groups and wherein R⁹ is methyl or CO₂ ¹Bu.

In one preferred embodiment, R⁴ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl.

More preferably, R⁴ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl.

Most preferably, R⁴ is hydrogen, methyl or ethyl.

In another preferred embodiment, -NR³R⁴ forms R^F, which is optionally substituted with one or more R 10 groups and wherein R^F is a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms containing at least one nitrogen atom and optionally one other atom selected from oxygen and sulphur.

More preferably, R^F is a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms containing one or two nitrogen atoms and optionally one other atom selected from oxygen and sulphur.

Most preferably, R^F is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 3- azabicyclo[3.1.0]hex-3-yl, homopiperazinyl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2- yl, 2,5-diazabicyclo[4.3.0]non-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, 3,8-diazabicyclo[3.2.1]oct-8-yl, 1 ,4- diazabicyclo[4.3.0]non-4-yl and 1 ,4-diazabicyclo[3.2.2]non-4-yl.

Preferably R¹⁰ is halo, OR¹², NR¹²R¹³, NR¹²CO₂R¹⁴, CO₂R¹³, oxo, C₁-C₆ alkyl or C₁-C₆ haloalkyl, the last two of which are optionally substituted by R¹¹.

More preferably, R¹⁰ is halo, methyl, ethyl, isopropyl, hydroxy, methoxy, NH₂, NHMe, NMe₂, NHCO₂ ¹Bu, CO₂H, CO₂ ¹Bu, oxo, benzyl, -CH₂OH, -CH₂NH₂, -CH₂NHMe, -CH₂NMe₂ or -CH₂NMeCO₂ ¹Bu.

In a particularly preferred embodiment -NR³R⁴ forms a piperazine ring that is optionally substituted by one or two methyl groups, and/or is bridged by a -CH₂- or -CH₂CH₂- group. Suitable bridged piperazines include 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl and 3,8-diazabicyclo[3.2.1]oct-8-yl ring systems.

In another preferred embodiment, R³ is C₁-C₆ alkyl, which is substituted by one R⁸ group, or R^E, which is substituted by one R⁹ group; or -NR³R⁴ forms a cyclic group R^F, which is substituted with one R¹⁰ group, and R⁸, R⁹ and R¹⁰ are all CO₂H.

Preferably, R⁵ is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each of which is optionally substituted by hydroxy, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy.

In one more preferred embodiment, R⁵ is C₁-C₄ alkyl, hydroxymethyl or C₁-C₄ alkoxymethyl. In another more preferred embodiment, R⁵ is methyl, ethyl or propyl, each of which is optionally substituted by hydroxy, methoxy or ethoxy.

Most preferably, R⁵ is methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, methoxymethyl or ethoxymethyl.

Preferably, R⁶ is R^6A.

When R⁶ is hydrogen, the compounds of formula (I) wherein R⁶ is attached at N¹ and at N² are tautomers. These tautomers will tend to co-exist in both the solid and solution state, and will not be readily separable. The amounts of each tautomer present in any equilibrium mixture will be determined by the relative thermodynamic stabilities of the two forms. In most cases, the 1 /-/-tautomer will tend to be the predominant form.

When R⁶ is R^6A, two regioisomers of the compounds of formula (I) can be distinguished. In one, preferred, embodiment of the invention, R^6A is positioned on N¹ to give the compounds of formula (I^A):

In an alternative embodiment, R^6A is positioned on N² to give the compounds of formula (I^B):

Preferably, R^6A is C₁-C₆ alkyl or CrC₆ haloalkyl, each of which is optionally substituted by C₁-C₆ alkoxy, CrC₆ haloalkoxy, (C₃-C₆ cycloalkyl)CrC₆ alkoxy or a cyclic group selected from R^J, R^L and R^M, or R^6A is

R^N;

R^J is a C₃-C₇ monocyclic cycloalkyl group;

R^L and R^N are each independently a monocyclic, saturated or partly unsaturated ring system containing between 4 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur; and R^M is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur.

More preferably, R^6A is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each of which is optionally substituted by C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, (C₃-C₆ cycloalkyl)C_rC₆ alkoxy or a cyclic group selected from R^J, R^L and R^M, or R^6A is R^N;

R^J is cyclopropyl or cyclobutyl;

R^L and R^N are each independently a monocyclic saturated ring system containing either 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur; and R^M is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulphur.

More preferably, R^6Λ is Ci-C₄ alkyl or C₁-C₄ haloalkyl, each of which is optionally substituted by C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, (C₃-C₆ cycloalkyl)methoxy or a cyclic group selected from R^J, R^L and R^M, or R^6A is R^N;

R^J is cyclopropyl or cyclobutyl;

R^L and R^N are each independently a monocyclic saturated ring system containing either 5 or 6 ring atoms containing one heteroatom selected from nitrogen, oxygen and sulphur; and

R^M is a 5- or 6-membered heteroaromatic ring containing one nitrogen atom.

More preferably, R^6A is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each of which is optionally substituted by CrC₄ alkoxy, C₁-C₄ haloalkoxy, (C₃-C₆ cycloalkyl)methoxy, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl or pyridinyl, or R^6A is tetrahydropyranyl.

Most preferably, R^6A is methyl, ethyl, isopropyl, isobutyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, n-propoxyethyl, isopropoxyethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxyethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, tetrahydropyranyl or pyridinylmethyl.

A particularly preferred embodiment is a compound of formula (I) wherein R⁶ is R^6A attached at the N¹- position, and R^6A is 2-(2,2,2-trifluoroethoxy)ethyl.

Preferred embodiments of compounds of formula (I) are those that incorporate two or more of the foregoing preferences.

A particularly preferred embodiment is a compound of formula (I) wherein R¹ is a cyclic group selected from R^A, R^B, R^c and R^D, each of which is optionally substituted with one or more R⁷ groups;

R² is hydrogen or C₁-C₂ alkyl;

R³ is hydrogen, C₁-C₄ alkyl, which is optionally substituted with one or more R⁸ groups, or R^ε, which is optionally substituted with one or more R⁹ groups; R⁴ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R⁶ is R^6A or hydrogen;

R^6A is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each of which is optionally substituted by C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or a cyclic group selected from R^J, R^L and R^M, or R^6A is R^N;

R⁷ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, phenyl, oxo, OR¹², OC(O)R¹², NO₂, NR¹²R¹³, NR¹²C(O)R¹³, NR¹²CO₂R¹⁴, C(O)R¹², CO₂R¹², CONR¹²R¹³ Or CN;

R⁸ is halo, phenyl, C₁-C₆ alkoxyphenyl, OR¹², OC(O)R¹², NO₂, NR¹²R¹³, NR¹²C(O)R¹³, NR¹²CO₂R¹⁴, C(O)R¹², CO₂R¹², CONR¹²R¹³, CN, R^G or R^H, the last two of which are optionally substituted with one or more R⁹ groups;

R⁹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl or CO₂R¹²;

R¹⁰ is halo, C₃-Ci₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, phenyl, OR¹², OC(O)R¹², NO₂, NR¹²R¹³, NR¹²C(O)R¹³, N NRR¹¹²²CCOO₂₂RR¹¹⁴⁴,, C C((OO))RR¹¹²²,, C COO₂₂RR¹¹³³,, C CONR¹²R¹³, CN, oxo, C₁-C₆ alkyl or C₁-C₆ haloalkyl, the last two of which are optionally substituted by R¹¹;

R¹¹ is OH, phenyl, NR¹²R¹³ or NR¹²CO₂R¹⁴;

R¹⁴ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^A is a monocyclic C₃-C₈ cycloalkyl group;

R^B is phenyl;

R^c is a monocyclic saturated or partly unsaturated ring system containing between 3 and 8 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur; R^D is a 5- or 6-membered heteroaromatic ring containing up to three heteroatoms independently selected from nitrogen, oxygen and sulphur;

R^E is a monocyclic saturated ring system containing between 3 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

R^F and R^G are each independently a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

R^J is cyclopropyl or cyclobutyl;

R^L and R^N are each independently a monocyclic saturated ring system containing either 5 or 6 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

and R^M is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulphur.

More preferably, R¹ is a cyclic group selected from R^A, R^B, R^c and R^D, each of which is optionally substituted with one or more R⁷ groups;

R² is hydrogen or C₁-C₂ alkyl;

R³ is hydrogen, C₁-C₄ alkyl, which is optionally substituted with one or more R⁸ groups, or R^E, which is optionally substituted with one or more R⁹ groups;

R⁴ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R⁵ is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each of which is optionally substituted by hydroxy, C₁-C₄ alkoxy or C₁- C₄ haloalkoxy;

R⁶ is R^6A or hydrogen; R^6A is C₁-C₄ alkyl or CrC₄ haloalkyl, each of which is optionally substituted by CrC₄ alkoxy, CrC₄ haloalkoxy or a cyclic group selected from R^J, R^L and R^M, or R^6A is R^N;

R⁷ is halo, CrC₆ alkyl, C₁-C₆ haloalkyl, oxo, OR¹² or CONR¹²R¹³;

R⁸ is halo, phenyl, CrC₆ alkoxyphenyl, OR¹², NR¹²R¹³, NR¹²CO₂R¹⁴, CO₂R¹², CONR¹²R¹³, R^G or R^H, the last two of which are optionally substituted with one or more R⁹ groups;

R⁹ is C₁-C₆ alkyl, C₁-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, C₁-C₆ alkyl or C₁-C₆ haloalkyl, the last two of which are optionally substituted by R¹¹;

R¹¹ is OH, phenyl, NR¹²R¹³ or NR¹²CO₂R¹⁴;

R¹⁴ is C₁O₆ alkyl or C₁-C₆ haloalkyl;

R^A is a monocyclic C₅-C₇ cycloalkyl group;

R^B is phenyl;

R^c is a monocyclic saturated ring system containing between 5 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur;

R^D is a 5-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulphur and optionally up to two further nitrogen atoms in the ring, or a 6-membered heteroaromatic ring including 1 , 2 or 3 nitrogen atoms;

R^E is a monocyclic saturated ring system containing between 3 and 7 ring atoms containing one nitrogen atom;

R^F is a monocyclic or, when there are an appropriate number of ring atoms, polycyclic saturated ring system containing between 3 and 10 ring atoms containing at least one nitrogen atom and optionally one other atom selected from oxygen and sulphur;

R^G is a monocyclic saturated ring system containing between 3 and 7 ring atoms, of which at least one is a heteroatom selected from nitrogen, oxygen and sulphur; R^H is a 5- or 6-membered heteroaromatic ring containing up to two nitrogen atoms;

and

R^M is a 5- or 6-membered heteroaromatic ring containing a heteroatom selected from nitrogen, oxygen and sulphur.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, pamoate, phosphate, saccharate, stearate, succinate, sulphate, D- and L-tartrate, and tosylate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).

A pharmaceutically acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O₁ acetone-d₆, DMSOd₆.

Also within the scope of the invention are clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in non-stoichiometric amounts. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). Hereinafter all references to compounds of formula (I) include references to salts thereof and to solvates and clathrates of compounds of formula (I) and salts thereof.

Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the compound contains, for example, a keto or oxime group, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all optical isomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallisation and chromatography.

Conventional techniques for the preparation/isolation of individual stereoisomers include the conversion of a suitable optically pure precursor, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, for example, tartaric acid.

The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula (I). An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹³C and ¹⁴C, nitrogen, such as ¹⁵N, oxygen, such as ¹⁷O and ¹⁸O, phosphorus, such as ³²P, sulphur, such as ³⁵S, fluorine, such as ¹⁸F, and chlorine, such as ³⁶CI.

Substitution of the compounds of the invention with isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Certain isotopic variations of the compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. lsotopic variations of the compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents.

The compounds of formula (I) may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.

The compounds of formula (I) are inhibitors of PDE-5. Accordingly, in a further aspect the present invention provides for the use of a compound of formula (I), or a tautomer, salt or solvate thereof, as a medicament, and particularly as a medicament for the treatment of a disease or condition where inhibition of PDE-5 is known, or can be shown, to produce a beneficial effect.

The term "treatment" includes palliative, curative and prophylactic treatment. The term "palliative treatment" refers to treatment that eases or reduces the effect or intensity of a condition in a subject without curing the condition. The term "preventative treatment" (and the corresponding term "prophylactic treatment") refers to treatment that prevents the occurrence of a condition in a subject. The term "restorative treatment" refers to treatment that halts the progression of, reduces the pathologic manifestations of, or entirely eliminates a condition in a subject.

The present invention further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds of Formulae (I) through (I-UU) as described above. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment.

In another embodiment, the treatment is restorative treatment.

The conditions that can be treated in accordance with the present invention include, but are not limited to, cardiovascular diseases, metabolic diseases, central nervous system diseases, pulmonary diseases, sexual dysfunction, and renal dysfunction. The present invention further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds of Formula (I) through (I-UU). In another embodiment, the condition is a cGMP-mediated condition. Conditions In one embodiment, the condition is a cardiovascular disease, including a cardiovascular disease selected from the group consisting of hypertension (such as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, and renovascular hypertension) ; complications associated with hypertension (such as vascular organ damage, congestive heart failure, angina, stroke, glaucoma and impaired renal function); valvular insufficiency; stable, unstable and variant (Prinzmetal) angina; peripheral vascular disease; myocardial infarct; stroke; thromboembolic disease; restenosis; arteriosclerosis; atherosclerosis; pulmonary arterial hypertension; angiostenosis after bypass; angioplasty (such as percutaneous transluminal angioplasty, or percutaneous transluminal coronary angioplasty); hyperlipidemia; hypoxic vasoconstriction; vasculitis, such as Kawasaki's syndrome; heart failure (such as congestive, decompensated, systolic, diastolic, left ventricular heart failure, right ventricular heart failure, left ventricular hypertrophy); Raynaud's disease; preeclampsia; pregnancy-induced high blood pressure; cardiomyopathy; and arterial occlusive disorders. In another embodiment, the condition is hypertension. In another embodiment, the condition is pulmonary arterial hypertension. In another embodiment, the condition is heart failure. In another embodiment, the condition is angina.

In another embodiment, the condition is a metabolic disease, including a metabolic disease selected from the group consisting of Syndrome X; insulin resistance or impaired glucose tolerance; diabetes (such as type I and type Il diabetes); syndromes of insulin resistance (such as insulin receptor disorders, Rabson- Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly, pheochomocytoma, glucagonoma, primary aldosteronism, somatostatinoma, Lipoatrophic diabetes, β-cell toxin induced diabetes, Grave's disease, Hashimoto's thyroiditis and idiopathic Addison's disease); diabetic complications (such as diabetic gangrene, diabetic arthropathy, diabetic nephropathy, diabetic glomerulosclerosis, diabetic deramatopathy, diabetic neuropathy, peripheral diabetic neuropathy, diabetic cataract, and diabetic retinopathy); hyperglycemia; and obesity. In another embodiment, the condition is insulin resistance.

In another embodiment, the condition is a diseases of the central nervous system, including a disease of the central nervous system selected from the group consisting of vascular dementia; craniocerebral trauma; cerebral infarcts; concentration disorders (e.g. dementia, amnestic disorders, and age-related cognitive decline (ARCD); Alzheimer's disease; Parkinson's disease (e.g. dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias); amyolateral sclerosis (ALS); Huntington's disease; multiple sclerosis; Creutzfeld-Jacob; anxiety, generalized anxiety disorder; depression (e.g. depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression); sleep disorders; and migraine. In one embodiment, the condition is Alzheimer's disease. In another embodiment, the condition is Parkinson's disease. In one embodiment, the condition is ALS. In another embodiment, the condition is a concentration disorder.

In one embodiment, the condition is a pulmonary disease, including a pulmonary disease selected from the group consisting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease (COPD); bronchitis; and chronic reversible pulmonary obstruction.

In one embodiment, the condition is sexual dysfunction, including sexual dysfunction selected from the group consisting of impotence (organic or psychic); male erectile dysfunction; clitoral dysfunction; sexual dysfunction after spinal cord injury; female sexual arousal disorder; female sexual orgasmic dysfunction; female sexual pain disorder; and female hypoactive sexual desire disorder. In another embodiment, the condition is erectile dysfunction.

In another embodiment, the condition is renal dysfunction, including a renal dysfunction selected from the group consisting of acute or chronic renal failure; nephropathy (such as diabetic nephropathy); glomerulopathy; and nephritis.

In another embodiment, the condition is acute pain associated with, for example, injury or surgery. In another embodiment, the condition is chronic pain including neuropathic pain (including postherpetic neuralgia and pain associated with peripheral, cancer or diabetic neuropathy), carpal tunnel syndrome, back pain (including pain associated with herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament), headache, cancer pain including tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome, post radiation syndrome, pain associated with immunotherapy, or pain associated with hormonal therapy), arthritic pain (including osteoarthritis and rheumatoid arthritis pain), chronic post-surgical pain, post herpetic neuralgia, trigeminal neuralgia HIV neuropathy, phantom limb pain, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. In another embodiment, the condition is nociceptive pain including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. In another embodiment, the condition is pain associated with inflammation, including arthritic pain (including osteoarthritis and rheumatoid disease pain), ankylosing spondylitis, visceral pain (including inflammatory bowel disease, functional bowel disorder, gastro- esophageal relux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreaitis and pelvic pain). In another embodiment, the condition is pain resulting from musculo-skeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis. In another embodiment, the condition is selected from the group consisting of heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia. In another embodiment, the condition is selected from the group consisting of head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

In another embodiment, the condition is selected from the group consisting of tubulointerstitial disorders; anal fissure; baldness; benign prostatic hyperplasia (BPH); bladder outlet obstruction; cancerous cachexia; cerebral apoplexy; disorders of gut motility; enteromotility disorders; dysmenorrhoea (primary and secondary); glaucoma; macular degeneration; antiplatelet; haemorrhoids; incontinence; irritable bowel syndrome (IBS); tumor metastasis; multiple sclerosis; neoplasia; nitrate intolerance; nutcracker oesophagus; osteoporosis; infertility; premature labor; psoriasis; retinal disease; skin necrosis; and urticaria. In another embodiment, the condition is osteoporosis.

In another embodiment, the condition is associated with endothelial dysfunction, including conditions selected from the group consisting of atherosclerotic lesions, myocardial ischaemia, peripheral ischaemia, valvular insufficiency, pulmonary arterial hypertension, angina, vascular complications after vascular bypass, vascular dilation, vascular repermeabilisation, and heart transplantation. In another embodiment, the condition is a cGMP-mediated condition.

The present invention additionally comprises methods for inhibiting the PDE-5 enzyme in a subject by administering to the subject a therapeutically-effective amount of one or more compounds of Formulae (I) through (I-EE) as described above.

The methods and compounds of the present invention are suitable for use with, for example, mammalian subjects such as humans, other primates (e.g., monkeys, chimpanzees), companion animals (e.g., dogs, cats, horses), farm animals (e.g., goats, sheep, pigs, cattle), laboratory animals (e.g., mice, rats), and wild and zoo animals (e.g., wolves, bears, deer). In another embodiment, the subject is human.

One or more compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states. The compound(s) of the present invention and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. For instance, in one embodiment, one or more compounds of Formulae (I) through (I-UU) may be administered with aspirin.

In one embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more angiotensin converting enzyme (ACE) inhibitors. Examples of the one or more ACE inhibitors for use with the one or morecompound of Formulae (I) - (I-UU) include quinapril (such as ACCUPRIL™), perindopril (such as ACEON™), captopril (such as CAPOTEN™), enalapril (such as VASOTEC™), ENALAPRILAT™, ramipril (such as ALT ACE™), cilazapril, delapril, fosenopril (such as MONOPRIL™), zofenopril, indolapril, benazepril (such as LOTENSIN™), lisinopril (such as PRINIVIL™ or ZESTRIL™), spirapril, trandolapril (such as MAVIK™), perindep, pentopril, moexipril (such as UNIVASC™) or pivopril In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more alpha blockers such as dozazosin (such as CARDURA™), phenoxybenzamine (such as DIBENZYLINE™), or terazosin (such as HYTRIN™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more alpha-beta blockers such as labetalol (such as NORMODYNE™ or TRANDATE™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more angiotensin Il receptor blockers such as candesartan (such as ATACAND™), eprosartan (such as TEVETEN™), irbesartan (such as AVEPRO™), losartan (such as COZAAR™), olmesartan, olmesartan medoxomil (such as BENICAR™), tasosartan, telmisartan (such as MICARDIS™), valsartan (such as DIOVAN™) or zolasartan. In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more alpha-2-delta ligands such as gabapentin, pregabalin, [(1 R,5R,6S)-6- - -

(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H- [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, (1 D,3π,5G)-(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3- amino-5-methyl-nonanoic acid and (3S,5R)-3-amino-5-methyl-octanoic acid), (2S,4S)-4-(3- Chlorophenoxy)praline, or (2S,4S)-4-(3-Fluorobenzyl)praline.

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more beta blockers such as timolol (such as BLOCARDEN™), carteolol (such as CARTROL™), carvedilol (such as COREG™), nadolol (such as CORGARD™), propranolol (such as INNOPRAN XL™), betaxolol (such as KERLONE™), penbutolol (such as LEVATOL™), metoprolol (such as LOPRESSOR™ or TOPROL-XL™), atenolol (such as TENORMIN™), or pindolol (such as VISKEN™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more calcium channel blockers such as nifedipine (such as ADALAT™, ADALAT CC™ or PROCARDIA™), verapamil (such as CALAN™, COVERA-HS™, ISOPTIN SR™ or VERELAN™), diltiazem (such as CARDIZEM™ CARDIZEM CD™, CARDIZEM LA™, CARDIZEM SR™, DILACOR™, TIAMATE™ or TIAZAC™), isradipine (such as DYNACIRC™ or DYNACIRC CR™), amlodipine (such as NORVASC™), felodipine (such as PLENDIL™), nisoldipine (such as SULAR™), or bepridil (such as VASCOR™). In another embodiment, one or more compounds Formulae (I) through (I-UU) may be co-administered with one or more central antiadrenergics such as methyldopa (such as ALDOMET™), clonidine (such as CATAPRES™ or CATAPRES-TTS™), guanfacine (such as TENEX™), or guanabenz (such as WYTENSIN™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more diruretics such as hydroclorothiazide (such as MICROZIDE™ or ORETIC™), hydroflumethiazide (such as SALURON™), bemetanide (such as BUMEX™), torsemide (such as

DEMADEX™), metolazone (such as ZAROXOLYN™), chlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), triamterene (such as DYRENIUM™), ethacrynic acid (such as EDECRIN™), chlorthalidone (such as HYGROTON™), furosemide (such as LASIX™), indapamide (such as LOZOL™), or amiloride (such as MIDAMOR™ or MODURETIC™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more glycosides / inotropic agents such as digoxin (such as LANOXIN™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more organic nitrates or an NO donors. "Nitric oxide donor" or "NO donor" refers to a compound that donates, releases and/or directly or indirectly transfers a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo. "NO donor" also includes compounds that are substrates for nitric oxide synthase. Examples of the one or more NO donors for use with one or more compounds of Formulae (I) through (I-UU) include S-nitrosothiols, nitrites, nitrates, N- oxo-N-nitrosamines, SPM 3672, SPM 5185, SPM 5186 and analogues thereof, sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine, SIN-1 or substrates of the various isozymes of nitric oxide synthase. - -

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more human B-type natriuretic peptides (hBNP) such as nesiritide (such as NATRECOR™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more renin inhibitors such as Aliskiren (SPP 100).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more soluble guanylate cyclase activator ("sGCa").

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more neutral endopeptidase (NEP) inhibitors, such as, for example, omapatrilat, fasidotril,

mixanpril, sampatrilat, Z13752A , BMS-189921 ■ or

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more aldosterone receptor antagonists such as eplerenone (such as INSPRA™) or spironolactone (such as ALDACTONE™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more endothelian antagonists, such as BMS-193884.

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with niacin or one or more nicotinic acid derivatives, such as NIACOR™, NIASPAN™, NICOLAR™, or SLO-NIACIN™.

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more fibric acid derivatives, such as clofibrate (such as ATROMID-S™), gemfibrozil (such as LOPID™), or fenofibrate (such as TRICOR™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more cholesteryl ester transport protein inhibitors (CETPi), such as torcetrapib. In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more bile acid sequestants, such as colestipol (such as COLESTID™), cholestyramine (such as LOCHOLEST™, PREVALITE™, QUESTRAN™, or QUESTRAN LIGHT™), colesevelam (such as WELCHOL™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with an apical sodium-dependent bile acid cotransporter inhibitors, such as AZD7806 or 264W94. In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more cholesterol absorbtion inhibitors, such as ezetimibe (such as ZETI A™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) such as fluvastatin (such as LESCOL™), atorvastatin (such as LIPITOR™), lovastatin (such as ALTOCOR™ or MEVACOR™), pravastatin (such as PRAVACHOL™), rosuvastatin (such as CRESTOR™), or simvastatin (such as ZOCOR™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more alpha glucosidase inhibitors, such as miglitol (such as GLYSET™), or acarbose (such as

PRECOSE™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more biguanides, such as roseiglitazone (such as AVANDAMET™), or metformin (such as GLUCOPHAGE™ or GLUCOPHAGE XR™).

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more insulins, such as HUMALOG™, HUMALOG 50/50™, HUMALOG 75/25™, HUMULIN 50/50™, HUMALIN 75/25™, HUMALIN L™, HUMALIN N™, HUMALIN R™, HUMALIN R U-500™, HUMALIN U™, ILETIN Il LENTE™, ILETIN Il NPH™, ILETIN Il REGULAR™, LANTUS™, NOVOLIN 70/30™, NOVILIN N™, NOVILIN R™, NOVOLOG™, or VELOSULIN BR™.

In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more meglitnides, such as repaglinide (such as PRANDIN™) or nateglinide (such as STARLIX™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more sulfonylureas, such as glimepiride (such as AMARYL™), glyburide (such as DIABET A™, GLYNASE PRESTAB™ or MICRONASE™), or glipizide (such as GLUCOTROL™, or GLUCOTROL XL™). In another embodiment, one or more compounds of Formulae (I) through (I-UU) may be co-administered with one or more thiazolidinediones, such as pioglitazone (such as ACTOS™) or rosiglitazone (such as AVANDIA™).

In a further aspect, the present invention provides for a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second pharmaceutically active agent selected from those listed in the preceding paragraph.

The compounds of the invention may be administered alone or in combination with other drugs and will generally be administered as 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 of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001 ).

The composition of a typical tablet in accordance with the invention may comprise:

* Quantity adjusted in accordance with drug activity.

A typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion. The tablet formulation may comprise one or more layers and may be coated or uncoated.

Examples of excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulphate, preservatives, anti-oxidants, flavours and colourants.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1- 14 (2001). Other modified release formulations are described in US Patent No. 6,106,864.

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use of solubility- enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.

The compounds of the invention may also be administered topically to the skin or mucosa, either dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated - see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).

Other means of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Thus compounds of the invention may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound. The compounds of the invention can 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 blend with lactose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as dichlorofluoromethane.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 10mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1μg to 20mg of the compound of formula (I). The overall daily dose will typically be in the range 1 μg to 80mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.

The compounds of the invention may 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 may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and andial 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 crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/andial administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted, or programmed release.

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste- masking, bioavailability and/or stability.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.1 mg to 500mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 0.1 mg to 500mg, while an intravenous dose may only require from 0.01 mg to 50mg. The total daily dose may be administered in single or divided doses.

These dosages are based on an average human subject having a weight of about 65 to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. _

Compounds of the invention may be prepared, in known manner in a variety of ways. In the following reaction schemes and hereafter, unless otherwise stated R¹ to R⁶ are as defined in the first aspect. These processes form further aspects of the invention.

I₁ Scheme 1 summarizes a synthetic route that is applicable to the synthesis of compounds of formula (I), and particularly for those compounds of formula (I) wherein R⁵ is hydrogen or unsubstituted alkyl or cycloalkyl. The starting materials are pyrazolecarboxylic acids of formula (II). Some compounds of formula (II) are items of commerce, and others are known in the literature. Where they are not known they may be prepared according to one or more of the methods that are available in the art, such as those discussed in part 2 below.

Scheme 1

- -

Step (a)

The carboxylic acid of formula (II) is converted to the corresponding amide of formula (III) either directly or, preferably, via an acid chloride intermediate. Direct conversion may be achieved by treating a solution of the acid with excess ammonia in the presence of a coupling agent such as a carbodiimide (e.g dicyclohexylcarbodiimide or 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide) and optionally a hydroxytriazole such as HOBT or HOAT. Suitable solvents include dichloromethane and ethyl acetate. Indirect conversion may be achieved by forming an acid chloride by treatment of Il with oxalyl chloride and Λ/,Λ/-dimethylformamide in a suitable solvent such as dichloromethane, or with thionyl chloride. A solution of the acid chloride in a suitable solvent such as dichloromethane, tetrahydrofuran or dioxan is then treated with gaseous ammonia or aqueous ammonia to provide the amide of formula (III).

Preferably, a solution of the acid of formula (II) in dichloromethane is treated at room temperature with oxalyl chloride and a catalytic quantity of Λ/,Λ/-dimethylformamide for 2 hours. The mixture is then cooled to -20⁰C, excess ammonia is added, and the mixture is stirred for 2 hours at a temperature of between -20°C and room temperature.

Step (b)

When R⁶ is R^6A, this group may be introduced in an Λ/-alkylation step. The compound of formula (III) may be treated with a base such as an alkaline metal carbonate or bicarbonate, for example potassium carbonate or cesium carbonate, or a tertiary amine, for example triethylamine, Λ/-ethyldiisopropylamine or pyridine, and the appropriate chloride (R^6A-CI), bromide (R^6A-Br), iodide (R^6A-I), mesylate (R^6A-OSO₂CH₃) or tosylate (R^6A-OSO₂Tol) in a suitable solvent at a temperature of between -2O⁰C and 100⁰C. Suitable solvents include ethers such as tetrahydrofuran and dioxan, lower alcohols such as methanol, ethanol and butanol, ketones such as acetone and 2-butanone, Λ/-methylpyrrolidinone, Λ/,Λ/-dimethylformamide and acetonitrile.

Alternatively, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide may be used as the base. Suitable solvents then include water and mixtures of water and water-miscible organic solvents.

Alternatively, an alkali metal (CrC₄)alkoxide such as sodium methoxide or potassium tert-butoxide may be used as the base. Suitable solvents then include the corresponding lower alcohols (i.e. methanol for sodium methoxide), ethers such as tetrahydrofuran and dioxan, Λ/-methylpyrrolidinone, N₁N- dimethylformamide and acetonitrile.

Stronger bases such as sodium hydride and sodium or potassium hexamethyldisilazide may also be used.

Suitable solvents then include ethers such as tetrahydrofuran and dioxan, Λ/-methylpyrrolidinone, and

Λ/,Λ/-dimethylformamide. The reaction may also be carried out under phase transfer conditions using aqueous sodium or potassium hydroxide as base, dichloromethane or chloroform as organic solvent, and a tetraalkylammonium chloride or hydroxide as phase transfer catalyst.

Alternatively, the transformation may be achieved using the Mitsunobu reaction (Organic Reactions 1992, 42), in which a solution of the compound of formula (III) and the appropriate alcohol R^6A-OH in a suitable solvent is treated with triphenylphosphine and a dialkyl azodicarboxylate such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. Suitable solvents include tetrahydrofuran and dioxan. The reaction is preferably performed at a temperature of between -1O⁰C and ambient temperature.

Preferably, the compounds of formula (III) is treated with either 1 equivalent of R^6A-Br and 1 equivalent of potassium carbonate in Λ/,Λ/-dimethylformamide at room temperature for 18 hours, or with 1.2 equivalents of R^6A-OH, 1.4 equivalents of diisopropyl azodicarboxylate and 1.4 equivalents of triphenylphosphine in tetrahydrofuran at a temperature of between 0⁰C and 25°C for 2 hours.

Depending on the precise choice of reagents and conditions chosen, the reaction may give the N¹- or N²- alkylated product, or a mixture of the two. Where a mixture is produced then the individual components may be separated using conventional methods such as chromatography or fractional crystallization.

Step (C)

Reduction of the nitro group of compounds of formula (IV) to provide the amines of formula (V) can be achieved by, for example, transfer or catalytic hydrogenation, or by a dissolving metal reduction.

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 transition metal salt catalyst, such as palladium or palladium(ll) hydroxide, optionally at elevated temperature and pressure.

For 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 a transition metal or transition metal salt catalyst, such as palladium or Raney^® nickel, optionally at elevated pressure. The catalyst may be in solution (homogeneous catalysis) or in suspension (heterogeneous catalysis).

For dissolving metal reduction, the nitro compound in ethanol 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(ll) chloride, may also be used.

Preferably, a solution of the compound of formula (IV) in methanol or ethanol is treated with 10% (by weight) of 10% Pd(OH)₂-on-carbon and 5 equivalents of ammonium formate, and the mixture is heated at reflux for between 2 and 18 hours. Step (d)

A solution of the pyrazolecarboxamide (V) and phosgene or an equivalent thereof, such as 1 ,1'- carbonyldiimidazole, trichloromethyl chloroformate or bis(trichloromethyl) carbonate, in a suitable solvent is stirred at a temperature of between ambient temperature and the boiling point of the solvent, optionally at elevated pressure, for between 2 and 18 hours to provide the corresponding pyrazolopyrimidinedione of formula (Vl). Suitable solvents include acetonitrile, dichloromethane and Λ/,Λ/-dimethylformamide. Preferably, a solution of the dione and 1 to 2 equivalents of carbonyl diimidazole in acetonitrile, N₁N- dimethylformamide or dichloromethane is heated at a temperature of between 50⁰C and 80⁰C for 18 hours.

Step (e)

The dione of formula (Vl) is treated with a large excess of a suitable chlorinating reagent such as phosphorus oxychloride (POCI₃) or phenylphosphonyl dichloride (PhP(O)CI₂) in the presence of a tertiary amine such as Λ/-ethyldiisopropylamine, Λ/-methylmorpholine, triethylamine or Λ/,Λ/-dimethylaniline at elevated temperature for 8-48 hours to provide the corresponding dichloropyrazolopyrimidine of formula (VII). Λ/,Λ/-Dimethylformamide can optionally be added as a catalyst. Alternatively, the dione is treated with POCI₃ or PhP(O)CI₂ in a suitable solvent in the presence of a tetraalkylammonium chloride, such as tetraethylammonium chloride, at elevated temperature. Suitable solvents include acetonitrile and propionitrile.

Preferably, the dione is treated with 10-30 equivalents of POCI₃ and 3-5 equivalents of tetraethylammonium chloride in propionitrile at reflux for 4-18 hours.

Step (f) A solution of the dichloride of formula (VII), the amine HNR¹R² and an excess of a tertiary amine such as Λ/-ethyldiisopropylamine, Λ/-methylmorpholine or triethylamine in a suitable solvent are stirred at ambient or elevated temperature for between 1 and 24 hours to provide the corresponding compound of formula (VIII). Suitable solvents include dichloromethane, dimethylsulfoxide, Λ/,Λ/-dimethylformamide, tetrahydrofuran and Λ/-methylpyrrolidinone.

Alternatively, the reaction may be carried out under microwave irradiation.

Alternatively, a solution of the amine HNR¹R² in a suitable solvent is treated with butyllithium or sodium hexamethyldisilazide at low temperature, and the dichloride is added to the resulting solution. Suitable solvents include tetrahydrofuran, dioxan and Λ/-methylpyrrolidinone.

Preferably, either the dichloride is treated with 3-5 equivalents of the amine HNR¹R² and optionally 3-5 equivalents of Λ/-ethyldiisopropylamine in dichloromethane, dimethylsulfoxide or a mixture of dimethylsulfoxide and Λ/-methylpyrrolidinone at 20-90°C for 1 -18 hours, or a solution of 2-4 equivalents of HNR¹R² in tetrahydrofuran is treated with an equimolar amount of butyllithium or sodium hexamethyldisilazide, 1 equivalent of the dichloride is added, and the mixture is stirred at a temperature of between 0⁰C and room temperature for between 2 and 3 hours.

It will be appreciated that any functional groups that are substituents on R¹, and particularly any primary or secondary amine groups, may need to be protected in order to allow this reaction to proceed successfully. Suitable protecting groups are well known in the art, and are described in, for example, "Protective Groups in Organic Synthesis", Greene, T. W. and Wutts, P. G. M., 3^rd edition, John Wiley & Sons, Ltd, Chichester, 1999. Examples of protecting groups for primary and secondary amines include tert- butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ or Z) and 9-fluorenylmethyloxycarbonyl (Fmoc) groups. Carboxylic acids may be protected as their methyl, ethyl, benzyl or fert-butyl esters. Alcohols may be protected as ester or ether derivatives.

Step (g)

A solution of the monochloride (VIII) and the amine HNR³R⁴ in a suitable dipolar aprotic solvent are stirred at elevated temperature for between 1 and 24 hours to provide the corresponding compound of formula (I). Suitable solvents include dimethylsulfoxide, Λ/,Λ/-dimethylformamide and Λ/-methylpyrrolidinone. An excess of a tertiary amine such as Λ/-ethyldiisopropylamine, Λ/-methylmorpholine or triethylamine and/or a fluoride source such as cesium fluoride or tetraethylammonium fluoride may optionally be included. It is sometimes necessary to perform the reaction at elevated pressure in a closed vessel, particularly when the amine HNR³R⁴ or the solvent is volatile.

