NZ737314B2 - 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors - Google Patents

Abstract

New 2-(pyrazolopyridin-3-yl)pyrimidine derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

Description

-(PYRAZOLOPYRIDINYL)PYRIMIDINE DERIVATIVES AS JAK INHIBITORS FIELD OF THE INVENTION The present ion s to novel compounds having JAK inhibitory activity. This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.

BACKGROUND OF THE INVENTION Cytokines have critical functions in regulating many aspects of immunity and mation, ranging from the development and differentiation of immune cells to the suppression of immune responses. Type I and type II cytokine receptors lack intrinsic enzymatic activity e of mediating signal transduction, and thus require association with ne kinases for this purpose. The JAK family of kinases comprises four different members, namely JAK1, JAK2, JAK3 and TYK2, which bind to type I and type II cytokine receptors for controlling signal transduction (Murray PJ, (2007). The JAK-STAT signalling pathway: input and output integration. J Immunol, 178: 2623).

Each of the JAK kinases is selective for the receptors of certain cytokines. In this regard, JAK-deficient cell lines and mice have validated the ial role of each JAK protein in receptor ling: JAK1 in class II cytokine receptors (IFN and IL-10 ), those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21) (Rodig et al. (1998). Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373; Guschin et al. (1995). A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 14: 1421; Briscoe et al. (1996). Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state. EMBO J. 15:799); JAK2 in hematopoietic factors (Epo, Tpo, GM-CSF, IL-3, IL-5) and type II IFNs (Parganas et al., (1998). JAK2 is essential for ling through a variety of cytokine ors. Cell, 93:385); JAK3 in receptors sharing the common gamma chain (IL-2 family) (Park et al., (1995). Developmental defects of lymphoid cells in JAK3 kinase-deficient mice. Immunity, 3:771; Thomis et al., (1995). Defects in B lymphocyte maturation and T cyte activation in mice lacking JAK3. Science, 270:794; Russell et al., (1995). Mutation of JAK3 in a partient with SCID: ial role of JAK3 in lymphoid development. Science, 270:797); and Tyk2 in the receptors of IL- 12, IL-23, IL-13 and type I IFNs (Karaghiosoff et al., . Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000).

Tyk2 plays a restricted role in IFNg signaling, although it is ed for ILmediated T cell function. Immunity, 13:561; shi et al., (2006). Human Tyrosine kinase 2 ency reveals its ite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745).

Receptor stimulation leads sequentially to JAK activation by orylation, receptor phosphorylation, STAT protein recruitment and STAT activation and dimerization. The STAT dimer then functions as a transcription factor, translocating to the s and activating the transcription of multiple response genes. There are seven STAT ns identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Each particular cytokine receptor associates preferentially with a particular STAT protein.

Some associations are independent of cell type (ex: IFNg- STAT1) while others may be cell type dependent y PJ, (2007). The JAK-STAT signaling pathway: input and output integration. J Immunol, 178: 2623).

The phenotype of deficient mice has provided insights on the function of each JAK and the cytokine receptors signaling through them. JAK3 associates ively with the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. By virtue of this exclusive association, JAK3 knock out mice and common gamma chain deficient mice have an identical phenotype (Thomis et al., (1995).

Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3.

Science, 270:794; DiSanto et al., . Lymphoid pment in mice with a targeted deletion of the interleukin 2 receptor gamma chain. PNAS, 92:377). Moreover, this phenotype is shared to a great extent with SCID patients that hold mutations/defects in the common gamma chain or JAK3 genes (O’Shea et al., (2004).

JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41: 727). JAK3-deficient mice are viable but display abnormal lymphopoiesis which leads to a reduced thymus size (10-100 fold smaller than wild type). JAK3-deficient peripheral T cells are unresponsive and have an activated/memory cell phenotype (Baird et al., (1998). T cell development and tion in JAK3-deficient mice. J. Leuk.

Biol. 63: 669). The thymic defect in these mice strongly resembles that seen in IL-7 and IL-7 receptor knockout mice, suggesting that the e of IL-7 signaling accounts for this defect in JAK3 -/-mice (von Freeden-Jeffry et al., (1995). Lymphopenia in Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant Cytokine. J Exp Med, 181:1519; Peschon et al, (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These mice, like SCID humans, have no NK cells, probably due to the e of IL-15 ing, a survival factor for these cells. JAK3 ut mice, unlike SCID patients, show deficient B cell lymphopoiesis while in human ts, B cells are present in circulation but are not responsive leading to obulinemia a et al., (2004). JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41: 727). This is explained by species-specific differences in IL-7 function in B and T cell development in mice and humans. On the other hand, Grossman et al. (1999. Dysregulated myelopoiesis in mice lacking JAK3. Blood, 94:932:939) have shown that the loss of JAK3 in the T-cell compartment drives the expansion of the myeloid lineages leading to dysregulated oiesis.

JAK2-deficient mice are embrionically lethal, due to the absence of definitive erythropoiesis. Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are not affected. JAK2 is not required for the generation, amplification or functional differentiation of lymphoid progenitors (Parganas et al., (1998). JAK2 is essential for signaling h a variety of cytokine receptors. Cell, 93:385).

JAK1-deficient mice die perinatally due to a nursing . JAK1 binds exclusively to the gp130 chain shared by the IL-6 cytokine family (i.e. LIF, CNTF, OSM, CT-1) and along with JAK3, is an essential component of the receptors g the common gamma chain, by binding to the non-shared receptor subunit. In this regard, JAK1- deficient mice show similar hematopoiesis defects as JAK3-deficient mice. In addition, they show defective responses to neurotrophic factors and to all interferons (class II cytokine receptors) (Rodig et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine-induced ical response. Cell, 93:373).

Finally, Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of ne responses in eficient mice. Immunity, 13:549; Shimoda et al., (2000).

Tyk2 plays a restricted role in IFNg signaling, gh it is required for ILmediated T cell function. Immunity, 13:561). However, human Tyk2 deficiency demonstrates that Tyk2 is involved in the signaling from IFN-α, IL-6, IL-10, IL-12 and IL-23 (Minegishi et al., (2006). Human ne kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745).

The role of JAK kinases in ucing the signal from a myriad of nes makes them ial targets for the treatment of diseases in which cytokines have a pathogenic role, such as dermatological diseases; respiratory diseases; allergic diseases; inflammatory or autoimmune-mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ lant rejection; myelo-dysplastic me; myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors.

In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of the JAK pathway or of the JAK Kinases it is immediately apparent that new compounds that modulate JAK pathways and use of these nds should e substantial therapeutic benefits to a wide variety of patients.

Some substituted pyrimidines as Janus kinase inhibitors were described in WO 2013/025628 and .

Provided herein are novel 2-(pyrazolopyridinyl)pyrimidine derivatives for use in the ent of conditions in which targeting of the JAK pathway or inhibition of JAK kinases can be therapeutically .

The compounds bed in the present invention are simultaneously potent JAK1, JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors.

SUMMARY OF THE INVENTION Thus the present invention is directed to a 2-(pyrazolopyridinyl)pyrimidine derivative which 2-(pyrazolopyridinyl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: Formula (I) wherein • X represents –O- or –NR3- group, • R1 and R2 are ndently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or branched C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a hydrogen atom, a linear or ed C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine group; • G1 is a –O-R6 group, • Q is selected from the group consisting of: wherein o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - CO(CH2)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6- membered heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, wherein the heterocyclyl and heteroaryl group independently are unsubstituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 hydroxyalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 ents a phenyl group, a pyrimidine group or a ne group, wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or ed C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or branched (C1-6 )-(C1-6 alkyl) group and a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group and –NR’R” group, • R’ and R’’ independently represents a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m ndently has a value from 0 to 3.

Described is a 2-(pyrazolopyridinyl)pyrimidine derivative for use in the treatment of the human or animal body, which 2-(pyrazolopyridinyl)pyrimidine tive is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or e, or stereoisomer or deuterated derivative thereof: Formula (I) wherein • X represents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or ed C1-4 alkyl, a linear or branched C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a en atom, a linear or branched C1-4 alkyl group, a 1-3NR’R’’ group and a –(CH2)1pyrrolidine group; • G1 is selected from the group consisting of –CN group, -CO-Ra group, a –O-R6 group, a -(CHR7)m-NR’R’’ group, a phenyl group, a monocyclic C5-7 cycloalkyl group, a clic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 6- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a yl group, a linear or branched C1-4 alkyl group, a linear or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a - (CH2)0-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra represents a hydrogen atom, a hydroxyl group, a linear or branched C1-3 alkyl group, a linear or branched C1-3 alkoxy group or an amino group, • Q is selected from the group consisting of: wherein o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - CO(CH2)1CF3 group, a hiazole group, a monocyclic 4- to 6- membered heterocyclyl group containing at least one heteroatom ed from O, S and N and a monocyclic 5- to 6- membered heteroaryl group ning at least one atom selected from O, S and N, wherein the heterocyclyl and heteroaryl group independently are tituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 hydroxyalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 represents a phenyl group, a pyrimidine group or a pyridine group, wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more tuents selected from a halogen atom, a yl group and –NR’R” group, • R7 represents a hydrogen atom, a hydroxyl or a C1-2 alkyl group, • R’ and R’’ ndently represents a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m independently has a value from 0 to 3, wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a] nylpyrimidinyl)amino]piperidinyl}oxopropanenitrile • 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxetanyl)acetonitrile • Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate • 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxoethanol • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile Also described is a 2-(pyrazolopyridinyl)pyrimidine tive, which 2- (pyrazolopyridinyl)pyrimidine tive is a nd of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: Formula (I) wherein • X represents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or branched C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine group; • G1 is selected from the group ting of –CN group, -CO-Ra group, a –O-R6 group, a -(CHR7)m-NR’R’’ group, a phenyl group, a monocyclic C5-7 cycloalkyl group, a monocyclic 5- to 6- membered aryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 6- ed heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a - -2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra represents a hydrogen atom, a hydroxyl group, a linear or branched C1-3 alkyl group, a linear or branched C1-3 alkoxy group or an amino group, • Q is selected from the group consisting of: wherein o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - )1CF3 group, a cyanothiazole group, a monocyclic 4- to 6- ed heterocyclyl group containing at least one heteroatom selected from O, S and N and a clic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, wherein the heterocyclyl and heteroaryl group ndently are unsubstituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 hydroxyalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 represents a phenyl group, a pyrimidine group or a pyridine group, wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents selected from a n atom, a linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group ting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group and –NR’R” group, • R7 ents a en atom, a hydroxyl or a C1-2 alkyl group, • R’ and R’’ independently represents a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m independently has a value from 0 to 3, wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile • 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) piperidinyl}oxopropanenitrile • (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxetanyl)acetonitrile • Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate • 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxoethanol • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • 3-[(3R)({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a] pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • )[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl} lo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a] pyridinyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile • (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl) pyrimidinyl)amino)piperidinyl)oxopropanenitrile Further described are synthetic processes and intermediates, which are useful for preparing said 2-(pyrazolopyridinyl)pyrimidine derivatives.

The invention is also directed to a azolopyridinyl)pyrimidine derivative of the invention as described herein for use in the treatment of the human or animal body by therapy.

The invention also provides a pharmaceutical composition comprising the 2- (pyrazolopyridinyl)pyrimidine tives of the invention and a pharmaceuticallyacceptable diluent or carrier.

The invention is also directed to the 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention as bed , for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmunemediated disease, a function disorder, a neurological er, a cardiovascular e, a viral infection, a lism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor. More in particular wherein the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, c hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering es including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus matosis, autoimmune hemolytic anemia, type I diabetes, , chronic obstructive ary disease , cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary is, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca.

The invention is also directed to use of the 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention as described , in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by ton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an matory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor. More in particular wherein the pathological condition or disease is selected from atopic itis, sis, contact dermatitis, eczema, c hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, ma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and molysis a, leukemia, mas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive ary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic ary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca.

Also described is a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or mune-mediated e, a on disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism/endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor. More in particular wherein the ogical condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic sis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell ma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to gus vulgaris, bullous pemphigoid and epidermolysis bullosa, ia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, matory bowel disease, ulcerative colitis, s disease, dry eye, uveitis, ic conjunctivitis and keratoconjuntivitis sicca.

Also described is a ation product sing (i) the 2-(pyrazolopyridin yl)pyrimidine tives of the invention as described herein; and (ii) one or more additional active substances.

DETAILED DESCRIPTION OF THE INVENTION When describing the azolopyridinyl)pyrimidine derivatives, itions, and methods of the invention, and ations described, the following terms have the following meanings, unless otherwise indicated.

As used herein the term C1-C6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, l, sec-butyl, tbutyl , n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1- dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, lbutyl, 2-ethylbutyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.

As used herein the term C1-C4 alkyl embraces linear or branched radicals having 1 to 4 carbon atoms. Analogously, the term C1-C3 alkyl embraces linear or branched radicals having 1 to 3 carbon atoms and the term C1-C2 alkyl embraces linear or branched ls having 1 to 2 carbon atoms.

As used herein, the term C1-C6 yalkyl es linear or branched alkyl radicals having 1 to 6 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl.

As used herein, the term C1-C3 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 3 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. es of such radicals include hydroxymethyl, hydroxyethyl or hydroxypropyl.

As used herein, the term C1-C2 hydroxyalkyl embraces linear or ed alkyl radicals having 1 to 2 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl or hydroxyethyl.

As used herein, the term C1-C6 alkoxy (or alkyloxy) embraces linear or branched oxycontaining radicals each having alkyl portions of 1 to 6 carbon atoms. Examples of C1- C6 alkoxy ls include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and n-hexoxy.

As used herein, the term C1-C4 alkoxy (or alkyloxy) es linear or branched oxycontaining radicals each having alkyl portions of 1 to 4 carbon atoms. Examples of C1- C4 alkoxy radicals include methoxy, ethoxy, n-propoxy, oxy, xy, toxy or t-butoxy.

As used herein, the term C1-C3 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 3 carbon atoms. Examples of C1- C3 alkoxy ls include methoxy, ethoxy, n-propoxy and oxy.

As used herein, the term (C1-6 alkoxy)-(C1-6 alkyl) es linear or branched radicals having 1 to 6 carbon atoms substituted with a C1-6 alkoxy group. Examples of (C1-6 alkoxy)-(C1-6 alkyl) e methoxy-methyl, ethoxy-methyl, y-ethyl, ethoxy-ethyl, methoxy-propyl, propoxy-methyl, ethoxy-propyl, propoxy-ethyl, propoxy-propyl, methoxy-butyl, ethoxy-butyl, methoxy-pentyl, ethoxy-pentyl and methoxy-hexyl.

As used herein, the term C5-7 lkyl embraces saturated monocyclic carbocyclic radicals having from 5 to 7 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term 5- to 6-membered heteroaryl radical embraces typically a 5- to 6- membered ring system sing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl or pyrrolyl.

As used herein, the term 4- to 6-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C4-6 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.

Examples of 4- to 6-membered heterocyclyl radicals include oxetanyl, azetidinyl, piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, triazolyl, lyl, olyl, imidazolidinyl, 4,5-dihydrooxazolyl , 1,3-dioxolone, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl or 1,4-azathianyl.

As used herein, the term 5- to 6-membered heterocyclyl radical es typically a non-aromatic, saturated or unsaturated C5-6 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.

Examples of 5- to 6-membered cyclyl radicals include piperidyl, idyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, 1,3-dioxolone, ydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl or 1,4-azathianyl.

As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are stituted or substituted”. This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically able atoms, radicals, moieties, chains and .

As used herein, the term halogen atom embraces ne, fluorine, bromine and iodine atoms. A halogen atom is typically a fluorine, chlorine or bromine atom. The term halo when used as a prefix has the same meaning.

Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures. tional ques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or tion of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an l, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or onal crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using tography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, lly heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to % of an alkylamine, typically 0.1 % lamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those d in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. ElieI (Wiley, New York, 1994).

As used , the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from ceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.

Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, , malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1-hydroxynaphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like.

Salts d from pharmaceutically-acceptable inorganic bases include um, um, m, copper, ferric, ferrous, lithium, magnesium, ic, manganous, potassium, sodium, zinc and the like.

Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, dine, polyamine resins, procaine, purines, theobromine, triethylamine, hylamine, pylamine, tromethamine and the like.

Other salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various mineral acids such as, for example, chloride, bromide, , sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, te, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.

As used herein, an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.

The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable t molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2- propanol, l, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures f.

It is specifically contemplated that in the t ion one t molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be ated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one t molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate.

Furthermore, solvates of the t invention are plated as solvates of compounds of the present invention that retain the biological effectiveness of the nonsolvate form of the compounds.

The invention also includes isotopically-labeled 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the nds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, en, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Preferred isotopically- labeled compounds include deuterated derivatives of the compounds of the invention.

As used herein, the term deuterated derivative embraces compounds of the invention [Link] http://en.wikipedia.org/wiki/Stable_isotope [Link] /en.wikipedia.org/wiki/Hydrogen where in a ular position at least one hydrogen atom is replaced by ium.

Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

Isotopically-labeled 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention can generally be ed by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopicallylabeled reagent in place of the non-labeled reagent otherwise ed. gs of the 2-(pyrazolopyridinyl)pyrimidine derivatives described herein are also within the scope of the invention. Thus certain derivatives of the 2-(pyrazolopyridin yl)pyrimidine derivatives of the present ion, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further ation on the use of prodrugs may be found in Pro-drugs as Novel ry Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, on Press, 1987 (ed. E. B. Roche, an Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of gs by H. Bundgaard (Elsevier, 1985).

In the case of 2-(pyrazolopyridinyl)pyrimidine derivatives that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of the present invention.

Typically, R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, for example, a fluorine atom, a hydrogen atom or a methyl group. Preferably, R1 represents a fluorine atom.

Typically, R2 represents a hydrogen atom or a fluorine atom. Preferably, R2 represents a hydrogen atom. lly, X represents a –NR3- group. atively, X may represent -O-.

Typically, R3 represents a hydrogen atom.

Typically, Q represents Qa.

If R4 is a -CO-R’ group, then R’ is lly not H. lly, R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group.

Preferably, R4 represents a –C(O)CH2OH group or a -C(O)CH2CN group.

Typically, Ra represents a hydroxyl group, a linear or branched C1-3 alkyl group, a linear or branched C1-3 alkoxy group or an amino group.

Typically, G1 represents a –O-R6 group, a CN group or a monocyclic 5- to 6-membered aryl group containing at least one heteroatom ed from O, S and N and being unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy group. Preferably, G1 represents a –O-R6 group or a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from O, S and N and being unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group or a linear or ed C1-4 alkoxy group. For instance, G1 may represent an – O-R6 group.

Typically, R6 represents a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group or a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group.

Typically, the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile • 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxopropanenitrile • (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxetanyl)acetonitrile • Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate • 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxoethanol • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • )[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile or a pharmaceutically acceptable salt, or solvate, or N-oxide, or isomer or deuterated derivative thereof.

Preferably, the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile • 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxopropanenitrile • (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxetanyl)acetonitrile • Ethyl -[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate • 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxoethanol • )({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • 3-[(3R)({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a] pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • ){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • )[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a] pyridinyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile • (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl) pyrimidinyl)amino)piperidinyl)oxopropanenitrile or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.

Preferably, the 2-(pyrazolopyridinyl)pyrimidine tive is not a compound of formula (I), wherein • X is NR3; • R1 is Me or F; • R2 is H; • R3 is H or -CH2CH2N(CH3)2; • G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, 4-hydroxymethyl-phenyl, 4- formyl-phenyl or phenyl substituted with hydroxyl and –CH2NHCH3; • Q is Qa; • R4 is –C(O)CH2CN, -C(O)CH2OH, -C(O)OCH2CH3, or oxetanyl substituted with –CH2CN.

Preferably, the 2-(pyrazolopyridinyl)pyrimidine derivative is not a compound of formula (I), n • X is NR3; • R1 is Me or F; • R2 is H; • R3 is H or -CH2CH2N(CH3)2; • G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, razinyl or phenyl, which phenyl is substituted with one or more, typically one or two, substituents independently selected from hydroxyl, fluoro, -CH2OH, -C(O)H and – CH2NHCH3; • Q is Qa; • R4 is –C(O)CH2CN, -C(O)CH2OH, -C(O)OCH2CH3, or oxetanyl substituted with Typically, the 2-(pyrazolopyridinyl)pyrimidine derivative is not a nd of a (I), wherein • X is NR3; • R1 is Me or F; • R2 is H; • R3 is H or -CH2CH2N(CH3)2; • G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, 4-hydroxymethyl-phenyl, 4- formyl-phenyl or phenyl substituted with hydroxyl and –CH2NHCH3; • Q is Qa; • R4 is –C(O)CH2CN, -C(O)CH2OH, -C(O)OCH2CH3, or oxetanyl tuted with –CH2CN or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.

Typically, the 2-(pyrazolopyridinyl)pyrimidine derivative is not a compound of formula (I), wherein • X is NR3; • R1 is Me or F; • R2 is H; • R3 is H or -CH2CH2N(CH3)2; • G1 is N-morpholino, 4-hydroxymethyl-N-piperidinyl, N-piperazinyl or phenyl, which phenyl is substituted with one or more, typically one or two, substituents independently selected from hydroxyl, fluoro, -CH2OH, -C(O)H and – CH2NHCH3; • Q is Qa; • R4 is –C(O)CH2CN, H2OH, -C(O)OCH2CH3, or oxetanyl substituted with –CH2CN; or a pharmaceutically able salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.

It is particularly preferred that: a. X represents -O-; or b. X represents -NR3- and R3 is selected from: i. a 1-3NR’R’’ group, wherein R’ and R’’ independently represents a linear or branched C1-3 yalkyl group or a linear or branched C1-3 alkoxy group; or ii. a ’R’’ group, wherein R’ and R’’ ndently represents a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy group; or iii. a CH2-pyrollidine group; or c. R1 is a linear or branched C1-4 alkoxy group or a -CN group; or d. R2 is a halogen atom or a -CN group; or e. G1 is selected from the group ting of –CN group, -CO-Ra group, a –O-R6 group, and a )m-NR’R’’ group; or f. G1 is selected from a phenyl group, a monocyclic C5-7 cycloalkyl group, a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a clic 5- to 6- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are substituted by one or more substituents selected from a linear or branched C3 hydroxyalkyl group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra represents a hydroxyl group, a linear or branched C1-3 alkyl group, a linear or branched C1-3 alkoxy group or an amino group; or g. Q is Qa and R4 is selected from the group consisting of a cyanothiazole group, and a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, wherein the heteroaryl group is unsubstituted or substituted with one or more substituents selected from – (CH2)m-CN group and a C1-2 hydroxyalkyl group; or h. Q is Qc and R’ is a linear or branched C1-3 yalkyl group or a linear or branched C1-3 alkoxy group.

In a preferred embodiment, • R1 represents a hydrogen atom, a ne atom, a chlorine atom or a methyl group, for example, a fluorine atom, a en atom or a methyl group, preferably a fluorine atom; • R2 represents a hydrogen atom or a fluorine atom, ably a hydrogen atom; • X ents a –O- or –NR3- group , preferably a –NR3- group; • R3 represents a en atom; • Q represents Qa; • R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; preferably R4 represents a –C(O)CH2OH group or a -C(O)CH2CN group; • G1 represents a –O-R6 group, a CN group or a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from O, S and N and being unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy group, preferably G1 represents a –O-R6 group or a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N and being unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C1-4 alkyl group or a linear or branched C1-4 alkoxy group; and • R6 represents a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group or a linear or ed C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group.

In a more preferred embodiment, • X ents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a fluorine atom and a methyl group; • R3 is selected from the group consisting of a hydrogen atom and a methyl group; • G1 is selected from the group consisting of –CN group, a –CONH2 group, a - CO2Et group, a –CO2iPr group, a –O-R6 group, a CH2OH group, a phenyl group, a pyridinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, wherein the phenyl, pyridinyl, pyrazolyl, piperidinyl, piperazinyl and morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a methyl group, a - CH2OH group, a –CH2-C(OH)(CH3)2 group, a methoxy group, an amino group, a –N(CH3)2 group, a –COOH group and a –CO2Et group; • R4 is selected from the group consisting of a -CO(CH2)-OH group; 2)- CN group, a pyrazinyl group and a pyrimidinyl group, n the pyrazinyl and pyrimidinyl groups independently are unsubstituted or substituted with a CN group or a –-CH2OH group; • R5 represents a N group; • G2 represents a pyrimidine group or a pyridine group, wherein the pyrimidine and pyridine groups are unsubstituted or substituted by a fluorine atom; and • R6 is selected from the group consisting of a hydrogen atom, a 2CH2Ph group, a –(CH2)2OCH3 group, a –(CH2)2OCH2CH3 group, a –CH(CH3)CH2OCH3 group, a methyl group, an ethyl group, a butyl group, a –CH2CF3 group, a – CH2CHF2 group, a CH(CH3)2 group, a –(CH2)2OH group, a –(CH2)2-3N(CH3)2 group, a -CH(CH3)-CH2OH group, a –CH2CH(OH)CH2OH group.

Particular individual compounds described herein include: (Trans{[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}cyclohexyl)acetonitrile; (Trans{[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}cyclohexyl)acetonitrile; [(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]cyclohexyl}acetonitrile; ({6-[4-(dimethylamino)piperidinyl]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; (Trans{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}cyclohexyl)acetonitrile; {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; {Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; [Trans({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl}amino)cyclohexyl]acetonitrile; [trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; [Trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; 6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazolo [1,5-a]pyridinylpyrimidinamine; 2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]etanol; (2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propane-1,2-diol; 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxopropanenitrile; 3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitril; 3-((3R){[6-(6-Aminopyridinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; ){[5-fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- mino}piperidinyl)oxopropanenitrile; 3-((3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-{(3R)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl](methyl)amino]piperidinyl}oxopropanenitrile; 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinol; 2-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; )({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 2-((3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; Ethyl luoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)methylpiperidinecarboxylate; 2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin ylpyrimidinyl]amino}piperidinyl)oxoethanol; Ethyl [(3R)(cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5- a]pyridinylpyrimidinyl)piperidinecarboxylate; 1-(6-{[(3R)(Cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinecarboxylic acid; 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(1H-pyrazolyl)pyrimidin yl]amino}piperidinyl)oxoethanol; 1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)-1H-pyrazolyl]methylpropanol; 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; Ethyl 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)pyridinecarboxylate; 2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinol; Benzyl [(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]acetate; 2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; Ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin midinecarboxylate; -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarbonitrile; -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarboxamide; 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin ]piperidinyl}oxoethanol; 3-{(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile; -((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; (5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinyl)methanol; -{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinecarbonitrile; 2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrimidinecarbonitrile; 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; )[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol; 3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxopropanenitrile; 2-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin midinyl]oxy}piperidinyl)oxopropanenitrile; 2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxoethanol; 3-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile; ){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]oxy}piperidinyl)oxopropanenitrile; 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile; 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxoethanol; 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinol; 3-((3R){[5-Fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile; 2-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl](methyl)amino]piperidinyl}oxoethanol; 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile; -(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)pyridinecarboxylic acid; 2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-[(3R)({6-[6-(Dimethylamino)pyridinyl]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 2-{(3R)[(5-Fluoro-2'-methylpyrazolo[1,5-a]pyridinyl-4,5'-bipyrimidin yl)amino]piperidinyl}oxoethanol; 2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; )({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 3-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile; 2-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile; 2-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 3-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin midinyl}amino)piperidinyl]oxopropanenitrile; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; 5-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile; Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinecarboxylate; 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin yl}oxoethanol; 3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin yl}oxopropanenitrile; ){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; ){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 5-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; -(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin yl)pyridinol; 3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; )[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)(methyl)amino]piperidinyl}oxoethanol; or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated derivative thereof.

Of outstanding interest are: ){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; ro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarbonitrile; 2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidin- 1-yl}oxoethanol; 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile; 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}- thanol; 3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}- 3-oxopropanenitrile; 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; ){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 5-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin yl)pyridinol; 3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer, or deuterated derivative thereof.

GENERAL TIC PROCEDURES The 2-(pyrazolopyridinyl)pyrimidine tives of the invention can be prepared using the methods and procedures described herein, or using similar s and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process ions can also be used unless otherwise stated.