Alternatively, the reaction may be carried out under microwave irradiation.

Preferred conditions are: the monochloride is treated with 3-5 equivalents of the amine HNR³R⁴ and optionally with 3-5 equivalents of Λ/-ethyldiisopropylamine in dimethylsulfoxide or Λ/-methylpyrrolidinone, optionally in a sealed vessel, at 80-125⁰C for 12-18 hours; or

the monochloride is treated with 3-5 equivalents of the amine HNR³R⁴ and 1 equivalent of cesium fluoride in dimethylsulfoxide or Λ/-methylpyrrolidinone, optionally in a sealed vessel, at 100-120⁰C; or

the monochloride is treated with 3-5 equivalents of the amine HNR³R⁴ and optionally with 3-5 equivalents of Λ/-ethyldiisopropylamine and/or optionally in the presence of cesium fluoride or tetraethylammonium fluoride in Λ/-methylpyrrolidinone or DMSO under microwave irradiation for 40 minutes.

It will be appreciated that, as for step (f) above, any functional groups in -NR³R⁴, and particularly any primary or secondary amine groups, may need to be protected in order to allow this reaction to proceed successfully.

In some cases, it is possible to perform the transformations of steps (f) and (g) as a "one-pot" operation, i.e. without isolating the monochloride of formula (VIII). The compound of formula (VII) is treated with the amine HNR¹R², as described in step (f), then the amine HNR³R⁴ is added to the mixture and the reaction is carried forward as described in step (g).

When one or more protecting groups have been used in the course of the synthesis, there will be a final deprotection protocol to unmask the functional groups of the target compound. This protocol may be a single operation or may proceed in several steps. It may also be combined with the preceding synthetic manipulation.

Deprotection is well known in the art, as described in "Protective Groups in Organic Synthesis", Greene, T. W. and Wutts, P. G. M., 3^rd edition, John Wiley & Sons, Ltd, Chichester, 1999. For example, tert- butyloxycarbonyl-protected amines and tert-butyl esters of carboxylic acids may be deprotected by treatment with acids such as trifluoroacetic acid or anhydrous hydrogen chloride in a suitable solvent, benzyloxycarbonyl-protected amines and benzyl esters of carboxylic acids may be deprotected by catalytic hydrogenolysis, 9-fluorenylmethyloxycarbonyl-protected amines may be deprotected by treatment with piperidine, and methyl and ethyl esters of carboxylic acids may be deprotected by treatment with an alkali metal hydroxide.

Preferably, tert-butyloxycarbonyl and fe/t-butyl protecting groups are removed by treatment with trifluoroacetic acid in dichloromethane at room temperature for between 1 and 18 hours, or, for tert- butyloxycarbonyl protecting groups, by treatment with excess hydrogen chloride in dioxan at room temperature for 18 hours. Benzyl protecting groups are preferably removed by hydrogenation at 60psi in the presence of Pd(OH)₂ in ethanolic hydrogen chloride at room temperature for 18 hours.

2. Scheme 2 summarizes two methods, the Knorr and the Pechmann syntheses, available for the synthesis pyrazolecarboxylic acids of formula (II). Other methods known in the art may also be used.

Scheme 2

Step (h)

The 1 ,3-diketones of formula (X) that are the starting materials for the Knorr pyrazole synthesis can be prepared from the corresponding methyl ketones of formula (IX) using a crossed Claisen condensation. The methyl ketone of formula (IX) is reacted with dimethyl oxalate in a suitable solvent in the presence of a suitable base. Suitable solvents include ethers, such as tetrahydrofuran. Suitable bases include sodium hydride, potassium tert-butoxide and lithium diisopropylamide. Alternatively, sodium methoxide may be used as the base and methanol as the solvent.

Step (i)

The 1 ,3-diketone of formula (X) may be reacted with hydrazine to give a pyrazole of formula (Xl) following the well-known methodology of the Knorr pyrazole synthesis.

It will be appreciated that substituted hydrazines R^6ANHNH₂ may also be used in the Knorr pyrazole synthesis to provide analogues of the compounds of formula (Xl) which are Λ/-alkylated. A mixture of N¹- and /^-alkylated product is normally produced and the individual components may be separated using conventional methods such as chromatography or fractional crystallization. Hydrolysis and nitration according to the methods described for steps (I) and (m) below, followed by amide formation according to the method described in part 1 , step (a), above, then provides the compounds of formula (IV) without the need for the alkylation reaction of part 1 , step (b).

Step (j) In this variant of the Pechmann pyrazole synthesis, a diazo compound of formula (XII) is reacted with methyl propiolate to provide a pyrazole of formula (Xl). The diazo compounds of formula (XII) can be prepared by known methods, such as from the corresponding primary amine R⁵CH₂NH₂ via an N- arylsulfonyl-Λ/-nitroso derivative.

Step (k)

In this alternative variant of the Pechmann pyrazole synthesis, an acetylene of formula (XIII) is reacted with methyl diazoacetate to provide a pyrazole of formula (Xl).

Step (I) Hydrolysis of the ester of the compounds of formula (Xl) then provides the compounds of formula (XIV). The conversion may conveniently be accomplished by treating the compound of formula (Xl) with an alkaline metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent at a temperature of between about 10⁰C and the boiling point of the solvent. Suitable solvents include water, methanol, ethanol and mixtures of water with methanol, ethanol, tetrahydrofuran and dioxan.

Step (m)

The nitration of pyrazoles is well known. The compounds of formula (XIV) are treated with a nitrating agent such as nitric acid or a mixture of nitric acid and sulphuric acid to provide the compounds of formula (II).

3. The esters of formula (XVIII^A), i.e. compounds of formula (XVIII) wherein R⁶ is attached at the N¹- position, and of formula (XVIII^B), i.e. compounds of formula (XVIII) wherein R⁶ is attached at the N²- position, can be prepared according to the methods summarized in Scheme 3.

- - Scheme 3

(XVIII^A)

Step (n)

Dimethyl 4-nitropyrazole-3,5-dicarboxylate (XV), which is readily prepared according to the method described in published international patent application WO00/24745 (see preparation 2, page 48), can be N-alkylated according to the methods described in part 1 , step (b), above. It will be appreciated that the sensitivity of the ester groups to hydrolysis and trans-esterification means that alkali metal hydroxides and alkoxides (other than methoxides) cannot be used as bases, and water and alcohols (other than methanol) cannot be used as a solvents or cosolvents.

Because the two nitrogen atoms of the pyrazole are equivalent, a single alkylation product is obtained.

Step (o)

Selective hydrolysis of the diesters of formula (XVI) with one equivalent of alkali metal hydroxide according to the method of Chambers et al. (J. Org. Chem. 50, 4736-4738, 1985) cleaves the ester adjacent to the substituted nitrogen to provide the monoacids of formula (XVII).

Preferably, the diester is treated with 1 equivalent of potassium hydroxide in methanol at room temperature for 18 hours. Step (P)

Compounds of formula (XVIII^A), i.e. compounds of formula (XVIII) wherein R⁶ is attached at the re¬ position of the pyrazolopyrimidine, may be obtained from the compounds of formula (XVII) following the methods of part 1 , steps (a) and (c) to (f).

The introduction of the -NR¹R² group is preferably achieved by treating the corresponding dichloride with 3-5 equivalents of HNR¹R² in dimethylsulfoxide at 3O⁰C for 1 hour.

4. Scheme 4 summarizes synthetic routes that are particularly useful for the preparation of compounds of formula (I) wherein R⁵ is hydroxymethyl, alkoxymethyl, haloalkoxymethyl or cycloalkoxymethyl. In Scheme 4, X represents a leaving group such as a chlorine, bromine or iodine atom or an alkyl, aryl or perfluoroalkylsulfonate group (for example a methanesulfonate, toluenesulfonate or trifluoromethanesulfonate group), and R^a represents an alkyl, cycloalkyl or haloalkyl group.

- -

Scheme 4

Step (q)

The reduction of the esters of formula (XVIII) to provide the primary alcohols of formula (XIX) can be achieved using a metal hydride reagent such as lithium aluminum hydride, lithium borohydride, lithium triethylborohydride or diisobutylaluminum hydride (DIBAL) in a suitable solvent at a temperature of less than 0⁰C. Suitable solvents include hydrocarbons such as pentane, hexane and toluene, ethers such as tetrahydrofuran, and mixtures thereof. Alternatively, the ester can be reduced by hydrogenation over a copper chromite catalyst at elevated temperature and pressure. Preferably, the ester is treated with 8-10 equivalents of DIBAL in tetrahydrofuran at a temperature of between -78°C and -5°C for 15 minutes to 1 hour. Step (r)

Compounds of formula (I^D), i.e. compounds of formula (I) wherein R⁵ is hydroxymethyl, may be obtained from the alcohols of formula (XIX) following the methods of part 1 , step (g).

Step (S)

Compounds of formula (XX) wherein X is Br may be prepared from the alcohols of formula (XIX) by treatment with hydrogen bromide or a mixture of triphenylphosphine and bromine, tetrabromomethane or Λ/-bromosuccinimide, optionally in the presence of pyridine, in a suitable solvent such as diethyl ether, dichloromethane or propionitrile. Preferably the alcohol is treated with triphenylphosphine and tetrabromomethane in dichloromethane at room temperature for 1 hour.

Compounds of formula (XX) wherein X is Cl may be prepared from the alcohols of formula (XIX) by treatment with thionyl chloride, phosphorus trichloride or a mixture of triphenylphosphine and N- chlorosuccinimide in a suitable solvent such as dichloromethane. Preferably the alcohol is treated with excess thionyl chloride in dichloromethane for 2-18 hours.

Compounds of formula (XX) wherein X is I may be prepared from the corresponding bromide or chloride by treatment with sodium iodide.

Compounds of formula (XX) wherein X is an alkylsulfonate, arylsulfonate or perfluoroalkylsulfonate may be prepared from the alcohols of formula (XIX) by treatment with a sulfonyl chloride or anhydride, such as methanesulfonyl chloride (mesyl chloride), toluenesulfonyl chloride (tosyl chloride) or trifluoromethanesulfonic anhydride (triflic anhydride), in the presence of a tertiary amine such as triethylamine, Λ/-ethyldiisopropylamine or Λ/-methylmorpholine, in a suitable solvent, for example dichloromethane. Alternatively, pyridine may be used as solvent, in which case there is no need for the use of a tertiary amine.

Step (t)

Compounds of formula (XXI) may be obtained by treating the corresponding compounds of formula (XX) with a sodium or potassium alkoxide, NaOR^a or KOR^a. Alternatively, the compounds of formula (XX) may be treated with an excess of the alcohol R^aOH and a catalyst such as silver tetrafluoroborate (AgBF₄).

Suitable solvents include acetonitrile, Λ/-methylpyrrolidinone and Λ/,Λ/-dimethylformamide. Alternatively, the alcohol R^aOH may be used as solvent provided that it can be removed easily after the reaction, for example by evaporation.

Preferably, a compound of formula (XX) wherein X is Cl or Br is treated with an excess of NaOR^a in N₁N- dimethylformamide or R^aOH at room temperature for between 30 minutes and 72 hours.

Step (u) Compounds of formula (XXI) may also be obtained from the primary alcohols of formula (XIX) by reaction with an alkylating agent R^a-X, using methods analogous to those discussed in part (t) above. Thus a solution of the alcohol of formula (XIX) in a suitable solvent, for example Λ/,Λ/-dimethylformamide or acetonitrile, may be treated with a strong base such as sodium hydride to form the sodium alkoxide, and then with the alkylating agent R^a-X.

It will be appreciated that this transformation may also be carried out using the primary alcohols of formula (I^D) as starting materials, which transformation leads to the production of compounds of formula (I^E).

Step (V)

Compounds of formula (I^E), i.e. compounds of formula (I) wherein R⁵ is R^aOCH₂-, may be obtained from the alcohols of formula (XXI) following the methods of part 1 , step (g).

5. The synthetic route illustrated in Scheme 5 can be low yielding in cases where the amine HNR¹R² is only weakly nucleophilic, such as when R¹ is a pyrimidine or pyrazine ring. In these cases, it is necessary to reduce the ester group prior to the introduction of the -NR¹R² group, as illustrated in Scheme 5.

Scheme 5

- -

Step (w)

Compounds of formula (XXII) may be obtained from the compounds of formula (XVII) following the methods of part 1 , steps (b) to (e), above.

Step (X)

Compounds of formula (XXIII) may be obtained from the compounds of formula (XXII) following the methods of part 4, step (q), above.

Step (y)

The primary alcohol is then protected to give compounds of formula (XXIV), wherein PG is an alcohol protecting group. A preferred protecting group is a trialkylsilyl group, particularly a terf-butyldimethylsilyl group. Preferably, the alcohol is treated with 1.1 equivalents of tert-butyldimethylsilyl chloride and 1.1 equivalents of imidazole in dichloromethane at room temperature for 18 hours.

Step (Z) Compounds of formula (XXV) may be obtained from the compounds of formula (XXIV) following the methods of part 1 , step (f), above.

Step (aa)

The compounds of formula (XXV) are deprotected to provide the primary alcohols of formula (XIX) using appropriate conditions. When PG is a trialkylsilyl group it may be removed by treatment with a fluoride salt, such as tetrabutylammonium fluoride, or with hydrogen chloride in methanol. Preferably, when PG is a tert-butyldimethylsilyl group it is removed by treatment with 2 equivalents of tetrabutylammonium fluorine in tetrahydrofuran at room temperature for 18 hours, or with hydrogen chloride in methanol at room temperature for 18 hours.

6. Scheme 6 summarizes four methods available for the synthesis of trifluoro methylpyrazole carboxylic acid esters of Formula (XXVII). Other methods known in the art may also be used.

Scheme 6

Cf^CH^ + HC=OOO₂Et Intermediate XXVII may be prepared using several synthetic approaches.

Step (ee)

Ethyl δ-trifluoromethyl-pyrazole-S-carboxylate (XXVII) may be prepared by reaction of ethyl diazoacetate and 2-bromo-3,3,3-trifluoro-1 -propene in ether according to the procedure of M. -A. Plancquaert, M. Redon, Z. Janousek, H. G. Viehe ( Tetrahedron, 52 (12), 4383-4396 (1996) ).

Step (ff)

Intermediate XXVII has been prepared by reaction of trifluoroacetyltriphenylsilane 2,4,6- triisopropylbenzenesulfonylhydrazone (0.5 equiv.), ethyl 2-bromoacrylate (1 equiv.), and triethylamine ( 1 equiv.) in THF at RT according to the procedure of F. Jin, Y. Xu and Y. Ma (Tett. Let., 33(41), 6161- 6164(1992)).

Step (gg) Ethyl propiolate may be reacted with 2,2,2-trifluorodiazoethane in ether to give XXVII according to the procedure of J. H. Atherton and R. Fields ( J. Chem Soc.(C) , 1968, 1507-1513).

Step (hh)

Commercially available 3-methyl-5-trifluoromethyl-pyrazole may be oxidized to the carboxylic acid derivative using, for example, potassium permanganate according to the procedure outlined in U.S. Patent 4,282,361.

Step (jj) The δ-trifluoromethyl-pyrazole-S-carboxylate prepared in Step (hh) may be converted to the ethyl ester, XXVII, for example, reacting with ethanolic HCI according to well known procedures.

7.

Scheme 7.

(XXIX)

(kk) (oo)

R₅ = CF₃

(xxvπ)

Step (kk)

3-methyl-5-trifluoromethyl-pyrazole (commercially available) is nitrated according to the procedure of U.S. Patent 4,282,361 , Example 4 using a sulfuric acid / nitric acid mixture.

Step (mm)

The nitro intermediate from Step (kk) can be oxidized to the carboxylic acid Formula XXIX using, for example, potassium permanganate oxidation according to U.S. Patent 4,282,361 , Example 5.

Step (nn)

XXIX can be converted to the ethyl ester using ethanolic HCI according to the procedure outlined in U.S. Patent 4,282,361 or by simply treating XXIX with ethanol and adding sufficient dioxane / HCI and refluxing.

Step (oo)

Nitration of XXVII may be accomplished using well known procedures, for example, contacting with sulfuric acid / nitric acid mixtures according to the procedure resulting in nitropyrazole, Figure ( XXVIII).

8. Scheme 8 outlines the conversion of compounds of Formula XXIX or Formula XXVIII to those of Formula II, where R₅ = CF₃. Scheme 8

Step (rr)

The carboxylic acid of Formula (XXIX) may be converted to the corresponding amide of Formula (XXXI) either directly or via an acid chloride intermediate. Direct conversion may be achieved by treating a solution of the acid with excess ammonia in the presence of a coupling agent such as a carbodiimide (e.gdicyclohexylcarbodiimide or 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide) and optionally a hydroxytriazole such as HOBT or HOAT. Suitable solvents include dichloromethane and ethyl acetate. Indirect conversion may be achieved by forming an acid chloride by treatment of XXIX with oxalyl chloride and Λ/,Λ/-dimethylformamide in a suitable solvent such as dichloromethane, or with thionyl chloride. A solution of the acid chloride in a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane may then treated with gaseous ammonia or aqueous ammonia to provide the amide of Formula (II, R₅ = CF₃).

Step (PP)

When R⁶ is R ,6^DA^A, this group may be introduced in an Λ/-alkylation step. The compounds of Formula (XXVIII) or Formula (XXXI) may be treated with a base such as an alkaline metal carbonate or bicarbonate, for example potassium carbonate or cesium carbonate, or a tertiary amine, for example triethylamine, Λ/-ethyldiisopropylamine or pyridine, and the appropriate chloride (R -Cl), bromide (R -,6A-Br), iodide (R^6A-I), mesylate (R^6A-OSO₂CH₃) or tosylate (R^6A-OSO₂Tol) in a suitable solvent at a temperature of between -2O⁰C and 100°C. Suitable solvents include ethers such as tetrahydrofuran and dioxane, or ethanol, ketones such as acetone and 2-butanone, Λ/-methylpyrrolidinone, Λ/,Λ/-dimethylformamide and acetonitrile. Alternatively, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide may be used as the base. Suitable solvents then include water and mixtures of water and water-miscible organic solvents.

Alternatively, an alkali metal (Ci-C₄)alkoxide such as sodium ethoxide or potassium tert-butoxide may be used as the base. Suitable solvents then include the corresponding alcohols (i.e. ethanol for sodium ethoxide), ethers such as tetrahydrofuran and dioxane, Λ/-methylpyrrolidinone, Λ/,Λ/-dimethylformamide and acetonitrile.

Stronger bases such as sodium hydride and sodium or potassium hexamethyldisilazide may also be used. Suitable solvents then include ethers such as tetrahydrofuran and dioxane, Λ/-methylpyrrolidinone, and Λ/,Λ/-dimethylformamide.

The reaction may also be carried out under phase transfer conditions using aqueous sodium or potassium hydroxide as base, dichloromethane or chloroform as organic solvent, and a tetraalkylammonium chloride or hydroxide as phase transfer catalyst.

Alternatively, the transformation may be achieved using the Mitsunobu reaction (Organic Reactions 1992, 42) in which a solution of a compound of Formula (XXVIII) or Formula (XXXI) and the appropriate alcohol R^6A-OH in a suitable solvent is treated with triphenylphosphine and a dialkyl azodicarboxylate such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. Suitable solvents include tetrahydrofuran and dioxane. The reaction is preferably performed at a temperature of between -10°C and 50⁰C.

The compound of Formula (XXVIII) or (XXXI) is treated with either 1 equivalent of R^6A-Br and 1 equivalent of potassium carbonate in Λ/,Λ/-dimethylformamide at room temperature for 18 hours, or with 1.2 equivalents of R^6Λ-OH, 1.4 equivalents of diisopropyl azodicarboxylate and 1.4 equivalents of triphenylphosphine in tetrahydrofuran at a temperature of between 0°C and 50°C.

Depending on the precise choice of reagents and conditions chosen, the reaction may give the N¹- or Λ/²- alkylated product, or a mixture of the two. Where a mixture is produced then the individual components may be separated using conventional methods such as chromatography or fractional crystallization.

Step (qq)

Compounds of Formula XXX may be directly converted to the corresponding compounds of Formula (II, R₅ = CF₃) by treating with ammonium hydroxide at reflux according to the procedure of U.S. Patent 4,282,361 , Example 7.

Alternatively, compounds of Formula XXX may be hydrolyzed to the corresponding carboxylic acid by well known means and converted to the amide using procedures outlined in Step (rr) above. 9.

Scheme 9

(I^D): Y NR ³R⁴ (XXXII)

(UU) (ww) I (yy)

Step (ss) The oxidation of the alcohols of formula (XIX) can be achieved using a chromium(VI) reagent such as pyridinium chlorochromate, an activated dimethylsulfoxide reagent as in the Swern oxidation protocol, a hypervalent iodine reagent such as the Dess-Martin periodinane, or a combination of tetra-n- propylammonium perruthenate and Λ/-methylmorpholine-Λ/-oxide in a suitable solvent at a temperature of between O⁰C and ambient temperature. Suitable solvents include dichloromethane. A preferred reagent is the Dess-Martin periodinane.

In principle, the aldehydes of formula (XXXII) may also be prepared from the corresponding esters by reduction with DIBAL at low temperature, but in practice it is very difficult to stop the reduction at the aldehyde stage, and the primary alcohol is generally the major product.

Step (tt)

Reaction of the aldehydes of formula (XXXII) with a Grignard reagent R^bMgHal, where R^b is an alkyl or cycloalkyl group and Hal is Cl, Br or I, or with an organolithium reagent R^bLi, provides the secondary alcohols of formula (XXXIII).

The compounds of formula (XXXIII) wherein Y is NR³R⁴ are themselves compounds of formula (I) wherein

R⁵ is alkyl substituted with a hydroxyl group.

Step (uu)

The compounds of formula (XXXIII) may be carried forward as discussed in Scheme 4 above for the primary alcohol analogues. For example, they may be alkylated to provide the compounds of formula (XXXIV) following the methods described in Scheme 4, steps (s) and (t), or Scheme 4, step (u), above.

Another possibility, not illustrated in Scheme 9, is to oxidize the secondary alcohol using the methods of step (ss) to obtain a ketone, which may be further elaborated in a manner analogous to the aldehydes of formula (XXXII).

Step (W)

Using the Wittig reaction methodology, the aldehydes of formula (XXXII) may be treated with a phosphorane reagent Ph₃P:C(R^c)R^d, where R^c and R^d are hydrogen, alkyl or cycloalkyl, to provide compounds of formula (XXXV), in which there is a double bond adjacent to the pyrazolopyrimidine nucleus.

Analogous compounds may also be prepared from the alcohols of formula (XXXIII) when R^a is CH(R^c)R^d by acid-catalysed dehydration, or by base-catalysed elimination from the corresponding chloride or mesylate.

Step (WW)

If not required in the final product, the double bond in compounds of formula (XXXV) may be reduced by catalytic hydrogenation.

Step (xx) The use of (methoxymethylene)triphenylphosphorane in the Wittig reaction of step (w) provides the enol ethers of formula (XXXVII). Step (yy)

The enol ethers of formula (XXXVII) may be hydrolysed in acid solution to provide the aldehydes of formula (XXXVIII). These may then be elaborated in the same ways as discussed above for the aldehydes of formula (XXXII).

EXAMPLES

Example 1

(1 -{1 -(2-Ethoxyethyl)-3-ethyl-7-r(4-methylpyridin-2-yl)aminol-1 H-pyrazolor4.3- dlPyrimidin-5-yl)piperidin-4-vl)methanol

A mixture of the monochloride from Preparation 57, procedure A (0.204 g, 0.57 mmol), 4- piperidinemethanol (0.227 g, 1.97 mmol), and 2-propanol (4.0 mL) were heated (175 ⁰C) in a sealed tube using a CEM Discover™ microwave reactor. After 30 min, the mixture was evaporated and the residue purified by column chromatography on silica gel using concentrated ammonium hydroxide/methanol/methylene chloride (1/9/90) as the eluant to afford the title compound as a white solid (171 mg). ¹H NMR (400 MHz, DMSO-Cf₆) δ: 9.56 (s, 1 H), 8.13 (d, 1 H), 8.03 (m, 1 H), 6.86 (m, 1 H), 4.55 (m, 4 H), 4.40 (m, 1 H)₁ 3.73 (m, 2 H), 3.49 (q, 2 H), 3.22 (m, 2 H), 2.81 (m, 2 H), 2.73 (q, 2 H), 2.28 (s, 3 H), 1.67 (m, 3 H), 1.24 (t, 3 H), 1.11 (m, 2 H), 1.05 (t, 3 H); HRMS (ESI) calcd for C₂₃H₃₃N₇(VH₁ 440.2769, found 440.2764.

Examples 2-3 The following compounds were prepared following a similar procedure to that described in Example 1.

Isolated as the hydrochloride salt. Example 4

1 -(1 -(2-Ethoxyethyl)-3-ethyl-7-r(4-fluorophenyl)aminol-1 H-pyrazolo[4.3- dipyrim idin-5-yl)piperidine-3-carboxam ide

A mixture of the monochloride from Preparation 58 (0.218 g, 0.60 mmol), nipecotamide (0.384 g, 3.00 mmol), and 2-propanol (4.0 mL) were heated (175 ⁰C) in a sealed tube using a CEM Discover™ microwave reactor. After 50 min, the mixture was evaporated and the residue purified by column chromatography on silica gel using concentrated ammonium hydroxide/methanol/methylene chloride (1/9/90) as the eluant to afford the title compound as a white solid (208 mg). ¹H NMR (400 MHz, CD₃OD) δ: 7.63 (m, 2 H), 7.06 (m, 2 H), 4.62 (m, 3 H), 4.48 (m, 1 H), 3.85 (t, 2 H), 3.57 (q, 2 H), 3.08 (m, 1 H), 2.96 (m, 1 H), 2.82 (q, 2 H), 2.43 (m, 1 H), 1.94 (m, 1 H), 1.72 (m, 2 H), 1.54 (m, 1 H), 1.31 (m, 3 H), 1.10 (t, 3 H); HRMS (ESI) calcd for C₂₃H₃₀FN₂O₂H-H₁ 456.2518, found 456.2520.

Examples 5-7

The following compounds were prepared following a similar procedure to that described in Example 4.

Isolated as a hydrochloride salt Example 8

1-(2-Ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1-yll-N-(4-methylpyrimidin-2- yl)-1 H-pyrazolor4.3-dlpvrimidin-7-amine

A mixture of the monochloride from Preparation 59 (0.180 g, 0.50 mmol), (/^-2-methylpiperazine (0.261 g,

2.61 mmol), and 2-propanol (4.0 mL) were heated (175 °C) in a sealed tube using a CEM Discover™ microwave reactor. After 45 min, the mixture was evaporated and the residue purified by column chromatography on silica gel using concentrated ammonium hydroxide/methanol/methylene chloride (1/9/90) as the eluant to afford the title compound as a yellow foam (140 mg). HRMS (ESI) calcd for C₂i H₃i N₉OH-H₁ 426.2724, found 426.2734.

Example 9

1-(3-Ethyl-7-(pyrimidin-4-ylamino)-1-f2-(2.2.2-trifluoroethoxy)ethvn-1 H-pyrazolo[4,3-dlPyrimidin-5- yl)piperidine-3-carboxam ide

A mixture of the monochloride from Preparation 99 (0.250 g, 0.62 mmol), nipecotamide (0.338 g, 2.64 mmol) and 2-propanol (4.0 mL) were heated (175 ⁰C) in a sealed tube using a CEM Discover™ microwave reactor. After 60 min, the mixture was evaporated and the residue purified by column chromatography on silica gel using concentrated ammonium hydroxide/methanol/methylene chloride

(1/9/90) as the eluant to afford the title compound as a yellow solid (197 mg). ¹H NMR (400 MHz, CDCI₃) δ: 9.30 (br. s., 1 H), 8.84 (d, 1 H), 8.59 (d, 1 H), 8.19 (dd, 1 H), 6.48 (br. s., 1 H), 5.39 (br. s., 1 H), 4.67 (m, 2 H), 4.14 (m, 4 H), 3.96 (m, 3 H), 3.72 (m, 1 H), 2.89 (q, 2 H), 2.55 (m, 1 H), 2.12 (m, 1 H), 1.92 (m, 1 H), 1.68 (m, 2 H), 1.37 (t, 3 H); HRMS (ESI) calcd for C₂₁H₂₆F₃N₉O₂-I-H₁ 494.2234, found 494.2238. Examples 10-29

The following compounds were prepared following a similar procedure to that described in Example 9.

^a Isolated as a hydrochloride salt ^b Also isolated as the L-tartrate salt ^c Reaction temperature 100 ⁰C with constant irradiation and rxn time 4 h. Example 30

3-Ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-vh-N⁷-Dyrazin-2-yl-1 -r2-(2.2.2-trifluoroethoxy)ethvn-1 H-

Pyrazolof4.3-dlpvrimidine-5.7-diamine

Following the procedure of Example 9, using the monochloride of Preparation 78 and 4-amino-1-methyl- piperidine, the title compound was prepared. HRMS (ESI) calcd for C₂₂H₃₀F₃N₉OH-H₁ 494.2598, found 494.2580.

Example 31 3-Ethyl-5-r(3R)-3-methylpiperazin-1-yll-N-pyrazin-2-yl-1-r2-(2.2,2-trifluoroethoxy)ethyll-1 H-pyrazolo[4.3- dlPyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 78 and (R)-2- methylpiperazine, the title compound was prepared. HRMS (ESI) calcd for C₂₀H₂₆F₃N₉O-HH₁ 466.2285, found 466.2319.

Example 32

1-(3-Ethyl-7-(pyrazin-2-ylamino)-1-[2-(2.2.2-trifluoroethoxy)ethvn-1 H-pyrazolo[4,3-d1pyrimidin-5- yl)piperidine-3-carboxam ide

Following the procedure of Example 9, using the monochloride of Preparation 78 and nipecotamide, the title compound was prepared. HRMS (ESI) calcd for C₂₁H₂₆F₃N₉O₂^-H₁ 494.2234, found 494.2224. Example 33

(1-{3-Ethyl-7-(pyrazin-2-ylamino)-1-f2-(2,2.2-trifluoroethoxy)ethvπ-1 H-pyrazolor4.3-dlpyrimidin-5- yl)piperidin-4-yl)methanol

Following the procedure of Example 9, using the monochloride of Preparation 78 and 4- piperidinemethanol, the title compound was prepared. HRMS (ESI) calcd for C_2IH₂₇F₃N₈O₂H-H₁ 481.2282, found 481.2250.

Example 34 3-Ethyl-5-piperazin-1-yl-N-pyrazin-2-yl-1-[2-(2,2.2-trifluoroethoxy)ethyl1-1 H-pyrazolof4,3-d1pyrimidin-7- amine

Following the procedure of Example 9, using the monochloride of Preparation 78 and piperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₁₉H₂₄F₃N₈O₂-I-H₁ 452.2129, found 452.2153.

Example 35

3-Ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-N⁷-(4-methylpyridin-2-yl)-1-f2-(2,2,2-trifluoroethoxy)ethyl1-

1 H-pyrazolo[4.3-dlpvrimidine-5.7-diamine

Following the procedure of Example 9, using the monochloride of Preparation 84 and 4-amino-1-methyl- piperidine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₂₄H₃₃F₃N₈O+^ 507.2802, found 507.2789. Example 36

3-Ethyl-5-f(3RV3-methylpiperazin-1-vn-N-(4-methylDyridin-2-yl)-1 -r2-(2.2.2-trifluoroethoxy)ethyll-1 H- pyrazolo[4.3-d1pvrim idin-7-am ine

Following the procedure of Example 9, using the monochloride of Preparation 84 and (R)-2- methylpiperazine, the title compound was prepared. HRMS (ESI) calcd for 0₂₂H₂₉F₃N₈O+!-!_! 479.2489, found 479.2518.

Example 37 1-(3-Ethyl-7-[(4-methylpyridin-2-yl)amino1-1-r2-(2.2.2-trifluoroethoxy)ethvn-1 H-pyrazolor4.3-dipyrimidin-5- vl}piperidine-3-carboxam ide

Following the procedure of Example 9, using the monochloride of Preparation 84 and nipecotamide, the title compound was prepared. HRMS (ESI) calcd for C₂₃H₂₉F₃N₈O^H₁ 507.2438, found 507.2455.

Example 38

(1-(3-Ethyl-7-[(4-methylpyridin-2-yl)amino1-1-r2-(2.2,2-trifluoroethoxy)ethyll-1 H-pyrazolof4,3-dipyrimidin-5- vl)piperidin-4-yl)methanol

Following the procedure of Example 9, using the monochloride of Preparation 84 and 4- piperidinemethanol, the title compound was prepared. HRMS (ESI) calcd for C₂₃H₃₀F₃N₇O^H₁ 494.2486, found 494.2469. Example 39

3-Ethyl-N-(4-methylpyridin-2-yl)-5-piperazin-1-yl-1-f2-(2,2.2-trifluoroethoxy)ethyll-1H-pyrazolof4,3- dipyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 84 and piperazine, the title compound was prepared. HRMS (ESI) calcd for C₂₁H₂₇F₃N₈OH₁ 465.2333, found 465.2330.

Example 40

3-Ethyl-N-(4-fluorophenyl)-5-R3RV3-methylpiperazin-1 -yll-1-r2-(2.2.2-trifluoroethoxy)ethvn-1 H- pyrazolor4.3-dlpyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 82 and (fl)-2- methylpiperazine, the title compound was prepared. HRMS calcd for C₂₂H₂₇F₄N₇OH-H₁ 482.2286, found 482.2249.

Example 41

3-Ethyl-5-[(3RV3-methylpiperazin-1-yll-N-(6-methylpyridin-2-yl)-1-r2-(2.2.2-trifluoroethoxy)ethvn-1 H- pyrazolof4.3-dlpyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 80 and (fl)-2- methylpiperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₂₂H₂₉F₃N₈O-HH₁ 479.2489, found 479.2466. Example 42

1-(3-Ethyl-7-[(6-methylPyridin-2-yl)aminol-i-r2-(2,2.2-trifluoroethoxy)ethyll-1 H-pyrazolor4.3-dlPyrimidin-5- yllpiperidine-3-carboxam ide

Following the procedure of Example 9, using the monochloride of Preparation 80 and nipecotamide, the title compound was prepared. HRMS (ESI) calcd for C₂₃H₂₉F₃N₈O₂H-H₁ 507.2438, found 507.2465.

Example 43 (1-(3-Ethyl-7-r(6-methylpyridin-2-yl)aminol-1-f2-(2.2.2-trifluoroethoxy)ethvn-1 H-pyrazolof4.3-dlPyrimidin-5- yl)piperidin-4-yl)methanol

Following the procedure of Example 9, using the monochloride of Preparation 80 and 4- piperidinemethanol, the title compound was prepared. HRMS (ESI) calcd for C₂₃H₃₀F₃N₇O₂H-H₁ 494.2486, found 494.2461.

Example 44

3-Ethyl-N-(6-methylpyridin-2-yl)-5-piperazin-1 -yl-1-r2-(2,2.2-trifluoroethoxy)ethyll-1 H-pyrazolor4,3- dlpyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 80 and piperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₂₁H₂₇F₃N₈OH-H₁ 465.2333, found 465.2304. Example 45

3-Ethyl-N-(4-fluorophenvh-5-piperazin-1-yl-1-r2-(2,2.2-trifluoroethoxy)ethyll-1 H-pyrazolor4,3-cnpyrimidin-

7-amine

Following the procedure of Example 9, using the monochloride of Preparation 82 and piperazine, the title compound was prepared as a hydrochloride salt. HRMS calcd for C_2IH₂₅F₄N₇O+!-!_! 468.2129, found 468.2159.

Example 46 3-Ethyl-5-[(3R)-3-methylpiperazin-1-yll-N-pyridin-2-yl-1-r2-(2.2.2-trifluoroethoxy)ethyll-1 H-pyrazolor4.3- dipyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 81 and (R)-2- methylpiperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₂₁H₂₇F₃N₈C^H₁ 465.2333, found 465.2330.

Example 47

1-l3-Ethyl-7-(pyridin-2-ylamino)-1-[2-(2.2.2-trifluoroethoxy)ethvn-1 H-pyrazolor4,3-dlpyrimidin-5- yl)piperidine-3-carboxamide

Following the procedure of Example 9, using the monochloride of Preparation 81 and nipecotamide, the title compound was prepared. HRMS (ESI) calcd for C₂₂H₂₇F₃N₈(VH₁ 493.2282, found 493.2261. Example 48

(1-(3-Ethyl-7-(pyridin-2-ylamino)-1-r2-(2.2.2-trifluoroethoxy)ethvπ-1H-pyrazolof4.3-d1pyrimidin-5- vl)piperidin-4-vl)methanol

Following the procedure of Example 9, using the monochloride of Preparation 81 and 4- piperidinemethanol, the title compound was prepared. HRMS (ESI) calcd for 0₂₂H₂₈F₃N₇O₂H-H₁ 480.2329, found 480.2369.

Example 49 3-Ethyl-5-piperazin-1 -yl-N-pyridin-2-yl-1-f2-(2.2.2-trifluoroethoxy)ethyll-1 H-pyrazolof4.3-dipyrimidin-7- amine

Following the procedure of Example 9, using the monochloride of Preparation 81 and piperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₂₀H₂₅F₃N₈OH-H₁ 451.2176, found 451.2177.

Example 50

3-Ethyl-N⁷-(4-fluorophenylVN⁵-methyl-N⁵-(1-methylpiperidin-4-vn-1-r2-(2.2,2-trifluoroethoxy)ethvn-1 H- pyrazolor4,3-d1pyrimidine-5,7-diamine

Following the procedure of Example 9, using the monochloride of Preparation 82 and 4-amino-1-methyl- piperidine, the title compound was prepared as a hydrochloride salt. HRMS calcd for C₂₄H₃₁ F₄N₇OH-H₁ 510.2599, found 510.2616. - -

Example 51

3-Ethyl-5-r(3R)-3-methylpiperazin-1 -vn-N-(4-methylpyrimidin-2-yl)-1-[2-(2.2,2-trifluoroethoxy)ethyl1-1 H- pyrazolof4.3-cπpvrim idin-7-am ine

Following the procedure of Example 9, using the monochloride of Preparation 79 and (fl)-2- methylpiperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C_2I H₂₈F₃N₉OH-H₁ 480.2442, found 480.2472.

Example 52 1. 1-l3-Ethyl-7-r(4-methylpyrimidin-2-yl)aminoM-r2-(2,2,2-trifluoroethoxy)ethyll-1 H-pyrazolor4.3- dipyrimidin-5-yl)piperidine-3-carboxamide

Following the procedure of Example 9, using the monochloride of Preparation 79 and nipecotamide, the title compound was prepared. HRMS (ESI) calcd for C₂₂H₂₈F₃N₉O₂H-H₁ 508.2391 , found 508.2399.

Example 53

(1-(3-Ethyl-7-[(4-methylpyrimidin-2-yl)aminol-1-r2-(2.2.2-trifluoroethoxy)ethyll-1 H-pyrazolof4,3-d1pyrimidin-

5-yl)piperidin-4-yl)tnethanol

Following the procedure of Example 9, using the monochloride of Preparation 79 and 4- piperidinemethanol, the title compound was prepared. HRMS (ESI) calcd for C₂₂H₂₉F₃N₈O₂-I-H₁ 495.2438, found 495.2404. Example 54

3-Ethyl-N-(4-methylpyrimidin-2-yl)-5-piperazin-1-yl-1-r2-(2.2,2-trifluoroethoxy)ethvπ-1 H-pyrazolof4,3- dlpyrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 79 and piperazine, the title compound was prepared as a hydrochloride salt. HRMS (ESI) calcd for C₂₀H₂₆F₃N₉O+!-!, 466.2285, found 466.2317.

Example 55 1 -{3-Ethyl-7-(pyrimidin-4-ylamino)-1 -f2-(2.2.2-trifluoroethoxy)ethvπ-i H-pyrazolor4.3-dipvrimidin-5- yl)piperidine-3-carboxam ide

A mixture of the monochloride from Preparation 99 (0.246 g, 0.63 mmol), nipecotamide (0.248 g, 1.93 mmol) and 2-propanol (4.0 mL) were heated (175 ⁰C) in a sealed tube using a CEM Discover™ microwave reactor. After 60 min, the mixture was evaporated and the residue purified by column chromatography on silica gel using concentrated ammonium hydroxide/methanol/methylene chloride (1/9/90) as the eluant to afford the title compound as a yellow solid (189 mg). HRMS (ESI) calcd for C₂₀H₂₄F₃N₉O₂H-H₁ 480.2078, 480.2065.

Examples 56-59 The following compounds were prepared following a similar procedure to that described in Example 55.

Also isolated as the L-tartrate salt

Example 60

3-Ethyl-N-(4-methylphenyl)-5-piperazin-1-yl-1-[2-(2.2.2-trifluoroethoxy)ethvπ-1H-pyrazolof4.3-dlpyrimidin-

7-amine

Following the procedure of Example 9, using the monochloride of Preparation 83 and piperazine, the title compound was prepared as a hydrochloride salt. HRMS calcd for C₂₂H₂₈F₃N₇OH-H₁ 464.2380, found 464.2416.

Example 61 3-Ethyl-N-(4-methylphenvn-5-[(3R)-3-methylpiperazin-1-yll-1-[2-(2,2.2-trifluoroethoxy)ethyll-1 H- pyrazolor4,3-dipvrimidin-7-amine

Following the procedure of Example 9, using the monochloride of Preparation 83 and (R)-2- methylpiperazine, the title compound was prepared as a hydrochloride salt. HRMS calcd for C₂₃H₃₀F₃F₇OH-H₁ 478.2537, found 478.2567.

Example 62

3-Ethyl-N⁵-methyl-N⁷-(4-methylphenyl)-N⁵-(1 -methylpiperidin-4-yl)-1-r2-(2,2.2-trifluoroethoxy)ethyll-1 H- pyrazolo[4.3-dlpyrimidine-5.7-diamine

Following the procedure of Example 9, using the monochloride of Preparation 83 and 4-amino-1-methyl- piperidine, the title compound was prepared as a hydrochloride salt. HRMS calcd for C₂₅H₃₄F₃N₇OH-H 506.2850, found 506.2887. Example 63

N⁵-(2-Aminoethyl)-3-ethyl-N⁷-pyrimidin-4-yl-1-r2-(2,2₁2-trifluoroethoxy)ethyll-1 H-Dyrazolof4.3-dlDyrimidine-

5,7-diamine

The material from Example 28 (0.207 g, 0.39 mmol) in dichloromethane (20 ml.) was treated with trifluoroacetic acid (1.0 mL). After stirring for 3 h, the mixture was evaporated and the residue was purified by column chromatography on silica gel using concentrated ammonium hydroxide/methanol/methylene chloride (1/9/90) as the eluant to afford the title compound as a yellow solid (95 mg). HRMS calcd for C₁₇H₂₂F₃N₉OH-H₁ 426.1972, found 426.1990.

Example 64

1-(2-Ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1-yl1-N-(6-methylpyridin-2-yl)-1 H-pyrazolor4,3- dipvrimidin-7-amine

To a microwave reaction vessel was added 5-chloro-1-(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine from Preparation 57, procedure B (0.15 mmol), 1 -methyl-2-pyyrolidinone (2 mL), (fl)-2-methylpiperazine (3 eq.) and diisopropylethylamine (3eq.) The reaction mixture was irradiated in a microwave at 190 ⁰C for 1h. After cooling, ethyl acetate and water were added and the layers separated. The organic layer was washed with water twice and brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (42.4 mg). 1H NMR (400 MHz, CDCI₃) δ ppm 1.16 (d, J=6.18 Hz, 3 H) 1.28 (t, J=6.98 Hz, 3 H) 1.39 (t, Λ=7.65 Hz, 3 H) 2.46 (s, 3 H) 2.90 (q, J=7.52 Hz, 3 H) 2.93 (m, 3 H) 3.11 (m, 1 H) 3.66 (q, J=6.98 Hz, 2 H) 3.89 (dd, J=4.83, 4.03 Hz, 2 H) 4.58 (m, J=2.95 Hz, 2 H) 4.63 (m, 2 H) 6.80 (d, J=7.25 Hz, 1 H) 7.55 (t, J=7.79 Hz, 1 H) 8.00 (d, J=8.59 Hz, 1 H) 9.69 (s, 1 H); HRMS (ESI+) for C₂₂H₃₃N₈O m/z 425.2762 (M+H)⁺.

Examples 65-104

The following compounds were prepared using the method of Example 64, substituting (fl)-2- methylpiperazine with the appropriate amine and with the appropriate chloride from Preparations 60-68.

Example 105

1-(2-Ethoxyethyl)-3-ethyl-5-f(3R)-3-methylpiperazin-1-vn-N-(3-methylpyridin-2-yl)-1 H-pyrazolor4,3- dipyrimidin-7-amine

To a microwave reaction vessel was added 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl-1 H-pyrazolo[4,3- d]pyrimidine (Preparation 45, 2.75 mmol), 2-amino-3-picoline (2 eq.) and Λ/,Λ/-diisopropylethylamine (2 eq.) in N, Λ/-dimethylacetamide (2 mL). The mixture was irradiated in a microwave reactor at 150 ⁰C for 30 minutes. An aliquot of this reaction mixture (0.5 mL, 0.34 mmol) was placed in another microwave reaction vessel. To this solution was added (f?)-2-methylpiperazine (3 eq.) and 1 -methyl-2-pyrrolidinone (1 mL) and the solution was heated in a microwave at 190 ⁰C for 30 min. To the cooled reaction mixture was added 3 mL chloroform and 3 mL water. The layers were separated and the chloroform evaporated. The residue was dissolved in methanol and purified by RP-HPLC to afford the title compound at the hydrochloride salt (124.5 mg). HRMS (ESI+) for C₂₂H₃₃N₈O m/z 425.2751 (M+H)⁺.

Examples 106-168

The following compounds were prepared according to the method of Example 105, substituting 2-amino- 3-picoline and (fl)-2-methylpiperazine with the appropriate amines and 5,7-dichloro-1-(2-ethoxyethyl)-3- ethyl-1 H-pyrazolo[4,3-d]pyrimidine with the appropriate pyrazolopyrimidine (Preparations 43-56).

^b(fl)-2-methylpiperazine was replaced with tert-butyl piperidin-4-ylcarbamate. ^c(/?)-2-methylpiperazine was replaced with tert-butyl 4-(aminomethyl)piperidine-1 -carboxylate. ^d(/^:?)-2-methylpiperazine was replaced with tert-butyl 4-aminopiperidine-1-carboxylate.

Example 169

5-r(1 S.4S)-2.5-Diazabicvclor2.2.1lhept-2-yll-1 -(2-ethoxyethyl)-3-(methoxymethvn-N-pyridin-2-yl-1 H- pyrazolof4.3-dipyrimidin-7-amine

To a solution of the chloride (Preparation 100, 230 mg, 0.63 mmol) in dimethylsulfoxide (3 ml.) was added Λ/,Λ/-diisopropylethylamine (878 DL, 5.04 mmol) and (1 S,4S)-2,5-diazabicyclo[2.2.1]heptane (490 mg, 1.89 mmol). The resulting mixture was heated to 110 ⁰C in a sealed 4-dram vial for 36 h. The reaction was then diluted with water and extracted with dichloromethane (6X). The organic layer was dried by filtration through Whatman 1 PS phase separator paper and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel. Eluting with dichloromethane/methanol/ammonia (95:5 → 95:4:1) yielded the title compound (30 mg). ¹H-NMR (300 MHz, CDCI₃) δ 8.67 (d, 1 H, J = 6.6 Hz), 8.48 - 8.42 (m, 1 H), 8.37 (d, 1 H, J = 4.2 Hz), 8.12 (t, 1 H, J = 6.0 Hz), 8.06 - 7.96 (br s, 1 H), 7.36 - 7.13 (m, 1 H), 5.0 - 4.84 (m, 3H), 4.00 - 3.60 (m, 9H), 3.51 (s, 3H), 2.24- 2.08 (m, 2H), 1.16-1.08 (m, 2H), 1.04 (t, 3H, J = 5.4 Hz); HRMS m/z 425.2394 (calcd for M + H, 425.2408). Example 170

1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-[(3R)-3-methylpipera2in-1-vn-N-pyridin-2-yl-1 H-pyrazolor4.3- dipyrimidin-7-amine.

The title compound was prepared by the method of Example 169 using (2R)-2-methylpiperazine as the starting material. ¹H-NMR (300 MHz, CDCI₃) δ 9.81 (s, 1 H), 8.23 (d, 1 H, J = 3.6 Hz), 8.20 (d, 1 H, J = 8.4 Hz), 7.67 (dt, 1 H, J = 7.2, 1.8 Hz), 6.97 (dd, 1 H, J = 7.2, 5.4 Hz), 4.74 - 4.65 (m, 6H), 3.92 (t, 2H₁ J = 4.2 Hz), 3.63 (q, 2H, J = 6.9 Hz), 3.51 (s, 3H), 3.28 - 2.83 (m, 7H), 1.33 (d, 2H₁ J = 6.0 Hz), 1.21 (t, 3H, J = 6.9 Hz); HRMS m/z 427.2541 (calcd for M + H, 427.2564).

Example 171

5-r(1 S,4S)-2.5-Diazabicvclor2.2.nhept-2-yll-1-(2-ethoxyethylV3-(ethoxymethyl)-N-pyridin-2-yl-1 H- pyrazolof4.3-dipyrim idin-7-am ine

The title compound was prepared by the method described in Example 169 using 5-chloro-1-(2- ethoxyethyl)-3-(ethoxymethyl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared via Preparation 100 using sodium ethoxide in step 3) and 2,5-diazabicyclo[2.2.1]heptane as the reagents. Calculated Exact Mass: M+H 439.2564, found: 439.2523

Example 172

1-(2-Ethoxyethyl)-3-(ethoxymethyl)-5-r(3R)-3-methylpiperazin-1-vn-N-pyridin-2-yl-1 H-pyrazolof4.3- dipvrim idin-7-am ine.

- -

The title compound was prepared by the method described in Example 169 using 5-chloro-1-(2- ethoxyethyl)-3-(ethoxymethyl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared via Preparation 100 using sodium ethoxide in step 3) and (2R)-2-methylpiperazine as the starting material. ¹H-NMR (300 MHz, CDCI₃) δ 8.38 (s, 1 H), 8.10 (d, 1 H, J = 5.7 Hz), 7.80 - 7.68 (m, 1 H), 7.16 - 7.0 (m, 1 H), 4.85 - 4.60 (m, 8H), 4.2 - 3.9 (m, 2H), 3.84 - 3.60 (m, 5H), 3.58 - 3.48 (m, 2H), 1.61 (d, 3H, J = 5.4 Hz), 1.34 (m, 6H, J = 6.9 Hz); HRMS m/z 441.2707 (calcd for M + H, 441.2721).

Example 173

5-[(1S,4S)-2.5-Diazabicvclor2.2.nhept-2-yl1-1-(2-ethoxyethyl)-3-(ethoxymethyl)-N-pyrimidin-4-yl-1 H- pyrazolo[4.3-dlpyrimidin-7-amine.

The title compound was prepared by the method of Example 169 using 2,5-diazabicyclo[2.2.1]heptane and Preparation 101 as the starting materials. ¹H-NMR (400 MHz, (CDs)₂SO) δ 8.82 (d, 1 H, J = 1.2 Hz), 8.62 (d, 1 H, J = 6.0 Hz), 8.26 - 8.14 (br s, 1 H), 4.70 (s, 1 H), 4.65 (t, 2H, J = 4.8 Hz), 4.56 (s, 2H), 3.79 (t, 2H, J = 4.4 Hz), 3.65 (s, 1 H), 3.57 - 3.49 (m, 5H), 3.40 (d, 1 H, J = 10 Hz), 3.29 (s, 2H), 2.85 (AB quar, 2H, J = 8.0 Hz), 1.70 (AB quar, 2H, J = 8.4 Hz), 1.12 - 1.05 (m, 6H); HRMS m/z 440.2514 (calcd for M + H, 440.2517).

Example 174 1-(2-Ethoxyethyl)-3-(ethoxymethyl)-5-r(3R)-3-methylpiperazin-1 -yll-N-pyrimidin-4-yl-1 H-pyrazolof4.3- dlpvrimidin-7-amine.

The title compound was prepared by the method of Example 169 using (2R)-2-methylpiperazine and Preparation 101 as the starting materials. ¹H-NMR (400 MHz, (CD₃)₂SO) δ 8.83 (s, 1 H), 8.63 (d, 1 H, J = 6.0 Hz), 8.02 (d, 1 H, J = 6.0 Hz), 4.64 (t, 2H, J = 4.0 Hz), 4.58 (s, 2H), 4.38 (d, 2H, J = 12 Hz), 3.78 (t, 2H, J = 4.4 Hz), 3.56 - 3.49 (m, 5H), 2.94 (d, 1 H, J = 11.6 Hz), 2.85 - 2.79 (M, 1 H), 2.68 - 2.64 (m, 2H), 1.12 - 1.01 (m, 11 H); HRMS m/z 442.2688 (calcd for M + H₁ 442.2673). - -

Example 175

1-(2-Ethoxyethvh-N-(4-fluorophenyl)-3-(methoxymethyl)-5-f(3R)-3-methylpiperazin-1-vn-1 H-pyrazolo[4.3- dipyrimidin-7-amine.

The title compound was prepared by the method of Example 169 using (2R)-2-methylpiperazine and Preparation 104 as the starting material. LRMS m/z 444.1-445.1 (calcd for M+H, 444.5).

Example 176 δ-rd SΛS^^.δ-Diazabicvclo^^.ilhept^-vn-i^-ethoxyethvD^-fethoxymethvn-N-K-fluorophenvn-I H- pvrazolor4.3-dlpyrimidin-7-amine.

The title compound was prepared by the method of Example 169 using 2,5-diazabicyclo[2.2.1]heptane and Preparation 104 (substituting sodium ethoxide for sodium methoxide in step 2) as the starting material. ¹H-NMR (400 MHz, CDCI₃) δ 8.99 (s, 1 H), 7.60 - 7.57 (m, 2H), 7.03 (t, 2H, J = 8.4 Hz), 4.99 (s, 1 H), 4.74 (s, 2H), 4.65 (t, 2H, J = 4.4 Hz), 4.27 (s, 1 H), 3.94 (t, 2H, J = 4.4 Hz), 3.88-3.80 (m, 2H), 3.72 - 3.67 (m, 4H), 3.61 (quar, 2H, J = 6.8 Hz), 3.40 - 3.32 (m, 2H), 1.27 (t, 3H, J = 6.8 Hz), 1.17 (t, 3H, J = 6.8 Hz); LRMS m/z 456.1 - 457.1 (calcd for M+H, 456.5).

Example 177

1 -(2-Ethoxyethyl)-3-(ethoxymethyl)-N-(4-fluorophenyl)-5-f(3R)-3-methylpiperazin-1 -yl1-1 H-pyrazolor4.3- dipyrimidin-7-amine.

The title compound was prepared by the method of Example 169 using (2R)-2-methylpiperazine and Preparation 104 (substituting sodium ethoxide for sodium methoxide in step 2) as the starting materials. ¹H-NMR (400 MHz, CDCI₃) δ 8.91 (s, 1 H), 7.58 - 7.54 (m, 2H), 7.06 - 7.02 (m, 2H), 4.76 (s, 2H), 4.66 (t, 2H, J = 4.4 Hz), 4.60 - 4.55 (m, 2H), 3.93 (t, 2H, J = 4.4 Hz), 3.69 (quar, 2H, J = 7.2 Hz), 3.62 (quar, 2H, J = 7.2 Hz), 3.10 - 3.07 (m, 1 H), 2.98 - 2.81 (m, 3H), 2.61 - 2.53 (m, 5H), 1.28 (t, 3H, J = 6.8 Hz), 1.15 (t, 3H, J = 6.8 Hz); HRMS m/z 458.2697 (calcd for M + H, 458.2674).

Example 178

1-(2-Ethoxyethyl)-3-(ethoxymethyl)-5-((R)-3-methylpiperazin-1 -yl)-N-(4.6-dirnethylpyridin-2-yl)-1 H- pyrazolo[4.3-dlpvrim idin-7-am ine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (ethoxymethyl)-N-(4,6-dimethylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 but using 2-amino-4,6-dimethylpyridine in step 1) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) δ 7.82 (s, 1 H), 6.67 (s, 1 H), 4.76 - 4.68 (m, 6H), 3.93 - 3.90 (m, 2H), 3.72 - 3.62 (m, 4H), 3.50 - 3.43 (m, 2H), 3.39 - 3.37 (m, 1 H), 3.21 - 3.01 (m, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.46 (d, 3H, J = 6.0 Hz), 1.27 (t, 8H, J = 7.1 Hz); HRMS m/z 469.3060 (calcd for M + H, 469.3034).

Example 179 5-f(1S.4S)-2.5-Diazabicvclo[2.2.1lhept-2-yll-N-(4,6-dimethylpyridin-2-yl)-1-(2-ethoxyethyl)-3-

(ethoxymethyl)-1 H-pvrazolor4,3-d1pyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (ethoxymethyl)-N-(4,6-dimethylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 but using 2-amino-4,6-dimethylpyridine in step 1) and 2,5-diazabicyclo[2.2.1]heptane as starting materials. LRMS m/z 467.2 - 468.2 (calc for M+H, 467.2)

Example 180

1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(4.6-dimethylpyridin-2-yl)-1 H- pyrazolof4.3-dlpvrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (methoxymethyl)-N-(4,6-dimethylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100 but using 2-amino-4,6-dimethylpyridine in step 1) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) δ 7.92 (s, 1 H), 7.25 (s, 1 H), 4.72 - 4.63 (m, 6H), 3.91 (t, 2H, J = 4.6 Hz), 3.66 - 3.61 (m, 2H), 3.50 (s, 3H), 3.14 - 3.11 (m, 1 H), 3.00 - 2.90 (m, 3H), 2.65 - 2.63 (m, 1 H), 2.42 (s, 3H), 2.31 (s, 3H), 1.27 - 1.18 (m, 8H); HRMS m/z 455.2867 (calcd for M + H, 455.2877).

Example 181

5-r(1 S.4S)-2.5-Diazabicvclor2.2.1lhept-2-yll-N-(4.6-dimethylPyridin-2-yl)-1-(2-ethoxyethylV3- (methoxymethyl)-1 H-pyrazolof4.3-dipvrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1 -(2-ethoxyethyl)-3- (methoxymethyl)-N-(4,6-dimethylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100 but using 2-amino-4,6-dimethylpyridine in step 1) and 2,5-diazabicyclo[2.2.1]heptane as starting materials. ¹H NMR (CDCI₃) δ 8.06 (s, 1H), 7.25 (s, 1 H), 4.93 (s, 1H), 4.72 - 4.67 (m, 4H), 3.92 - 3.90 (m, 3H), 3.74 - 3.56 (m, 5H), 3.50 (s, 3H), 3.21 - 3.14 (m, 2H), 2.45 (s, 3H), 2.30 (s, 3H), 1.93 - 1.84 (m, 2H), 1.25 - 1.22 (m, 3H); HRMS m/z 453.2767 (calcd for M + H, 453.2721 ).

Example 182

1-(2-Ethoxyethyl)-3-(ethoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(4-methylpyridin-2-yl)-1 H-

Pvrazolo[4,3-dlpyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (ethoxymethyl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 , but substituting 2-amino-4-methylpyridine in step 1) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) δ 8.21 (s, 1 H), 8.18 (d, 1 H₁ J = 5.1 Hz), 6.78 (d, 1 H, J = 4.9 Hz), 4.77 (s, 2H), 4.69 - 4.64 (m, 3H), 3.92 - 3.89 (m, 2H), 3.72 - 3.60 (m, 4H), 3.16 - 3.14 (m, 1H), 3.01 - 2.91 (m, 3H), 2.68 - 2.63 (m, 1 H), 2.36 (s, 3H), 1.29 - 1.16 (m, 12H); HRMS m/z 453.2713 (calcd for M + H, 453.2721).

Example 183 1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(4-methylpyridin-2-yl)-1 H- pyrazolof4,3-dipyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (methoxymethyl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100, but substituting 2-amino-4-methylpyridine in step 1) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) δ 8.20 (s, 1 H), 8.18 (d, 1 H, J = 5.1 Hz), 6.79 (s, 1 H, J = 5.1 Hz), 4.73 - 4.64 (m, 6H), 3.92 - 3.89 (m, 2H), 3.61 (q, 2H₁ J = 7.1 Hz), 3,51 (s, 3H), 3.16 - 3.14 (m, 1 H), 3.05 - 2.92 (m, 3H), 2.67 (t, 1 H, J = 9.0 Hz), 2.36 (s, 3H), 1.24 - 1.16 (m, 6H); HRMS m/z 441.2726 (calcd for M + H, 441.2721).

Example 184

1-(2-Ethoxyethyl)-N-(6-ethylpyridin-2-yl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1 -Vl)-I H- pyrazolor.4,3-dipvrim idin-7-am ine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-N-(6- ethylpyridin-2-yl)-3-(methoxymethyl)-1 H-pyrazolo[4,3-d]pyrim idin-7-am ine (prepared following Preparation 100, but using 2-amino-6-ethylpyridine in step 1 ) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) δ 7.96 (d, 1 H, J = 8.1 Hz), 7.57 (t, 1 H, J = 7.8 Hz), 6.81 (d, 1 H, J = 7.6 Hz), 4.73 (s, 2H), 4.69 - 4.61 (m, 4H), 3.91 (t, 2H, J = 4.6 Hz), 3.65 (q, 2H, J = 7.1 Hz), 3.51 (s, 3H), 3.13 - 3.11 (m, 1 H), 3.05 - 2.88 (m, 3H), 2.75 - 2.60 (m, 3H), 1.30 - 1.25 (m, 7H), 1.18 (d, 3H, J = 6.3 Hz); HRMS m/z 455.2826 (calcd for M + H, 455.2877).

Example 185

5-[(1S,4S)-2,5-Diazabicvclor2.2.11hept-2-vn-1-(2-ethoxyethyl)-N-(6-ethylpyridin-2-yl)-3-(methoxymethyl)-

1 H-pyrazolor4.3-dlpyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-N-(6- ethylpyridin-2-yl)-3-(methoxymethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100, but using 2-amino-6-ethylpyridine in step 1 ) and 2,5-diazabicyclo[2.2.1]heptane as starting materials. ¹H NMR (CDCI₃) δ 8.13 (d, 1 H, J= 8.0 Hz), 7.57 (t, 1 H, J = 8.0 Hz), 6.81 (d, 1 H, 7.6 Hz), 4.91 (S₁ 1 H), 4.75 - 4.67 (m, 4H), 3.91 (t, 2H, J = 4.4 Hz), 3.83 (s, 1 H), 3.71 - 3.62 (m, 3H), 3.53 - 3.50 (m, 4H), 3.11 (q, 2H, J = 9.8 Hz), 2.72 (q, 2H, J = 7.6 Hz), 1.90 - 1.81 (m, 2H), 1.29 - 1.23 (m, 7H); HRMS m/z 453.2735 (calcd for M + H, 453.2721).

Example 186 1-(2-Ethoxyethyl)-3-(ethoxymethyl)-N-(6-ethylpyridin-2-yl)-5-((R)-3-rnethylpiperazin-1-yl)-1 H-pyrazolo[4.3- dlpyrimidin-7-amine.

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-N-(6- ethylpyridin-2-yl)-3-(methoxymethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100, but using 2-amino-6-ethylpyridine in step 1) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) § 7.96 (d, 1 H, J = 8.2 Hz), 7.57 (t, 1 H, J = 7.8 Hz), 6.82 (d, 1 H, J = 7.3 Hz), 4.76 (s, 2H), 4.68 - 4.60 (m, 4H), 3.92 - 3.91 (m, 2H), 3.74 - 3.62 (m, 4H), 3.17 - 2.93 (m, 7H), 2.76 - 2.65 (m, 4H), 1.31 - 1.20 (m, 9H); HRMS m/z 467.2909 (calcd for M + H, 467.2877).

Example 187 1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1 -yl)-N-(pyrimidin-4-yl)-1 H-pyrazolor4.3- dipvrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (methoxymethyl)-N-(pyrimidin-4-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 , but using sodium methoxide in step 2) and (R)-2-methylpiperazine as starting materials. ¹H NMR

(CDCI₃) § 8.86 (S, 1 H), 8.56 (d, 1 H, J = 5.9 Hz), 8.16 (d, 1 H, J = 5.9 Hz), 4.74 - 4.57 (m, 7H), 3.93 (t, 2H, J = 4.2 Hz), 3.69 - 3.62 (m, 2H), 3.51 (s, 3H), 3.17 - 2.89 (m, 6H), 2.69 - 2.61 (m, 2H), 1.26 - 1.08 (m, 3H); HRMS m/z 428.2484 (calcd for M + H, 28.2517).

Example 188 3-(Methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-1-(2-propoxyethyl)-N-(pyridin-2-yl)-1H-pyrazolor4.3- dlpvrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-3-(methoxymethyl)-1-(2- propoxyethyl)-N-(pyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100, but starting with Preparation 91 with R¹ = ethoxypropyl instead of ethoxyethyl) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) § 8.33 (d, 1 H, J = 3.3 Hz), 8.21 (d, 1 H, J = 8.4 Hz), 7.71 - 7.65 (m, 1 H), 6.99 - 6.95 (m, 1 H), 4.74 - 4.65 (m, 5H), 3.92 (t, 2H, J = 4.4 Hz), 3.55 - 3.45 (m, 5H), 3.25 - 3.17 (m, 2H), 3.13 - 2.98 (m, 2H), 2.86 - 2.78 (m, 1 H), 1.67 - 1.60 (m, 2H), 1.29 (d, 3H, J = 6.4 Hz), 0.77 (t, 3H, J = 7.3 Hz); HRMS m/z 441.2700 (calcd for M + H, 441.2721).

Example 189

1-(2-EthoxyethylV5-(4-ethylpiperazin-1-yl)-3-(methoxymethyl)-N-(pyrimidin-4-yl)-1 H-pyrazolof4.3- dipvrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1 -(2-ethoxyethyl)-3-

(methoxymethyl)-N-(pyrimidin-4-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 , but using sodium methoxide in step 2) and 1 -ethylpiperazine as starting materials. ¹H NMR (CDCI₃) § 8.85 (s, 1 H), 8.56 (d, 1 H, J = 5.9 Hz), 8.17 (d, 1 H, J = 5.3 Hz), 4.73 (s, 2H), 4.69 - 4.66 (m, 2H), 3.93 - 3.85 (m, 6H), 3.68 - 3.61 (m, 2H), 3.51 (s, 3H), 2.58 - 2.42 (m, 7H), 1.25 - 1.08 (m, 6H); HRMS m/z 442.2708 (calcd for M + H, 442.2673).

Example 190

3-(Ethoxymethyl)-5-((R)-3-methylpiperazin-1 -yl)-N-(6-methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H- pyrazolo[4.3-d1pyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-3-(ethoxymethyl)-N-(6- methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 , but using 2-amino-6-methylpyridine in step 1 and starting with Preparation 91 with R¹ = ethoxypropyl instead of ethoxyethyl) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) δ 7.95 (d, 1 H. J = 8.2 Hz),7.56 (t, 1 H, J = 7.7 Hz), 6.82 (d, 1H₁ J = 7.3 Hz), 4.77 (s, 2H), 4.71 - 4.62 (m, 4H), 3.92 (t, 2H, J = 4.4 Hz), 3.74 - 3.67 (m, 2H), 3.55 (t, 2H, J = 6.9 Hz), 3.20 - 2.95 (m, 3H), 2.78 - 2.70 (m, 1 H), 2.46 (s, 3H), 1.76 - 1.68 (m, 2H), 1.31 - 1.23 (m, 7H), 0.82 (t, 3H, J = 7.32 Hz); HRMS m/z 469.3019 (calcd for M + H, 469.3034).

Example 191 5-[(1 S,4S)-2,5-Diazabicvclor2.2.1lhept-2-yl1-3-(ethoxymethyl)-N-(6-methylpyridin-2-ylV1-(2-propoxyethyl)- 1 H-pyrazolo[4.3-dipyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-3-(ethoxymethyl)-N-(6- methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 but using 2-amino-6-methylpyridine in step 1 and starting with Preparation 91 with R¹ = ethoxypropyl instead of ethoxyethyl) and 2,5-diazabicyclo[2.2.1]heptane as starting materials. ¹H NMR (CDCI₃) § 8.11 (d, 1 H, J = 8.2 Hz), 7.55 (t, 1H₁ J = 7.9 Hz), 6.81 (d, 1H₁ J = 7.5 Hz),4.96 (b, 1 H), 4.79 (s, 2H), 4.69 (t, 2H, J = 4.3 Hz), 4.00 (b, 1 H), 3.92 (t, 2H, J = 4.6 Hz), 3.74 - 3.57 (m, 4H), 3.55 (t, 2H, J = 6.8 Hz), 3.25 - 3.20 (m, 2H), 2.45 (s, 3H), 1.95 - 1.93 (m, 2H), 1.74 - 1.67 (m, 2H), 1.27 (t, 3H, J = 6.9 Hz), 0.82 (t, 3H, J = 7.5 Hz); HRMS m/z 467.2853 (calcd for M + H, 467.2877). Example 192

5-f(1S,4S)-2.5-Diazabicvclor2.2.1lhept-2-vn-3-(ethoxymethylV1 -(2-propoxyethyl)-N-pyridin-2-yl-1 H- pyrazolor4,3-dipyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-3-(ethoxymethyl)-N-(6- methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100 but using sodium ethoxide in step 3 and starting with Preparation 91 with R¹ = ethoxypropyl instead of ethoxyethyl) and 2,5-diazabicyclo[2.2.1]heptane as starting materials. ¹H NMR (CDCI₃) δ 8.36 - 8.31 (m, 2H), 7.69 - 7.64 (m, 1 H), 6.97 - 6.93 (m, 1 H), 5.03 (b, 1 H), 4.76 (s, 2H), 4.70 (t, 2H, J = 4.0 Hz), 4.20 (b, 1 H), 3.93 (t, 2H, J = 4.6 Hz), 3.84 - 3.66 (m, 4H), 3.53 (t, 2H, J = 7.2 Hz), 3.34 (b, 1 H), 2.24 (s, 2H), 1.66 - 1.62 (m, 2H), 1.59 (t, 3H, J = 7.2 Hz), 0.76 (t, 3H, J = 7.5 Hz). HRMS m/z 453.2693 (calcd for M + H, 453.2721).

Example 193

3-(Methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(6-methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H- pyrazolor4.3-dlpyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-3-(ethoxymethyl)-1-(2- propoxyethyl)-N-(pyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 100 but using 2-amino-6-methylpyridine in step 1 and starting with Preparation 91 with R¹ = ethoxypropyl instead of ethoxyethyl) and (R)-2-methylpiperazine as starting materials. ¹H NMR (CDCI₃) § 7.94 (d, 1 H, J = 8.2 Hz)₁ 7.56 (t, 1 H, J = 7.7 Hz), 6.83 (d, 1 H₁ J = 7.3 Hz), 4.73 - 4.64 (m, 6H), 3.92 (t, 2H, J = 4.4 HZ), 3.57 - 3.47 (m, 6H), 3.23 - 2.76 (m, 4H), 2.46 (s, 3H), 1 ,76 - 1.66 (m, 2H), 1.28 (d, 3H, J = 6.4 Hz), 0.87 - 0.79 (m, 4H); HRMS m/z 455.2840 (calcd for M + H, 455.2877).

Example 194

5-r(1S.4S)-2.5-Diazabicvclor2.2.nhept-2-vn-1-(2-etrioxyethyl)-3-(ethoxymethyl)-N-(6-ethylpyridin-2-yl)-1 H- pvrazolor4.3-dlpyrimidin-7-amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3- (ethoxymethyl)-N-(6-ethylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following

Preparation 101 but starting with 2-amino-6-ethylpyridine) and 2,5-diazabicyclo[2.2.1]heptane as starting materials. ¹H NMR (CDCI₃) 58.08 (d, 1 H, J = 8.1 Hz), 7.57 (t, 1H, J = 7.8 Hz), 6.81 (d, 1 H, J = 7.6 Hz), 4.97 (b, 1 H), 4.75 (s, 2H), 4.73 (t, 2H, J = 7.3 Hz), 4.04 (b, 1 H), 3.92 (t, 2H, J = 4.6 Hz), 3.74 - 3.63 (m, 6H), 3.27 - 3.20 (m, 2H), 2.75 - 2.69 (m, 2H), 1.98 - 1.92 (m, 2H), 1.29 - 0.85 (m, 9H); HRMS m/z 467.2871 (calcd for M + H, 467.2877).

Example 195

1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-(piperazin-1-yl)-N-(pyrimidin-4-yl)-1 H-pyrazolor4.3-diPyrimidin-7- amine

The title compound was prepared by the method of Example 169 using 5-chloro-1-(2-ethoxyethyl)-3-

(methoxymethyl)-N-(pyrimidin-4-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (prepared following Preparation 101 but using sodium methoxide in step 2) and piperazine as starting materials. ¹H NMR (CDCI₃) § 8.84 (s, 1H), 8.55 (d, 1H, 5.9 Hz), 8.12 (d, 1H, J = 5.9 Hz), 4.72 (s, 2H), 4.67 (t, 2H, J = 4.6 Hz), 3.92 - 3.84 (m, 6H), 3.67 - 3.60 (m, 2H), 3.49 (s, 3H), 3.04 - 2.96 (m, 4H), 1.22 (t, 3H, J = 6.9 Hz); HRMS m/z414.2321 (calcd for M + H, 414.2360).