Optimum reaction conditions may vary with the particular nts or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be ary to prevent certain functional groups from undergoing red reactions. The choice of a le protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, us protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

Processes for ing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.

According to one embodiment of the present invention, compounds of general formula (I) may be prepared by the following synthetic route as illustrated in Scheme 1: Scheme 1 Treatment of dichloropyrimidines of formula (II) with amines or alcohols of formula (III) in the presence of a base such as triethylamine or sodium hydrogencarbonate in a solvent such as ol or ethanol at temperatures ranging from ambient temperature to reflux gives rise to compounds of formula (IV).

In the particular case where G1 is an aryl or heteroaryl ring, nds of formula (I) may be obtained from chloropyrimidines of formula (IV) by reaction with compounds of formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457). Such reactions may be catalysed by a suitable ium catalyst such as [1,1'- phenylphosphino)ferrocene]palladium(II) dichloride romethane complex or tetrakis(triphenylphosphine)palladium(0) in a solvent such as e, 1,4-dioxane or 1,2-dimethoxyethane in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 ºC to 110 ºC with or without the use of microwave irradiation.

Boronic acids or boronates of formula (V) where G1 is an aryl or heteroaryl ring and Y is a boronic acid or te ester may be commercially available or may be prepared from the corresponding haloderivatives of formula (V), where Y is a bromine atom or a chlorine atom, by treatment with an riate boron reagent such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) with a palladium catalyst such as bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex or bis(dibenzylideneacetone)palladium(0), in a solvent such as 1,4-dioxane or 1,2- dimethoxyethane, with or without the presence of a ligand such as lohexylphosphine, in the presence of a base such as potassium acetate at temperatures g from 80-150 ºC with or without the use of microwave irradiation.

In another particular case where G1 is an heterocyclyl group attached to the pyrimidine ring through a nitrogen atom, a –CN group, a (CHR7)m-NR’R’’, or a –O-R6 group, compounds of formula (I) may be prepared by reaction of chloroderivatives of formula (IV) with heterocyclic or linear amines, alcohols or cyanides of formula (V), where Y is an hydrogen or metal atom, in the presence of a base such as sodium hydrogencarbonate or N-ethyl-N-isopropylpropanamine without the use of a solvent or in a t such as N,N’-dimethylacetamide or 1-methylpyrrolidinone at temperatures ranging from 80-130 ºC with or without the use of microwave irradiation.

Compounds of a (II) may be prepared as illustrated in Scheme 2: Scheme 2 Reaction of ethyl propiolate with N-aminopyridinium salts of formula (VII) in the presence of a base, for example ium carbonate, in a solvent such as N,N’- dimethylformamide at temperatures ranging from 0 ºC to ambient temperature, furnishes esters of a (VIII). N-Aminopyridinium salts of formula (VII) may be commercially available or may be prepared by reaction of the corresponding pyridines of formula (VI) with O-(mesitylsulfonyl)hydroxylamine in a suitable t such as dichloromethane at temperatures ranging from 0 ºC to ambient temperature. Treatment of esters of formula (VIII) with a mixture of trimethylaluminum and ammonium chloride in a solvent such as toluene at 80 ºC provides amidine intermediates of formula (IX).

Amidines of formula (IX) may be reacted with malonate esters of formula (X) to give dihydroxypirimidines of formula (XI). Such reactions may be carried out in the presence of a suitable base such as sodium ide in a t such as methanol at temperatures ranging from 0 ºC to ambient temperature. Dihydroxypirimidines of formula (XI) may be converted to dichloropyrimidines of formula (II) by treatment with a suitable chlorinating agent, for example phosphorus(V) oxychloride, at temperatures ranging from 25 ºC to reflux.

In the particular case where G1 is an aryl or heteroaryl ring, compounds of l formula (I) may also be prepared by an alternative synthetic approach as shown in Scheme 3: Scheme 3 Treatment of trichloropyrimidines of formula (XII) with amines of formula (III) in the presence of a base such as triethylamine or sodium hydrogencarbonate in a solvent such as ethanol at -20 ºC gives rise to compounds of formula (XIII).

In the particular case where G1 is an aryl or aryl ring, compounds of formula (XIV) may be ed from dichloropyrimidines of formula (XIII) by reaction with nds of formula (V), where Y is a boronic acid or a boronate ester, under -Miyaura reaction conditions. Such reactions may be catalysed by a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as 1,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 ºC.

Reaction of chloropyrimidines of formula (XIV) with stannanes of formula (XV) in the presence of a palladium catalyst such as tetrakis (triphenylphosphine)palladium(0) in a solvent such as 1,4-dioxane at 100 ºC es compounds of formula (I).

In yet another particular case, compounds of formula (I), in which the residue at G1, or Q contains an alcohol, phenol or carboxylic acid moiety functionalized with an riate protecting group such as benzyl (Bn) or methoxy (OMe), may be deprotected at the alcohol, phenol or carboxylic acid moiety under standard ions e's Protective Groups in Organic sis, ISBN: 0471697540). In the particular case of primary alcohols, the free alcohol moiety may then be oxidized under standard conditions to give the corresponding aldehyde.

In yet r particular case, compounds of formula (I), in which the residue at G1, or Q contains an amine moiety functionalized with an appropriate protecting group such as tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), may be deprotected at the amine moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). The corresponding free amine may then be further functionalized under standard conditions to give the corresponding amides, carbamates and N-alkylated and N-arylated amines.

Starting nds are commercially available or may be obtained following the conventional synthetic methods y known in the art.

The synthesis of the compounds of the invention and of the intermediates for use therein are illustrated by the following Examples (1-63) (including Preparations 1-8) and are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description.

PREPARATIONS PREPARATION 1 Pyrazolo[1,5-a]pyridinecarboximidamide a) Ethyl pyrazolo[1,5-a]pyridinecarboxylate ium carbonate (6.10 g, 44.14 mmol) was added to a stirred solution of 1- aminopyridinium iodide (6.57 g, 29.59 mmol) in anhydrous N,N-dimethylformamide (44 mL) at 0 °C. Ethyl propiolate (3 mL, 29.7 mmol) was then added se and the resulting mixture was stirred overnight at room temperature. The on mixture was ioned between water and chloroform. The c phase was separated, washed with water and brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (5.51 g, 96%) as a red oil.

LRMS (m/z): 191 (M+1)+. b) lo[1,5-a]pyridinecarboximidamide A 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 118.29 mmol) was added se to a stirred suspension of ammonium de (5.90 g, 118.29 mmol) in toluene (100 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 1 hour. A solution of ethyl pyrazolo[1,5-a]pyridinecarboxylate (Preparation 1a, 7.50 g, 39.43 mmol) in toluene (20 mL) was then added and the resulting mixture was stirred overnight at 80 ºC. Additional 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 118.29 mmol) and ammonium chloride (5.90 g, 118.29 mmol) in toluene (100 mL) were added and the reaction e was stirred at 80 ºC for further 24h. After cooling to 0 ºC in an ice bath, methanol (40 mL) was added dropwise. The solid formed was filtered and washed with methanol and the filtrate was evaporated to dryness. Purification of the e by flash chromatography (dichloromethane to 7:3 dichloromethane/ethanol) gave the title compound (4.72 g, 74%) as a yellow solid.

LRMS (m/z): 161 (M+1)+. c) 5-Fluoropyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol Pyrazolo[1,5-a]pyridinecarboximidamide (Preparation 1b, 4.75 g, 29.47 mmol) was added nwise to a stirred solution of sodium (1.63 g, 71.02 mmol) in methanol (120 mL) at 0 °C. l 2-fluoromalonate (7.0 mL, 44.20 mmol) was then added and the reaction mixture was stirred from 0 ºC to room temperature overnight. The solvent was evaporated to dryness to yield the title compound (7.25 g, 99%) as a solid that was used in the next synthetic step without further purification.

LRMS (m/z): 247 (M+1) +. 1H-NMR  (300 MHz, DMSO-d 6): 7.23 (t, 1H), 7.50 - 7.73 (m, 1H), 8.71 (d, 1H), 8.85 - 8.94 (m, 2H), 11.83 (bs, 1H), 12.70 (br.s., 1H). d) 3-(4,6-Dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine A mixture of ropyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol (Preparation 1c, 7.00 g, 28.43 mmol) and phosphorus(V) oxychloride (55 mL, 589 mmol) was d at 110 ºC for 24 hours. The solvent was then removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over magnesium e and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (hexanes to dichloromethane) to yield the title compound (5.3 g, 65%) as a yellow solid.

LRMS (m/z): 283 (M+1) +. 1H -NMR  (300 MHz, CDCl 3): 7.00 (td, 1H), 7.44 (ddd, 1H), 8.62 (ddt, 2H), 8.74 (s, 1H).

PREPARATION 2 {Trans[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino] cyclohexyl}acetonitrile A mixture of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 1d, 0.30 g, 1.06 mmol), (transaminocyclohexyl)acetonitrile hydrochloride* (0.22 g, 1.27 mmol) and sodium hydrogencarbonate (0.39 g, 4.63 mmol) in ethanol (6 mL) was heated at reflux overnight. The solvent was evaporated and the residue was partitioned n water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium e and the solvent was evaporated in vacuo. The resulting crude was purified by flash chromatography (gradient from hexanes to ethyl acetate) to yield the title compound (0.30 g, 72%) as a solid.

*Prepared following the experimental procedure described in WO2011157397, Preparation 50.

LRMS (m/z): 385 (M+1)+.

PREPARATION 3 (S)Chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl)(pyrazolo[1,5-a]pyridin yl)pyrimidinamine A mixture of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 1d, 1.00 g, 3.53 mmol), (1S)(5-fluoropyridinyl)ethanamine dihydrochloride (0.85 g, 6.06 mmol) and sodium hydrogencarbonate (1.40 g, 16.66 mmol) in ethanol (20 mL) was heated at reflux overnight. The t was evaporated and the residue was crystallized from methanol to yield the title compound (1.25 g, 82%) as a solid.

LRMS (m/z): 387 (M+1)+.

PREPARATION 4 6-Chlorofluoro-N-[(1S)(5-fluoropyrimidinyl)ethyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinamine ed as a solid (70%) from 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5- a]pyridine (Preparation 1d) and (1S)(5-fluoropyrimidinyl)ethanamine following the experimental procedure as described in Preparation 3, followed by purification of the crude product by flash chromatography ent from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 388 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.72 (d, 3H), 5.63 (m, 1H), 6.32 (m, 1H), 6.94 (t, 1H), 7.43 (m, 1H), 8.52 (m, 2H), 8.64 (d, 2H).

PREPARATION 5 Tert-butyl -[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinecarboxylate rt-butyl 3-aminopiperidinecarboxylate (2.97 g, 14.83 mmol) was added to a solution of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 1d, 3.50 g, 12.36 mmol) and triethylamine (2.0 mL, 15.08 mmol) in ethanol (80 mL) and the resulting mixture was stirred at 80 ºC for 48 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and water was added. The precipitate was filtered and dried in vacuo to give the title compound (5.60 g, 100%) as a white solid.

LRMS (m/z): 447 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.6 (s, 9H), 1.7 - 1.9 (m, 3H), 2.0 - 2.1 (m, 1H), 3.5 (bs, 4H), 4.3 (d, 1H), 5.2 (s, 1H), 6.9 (t, 1H), 7.3 - 7.4 (m, 1H), 8.5 (t, 2H), 8.3 (s, 1H).

PREPARATION 6 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino] piperidinyl}oxopropanenitrile a) 6-Chlorofluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin- 4-amine 4.0 M Hydrogen chloride solution in oxane (31.4 mL, 125.6 mmol) was added to a on of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate (Preparation 5, 5.61 g, 12.55 mmol) in oxane (150 mL) and the resulting mixture was stirred overnight at room temperature. The precipitate formed was filtered and washed with 1,4-dioxane and diethyl ether and dried in vacuo to give the hydrochloride salt of the title compound (5.50 g, 100%) as a white solid.

LRMS (m/z): 347 . 1H-NMR  (300 MHz, CD 3OD): 1.73 - 2.24 (m, 5H), 2.93 - 3.15 (m, 2H), 3.43 (t, 1H), 3.61 - 3.73 (m, 1H), 4.44 - 4.75 (m, 1H), 7.10 (td, 1H), 7.50 (ddd, 1H), 8.53 (d, 1H), 8.61 (dd, 2H). b) 3-{(3R)[(6-Chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino] piperidinyl}oxopropanenitrile -Dioxopyrrolidinyl)oxy]oxopropanenitrile (prepared as described in BE875054(A1), 3.58 g, 19.66 mmol) was added to a solution of 6-chlorofluoro-N- [(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl-pyrimidinamine (Preparation 6a, .5 g, 13.10 mmol) and triethylamine (9.1 mL, 65.7 mmol) in dichloromethane (10 mL).

The resulting mixture was stirred overnight at room temperature. Additional 3-[(2,5- dioxopyrrolidinyl)oxy]oxopropanenitrile (0.80 g, 4.39 mmol) was added and the reaction mixture was d at room temperature for further 5 hours. The resulting mixture was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting crude was purified by flash chromatography (gradient from hexanes to ethyl acetate) to yield the title compound (0.37 g, 80%) as a white solid.

LRMS (m/z): 414 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.71 - 2.02 (m, 4H), 2.20 (t, 1H), 3.34 - 3.51 (m, 2H), 3.62 - 3.71 (m, 1H), 3.92 (dd, 1H), 4.30 (bs, 1H), 4.60 (d, 1H), 5.03 (d, 1H), 6.91 (dt, 1H), 7.39 (ddd, 1H), 8.40 - 8.61 (m, 2H), 8.7 (s, 1H).

PREPARATION 7 (R)(3-((6-Chlorofluoro(pyrazolo[1,5-a]pyridinyl)pyrimidinyl)amino) piperidinyl)hydroxyethanone A e of 6-chlorofluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl dinamine (Preparation 6a, 0.46 g, 1.10 mmol), 2-hydroxyacetic acid (0.10 g, 1.10 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium oxide hexafluorophosphate (0.54 g, 1.42 mmol) and triethylamine (0.53 mL, 3.82 mmol) in methylformamide (2 mL) was d at room temperature for 18 hours. The resulting mixture was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous phase was extracted twice with ethyl e. The combined organic layers were washed with water, brine, dried over ium sulfate and concentrated in vacuo. The resulting crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.37 g, 80%) as a white solid.