Example 196

3-(Ethoxymethyl)-5-[(3R)-3-methylpiperazin-1-yll-N-pyrimidin-4-yl-1-f2-(2,2,2-trifluoroethoxy)ethvn-1 H- pyrazolo[4.3-dlPvrimidin-7-amine trifluoroacetate - -

5-Chloro-3-(ethoxymethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin- 7-amine (Preparation 102, 80 mg, 0.185 mmol), (R)(-)-2-methylpiperazine (74 mg, 0.74 mmol) and N₁N- diisopropylethylamine (95.7 mg, 0.185 mmol) were mixed in methyl sulfoxide (0.5 ml) in a reaction vial. The reaction mixture was heated at 110 ⁰C for 18 hours. The reaction was cooled to room temperature and brought to acidic condition by adding trifluoroacetic acid. The crude reaction mixture was purified on reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) to give 3-(ethoxymethyl)- 5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine trifluoroacetate (25.9 mg, 0.04 mmol). ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.12 (bs, 1H), 8.99 (m, 1 H), 8.68 (m, 2H), 7.86 (m, 1 H), 4.70 (t, 2H, J = 4.9 Hz), 4.61 (s, 2H), 4.48 (m, 2H), 3.98 (q, 2H, J = 9.3 Hz), 3.90 (t, 2H, J = 4.9 Hz), 3.49 (q, 2H, J = 7.0 Hz), 3.30 (m, 3H), 3.11 (m, 2H), 1.22 (d, 3H, J = 6.44 Hz), 1.05 (t, 3H, J = 6.98 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.56 (t, 3F, J = 9.8 Hz). Calculated Exact Mass: M+H 496.2391 , found: 496.2364.

Example 197 5-r(i S,4S)-2.5-Diazabicvclor2.2.1lhept-2-vn-3-(ethoxymethylVN-pyrimidin-4-yl-1 -[2-(2.2.2- trifluoroethoxy)ethyl1-1 H-pyrazolo[4.3-dipyrimidin-7-amine trifluoroacetate

Example 197 was prepared by a method similar to that described in Example 196 using (1 S,4S)-(+)-2,5- diazabicyclo[2.2.1]heptane dihydrobromide in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃OD) δ: 8.84 (m, 1 H), 8.60 (m, 1 H), 8.28 (m, 1 H), 5.11 (s, 1 H), 4.73 (m, 2H), 4.51 (s, 2H), 4.10 (t, 2H, J=4.5 Hz), 4.03 (q, 2H, J=8.8 Hz), 3.83 (m, 2H), 3.61 (q, 2H, J=7.02 Hz), 3.44 (s, 2H), 2.18 (m, 2H), 1.18 (t, 3H, J=7.0 Hz). ¹⁹F NMR 400 MHz, (CD₃)₂SO) δ: -76.28 (t, 3F, J=8.6 Hz). Calculated Exact Mass: M+H 494.2234, found: 494.2196.

Example 198 tert-Butyl 4-(3-(ethoxymethyl)-7-(pyrimidin-4-ylamino)-1-r2-(2.2,2-trifluoroethoxy)ethvn-1 H-pyrazolor4.3- diPyrimidin-5-yl)piperazine-1-carboxvlate trifluoroacetate

Example 198 was prepared by a method similar to that described in Example 196 using tert-butyl piperazine-1-carboxylate in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 8.87 (bs, 1 H), 8.62 (m, 1 H), 7.89 (m, 1 H), 4.71 (t, 2H, J=5.0 Hz), 4.58 (s, 2H), 3.96 (q, 2H, J=9.3 Hz), 3.90 (t, 2H, J=5.0 Hz), 3.66 (m, 4H), 3.49 (q, 2H, J=7.0 Hz), 3.40 (m, 4H), 1.38 (s, 9H), 1.07 (t, 3H, J=7.0 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.54 (t, 3F, J=9.0 Hz). Calculated Exact Mass: M+H 582.2759, found: 582.2740.

Example 199

3-(Ethoxymethyl)-5-piperazin-1 -yl-N-pyrimidin-4-yl-1-r2-(2.2.2-trifluoroethoxy)ethyl1-1 H-pyrazolof4.3- dipyrim idin-7-am ine trif luoroacetate

The tert-butyl 4-{3-(ethoxymethyl)-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate trifluoroacetate (Example 198, 110 mg, 0.19 mmol) was treated with neat trifluoroacetic acid (4 ml). The reaction mixture was stirred 30 minutes at room temperature and then concentrated under vacuum. The concentrated residue was dissolved in 50% acetonitrile in water and freeze-dried to give 3-(ethoxymethyl)-5-piperazin-1-yl-N-pyrimidin-4-yl-1 -[2- (2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrim idin-7-am ine trifluoroacetate (99 mg, 0.1 mmol). ¹H NMR (400 MHz, (CD₃)₂SO) δ: 8.88 (bs, 1 H), 8.74 (bs, 2H), 8.59 (m, 1 H), 7.86 (m, 1 H), 4.73 (t, 2H, J=5.0 Hz), 4.58 (s, 2H), 3.93 (m, 8H), 3.49 (q, 2H, J=7.0 Hz), 3.17 (m, 4H), 1.07 (t, 3H, J=6.98 Hz). ¹⁹F NMR (400 MHz, (CDa)₂SO) δ: -73.57 (t, 3F, J=9.2 Hz). Calculated Exact Mass: M+H 482.2234, found: 482.2194.

Example 200

3-(Ethoxymethyl)-5-(4-methylpiperazin-1-yl)-N-pyrimidin-4-yl-1-f2-(2,2,2-trifluoroethoxy)ethyll-1 H- pyrazolo[4.3-dlpyrim idin-7-am ine trifluoroacetate

Example 200 was prepared by a method similar to that described in Example 196 using 1- methylpiperazine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 8.83 (m, 1 H), 8.60 (m, 1 H), 7.86 (m, 1 H), 4.74 (t, 2H, J=5.0 Hz), 4.57 (m, 4H), 3.98 (q, 2H, J=9.3 Hz), 3.91 (t, 2H, J=4.9 Hz), 3.48 (m, 4H), 3.2 (m, 2H), 3.15 (m, 2H), 2.80 (s, 3H), 1.07 (t, 3H, J=7.0 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.55 (t, 3F, J=9.8 Hz). Calculated Exact Mass: M+H 496.2391 , found: 496.2384.

Example 201

3-(Ethoxymethyl)-5-r(3S)-3-methylpiperazin-1-yll-N-pyrimidin-4-yl-1 -f2-(2.2.2-trifluoroethoxy)ethvn-1 H-

Pyrazolof4.3-dlpyrimidin-7-amine trifluoroacetate

Example 201 was prepared by a method similar to that described in Example 196 using (S)(+)-2- methylpiperazine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.10 (bs, 1 H), 8.96 (m, 1 H), 8.65 (m, 2H), 7.87 (m, 1 H), 4.69 (t, 2H, J=5.0 Hz), 4.60 (s, 2H), 4.48 (m, 2H), 3.83 (m, 4H), 3.47 (q, 2H, J=7.0 Hz), 3.25 (m, 3H), 3.03 (m, 2H), 1.21 (d, 3H, J=6.4 Hz), 1.03 (t, 3H, J=6.98 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.56 (t, 3F, J=9.0 Hz). Calculated Exact Mass: M+H 496.2391 , found: 496.2433.

Example 202

N⁵-[2-(Dimethylamino)ethvn-3-(ethoxymethyl)-N⁵-methyl-N⁷-pyrimidin-4-yl-1-r2-(2.2.2- trifluoroethoxy)ethyll-1 H-pyrazolor4.3-dlpyrimidine-5,7-diamine trifluoroacetate

- -

Example 202 was prepared by a method similar to that described in Example 196 using N, N, N'- trimethylethylenediamine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.26 (bs, 1 H), 9.11 (m, 1 H), 8.67 (m, 1 H), 7.90 (m, 1 H), 4.70 (t, 2H, J=4.6 Hz), 4.61 (s, 2H), 3.90 (m, 6H), 3.45 (m, 2H), 3.31 (m, 2H), 3.12 (s, 3H), 2.82 (s, 6H), 1.03 (t, 3H, J=6.8 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: - 73.47 (t, 3F, J=9.2 Hz).

Calculated Exact Mass: M+H 498.2547, found: 498.2578.

Example 203

3-(Ethoxymethvπ-N-7-pyrimidin-4-yl-N-5-(2,2.6.6-tetramethylpiperidin-4-yl)-1-[2-(2,2.2- trifluoroethoxy)ethvH-1 H-pyrazolor4.3-d1pyrimidine-5.7-diamine trifluoroacetate

Example 203 was prepared by a method similar to that described in Example 196 using 4-amino-2,2-6,6- tetramethylpiperidine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 8.98 (bs,1 H), 8.67 (m, 2H), 8.59 (m, 1 H), 7.98 (m, 1 H), 7.77 (m, 1 H), 4.84 (m, 2H), 4.60 (s, 2H), 4.32 (m, 1 H), 3.94 (m, 4H), 3.49 (q, 2H, J=7.0 Hz), 2.05 (m, 2H), 1.52 (m, 2H), 1.33 (m, 12H),1.07 (t, 3H, J=7.0 Hz). ¹⁹F NMR (400 MHz, (CD₃J₂SO) δ: -73.53 (t, 3F, J=9.2 Hz). Calculated Exact Mass: M+H 552.3017, found: 552.3035.

Example 204

1-{3-(Ethoxymethyl)-7-(pyrimidin-4-ylamino)-1-f2-(2₁2,2-trifluoroethoxy)ethyll-1 H-pyrazolor4.3-diPyrimidin- 5-yl)piperidin-4-ol trifluoroacetate

Example 204 was prepared by a method similar to that described in Example 196 using 4- hydroxypiperidine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.04 (bs, 1 H), 8.66 (m, 1 H), 7.88 (m, 1 H), 4.75 (t, 2H, J=5.0 Hz), 4.61 (s, 2H), 4.07 (m, 2H), 3.9 (m, 4H), 3.74 (m, 1 H), 3.46 (q, 2H, J=7.0 Hz), 3.39 (m, 2H), 1.79 (m, 2H), 1.41 (m, 2H), 1.04 (t, 3H, J=7.0 Hz). ¹⁹F NMR (400 MHz, (CDa)₂SO) δ: -73.54 (t, 3F, J=9.2 Hz). Calculated Exact Mass: M+H 497.2231 , found: 497.2191. Example 205

(1-l3-(Ethoxymethyl)-7-(pyrimidin-4-ylamino)-1-[2-(2.2.2-trifluoroethoxy)ethvπ-1 H-ρyrazolor4.3-dlpyrimidin-

5-yl)piperidin-4-vl)methanol trifluoroacetate

Example 205 was prepared by a method similar to that described in Example 196 using 4- piperidinemethanol in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.04 (m, 1 H), 8.65 (m, 1 H), 7.88 (m, 1 H), 4.76 (m, 2H), 4.61 (s, 2H), 4.46 (m, 2H), 4.07 (m, 2H), 3.87 (m, 4H), 3.46 (m, 2H), 3.23 (d, 2H, J=6.0 Hz), 3.00 (m, 2H), 1.72 (m, 2H), 1.16 (m, 2H), 1.04 (t, 3H, J=7.0 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.54 (t, 3F, J=9.6 Hz). Calculated Exact Mass: M+H 511.2387, found:: 511.2364.

Example 206

3-(lsopropoxymethyl)-5-[(3R)-3-methylpiperazin-1-vn-N-pyrimidin-4-yl-1-f2-(2.2.2-trifluoroethoxy)ethvn-1 H- pyrazolof4.3-dipyrimidin-7-amine trifluoroacetate

Example 206 was prepared by a method similar to that described in Example 196, using sodium isopropoxide in place of sodium ethoxide and 2-propanol in place of ethanol in Preparation 102 (step 2). ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.10 (m, 1 H), 8.87 (m, 1 H), 8.68 (m, 2H), 7.86 (d, 1 H), 4.70 (t, 2H, J=4.9 Hz), 4.61 (s, 2H), 4.48 (m, 2H), 3.86 (m, 4H), 3.71 (m, 1 H), 3.28 (m, 3H), 3.04 (m, 2H), 1.22 (d, 3H, J=6.4 Hz), 1.07 (d, 6H, J=6.0 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.54 (t, 3F, J=9.2 Hz); Calculated Exact Mass: M+H 510.2547, found: 510.2521.

Example 207 teff-Butyl 4-(3-(isopropoxymethyl)-7-(pyrimidin-4-ylaminoM -r2-(2.2.2-trifluoroethoxy)ethyll-1 H- Pyrazolo[4,3-dipyrimidin-5-yl)piperazine-1-carboxvlate trifluoroacetate

Example 207 was prepared by a similar to that Example 196 using sodium isopropoxide in place of sodium ethoxide and 2-propanol in place of ethanol in Preparation 102 (step 2) and 1 -boc-piperazine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.85 (m, 1 H), 8.81 (s, 1 H), 8.60 (m, 1 H), 7.90 (m, 1 H), 4.70 (m, 2H), 4.57 (s, 2H), 3.95 (q, 2H, J=9.30 Hz), 3.90 (t, 2H, J=4.9 Hz), 3.68 (m, 5H), 3.40 (m, 4H), 1.38 (s, 9H), 1.08 (d, 6H, J=6.0 Hz); ¹⁹F NMR (400 MHz, (CDa)₂SO) δ: -73.51 (t, 3F, J=9.2 Hz); Calculated Exact Mass: 596.2915, found: 596.2877.

Example 208

3-(lsopropoxymethyl)-5-piperazin-1 -yl-N-pyrimidin-4-yl-1-r2-(2,2.2-trifluoroethoxy)ethyll-1 H-pyrazolof4.3- diPyrimidin-7-amine trifluoroacetate

Example 208 was prepared by a method similar to that described in Example 199. ¹H NMR (400 MHz, (CD₃J₂SO) δ: 9.92 (s, 1 H), 8.12 (s, 1 H), 8.78 (m, 2H), 8.57 (m, 1 H), 7.86 (m, 1 H), 4.73 (t, 2H, J=5.0 Hz), 4.58 (s, 2H), 3.98 (m, 2H), 3.90 (m, 2H), 3.86 (m, 4H), 3.70 (m, 1 H), 3.18 (m, 4H), 1.08 (d, 6H, J=6.0 Hz). ¹⁹F NMR (400 MHz, (CD₃J₂SO) δ: -73.55 (t, 3F, J=9.2 Hz). Calculated Exact Mass: 496.2391 , found: 496.2358.

Example 209 5-f(3R)-3-Methylpiperazin-1 -yl1-N-pyrimidin-4-yl-1-r2-(2.2.2-trifluoroethoxy)ethyll-3-r(3.3.3- trifluoropropoxy)methvn-1 H-pyrazolo[4,3-d1pyrimidin-7-amine trifluoroacetate

Example 209 was prepared by a method similar to that described in Example 196 using sodium trifluoropropoxide in place of sodium ethoxide and tetrahydrofuran in place of ethanol in Preparation 102 (step 2). ¹H NMR (400 MHz, CD₃OD) δ: 8.82 (s, 1 H), 8.59 (m, 1 H), 8.12 (m, 2H), 4.78 (m, 6H), 4.08 (t, 2H, J=4.6 Hz), 4.02 (q, 2H, J=8.9 Hz), 3.78 (t, 2H, J=6.5 Hz), 3.44-3.26 (m, 5H), 2.44 (m, 2H), 1.38 (d, 3H, J=6.6 Hz). ¹⁹F NMR (400 MHz, CD30D) δ: -66.67(t, 3F, J=10.7 Hz), -76.30 (t, 3F, J=9.2 Hz). Calculated Exact Mass: 564.2265, found: 564.2240.

Example 210 5-r(3R)-3-Methylpiperazin-1 -vn-N-pyrimidin-4-yl-1-f2-(2,2,2-trifluoroethoxy)ethvn-3-r(2,2.2- trifluoroethoxy)methyl1-1 H-pyrazolor4.3-dipyrimidin-7-amine

5-Chloro-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(2,2,2-trifluoroethoxy)methyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine (Preparation 105, 0.280 g, 0.576 mmol) and ( R )-(-)-2-methylpiperazine (0.232 gm, 2.31 mmol, 4 equivalents ) are combined in a 10 mL reacti-vial with a spin vane stirrer along with DMSO ( 5 mL) and diisopropylethylamine ( 0.311 mL, 2.31 mmol, 4 equivalents ). The reaction mixture was heated to 120 °C in a sand bath for 12 hours. The desired product was isolated by preparative rphplc (C18: solvent program: 95:5 water: acetonitrile both 0.05% TFA to 10:90 over 40 minutes at 254 nm) and the product isolated as a solid TFA salt by lyophilization ( 201 mg ). ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.83 (bs, 1 H), 8.64 (bs, 1 H), 7.98 (bs, 1 H), 4.87 (s, 2H), 4.85 (m, 2H), 3.97 (m, 4H). ¹⁹F NMR (DMSO, 400 MHz) δ: -73.14(t, 3F), -73.60 (t, 3F), - 74.31 (s, 3F). Calculated MS: m/z 550.48 (MH⁺), found: 550.2.

Example 211 tert-Butyl 4-{7-(pyrimidin-4-ylamino)-1-f2-(2.2.2-trifluoroethoxy)ethyl1-3-r(2.2,2-trifluoroethoxy)methvn-1 H- pyrazolor4.3-dlpyrim idin-5-yl)piperazine-1 -carboxylate

The title compound was prepared in s fashion to Example 210 by substituting an equivalent quantity of 1-BOC-piperazine for (R)-(-)-2-methylpiperazine. ¹H NMR (d₆-DMSO, 400 MHz) δ: 8.93 (s, 1 H), 8.64 (m, 1H), 8.18 (m, 1 H), 4.90 (s, 2H), 4.06 (m, 6H), 3.82 (m, 4H), 3.54 (bs, 4H), 1.46 (s, 9H). ¹⁹F NMR (DMSO-d₆, 400 MHz): -76.36 (m, 6F), - 77.85 (s, 3F). Calculated MS: m/z 636.57 MH⁺:, found: 636.6 MH⁺.

Example 212

5-Piperazin-1-yl-N-pyrimidin-4-yl-1 -f2-(2.2.2-trifluoroethoxy)ethyll-3-r(2.2.2-trifluoroethoxy)methyll-1 H- pyrazolor4.3-dlpyrimidin-7-amine

tert-Butyl 4-{7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(2,2,2-trifluoroethoxy)methyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1 -carboxylate (57 mgs ) from Example 211 was treated with neat trifluoroacetic acid (10 ml_). After one hour the reaction was complete by analytical rphplc. Volatiles were removed in vacuo and the residue lyophilized to obtain a yellow solid (60 mg TFA salt). Calculated MS: m/z 536.55 (MH⁺), found: 536.4 MH⁺.

Example 213

5-r(3S)-3-Methylpiperazin-1 -vn-N-pyrimidin-4-yl-1-f2-(2.2.2-trifluoroethoxy)ethvn-3-r(2.2.2- trifluoroethoxy)methyll-1 H-pyrazolor4.3-dlpyrimidin-7-amine

The title product was obtained by substituting an equivalent quantity of (S)-(+)-2-methylpiperazine for (R)- (-)-2-methylpiperazine in Example 210. Spectral data was identical to Example 210.

Example 214 3-r(Cvclopropylmetrioxy)methyl1-5-f(3S)-3-methylpiperazin-1-yll-N-pyrimidin-4-yl-1 -f2-(2.2.2- trifluoroethoxy)ethyl1-1 H-pyrazolor4.3-dlpyrimidin-7-amine

Example 214 was prepared by a method similar to that described in Example 196 using sodium cyclopropylmethoxide in place of sodium ethoxide and tetrahydrofuran in place of ethanol in Preparation 102 (step 2) and (S)(+)-2-methylpiperazine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) 8: 9.91 (bs, 1 H), 8.96 (m, 1 H), 8.82 (s, 1 H), 8.65 (m, 1 H), 8.59 (m, 1 H), 7.85 (m, 1 H), 4.73 (t, 2H, J=5.0 Hz), 4.61 (s, 2H), 4.49 (m, 2H), 3.98 (q, 2H, J=9.30), 3.90 (t, 2H, J=4.9Hz), 3.38-3.19 (m, 5H), 3.08-2.97 (m, 2H), 1.23 (d, 3H, J=6.4 Hz), 0.98-0.94 (m, 1 H), 0.43-0.38 (m, 2H), 0.13-0.1 (m, 2H). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.55 (t, 3F, J=9.2 Hz). Calculated Exact Mass: M+H 522.2547, found: 522.2516.

Example 215

3-r(Cvclopropylmethoxy)methyll-5-piperazin-1 -yl-N-pyrimidin-4-yl-1-r2-(2.2.2-trifluoroethoxy)ethyll-1 H- pvrazolor4.3-dlpyrimidin-7-amine

Example 215 was prepared by a method similar to that described in Example 196 using sodium cyclopropylmethoxide in place of sodium ethoxide and tetrahydrofuran in place of ethanol in Preparation 102 (step 2) and piperazine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.14 (bs, 1 H), 8.82 (m, 2H), 8.68 (m, 1 H), 7.89 (m, 1 H), 4.72 (t, 2H, J=5.0 Hz), 4.65 (s, 2H), 3.91-3.85 (m, 8H), 3.30 (d, 2H, J=6.7 Hz), 3.19 (m, 4H), 0.97 (m, 1 H), 0.42-0.40 (m, 2H), 0.12-0.10 (m, 2H). ¹⁹F NMR (400 MHz, (CDa)₂SO) δ: -73.55 (t, 3F, J=9.2 Hz). Calculated Exact Mass: M+H 508.2391 , found: 508.2398.

Example 216

3-r(Cvclopropylmethoxy)methyll-5-r(3R)-3-methylpiperazin-1-vn-N-pyrimidin-4-yl-1-r2-(2.2.2- trifluoroethoxy)ethyll-1 H-pyrazolor4,3-dlpyrimidin-7-amine

Example 216 was prepared by a method similar to that described in Example 196 using sodium cyclopropylmethoxide in place of sodium ethoxide and tetrahydrofuran in place of ethanol in Preparation 102 (step 2). ¹H NMR (400 MHz, (CD₃OD) δ: 8.82 (bs, 1 H), 8.59 (m, 1 H), 8.12 (m, 1 H), 4.09-3.99 (m, 4H), 3.48-3.06 (m, 9H), 1.38 (d, 3H, J=6.6 Hz), 1.06-1.02 (m, 1 H), 0.51-0.47 (m, 2H), 0.19-0.16 (m, 2H). ¹⁹F NMR (400 MHz, (CDg)₂SO) δ: -73.55 (t, 3F, J=8.8 Hz). Calculated Exact Mass: M+H 522.2547, found: 522.2504.

Example 217

5-r(3R)-3-Methylpiperazin-1 -vn-N-pyrimidin-4-yl-3-r(4,4,4-trifluorobutoxy)methvn-1-r2-(2,2.2- trifluoroethoxy)ethvn-1 H-pvrazolor4.3-dlpyrimidin-7-amine

Example 217 was prepared by a method similar to that described in Example 196 using sodium 4,4,4- trifluorobutoxide in place of sodium ethoxide and tetrahydrofuran in place of ethanol in Preparation 102 (step 2). ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.23 (bs, 1 H), 8.96 (m, 1 H), 8.69-8.64 (m, 2H),7.87 (m, 1 H), 4.69 (t, 2H, J=5.1 Hz), 4.62 (s, 2H), 4.51-4.73 (m, 2H), 3.82-3.76 (m, 4H), 3.49 (t, 2H, J=6.0 Hz), 3.31- 3.21 (m, 3H), 3.05-2.99 (m, 2H), 2.18-2.11 (m, 2H), 1.69-1.62 (m, 2H), 1.19 (d, 3H, J= 6.4 Hz). ¹⁹F NMR (400 MHz, (CDa)₂SO) δ: -73.59 (t, 3F, J=9.2 Hz), -65.27 (t, 3F, J=11.7 Hz). Calculated Exact Mass: M+H 578.2421 , found: 578.2420. Example 218

5-Piperazin-1-yl-N-pyrimidin-4-yl-1-r2-(2.2.2-trifluoroethoxy)ethyl1-3-r(3.3.3-trifluoropropoxy)methyll-1 H-

Pyrazolor4.3-dlpyrimidin-7-amine

Example 218 was prepared by a method similar to that described in Example 196 using sodium 3,3,3- trifluoropropoxide in place of sodium ethoxide and tetrahydrofuran in place of ethanol in Preparation 102 (step 2) and piperazine in place of (R)(-)-2-methylpiperazine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.12 (bs, 1 H), 8.80 (m, 2H), 8.67-8.65 (m, 1 H),7.89-7.88 (m, 1 H), 4.71 (t, 2H, J=5.0 Hz), 4.66 (s, 2H), 3.89-3.83 (m, 8H), 3.69 (t, 2H, J=6.4 Hz), 3.16 (m, 4H), 2.48 (m, 2H). ¹⁹F NMR (400 MHz, (CD₃J₂SO) δ: -73.59 (t, 3F, J=9.6 Hz), -63.47 (t, 3F, J=11.7 Hz). Calculated Exact Mass: M+H 550.2108, found: 550.2080.

Example 219 1.3-ά/s-(2-Ethoxyethyl)-N⁵.N⁵-dimethyl-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolor4.3-dlPyrimidine-5,7-diamine

3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N⁵,N⁵-dimethyl-N⁷-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidine- 5,7-diamine prepared in Preparation 148 may be converted to 1 ,3-b/s-(2-ethoxyethyl)-N⁵,N⁵-dimethyl-N⁷- (4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine by treating the chloride with sodium ethoxide according to the procedure of Preparation 101 , step 2. ^•

PREPARATIONS Starting Materials

The following pyrazoles were used as starting materials: 5-Methyl-4-nitro-2H-pyrazole-3-carboxamide (US 4,282,361 , ex. 7) 5-Ethyl-4-nitro-2/-/-pyrazole-3-carboxamide (WO 02/10171 , pg. 17, prep. 1, synthesis j.) 4-Nitro-5-propyl-2H-pyrazole-3-carboxamide (WO 02/10171 , pg. 17, prep. 1 , synthesis k.) 5-lsopropyl-4-nitro-2H-pyrazole-3-carboxamide - see Preparation 1 4-Nitro-2W-pyrazole-3-carboxamide - (WO 2000024745) Preparation 1

5-lsopropyl-4-nitro-2/-/-pyrazole-3-carboxamide

A solution of 5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (Farmaco, 46, 11, 1991, 1337-1350) (6g, 0.03mol) in Λ/,Λ/-dimethylformamide (69μL) and dichloromethane (67 mL) was cooled to -5°C in ice/acetone. Oxalyl chloride (11.48g, 0.09mol) was added over 30 minutes and the reaction mixture stirred for 1 hour, the reaction mixture was then allowed to return to room temperature for 2 hours. The reaction mixture was concentrated in vacuo and remaining solvent azeotroped with dichloromethane. The resulting solid was suspended in tetrahydrofuran (7OmL), cooled to 0⁰C and 0.880 ammonia (25mL) added. The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The resulting solid was suspended in water, filtered and dried at 70⁰C under vacuum to yield the product. ¹H NMR (DMSOd₆, 400 MHz) δ: 1.28 (d, 6H), 3.55 (m, 1 H), 7.59 (s, 1 H), 7.89 (s, 1 H), 13.72 (br s, 1 H). LRMS:m/z ES+ 199 [MH]⁺ Preparations 2 to 14

Potassium carbonate (1eq) and the appropriate R⁶Br (1eq) were added to a solution of the appropriate pyrazole (see above starting materials) (1eq) in Λ/,Λ/-dimethylformamide (2-3mL.mmor¹) and the reaction mixture stirred under nitrogen at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water, the organic phase dried over magnesium sulphate and concentrated in vacuo. The crude product was purified using column chromatography on silica gel eluting with ethyl acetate:pentane 50:50 to 100:0 to yield the desired products.

'made using 1-(2-bromoethoxy)propane (EP 1072595)

'made using 1 -ethoxy-3-iodopropane (EP 319479 pg21 ex. 23) made using 2-(2-bromoethoxy)propane (FR 2638745 pg7 ex. 4.1)

Preparations 15 to 28

Ammonium formate (5eq) was added portionwise to a suspension of 10% palladium(ll) hydroxide on carbon (10% w/w) and the required 4-nitro pyrazole (1eq) in ethanol (4-5mL.mmol^'1) and the reaction mixture refluxed under nitrogen for 2 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol and the filtrates concentrated in vacuo. If present, remaining ethanol was azeotroped with toluene, yielding the desired product.

Preparations 29 to 42

A mixture of the appropriate 4-aminopyrazole-5-carboxamide (see Preparations 15-28) (1eq) and carbonyl diimidazole (1eq) in Λ/,Λ/-dimethylformamide (3.8mL.mmol^"1) was stirred under nitrogen at room temperature for 1 hour. The reaction was then heated at 80⁰C for 18 hours. The reaction mixture was concentrated in vacuo and the residue triturated with acetone. The resulting solid was filtered and dried to give the required product.

Preparations 43 to 56

Method A (Preparations 43. 46, 47. 49 and 56V Λ/-ethyldiisopropylamine (2-2.5eq) was added to a solution of the appropriate dione (see Preparations 29, 32, 33, 35 and 41) (1eq) in phosphorous oxychloride (3mL.mmol^'1) and the resulting solution heated under reflux for 18 hours. The cooled mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (3.5mL.mmor¹) and carefully washed with water (3.5mLmmol^"1). The organic solution was evaporated in vacuo and the crude product purified by column chromatography on silica gel using ethyl acetate:pentane (20:80 to 60:40) to give the required compound.

Method B (Preparations 44. 45. 48. 50. 51. 52, 53 and 54): Tetraethylammonium chloride (3eq) and phosphorous oxychloride (15 eq) were added to a solution of the appropriate dione (see Preparations 30, 31 , 34, 36-39 and 42) (1eq) in acetonitrile (5-10mL.mmol ¹) and the resulting solution heated under reflux for 18 hours. The cooled mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (3.5mL.mmol^"1) and carefully washed with water (3.5mL.mmor¹). The organic solution was evaporated in vacuo and the crude product purified by column chromatography on silica gel using ethyl acetate:pentane (20:80 to 60:40) to give the required compound.

Under N₂, a mixture of the compound from Preparation 45 (1.40 g, 4.8 mmol), 2-amino-4-methylpyridine (2.62 g, 24.2 mmol) in dichloromethane (10 mL) was heated using a 40 ⁰C aluminum heating block. After 2 h, Λ/,Λ/-diisopropylethylamine (0.9 mL) was added. After 18 h, the mixture was treated with water and dichloromethane. The layers were partitioned, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as the eluant to afford the title compound as an orange solid, 0.55 g. ¹H NMR (400 MHz, CDCI₃) δ 10.04 (br s, 1 H), 8.38 (s, 1 H), 8.19 (d, 1 H), 6.88 (d, 1 H), 4.76 (m, 2 H), 3.93 (m, 2 H), 3.64 (m, 2 H), 3.00 (q, 2 H), 2.45 (s, 3 H), 1.40 (t, 3 H), 1.18 (t, 3 H); LRMS: m/z(ESI+) 361 [MH]⁺

Preparation 57, Procedure B

5-Chloro-1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-ylV1 H-pyrazolor4.3-cnpyrimidin-7-amine

To a microwave reaction vessel was added 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl-1 H-pyrazolo[4,3- d]pyrimidine (Preparation 45, 2.76 mmol), 2-amino-4-picoline (2 eq.) and Λ/,Λ/-diisopropylethylamine (2 eq.) in N, Λ/-dimethylacetamide (2 ml_). The mixture was irradiated in a microwave reactor at 150 °C for 30 minutes. The reaction mixture was cooled and ethyl acetate and water were added. The layers were separated and the organics were washed with water twice and brine, dried over magnesium sulfate, filtered and evaporated to afford the title product (980 mg). 1 H NMR (400 MHz, CDCI₃) δ ppm 1.18 (t, J=7.12 Hz, 3 H) 1.39 (t, J=7.65 Hz, 3 H) 2.43 (s, 3 H) 2.99 (q, J=7.61 Hz, 2 H) 3.64 (q, J=6.98 Hz, 2 H) 3.92 (t, J=4.56 Hz, 2 H) 4.72 (t, J=4.57 Hz, 2 H) 6.85 (d, J=4.83 Hz, 1 H) 8.19 (d, J=5.10 Hz, 1 H) 8.32 (s, 1 H) 9.98 (s, 1 H). MS (ESI+) for m/z 361 , 363 (M+H)⁺.

Preparations 58-59

The following compounds were prepared following a similar procedure to that described in Preparation 57, procedure A.

Preparations 60-68

Following the method for Preparation 57, procedure B, the following compounds were prepared substituting 2-amino-4-picoline with the appropriate amine and with the appropriate bicyclic heterocycle. (Preparations 43-56)

Preparation 69

2-(2.2,2-Trifluoroethoxytethanol

Trifluoroethanol (36mL, 494mmol), ethylene carbonate (66.Og, 741 mmol), triethylamine (7OmL, 494mmol) and tetrabutylammonium bromide (3.2Og, 9.90mmol) were combined and the reaction mixture heated to reflux for 24 hours. The reaction mixture was distilled at atmospheric pressure, yielding the title product in the range 132⁰C to 142⁰C. ¹H NMR (CDCI₃, 400 MHz) δ: 3.69-3.77 (m, 4H), 3.88 (m, 2H). Preparation 70

5-Methvl-4-nitro-2-r2-(2 ,2,2-trifluoroethoxv)ethvll-2H-pvrazole-3-carboxamide

5-Methyl-4-nitro-2H-pyrazole-3-carboxamide (US 4282361 ) (2.Og, 11.80mmol), the alcohol of Preparation 69 (2.03g, 14.16mmol) and triphenylphosphine (4.29g, 16.52mmol) were dissolved in tetrahydrofuran (3OmL) and the mixture cooled in an ice bath. A solution of diisopropyl azodicarboxylate (3.2OmL, 16.52mmol) in tetrahydrofuran (5mL) was added dropwise and the reaction mixture stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue triturated with dichloromethane:ether 80:20 to yield a white solid, 884mg. The mother liquors were concentrated in vacuo and the residue triturated again with dichloromethane and the solid filtered to yield another batch of white solid, 584mg. The dichloromethane solution was then purified by column chromatography on silica gel eluting with dichloromethane:ether 70:30 to yield additional product, 1.49g. ¹H NMR (CD₃OD, 400 MHz) δ: 2.46 (s, 3H), 3.91 (q, 2H), 4.02 (t, 2H), 4.35 (t, 2H)

Preparation 71

4-Amino-5-methyl-2-f2-(2,2,2-trifluoroethoxy)ethyll-2/-/-pyrazole-3-carboxamide

A mixture of the pyrazole from Preparation 70 (1.46g, 4.93mmol), and palladium hydroxide (150mg) in methanol (5OmL) was heated to reflux, and ammonium formate (1.55g, 24.6mmol) added portionwise. Once addition was complete, the reaction was stirred for a further hour under reflux. The cooled mixture was filtered through Arbocel®, and the filtrate evaporated in vacuo to give the title compound as an orange solid, 1.3Og. ¹H NMR (CD₃OD, 400 MHz) δ: 2.16 (s, 3H), 3.84 (q, 2H), 3.91 (t, 2H), 4.53 (t, 2H). LRMS:m/z ES+ m/z 289 [MNa]⁺ Preparation 72

3-Methyl-1-[2-(2.2.2-trifluoroethoxy)ethyll-1 ,4-dihvdropyrazolof4,3-c/lpyrimidine-5.7-dione

A solution of 1 ,1'-carbonyl diimidazole (1.2g, 7.4mmol) in acetonitrile (15mL) was heated to reflux, and a solution of the pyrazole from Preparation 71 (1.3g, 4.93mmol) in acetonitrile (15mL) was added dropwise over 25 minutes. The reaction was heated under reflux for a further 1.5 hours, then additional 1 ,1 '- carbonyl diimidazole (400mg, 2.5mmol) added, and the reaction heated under reflux for a further 18 hours. The cooled mixture was evaporated in vacuo and the residue triturated with ether, the resulting solid filtered off and dried to afford the title compound as a white solid, 864mg. ¹H NMR (DMSO-d₆, 400 MHz) δ: 2.20 (s, 3H), 3.92 (t, 2H), 4.00 (q, 2H), 4.51 (t, 2H), 11.08 (s, 2H).

Preparation 73 5,7-Dichloro-3-methyl-1 -f2-(2.2,2-trifluoroethoxy)ethyll-1 /-/-pyrazolof4.3-c/|pyrimidine

A mixture of the compound from Preparation 72 (2.1 g, 7.18mmol), phosphorous oxychloride (10.02ml_) and tetraethylammonium chloride (3.57g, 21.6mmol) in propionitrile (3OmL) was heated to 100⁰C and stirred for 18 hours. The cooled mixture was evaporated in vacuo and the residue azeotroped with toluene. The residue was partitioned between ethyl acetate and water and the layers separated. The organic phase was dried over magnesium sulphate, concentrated in vacuo and the crude product purified by column chromatography on silica gel using dichloromethane:ethyl acetate (50:50) to give the title compound as a gum, 776mg. ¹H NMR (CDCI₃, 400 MHz) δ: 2.62 (s, 3H), 3.72 (q, 2H), 4.03 (t, 2H), 4.89 (t, 2H) Preparation 74

3-Ethyl-4-nitro-1-(2,2.2-trifluoroethoxy)ethylDyrazole-5-carboxamide

A solution of diisopropyl azodicarboxylate (53.74g, 266mmol) in tetrahydrofuran (5OmL) was added dropwise to a solution of 3-ethyl-4-nitropyrazole-5-carboxamide (EP 1176142, pg 18) (35.Og, 190mmol), and triphenylphosphine (69.79g, 266mmol) in tetrahydrofuran (45OmL) with stirring under nitrogen, keeping the reaction temperature between 0°C and 10⁰C by cooling in an ice bath. After the addition was complete, the mixture was allowed to stir for 2 hours, then warmed to room temperature. The solvent was removed in vacuo and the residue was recrystallized twice from hot isopropanol to afford the title compound as a colorless solid, 49.06g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.25 (t, 3H), 2.92 (q, 2H), 3.78 (q, 2H), 3.98 (t, 2H), 4.56 (t, 2H), 5.95 (br s, 1H), 7.11 (br s, 1H).

Preparation 75

4-Amino-3-ethyl-1-(2.2,2-trifluoroethoxy)ethylpyrazole-5-carboxamide

A solution of the compound from Preparation 74 (23.34g, 75mmol) in methanol (40OmL) was hydrogenated over 10% palladium on charcoal (6.Og) at 30OkPa and 5O⁰C for 2 hours. Another 2.0 g of catalyst was added and hydrogenation continued for another 14 hours. The hot solution was filtered through Arbocel® and the filter cake was washed with methanol (4 x 10OmL). The filtrate was concentrated in vacuo and the residue azeotroped with toluene (10OmL) to give the title compound as a red oil, 19.06g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.21 (t, 3H), 2.55 (q, 2H), 3.16 (br s, 2H), 3.79 (q, 2H), 3.99 (t, 2H), 4.61 (t, 2H), Preparation 76

3-Ethvl-1-r2-(2,2.2-trifluoroethoxv)ethvn-1.4-dihvdroDvrazolor4.3-cflDvrimidine-5.7-dione

A solution of the compound from Preparation 75 (19.06g, 68.0mmol) in acetonitrile (15OmL) was added dropwise over 2 hours to a stirred solution of N,N-carbonyl diimidazole (16.55g, l OOmmol) in refluxing acetonitrile (85OmL) under nitrogen. The mixture was heated under reflux for 2 hours, cooled and the solvent was removed in vacuo. The residue was triturated with water (150 mL), the resulting colorless solid was filtered off and washed with water (10OmL), and dried in vacuo at 8O⁰C, to afford the title compound, 17.53g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.26 (t, 3H), 2.67 (q, 2H), 3.78 (q, 2H), 4.00 (t, 2H), 4.63 (t, 2H), 7.94 (br s, 1 H), 8.43 (br s, 1H). LRMS:m/z ES- 305 [M-H]^"

Preparation 77 5,7-Dichloro-3-ethyl-1 -r2-(2,2,2-trifluoroethoxy)ethvn-1 H-pyrazolor4,3-d|pvrimidine

Phosphorous oxychloride (22.8mL, 0.24mol) was added to a suspension of the dione from Preparation 76 (5g, 16mmol) and tetraethylammonium chloride (8.11 g, 48mmol) in propionitrile (75mL), and the mixture stirred at 106⁰C for 18 hours. The cooled mixture was concentrated in vacuo and the residue azeotroped with toluene (2x50mL). The residual oil was dissolved in ethyl acetate (5OmL), washed with water (20OmL), dried over magnesium sulphate and evaporated in vacuo, to afford the title compound, 4.98g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.40 (t, 3H), 3.05 (q, 2H), 3.70 (q, 2H), 4.05 (t, 2H), 4.90 (t, 2H).

Preparation 78 5-Chloro-3-ethyl-N-pyrazin-2-yl-1-f2-(2.2,2-trifluoroethoxy)ethvn-1 H-pyrazolof4,3-d1pyrimidin-7-amine

Following the procedure of Preparation 57 procedure A, but using aminopyrazine and the compound of Preparation 77 the title compound was prepared. LRMS: m/z ESI+ 402 [MH]⁺ Preparation 79

5-Chloro-3-ethyl-N-(4-m6thylpyrimidin-2-yl)-1-f2-(2.2.2-trifluoroethoxy)ethvn-1 H-pyrazolof4,3-cnpyfimidin-

7-amine

Following the procedure of Preparation 57 procedure A, but using 2-amino-4-methyl pyrimidine and the compound of Preparation 77 the title compound was prepared. LRMS: m/z ESI+ 416 [MH]⁺

Preparation 80

5-Chloro-3-ethyl-N-(6-methylpyridin-2-yl)-1-r2-(2.2,2-trifluoroethoxy)ethyll-1 H-pyrazolof4,3-d1pyrimidin-7- amine

Following the procedure of Preparation 57 procedure A, but using 2-amino-6-methyl pyridine and the compound of Preparation 77 the title compound was prepared. LRMS: m/z ESI+ 415 [MH]⁺

Preparation 81

5-Chloro-3-ethyl-N-(4-methylpyrimidin-2-yl)-1-[2-(2.2.2-trifluoroethoxy)ethyll-1 H-pyrazolof4.3-d1pyrimidin- 7-amine

Following the procedure of Preparation 57 procedure A, but using 2-amino-pyridine and the compound of Preparation 77 the title compound was prepared. LRMS: m/z ESI+ 401 [MH]⁺

Preparation 82 5-Chloro-3-ethyl-N-(4-fluorophenylV1-f2-(2.2.2-trifluoroethoxy)ethyll-1 H-pyrazolor4.3-dipyrimidin-7-amine

A mixture of 4-fluoroaniline (0.84 g, 7.6 mmol), the compound of Preparation 77 (0.649 g, 1.89 mmol), N- ethyldiisopropyl amine (0.25 mL), and methylene chloride (4.0 mL) were heated in a sealed tube using a CEM Discover™ microwave reactor. After heating for 2 h, the mixture was diluted with methylene chloride, 2.5 N NaOH (5 mL, 10 mmol). Then excess 10% Citric acid solution was added and the organic layer was partitioned, dried over magnesium sulfate, and evaporated to afford the title compound as an off white solid, 546 mg. LRMS: m/z ESI+ 418 [MH]⁺

Preparation 83 5-Chloro-3-ethyl-N-(4-methylphenyl)-1 -r2-(2.2.2-trifluoroethoxy)ethyll-1 H-pyrazolof4.3-dlDyrimidin-7-amine

Following the procedure of Preparation 82, but using 4-aminotoluene and the compound of Preparation 77 the title compound was prepared LRMS: m/z ESI+ 414 [MH]⁺

Preparation 84 5-Chloro-3-ethyl-N-(4-methylpyridin-2-yl)-1-r2-(2.2,2-trifluoroethoxy)ethyl1-1 H-pyrazolor4.3-dlpyrimidin-7- amine compound with methane (1 :1 )

Following the procedure of Preparation 82, but using 2-amino-4-methyl pyridine and the compound of Preparation 77 the title compound was prepared. LRMS: m/z ESI+ 415 [MH]⁺ Preparation 85

Dimethyl 1 -(2-ethoxyethyl)-4-nitro-1 H-pyrazole-3.5-dicarboxylate

4-Nitro-1 H-pyrazole-3,5-dicarboxylic acid dimethyl ester (2.Og, 8.83mmol) was added to a solution of 2- ethoxyethyl bromide (1.18mL, 10.45mmol) and potassium carbonate (1.32g, 9.56mmol) in N₁N- dimethylformamide (35mL) and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (20OmL) and water (10OmL). The organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 100:0 to 70:30 to yield the title product, 1.63g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.07 (t, 3H), 3.41 <q, 2H), 3.73 (t, 2H),3.89 (s, 3H), 3.94 (s, 3H), 4.76 (t, 2H). LRMS:m/z APCI+ 302, [MH]⁺ Preparation 86

1-(2-Ethoxyethyl)-4-nitro-1 H-pyrazole-3.5-dicarboxylic acid 3-methyl ester

The di-ester of Preparation 85 (1.63g, 5.4mmol) was added to a solution of potassium hydroxide (330mg, 5.9mmol) in methanol (2OmL) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product dissolved in water and washed with ether. The aqueous phase was acidified with 2M hydrochloric acid and extracted into dichloromethane (3x10OmL). The organics were combined, dried over magnesium sulphate and concentrated in vacuo Xo yield the title product, 1.34g. ¹H NMR (CD3OD, 400 MHz) δ: 1.07 (t, 3H), 3.47 (q, 2H), 3.80 (t, 2H),3.88 (s, 3H), 4.77 (t, 2H). LRMS:m/z APCI+ 288, [MH]⁺

Preparation 87 Methyl 5-carbamoyl-1 -(2-ethoxyethyl)-4-nitro-1 H-pvrazole-3-carboxvlate

Oxalyl chloride (1.2mL, 13.76mmol) and Λ/,Λ/-dimethylformamide (39μL) were added to a solution of the carboxylic acid of Preparation 86 (1.33g, 4.63mmol) in dichloromethane (2OmL) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped from dichloromethane (3x50mL). The reaction mixture was dissolved in tetrahydrofuran (5OmL), cooled in an ice bath and treated with 0.880 ammonia solution (1OmL). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the remaining solution partitioned between dichloromethane (20OmL) and water (5OmL). The organics were combined, dried over magnesium sulphate and concentrated in vacuo Xo yield the title product , 0.98g. ¹H NMR (DMSO-d₆, 400 MHz) δ: 1.03 (t, 3H), 3.38 (q, 2H), 3.70 (t, 2H), 3.86 (s, 3H), 4.36 (t, 2H), 8.30 (br s, 1 H), 8.46 (br s, 1 H). LRMS APCI+ m/z 287 [MH]⁺ Preparation 88

Methyl 4-amino-5-carbamoyl-1 -(2-ethoxyethylM H-pyrazole-3-carboxylate

Pd(OH)₂ (100mg) was added to a solution of the nitro compound of Preparation 87 (970mg, 3.39mmol) in methanol (2OmL) and the reaction mixture warmed to reflux. Ammonium formate (1.07g, 16.97mmol) was added and the reaction mixture stirred at reflux for 2 hours. The catalyst was removed by filtration and the reaction mixture concentrated in vacuo Xo yield the title product, 870mg.

¹H NMR (DMSOd₆, 400 MHz) δ: 1.04 (t, 3H), 3.32 (q, 2H), 3.66 (t, 2H), 3.78 (s, 3H)₁ 4.49 (t, 2H), 5.12 (br s, 2H), 7.50 (br s, 2H). LRMS APCI+ m/z 257 [MH]⁺

Preparation 89 Methyl 1-(2-ethoxyethyl)-5,7-dioxo-4.5.6.7-tetrahvdro-1 H-pyrazolor4.3-dlpyrimidine-3-carboxvlate

A solution of the amine of Preparation 88 (570mg, 3.38mmol) in Λ/,Λ/-dimethylformamide (3OmL) was treated with carbonyl diimidazole (658mg, 4.06mmol) and the reaction mixture stirred at room temperature for 1 hour and then at 90°C for 18 hours. The reaction mixture was concentrated in vacuo and the crude product suspended in acetone and sonicated for 30 minutes. The solid product was filtered off and dried in vacuo. ¹H NMR (DMSOd₆, 400 MHz) δ: 1.03 (t, 3H), 3.40 (q, 2H), 3.87 (t, 2H), 4.06 (s, 3H), 4.98 (t, 2H). LRMS ES- m/z 281 [M-H]^".

Preparation 90 Methyl 5.7-dichloro-1 -(2-ethoxyethyl)-1 H-pyrazolof4.3-d1pyrimidine-3-carboxylate

H₃C

Phosphorous oxychloride (934μl_, lO.Ommol) and tetraethylammonium chloride (195mg, 1.50mmol) were added to a solution of the dione of Preparation 89 (140mg, O.δOmmol) in propionitrile (5mL) and the reaction mixture refluxed for 18 hours. The reaction mixture was concentrated in vacuo and the crude product partitioned between ethyl acetate (5OmL) and water (5OmL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 100:0 to 75:25 to yield the title product. ¹H NMR (CDCI₃, 400 MHz) δ: 1.03 (t, 3H), 3.40 (q, 2H), 3.87 (t, 2H), 4.06 (s, 3H), 4.98 (t, 2H). LRMS APCI+ m/z 319 [MH]⁺

Preparation 91 f5.7-Dichloro-1-(2-ethoxyethyl)-1 H-pyrazolor4,3-dlPyrimidin-3-yl1methanol

DIBAL (62.5mL, 1 M in tetrahydrofuran, 62.5mmol) was added dropwise to a cooled (-78°C) solution of the ester from Preparation 90 (4g, 12.5mmol) in tetrahydrofuran (10OmL), and once addition was complete, the reaction was stirred for 10 minutes. The mixture was then allowed to warm to -10°C over 1 hour, then re-cooled to -78°C. Saturated ammonium chloride solution (45mL) was carefully added, the mixture warmed to room temperature and partitioned between water (175mL) and dichloromethane (35OmL). The mixture was filtered through Arbocel®, washing through with dichloromethane (3x10OmL), the combined organic solutions dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using methanol:dichloromethane (1 :99) as eluant to afford the title compound, 2.56g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.07 (t, 3H), 3.44 (q, 2H), 3.84 (m, 2H), 4.86 (t, 2H), 5.09 (s, 2H).

Preparation 92 3-(tert-Butyldimethylsilanyloxymethyl)-5.7-dichloro-1-(2-ethoxyethyl)-1 /-/-pyrazolor4.3-d|pyrimidine

Imidazole (637mg, 9.35mmol) and tert-butyldimethylsilyl chloride (1.41g, 9.35mmol) were added to a solution of the alcohol from Preparation 91 (2.47g, 8.5mmol) in dichloromethane (5OmL), and the reaction stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (25OmL), and washed with 10% aqueous potassium carbonate solution (175mL). The organic solution was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using methanol:dichloromethane (1 :99) as eluant to afford the title compound, 2.9g. "I-Jo-

¹H NMR (CDCI₃, 400 MHz) δ: 0.00 (s, 6H), 0.78 (s, 9H), 0.93 (t, 3H), 3.29 (q, 2H), 3.71 (m, 2H), 4.72 (m, 2H), 4.94 (s, 2H). LRMS : m/z APCI+ 405 [MH⁺]

Preparation 93A 3-(Methoxycarbonyl)-4-nitro-1-r2-(2,2,2.-trifluoroethoxy)ethvn-1 H-Pyrazole-5-carboxylic acid

A solution of diisopropyl azodicarboxylate (71.9ml_, 366mmol) in tetrahydrofuran (8OmL) was added dropwise to a solution of dimethyl 4-nitropyrazole-3,5-dicarboxylate (6Og, 260mmol), 2,2,2- trifluoroethoxyethanol (45.27g, 314 mmol), and triphenylphosphine (96.15g, 366mmol) in tetrahydrofuran (65OmL) with stirring under nitrogen, keeping the reaction temperature between 0⁰C and 10⁰C by cooling in an ice bath. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 days. The solvent was removed under reduced pressure and the residue was dissolved in methanol (80OmL) and cooled to 0⁰C. A solution of potassium hydroxide (16.16g, 288mmol) in methanol (20OmL) was added at 0°C and the reaction was allowed to warm to room temperature and stirred for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water (600 mL) and ethyl acetate (60OmL). The aqueous layer was washed with ethyl acetate (2 x 20OmL) and the aqueous phase was acidified with hydrochloric acid to pH1. The aqueous solution was extracted with ethyl acetate (3 x 40OmL), and these combined extracts were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colorless solid, 52.86g, 59%. ¹H NMR (CDCI₃, 400 MHz) δ: 3.77 (q, 2H), 3.93 (s, 3H), 4.00 (t, 2H), 4.84 (t, 2H). Preparation 93B

3-(Methoxycarbonyl)-4-nitro-1 -f2-(2.2.2-trif Iuoroethoxy)ethyl1-1 H-pyrazole-5-carboxylic acid

Step 1. A solution of diisopropyl azodicarboxylate (21.23 g, 0.105 mol) was added portion wise via syringe to a solution of dimethyl 4-nitropyrazole-3,5-dicarboxylate (20.Og, 0.0873 mole), 2-(2,2,2- trifluoroethoxy)ethanol (13.8 g, 0.096 mol) and triphenylphosphine (27.6 g, 0.105 mol) in tetrahydrofuran (100 mL) with stirring under nitrogen, keeping the reaction temperature between 0 ⁰C and 40 ⁰C by cooling in an ice bath. After the addition was complete (about 10 min), the mixture was allowed to warm to room temperature and stirred for 4 h. The solvent was removed under reduced pressure at about 50 ⁰C to afford the crude reaction mixture as a yellow oil. Silica gel chromatography (hexane: methylene chloride) gave the desired product as a white solid (28.8 g, 93% isolated yield). ¹H NMR (CDCI₃, 400 MHz) 5: 4.82 (t, 2H). 3.92 (t, 2H), 3.89 (s, 3H), 3.75 (q, 2H). ¹⁹F NMR (400 MHz, (CDCI₃) δ: -74.83 (t, J = 8.68 Hz).

Calculated MS: m/z 356.1 [MH]⁺: Observed API-MS (relative intensity): m/z 356.1 [MH]⁺ (I OO), 357.1 (15).

Step 2. Dimethyl 1-(2-(2,2,2-trifluoroethoxy)ethyl)-4-nitro-1 H-pyrazole-3,5-dicaboxylate (18.4 g, 0.052 mole) from Step 1 was dissolved in methanol (150 ml_) and cooled to room temperature. A solution of potassium hydroxide (3.2 g, 0.057 mol) in methanol (150 mL) was added at room temperature and the reaction to proceed with stirring until complete conversion noted by hplc (0.5 h). The solvent was removed in vacuo and the residue was partitioned between water (600 mL) and ethyl acetate (600 mL). The aqueous layer was washed with ethyl acetate (2 x 5OmL) and the aqueous phase was subsequently acidified with hydrochloric acid to pH 2. The aqueous solution was extracted with ethyl acetate (3 x 100 mL), and these combined extracts were dried over sodium sulphate and concentrated in vacuo \o afford the title compound as a colorless solid (13.7 g, 78% isolated yield). ¹H NMR (CDCI₃, 400 MHz) δ: 4.84 (t, 2H), 4.00 (t, 2H), 3.93 (s, 3H), 3.77 (q, 2H). Calculated MS: m/z 342.2 [MH] : Observed API-MS (relative intensity): m/z 342.1 (100) [MH]⁺ . Preparation 94

Methyl 5-(carbamoyl)-4-nitro-1 -[2-(2.2.2.-trif luoroethoxy)ethyll-1 /-/-pyrazole-3-carboxylate

The acid from Preparation 93 (70.0g, 204mmol) was dissolved in a mixture of dichloromethane (100OmL) and Λ/,Λ/-dimethylformamide (1mL) under nitrogen at 20°C. Oxalyl chloride (25mL, 366mmol) was added dropwise with stirring. The mixture was stirred for 16 hours then concentrated in vacuo, and the residue azeotroped with dichloromethane (3x200mL). The residue was dissolved in tetrahydrofuran (100OmL), cooled to -78⁰C and 0.88 ammonia (70 mL) was added dropwise keeping the mixture at -78°C. After the addition was complete the mixture was stirred for 1 hour, and then an excess of hydrochloric acid was added at -78°C (to give pH1). The mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The resulting cream-colored solid was collected by filtration and washed with water (3 x 10OmL). The solid was triturated with a mixture of diethyl ether and methanol (20:1 , 20 ml_/g) to give the title compound as a colorless solid, 40.0g. ¹H NMR (CDCI₃, 400 MHz) δ: 3.78 (q, 2H), 3.95 (s, 3H), 3.98 (t, 2H), 4.76 (t, 2H), 5.91 (br s, 1 H), 7.03 (br s, 1 H). - -

Preparation 95

Methvl 4-amino-5-carbamovl-1 -[2-(2,2.2,-trifluoroethoxv)ethvll-1 H-Dvrazole-3-carboxvlate

A solution of the compound from Preparation 94 (40.Og, 118mmol) in methanol (64OmL) was hydrogenated over 10% palladium on charcoal (10.0g) at 30OkPa and 50⁰C for 3 hours. The hot solution was filtered through Arbocel® and the filter cake was washed with dichloromethane. The filtrate was concentrated in vacuo to give the title compound as an off-white solid, 34.2g. ¹H NMR (CDCI₃, 400 MHz) δ: 3.80 (q, 2H), 3.91 (s, 3H), 4.07 (t, 2H), 4.63 (t, 2H), 6.29 (br s, 2H).

Preparation 96 Methyl 5.7-dioxo-1-[2-(2,2.2-trifluoroethoxy)ethyll-4.5.6.7-tetrahvdro-1 H-pyrazolo[4,3-d|pyrimidine-3-

A solution of the compound from Preparation 95 (21.7g, 70.0mmol) in acetonitrile (15OmL) was added dropwise over 2 hours to a stirred solution of N,N-carbonyl diimidazole (17.02g, 105mmol) in refluxing acetonitrile (85OmL) under nitrogen. The mixture was heated under reflux for 2 hours, cooled and the solvent was removed in vacuo. The residue was triturated with water (150 mL) and the resulting pale grey solid was filtered off, washed with water (3 x 10OmL), and dried in vacuo at 80⁰C, to afford the title compound, 21.26g. ¹H NMR (CDCI₃, 400 MHz) δ: 3.79 (q, 2H), 3.98 (s, 3H), 4.07 (t, 2H), 4.77 (t, 2H), 7.87 (br s, 1 H), 8.41 (br s, 1 H). LRMS:m/z ES- 335 [M-H]- Preparation 97

Methyl 5.7-dichloro-1-r2-(2,2.2.-trifluoroethoxv)ethvl1-1 H-pvrazolo[4.3-d|pvrimidine-3-carboxvlate

Phosphorous oxychloride (56mL, O.βOmol) was added to a suspension of the dione from Preparation 96 (13.5g, 40mmol) and tetraethylammonium chloride (20.Og, 120mmol) in propionitrile (15OmL), and the mixture stirred under reflux for 18 hours. The cooled mixture was concentrated in vacuo and the residue azeotroped with toluene (2x50ml_). The residue was partitioned between dichloromethane (50OmL) and water (50OmL), the layers separated, and the aqueous extracted with further dichloromethane (50OmL). The combined organic solutions were washed with water (20OmL), brine (10OmL), dried over magnesium sulphate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (34:66 to 50:50) to afford the title compound as a white solid, 9.4g. ¹H NMR (CDCI₃, 400 MHz) δ: 3.75 (q, 2H), 4.10 (m, 5H), 5.05 (t, 2H).

Preparation 98 (5.7-Dichloro-1-r2-(2.2.2-trifluoroethoxy)ethvπ-1 H-pyrazolof4.3-c/|pyrimidin-3-yl)methanol

Diisobutylaluminium hydride (33.2mL, 1 M in tetrahydrofuran , 33.2mmol) was added dropwise to a cooled (-78⁰C) solution of the ester from Preparation 97 (3.1 g, 8.31 mmol) in tetrahydrofuran (5OmL), so as to maintain the temperature below -70°C. Once addition was complete the reaction was allowed to warm to -10⁰C and stirred for 1 hour. TIc analysis showed starting material remaining, so the reaction was re- cooled to -78°C, additional diisobutylaluminium hydride (8.3mL, 1 M in tetrahydrofuran , 8.3mmol) was added, the reaction warmed again to -10⁰C and the reaction stirred for a further 20 minutes. The reaction was cooled again to -78⁰C, hydrochloric acid (2M, 3OmL) added and the mixture allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water and extracted with dichloromethane (2x). The combined organic solutions were washed with water and brine, dried over magnesium sulphate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 97:3) to afford the title compound as an orange oil, 2.22g. ¹H NMR (CDCI₃, 400 MHz) δ: 2.69 (s, 1 H), 3.75 (q, 2H), 4.08 (t, 2H), 4.91 (t, 2H), 5.09 (s, 2H). LRMS:m/z APCI+ 345 [MH]⁺

Preparation 99 Λ/-(5-Chloro-3-ethvl-1-r2-(2.2.2-trifluoroethoxv)ethvll-1 /-/-Dvrazolor4,3-(-^/lpvrimidin-7-vl)pvrimidin-4-vlamine

A solution of sodium bis(trimethylsilyl)amide (1.07g, 5.82mmol) in tetrahydrofuran (1OmL) was added to a solution of 4-aminopyrimidine (550mg, 5.82mmol) in tetrahydrofuran (1OmL) with ice cooling. The solution was stirred for 15 minutes, then a solution of the compound from Preparation 77 (1g, 2.91 mmol) in tetrahydrofuran (1OmL) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate (10OmL) and washed with water. The aqueous solution was extracted with ethyl acetate (10OmL) and the combined organic solutions dried over magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate as eluant to afford the title compound as a yellow solid, 770mg. ¹H NMR (CDCI₃, 400 MHz) δ: 1.40 (t, 3H), 3.00 (q, 2H), 4.05 (q, 2H), 4.20 (t, 2H), 4.80 (t, 2H), 8.40 (m, 1 H), 8.70 (dd, 1 H), 8.90 (s, 1 H), 9.55 (br s, 1 H). LRMS:m/z APCI+ 403 [MH]⁺

Preparation 100 5-Chloro-1-(2-ethoxyethyl)-3-(methoxymethyl)-N-pyridin-2-yl-1 H-pyrazolo[4.3-dipyrimidin-7-amine.

Step i : To a solution of 2-aminopyridine (1.5 g, 15.9 mmol) in tetrahydrofuran (11 m L) at 0⁰C was added via syringe a 1.0 N lithium bis(trimethylsilyl)amide (16.4 mL) solution. The resulting anilide was maintained at 0 ⁰C for 30 min. The dichloropyrimidine (Preparation 92, 2.1 g, 5.30 mmol) was then added dropwise via a pressurized addition funnel (ca. 20 min) to the anilide as a solution in tetrahydrofuran (5 mL). The reaction was stirred at 0 ⁰C for 1.5h. The ice bath was removed and the reaction was allowed to warm to rt and stir overnight. The tetrahydrofuran was removed under vacuum and the reaction was quenched by addition of a 1 N ammonium chloride solution. The reaction was diluted with dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (4x). The organics were then combined, dried by filtration through Whatman phase separator paper, and concentrated in vacuo to give the crude product, which was carried on to the next step without further purification.

Step 2: A solution of the above silyl ether (~ 5.3 mmol) in tetrahydrofuran (20 ml_) was cooled to 0 ⁰C. To this mixture was added a 1.0 N tetrabutylammonium chloride (7 ml_, 7.0 mmol) solution. The reaction was maintained at 0 ⁰C, for 20 min, then allowed to warm slowly to rt and stir overnight. The tetrahydrofuran was removed under vacuum and the reaction was quenched by addition of a 1 N ammonium chloride solution. The reaction was diluted with dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (4x). The organics were then combined, dried by filtration through Whatman phase separator paper, and concentrated in vacuo. The crude product was purified on silica gel. Elution with dichloromethane:methanol (96:4) afforded the title compound (1.45g). ¹H-NMR (300 MHz, CDCI₃) δ 8.84 - 8.70 (s, 1 H), 8.34 (dd, 1 H₁ J = 5.4, 0.9 Hz), 8.04 (t, 1 H, J = 8.1 Hz), 7.27 - 7.21 (m, 2H), 5.07 (s, 2H), 4.97 (t, 2H, J = 4.5 Hz), 4.0 - 3.92 (m, 2H), 3.76 - 3.58 (m, 2H), 1.8 (t, 3H, J = 6.9 Hz); LRMS m/z 349.1 - 350.1 (calcd for M + H, 349.8).

Step 3: To a solution of [5-chloro-1-(2-ethoxyethyl)-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-3- yl]methanol (592 mg, 1.7 mmol) in dichloromethane (10 ml_) was slowly added thionyl chloride (880 μl_, 6.8 mol). The resulting yellow mixture was stirred at rt for 3h. The solvent was then removed under vacuum to give after drying a yellow solid. To the crude solid was slowly added a 0.5 N sodium methoxide/methanol (13.5 ml_, 6.75 mmol) solution. The resulting mixture was allowed to stir at rt overnight. The methanol was then removed under vacuum. The crude residue was quenched by addition of a 1 N ammonium chloride solution and extracted with dichloromethane (5x). The organics were combined, dried by filtration through Whatman phase separator paper, and concentrated in vacuo. The title compound (530 mg) was isolated by precipitation and filtration from diethyl ether. ¹H-NMR (300 MHz, CDCI₃) δ 9.19 (d, 1 H, J = 9.0 Hz), 8.32 - 8.23 (m, 2H), 7.36 (t, 1 H, J = 6.0 Hz), 5.15 (t, 2H, J = 4.8 Hz), 4.77 (s, 2H), 3.86 (t, 2H, J = 5.1 Hz), 3.51 - 3.43 (m, 5H), 0.84 (t, 3H, J = 6.9 Hz); LRMS m/z 363.0 - 365.1 (calcd for M+H, 363.8).

Preparation 101 5-Chloro-1-(2-ethoxvethvl)-3-(ethoxymethvl)-N-pvrimidin-4-vl-1 H-pvrazolor4,3-d1pvrimidin-7-amine

Step 1 : To a slurry of [5-chloro-1-(2-ethoxyethyl)-7-(pyrimidin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-3- yl]methanol prepared as described in Preparation 100, steps 1 and 2, (490 mg, 1.4 mmol) in dichloromethane (7 mL) was slowly added, via syringe, thionyl chloride (720 μL, 5.6 mmol). The resulting yellow mixture was stirred at rt overnight. The mixture was then concentrated in vacuo to give a yellow residue that was used without further purification. _

Step 2: To a solution of the above chloride (~ 1.4 mmol) in ethanol (3 mL) was slowly added a 21% sodium ethoxide/ethanol (2.6 mL) solution. The resulting orange solution was stirred at rt overnight. The reaction was concentrated in vacuoio remove ~ 70-80% of the ethanol. The resulting mixture was then quenched with a 1 N ammonium chloride solution and extracted with dichloromethane (4X). The organics were combined, dried by filtration through Whatman phase separator paper, and concentrated in vacuo to give the crude product. The yellow solid was taken up in (2:1) diethyl ether-ethyl acetate and sonicated for 5 min. The mixture was filtered to give the titled compound (360 mg) as an off-white solid. ¹H-NMR (300 MHz, ((CD₃)₂SO) 58.92 (s, 1 H), 8.73 (d, 1 H, J = 5.7 Hz), 8.16 (d, 1 H, J = 5.7 Hz), 4.82 (t, 2H, J = 4.8 Hz), 4.68 (S, 2H), 3.84 (t, 2H, J = 4.8 Hz), 3.59 - 3.50 (m, 4H), 1.12 (t, 3H, J = 6.9 Hz), 1.06 (t, 3H, J = 6.9); HRMS m/z 378.1429 (calcd for M + H, 378.1440).

Preparation 102

Preparation of 5-chloro-3-(ethoxymethyl)-N-pyrimidin-4-yl-1 -f2-(2.2.2-trif luoroethoxytethylH H- pyrazolor4.3-d1pyrimidin-7-amine

Step 1 : A solution of 5-chloro-7-(pyrimidin-4-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-3-yl}methanol, prepared as described in Preparation 100, but starting with 4-aminopyrimidine in place of 2-aminopyrimidine and Preparation 98 (4.3 g, 10.6 mmol), in place of dichloropyrimidine (Preparation 92) (Step 1 ) in dichloromethane (60 ml) was treated with thionyl chloride (5.2 g, 42.2 mmol). The reaction mixture was stirred 3 hours at room temperature and then concentrated under vacuum to give 4.7 g solid of 5-chloro-3-(chloromethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine. ¹H NMR (400 MHz, (CD₃)₂SO) δ: 9.00 (s, 1H), 8.70 (m, 1 H), 7.98 (m, 1H), 5.01 (s, 2H), , 4.88 (t, 2H, J=5.0 Hz), 3.92 (m, 4H). ¹⁹F NMR (DMSO, 400 MHz) δ: -73.73 (t, 3F, J=8.1 Hz). Calculated Exact Mass: M+H 422.0505, found: 422.0509.

Step 2: A solution of 5-chloro-3-(chloromethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine (1 g, 2.37 mmol) in ethanol (10 ml) was treated with sodium ethoxide (21 wt. % solution in ethanol, 3.9 ml). The reaction mixture was stirred 18 hours at room temperature. Another 2 ml of sodium ethoxide (21 wt. % solution in ethanol) was added and the reaction mixture was stirred 24 hours at room temperature and quenched with citric acid (0.5 M, 40 ml). The solid was filtered and washed with water to give 5-chloro-3-(ethoxymethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine (0.6 g, 1.39 mmol). ¹H NMR (400 MHz, (CD₃)₂SO) δ: 8.83 (s, 1 H), 8.64 (m, 2H), 7.98 (m, 1H), 4.86 (t, 2H₁ J=4.9 Hz), 4.65 (s, 2H), 3.95 (m, 4H), 3.50 (q, 2H, J=6.98 Hz), 1.07 (t, 3H, J=7.0 Hz). ¹⁹F NMR (400 MHz, (CD₃)₂SO) δ: -73.70 (t, 3F, J=9.0 Hz). Calculated Exact Mass: M+H 432.1157, found: 432.1163.

Preparation 103

3-(2-Cvclopentyl-2-ethoxyethyl)-1 -(2-ethoxyethyl)-N-5-.N-5-dimethyl-N-7-(4-methylpyridin-2-vn-1 H- pyrazolor4.3-d1pyrimidine-5.7-diamine

The title compound may be prepared according to the conditions of Preparation 222 but substituting 3-(2- chloro-2-cyclopentylethyl)-1 -(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine (Preparation 235) for the 3-(2-Chloroethyl)-1 -(2-ethoxyethyl)-N-5-,N-5-dimethyl- N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine.

Preparation 104 5-Chloro-1-(2-ethoxyethyl)-N-(4-fluorophenyl)-3-(methoxymethyl)-i H-pyrazolof4.3-d1pyrimidin-7-amine

Step 1 : To a solution of 4-fluoroaniline (1.5 mL, 15.2 mmol) in tetrahydrofuran (10 mL) cooled to 0 ⁰C was added, via syringe, a 1.0 N lithium bis(trimethylsilyl)amide (16 mL) solution. The anilide was maintained at 0 ⁰C for 20 min. The dichloropyrimidine (Preparation 91 , 2.0 g, 5.08 mmol) was then added dropwise over 10 min to the reaction mixture as a solution in tetrahydrofuran (10 mL). The reaction was stirred at 0 ⁰C for 1.5h. The ice bath was removed and the reaction was allowed to warm to rt and stir overnight. The reaction was quenched by addition of water and extracted with dichloromethane (5x). The organics were combined, dried by filtration through Whatman phase separator paper, and concentrated in vacuo to give the crude product. Trituration with diethyl ether and filtration led to the isolation of [5-chloro-1-(2- ethoxyethyl)-7-[(4-fluorophenyl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl]methanol (1.15g). ¹H-NMR (300 MHz, CDCI₃) δ 9.35 (s, 1 H), 7.70 - 7.66 (m, 2H), 7.16 - 7.06 (m, 3H), 5.04 (s, 2H), 4.73 (t, 2H, J = 4.2 Hz), 3.98 (t, 2H, J = 4.5 Hz), 3.65 (quar, 2H, J = 7.2 Hz), 1.18 (t, 3H, J = 6.9 Hz). LRMS m/z 366.0 - 367.0 (calcd for M + H, 366.8). -1 Jo- Step 2: To a solution of the above alcohol (530 mg, 1.5 mmol) in dichlorom ethane (8 ml_) was slowly added thionyl chloride (766 DL, 5.9 mol). The resulting yellow mixture was stirred at rt overnight. The solvent was removed under vacuum to give after drying a yellow solid residue. The crude mixture was then treated with a 0.5 N sodium methoxide/methanol (12 mL, 6 mmol) solution. The reaction was allowed to stir for 2h. The methanol was then removed under vacuum. The crude residue was quenched by addition of a 1N ammonium chloride solution and extracted with dichloromethane (5x). The organics were combined, dried by filtration through Whatman phase separator paper, and concentrated in vacuo. The crude residue was taken up in diethyl ether and allowed to precipitate. Filtration gave the titled (150 mg) compound. A second crop (125 mg) was later obtained. ¹H-NMR (400 MHz, CDCI₃) δ 9.33 (s, 1 H), 7.69 - 7.66 (m, 2H), 7.09 (t, 1 H, J = 8.8 Hz), 4.78 (s, 2H), 4.74 (t, 2H, J = 4.8 Hz), 3.98 (t, 2H, J = 4.4 Hz), 3.64 (quar, 2H, J = 7.2 Hz), 3.52 (s, 3H)₁I 1.16 (t, 3H, J = 7.2 Hz); LRMS m/z 380.0 - 383.0 (calcd for M+H, 380.8).

Preparation 105

1 -(2-(2,2,2-Trifluoroethoxy)ethyl)-3-((2.2.2-trifluoroethoxy)methyl)-5-chloro-N-(pyridin-2-yl)-1 H- pyrazolor4.3-dlpyrimidin-7-amine

Step 1 : A solution of (1-(2-(2,2,2-trifluoroethoxy)ethyl)-5-chloro-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3- d]pyrimidin-3-yl)methanol, prepared as described in Preparation 100, but starting with 2- aminopyridine and the silyl protected alcohol dichloride from Preparation 239, can be reacted according to Preparation 102, Step 1 to give 1-(2-(2,2,2-trifluoroethoxy)ethyl)-5-chloro-3-

(chloromethyl)-N-(pyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine.