LRMS (m/z): 405 (M+1)+.

PREPARATION 8 Tert-butyl(3R)[(6-chloromethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino] piperidinecarboxylate a) 5-Methyl(pyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-diol Pyrazolo[1,5-a]pyridinecarboximidamide (Preparation 1b, 2.89 g, 18.05 mmol) and diethyl methylmalonate (6.44 mL, 37.45 mmol) were added nwise to a solution of sodium (1.24 g, 53.91 mmol) in methanol (14 mL) at 0 ºC and the resulting suspension was stirred at room ature ght. The solvent was evaporated to dryness and the residue was dissolved in water and acidified to pH=1 using a 6N hydrochloric acid solution. The precipitate was filtered, washed with water and dried under vacuum to yield the title compound (3.54 g, 81%) as a yellow solid.

LRMS (m/z): 243 (M+1)+. 1H-NMR  (400 MHz, DMSO-d6): 1.79 (s, 3H), 7.10 - 7.14 (t, 1H), 7.52 - 7.56 (dd, 1H), 8.73 - 8.75 (d, 1H), 8.81 - 8.83 (d, 1H), 8.91 (s, 1H). b) 3-(4,6-Dichloromethylpyrimidinyl)pyrazolo[1,5-a]pyridine Obtained as a solid (30%) from yl(pyrazolo[1,5-a]pyridinyl)pyrimidine-4,6- diol (Preparation 8a) and phosphorus(V) oxychloride following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (hexanes/ ethyl acetate 1:4).

LRMS (m/z): 279 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 2.47 (s, 3H), 6.93 - 6.97 (t, 1H), 7.39 - 7.44 (dd, 1H), 8.53 - 8.56 (m, 1H), 8.71 (s, 1H). c) (R)-Tert-butyl 3-((6-chloromethyl(pyrazolo[1,5-a]pyridinyl)pyrimidin yl)amino)piperidinecarboxylate A mixture of 3-(4,6-dichloromethylpyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 8b, 1.11 g, 3.98 mmol), (R)-tert-butyl 3-aminopiperidinecarboxylate (0.93 g, 4.65 mmol) and diisopropylethylamine (1.04 mL, 5.97 mmol) in ethanol (12 mL) was stirred 68 hours at 80 ºC. N,N’-dimethylacetamide (9 mL) was then added and the reaction mixture was stirred at 100 ºC for r 68 hours. Ethanol was evaporated and excess of water was added. The precipitate was filtered, washed with water and dried to give the title compound (1.49 g, 85%).

LRMS (m/z): 443 (M+1)+.

PREPARATION 9 Tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin ]piperidinecarboxylate To a on of tert-butyl (3R)hydroxypiperidinecarboxylate (853 mg, 4.24 mmol) in dioxane (50 mL) was added potassium tert-butoxide (476 mg, 4.24 mmol). The mixture was stirred at room temperature for 15 minutes and then 3-(4,6-dichloro fluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 1d, 1.00 g, 2.53 mmol) was added. The mixture was stirred at room temperature for 3 hours and then at 50 ºC for 1 hour and then the t was removed. The residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium e and evaporated to dryness. The resulting crude was purified by flash chromatography ent from hexane to 30% hexane/ethyl acetate ) to yield the title compound (1.40 g, 89%) as a pale solid.

LRMS (m/z): 448 (M+1)+.

PREPARATION 10 Tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate a) 2-Pyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol To an ice-bath cooled solution of sodium methoxide (prepared from 0.77 g of metal sodium in 30 mL methanol were added pyrazolo[1,5-a]pyridinecarboximidamide chlorohydrate (Preparation 1b, 1.68 g, 8.54 mmol) and diethyl malonate (3.16 mL, 20.8 mmol). The mixture was stirred at room ature overnight. Excess sodium meythoxyde (0.200 g of sodium in 10 mL of ol) and diethyl te (1 mL, 9.75 mmol) were added and the e was stirred for an additional 24 hours. The solvent was removed under reduced pressure and the residue was redissolved in water (50 mL). After stirring for 30 minutes the solution was using a 2N hydrochloric acid solution. The precipitate was filtered, washed with water and dried under vacuum to yield the title compound (993 mg, 51%) as a pale solid.

LRMS (m/z): 229 (M+1)+. b) 3-(4,6-Dichloropyrimidinyl)pyrazolo[1,5-a]pyridine Obtained as a solid (69%) from 2-pyrazolo[1,5-a]pyridinylpyrimidine-4,6-diol (Preparation 10a) and orus(V) oxychloride following the experimental procedure as described in Preparation 1d.

LRMS (m/z): 265 (M+1)+. c) utyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate Tert-butyl (3R)aminopiperidinecarboxylate (716 mg, 3.58 mmol) was added to a solution of 3-(4,6-dichloropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 10b, 790 mg, 2.98 mmol) and triethylamine (623 µL, 4.46 mmol) in ethanol (20 mL) and the resulting mixture was stirred at reflux temperature for 64 hours. After g to room temperature, the solvent was evaporated under d pressure. The residue was redissolved in ethyl acetate and the solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude was purified by flash chromatography (gradient from chloroform to 5% chloroform/methanol) to yield the title compound (1.22 g, 95%) as a white solid.

LRMS (m/z): 430 (M+1)+.

EXAMPLE 1 (Trans{[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}cyclohexyl)acetonitrile A suspension of {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin no]cyclohexyl}acetonitrile (Preparation 2, 0.060 g, 0.16 mmol) and piperidinol (0.063 g, 0.62 mmol) in N,N’-dimethylacetamide (0.3 mL) was stirred at 100 ºC for 3 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined c layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by flash tography (gradient from dichloromethane to dichloromethane /methanol 95:5) to yield the title compound (0.045 mg, 64%) as a yellow solid.

LRMS (m/z): 450 (M+1)+. 1H-NMR  (300 MHz, DMSO-d 6): 1.18 - 1.50 (m, 6H), 1.57 - 1.72 (m, 1H), 1.78 - 1.93 (m, 4H), 1.97 - 2.09 (m, 2H), 3.11 - 3.28 (m, 2H), 3.62 - 3.78 (m, 1H), 3.86 - 3.98 (m, 1H), 3.98 - 4.15 (m, 2H), 4.72 (d, 1H), 6.64 - 6.74 (m, 1H), 6.94 - 7.06 (m, 1H), 7.36 - 7.47 (m, 1H), 8.40 (d, 1H), 8.46 (s, 1H), 8.75 (d, 1H).

EXAMPLE 2 (Trans{[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}cyclohexyl)acetonitrile a)Tert-butyl[1-(6-{[trans(cyanomethyl)cyclohexyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)piperidinyl]carbamate A mixture of (S)chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl)(pyrazolo[1,5- a]pyridinyl)pyrimidinamine (Preparation 2, 0.080 g, 0.21 mmol), tert-butyl piperidinylcarbamate (0.060 g, 0.30 mmol) and sodium hydrogencarbonate (0.070 g, 0.83 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred overnight at 100 ºC. After cooling to room temperature, water was added and the solid formed was ed and dried in vacuo to yield the title compound (0.095 g, 79%).

LRMS (m/z): 551 (M+1)+. b) {[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}cyclohexyl)acetonitrile 4.0 M Solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.60 mmol) was added to a solution of tert-butyl [1-(6-{[trans(cyanomethyl)cyclohexyl]amino}fluoro lo[1,5-a]pyridinylpyrimidinyl)piperidinyl]carbamate (Example 2a, 0.095 g, 0.17 mmol) and the resulting mixture was stirred at room temperature for 5 hours. The solvent was evaporated to dryness and the residue was diluted with water. The pH was adjusted to 9 by addition of 2N aqueous sodium hydroxide solution, extracted with romethane (x3), the combined c layers were washed with brine, dried and the solvent was evaporated to dryness. The resulting crude was purified by flash chromatography (gradient from romethane to dichloromethane /methanol/ammonia 100:8:1) to yield the title compound (0.029 g, 37%) as a beige solid.

LRMS (m/z): 449 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.20 - 1.53 (m, 6H), 1.70 - 1.85 (m, 1H), 1.87 - 2.07 (m, 4H), 2.25 - 2.41 (m, 4H), 2.88 - 3.13 (m, 3H), 3.92 - 4.16 (m, 1H), 4.32 - 4.46 (m, 2H), 4.52 (dd, 1H), 6.79 - 6.87 (m, 1H), 7.22 - 7.32 (m, 1H), 8.40 - 8.52 (m, 2H), 8.55 (s, 1H).

EXAMPLE 3 {Trans[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]cyclohexyl}acetonitrile a)Tert-butyl4-(6-{[trans(cyanomethyl)cyclohexyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)piperazinecarboxylate Obtained as a solid (60%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and tert-butyl piperazine- 1-carboxylate following the mental procedure as described in Example 2a.

LRMS (m/z): 535 (M+1)+. b){Trans[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) cyclohexyl}acetonitrile Obtained as a solid (47%) from tert-butyl 4-(6-{[trans(cyanomethyl)cyclohexyl] amino}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)piperazinecarboxylate (Example 3a) following the experimental ure as described in Example 2b.

LRMS (m/z): 435 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.17 - 1.49 (m, 5H), 1.92 - 2.08 (m, 2H), 2.25 - 2.39 (m, 4H), 2.94 - 3.11 (m, 4H), 3.65 - 3.77 (m, 4H), 3.95 - 4.12 (m, 1H), 4.53 (dd, 1H), 6.77 - 6.88 (m, 1H), 7.22 - 7.31 (m, 1H), 8.40 - 8.51 (m, 2H), 8.54 (s, 1H).

EXAMPLE 4 [Trans({6-[4-(dimethylamino)piperidinyl]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile Obtained as a solid (33%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinyl dinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and N,N-dimethyl piperidin- 4-amine following the experimental procedure as described in Example 2a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1).

LRMS (m/z): 477 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.17 - 1.46 (m, 4H), 1.60 - 1.81 (m, 2H), 1.90 - 2.09 (m, 4H), 2.27 - 2.40 (m, 4H), 2.34 (s, 6H), 2.40 - 2.54 (m, 1H), 2.96 (t, 2H), 3.95 - 4.19 (m, 1H), 4.53 (d, 3H), 6.75 - 6.90 (m, 1H), 7.23 - 7.33 (m, 1H), 8.41 - 8.52 (m, 2H), 8.55 (s, 1H).

EXAMPLE 5 {[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}cyclohexyl)acetonitrile Ethylene glycol (0.32 mL, 5.83 mmol) was added to a suspension of potassium tert- de (0.043 g, 0.38 mmol) in 1,4-dioxane (0.5 mL) and the resulting mixture was stirred at room temperature for 15 minutes. {Trans[(6-chlorofluoropyrazolo[1,5- a]pyridinyl pyrimidinyl)amino]cyclohexyl}acetonitrile ration 2, 0.050 g, 0.13 mmol) was then added and the on e was stirred at 90 ºC overnight. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined c layers were washed with brine, dried over magnesium e and evaporated to dryness. The resulting crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.035 g, 65%) as a solid.

LRMS (m/z): 411 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.20 - 1.50 (m, 4H), 1.69 - 1.89 (m, 1H), 1.97 - 2.09 (m, 2H), 2.26 - 2.42 (m, 4H), 3.11 - 3.29 (m, 1H), 3.98 - 4.14 (m, 3H), 4.64 - 4.81 (m, 3H), 6.84 - 6.92 (m, 1H), 7.29 - 7.38 (m, 1H), 8.35 - 8.54 (m, 2H), 8.55 (s, 1H).

EXAMPLE 6 {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile ns[(6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclohexyl}acetonitrile Obtained as a solid (51%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinyl pyrimidinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and [(4R)-2,2-dimethyl-1,3- dioxolanyl]methanol following the experimental procedure as described in Example 5.

LRMS (m/z): 481 (M+1)+. b) {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)amino]cyclohexyl}acetonitrile To a solution of {trans[(6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro pyrazolo [1,5-a]pyridinylpyrimidinyl)amino]cyclohexyl}acetonitrile (Example 6a, 0.051 g, 0.11 mmol) in tetrahydrofurane (1 mL), 1M hydrochloric acid solution (1 mL, 1 mmol) and the resulting solution was d at room temperature for 3 hours. The solvent was evaporated to dryness, the pH of the resulting solution was adjusted to 8 by addition of saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate (x3), the combined organic layers were washed with brine, dried and the t was evaporated in vacuo to yield the title compound (0.036 g, 76%) as a yellow solid.

LRMS (m/z): 441 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.43 (m, 3H), 1.80 (m, 1H), 2.05 (m, 2H), 2.42 (m, 4H), 3.80 (m, 2H), 4.12 (m, 2H), 4.73 (d, 2H), 4.82 (d, 1H), 6.91 (m, 1H), 7.40 (dd, 1H), 8.44 (d, 1H), 8.55 (m, 2H).

EXAMPLE 7 {Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile a){Trans[(6-{[(4S)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro pyrazolo[1,5-a] pyridinylpyrimidinyl)amino]cyclohexyl}acetonitrile Obtained as a solid (71%) from {trans[(6-chlorofluoropyrazolo[1,5-a]pyridinyl pyrimidinyl)amino]cyclohexyl}acetonitrile (Preparation 2) and 2,2-dimethyl-1,3- anyl]methanol following the experimental procedure as described in Example LRMS (m/z): 481 (M+1)+. b){Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin- 3-yl pyrimidinyl)amino]cyclohexyl}acetonitrile Obtained as a light yellow solid (70%) from {trans[(6-{[(4S)-2,2-dimethyl-1,3- dioxolanyl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]cyclohexyl}acetonitrile (Example 7a) following the experimental procedure as described in Example 6b.

LRMS (m/z): 441 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.35 (m, 4H), 1.78 (m, 1H), 2.02 (m, 2H), 2.31 (m, 2H), 2.36 (d, 2H), 2.48 (t, 1H), 3.75 (m, 3H), 4.07 (m, 2H), 4.63 (d, 2H), 4.75 (d, 1H), 6.87 (m, 1H), 7.33 (m, 1H), 8.41 (d, 1H), 8.51 (m, 2H).