Step 2: The title compound may be obtained by using substantially the procedure of Preparation 149 but substituting 1-(2-(2,2,2-trifluoroethoxy)ethyl)-5-chloro-3-(chloromethyl)-N-(pyridin-2-yl)-1H- pyrazolo[4,3-d]pyrimidin-7-amine for (5-chloro-3-chloromethyl-N-pyrimidin-4-yl-1 -[2-(2,2,2- trif luoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (Preparation 149).

Preparation 106

1-(2-(2,2,2-Trifluoroethoxy)ethyl)-3-((2,2,2-trifluoroethoxy)methyl)-5-chloro-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine

The title compound can be prepared by a method similar to that described in Preparation 105 but substituting 4-methylpyridin-2-amine for 2-aminopyridine in Step 1.

Preparation 107 3-Trifluoromethyl-4-nitro-5-methyl-1 H-pyrazole

3-Trifluoromethyl-5-methyl-1 H-pyrazole (8.0 g, 0.053 mol) was dissolved in concentrated sulfuric acid (16 m L) in a round bottom flask with magnetic stirring. The solution was cooled to 3-5° C with an ice-water bath and fuming nitric acid (9.6 mL) added portion wise over about five minutes. After an hour an additional quantity of concentrated sulfuric acid (10 mL) was added and the solution brought to 60° C for three hours. The reaction mixture was allowed to cool to room temperature and after 16 hours poured onto cracked ice (500 mL). Dichloromethane (100 mL) was added and the pH adjusted to 8 by addition of aqueous sodium hydroxide (50%). The reaction mixture was transferred to a separatory funnel and organics removed. The aqueous layer was washed with dichloromethane (100 mL) and the combined organics dried (Na₂SO₄) andconcentrated to give desired product as a yellow oil (6.3 g) that solidified on standing. The resulting aqueous layer was acidified with concentrated hydrochloric acid and washed with dichloromethane (2 x 100 mL). Combined organics were dried as before and concentrated to yield desired product as yellowish oil (2.84 g) for a total of 9.1 g of desired nitro analog (88 % isolated yield). ¹H NMR (CDCI₃, 400 MHz) δ: 10.4 (vbs, 1 H), 2.70 (s, 3H). ¹⁹F NMR (DMSO-d₆, 400 MHz) δ: -63.72 (s). Calculated MS: m/z 196.1 [MH]⁺: Observed API-ES: m/z: 196.0. Preparation 108

3-Trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxylic acid

3-Trifluoromethyl-4-nitro-5-rnethyl-1 H-pyrazole prepared in Preparation 107 may be converted to the corresponding 3-trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxylic acid by potassium permanganate oxidation ir water using the procedure according to U.S. Patent 4,282,361 , Example 5.

Preparation 109 3-Trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxamide • ^HN P n

XH NH₂

-o-^N-°

3-Trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxylic acid prepared in Preparation 108 may be converted to the corresponding 3-trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxamide using substantially the procedure of

Preparation 1 and substituting 3-trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxylic acid for 5-isopropyl-4-nitro-2/-/ pyrazole-3-carboxylic acid. Preparation 110

Ethyl 3-trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxylate

S-TrifluoromethyM-nitro-I H-pyrazole-δ-carboxylic acid prepared according to Preparation 108 may be converi to ethyl S-trifluoromethyl^-nitro-I H-pyrazole-δ-carboxylate by treating with excess ethanolic HCI at room temperature or at elevated temperature until the conversion from the acid to the ethyl ester is substantially complete.

Preparation 111 3-Trifluoromethyl-4-nitro-1 H-pvrazole-5-carboxamide

Ethyl S-trifluoromethyM-nitro-IH-pyrazole-δ-carboxylate prepared in Preparation 110 may be converted to 3- trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxamide by treating the ester with refluxing concentrated ammonium hydroxide according to the procedure of U.S. Patent 4,282,361 , Example 7.

Preparation 112 Ethyl 1-(2-ethoxyethyl)-3-trifluoromethyl-4-nitro-1H-pyrazole-5-carboxamide

3-(Trifluoromethyl)-4-nitro-1 H-pyrazole-5-carboxamide prepared according to the procedure of Preparation 11 may be alkylated to ethyl 1 -(2-ethoxyethyl)-3-trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxamide according substantially to the procedure of Preparations 2 to 14 where R⁶Br is 1-bromo-2-ethoxyethane. Preparation 113

1-(2-(2.2.2-Trifluoroethoxy)-3-(trifluoromethyl)-4-nitro-1 H-pvrazole-5-carboxamide

3-(Trifluoromethyl)-4-nitro-1 H-pyrazole-5-carboxamide (Preparation 111) may be alkylated to the corresponding 1-(2-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)-4-nitro-1 H-pyrazole-5-carboxamide using substantially the procedure outlined in Preparation 74 and substituting 3-(trifluoromethyl)-4-nitro-1 H- pyrazole-5-carboxamide for 3-ethyl-4-nitro-1 H-pyrazole-5-carboxamide.

Preparation 114 4-Amino-1 -(2-ethoxyethyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide

1-(2-Ethoxyethyl)-3-trifluoromethyl-4-nitro-1 H-pyrazole-5-carboxamide (Preparation 112) may be reduced to 4- amino-1-(2-ethoxyethyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide using substantially the conditions of Procedure 75.

Preparation 115

1-(2-(2.2,2-Trifluoroethoxy)ethyl)-4-amino-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide

1 -(2-(2,2,2-Trifluoroethoxy)-3-(trifluoromethyl)-4-nitro-1 H-pyrazole-5-carboxamide may be reduced to the corresponding amino compound, 1 -(2-(2,2,2-trif luoroethoxy)ethyl)-4-amino-3-(trif luoromethyl)-1 H-pyrazole-5- carboxamide, using substantially the conditions of Preparation 74.

Preparation 116 1-(2-Ethoxyethyl)-3-(trifluoromethylV1 H-pyrazolor4.3-dlpyrimidine-5.7(4H.6H)-dione.

4-Amino-1-(2-ethoxyethyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (Preparation 114) may be substituted for the pyrazole of Preparation 75 and reacted with 1 ,1'-carbonyl diimidazole according to substantially the conditions of Preparation 76 to obtain 1-(2-ethoxyethyl)-3-(trifluoromethyl)-1H- pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione.

Preparation 117 1-(2-(2,2.2-Trifluoroethoxy)ethyl)-3-(trifluoromethyl)-1 H-pyrazolor4,3-dlpyrimidine-5.7(4H,6H)-dione.

1-(2,2,2-Trifluoroethoxy)ethyl)-4-amino-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Preparation 115) may be substituted for the pyrazole of Preparation 75 and reacted with 1 ,1'-carbonyl diimidazole according to substantially the conditions of Preparation 76 to obtain 1-(2,2,2-trifluoroethoxy)ethyl)-4- amino-3-(trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione.

Preparation 118 5.7-Pichloro-1-(2-ethoxyethyl)-3-(trifluoromethyl)-1 H-pyrazolor4.3-dlpyrimidine

1 -(2-Ethoxyethyl)-3-(trif luoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione (Preparation 116) may be substituted for the dione from Preparation 76 and treated with POCI₃ and tetraethyl ammonium chloride in propionitrile according to substantially the conditions of Preparation 77 to prepare 5,7-dichloro- 1-(2-ethoxyethyl)-3-(trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine. Preparation 119

1-(2-(2,2,2-Trifluoroethoxy)ethyl)-5.7-dichloro-3-(trifluoromethyl)-1 H-pyrazolor4,3-dlpyrimidine. - -

F,C

1-(2,2,2-Trifluoroethoxy)ethyl)-4-amino-3-(trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione (Preparation 117) may be substituted for the dione from Preparation 76 and reacted with POCI₃ and tetraethyl ammonium chloride in propionitrile according to substantially the conditions of Preparation 77 to prepare 1 -(2-(2,2,2-trifluoroethoxy)ethyl)-5,7-dichloro-3-(trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine.

Preparation 120

5-Chloro-1-(2-ethoxyethyl)-3-(trifluoromethyl)-N-(5-methylpyridin-2-yl)-1H-pyrazolor4.3-d1pyrimidin-7- amine

The title compound may be obtained by substituting 5,7-dichloro-1-(2-ethoxyethyl)-3-(trifluoromethyl)-1 H- pyrazolo[4,3-d]pyrimidine (Preparation 120) for 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl-1 H-pyrazolo[4,3- d]pyrimidine (Preparation 45) following Preparation 57 Procedure A or Procedure B.

Preparation 121

5-Chloro-1 -(2-(2.2,2-trifluoroethoxy)ethyl)-3-(trifluoromethyl)-N-(5-methylpyridin-2-yl)-1 H-pyrazolof4,3- dlpyrimidin-7-amine

The title compound may be obtained by substituting 5,7-dichloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-3- (trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine (Preparation 121) for 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl- 1 H-pyrazolo[4,3-d]pyrimidine (Preparation 45) following Preparation 57 Procedure A or Procedure B.

The following compounds may be obtained by substituting 5,7-dichloro-1-(2-ethoxyethyl)-3- (trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine (Preparation 120) for 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl- 1 H-pyrazolo[4,3-d]pyrimidine (Preparation 45) following Preparation 57, Procedure A or Procedure B and substituting the appropriate amine for 2-amino-4-methylpyridine.

The following compounds may be obtained by substituting 1-(2-(2,2,2-trifluoroethoxy)ethyl)-5,7-dichloro-3- (trifluoromethyl)-1 H-pyrazolo[4,3-d]pyrimidine (Preparation 119) for 5,7-dichloro-1 -(2-ethoxyethyl)-3-ethyl- 1 H-pyrazolo[4,3-d]pyrimidine (Preparation 45) following Preparation 57, Procedure A or Procedure B and substituting the appropriate amine, NHR₂R₃ for 2-amino-4-methylpyridine.

Preparation 142

Methyl 5-chloro-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolor4.3-d|pyrimidine-3- carboxylate

2-Amino-4-methylpyridine (1.34 g, 12.4 mmol) was added to a solution of the dichloro compound of Preparation 90 (1.98 g, 6.2 mmol) in dimethylsulphoxide (10 ml_) and the reaction stirred at 35 °C for 5 hours. The reaction mixture was partitioned between dichloromethane (300 ml_) and water (500 mL). The organics were separated, washed with water (3x100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with dichloromethane:acetonitrile 98:2. Appropriate fractions were concentrated in vacuo, triturated with ether (50 mL), filtered and the solid dried to yield the title product, 1.2g. ¹H NMR (CDCI₃, 400 MHz) δ: 1.06 (t, 3H), 2.49 (S, 3H), 3.62 (m, 2H), 4.00 (t, 2H), 4.06 (s, 3H), 5.05 (m, 2H), 6.98 (m, 1 H), 8.16 (m, 1 H), 8.50 (m, 1 H). MS APCI+ m/z 391 [MH]⁺

Preparation 143 r5-Chloro-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolor4.3-(y|pyrimidin-3-vnmethanol

The ester of Preparation 142 (1.89 g, 4.84 mmol) was suspended in tetrahydrofuran (450 mL) and the reaction mixture cooled to -78 ⁰C. Diisobutylaluminium hydride (39 mL, 1 M solution in toluene, 39 mmol) was added and the reaction mixture allowed to warm to -5 °C. The reaction mixture was stirred at -5 ⁰C for 15 minutes before being re-cooled to -78 ⁰C and being quenched 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 layer separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was triturated with ethyl acetate and the solid filtered off to yield the title product. ¹H NMR (CDCI₃, 400 MHz) δ: 1.11 (t, 3H), 2.46 (s, 3H), 3.61 (m, 2H), 3.94 (m, 2H), 4.86 (m, 2H), 5.07 (m, 2H), 6.96 (m, 1 H), 8.19 (m, 1 H), 8.48 (m, 1 H). MS APCI+ m/z 363 [MH]⁺ Preparation 144 r5-Dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolof4.3-c/|pyrimidin-3- ylimethanol

The chloro compound of Preparation 143 (780 mg, 2.15 mmol) and N-ethyldiisopropylamine (1.125 ml_, 6.46 mmol) were dissolved in dimethylsulphoxide (6 ml_) and the mixture treated with a 5.6 M solution of dimethylamine in ethanol (1.15 ml_, 6.46 mmol) and heated to 120 ⁰C for 18 hours in a sealed vessel. The reaction mixture was partitioned between dichloromethane (100 mL) and water (100 mL) and the organic phase separated and washed with water (3x200 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 to yield the title product, 230 mg. ¹H NMR (CD₃OD, 400 MHz) δ: 1.07 (t, 3H), 2.38 (s, 3H), 3.20 (s, 6H), 3.60 (q, 2H), 3.85 (t, 2H), 4,65 (t, 2H), 4.80 (s, 2H), 6.90 (d, 1 H), 8.12 (d, 1 H), 8.39 (s, 1 H). MS APCI+ m/z 372 [MH]⁺.

Preparation 145 5-Dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolor4.3-d|pyrimidine-3- carbaldehvde

The alcohol of Preparation 144 (330 mg, 0.89 mmol) was dissolved in dichloromethane (15.5 mL) and the solution cooled to O ⁰C and treated with 1 ,1 ,1-triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 H)-one (394 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 2 hours and was then treated with saturated sodium thiosulphate 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 (3x100 mL). The organics were combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 98:2 to yield the title product, 300 mg. ¹H NMR (CDCI₃, 400MHz) δ: 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, 1 H), 8.40 (m, 1 H), 10.35 (s, 1 H). MS APCI+ m/z 370 [MH]⁺

Preparation 146

(5-(Dimethylamino)-1-(2-ethoxyethyl)-7-r(4-methylpyridin-2-yl)aminol-1 H-pyrazolor4.3-d1pyrimidin-3-

5-Dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolo[4,3-c(lpyrimidine-3- carbaldehyde prepared in Preparation 145 may be homologated to {5-(dimethylamino)-1 -(2-ethoxyethyl)- 7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl}acetaldehyde by treating the aldehyde with (methoxymethyl)triphenylphosphonium chloride with the present of sodium bis(trimethylsilyl)amide then acid hydrolysis of the resulting enol ether according the procedures of Derrick L. J. Clive and Jian Wang. Tetrahedron Lett. 2003, 44(42), 7731-7733.

Preparation 147

2-(5-(Dimethylamino)-1-(2-ethoxyethyl)-7-r(4-methylpyridin-2-yl)amino1-1 H-pyrazolof4.3-dlpyrimidin-3- yllethanol

{5-(Dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3- yljacetaldehyde prepared in Preparation 146 may be reduced to 2-{5-(dimethylamino)-1-(2-ethoxyethyl)-7- [(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl}ethanol by treating the aldehyde with DIBAL-H according the procedures of Derrick L. J. Clive and Jian Wang. Tetrahedron Lett. 2003, 44(42), 7731-7733. Preparation 148

3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N⁵.N⁵-dimethyl-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4.3-dlpyrimidine-

5,7-diamine

2-{5-(Dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3- yljethanol prepared in Preparation 147 may be converted to 3-(2-chloroethyl)-1-(2-ethoxyethyl)-N⁵,N⁵- dimethyl-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine by treating the alcohol with thionyl chloride according to the procedure of Preparation 101 , step 1.

Preparation 149

5-Chloro-N-pyrimidin-4-yl-1 -[2-(2.2.2-trifluoroethoxy)ethyl1-3-r(2.2,2-trifluoroethoxy)methyll-1 H- pyrazolor4,3-diPyrimidin-7-amine

2,2,2-Trifluoroethanol (5 mL) in a 10 mL reacti-vial was added hexane washed sodium hydride (85.5 mg, 3.6 mmol) with stirring. After 0.5 hr (5-chloro-3-chloromethyl-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (Preparation 102 step 1 , 0.30 gm, 0.71 mmol) was added at RT along with sodium iodide and tetrabutylammonium bromide ( several mgs each ). After allowing the reaction to proceed overnight concentrated aqueous citric acid (4 mL) was added and the solution partitioned between dichlorom ethane and water ( 50 mL each). The aqueous layer was re- extracted with DCM and the combined organics dried (Na₂SO₄) and volatiles removed in vacuo to obtain a yellow oil (290 mg). Chromatography (Merck silica gel, EtOAc elution solvent) gives analytically pure product. ¹H NMR (CDCI₃, 400 MHz) δ: 8.88 (s, 1 H), 8.68 (bm, 1 H), 8.43 (bs, 1 H), 5.00 (m, 2H), 4.84 (m, 2H), 4.22 (m, 2H), 4.01 (m, 4H). ¹⁹F NMR (DMSO, 400 MHz) δ: -73.98 (s, 3F), -74.33 (t, 3F). Calculated MS: m/z 486.775 MH⁺, found: 486.1. Preparation 150

Methyl 5-chloro-1 -(2-ethoxyethylV7-(4-methylpyridin-2-ylamino)-1 H-Pyrazolof4,3-d|pyrimidine-3- carboxylate

2-Amino-4-methylpyridine (1.34g, 12.4mmol) was added to a solution of the dichloro compound of Preparation 90 (1.98g, 6.2mmol) in dimethyl sulphoxide (1OmL) and the reaction stirred at 35°C for 5 hours. The reaction mixture was partitioned between dichloromethane (30OmL) and water (50OmL). The organics were separated, washed with water (3x100mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with dichloromethaneiacetonitrile 98:2. Appropriate fractions were concentrated in vacuo, triturated with ether (5OmL), filtered and the solid dried to yield the title product, 1.2g. ¹H NMR (CDCI₃, 400MHz) δ: 1.06 (t, 3H), 2.49 (s, 3H), 3.62 (m, 2H), 4.00 (t, 2H), 4.06 (s, 3H), 5.05 (m, 2H), 6.98 (m, 1H), 8.16 (m, 1 H), 8.50 (m, 1 H). MS APCI+ m/z 391 [MH]⁺ Preparation 151

[5-Chloro-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolor4.3-c/|pyrimidin-3-vnmethanol

The ester of Preparation 150 (1.89g, 4.84mmol) was suspended in tetrahydrofuran (45OmL) and the reaction mixture cooled to -78°C. Diisobutylaluminium hydride (39mL, 1 M solution in toluene, 39mmol) was added and the reaction mixture allowed to warm to -5°C. The reaction mixture was stirred at -5°C for 15 minutes before being re-cooled to -78°C and being quenched with aqueous ammonium chloride solution (1OmL). The reaction mixture was allowed to warm to room temperature and partitioned between dichloromethane (20OmL) and water (20OmL). The mixture was filtered through Arbocel® and the organic layer separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was triturated with ethyl acetate and the solid filtered off to yield the title product. ¹H NMR (CDCI₃, 400MHz) δ: 1.11 (t, 3H), 2.46 (S, 3H), 3.61 (m, 2H)₁ 3.94 (m, 2H), 4.86 (m, 2H), 5.07 (m, 2H), 6.96 (m, 1 H), 8.19 (m, 1 H), 8.48 (m, 1H) MS APCI+ m/z 363 [MH]⁺

Preparation 152

[5-Dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolor4.3-(yipyrimidiπ-3- ylimethanol

The chloro compound of Preparation 151 (780mg, 2.15mmol) and N-ethyldiisopropylamine (1.125mL, 6.46mmol) were dissolved in dimethyl sulphoxide (6mL) and the mixture treated with a 5.6M solution of dimethylamine in ethanol (1.15ml_, 6.46mmol) and heated to 120⁰C for 18 hours in a sealed vessel. The reaction mixture was partitioned between dichloromethane (10OmL) and water (10OmL) and the organic phase separated and washed with water (3x200mL). 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 to yield the title product, 230mg. ¹H NMR (CD₃OD, 400MHz) δ: 1.07 (t, 3H), 2.38 (s, 3H), 3.20 (s, 6H), 3.60 (q, 2H), 3.85 (t, 2H), 4,65 (t, 2H), 4.80 (s, 2H), 6.90 (d, 1 H), 8.12 (d, 1 H), 8.39 (s, 1 H) MS APCI+ m/z 372 [MH]⁺

Preparation 153

5-Dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolor4.3-d|pyrimidine-3- carbaldehvde

The alcohol of Preparation 152 (330mg, 0.89mmol) was dissolved in dichloromethane (15.5mL) and the solution cooled to 0⁰C and treated with 1 ,1 ,1-triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 A7)-one (394mg, 0.93mmol). The reaction mixture was stirred at room temperature for 2 hours and was then treated with saturated sodium thiosulphate solution (13mL), sodium hydrogencarbonate solution (13mL) and ether (13mL). The mixture was allowed to stand for 15 minutes before being extracted into dichloromethane (3x100mL). The organics 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 to yield the title product, 300mg.

¹H NMR (CDCI₃, 400MHz) δ: 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, 1 H), 8.20 (d, 1 H), 8.40 (m, 1 H), 10.35 (s, 1 H). MS APCI+ m/z 370 [MH]⁺

Preparation 154 Λ/-r5-Chloro-3-chloromethvl-1-(2-ethoxvethvl)-1 H-pvrazolof4.3-d|pyrimidin-7-vl1-4-methvlpvridin-2-vlamine

The alcohol of preparation 151 (1.8Og, δ.OOmmol) was dissolved in dichloromethane (15mL) and the solution treated with thionyl chloride (1.5OmL, 17mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo, the residue was azeotroped with toluene and then dried in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 95:5 to yield the title product, 980mg. ¹H NMR (CDCI₃, 400MHz) δ: 0.92 (t, 3H), 2.63 (s, 3H), 3.58 (m, 2H), 3.91 (m, 2H), 4.81 (s, 2H), 5.20 (m, 2H), 7.14 (m, 1 H), 8.16 (m, 1 H), 8.97 (m, 1 H)

MS APCI+ m/z 381 [MH]⁺

Preparation 155 5-Chloro-1 -(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolor4.3-(y|pyrimidine-3-carbaldehvde

The alcohol of Preparation 149 (90mg, 0.25mmol) was dissolved in dichloromethane (15.5mL) and the solution cooled to 0⁰C and treated with 1 ,1 ,1-triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 /-/)-one (112mg, 0.93mmol). The reaction mixture was stirred at room temperature for 2 hours and was then treated with saturated sodium thiosulphate solution (13mL), sodium hydrogencarbonate solution (13mL) and ether (13mL). The mixture was allowed to stand for 15 minutes before being extracted into dichloromethane (3x10OmL). The organics 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 to yield the title product, 53mg.

¹H NMR (CDCI₃, 400MHz) δ: 1.10 (m, 3H), 2.40 (s, 3H), 3.62 (m, 2H), 3.99 (t, 2H), 4.85 (m, 2H)₁ 6.90 (d, 1 H), 8.20 (d, 1H), 8.40 (m, 1 H), 10.35 (m, 1 H)

Preparation 156

Λ/-r3-(fe/t-Butyldimethylsilyloxymethyl)-5-chloro-1-f2-ethoxyethyl)-1 H-Pyrazolo[4.3-dlPyrimidin-7- vπpyrimidin-4-ylamine

Pyrimidin-4-ylamine (1.10g, 11.55mmol) was dissolved in tetrahydrofuran (3OmL) and the solution treated with sodium hexamethyldisilazide (2.12g, 11.55mmol) and stirred at room temperature for 20 minutes. The solution was treated with a solution of the dichloro compound of Preparation 92 (1.56g, 3.85mmol) in tetrahydrofuran (1OmL) and the reaction mixture stirred for 90 minutes at room temperature. The reaction mixture was quenched with ammonium chloride solution (10OmL) and extracted with dichloromethane (20OmL). The organic phase was separated, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 97:3 to yield the title product, 830mg.

¹H NMR (CDCI₃, 400MHz) δ: 0.00 (s, 6H), 0.77 (s, 9H), 1.08 (t, 3H), 3.54 (q, 2H), 3.80 (m, 2H), 4.63 (m, 2H), 4.90 (s, 2H), 8.33 (d, 1 H), 8.51 (d, 1 H), 8.77 (s, 1 H). MS APCI+ m/z 464 [MH]⁺

Preparation 157 [5-Chloro-1 -(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 /-/-pyrazolor4.3-dlpyrimidin-3-vπmethanol

The protected alcohol of Preparation 156 (2.Og, 1.76mmol) was dissolved in tetrahydrofuran (4OmL) and the solution treated with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (8.63mL, 8.63mmol). The reaction mixture was stirred for 90 minutes at room temperature and was then treated with additional tetrabutylammonium fluoride solution in tetrahydrofuran (4.32mL, 4.32mmol) and stirred for another hour. The reaction mixture was diluted with water (5OmL) and the aqueous extracted with ethyl acetate (3x50mL). The combined organics were dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 99:1 to 95:5 to yield the title product, 1.25g. ¹H NMR (CDCI₃, 400MHz) δ: 1.26 (t, 3H), 3.70 (q, 2H), 3.97 (m, 2H), 4.76 (m, 2H), 5.10 (s, 2H), 8.51 (d, 1 H), 8.72 (d, 1 H), 8.99 (s, 1 H). MS APCI+ m/z 350 [MH]⁺

Preparation 158 5-Chloro-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4,3-dlPyrimidine-3-carbaldehvde

The title aldehyde may be prepared by using the procedure of Preparation 155 by substituting [5-chloro-1- (2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 /-/-pyrazolo[4,3- c(|pyrimidin-3-yl]methanol (Preparation 143) for

[5-dimethylamino-1 -(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-3- yl]methanol (Preparation 151).

Preparation 159

3-(te/t-Butyldimethylsilyloxymethyl)-5-chloro-1 -(2-ethoxyethyl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolor4,3- dlpvrimidin-7-amine

The title compound may be prepared by reacting 3-(tert-Butyldimethylsilyloxymethyl)-5,7-dichloro-1 -(2- ethoxyethyl)-1 A7-pyrazolo[4,3-c/]pyrimidine (Preparation 92) according to the procedure of Preparation 156 by substituting 4-methyl-2-aminopyridine for 2-aminopyrimidine.

Preparation 160 tert-Butyl-4-(3-f[tert-butyl(dimethyl)silyl1oxy)-1-(2-ethoxyethyl)-7-r(4-methylpyridin-2-yl)amino1-1H- pyrazolof4.3-dlpyrimidin-5-yl)piperazine-1-carboxylate

3-{[tert-Butyl(dimethyl)silyl]oxy}-5-chloro-1-(2-ethoxyethyl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine (Preparation 159) may be converted to the title compound by using the procedure of Preparation 144 but substituting N-BOC-piperazine for dimethylamine in ethanol.

Preparation 161 tert-Butyl 4-(1-(2-ethoxyethyl)-3-(hvdroxymethyl)-7-[(4-methylPyridin-2-yl)aminol-1 H-pyrazolof4.3- dlpyrimidin-5-vl)piperazine-1 -carboxvlate

The title compound may be obtained by reacting tert-butyl-4-{3-{[tert-butyl(dimethyl)silyl]oxy}-1-(2- ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate (Preparation 160) according to substantially the conditions of Procedure 157 substituting Λ/-[3-(te/t- butyldimethylsilyloxymethyl)-5-chloro-1-(2-ethoxyethyl)-1 H-pyrazolo[4,3-cdpyrimidin-7-yl]pyrimidin-4- ylamine (Preparation 160) for [5-chloro-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 /-/-pyrazolo[4,3- cflpyrimidin-3-yl]methanol (Preparation 156). Preparation 162 tert-Butyl 4-(1-(2-ethoxyethyl)-3-formyl-7-[(4-methylpyridin-2-yl)amino1-1 H-pyrazolo[4.3-dlpyrimidin-5- vl}piperazine-1 -carboxvlate

The title compound may be prepared by tert-butyl 4- V{1-(2-ethoxyethyl)-3-(hydroxymethyl)-7-[(4- methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate (Preparation 161 ) in place of [5-dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolo[4,3-cdpyrimidin-3- yljmethanol (Preparation 144) according to Preparation 145. Preparation 163 tert-Butyl 4-(7-(4-methylpyridin-2-ylaminoM-(2-ethoxyethyl)-3-(1-hvdroxyethyl)-1 H-pyrazolor4,3- dlpyrimidin-5-vl)piperazine-1-carboxylate

The title alcohol may be obtained by employing the conditions of Example 320 but substituting the aldehyde from Preparation 162 for the aldehyde in Example 320.

Preparations 164 - 172

By following the procedure of Preparation 163 but substituting the specified alkyl magnesium halide, R₇MgX, for methylmagnesium halide the following compounds may be prepared:

Preparation 173 tert-ButvU-rs-drtert-butvKdimethvDsilylloxylmethvD-i -^-ethoxyethvD-y-fpyrimidin^-ylaπninoVI H- Pvrazolo[4.3-dlpvrimidin-5-vllpiperazine-1 -carboxvlate

The silyl protected alcohol from Preparation 156 can be treated according to the procedure of Preparation 160 where the product of Preparation 156 is substituted for 3-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-1-(2- ethoxyethyl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (Preparation 159) to obtain the title compound.

Preparation 174 tert-Butyl 4-(1-(2-ethoxyethyl)-3-(hvdroxymethvπ-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4.3-dlPyrimidin-5- vl)piperazine-1 -carboxvlate

The title compound may be prepared by treating the the silyl protected alcohol prepared in Preparation 173 according to the conditions of Preparation 161 but substituting tert-butyl 4-(1-(2-ethoxyethyl)-3- (hydroxymethyl)-7-(pyrimidin-4-ylamino)-i H-pyrazolo[4,3-d]pyrimidin-5-yl)piperazine-1-carboxylate ( Preparation 173) for tert-butyl-4-{3-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2-ethoxyethyl)-7-[(4-methylpyridin-2- yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate (Preparation 160).

Preparation 175 tert-Butyl 4-(1-(2-ethoxyethyl)-3-formyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4.3-dlpyrimidin-5- vl)piperazine-1 -carboxvlate

The title compound may be prepared by treating tert-butyl 4-(1-(2-ethoxyethyl)-3-(hydroxymethyl)-7- (pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)piperazine-1-carboxylate (Preparation 174) in place of 5-dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidine-3- carbaldehyde according to Preparation 145.

Preparation 176 tert-Butyl 4-(1 -(2-ethoxyethyl)-3-(1-hvdroxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolof4.3-dipyrimidin-5- vl)piperazine-1 -carboxvlate

The title alcohol may be obtained by employing the conditions of Example 320 but substituting the aldehyde from Preparation 175 for the aldehyde in Preparation 145.

Preparation 177 - 184

By following the procedure of Preparation 176 but substituting the specified alkyl magnesium halide, R₇MgX₁ for methylmagnesium halide the following compounds may be prepared:

Preparation 185

3-(([tert-Butyl(dimethyl)silylloxy)methyl)-1 -(2-ethoxyethyl)-5-r(3R)-3-methylpiperazin-1-vn-N-pyrimidin-4-yl-

1 H-pyrazolo[4.3-dlpyrimidin-7-amine

3-{[tert-Butyl(dimethyl)silyl]oxy}-5-chloro-1 -(2-ethoxyethyl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine (Preparation 156) may be converted to the title compound by using the procedure of Preparation 144 but substituting 2-( R ) - methylpiperazine for dimethylamine in ethanol.

Preparation 186

Benzyl (2R)-4-f3-((rtert-butyl(dimethyl)silyl1oxy)methyl)-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H- Pyrazolof4.3-d1pyrimidin-5-yl1-2-methylpiperazine-1-carboxylate

The Cbz protected derivative of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(2-ethoxyethyl)-5-[(3R)-3- methylpiperazin-1 -yl]-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine (Preparation 185) may be prepared according to the procedure of Biorg. Med. Chem., 12, 2027 - 2030 (2002). Preparation 187

Benzyl (2R)-4-f1 -(2-ethoxyethyl)-3-(hvdroxymethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4,3-dlpyrimidin-5- yll-2-methylpiperazine-i-carboxylate

The title compound may be prepared by treating the the silyl protected alcohol prepared in Preparation 186 according to the conditions of Preparation 161 but substituting benzyl (2R)-4-[3-({[tert- butyl(dimethyl)silyl]oxy}methyl)-1 -(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5- yl]-2-methylpiperazine-1-carboxylate (Preparation 186) for tert-butyl-4-{3-{[tert-butyl(dimethyl)silyl]oxy}-1- (2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate (Preparation 161 ).

Preparation 188

(R)-Benzyl 4-(1-(2-ethoxyethyl)-3-formyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4.3-dlpyrimidin-5-yl)-2- methvlpiperazine-1 -carboxylate

The title compound may be prepared according to Preparation 145 by substituting benzyl (2R)-4-[1-(2- ethoxyethyl)-3-(hydroxymethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]-2- methylpiperazine-1 -carboxylate (Preparation 187) for [5-dimethylamino-1-(2-ethoxyethyl)-7-(4- methylpyridin-2-ylamino)-1 /-/-pyrazolo[4,3-c/|pyrimidin-3-yl]methanol (Preparation 144).

Preparation 189

(R)-Benzyl 4-(1-(2-ethoxyethyl)-3-(1-hvdroxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolof4.3-dlpyrimidin-5- yl)-2-methvlpiperazine-1-carboxylate

The title compound may be prepared by reacting (R)-benzyl 4-(1-(2-ethoxyethyl)-3-formyl-7-(pyrimidin-4- ylamino)-i H-pyrazolo[4,3-d]pyrimidin-5-yl)-2-methylpiperazine-1 -carboxylate ( Preparation 188) with methylmagnesium halide according to the conditions of Example 320 but substituting the aldehyde of Preparation 188 for 5-dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolo[4,3- cdpyrimidine-3-carbaldehyde (Preparation 145).

Preparations 190 - 198

By following the procedure of Preparation 189 but substituting the specified alkyl magnesium halide, R₇MgX, for methylmagnesium halide the following compounds may be prepared:

Preparation 199

(R)-Benzyl 4-(3-(1 -chloroethyl)-1 -(2-ethoxyethylV7-(pyrimidin-4-ylamino)-1 H-pyrazolor4.3-dlpyrimidin-5- yl)-2-methylpiperazine-1-carboxylate

The alcohol prepared in Preparation 189 may be converted to the corresponding title compound by reaction with thionyl chloride according to Preparation 154 but substituting (R)-benzyl 4-(1-(2-ethoxyethyl)- 3-(1-hydroxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-2-methylpiperazine-1 - carboxylate (Preparation 189) for 5-chloro-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H- pyrazolo[4,3-αf|pyrimidin-3-yl]methanol (Preparation 143).

Preparations - 200-208

The following chloro-compounds may be prepared by substituting the appropriate alcohol prepared according to Preparation 189 -198 for (R)-benzyl 4-(1-(2-ethoxyethyl)-3-(1 -hydroxyethyl)-7-(pyrimidin-4- ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-2-methylpiperazine-1 -carboxylate ( Preparation 199).

Preparation 209

(R)-Benzyl 4-(3-(1-ethoxyethyl)-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylannino)-1 H-pyrazolor4.3-dlPyrimidin-5- yl)-2-methvlpiperazine-1-carboxvlate

The title compound may be prepared according to the conditions of Preparation 101 , step 2 but using (R)- benzyl 4-(3-(1-chloroethyl)-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-2- methylpiperazine-1-carboxylate (Preparation 189) for the dichloride prepared in Example 196 Preparation 101 , Step 1.

Preparations 210 - 218

The following ethyloxy-compounds may be prepared according to Preparation 209 by substituting the appropriate chloro derivative prepared according to Preparation 200 - 208 for (R)-benzyl 4-(3-(1 - chloroethyl)-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)-2- methylpiperazine-1-carboxylate ( Preparation 199).

Preparation 219

(5-(Dimethylamino)-1-(2-ethoxyethyl)-7-r(4-methylpyridin-2-yl^aminol-1 H-pyrazolor4.3-dlPyrimidin-3- vDacetaldehyde

5-Dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolo[4,3-d]pyrimidine-3- carbaldehyde prepared in Preparation 153 may be homologated to {5-(dimethylamino)-1-(2-ethoxyethyl)- 7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl}acetaldehyde by treating the aldehyde with (methoxymethyl)triphenylphosphonium chloride with the present of sodium bis(trimethylsilyl)amide then acid hydrolysis of the resulting enol ethers according the procedures of Tetrahedron Lett. 2003, 44(42), 7731-7733.

Preparation 220

2-{5-(Dimethylamino)-1-(2-ethoxyethyl)-7-r(4-methylpyridin-2-yl)aminol-1 H-pyrazolof4.3-dlpyrimidin-3- vPethanol

{5-(Dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3- yljacetaldehyde prepared in Preparation 219 may be reduced to 2-{5-(dimethylamino)-1-(2-ethoxyethyl)-7- [(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl}ethanol by treating the aldehyde with DIBAL-H according the procedures of Tetrahedron Lett. 2003, 44(42), 7731-7733.

Preparation 221

3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N-5-.N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolof4.3- dlpvrimidine-5,7-diamine

2-{5-(Dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3- yljethanol prepared in Preparation 220 may be converted to 3-(2-chloroethyl)-1-(2-ethoxyethyl)-N-5-,N-5- dimethyl-N-7-(4-methylpyridin-2-yl)-1H-pyrazo!o[4,3-d]pyrimidine-5,7-diamine by a method described in Preparation 154.

Preparation 222

1 ,3-Bis(2-ethoxyethyl)-N-5-.N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolor4,3-dlpyrimidine-5.7- diamine

3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine prepared in Preparation 221 may be converted to 1 ,3-bis(2-ethoxyethyl)-N-5-,N- 5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine by treating the chloride with sodium ethanoxide according to the procedure of Preparation 101 , Step 2.