EXAMPLE 8 [Trans({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile ed as a light yellow solid (41%) from {trans[(6-{[(4R)-2,2-dimethyl-1,3- dioxolanyl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclo hexyl}acetonitrile (Preparation 2) and 2-aminoethanol following the experimental procedure as described in Example 2a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 410 . 1H-NMR  (300 MHz, CDCl3): 1.16 - 1.51 (m, 4H), 1.72 - 1.88 (m, 1H), 1.96 - 2.12 (m, 2H), 2.25 - 2.44 (m, 4H), 3.66 - 3.83 (m, 2H), 3.86 - 3.95 (m, 2H), 3.99 - 4.13 (m, 1H), 4.26 (br. s., 1H), 4.48 (d, 1H), 5.03 (br. s., 1H), 6.86 (t, 1H), 7.33 (d, 1H), 8.41 - 8.54 (m, 2H), 8.56 (s, 1H).

EXAMPLE 9 [trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile Obtained as a light yellow solid (56%) from {trans[(6-{[(4R)-2,2-dimethyl-1,3- dioxolanyl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclo hexyl}acetonitrile (Preparation 2) and 2-(dimethylamino)ethanol ing the experimental procedure as described in Example 5 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 438 (M+1)+. 1H-NMR  (300 MHz, : 1.16 - 1.52 (m, 3H), 1.62 - 1.86 (m, 5H), 1.94 - 2.13 (m, 2H), 2.23 - 2.50 (m, 7H), 2.87 (t, 2H), 3.80 - 4.21 (m, 1H), 4.66 (t, 2H), 6.81 - 6.96 (m, 1H), 7.26 - 7.39 (m, 2H), 8.43 - 8.65 (m, 2H).

EXAMPLE 10 [Trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile ed as a white solid (42%) from {trans[(6-{[(4R)-2,2-dimethyl-1,3-dioxolan yl]methoxy}fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]cyclohexyl} acetonitrile (Preparation 2) and 3-(dimethylamino)propanol following the experimental procedure as described in Example 5 followed by purification of the crude product by flash tography ent from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 453 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.05 - 1.45 (m, 4H), 1.50 - 1.83 (m, 7H), 1.89 - 2.10 (m, 3H), 2.25 (s, 5H), 2.38 - 2.55 (m, 2H), 3.86 - 4.16 (m, 1H), 4.31 - 4.70 (m, 2H), 6.68 - 6.93 (m, 1H), 7.07 - 7.39 (m, 2H), 8.08 - 8.72 (m, 2H).

E 11 6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazolo [1,5-a]pyridinylpyrimidinamine a)Tert-butyl[1-(5-fluoro{[(1S)(5-fluoropyridinyl)ethyl]amino} pyrazolo[1,5-a] pyridineylpyrimidinyl)piperidinyl]carbamate Obtained as a solid (60%) from (S)chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl) (pyrazolo[1,5-a]pyridinyl)pyrimidinamine (Preparation 4) and tert-butyl piperidin ylcarbamate ing the experimental procedure as described in Example 2a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 551 (M+1)+. b) 6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl] pyrazolo [1,5-a]pyridinylpyrimidinamine Obtained as a solid (68%) from utyl fluoro{[(1S)(5-fluoropyridinyl) ethyl]amino}pyrazolo[1,5-a]pyridinylpyrimidinyl)piperidinyl]carbamate (Example 11a) following the experimental procedure as described in Example 2b.

LRMS (m/z): 451 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.33 - 1.54 (m, 3H), 1.65 (s, 3H), 1.85 - 2.10 (m, 3H), 2.88 - 3.26 (m, 3H), 4.41 (d, 2H), 5.36 - 5.51 (m, 1H), 5.60 (d, 1H), 6.81 (t, 1H), 7.17 - 7.26 (m, 1H), 7.31 - 7.47 (m, 2H), 8.28 (d, 1H), 8.43 - 8.55 (m, 2H).

EXAMPLE 12 2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]ethanol Obtained as a solid (26%) from 6-chlorofluoro-N-[(1S)(5-fluoropyrimidin yl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Preparation 5) and ethylene glycol following the experimental procedure as described in Example 5.

LRMS (m/z): 414 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.72 (d, 3H), 3.08 - 3.37 (m, 1H), 4.04 (d, 2H), 4.55 - 4.79 (m, 2H), 5.50 - 5.73 (m, 1H), 6.01 (d, 1H), 6.79 - 6.97 (m, 1H), 7.28 - 7.43 (m, 1H), 8.38 - 8.68 (m, 5H).

EXAMPLE 13 (2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propane-1,2-diol a)6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}fluoro-N-[(1S)(5- fluoropyrimidinyl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidinamine Obtained as a solid (77%) from 6-chlorofluoro-N-[(1S)(5-fluoropyrimidin yl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Preparation 5) and ,2- dimethyl-1,3-dioxolanyl)methanol following the experimental procedure as bed in Example 5.

LRMS (m/z): 484 (M+1)+. b)(2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propane-1,2-diol ed as a white solid (12%) from 6-{[(4R)-2,2-dimethyl-1,3-dioxolanyl]methoxy}- 5-fluoro-N-[(1S)(5-fluoropyrimidinyl)ethyl]pyrazolo[1,5-a]pyridinylpyrimidin amine (Example 13a) following the experimental procedure as described in Example LRMS (m/z): 444 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.72 (d, 3H), 3.56 - 3.92 (m, 2H), 4.15 (br. s., 1H), 4.65 (d, 2H), 5.49 - 5.77 (m, 1H), 6.00 - 6.26 (m, 1H), 6.88 (t, 1H), 7.35 (t, 1H), 8.26 - 8.77 (m, 5H).

EXAMPLE 14 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile a)Tert-butyl(3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained as an orange solid (76%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinecarboxylate (Preparation ) and ethylene glycol following the experimental procedure as described in Example 5.

LRMS (m/z): 473 (M+1)+. b)2-({5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl} oxy)ethanol To a solution of tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5- a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 14a, 0.16 g, 0.34 mmol) in 1,4-dioxane (1 mL), 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.30 mL, 5.2 mmol) was added. The resulting mixture was stirred at room temperature for 5 hours and ated in vacuo to yield the ochloride salt of the title compound (0.15 g, 93%) as a yellow solid.

LRMS (m/z): 373 (M+1)+. c) 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile Obtained as a light yellow solid (38%) from fluoro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)ethanol (Example 15b) following the experimental procedure as described in Preparation 7. The crude was ed by flash tography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 440 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.71 - 2.08 (m, 3H), 2.15 - 2.32 (m, 1H), 2.67 - 2.85 (m, 1H), 2.97 - 3.15 (m, 1H), 3.26 - 3.52 (m, 3H), 3.55 - 3.74 (m, 2H), 3.78 - 3.99 (m, 1H), 4.00 - 4.13 (m, 1H), 4.19 - 4.36 (m, 2H), 4.59 - 4.73 (m, 3H), 4.76 - 4.91 (m, 1H), 6.80 - 7.01 (m, 1H), 7.33 - 7.48 (m, 1H), 8.29 - 8.66 (m, 3H).

EXAMPLE 15 3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxopropanenitrile a)Tert-butyl(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino] piperidinecarboxylate Metal sodium (0.058 g, 2.52 mmol) was added to butanol (7 mL) and the mixture was stirred at room temperature until metal sodium was consumed. Tert-butyl (3R) [(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine carboxylate (Preparation 5, 0.25 g, 0.56 mmol) was added, the reaction mixture was stirred overnight at 90 ºC, then cooled to room ature and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed with brine, dried and concentrated in vacuo. The resulting crude was purified by flash chromatography (gradient from hexanes to dichloromethane) to yield the title compound (0.174 g, 64%) as a solid.

LRMS (m/z): 485 (M+1)+. toxyfluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin- ed as a yellow solid dihydrochloride salt (100%) from tert-butyl (3R)[(6- butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine carboxylate le 15a) following the experimental procedure as described in Example 14b.

LRMS (m/z): 385 (M+1)+. c)3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino] piperidinyl}oxopropanenitrile Obtained as a light yellow solid (58%) from xyfluoro-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 15b) ing the experimental procedure as described in Preparation 7b. The crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 452 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 0.96 - 1.10 (m, 3 H), 1.26 (s, 2 H), 1.47 - 1.69 (m, 2 H), 1.69 - 2.01 (m, 4 H), 2.11 - 2.30 (m, 1 H), 2.93 (d, 1 H), 3.22 - 3.47 (m, 2 H), 3.52 - 3.73 (m, 1 H), 3.78 - 4.02 (m, 1 H), 4.15 - 4.31 (m, 1 H), 4.45 - 4.60 (m, 2 H), 4.63 - 4.82 (m, 1 H), 6.82 - 6.98 (m, 1 H), 7.30 - 7.42 (m, 1 H), 8.33 - 8.70 (m, 3 H).

EXAMPLE 16 3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile a) Tert-butyl (3R)-3)fluoropyrazolo[1,5-a]pyri-{[6-(2-ethoxyethoxy din ylpyrimidinyl]amino}piperidinecarboxylate Obtained as a colourless oil (81%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5) and 2-ethoxyethanol following the experimental procedure as described in Example LRMS (m/z): 501 (M+1)+. b)6-(2-Ethoxyethoxy)fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a light yellow solid (100%) from tert-butyl (3R)-3)fluoropyrazolo[1,5- a]pyri-{[6-(2-ethoxyethoxydinylpyrimidinyl]amino}piperidinecarboxylate (Example 16a) ing the experimental ure as described in Example 15b.

LRMS (m/z): 401 (M+1)+. c)3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl] amino}piperidinyl)oxopropanenitrile Obtained as a light yellow solid (60%) from 6-(2-ethoxyethoxy)fluoro-N-[(3R)- piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 16b) ing the experimental procedure as described in Preparation 7b. The crude was purified by flash tography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 468 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 0.73 - 1.01 (m, 1H), 1.14 - 1.36 (m, 4H), 1.69 - 2.08 (m, 3H), 2.13 - 2.30 (m, 1H), 2.93 (d, 1H), 3.19 - 3.47 (m, 2H), 3.54 - 3.74 (m, 3H), 3.77 - 4.02 (m, 2H), 4.12 - 4.32 (m, 1H), 4.59 - 4.87 (m, 3H), 6.79 - 6.98 (m, 1H), 7.29 - 7.43 (m, 1H), 8.33 - 8.68 (m, 3H).

E 17 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile A Schlenk tube was charged with from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 7b, 0.35 g, 0.85 mmol), 4-hydroxymethylphenylboronic acid (0.19 g, 1.28 mmol), 2.0 M aqueous sodium carbonate solution (0.64 mL, 1.28 mmol) and 1,2-dimethoxyethane (4 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 ºC overnight. The solvent was removed and the residue was purified by flash chromatography (gradient from hexanes to hexanes/ethyl e 1:9) to yield the title compound (0.32 g, 77%) as a white solid.

LRMS (m/z): 486 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.71 - 1.90 (m, 2H), 2.10-2.35 (m, 2H), 3.21 - 3.54 (m, 4H), 3.63 - 3.70 (m, 1H), 3.91 (dd, 1H), 4.30 (br.s., 2H), 4.62 (dd, 1H), 4.81 (t, 2H), 5.10 (bs, 1H), 6.94 (dt, 1H), 7.33 - 7.45 (m, 1H), 7.53 - 7.62 (m, 2H), 8.10 (d, 2H), 8.54 - 8.26 (m, 2H), 8.70 (s, 1H).

EXAMPLE 18 3-((3R){[6-(6-Aminopyridinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile Obtained as a solid (44%) from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 6b) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinamine following the experimental procedure as described in Example 18 followed by purification of the crude t by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 472 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.70 - 2.07 (m, 3H), 2.16 - 2.30 (m, 1H), 3.33 - 3.54 (m, 4H), 3.84 - 4.04 (m, 1H), 4.23 - 4.41 (m, 1H), 4.74 (d, 2H), 4.96 - 5.15 (m, 1H), 6.57 - 6.69 (m, 1H), 6.78 - 6.96 (m, 1H), 7.32 - 7.44 (m, 1H), 8.26 (d, 1H), 8.48 - 8.59 (m, 2H), 8.65 (d, 1H), 8.93 (dd, 1H).

EXAMPLE 19 3-((3R){[5-fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile Obtained as a solid (42%) from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin midinyl)amino]piperidinyl}oxopropanenitrile (Preparation 6b) and (6- methoxypyridinyl)boronic acid following the experimental procedure as described in Example 18 followed by cation of the crude product by flash tography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 487 (M+1)+. 1H-NMR  (400 MHz, CDCl3): 1.68 - 2.08 (m, 3H), 2.18 - 2.33 (m, 1H), 3.13 - 3.52 (m, 4H), 3.57 - 3.72 (m, 1H), 3.87 - 3.99 (m, 1H), 4.05 (s, 3H), 4.27 - 4.44 (m, 1H), 5.09 (d, 1H), 6.85 - 6.97 (m, 2H), 7.34 - 7.44 (m, 1H), 8.38 (dd, 1H), 8.49 - 8.60 (m, 2H), 8.67 (d, 1H), 8.98 - 9.06 (m, 1H).

EXAMPLE 20 3-((3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile a)tert-Butyl(3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl] amino}piperidinecarboxylate To a solution of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]piperidinecarboxylate (1.0 g, 2.24 mmol), (2-methylpyridin yl)boronic acid (0.46g , 3.36 mmol) and 0.18 g (0.22 mmol) of [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with romethane in dioxane (50 mL) was added a 2M aqueous solution of cesium ate (3.36 mL).

The resulting mixture was stirred at 90 ºC under nitrogen atmosphere overnight, then cooled to room temperature, filtered h Celite®, the solvent was removed and the residue was purified first by flash chromatography oromethane to dichloromethane/methanol 90:10) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to yield the title compound (0.827 g, 73%) as a light yellow solid.

LRMS (m/z): 504 (M+1)+. b)5-Fluoro(2-methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5- a]pyridinylpyrimidinamine To a solution of tert-butyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5- a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 20a, 0.087 g, 0.17 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.5 mL) and the resulting mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure and the residue was partitioned between water and dichloromethane. The aqueous layer was ted and the pH was adjusted with diluted solution of sodium ide until it reached basic pH. The product was ted with dichloromethane (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness to yield the title compound (0.064 g, 92%) as a light yellow solid.

LRMS (m/z): 404 (M+1)+. c)3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile Obtained as a light yellow solid (66%) from ro(2-methylpyridinyl)-N-[(3R)- piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine le 20b) following the mental procedure as described in Preparation 6b. The crude was purified by flash tography (gradient from romethane to romethane/methanol 90:10).

LRMS (m/z): 471 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.80 – 2.31 (m, 5H), 2.68 – 2.85 (m, 3H), 3.20 – 4.61 (m, 7H), 5.14 – 5.35 (m, 1H), 6.85 – 6.98 (m, 1H), 7.35 – 7.45 (m, 1H), 7.82 – 8.04 (m, 2H), 8.43 – 8.77 (m, 4H).

EXAMPLE 21 )[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl](methyl)amino]piperidinyl}oxopropanenitrile -butyl(3R)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl](methyl)amino]piperidinecarboxylate To a solution of tert-butyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5- a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 20a, 0.218 g, 0.43 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% dispersion in mineral oil, 0.034 g, 1.42 mmol). The resulting suspension was stirred at room temperature for 15 min. and then methyl iodide (0.040 mL, 0.64 mmol) were added.

The mixture was stirred for 2 hours and then it was partitioned between water and ethyl acetate. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure to give 196 mg (88% yield) of the title compound as a light yellow solid.

LRMS (m/z): 518 (M+1)+. b)5-Fluoro-N-methyl(2-methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo [1,5-a] pyridinylpyrimidinamine Obtained as a light yellow solid (94%) from tert-butyl (3R)[[5-fluoro(2- methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidinyl](methyl)amino]piperidine- 1-carboxylate (Example 21a) following the experimental procedure as described in Example 20b.

LRMS (m/z): 418 (M+1)+. c)3-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinyl pyrimidinyl](methyl)amino]piperidinyl}oxopropanenitrile Obtained as a pale white solid (56%) from 5-fluoro-N-methyl(2-methylpyridinyl)-N- [(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 21b) following the experimental procedure as described in Example 20c. The crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 418 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.65 – 2.27 (m, 6H), 2.79 – 3.06 (m, 4H), 3.10 – 3.65 (m, 6H), 3.73 – 3.91 (m, 1H), 4.46 – 4.92 (m, 2H), 6.86 – 7.04 (m, 1H), 7.30 – 7.51 (m, 1H), 7.98 – 8.26 (m, 2H), 8.40 (d, 1H), 8.50 – 8.75 (m, 3H).

EXAMPLE 22 luoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinol A suspension of )[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.060 g, 0.15 mmol) and piperidin- 4-ol (0.060 g, 0.59 mmol) in N,N’-dimethylacetamide (0.3 mL) was d at 110 ºC for 2 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (gradient from romethane to dichloromethane /methanol 95:5) to yield the title compound (0.046 mg, 62%) as a yellow solid.

LRMS (m/z): 470 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.66 - 1.95 (m, 4H), 1.97 - 2.09 (m, 2H), 2.11 - 2.28 (m, 1H), 2.98 - 3.35 (m, 3H), 3.41 - 3.59 (m, 2H), 3.64 - 3.81 (m, 1H), 3.84 - 4.06 (m, 3H), 4.16 - 4.32 (m, 5H), 4.54 - 4.71 (m, 1H), 6.75 - 6.93 (m, 1H), 7.17 - 7.37 (m, 1H), 8.39 (d, 2H), 8.44 - 8.53 (m, 1H), 8.58 (d, 1H).

EXAMPLE 23 2-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxoethanol Obtained as a yellow solid (54%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5- a]pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and dinylmethanol ing the experimental procedure as described in Example LRMS (m/z): 484 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.30 - 1.51 (m, 3H), 1.68 - 1.95 (m, 6H), 2.05 - 2.24 (m, 1H), 2.93 - 3.29 (m, 4H), 3.36 - 3.61 (m, 4H), 3.62 - 3.80 (m, 1H), 3.83 - 4.07 (m, 1H), 4.14 - 4.29 (m, 2H), 4.51 (d, 2H), 4.58 - 4.71 (m, 1H), 6.75 - 6.95 (m, 1H), 7.20 - 7.33 (m, 1H), 8.37 - 8.52 (m, 2H), 8.53 - 8.64 (m, 1H).

E 24 2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol Obtained as a solid (28%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 2-amino ethanol following the mental procedure as bed in Example 22.

LRMS (m/z): 431 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.67 - 1.80 (m, 2H), 1.78 - 1.93 (m, 1H), 2.08 - 2.26 (m, 1H), 2.99 - 3.31 (m, 1H), 3.34 - 3.58 (m, 2H), 3.59 - 3.83 (m, 3H), 3.84 - 4.06 (m, 3H), 4.09 - 4.32 (m, 3H), 4.47 - 4.72 (m, 2H), 4.97 - 5.17 (m, 1H), 6.77 - 6.94 (m, 1H), 7.28 - 7.36 (m, 1H), 8.29 - 8.62 (m, 3H).

EXAMPLE 25 2-((3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol Obtained as a beige solid (61%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 1- methylpiperazine following the experimental procedure as described in Example 22.

LRMS (m/z): 469 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.26 - 1.38 (m, 1H), 1.71 - 1.96 (m, 3H), 2.10 - 2.24 (m, 1H), 2.36 (s, 3H), 2.48 - 2.58 (m, 3H), 2.93 - 3.31 (m, 2H), 3.35 - 3.55 (m, 1H), 3.62 - 3.84 (m, 5H), 3.86 - 4.06 (m, 2H), 4.13 - 4.29 (m, 2H), 4.53 - 4.71 (m, 1H), 6.76 - 6.90 (m, 1H), 7.22 - 7.35 (m, 1H), 8.30 - 8.64 (m, 3H).

EXAMPLE 26 2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol a)Tert-butyl(3R)[(5-methylmorpholinylpyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]piperidinecarboxylate A mixture of tert-butyl (3R)[(6-chloromethylpyrazolo[1,5-a]pyridinylpyrimidin- mino]piperidinecarboxylate (Preparation 8c) and morfoline was heated for 48 hours at 100ºC. The reaction e was cooled to room temperature and poured into water. The resulting precipitate was filtered off, washed with water and dried under vacuum to yield the title compound (0.13 g, 59%) as a yellow solid.

LRMS (m/z): 494 (M+1)+. thylmorpholinyl-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a yellow solid dihydrochloride salt (100%) from tert-butyl (3R)[(5- methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine carboxylate (Example 26a) following the experimental procedure as described in Example 14b.

LRMS (m/z): 394 (M+1)+. c)2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol Obtained as a solid (43%) from ylmorpholinyl-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 26b) following the experimental procedure as described in Preparation 7. The crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 452 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.67 - 1.93 (m, 4H), 2.00 (s, 3H), 2.09 - 2.30 (m, 1H), 3.08 - 3.44 (m, 5H), 3.44 - 4.02 (m, 7H), 4.11 - 4.61 (m, 4H), 6.70 - 6.98 (m, 1H), 7.15 - 7.42 (m, 1H), 8.33 - 8.78 (m, 3H).

E 27 2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol a) Tert-butyl -{[6-(2-methoxyethoxy)methylpyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained as a colourless oil (65%) from (3R)[(6-chloromethylpyrazolo[1,5- a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 9c) and 2- methoxyethanol following the experimental procedure as described in Example 5.

LRMS (m/z): 483 (M+1)+. b) Methoxyethoxy)methyl-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a yellowish solid dihydrochloride salt (98%) from tert-butyl (3R){[6-(2- methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine- 1-carboxylate (Example 27a) following the experimental procedure as described in Example 15b.

LRMS (m/z): 383 (M+1)+. c)2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol Obtained as a white solid (23%) from methoxyethoxy)methyl-N-[(3R)-piperidinyl]- 2-pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 27b) following the experimental procedure as described in Preparation 7. The crude was purified by flash chromatography (gradient from romethane to dichloromethane/methanol 95:5).

LRMS (m/z): 441 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 0.78 - 1.21 (m, 2H), 1.68 - 1.89 (m, 3H), 1.96 (s, 3H), 2.09 - 2.27 (m, 1H), 3.06 - 3.28 (m, 1H), 3.34 - 3.58 (m, 4H), 3.63 - 4.01 (m, 4H), 4.09 - 4.44 (m, 3H), 4.53 - 4.71 (m, 2H), 6.75 - 6.96 (m, 1H), 7.21 - 7.35 (m, 1H), 8.40 - 8.77 (m, 3H).

EXAMPLE 28 Ethyl 1-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)methylpiperidinecarboxylate Obtained as a deep yellow solid (58%) from 2-{(3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and ethyl ylpiperidinecarboxylate following the experimental procedure as described in Example 2a followed by cation of the crude product by flash chromatography ent from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 540 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.14 - 1.39 (m, 5H), 1.49 - 1.67 (m, 6H), 1.68 - 1.98 (m, 4H), 2.13 - 2.38 (m, 2H), 3.06 - 3.63 (m, 3H), 3.62 - 4.08 (m, 3H), 4.08 - 4.36 (m, 4H), 4.50 - 4.80 (m, 1H), 6.77 - 6.95 (m, 1H), 6.78 - 6.97 (m, 1H), 7.26 - 7.38 (m, 1H), 8.28 - 8.60 (m, 3H).

EXAMPLE 29 2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin ylpyrimidinyl]amino}piperidinyl)oxoethanol a) 1-Aminomethylpyridinium 2,4,6-trimethylbenzenesulfonate A solution of O-(mesitylsulfonyl)hydroxylamine (23.11 g, 107.4 mmol) in dichloromethane (272 mL) was added dropwise to a cooled (0 ºC) solution of 4- methylpyridine (10.0 g, 107.4 mmol) in dichloromethane (136 mL) and the resulting mixture was stirred for 2 hours at room temperature. The solvent was partially evaporated and diethyl ether was added to precipitate an oil. The reaction mixture was cooled to 0 ºC and the solvents were decanted. The oil was dried under vacuum to yield the title compound (33.11 g, 99%).

LRMS (m/z): 109 (M)+. 1H-NMR  (300 MHz, CDCl 3): 2.22 (s, 3H), 2.42 (s, 3H), 2.61 (s, 6H), 6.80 (s, 2H), 7.26 - 7.39 (d, 2H), 8.84 - 8.86 (d, 2H). b) Ethyl 5-methylpyrazolo[1,5-a]pyridinecarboxylate Obtained as a solid (54%) from 1-aminomethylpyridinium 2,4,6-trimethylbenzene sulfonate (Example 29a) and ethyl propiolate following the experimental procedure as bed in Preparation 1a ed by purification of the crude t by flash chromatography (hexanes/ethyl e).

LRMS (m/z): 205 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.38 - 1.42 (t, 3H), 2.46 (s, 3H), 4.34 - 4.40 (q, 2H), 6.75 - 6.77 (d, 1H), 7.92 (s, 1H), 8.33 (s, 1H), 8.37 - 8.39 (d, 1H). c) 5-Methylpyrazolo[1,5-a]pyridinecarboximidamide 2.0 M Trimethylaluminium solution in toluene (62 mL, 124 mmol) was added se to a cooled (0 ºC) suspension of ammonium chloride (6.18 g, 115.6 mmol) in toluene (133 mL) and the resulting mixture was stirred until no more gas was formed. A solution of ethyl ylpyrazolo[1,5-a]pyridinecarboxylate (Example 29b, 7.87 g, 38.53 mmol) in toluene (25 mL) was then added dropwise and the reaction mixture was stirred overnight at 80 ºC. Additional ammonium chloride (6.18 g, 115.6 mmol) and 2.0 M trimethylaluminium solution in toluene (62 mL, 124 mmol) were added and the suspension was d overnight at 80 ºC and a weekend at room temperature. The reaction mixture was cooled at 0 ºC and methanol (30 mL) was added dropwise. The suspension was ed over diatomaceous earth (Celite©) and the solid was washed with methanol. The organic phases were ed, solvents were partially evaporated (up to 100 mL of solution) and dichloromethane (100 mL) was added. The solid formed was filtered and the solvents were ated to dryness. Purification of the residue by flash chromatography (dichloromethane/methanol) gave the title nd (6.7 g, 98%).

LRMS (m/z): 175 (M+1)+. 1H-NMR  (300 MHz, DMSO-d 6): 2.50 (s, 3H), 7.08 - 7.10 (d, 1H), 7.88 (s, 1H), 8.65 (s, 1H), 8.81 - 8.83 (d, 1H), 8.97 (bs, 3H). d) ro(5-methylpyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-diol Obtained as a yellow solid (80%) from 5-methylpyrazolo[1,5-a]pyridine carboximidamide (Example 29c) and diethyl 2-fluoromalonate ing the experimental procedure as bed in Preparation 4a.

LRMS (m/z): 261(M+1)+. 1H-NMR  (400 MHz, DMSO-d 6): 2.50 (s, 3H), 6.99 - 7.01 (d, 1H), 8.47 (s, 1H), 8.71 - 8.73 (d, 1H), 8.82 (s, 1H), 12.59 (bs, 1H). e) 3-(4,6-Dichlorofluoropyrimidinyl)methylpyrazolo[1,5-a]pyridine A mixture of 5-fluoro(5-methylpyrazolo[1,5-a]pyridinyl)pyrimidine-4,6-diol (Example 29d, 1.19 g, 4.57 mmol) and phosphorus(V) oxychloride (9.3 mL, 99.6 mmol) was stirred at 110 ºC for 75 minutes. The solvent was removed under reduced pressure and water was added. The precipitate was filtered, washed with water and dried under vacuum to yield the title compound (1.08 g, 79%) as a yellow solid.

LRMS (m/z): 297 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 2.51 (s, 3H), 6.78 - 6.80 (d, 1H), 8.23 (s, 1H), 8.41 - 8.43 (d, 1H), 8.62 (s, 1H). f)Tert-butyl(3R){[6-chlorofluoro(5-methylpyrazolo[1,5-a]pyridin yl)pyrimidinyl]amino}piperidinecarboxylate Obtained as a pink solid (93%) from 3-(4,6-dichlorofluoropyrimidinyl) methylpyrazolo[1,5-a]pyridine (Example 29e) and (R)-tert-butyl 3-aminopiperidine carboxylate following the experimental procedure described in Preparation 5.