Preparation 223

Benzyl 4-f3-(([tert-butyl(dimethyl)silylloxy)methyl)-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H- pyrazolof4.3-dipyrimidin-5-yl1piperazine-1 -carboxylate

Λ/-[3-(tert-Butyldimethylsilyloxymethyl)-5-chloro-1-(2-ethoxyethyl)-1 H-pyrazolo[4,3-c(]pyrimiclin-7- yl]pyrimidin-4-ylamine prepared in Preparation 156 may be converted to the title compound by using the procedure of Preparation 144 but substituting benzyl piperazine-1-carboxylate for dimethylamine in ethanol.

Preparation 224

Benzyl 4-[1-(2-ethoxyethyl)-3-(hvdroxymethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4.3-d1pyrimidin-5- ylipiperazine-1 -carboxylate

The title compound may be obtained by treating the silyl ether prepared in Preparation 223 with 1.0 N tetrabutylammonium chloride solution in tetrahydrofuran according to the procedure step 2 in Preparation 157.

Preparation 225

Benzyl 4-ri-(2-ethoxyethyl)-3-formyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolof4.3-dlpyrimidin-5-ylipiperazine-

1 -carboxylate

The title compound may be obtained by substituting benzyl 4-[1 -(2-ethoxyethyl)-3-(hydroxymethyl)-7- (pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate for [5-dimethylamino-1-(2- ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 /-/-pyrazolo[4,3-c(]pyrimidin-3-yl]methanol in Preparation 153.

Preparation 226

Benzyl 4-[1 -(2-ethoxyethyl)-3-(2-oxoethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolof4.3-d1pyrimidin-5- vllpiperazine-i -carboxvlate

Benzyl 4-[1-(2-ethoxyethyl)-3-formyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine- 1 -carboxylate prepared in Preparation 225 may be homologated to benzyl 4-[1-(2-ethoxyethyl)-3-(2- oxoethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1 -carboxylate by treating the aldehyde from Preparation 225 with (methoxymethyl)triphenylphosphonium chloride with the present of sodium bis(trimethylsilyl)amide then acid hydrolysis of the resulting enol ethers according the procedures of Tetrahedron Lett. 2003, 44(42), 7731-7733.

Preparation 227

Benzyl 4-[1-(2-ethoxyethyl)-3-(2-hvdroxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4.3-dlpyrimidin-5- yllpiperazine-1 -carboxylate

Benzyl 4-[1-(2-ethoxyethyl)-3-(hydroxymethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5- yl]piperazine-1 -carboxylate prepared in Preparation 226 may be reduced to benzyl 4-[1 -(2-ethoxyethyl)-3- (2-hydroxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1 -carboxylate by treating the aldehyde with NaBH4 according the procedures of J. O. C. 57(13), 3732-5; 1992.

Preparation 228

Benzyl 4-r3-(2-chloroethyl)-1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolor4.3-d1Pyrimidin-5- vHpiperazine-1 -carboxylate

The title compound may be obtained by substituting benzyl 4-[1-(2-ethoxyethyl)-3-(2-hydroxyethyl)-7- (pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1 -carboxylate prepared in Preparation 227 for 2-{5-(dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4₎3- d]pyrimidin-3-yl}ethanol in Preparation 148.

Preparation 229

Benzyl 4-f1 ,3-bis(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolof4.3-dlPyrimidin-5-vnpiperazine-1- carboxylate

The title compound may be obtained by substituting benzyl 4-[3-(2-chloroethyl)-1 -(2-ethoxyethyl)-7- (pyrimidin-4-ylamino)-i H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate prepared in Preparation 228 for 3-(2-chloroethyl)-1 -(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine in Preparation 222.

Preparation 230 1.3-Bis(2-ethoxyethyl)-5-piperazin-1-yl-N-pyrimidin-4-yl-1 H-pyrazolor4.3-d1pyrimidin-7-amine

The title compound may be obtained by reacting benzyl 4-[1 ,3-bis(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperazine-1-carboxylate prepared in Preparation 229 in ethanol and cone. HCI under a hydrogen atmosphere according the procedures of Tetrahedron: Asymmetry 15 (2004) 1259-1267.

Preparation 231 3-(2-chlorobutyl)-1-(2-ethoxyethyl)-N-5~.N~5~-dimethyl-N~7~-(4-methylpyridin-2-yl)-1 H-pyrazolof4.3- dipyrim idine-5.7-diam ine

The alcohol prepared in Example 423 may be converted to the corresponding title compound by reaction with thionyl chloride according to Preparation 154 but substituting 1-{5-(dimethylamino)-1-(2-ethoxyethyl)- 7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl}butan-2-ol for [5-Chloro-1 -(2-ethoxyethyl)- 7-(4-methylpyridin-2-ylamino)-1 H-pyrazolo^.S-Gflpyrimidin-S-yllmethanol (Preparation 152).

Preparation 232-235

The following chloro-compounds may be prepared by substituting the appropriate alcohol prepared according Preparation 231 for 1-{5-(dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin-2-yl)amino]-1 H- pyrazolo[4,3-d]pyrimidin-3-yl}butan-2-ol in Preparation 231.

Preparation 236

3-(2-ethoxybutyl)-1-(2-ethoxyethyl)-N-5-.N-5-dimethyl-N-7-(4-methylpyridin-2-vπ-1 H-pyrazolof4.3- d1pvrimidine-5.7-diamine

The title compound may be prepared according to the conditions of Preparation 222 but substituting 3-(2- chlorobutyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidine- 5,7-diamine (Preparation 233) for 3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4- methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine.

Preparation 237

1-(2-ethoxyethyl)-3-(2-ethoxy-3-methylbutyl)-N-5-.N-5-dimethyl-N-7-(4-methylpyridin-2-vn-1 H-

Pyrazolof4,3-d1pyrimidine-5.7-diamine

The title compound may be prepared according to the conditions of Preparation 222 but substituting 3-(2- chloro-3-methylbutyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine (Preparation 233) for 3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7- (4-methylpyridin-2-yl)-1H-pyrazolo[4,3-d]pyrimidine-5,7-diamine.

Preparation 238

3-(2-Cvclopropyl-2-ethoxyethyl)-1-(2-ethoxyethyl)-N-5-.N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H- pyrazolor4.3-dipyrimidine-5.7-diamine

The title compound may be prepared according to the conditions of Preparation 222 but substituting 3-(2- chloro-2-cyclopropylethyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine (Preparation 234) for 3-(2-Chloroethyl)-1-(2-ethoxyethyl)-N-5-,N-5-dimethyl-N-7- (4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrim idine-5,7-diam ine.

Preparation 239

3-(terf-Butyldimethylsilanyloxymethyl)-5.7-dichloro-r2-(2.2.2-trifluoroethoxy)ethvn-11H-pyrazolor4.3- dlpyrimidine

Imidazole (1.10g, 16.2mmol) and tert-butyldimethylsilyl chloride (2.24g, 14.9mmol) were added to a solution of the alcohol from Preparation 98 (4.66g, 13.5mmol) in dichloromethane (7OmL), and the reaction stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane (15OmL), and washed with water (2 x 50 ml_). The organic solution was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane as eluant to afford the title compound, 5.44g.

¹H NMR (d₆-DMSO, 400 MHz) δ: 0.07(s, 6H), 0.83 (s, 9H), 4.0 (m, 4H), 4.85 (m, 2H), 4.95 (s, 2H). MS : calc: 459.1 ; found(relative intensity), m/z API-ES [MH⁺], 459.1 (90), 461.1(60), 462.1 (20).

Additional compounds of Formula I that can be prepared in accordance with the synthetic methods of the present invention include those compounds described below:

H-

ine

H-

- H-

- -

-

H-

- -

H-

Example 320

1 -(7-(4-Methylpyridin-2-ylamino)-5-(dimethylamino)-1 -(2-ethoxyethyl)-1 H-pyrazolo[4.3-dlpyrimidin-3- vDethanol

The title alcohol may be obtained by reacting the aldehyde from Preparation 145 with substantially equivalent quantities of methylmagnesium halide (e.g. chloride or bromide, commercially available in ether solvents from e.g. Aldrich) in an anhydrous ether solvent (e.g. tetrahydrofuran or diethyl ether) according to substantially the procedure and purification conditions of either Eur. J. Med. Chem., 38(1 ) 75 -87(2003) or J. Org. Chem., 51(25) 4920-4924(1998).

Example 321 - 328

The by following the procedure of Example 320 but substituting the specified alkyl magnesium halide, R₇MgX, for methylmagnesium halide the following compounds may be prepared:

Example 329

1 -(7-(4-Methylpyridin-2-ylamino)-1 -(2-ethoxyethyl)-5-(piperazin-1 -yl)-1 H-pyrazolor4.3-dlpyrimidin-3-

The title compound may be obtained by reacting tert-butyl 4-(7-(4-methylpyridin-2-ylamino)-1-(2- ethoxyethyl)-3-(1 -hydroxyethyl)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)piperazine-1 -carboxylate ( Preparation 159) with either neat trifluoroacetic acid (TFA) or TFA in dichloromethane and purifying by reverse phase chromatography to obtain the TFA salt.

Examples 330-338

By following the procedure of Example 329 but substituting the specified alcohol in Example 329 for the appropriate alcohol from Preparation 164-172 the following compounds may be prepared:

Example 339

1-(1-(2-Ethoxvethvl)-5-(piperazin-1-vl)-7-(pvrimidin-4-vlamino)-1 H-Dvrazolof4.3-dlpvrimidin-3-vl)ethanol

The title compound may be obtained by reacting tert-butyl 4-(1-(2-ethoxyethyl)-3-(1-hydroxyethyl)-7- (pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)piperazine-1-carboxylate (Preparation 176) with either neat trifluoroacetic acid (TFA) or TFA in dichloromethane and purifying by reverse phase chromatography.

Examples 340 - 348

By following the procedure of Example 339 but substituting the appropriate alcohol from Preparation 177- 184 for tert-butyl 4-(1-(2-ethoxyethyl)-3-(1-hydroxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3- d]pyrimidin-5-yl)piperazine-1-carboxylate (Preparation 176) the following compounds may be prepared:

Examples 349 - 358

The following compounds may be prepared using the compounds prepared in Preparations 189 - 198 and removing the benzyl carbamate (Cbz) group according to the procedures outlined in T. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John-Wiley and Sons, New York, 1991 , pp. 335- 338.

Examples 359 - 368

The following compounds may be prepared using the compounds prepared in Preparations 209 - 219 and removing the benzyl carbamate (Cbz) group according to the procedures outlined in T. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John-Wiley and Sons, New York, 1991 , pp. 335- 338.

-

-(2-

H-

- -

-yl-

Example 423

1-(5-(dimethylamino)-1-(2-ethoxyethyl)-7-r(4-methylpyridin-2-yl)aminol-1 H-pyrazolor4.3-dlpyrimidin-3- vl)butan-2-ol

The title alcohol may be obtained by substituting {5-(dimethylamino)-1-(2-ethoxyethyl)-7-[(4-methylpyridin- 2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-3-yl}acetaldehyde prepared in Preparation 219 for 5- dimethylamino-1-(2-ethoxyethyl)-7-(4-methylpyridin-2-ylamino)-1 H-pyrazolo[4,3-c(lpyrimidine-3- carbaldehyde in Example 320.

The following compounds form further aspects of the present invention:

In another embodiment, compounds of the present invention are selected from the group consisting of

1-(2-ethoxyethyl)-3-ethyl-5-piperazin-1-yl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

S-methyl-δ-piperazin-i-yl-N-pyrimidin^-yl-i-^^^^-trifluoroethoxyJethylJ-IH-pyrazoloK.S-dJpyrimidin^- amine;

1-(2-ethoxyethyl)-3-methyl-5-piperazin-1-yl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 1-(2-ethoxyethyl)-3-isopropyl-5ψiperazin-1-yl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-isopropyl-5-piperazin-1 -yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-

7-amine;

5-piperazin-1 -yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-annine; 1-(2-ethoxyethyl)-5-piperazin-1 -yl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-isopropyl-5-piperazin-1 -yl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-isopropyl-5-piperazin-1 -yl-N-pyridin-2-yl-1-[2-(2,2,2-trifiuoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-piperazin-1-yl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 1 -(2-ethoxyethyl)-5-piperazin-1 -yl-N-pyridin-2-yl- 1 H-pyrazolo[4,3-d]pyrim idin-7-am ine;

3-ethyl-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-methyl-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine; 1-(2-ethoxyethyl)-3-methyl-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-isopropyl-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

3-isopropyl-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; N-(5-methylpyridin-2-yl)-5-piperazin-1 -yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-isopropyl-5-[(3S)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-

7-amine; and 3-isopropyl-5-[(3S)-3-methylpiperazin-1 -yl]-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine.

In another embodiment, compounds of the present invention are selected from the group consisting of5-

[(3S)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-isopropyl-5-[(3S)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

3-isopropyl-5-[(3S)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine; 5-[(3S)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3S)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-ethyl-5-[(3S)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine; 3-methyl-5-[(3S)-3-methylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 1-(2-ethoxyethyl)-3-isopropyl-5-[(3S)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-isopropyl-5-[(3S)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3S)-3-methylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3S)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-3-isopropyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin- 7-amine;

3-isopropyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R)-3-methylpiperazin-1 -yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 1 -(2-ethoxyethyl)-3-isopropyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

3-isopropyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

5-[(3R)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolot4,3-d]pyrimidin-7-amine;

3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

3-methyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1-[2-(2_>2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; and

1-(2-ethoxyethyl)-3-isopropyl-5-[(3R)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine.

In another embodiment, compounds of the present invention are selected from the group consisting of 3-isopropyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R)-3-methylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1-(2-ethoxyethyl)-3-methyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-isopropyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-t(3R,5S)-3,5-dimethylpipera2in-1-yl]-3-isopropyl-N-pyrimidin-4-yl-1-t2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine; 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[(3R_>5S)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine; 5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1 -(2-ethoxyethyl)-3-isopropyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-3-isopropyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

5-[(3R_I5S)-3,5-dimethylpiperazin-1-yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[(3R,5S)-3,5-dimethy!piperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-

1 H-pyrazolo[4,3-d]pyrim idin-7-am ine; and

5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-3-methyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-

1 H-pyrazolo[4,3-d]pyrimidin-7-amine.

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-(5-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-isopropyl-N-(5-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-[2-(2_l2_I2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine; 5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5R)-3,5-dimethylpiperazin-1 -yl]-i -(2-ethoxyethyl)-3-methyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-i-(2-ethoxyethyl)-3-isopropyl-N-pyrinnidin-4-yl-1 l-l-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-isopropyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 l-|- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-t(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine; 5-[(3R,5R)-3,5-dimethylpiperazin-1 -yl]-3-ethyl-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-pyridin-2-yl-1 l-l-pyrazolot4,3- d]pyrimidin-7-amine;

5-t(3R,5R)-3,5-dimethylpiperazin-1-yl]-1 -(2-ethoxyethyl)-3-isopropyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-isopropyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5R)-3,5-dimethylpiperazin-1 -yl]-N-pyridin-2-yl-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine; and

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine.

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-

1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-

1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-(5-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-isopropyl-N-(5-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine; 5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-t2-(2,2_l2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5R)-3,5-dimethylpiperazin-1 -yl]-i -(2-ethoxyethyl)-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

S-pR.SSJ-S.δ-dimethylpiperazin-i-ylJ-S-ethyl-N-pyrimidin^-yl-i-^^^^-trifluoroethoxyJethyll-I H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-pyrimidin-4-yl-1 H-pyrazolot4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-isopropyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-3-isopropyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1 -(2-ethoxyethyl)-3-methyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-isopropyl-N-pyridin-2-yl-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-3-isopropyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; and

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine.

In another embodiment, compounds of the present invention are selected from the group consisting of 5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1-(2-ethoxyethyl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-ethyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-

1 H-pyrazolo[4,3-d]pyrim idin-7-am ine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-methyl-N-(5-methylpyridin-2-yl)-1H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-t(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1 -(2-ethoxyethyl)-3-isopropyl-N-(5-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-t(3R,5S)-3,5-dimethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-ethyl-5-[(3S)-3-ethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 5-[(3S)-3-ethylpiperazin-1 -yl]-3-methyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-3-methyl-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-3-isopropyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[(3S)-3-ethylpiperazin-1-yl]-3-isopropyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3S)-3-ethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-5-[(3S)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-ethyl-5-[(3S)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3S)-3-ethylpiperazin-1-yl]-3-methyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; and

1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-3-methyl-N-pyridin-2-yl-1H-pyrazolo[4,3-d]pyrimidin-7- amine.

In another embodiment, compounds of the present invention are selected from the group consisting of 1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-3-isopropyl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[(3S)-3-ethylpiperazin-1-yl]-3-isopropyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3S)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin- 7-amine;

1 -(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 1-(2-ethoxyethyl)-3-ethyl-5-[(3S)-3-ethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

S-ethyl-S-KSSJ-a-ethylpiperazin-i-yll-N^S-methylpyridin-Z-yO-i-^^Z^^-trifluoroethoxyJethyll-IH- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3S)-3-ethylpiperazin-1 -yl]-3-methyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-3-methyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1 -yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-annine;

5-[(3S)-3-ethylpiperazin-1 -yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3S)-3-ethylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolot4,3- d]pyrimidin-7-amine; 1-(2-ethoxyethyl)-5-[(3S)-3-ethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

3-ethyl-5-[(3R)-3-ethylpiperazin-1-yl]-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

5-[(3R)-3-ethylpiperazin-1-yl]-3-methyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-3-methyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1 -yl]-3-isopropyl-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7- amine; 5-[(3R)-3-ethylpiperazin-1 -yl]-3-isopropyl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R)-3-ethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; and 1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1H-pyrazolo[4,3-d]pyrimidin-7- amine.

3-ethyl-5-[(3R)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R)-3-ethylpiperazin-1 -yl]-3-methyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-3-methyl-N-pyridin-2-yl-1H-pyrazolo[4,3-d]pyrimidin-7- amine; 1 -(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1 -yl]-3-isopropyl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine; 5-[(3R)-3-ethylpiperazin-1-yl]-3-isopropyl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-

7-amine; 1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-ethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-ethy!-5-[(3R)-3-ethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-[(3R)-3-ethylpiperazin-1 -yl]-3-methyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-3-methyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R)-3-ethylpiperazin-1-yl]-3-isopropyl-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R)-3-ethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine; 1 -(2-ethoxyethyl)-5-[(3R)-3-ethylpiperazin-1-yl]-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

(3S)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyrimidin-4-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid;

(3S)-1-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-methyl-7-(pyrimidin-4-ylarnino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-

3-carboxylic acid; and (3S)-1-{3-isopropyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-

5-yl}piperidine-3-carboxylic acid.

(3S)-1-{7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3S)-1-[1 -(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3-carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid; (3S)-1 -{3-ethyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid; - -

(3S)-1-{3-methyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5- ylJpiperidine-3-carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-methyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid; (3S)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid;

(3S)-1-{3-isopropyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3S)-1-{7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine- 3-carboxylic acid;

(3S)-1 -[1-(2-ethoxyethyl)-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3-carboxylic acid;

(3S)-1-{1-(2-ethoxyethyl)-3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid; (3S)-1-{3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxylic acid;

(3S)-1 -{3-methyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxylic acid;

(3S)-1 -{1-(2-ethoxyethyl)-3-methyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3S)-1-{1-(2-ethoxyethyl)-3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3S)-1-{3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxylic acid; (3S)-1-{7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3S)-1-{1-(2-ethoxyethyl)-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine-3- carboxylic acid;

(3R)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid; and

(3R)-1-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid.

In another embodiment, compounds of the present invention are selected from the group consisting of (3R)-1-[1-(2-ethoxyethyl)-3-methyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid;

(3R)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-

3-carboxylic acid;

(3R)-1-{3-isopropyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin- 5-yl}piperidine-3-carboxylic acid; (3R)-147-(pyrimidin-4-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3R)-1 -[1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3-carboxylic acid; (3R)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid;

(3R)-1-{3-ethyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3R)-1-{3-methyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3R)-1 -[1-(2-ethoxyethyl)-3-methyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid;

(3R)-1 -[1-(2-ethoxyethyl)-3-isopropyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]piperidine-3- carboxylic acid; (3R)-1-{3-isopropyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3R)-1-{7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine-

3-carboxylic acid;

(SRJ-i-ti^-ethoxyethyO^^pyridin^-ylaminoJ-I H-pyrazolo^.S^pyrimidin-S-yllpiperidine-S-carboxylic acid;

(3R)-1 -{1-(2-ethoxyethyl)-3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(SRJ-i -iS-ethyl^-KS-rnethylpyridin^-yOaminol-i-^^^^-trifluoroethoxyJethyll-I H-pyrazolo^.S- d]pyrimidin-5-yl}piperidine-3-carboxylic acid; (3R)-1-{3-methyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxylic acid;

(3R)-1-{1-(2-ethoxyethyl)-3-methyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3R)-1-{1-(2-ethoxyethyl)-3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxylic acid;

(3R)-1 -{1-(2-ethoxyethyl)-3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxylic acid; and

(3R)-1-{3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- dlpyrimidin-S-ylJpyrrolidine-S-carboxylic acid.

(3R)-1 -{3-methyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}pyrrolidine-3-carboxylic acid;

(3R)-1-{1-(2-ethoxyethyl)-3-methyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxylic acid; (3R)-1-{1-(2-ethoxyethyl)-3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxylic acid;

(3R)-1-{3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- dlpyrimidin-δ-ylJpyrrolidine-S-carboxylic acid; (3R)-1-{7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-S-carboxylic acid;

(3R)-1-{1-(2-ethoxyethyl)-7-[(5-methylpyridin-2-yl)amino]-1H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidiπe-3- carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxylic acid;

(3S)-1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-S-carboxylic acid;

(3S)-1-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-S-carboxylic acid; (3S)-1-[1-(2-ethoxyethyl)-3-methyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrirτiidin-5-yl]pyrrolidine-

3-carboxylic acid;

(3S)-1 -{3-isopropyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4_>3-d]pyrimidin- δ-ylJpyrrolidine-S-carboxylic acid;

(3S)-1-{7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxylic acid;

(SSJ-i-ti^-ethoxyethyl^^pyrimidin^-ylaminoJ-I H-pyrazoloK.S-dlpyrimidin-S-yllpyrrolidine-S-carboxylic acid; (3S)-1-[1 -(2-ethoxyethyl)-3-ethyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxylic acid;

(3S)-1-{3-ethyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-3-carboxylic acid;

(3S)-1-{3-methyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxylic acid;

(3S)-1 -[1 -(2-ethoxyethyl)-3-methyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxylic acid;

(3S)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxylic acid; and (3S)-1-{3-isopropyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-S-carboxylic acid.

In another embodiment, compounds of the present invention are selected from the group consisting of (3S)-1-{7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidine- 3-carboxylic acid; (3S)-1-[1-(2-ethoxyethyl)-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3-carboxylic acid;

(3S)-1 -{ 1 -(2-ethoxyethyl)-3-ethyl-7-[(5-methylpyridin-2-yl)am ino]-1 H-pyrazolo[4,3-d]pyrim idin-5- yl}pyrrolidine-3-carboxylic acid; (3S)-1 -{3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- djpyrim idin-δ-ylJpyrrolidine-S-carboxylic acid;

(3S)-1-{3-methyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrim idin-δ-ylJpyrrolidine-S-carboxylic acid;

(3S)-1-{1-(2-ethoxyethyl)-3-methyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-3-carboxylic acid;

(3S)-1-{1 -(2-ethoxyethyl)-3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- ylJpyrrolidine-S-carboxylic acid;

(3S)-1-{3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-5-yl}pyrrolidine-3-carboxylic acid; (3S)-1-{7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxylic acid;

(3S)-1-{1 -(2-ethoxyethyl)-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidine-3- carboxylic acid;

(3S)-N-[I -(2-ethoxyethyl)-3-ethyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3S)-N-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3S)-N-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide; (3S)-N-[I -(2-ethoxyethyl)-3-methyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3S)-N-[I -(2-ethoxyethyl)-3-isopropyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-

3-carboxamide;

(3S)-N-{3-isopropyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin- 5-yl}pyrrolidine-3-carboxamide;

(3S)-N-{7-(pyrimidin-4-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3S)-N-[I -(2-ethoxyethyl)-7-(pyrimidiπ-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide; (3S)-N-[I -(2-ethoxyethyl)-3-ethyl-7-(pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide; and

(3S)-N-{3-ethyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide.

In another embodiment, compounds of the present invention are selected from the group consisting of (3S)-N-{3-methyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxam ide;

(3S)-N-[I -(2-ethoxyethyl)-3-methyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide; (3S)-N-[I -(2-ethoxyethyl)-3-isopropyl-7-(pyridin-2-ylamino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3S)-N-{3-isopropyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3S)-N-{7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidine- 3-carboxamide;

(3S)-N-[I -(2-ethoxyethyl)-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3S)-N-{1-(2-ethoxyethyl)-3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxam ide; (3S)-N-{3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}pyrrolidine-3-carboxamide;

(3S)-N-{3-methyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}pyrrolidine-3-carboxamide;

(3S)-N-{1-(2-ethoxyethyl)-3-methyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3S)-N-{1-(2-ethoxyethyl)-3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3S)-N-{3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- djpyrim idin-5-yl}pyrrolidine-3-carboxam ide; (3S)-N-{7-[(5-methylpyridin-2-yl)amino]-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3S)-N-{1-(2-ethoxyethyl)-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidine-3- carboxamide;

(3R)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3R)-1-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide; (3R)-1 -[1 -(2-ethoxyethyl)-3-methyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-

3-carboxamide; and

(3R)-1-{3-isopropyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin- 5-yl}pyrrolidine-3-carboxamide. In another embodiment, compounds of the present invention are selected from the group consisting of

(3R)-1-{7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3R)-1-[1-(2-ethoxyethyl)-7-(pyrimidin-4-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-[1-(2-ethoxyethyl)-3-ethyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-{3-ethyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxam ide; (3R)-1 -{3-methyl-7-(pyridin-2-ylamino)-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxam ide;

(3R)-1-[1-(2-ethoxyethyl)-3-methyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-[1-(2-ethoxyethyl)-3-isopropyl-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-{3-isopropyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3R)-1-{7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidine-

3-carboxamide; (3R)-1 -[1-(2-ethoxyethyl)-7-(pyridin-2-ylamino)-1 H-pyrazolo[4,3-d]pyrimidin-5-yl]pyrrolidine-3- carboxamide;

(3R)-1-{1 -(2-ethoxyethyl)-3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3R)-1-{3-ethyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}pyrrolidine-3-carboxamide;

(3R)-1-{3-methyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- djpyrim idin-5-yl}pyrrolidine-3-carboxam ide;

(3R)-1-{1-(2-ethoxyethyl)-3-methyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxam ide; (3R)-1 -{1 -(2-ethoxyethyl)-3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3R)-1-{3-isopropyl-7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- dlpyrimidin-δ-ylJpyrrolidine-S-carboxamide;

(3R)-1-{7-[(5-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}pyrrolidine-3-carboxamide;

(3R)-1 -{1-(2-ethoxyethyl)-7-[(5-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidine-3- carboxamide;

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-pyrimidin-4-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine; and

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-methyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine.

In another embodiment, compounds of the present invention are selected from the group consisting of 5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-isopropyl-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-3-isopropyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4_l3- d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-(1 ,4-diazepan-1 -yl)-1-(2-ethoxyethyl)-N-pyrimidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-3-ethyl-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-

7-amine; 5-(1 ,4-diazepan-1-yl)-3-methyl-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-

7-amine;

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-methyl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1 -yl)-1-(2-ethoxyethyl)-3-isopropyl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1 -yl)-3-isopropyl-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1-yl)-1 -(2-ethoxyethyl)-3-ethyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine; 5-(1 ,4-diazepan-1-yl)-3-ethyl-N-(5-methy!pyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1 -yl)-3-methyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(1 ,4-diazepan-1 -yl)-1 -(2-ethoxyethyl)-3-methyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-isopropyl-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-(1 ,4-diazepan-1 -yl)-3-isopropyl-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-(1 ,4-diazepan-1 -yl)-N-(5-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; and

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine.

The following compounds form further aspects of the present invention: A compound of formula (VII)

(VII) - - wherein R and R are as defined above.

Preferred is a compound of formula (VII^A)

wherein R and R are as defined above.

A compound of formula (VIII)

(VIII) wherein R¹, R², R⁵ and R⁶ are as defined above.

Preferred is a compound of formula (VIII )

(VIII^A) wherein R¹, R², R⁵ and R⁶ are as defined above.

The invention is further illustrated by the following, non-limiting examples.

Melting points were determined on a Gallenkamp melting point apparatus using glass capillary tubes and are uncorrected. Unless otherwise indicated all reactions were carried out under a nitrogen atmosphere, using commercially available anhydrous solvents. Reactions performed under microwave irradiation were carried out using an Emrys Creator machine (Personal Chemistry Ltd.) with a power output of 15 to 300W at 2.45GHz. '0.88 Ammonia' refers to commercially-available aqueous ammonia solution of about 0.88 specific gravity. Thin-layer chromatography was performed on glass-backed pre-coated Merck silica gel (60 F254) plates, and silica gel column chromatography was carried out using 40-63Dm silica gel (Merck silica gel 60). Ion exchange chromatography was performed using with the specified ion exchange resin which had been pre-washed with deionised water. Proton NMR spectra were measured on a Varian Inova 300, Varian Inova 400, or Varian Mercury 400 spectrometer in the solvents specified. In the NMR spectra, only non-exchangeable protons which appeared distinct from the solvent peaks are reported. Low resolution mass spectra were recorded on either a Fisons Trio 1000, using thermospray positive ionisation, or a Finnigan Navigator, using electrospray positive or negative ionisation. High resolution mass spectra were recorded on a Bruker Apex Il FT-MS using electrospray positive ionisation. Combustion analyses were conducted 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. Example compounds designated as (+) or (-) optical isomers are assigned based on the sign of optical rotation when determined in a suitable solvent.

Abbreviations and Definitions

Arbocel™ Filtration agent, from J. Rettenmaier & Sohne, Germany

Amberlyst^® 15 Ion exchange resin, available from Aldrich Chemical Company

APCI Atmospheric Pressure Chemical Ionisation atm Pressure in atmospheres (1 atm = 760 Torr = 101.3 kPa)

Biotage™ Chromatography performed using Flash 75 silica gel cartridge, from Biotage,

UK

BOC fe/t-Butyloxycarbonyl group br Broad c Concentration used for optical rotation measurements in g per 100 ml (1 mg/ml is c 0.10) cat Catalytic d Doublet dd Doublet of doublets

Degussa^® 101 10 wt% palladium on activated carbon, Degussa type E101 available from

Aldrich Chemical Company

Develosil Combi- Supplied by Phenomenex - manufactured by Nomura Chemical Co. RP C₃₀ hplc Composed of spherical silica particles ( size 3 μm or 5 μm) which have a column chemically bonded surface of C30 chains. These particles are packed into stainless steel columns of dimensions 2 cm internal diameter and 25 cm long.

Dowex^® Ion exchange resin, from Aldrich Chemical Company ee Enantiomeric excess

HRMS High Resolution Mass Spectrocopy (electrospray ionisation positive scan)

Hyflo™ Hyflo supercel®, from Aldrich Chemical Company liq Liquid

LRMS Low Resolution Mass Spectroscopy (electrospray or thermospray ionisation positive scan)

LRMS (ES^") Low Resolution Mass Spectroscopy (electrospray ionisation negative scan) - - m Multiplet m/z Mass spectrum peak

MCI™ gel High porous polymer, CHP20P 75-150Dm, from Mitsubishi Chemical

Corporation

Phenomenex Luna Supplied by Phenomenex. Composed of spherical silica particles (size 5 μm or C18 hplc column 10 μm) which have a chemically bonded surface of C18 chains. These particles are packed into a stainless steel column of dimensions 2.1cm internal diameter and 25 cm long. psi Pounds per square inch (1 psi = 6.9 kPa) q Quartet

R_f Retention factor on TLC s Singlet

Sep-Pak^® Reverse phase C₁₈ silica gel cartridge, Waters Corporation t Triplet

TLC Thin Layer Chromatography δ Chemical shift

Unless otherwise provided herein:

PyBOP® means Benzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate;

PyBrOP® means bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; CDI means N,N'-carbonyldiimidazole;

WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

Mukaiyama's reagent means 2-chloro-1-methylpyridinium iodide;

DCC means N,N'-dicyclohexylcarbodiimide;

HOAT means 1-hydroxy-7-azabenzotriazole; HOBT means 1 -hydroxybenzotriazole hydrate;

Hϋnig's base means Λ/-ethyldiisopropylamine;

Et₃N means triethylamine;

NMM means Λ/-methylmorpholine;

NMP means 1-methyl-2-pyrrolidinone; DMAP means 4-dimethylaminopyridine;

NMO means 4-methylmorpholine Λ/-oxide;

KHMDS means potassium bis(trimethylsilyl)amide;

NaHMDS means sodium bis(trimethylsilyl)amide;

DIAD means diisopropyl azodicarboxylate; DEAD means diethyl azodicarboxylate;

DIBAL means diisobutylaluminium hydride;

Dess-Martin periodinane means 1 ,1 ,1-triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 /-/)-one;

TBDMS-CI means fert-butyldimethylchlorosilane;

TMS-CI means chlorotrimethylsilane; BOC means tert-butoxycarbonyl; CBz means benzyloxycarbonyl;

MeOH means methanol, EtOH means ethanol, and EtOAc means ethyl acetate; THF means tetrahydrofuran, DMSO means dimethylsulfoxide, and DCM means dichloromethane; DMF means Λ/,Λ/-dimethylformamide; AcOH means acetic acid,

TFA means trifluoroacetic acid.

The following Examples illustrate the preparation of the compounds of the formula (I):-

Assay

The compounds of the invention are inhibitors of cyclic guanylate monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE-5 inhibitors). Preferred compounds suitable for use in accordance with the present invention are potent and selective PDE-5 inhibitors. In vitro PDE inhibitory activities against cyclic guanosine 3',5'-monophosphate (cGMP) and cyclic adenosine 3',5'-monophosphate (cAMP) phosphodiesterases can be determined by measurement of their IC₅₀ values (the concentration of compound required for 50% inhibition of enzyme activity).

The required PDE enzymes can be isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by a modification of the method of Thompson, WJ et al.; Biochemistry 18(23), 5228- 5237, 1979, as described by Ballard SA et al.; J. Urology 159(6), 2164-2171 , 1998. In particular, cGMP- specific PDE-5 and cGMP-inhibited cAMP PDE-3 can be obtained from human corpus cavernosum tissue, human platelets or rabbit platelets; cGMP-stimulated PDE-2 was obtained from human corpus cavernosum; calcium/calmodulin (Ca/CAM)-dependent PDE-1 from human cardiac ventricle; cAMP- specific PDE-4 from human skeletal muscle; and photoreceptor PDE-6 from bovine retina.

Phosphodiesterases 7-11 can be generated from full length human recombinant clones transfected into SF9 cells.

Assays can be performed either using a modification of the "batch" method of Thompson WJ and Appleman MM; Biochemistry 10(2),311 -316, 1971 , essentially as described by Ballard SA et al.; J.

Urology 159(6), 2164-2171 , 1998, or using a scintillation proximity assay for the direct detection of [³H]- labelled AMP/GMP using a modification of the protocol described by Amersham pic under product code TRKQ7090/7100.

In Vitro Assays

Method A: PDE-5 Inhibition Scintillation Proximity Assay (SPA)- human platelet

The assay measures the inhibition of human platelet PDE5 enzyme activity by a test compound in an in vitro assay that utilizes PDE5 isolated from human platelets. The PDE5 enzyme can be isolated from platelets essentially by a modification of the method of Thompson, WJ et 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 [³H]CGMP to the 5' nucleotide [³H]GMP. [³H]GMP binds to yttrium silicate SPA beads 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 test compound concentrations and low substrate, (cGMP or cAMP in a 3:1 ratio unlabelled to [³H]-labeled at a concentration of -1/3 K_n, or less) such that IC₅₀ = K_h The inhibition of enzyme activity is calculated relative to total PDE5 activity of uninhibited controls.

PDE5 ICgn Assay: 96-well microtiter plate format

Reagents

Buffer A: 20 mM Tris-HCI, 5 mM MgCI_2, pH 7.4 Buffer B: 2 mg/ml BSA in Buffer A (enzyme buffer) cGMP substrate: Final concentration of 500 nM in assay

The amount of ³H-labeled substrate added depends upon the specific activity of [³H]cGMP, and it is diluted with a 10 mM stock of cold cGMP in Buffer A for a final substrate concentration of 500 nM in the assay. PDE enzyme: Prepared in Buffer B. The dilution factor is determined by enzyme activity.

SPA beads: 20 mg/ml suspension prepared in dH2O.