LRMS (m/z): 460 (M+1)+. g)Tert-butyl(3R){[5-fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin- 4-ylpyrimidinyl]amino}piperidinecarboxylate Obtained as a solid (47%) from tert-butyl (3R){[6-chlorofluoro(5- methylpyrazolo[1,5-a]pyridinyl)pyrimidinyl]amino}piperidinecarboxylate (Example 29f) and morfoline following the experimental ure described in e 32a followed by purification by flash chromatography ent from hexanes to ethyl acetate).

LRMS (m/z): 512 (M+1)+. h)5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholinyl-N-[(3R)- piperidinyl] pyrimidinamine Obtained as a solid (85%) from tert-butyl (3R){[5-fluoro(5-methylpyrazolo[1,5- a]pyridinyl)morpholinylpyrimidinyl]amino}piperidinecarboxylate (Example 29g) following the experimental procedure as described in Example 15b.

LRMS (m/z): 412 (M+1)+. i)2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin ylpyrimidin-yl] amino}piperidinyl)oxoethanol Obtained as a deep yellow solid (40%) from 5-fluoro(5-methylpyrazolo[1,5-a]pyridin- 3-yl)morpholinyl-N-[(3R)-piperidinyl]pyrimidinamine (Example 29h) following the experimental procedure as described in Preparation 7. The crude was purified by flash chromatography (gradient from hexanes to ethyl acetate).

LRMS (m/z): 470 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.66 - 1.81 (m, 2H), 1.80 - 1.99 (m, 1H), 2.09 - 2.27 (m, 1H), 2.41 (s, 3H), 3.09 - 3.29 (m, 2H), 3.32 - 3.58 (m, 1H), 3.65 - 3.79 (m, 5H), 3.81 - 3.90 (m, 4H), 3.92 - 4.04 (m, 1H), 4.11 - 4.34 (m, 2H), 4.47 - 4.75 (m, 1H), 6.60 - 6.75 (m, 1H), 8.07 - 8.62 (m, 3H).

E 30 Ethyl 1-(6-{[(3R)(cyanoacetyl)piperidinyl]amino}fluoropyrazolo [1,5-a]pyridinylpyrimidinyl)piperidinecarboxylate Obtained as a solid (48%) from )[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino] piperidinyl}oxopropanenitrile (Preparation 7b) and ethyl piperidinecarboxylate following the experimental procedure as bed in Example 2a followed by cation of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 535 (M+1) +. 1H-NMR  (300 MHz, CDCl3): 1.29 (t, 3H), 1.66 - 2.12 (m, 7H), 2.10 - 2.28 (m, 1H), 2.50 - 2.72 (m, 1H), 3.01 - 3.27 (m, 3H), 3.31 - 3.69 (m, 4H), 3.75 - 3.92 (m, 1H), 4.07 - 4.29 (m, 2H), 4.33 - 4.46 (m, 2H), 4.47 - 4.77 (m, 1H), 6.75 - 6.95 (m, 1 H), 7.32 (d, 1 H), 8.25 - 8.59 (m, 3 H).

EXAMPLE 31 1-(6-{[(3R)(Cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)piperidinecarboxylic acid To a solution of ethyl 1-(6-{[(3R)(cyanoacetyl)piperidinyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)piperidinecarboxylate (Example 30, 0.046 g, 0.08 mmol) in a mixture of tetrahydrofuran and water (1:1) (1.4 mL), lithium hydroxide monohydrate (0.014 g, 0.34 mmol) was added and the mixture was stirred at room ature for 2 hours. The solvent was evaporated in vacuo, water was added and the pH of the s solution was adjusted to 3 by addition of 0.5 N hloric acid.

The aqueous solution was extracted with dichloromethane (x3), the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness to yield the title nd (0.019 g, 40%) as a brown solid.

LRMS (m/z): 507 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.63 - 2.25 (m, 6H), 2.55 - 2.81 (m, 1H), 3.07 - 3.31 (m, 3H), 3.30 - 3.67 (m, 4H), 3.70 - 3.93 (m, 2H), 4.12 - 4.30 (m, 1H), 4.32 - 4.47 (m, 2H), 4.47 - 4.86 (m, 1H), 6.76 - 7.00 (m, 1H), 7.29 - 7.45 (m, 1H), 8.27 - 8.66 (m, 3H).

EXAMPLE 32 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(1H-pyrazolyl)pyrimidin yl]amino}piperidinyl)oxoethanol A Schlenk tube was charged with 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7, 0.047 g, 0.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.034 g, 0.18 mmol), 2M aqueous on of potassium triphosphate (0.17 mL, 0.35 mmol) and 1,4- e (0.5 mL). The Schlenk tube was subjected to three cycles of evacuationbackfilling with argon and then [1,1'-bis(diphenylphosphino) ferrocene]palladium(II) dichloride complex with dichloromethane (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 ºC. The reaction mixture was cooled to room temperature and more 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.034 g, 0.18 mmol) and 1,1'-bis(diphenylphosphino) ferrocene]palladium(II) dichloride complex with dichloromethane (0.01 g, 0.01 mmol) were added. After three cycles of evacuation-backfilling, the e was stirred at 90ºC for 6 hours. The mixture was cooled to room temperature, filtered through Celite®, the solvent was removed and the residue was ed by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.018 g, 35%) as a light yellow solid.

LRMS (m/z): 437 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.47 - 1.76 (m, 2H), 2.11 - 2.33 (m, 1H), 3.10 - 3.31 (m, 1H), 3.37 - 3.55 (m, 1H), 3.68 - 3.82 (m, 4H), 3.91 - 4.10 (m, 1H), 4.19 - 4.30 (m, 2H), 4.29 - 4.71 (m, 1H), 4.92 - 5.08 (m, 1H), 6.82 - 6.99 (m, 1H), 7.30 - 7.42 (m, 1H), 8.33 (br. s., 2H), 8.49 - 8.62 (m, 2H), 8.69 (d, 1H).

EXAMPLE 33 1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)-1H-pyrazolyl]methylpropanol a)2-Methyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol yl]propanol A microwave r was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1H-pyrazole (0.50 g, 2.58 mmol), 2,2-dimethyloxirane (0.57 mL, 6.44 mmol), cesium carbonate (1.25 g, 3.84 mmol) and acetonitrile (5 mL). The reaction mixture was subjected to microwave irradiation for 1 hour at 130 ºC. The solid was filtered, washed with dichloromethane and the filtrate and gs were concentrated in vacuo to yield the title compound (0.28 g, 42%) as an oil. b)1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinyl pyrimidinyl)-1H-pyrazolyl]methylpropanol Obtained as a solid (57%) from )[(6-chlorofluoropyrazolo[1,5-a]pyridin midinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 2-methyl[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl]propanol (Example 33a) following the experimental procedure as described in Example 32.

LRMS (m/z): 509 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.23 (s, 6H), 1.70 - 1.98 (m, 3H), 2.13 - 2.31 (m, 1H), 3.10 - 3.32 (m, 1H), 3.38 - 3.58 (m, 1H), 3.67 - 3.83 (m, 2H), 3.89 - 4.09 (m, 2H), 4.19 (d, 2H), 4.23 - 4.39 (m, 2H), 4.55 - 4.77 (m, 1H), 4.98 (t, 1H), 6.82 - 6.95 (m, 1H), 7.11 - 7.44 (m, 1H), 7.44 - 7.66 (m, 1H), 8.14 (s, 1H), 8.26 (d, 1H), 8.46 - 8.60 (m, 1H), 8.67 (d, 1H).

EXAMPLE 34 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol A Schlenk tube was charged with 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol ration 8, 0.080 g, 0.20 mmol), (2-methylpyridinyl)boronic acid (0.041 g, 0.30 mmol), 2M aqueous solution of cesium carbonate (0.29 mL), 0.59 mmol) and 1,4-dioxane (1 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then bis(diphenylphosphino) ferrocene]palladium(II) dichloride complex with dichloromethane (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 ºC. The mixture was cooled to room temperature, filtered through Celite®, the solvent was removed and the residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.036 g, 39%) as a light orange solid.

LRMS (m/z): 462 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.73 - 2.02 (m, 3H), 2.12 - 2.33 (m, 1H), 2.70 (s, 3H), 3.12 - 3.30 (m, 1H), 3.37 - 3.61 (m, 2H), 3.69 - 3.85 (m, 1H), 3.95 - 4.13 (m, 1H), 4.20 - 4.43 (m, 2H), 4.66 (dd, 1H), 5.16 (t, 1H), 6.85 - 6.98 (m, 1H), 7.31 - 7.44 (m, 1H), 7.80 (d, 1H), 7.87 (br. s., 1H), 8.47 - 8.61 (m, 2H), 8.63 - 8.80 (m, 2H).

EXAMPLE 35 2-((3R){[5-Fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol Obtained as a light yellow solid (58%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5- a] pyridin yrimidinyl)amino]piperidinyl}oxoethanol ration 7) and (6- ypyridinyl)boronic acid following the experimental procedure as bed in Example 17 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 478 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 0.74 - 0.97 (m, 2H), 1.00 - 1.34 (m, 1H), 1.70 - 2.03 (m, 3H), 2.13 - 2.33 (m, 1H), 3.11 - 3.31 (m, 1H), 3.34 - 3.51 (m, 1H), 3.51 - 3.85 (m, 1H), 4.05 (s, 3H), 4.13 - 4.43 (m, 2H), 4.70 (dd, 1H), 5.07 (t, 1H), 6.74 - 7.07 (m, 2H), 7.29 - 7.56 (m, 1H), 8.28 - 8.83 (m, 3H), 9.01 (s, 1H).

EXAMPLE 36 2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol Obtained as a light yellow solid (61%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5- a] n ylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and (6- methylpyridinyl)boronic acid ing the experimental procedure as described in Example 17 followed by purification by flash tography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 462 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 0.70 - 1.37 (m, 1H), 1.55 - 2.07 (m, 1H), 2.10 - 2.32 (m, 1H), 2.49 (s, 1H), 2.67 (s, 3H), 3.03 - 3.32 (m, 2H), 3.37 - 3.56 (m, 1H), 3.90 - 4.13 (m, 1H), 4.19 - 4.40 (m, 3H), 4.68 (dd, 1H), 5.03 - 5.25 (m, 1H), 6.76 - 7.21 (m, 1H), 7.29 - 7.42 (m, 2H), 8.28 - 8.40 (m, 1H), 8.50 - 8.81 (m, 3H), 9.28 (s, 1H).

EXAMPLE 37 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol a) 4-Bromo[(tetrahydro-2H-pyranyloxy)methyl]pyridine To a solution of (4-bromopyridinyl)metanol (0.30 g, 1.60 mmol) in dichloromethane (8 mL) and tetrahydrofuran (4 mL), pyridinium para-toluenesulfonate (0.080 g, 0.32 mmol) and 3,4-dihydro-2H-pyran (0.32 mL, 3.51 mmol) were added. The reaction mixture was d at for 3.5 hours at 50ºC and for 60 hours at room temperature. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.33 g, 76%) as a colorless oil.

LRMS (m/z): 272, 274 (M+1, M+3)+. 1H-NMR  (300 MHz, CDCl3): 1.46 - 1.65 (m, 2H), 1.69 - 1.83 (m, 2H), 1.83 - 2.02 (m, 2H), 3.51 - 3.65 (m, 1H), 3.81 - 3.96 (m, 1H), 4.62 (d, 1H), 4.78 (t, 1H), 4.89 (d, 1H), 7.37 (d, 1H), 7.67 (s, 1H), 8.37 (d, 1H). b) 2-[(Tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)pyridine A Schlenk tube was charged with 4-bromo[(tetrahydro-2H-pyran yloxy)methyl]pyridine (Example 37a, 0.32 g, 1.18 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi-1,3,2-dioxa borolane (0.45 g, 1.76 mmol), potassium acetate (0.35 g, 3.53 mmol) and oxane (6 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then bis (diphenylphosphino) ferrocene] palladium(II) dichloride (0.058 g, 0.07 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 ºC overnight. The mixture was , filtered through diatomaceous earth (Celite®) and the t was concentrated to dryness to yield the title compound as a black oil (0.35 g, 93%).

LRMS (m/z): 238 (M+1)+. c) )[(5-Fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H-pyran yloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinyl}oxoethanol Obtained as na Orange oil (59%) from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxoethanol (Preparation 7) and 2- [(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyridine (Example 37b) following the experimental procedure as described in Example 40.

LRMS (m/z): 562 (M+1)+. d) 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxoethanol To a solution of 2-{(3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H- pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinyl}oxoethanol (Example 37c, 0.055 g, 0.10 mmol) in tetrahydrofuran (0.3 mL), 1N hydrochloric acid (0.30 mL, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 4.5 hours, the solvent was concentrated in vacuo and saturated sodium bicarbonate aqueous solution was added until the pH was adjusted to 8. The mixture was extracted with ethyl acetate (x3), the combined organic layers were washed with brine, dried over magnesium e and the solvent was evaporated to dryness. The crude was ed by preparative HPLC (gradient from water to methanol) to yield the title compound (0.022 g, 47%) as a yellow solid.

LRMS (m/z): 478 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.82 - 2.03 (m, 3H), 2.15 - 2.33 (m, 2H), 3.26 (dd, 2H), 3.35 - 3.58 (m, 1H), 3.94 - 4.13 (m, 1H), 4.20 - 4.46 (m, 2H), 4.65 (d, 1H), 4.91 (s, 2H), 5.11 - 5.27 (m, 1H), 6.92 (q, 1H), 7.31 - 7.45 (m, 1H), 7.85 - 8.03 (m, 2H), 8.43 - 8.61 (m, 2H), 8.61 - 8.84 (m, 2H).

EXAMPLE 38 Ethyl 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)pyridinecarboxylate a) Ethyl 5-(6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)pyridinecarboxylate Obtained as a light yellow solid (72%) from utyl 3-[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5, 0.300 g, 0.67 mmol) and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine- 2-carboxylate (0.600 g, 2.17 mmol) following the experimental procedure as bed in Example 20a. The crude product was purified by flash chromatography es to hexanes/ethyl acetate 20:80).

LRMS (m/z): 562 (M+1)+. b) Ethyl luoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin midinyl}pyridinecarboxylate Obtained as a light yellow solid (89%) from ethyl 5-(6-{[(3R)(tertbutoxycarbonyl )piperidinyl]amino}fluoropyrazolo[1,5-a]pyridinylpyrimidin yl)pyridinecarboxylate (Example 38a) following the experimental procedure as described in Example 20b.