Positive Control Negative Control Standard/Test compound

2 μl 100% DMSO 2 μl 100% DMSO 2 μl Standard/Test compound 25 μl Buffer A 25 μl Buffer A 25 μl Buffer A

25 μl Enzyme 25 μl Buffer B 25 μl Enzyme

50 μl Substrate 50 μl Substrate 50 μl Substrate

50 μl SPA to stop 50 μl SPA to stop 50 μl SPA to stop

Stocks of standard and test compounds are prepared at 5 mM in 100% DMSO. Compounds are serially diluted in separate dilution plates using a 10-point Vέ log dilution format. 2 μl of the compound dilutions are added in duplicate to the wells of the assay plate; 2 μl of 100% DMSO are added to designated control wells. 25 μl of Buffer A are added to all wells. 25 μl of Buffer B are added to the negative control wells, and 25 μl of enzyme are added to the remaining wells. 50 μl of substrate are added to each well. Plates are sealed and incubated for 60 minutes on a plate shaker at 30 C. 50 μl of SPA beads are added to stop the reaction. The plates are again sealed and shaken for 15 minutes to allow the beads to bind the GMP product. The beads are allowed to settle for 30 minutes and then read on a NXT TopCount. Data is analyzed with the ECADA application. In this analysis, % inhibition is calculated: (mean maximum - compound value/ (mean maximum - mean minimum) x 100. IC₅₀S are determined from sigmoid dose-response curves of enzyme activity vs compound concentration.

Method B: PDE-5 Inhibition Scintillation Proximity Assay (SPA) - human platelet

This method is a modified protocol of Method A. The assay measures the inhibition of human platelet PDE5 enzyme activity by a test compound in an in vitro assay that utilizes PDE5 isolated from human platelets. PDE5 catalyzes the hydrolysis of [³H]cGMP to the 5' nucleotide [³H]GMP. [³H]GMP binds to yttrium silicate SPA beads and is detected by scintillation counting. The inhibition of enzyme activity is calculated relative to total PDE5 activity of uninhibited controls.

PDE5 IC_5Q Assay: 96-well microtiter plate format

Reagents

Buffer A: 20 mM Tris-HCI, 5 mM MgCI_2, pH 7.4 Buffer B: 2 mg/ml BSA in Buffer A (enzyme buffer) cGMP substrate: ^' Final concentration of 50 n M in assay

The amount of ³H-labeled substrate added depends upon the specific activity of [³H]cGMP, and it is diluted in Buffer A.

PDE enzyme: Prepared in Buffer B. The dilution factor is determined by enzyme activity. SPA beads: 4 mg/ml suspension prepared in dH₂O.

Positive Control Negative Control Standard/Test compound

3 μl 100% DMSO 3 μl 100% DMSO 3 μl Standard/Test compound

27 μl Buffer A 27 μl Buffer A 27 μl Buffer A 30 μl Enzyme 30 μl Buffer B 30 μl Enzyme

30 μl Substrate 30 μl Substrate 30 μl Substrate

30 μl SPA to stop 30 μl SPA to stop 30 μl SPA to stop

Stocks of standard and test compounds are prepared at 2 mM in 100% DMSO. Compounds are serially diluted in separate dilution plates using an 8-point 1/5 log dilution format such that the starting concentration in the assay is 2 μM for an initial IC₅₀ screen. 27 μl of Buffer A are added to the wells of the assay plates. From the dilution plates, 3 μl of diluted compounds are delivered in duplicate or 3 μl of 100 % DMSO (for positive and negative controls) are added. 30 μl of enzyme are added. For the negative control wells, Buffer B is substituted in place of the enzyme. 30 μl 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 yttrium silicate beads. These beads are dense and require constant agitation while being added to the plate. The plates are sealed and shaken on a plate shaker for fifteen minutes to allow the beads to bind the GMP product. After allowing the beads to settle for 30 minutes, plates are read on a NXT TopCount and data is analyzed in the Bioassay Solver application. Percent inhibition values are calculated using the means of the 0% and 100% controls on each plate. The estimates of the 4-parameters of the logistic, sigmoid dose- response model are then calculated using the well-level percent inhibition values for each compound. These estimates are used to calculate the concentration that corresponds to 50% inhibition. Ex Vivo Assays

Method C: Aortic Ring Assay

This protocol describes the procedure for measuring the direct relaxation of rat aortic rings exposed to test compounds. In this assay, PDE5 inhibiting compounds elicit a relaxation of aortic rings by enhancing the cGMP signal evoked by a stable exogenous NO-donor, DETA-NO. An EC₅₀, with 95% confidence intervals, for compound-evoked relaxation is calculated as an index of potency.

Male Sprague-Dawley rats (250-35Og) are asphyxiated by CO₂ gas and their thoracic aorta carefully excised and placed in Krebs buffer. The aortas are then carefully dissected free of connective tissue and divided into 8 sections, each 3-4mm in length. Aortic rings are suspended between parallel stainless steel wires in a water jacketed (37°C), 15 mL tissue bath under a resting tension of 1 gram. Tension is measured using isometric tension transducers and recorded using Ponemah tissue platform system. Each preparation is allowed to equilibrate for at least 60 minutes prior to drug testing. During this time, the tissues are also incubated with 200 uM L-NMMA, and the incubation media changed every 15-20 minutes (L-NMMA is added after each wash to maintain the final concentration at 20OuM in each tissue bath).

Following the equilibration period, baseline tensions are recorded for each tissue. The vasoconstrictor response to phenylepherine (1 uM) is assessed and when the response to phenylepherine reached a maximum, vascular reactivity was subsequently assessed by a challenge of acetylcholine (1 uM). Following another washout period, a second baseline value is recorded, the vasoconstrictor noradrenaline ( 25 nM) is added to each bath and the tissues incubated for a time period (-15 minutes) to achieve a stable tone. An exogenous NO drive is supplied using the stable NO-donor, DETA-NO. The concentration of DETA-NO is titrated (cumulatively in half-log increments) to achieve approximately 5-15 % relaxation of the noradrenaline-evoked preconstriction. Cumulative concentration-response curves are constructed in a single ring, typically using 5 doses/ ring and allowing 15 minutes between each addition.

Method D: Aortic Ring Assay

The protocol of Method C can be modified to provide an alternative protocol to generate aortic ring data. For the modified protocol, the endothelium is first removed by gently rubbing the lumen of the vessel together between the fingers prior to preparing the rings (denuded rings). The resting tension is set at 2 grams and the vasoconstrictor response to a maximal concentration of phenylepherine (1 μM) is assessed, followed (after a washout period) by two further exposures to 300 nM of pheylephrine. The concentration-response relationship to noradrenaline is constructed in each tissue over concentration range 0.1 to 300 nM. After another washout period, the tissues are constricted with an EC₉₀ concentration of noradrenaline for compound testing.

In Vivo Assays

Method E: Culex™ Assay

A conscious pre-cannulated spontaneously hypertensive rat (SHR) model is used for evaluating the efficacy of test compounds and other anti-hypertensive agents in lowering systemic arterial blood pressure. An automated blood sampler (ABS) system is incorporated into this model. The Culex™ ABS system is comprised of a laptop computer, four control units and metabolic cages. This system allows for the collection of multiple blood samples from a single rat without causing undue stress to the animal. In addition, the system allows for the collection of urine samples that can be potentially used for biomarker identifications. Through this approach, efficacy and standard PK studies are conducted in the conscious unrestrained SHR rats simultaneously to accelerate the speed of compound screenings, and to define the relationship between plasma free drug concentration or potential biomarker(s) and pharmacological effect (reduction of mean arterial blood pressure).

SHR rats at age of 14 week old, weighing about 30Og, undergo surgeries of bilateral jugular veins and right carotid artery cannulations. After surgical recovery, animals are placed on the Culex™ cages and tethered to a movement-responsive arm with a sensor that controls cage movement when animal moves to prevent the catheters from being twisted. Connections are made between right jugular catheter and the Culex™ sterile tubing set for blood sampling, or left jugular catheter and the extend tubing for drug administration, or catheter in the right carotid artery and the extend tubing that is connected to a pressure transducer for monitoring blood pressure. To keep the patency of the catheters, right jugular cannula is maintained by the "tend" function of the Culex™ that flushes catheter with 20 μL heparin saline (10 units/mL) every 12 minutes or between sampling events, and left jugular cannula is filled with heparin saline (20 units/mL). The patency of the right carotid cannula is maintained by slow infusion of heparin saline either directly into the extend tubing when blood pressure is not recorded or through the pressure transducer during the blood pressure monitoring. Animals are allowed to acclimate for at least 2 hours before being used for evaluating any compounds. Animals receive three testing compounds over a 5 days study period with 30-40 hours washout period between two consecutive testing compounds. All testing compound may be administered via iv or oral gavage. Blood sampling protocols (sampling time and volume) are programmed using the Culex™ software. The total amount of blood withdrawn from each animal will not exceed 750 μl_/24 hrs and 10 ml_/kg within two weeks. Systemic arterial blood pressure is recorded by a pressure transducer through a data acquisition system (PONEMAH) for 6-24 hrs based on experimental protocol. Mean arterial blood pressure (primary endpoint) is analyzed for assessing the efficacy of the compounds. Blood samples will be analyzed for measuring plasma drug concentration and for evaluating potential biomarkers.

Method F: Implantation of Radio Transmitters and Subsequent Blood Pressure Screening by Telemetry in Spontaneously Hypertensive Rats

Spontaneously Hypertensive Rats (SHR) are anesthetized with isoflurane gas via an isoflurane anesthesia machine that is calibrated to deliver isoflurane over a range of percentages as oxygen passes through the machine's inner chambers. The animals are placed in an induction chamber and administered isoflurane at 4-5% to reach a surgical plane of anesthesia. They are then maintained at 1-2% during the surgical procedure via a nose cone, with isoflurane delivered via a smaller isoflurane anesthesia device on the surgical table.

Following administration of anesthesia, the rats are implanted with transmitters using aseptic procedures with commercially available sterile radio-telemetry units (Data Sciences, International, Roseville, MN 55113-1136). Prior to surgery the surgical field is shaved, scrubbed with Dial™ brand antimicrobial solution (containing 4% chlorhexidine gluconate and 4% isopropyl alcohol) followed by an application of iodine (10%) spray solution. A 2.5 to 3.0 cm laparotomy is preformed and the radio-telemetry units implanted into the abdomen, with the catheter tip inserted into the abdominal aorta. Baby Weitlaner retractors are used to retain soft tissue. A 1 cm section of the abdominal aorta is partially dissected and that section cross-clamped briefly, punctured with a 21 -gauge needle and the transmitter catheter tip introduced into the vessel and secured by a single 4.0 silk suture anchored to the adjacent psoas muscle. The transmitter body is then inserted into the abdominal cavity and simultaneously secured to the abdominal muscle wall while closing with running 4.0 silk suture. The skin layer is closed with subdermal continuous 4.0 absorbable suture. A subcutaneous (s.c.) administration of marcaine followed by a topical application of iodine is administered into and around the suture line, respectively, upon closing. All rats receive a postoperative injection of buprenorphine @ 0.05mg/kg, s.c. before regaining consciousness. A typical dose volume for a 0.300kg rat will be 0.050ml. The rats must be fully recovered from their operative anesthesia before the administration of buprenorphine. They then receive the same dose once daily for 2 consecutive days, unless the animal demonstrates that it is in compromising postoperative pain.

Following surgery, the rats are returned to their cages and housed individually on solid bottom caging with paper bedding. A period of no less than 7 days is allowed for recovery before experimental procedures are initiated. It has been observed that the rats are typically hypertensive for several days following surgery and return to "normotensive" levels by approximately the 7^th day post-surgery. They are fed standard rat chow and water ad libitum throughout the experimental time line.

Test compounds are administered intragastrically (i.g.) via gavage, using of a stainless steel, 2V∑ inch, 18 gauge gavage needle with a balled end. For single daily dosing, the target volume is 3.33 ml/kg, i.g. The vehicles in which the test compounds are administered will vary depending on solubility of the compound, however, methylcellulose (0.5%) in water will be the primary choice.

Blood pressure data will be obtained using Data Sciences International's data acquisition program. Blood pressure samples are recorded at 1.5-3 minute intervals for a 5 second duration 24 hours per day for the entire study. This data is processed by Data Science's data analysis software into averages of a desired time inervals. All other data reduction is performed in Microsoft Excel™ spreadsheets.

Method G: SHR Rat

This experimental protocol is designed to screen for blood pressure lowering by test compounds. The spontaneously hyperentsive rat (SHR) is cannulated in the jugular vein and carotid artery; one for compound administration and one for direct blood pressure measurement, respectively. The animals are fully conscious following surgery and all experimentation takes place within one working day. Blood pressure lowering is the primary parameter to be evaluated. However, systolic and diastolic pressure and heart rate data is collected as well. Rats will be dosed in an escalating, or cumulative manner to observe the responses following this regimen. This particular method will also permit screening of more than one compound or multiple doses of a compound in one day using the same animals. Methods:

Anesthesia: Rats are anesthetized with 5% isoflurane to effect. Incision sites are shaved and aseptically prepared for surgery. Rats are then transferred to the surgical field with a heating pad, supplemental isoflurane and maintained at 37⁰C, and isoflurane to effect throughout the surgical procedure.

Surgery. Arterial and venous cannula are implanted in the jugular vein and carotid artery, respectively. Cannulas are tunneled subcutaneously to the back of the neck where they exit percutaneously. Stainless steel staples are used to close each incision site. The cannulae are then run through a spring-tether to a swivel apparatus by which protects the cannulae from the animals chewing throughout the experiment.

Recovery. Rats are placed into an opaque polycarbonate cage instrumented with a counter balance arm that supports the weight of the tether and swivel apparatus. A paper bedding material is used to cover the bottom of the cage. The rats are allowed to recover from surgery at this point and receive 2 ml. of volume early during their recovery stage. No food is provided to the animals. The timeline shown in Figure 1 shows the experimental time course used for the test period.

IC₅₀ values (in nM) are shown in Table A for compounds tested in the SPA enzyme assay (Method B). IC₅₀ values are given as the mean of the number of assay runs (wherein the number of runs is the n= number shown in parentheses after the mean value). Table A

- -

Claims

- - Claims

1. A compound selected from the group consisting of

(1 -{1 -(2-Ethoxyethyl)-3-ethyl-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-yl)methanol;

5-(1 ,4-diazepan-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -{1 -(2-ethoxyethyl)-3-ethyl-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxamide;

1 -{1 -(2-Ethoxyethyl)-3-ethyl-7-t(4-fluorophenyl)amino]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxamide;

5-(1 ,4-diazepan-1 -yl)-1 -(2-ethoxyethyl)-3-ethyl-N-(4-f luorophenyl)-1 H-pyrazolo[4, 3-d]pyrimidin-7-amine;

(1-{1-(2-ethoxyethyl)-3-ethyl-7-[(4-fluorophenyl)amino]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-yl)methanol;

1-(2-ethoxyethyl)-3-ethyl-N-(4-fluorophenyl)-5-[(3R)-3-methylpiperazin-1 -yl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(4-methylpyrimidin-2- yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine ;

1 -{3-Ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxamide;

3-ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-N⁷-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine;

3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-ethyl-5-[(3S)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; 3-ethyl-N-pyrimidin-4-yl-5-[(2S)-2-(pyrrolidin-1 -ylmethyl)pyrrolidin-1 -yl]-1 -[2-(2,2, 2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-{3-ethyl-7-(pyrimidin-4-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4, S-dJpyrimidin-S-ylJpiperidine-S-carboxylic acid;

1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4, 3-d]pyrim idin-δ-ylJpiperidine-S-carboxylic acid;

2-(4-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-5-yl}piperazin-1-yl)ethanol;

N,N-diethyl-1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperidine-3-carboxamide;

(1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrim idin-5-yl}piperidin-3-yl)methanol; and

5-(1 ,4-diazepan-1 -yl)-3-ethyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

and tautomers thereof and pharmaceutically acceptable salts of said compound or tautomer.

2. A compound selected from the group consisting of 3-ethyl-5-(4-methyl-1 ,4-diazepan-1 -yl)-N-pyrimidin-4-yl-1 -[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

((3R)-1-{3-ethyl-7-(pyrimidin-4-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}pyrrolidin-3-yl)methanol;

((3S)-1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}pyrrolidin-3-yl)methanol;

3-ethyl-5-(4-ethylpiperazin-1-yl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(4-acetylpiperazin-1 -yl)-3-ethyl-N-pyrim idin-4-yl-1 -[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-ethyl-5-[4-(ethylsulfonyl)piperazin-1 -yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; - -

5-[(3R)-3,4-dimethylpiperazin-1-yl]-3-ethyl-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

(1-{3-ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperidin-4-yl)methanol;

3-Ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-N⁷-pyrazin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

3-Ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyrazin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-{3-Ethyl-7-(pyrazin-2-ylamino)-1-t2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxamide;

(1 -{3-Ethyl-7-(pyrazin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidin-4-yl)methanol;

3-Ethyl-5-piperazin-1-yl-N-pyrazin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin- 7-amine;

3-Ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-N⁷-(4-methylpyridin-2-yl)-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine;

3-Ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-(4-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrim idin-7-am ine;

1-{3-Ethyl-7-[(4-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidine-3-carboxamide;

(1 -{3-Ethyl-7-[(4-methylpyridin-2-yl)amino]-1-[2-(2,2_I2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-yl)methanol;

3-Ethyl-N-(4-methylpyridin-2-yl)-5-piperazin-1-yl-1-[2-(2₎2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrim idin-7-am ine; and

3-Ethyl-N-(4-fluorophenyl)-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine; and tautomers thereof and pharmaceutically acceptable salts and solvates of said compound or tautomer. 3. A compound selected from the group consisting of

3-Ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-(6-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrim idin-7-am ine;

1 -{3-Ethyl-7-[(6-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-5-yl}piperidine-3-carboxam ide;

(1-{3-Ethyl-7-[(6-methylpyridin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-yl)methanol;

3-Ethyl-N-(6-methylpyridin-2-yl)-5-piperazin-1-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

3-Ethyl-N-(4-fluorophenyl)-5-piperazin-1 -yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-Ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -{3-Ethyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxam ide;

(1 -{3-Ethyl-7-(pyridin-2-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidin-4-yl)methanol;

3-Ethyl-5-piperazin-1-yl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-Ethyl-N⁷-(4-fluorophenyl)-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-1-t2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine;

3-Ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-(4-methylpyrimidin-2-yl)-1 -[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1 -{3-Ethyl-7-[(4-methylpyrimidin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrim idin-5-yl}piperidine-3-carboxam ide;

(1-{3-Ethyl-7-[(4-methylpyrimidin-2-yl)amino]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-yl)methanol;

3-Ethyl-N-(4-methylpyrimidin-2-yl)-5-piperazin-1 -yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-{3-Ethyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-3-carboxamide;

(1-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperidin-3-yl)methanol;

5-(1 ,4-diazepan-1-yl)-3-methyl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

(1-{3-methyl-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperidin-4-yl)methanol;

3-Ethyl-N-(4-methylphenyl)-5-piperazin-1 -yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

and tautomers thereof and pharmaceutically acceptable salts and solvates of said compound or tautomer.

4. A compound selected from the group consisting of

3-Ethyl-N-(4-methylphenyl)-5-[(3R)-3-methylpiperazin-1-yl]-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

3-Ethyl-N⁵-methyl-N⁷-(4-methylphenyl)-N⁵-(1 -methylpiperidin-4-yl)-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine; - 1-

N⁵-(2-Aminoethyl)-3-ethyl-N⁷-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-3-ethyl-5-[(3S)-3-methylpiperazin-1-yl]-N-(6-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-5-(4-methylpiperazin-1-yl)-N-(6-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3- djpyrim idin-7-am ine;

1-(2-ethoxyethyl)-3-ethyl-5-[(3S)-3-methylpiperazin-1-yl]-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-5-(4-methylpiperazin-1-yl)-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(5-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

1-(2-ethoxyethyl)-3-ethyl-N-(6-ethylpyridin-2-yl)-5-[(3R)-3-methylpiperazin-1-yl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

N-(4,6-dimethylpyridin-2-yl)-1 -(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

1 -(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

5-(3,4-dimethylpiperazin-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-( 1 -methylpiperidin-4-yl)-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine; N⁵-(1-benzylpyrrolidin-3-yl)-1-(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁷-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁷-(4-methylpyridin-2-yl)-N⁵-(1-methylpyrrolidin-3-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine; and tautomers thereof and pharmaceutically acceptable salts and solvates of said compound or tautomer.

5. A compound selected from the group consisting of

1-benzylpyrrolidin-3-yl)-1-(2-ethoxyethyl)-3-ethyl-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁵-(1 -methylpiperidin-4-yl)-N⁷-pyridin-2-yl-1H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

ethyl 4-({1-(2-ethoxyethyl)-3-ethyl-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}amino)piperidine-1-carboxylate;

1-(2-ethoxyethyl)-3-ethyl-5-piperazin-1-yl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-N⁷-(5-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N-(5-methylpyridin-2-yl)-5-piperazin-1-yl-1H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁵-(1-methylpipehdin-4-yl)-N⁷-(6-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(6-ethylpyridin-2-yl)-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

N⁷-(4,6-dimethylpyridin-2-yl)-1 -(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁵-(1 -methylpyrrolidin-3-yl)-i H- pyrazolo[4,3-d]pyrim idine-5,7-diam jne;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(6-ethylpyridin-2-yl)-N⁵-methyl-N⁵-(1-methylpyrrolidin-3-yl)-1H- pyrazolo[4,3-d]pyrimidine-5,7-diamine; N⁷-(4,6-dimethylpyridin-2-yl)-1-(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-iH- pyrazolo[4,3-d]pyrϊmidine-5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁷-(3-methylphenyl)-N⁵-(1-methylpiperidin-4-yl)-1 H- pyrazolot4,3-d]pyrimidine-5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-N-(3-methylphenyl)-5-[(3R)-3-methylpiperazin-1-yl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁷-(3-methylphenyl)-N⁵-(1 -methylpyrrolidin-3-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-5-(4-nnethylpiperazin-1-yl)-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-methyl-N⁵-(1-methylpiperidin-4-yl)-N⁷-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

3-methyl-5-[(3R)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

3-methyl-N-(4-methylpyridin-2-yl)-5-piperazin-1 -yl-1 -[2-(2,2,2-trif luoroethoxy)ethyl]-1 H- pyrazolot4,3-d]pyrimidin-7-amine; and tautomers thereof and pharmaceutically acceptable salts and solvates of said compound or tautomer.

6. A compound selected from the group consisting of

3-methyl-5-piperazin-1-yl-N-pyridin-2-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-methyl-5-(4-methylpiperazin-1-yl)-N-(6-methylpyridin-2-yl)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

3-methyl-5-(4-methylpiperazin-1 -yl)-N-pyridin-2-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; 3-methyl-5-(4-methylpiperazin-1 -yl)-N-(4-methylpyridin-2-yl)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(3-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-({1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-1 H-pyrazolo[4,3-d]pyrimidin-7- yl}amino)pyridin-2(1 H)-one;

1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-N-phenyl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-3-ethyl-N-(3-methylpyridin-2-yl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1-(2-ethoxyethyl)-3-ethyl-N-(3-fluorophenyl)-5-piperazin-1-yl-1 H-pyrazolot4,3-d]pyrimidin-7-amine;

5-{[1-(2-ethoxyethyl)-3-ethyl-5-piperazin-1-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]amino}pyridin- 2(1H)-one;

1-(2-ethoxyethyl)-3-ethyl-5-(4-methylpiperazin-1-yl)-N-phenyl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

1 -(2-ethoxyethyl)-3-ethyl-5-(4-methylpiperazin-1-yl)-N-(3-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-N-(3-methoxyphenyl)-5-[(3R)-3-methylpiperazin-1-yl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

1-(2-ethoxyethyl)-3-ethyl-N-phenyl-5-piperazin-1-yl-1H-pyrazolo[4,3-d]pyrimidin-7-amine;

N-(3-chlorophenyl)-1-(2-ethoxyethyl)-3-ethyl-5-[(3R)-3-methylpiperazin-1-yl]-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-{[1-(2-ethoxyethyl)-3-ethyl-5-(4-methylpiperazin-1-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7- yl]amino}pyridin-2(1 H)-one;

1-(2-ethoxyethyl)-3-ethyl-N-(3-fluorophenyl)-5-[(3R)-3-methylpiperazin-1-yl]-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine; 1 -(2-ethoxyethyl)-3-ethyl-N-(3-methoxyphenyl)-5-(4-methylpiperazin-1 -yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

N^S-chlorophenyO-i^-ethoxyethyO-S-ethyl-S-piperazin-i-yl-I H-pyrazolo^.S-^pyrimidin-?- amine;

1-(2-ethoxyethyl)-3-ethyl-N-(3-methoxyphenyl)-5-piperazin-1-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

nd tautomers thereof and pharmaceutically acceptable salts and solvates of said compound or tautomer.

7. A compound selected from the group consisting of

1 -(2-ethoxyethyl)-3-ethyl-N-(3-f luorophenyl)-5-(4-methylpiperazin-1 -yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

N-(3-chlorophenyl)-1 -(2-ethoxyethyl)-3-ethyl-5-(4-methylpiperazin-1 -yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[4-(2-aminoethyl)piperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(4-aminopiperidin-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1 -(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-ethoxyethyl)-3-ethyl-N⁷-(6-methylpyridin-2-yl)-N⁵-(2-morpholin-4-ylethyl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

5-[(3R,5S)-3,5-dimethylpiperazin-1 -yl]-1-(2-ethoxyethyl)-3-ethyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(4-aminopiperidin-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7- amine;

5-[4-(2-aminoethyl)piperazin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-1H- pyrazolo[4,3-d]pyrimidin-7-amine; 5-(4-aminopiperidin-1-yl)-1 -(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-annine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(4-methylpyridin-2-yl)-N⁵-(2-morpholin-4-ylethyl)-1H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

5-[4-(2-aminoethyl)piperazin-1-yl]-1 -(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[4-(aminomethyl)piperidin-1 -yl]-1 -(2-ethoxyethyl)-3-ethyl-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(4-methylpyridin-2-yl)-N⁵-piperidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidine- 5,7-diamine;

5-[4-(aminomethyl)piperidin-1-yl]-1-(2-ethoxyethyl)-3-ethyl-N-(6-methylpyridin-2-yl)-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[4-(aminomethyl)piperidin-1-yl]-1 -(2-ethoxyethyl)-3-ethyl-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(4-methylpyridin-2-yl)-N⁵-(piperidin-4-ylmethyl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-piperidin-4-yl-N⁷-pyridin-2-yl-1H-pyrazolo[4,3-d]pyrimidine-5,7- diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(6-methylpyridin-2-yl)-N⁵-(piperidin-4-ylmethyl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-(1-ethylpiperidin-4-yl)-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

8. A compound selected from the group consisting of

1-(2-ethoxyethyl)-3-ethyl-N⁵-(piperidin-4-ylmethyl)-N⁷-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidine-

5,7-diamine; 1 -(2-ethoxyethyl)-3-ethyl-N⁵-(1-ethylpiperidin-4-yl)-N⁷-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidine- 5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁵-(1-ethylpiperidin-4-yl)-N⁷-(6-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(6-methylpyridin-2-yl)-N⁵-piperidin-4-yl-1 H-pyrazolo[4,3-d]pyrimidine- 5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-(1-isopropylpiperidin-4-yl)-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-(1 -isopropylpiperidin-4-yl)-N⁷-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1 -(2-ethoxyethyl)-3-ethyl-N⁵-(1-isopropylpiperidin-4-yl)-N⁷-(6-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1 -{1 -(2-ethoxyethyl)-3-ethyl-7-[(6-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-4-carboxamide;

1 -{1 -(2-ethoxyethyl)-3-ethyl-7-[(4-methylpyridin-2-yl)amino]-1 H-pyrazolo[4,3-d]pyrimidin-5- yl}piperidine-4-carboxam ide;

1 -[1 -(2-ethoxyethyl)-3-ethyl-7-(pyridin-2-ylam ino)-1 H-pyrazolo[4,3-d]pyrim idin-5-yl]piperidine-4- carboxamide;

5-(4-aminopiperidin-1 -yl)-1 -(2-ethoxyethyl)-3-ethyl-N-(3-methoxyphenyl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(4-aminopiperidin-1-yl)-1-(2-ethoxyethyl)-3-ethyl-N-phenyl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-(4-aminopiperidin-1 -yl)-N-(3-chlorophenyl)-1 -(2-ethoxyethyl)-3-ethyl-1 H-pyrazolo[4,3- d]pyrim idin-7-am ine;

5-(4-aminopiperidin-1 -yl)-1 -(2-ethoxyethyl)-3-ethyl-N-(3-fluorophenyl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(4-aminopiperidin-1-yl)-1 -(2-ethoxyethyl)-3-ethyl-N-(4-fluorophenyl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; _ _

1-(2-ethoxyethyl)-3-ethyl-N⁷-phenyl-N⁵-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidine-5,7- diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(3-fluorophenyl)-N⁵-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(3-methoxyphenyl)-N⁵-(piperidin-4-ylmethyl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

1-(2-ethoxyethyl)-3-ethyl-N⁷-(4-fluorophenyl)-N⁵-(piperidin-4-ylmethyl)-1 H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

N⁷-(3-chlorophenyl)-1-(2-ethoxyethyl)-3-ethyl-N⁵-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3- d]pyrimidine-5,7-diamine;

9. A compound selected from the group consisting of

1 -(2-ethoxyethyl)-3-methyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-methyl-5-piperazin-1-yl-N-pyridin-2-yl-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-ethoxyethyl)-3-methyl-5-(4-methylpiperazin-1-yl)-N-pyridin-2-yl-1H-pyrazolo[4,3-d]pyrimidin- 7-amine;

1-(2-ethoxyethyl)-3-methyl-5-(4-methylpiperazin-1-yl)-N-(6-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

1 -(2-ethoxyethyl)-3-methyl-5-[(3R)-3-methylpiperazin-1 -yl]-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-ethoxyethyl)-3-methyl-N-(6-methylpyridin-2-yl)-5-piperazin-1-yl-1H-pyrazolo[4,3-d]pyrimidin- 7-amine;

1-(2-ethoxyethyl)-3-methyl-5-(4-methylpiperazin-1-yl)-N-(4-methylpyridin-2-yl)-1H-pyrazolo[4,3- d]pyrimidin-7-amine;

5-(4-aminopiperidin-1 -yl)-1-(2-ethoxyethyl)-3-methyl-N-(6-methylpyridin-2-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine; 5-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-1-(2-ethoxyethyl)-3-(methoxymethyl)-N-pyridin-2-yl- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(methoxymethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(iS,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-1-(2-ethoxyethyl)-3-(ethoxymethyl)-N-pyridin-2-yl-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(ethoxymethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-pyridin-2-yl-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

δ-KIS^SJ^.δ-Diazabicyclo^^.^hept^-yll-i^-ethoxyethyO-S^ethoxymethyO-N-pyrimidin^-yl- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(ethoxymethyl)-5-[(3R)-3-methylpiperazin-1 -yl]-N-pyrimidin-4-yl-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-N-(4-f luorophenyl)-3-(methoxymethyl)-5-[(3R)-3-methylpiperazin-1 -yl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(iS,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-1 -(2-ethoxyethyl)-3-(ethoxymethyl)-N-(4- fluorophenyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(ethoxymethyl)-N-(4-fluorophenyl)-5-[(3R)-3-methylpiperazin-1 -yl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(ethoxymethyl)-5-((R)-3-methylpiperazin-1 -yl)-N-(4,6-dimethylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(1 S,4S)-2,5-Diazabicyclo[2.2.1 ]hept-2-yl]-N-(4,6-dimethylpyridin-2-yl)-1 -(2-ethoxyethyl)-3- (ethoxymethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(4,6-dimethylpyridin-2-yl)- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

and tautomers thereof and pharmaceutically acceptable salts and solvates of said compound or tautomer. - -

10. A compound selected from the group consisting of

5-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-N-(4,6-dimethylpyridin-2-yl)-1 -(2-ethoxyethyl)-3-

(methoxymethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-3-(ethoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(4-methylpyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-N-(6-ethylpyridin-2-yl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-1 H- pyrazolo[4,3-d]pyrim idin-7-am ine;

δ-KIS^SJ^.δ-Diazabicyclo^^.ilhept^-yll-i^-ethoxyethylJ-N^e-ethylpyridin^-yO-S- (methoxymethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-3-(ethoxymethyl)-N-(6-ethylpyridin-2-yl)-5-((R)-3-methylpiperazin-1-yl)-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

1 -(2-Ethoxyethyl)-3-(methoxymethyl)-5-((R)-3-methylpiperazin-1 -yl)-N-(pyrimidin-4-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

3-(Methoxymethyl)-5-((R)-3-methylpiperazin-1 -yl)-1 -(2-propoxyethyl)-N-(pyridin-2-yl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-5-(4-ethylpiperazin-1-yl)-3-(methoxymethyl)-N-(pyrimidin-4-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-(Ethoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(6-methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(1 S,4S)-2,5-Diazabicyclo[2.2.1 ]hept-2-yl]-3-(ethoxymethyl)-N-(6-methylpyridin-2-yl)-1 -(2- propoxyethyl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(1 S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-3-(ethoxymethyl)-1-(2-propoxyethyl)-N-pyridin-2-yl- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-(Methoxymethyl)-5-((R)-3-methylpiperazin-1-yl)-N-(6-methylpyridin-2-yl)-1-(2-propoxyethyl)-1 H- pyrazolo[4,3-d]pyrimidin-7-amine; - -

5-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-1-(2-ethoxyethyl)-3-(ethoxymethyl)-N-(6-ethylpyridin- 2-yl)-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

1-(2-Ethoxyethyl)-3-(methoxymethyl)-5-(piperazin-1-yl)-N-(pyrimidin-4-yl)-1 H-pyrazolo[4,3- d]pyrimidin-7-amine;

3-(Ethoxymethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolot4,3-d]pyrimidin-7-amine trifluoroacetate;

δ-^IS^S^.S-Diazabicyclo^^.ijhept^-yll-S^ethoxymethyO-N-pyrimidin^-yl-i-^^^^- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

tert-Butyl 4-{3-(ethoxymethyl)-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate trifluoroacetate;

3-(Ethoxymethyl)-5-piperazin-1-yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

3-(Ethoxymethyl)-5-(4-methylpiperazin-1 -yl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

11. A compound selected from the group consisting of 3-(Ethoxymethyl)-5-[(3S)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

N⁵-[2-(Dimethylamino)ethyl]-3-(ethoxymethyl)-N⁵-methyl-N⁷-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine trifluoroacetate;

3-(Ethoxymethyl)-N-7-pyrimidin-4-yl-N-5-(2,2,6,6-tetramethylpiperidin-4-yl)-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidine-5,7-diamine trifluoroacetate;

1-{3-(Ethoxymethyl)-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-ol trifiuoroacetate;

(1-{3-(Ethoxymethyl)-7-(pyrimidin-4-ylamino)-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3- d]pyrimidin-5-yl}piperidin-4-yl)methanol trifluoroacetate; - -

3-(lsopropoxymethyl)-5-[(3R)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

tert-Butyl 4-{3-(isopropoxymethyl)-7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate trifluoroacetate;

3-(lsopropoxymethyl)-5-piperazin-1-yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1 H- pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

5-[(3R)-3-Methylpiperazin-1 -yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-3-t(3,3,3- trifluoropropoxy)methyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate;

5-[(3R)-3-Methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(2_I2,2- trifluoroethoxy)methyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

tert-Butyl 4-{7-(pyrimidin-4-ylamino)-1-[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(2,2,2- trifluoroethoxy)methyl]-1 H-pyrazolo[4,3-d]pyrimidin-5-yl}piperazine-1-carboxylate;

5-Piperazin-1-yl-N-pyrimidin-4-yl-1 -[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(2,2,2-trifluoroethoxy)methyl]- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3S)-3-Methylpiperazin-1 -yl]-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(2,2,2- trifluoroethoxy)methyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-[(Cyclopropylmethoxy)methyl]-5-[(3S)-3-methylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trif!uoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-[(Cyclopropylmethoxy)methyl]-5-piperazin-1-yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]- 1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

3-[(Cydopropylmethoxy)methyl]-5-[(3R)-3-rτιethylpiperazin-1-yl]-N-pyrimidin-4-yl-1-[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-[(3R)-3-Methylpiperazin-1 -yl]-N-pyrimidin-4-yl-3-[(4,4,4-trifluorobutoxy)methyl]-1 -[2-(2,2,2- trifluoroethoxy)ethyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine;

5-Piperazin-1-yl-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-3-[(3,3,3- trifluoropropoxy)methyl]-1 H-pyrazolo[4,3-d]pyrimidin-7-amine; _ _

1 ,3-/?/s<2-Ethoxyethyl)-N^N⁵-dimethyl-N⁷-(4-methylpyridin-2-yl)-1 H-pyrazolo[4,3-d]pyrimicJine-5_>7- diamine;

12. A pharmaceutical composition comprising a compound of formula (I) as claimed in any of claims 1 -11 , or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable diluent or carrier.

13. A compound as claimed in any of claims 1 -11 , or a pharmaceutically acceptable salt thereof, for use as a medicament.

14. A method of treatment of a disorder or condition where inhibition of PDE-5 is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as claimed in any of claims 1 -10, or a pharmaceutically acceptable salt or solvate thereof.

15. Use of a compound of formula (I) as claimed in claims 1 or 14, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of a disorder or condition where inhibition of PDE-5 is known, or can be shown, to produce a beneficial effect.