LRMS (m/z): 462 (M+1)+. c) 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)pyridinecarboxylate Obtained as a light yellow solid (72%) from ethyl 5-{5-fluoro[(3R)-piperidin ylamino]pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinecarboxylate (Example 38b) following the experimental procedure as described in Preparation 7. The crude was purified by flash chromatography (gradient from hexanes to ethyl acetate and then to ethyl acetate/ethanol 70:30).

LRMS (m/z): 520 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.44 – 1.53 (m, 3H), 1.69 – 2.29 (m, 4H), 3.11 – 3.53 (m, 3H), 3.69 – 4.41 (m, 5H), 4.47 – 4.59 (m, 2H), 5.09 – 5.29 (m, 1H), 6.82 – 6.97 (m, 1H), 7.29 – 7.41 (m, 1H), 8.22 – 8.35 (m, 1H), 8.45 – 8.81 (m, 4H), 9.53 (s, 1H).

EXAMPLE 39 2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol a) Tert-butyl (3R){[5-fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate 2-Methoxyethanol (0.11 mL, 1.45 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 0.10 g, 1.13 mmol) in tetrahydrofurane (1.5 mL) and the mixture was stirred at room temperature for 1 hour. Tert-butyl (3R)[(6-chloro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5, 0.10 g, 0.22 mmol) was then added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The c layer was separated and the aqueous layer was extracted with ethyl acetate. The combined c layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The ing crude was purified by flash chromatography ent from dichloromethane to dichloromethane/methanol 90:10) to yield the title compound (0.067 g, 60%) as a solid.

LRMS (m/z): 487 (M+1)+. b) 5-Fluoro(2-methoxyethoxy)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinamine Obtained as a solid dihydrochloride salt (100%) from 5-fluoro(2-methoxyethoxy)-N- [(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 39a) following the mental procedure as bed in Example 14b.

LRMS (m/z): 387 (M+1)+. c)2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol Obtained as an off-white solid (47%) from 5-fluoro(2-methoxyethoxy)-N-[(3R)- piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 39b) following the experimental procedure as described in Preparation 7 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 445 (M+1)+. 1H-NMR  (300 MHz, : 1.69 - 2.01 (m, 4H), 2.12 - 2.30 (m, 1H), 2.91 - 3.23 (m, 1H), 3.31 - 3.44 (m, 1H), 3.48 (s, 3H), 3.54 (t, 1H), 3.68 - 3.78 (m, 1H), 3.80 - 3.90 (m, 2H), 3.96 - 4.08 (m, 1H), 4.14 - 4.32 (m, 2H), 4.62 - 4.84 (m, 3H), 6.78 - 6.96 (m, 1H), 7.29 - 7.39 (m, 1H), 8.33 - 8.54 (m, 2H), 8.60 (d, 1H).

EXAMPLE 40 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxoethanol a) Tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin midinyl]amino}piperidinecarboxylate Ethylene glycol (0.5 mL, 8.94 mmol) was added to a suspension of potassium tert- de (0.08 g, 0.67 mmol) in 1,4-dioxane (0.7 mL) and the resulting mixture was stirred at room temperature for 15 minutes. Tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5, 0.10 g, 0.22 mmol) was then added and the reaction mixture was d at 90 ºC overnight. After cooling to room temperature, the on mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and ated to dryness. The resulting crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.081 g, 77%) as a solid.

LRMS (m/z): 473 (M+1)+. b) Tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained as a solid dihydrochloride salt (100%) from tert-butyl (3R){[5-fluoro(2- hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine carboxylate (Example 40a) following the mental procedure as described in Example 14b.

LRMS (m/z): 373 (M+1)+. c)2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol Obtained as a solid (46%) from tert-butyl (3R){[5-fluoro(2-hydroxyethoxy) pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 40b) following the experimental procedure described in Preparation 7 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 431 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.67 - 1.81 (m, 1H), 1.82 - 1.99 (m, 1H), 2.09 - 2.29 (m, 1H), 2.97 - 3.26 (m, 2H), 3.33 - 3.58 (m, 2H), 3.66 - 3.81 (m, 1H), 3.92 - 4.10 (m, 3H), 4.13 - 4.35 (m, 3H), 4.61 - 4.87 (m, 4H), 6.83 - 6.95 (m, 1H), 7.30 - 7.38 (m, 1H), 8.41 (dd, 1H), 8.51 (d, 1H), 8.59 (d, 1H).

EXAMPLE 41 3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin midinyl)oxy]propanol a)Tert-butyl(3R){[5-fluoro(3-hydroxypropoxy)pyrazolo[1,5-a]pyridinyl pyrimidinyl]amino}piperidinecarboxylate Obtained as an orange oil (78%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and propane-1,3-diol following the experimental procedure as described in Example 5.

LRMS (m/z): 487 (M+1)+. b)3-({5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl}oxy)propanol Obtained as a yellow solid dihydrochloride salt (97%) from tert-butyl (3R){[5-fluoro roxypropoxy)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine ylate le 41a) following the experimental ure as described in Example 14b.

LRMS (m/z): 387 (M+1)+. c)3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol Obtained as a white solid (52%) from 3-({5-fluoro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)propanol (Example 41b) following the experimental procedure as described in Preparation 7 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 445 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.64 - 1.79 (m, 2H), 1.78 - 1.94 (m, 1H), 1.95 - 2.59 (m, 3H), 2.87 - 3.26 (m, 2H), 3.29 - 3.57 (m, 2H), 3.59 - 3.89 (m, 2H), 3.88 - 4.06 (m, 1H), 4.08 - 4.32 (m, 2H), 4.54 - 4.87 (m, 3H), 6.73 - 6.95 (m, 1H), 7.27 - 7.40 (m, 1H), 8.22 - 8.73 (m, 4H).

EXAMPLE 42 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol a)Tert-butyl(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate Metal sodium (0.039 g, 1.69 mmol) was added to methanol (5 mL) and the mixture was stirred at room temperature until metal sodium was consumed. Tert-butyl (3R)[(6- chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine carboxylate (Preparation 5, 0.300 g, 0.67 mmol) was added, the reaction mixture was stirred overnight at reflux under nitrogen atmosphere, then cooled to room temperature, the solvent was d under d pressure and the residue was ioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried and concentrated in vacuo to yield 0.297 g (100% yield) of the title compound, which was used without further purification in the next synthetic step.

LRMS (m/z): 443 (M+1)+. uoromethoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl pyrimidinamine Obtained as a pale white solid (100%) from tert-butyl (3R)[(5-fluoromethoxy lo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 42a) ing the experimental procedure as described in Example 20b.

LRMS (m/z): 343 (M+1)+. c)2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol Obtained as a white solid (80%) from 5-fluoromethoxy-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 42b) following the experimental procedure as described in Preparation 7. The crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 93:7).

LRMS (m/z): 401 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.64 – 2.28 (m, 4H), 2.93 – 3.79 (m, 5H), 3.90 – 4.31 (m, 5H), 4.59 – 4.79 (m, 1H), 6.80 – 6.93 (m, 1H), 7.27 – 7.36 (m, 1H), 8.33 – 8.74 (m, 3H).

EXAMPLE 43 -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinol a)5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidinol A sion of 2-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)amino]piperidinyl}oxoethanol (Example 42c, 0.086 g, 0.21 mmol) in a 4M solution of hydrochloric acid in dioxane (6 mL) was heated at 80 ºC in a sealed tube overnight. Then the mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure to give 0.078 g (100% yield) of the title compound as its hydrochloric salt.

LRMS (m/z): 329 (M+1)+. b)5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinol Obtained as a white solid (100%) from ro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinol (Example 43a) following the experimental procedure as bed in Preparation 7. The crude was ed by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as s [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 387 (M+1)+.

EXAMPLE 44 Benzyl[(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a] pyridinylpyrimidinyl)oxy]acetate To a solution of 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinol (Example 43b, 0.062 g, 0.16 mmol) in N,N- dimethylformamide (5 mL) was added silver (I) carbonate (0.530 g, 1.92 mmol) and benzyl 2-bromoacetate (0.220 g, 0.96 mmol) and the e was stirred at room temperature for 24 hours. Then it was diluted with water and the resulting suspension was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over ium sulfate, filtered and the solvents were evaporated in vacuo. The crude product was ed first by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 90:10) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to give 0.045 g (53% yield) of the title compound as a white solid.

LRMS (m/z): 535 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.67 – 1.81 (m, 2H), 1.82 – 1.97 (m, 1H), 2.12 – 2.27 (m, 1H), 2.95 – 4.31 (m, 8H), 4.68 – 4.88 (m, 2H), 5.05 (s, 2H), 5.22 (s, 2H), 6.76 – 6.88 (m, 1H), 7.11 – 7.36 (m, 5H), 8.19 – 8.37 (m, 1H), 8.42 – 8.59 (m, 2H).

EXAMPLE 45 2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol a)Tert-butyl(3R)[(6-ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate Obtained as an oil (63%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5- a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and ethanol following the experimental procedure as described in Example 15a.

LRMS (m/z): 457 (M+1)+. b) 6-Ethoxyfluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin- 4-amine Obtained as a solid dihydrochloride salt (100%) from utyl (3R)[(6-ethoxy fluoropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 45a) following the experimental ure as described in Example 14b.

LRMS (m/z): 357 (M+1)+. c)2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol ed as a white solid (42%) from xyfluoro-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 45b) following the experimental procedure described in Preparation 7 followed by purification by flash chromatography (gradient from romethane to dichloromethane/methanol 95:5).

LRMS (m/z): 415 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.43 - 1.56 (m, 3H), 1.75 (br. s., 2H), 1.90 (br. s., 1H), 2.21 (br. s., 1H), 2.91 - 3.28 (m, 2H), 3.31 - 3.64 (m, 2H), 3.73 (d, 1H), 4.02 (d, 1H), 4.15 - 4.36 (m, 2H), 4.50 - 4.86 (m, 3H), 6.89 (q, 1H), 7.33 (br. s., 1H), 8.34 - 8.61 (m, 3H).

EXAMPLE 46 Ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinecarboxylate a)Tert-butyl(3R)[(6-cyanofluoropyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinecarboxylate A solution of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)amino]piperidinecarboxylate (Preparation 5, 0.892 g, 2.00 mmol), ylstannanecarbonitrile (1.26 g, 3.99 mmol), is(triphenylphosphine)palladium (0) (0.923 g, 0.80 mmol) and bis(tri-tert-butylphosphine)palladium (0) (0.408 g, 0.80 mmol) in dioxane (20 mL) was heated in a sealed tube under en atmosphere overnight. Then the reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and filtered through Celite®. The filtered solution was washed with water and brine, dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography es/ethyl acetate from 0% to 100%) to yield 1.04 g of a semisolid that contained mostly the title compound.

LRMS (m/z): 438 (M+1)+. b)6-{[(3R)(Tert-butoxycarbonyl)piperidinyl]amino}fluoropyrazolo[1,5- a]pyridinylpyrimidinecarboxylic acid The product obtained in Example 46a was dissolved in 2-propanol (4 mL) an 2M aqueous on of sodium hydroxide (15 mL) and heated for 35 s at 80 ºC under microwave irradiation. Then the reaction mixture was partitioned between dichloromethane and water and the layers were separated. The s layer was acidified with hloric acid 2M and extracted with dichloromethane/methanol (98:2) several times. The combined organic solution was dried over ium sulfate, filtered and the solvents were removed. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonia in both eluent systems] 0% to 100%) to give 0.193 g (21% yield in two steps) of the title compound as a white solid.

LRMS (m/z): 456 (M+1)+. c)Ethylfluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinyl pyrimidine carboxylate A solution of R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinecarboxylic acid (Example 46b, 0.299 g, 0.66 mmol) and concentrated sulfuric acid (0.174 mL, 3.3 mmol) in ethanol (8 mL) was heated to 100 ºC overnight. Then the volatiles were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and the pH was adjusted to 8 by slow addition of a diluted solution of sodium hydroxide and it was extracted with dichloromethane. The organic solution was washed with brine, dried over magnesium sulfate, filtered and the solvent was removed under d pressure to give 0.101 g of the title compound (30% yield).

LRMS (m/z): 385 (M+1)+. lfluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a] pyridinylpyrimidinecarboxylate Obtained as a light yellow solid (24%) from 5-fluoro[(3R)-piperidinylamino] lo[1,5-a]pyridinylpyrimidinol (Example 46c) following the experimental procedure as described in ation 7. The crude was purified first by flash chromatography (dichloromethane/methanol from 0% to 15%) and then by e phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 443 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.37 – 1.53 (m, 3H), 1.62 – 1.96 (m, 4H), 3.07 – 3.83 (m, 3H), 3.97 – 4.10 (m, 1H), 4.17 – 4.73 (m, 5H), 5.20 (d, J = 7.6 Hz, 1H), 6.82 – 6.95 (m, 1H), 7.29 – 7.42 (m, 1H), 8.47 – 8.76 (m, 3H).

EXAMPLE 47 -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarbonitrile a)5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidine carbonitrile A solution of tert-butyl (3R)[(6-cyanofluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)amino]piperidinecarboxylate (Example 46a, 0.150 g, 0.34 mmol) and trated sulfuric acid (0.091 mL, 1.7 mmol) in l (6 mL) was heated to 100 ºC overnight. Then the volatiles were removed under reduced pressure and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and the pH was adjusted to 8 by slow addition of aqueous solution of sodium hydrogencarbonate and it was extracted with dichloromethane. The c solution was washed with brine, dried over ium sulfate, filtered and the solvent was removed under reduced pressure to give 0.083 g of the title compound as a deep yellow solid (63% yield).

LRMS (m/z): 338 (M+1)+. b)5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarbonitrile Obtained as a yellow solid (38%) from 5-fluoro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinecarbonitrile (Example 47a) following the experimental procedure as bed in ation 7. The crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 396 (M+1)+. 1H-NMR  (400 MHz, DMSO-d 6): 1.44 – 1.90 (m, 3H), 1.93 – 2.12 (m, 1H), 2.56 – 3.09 (m, 3H), 3.58 – 3.87 (m, 1H), 3.91 – 4.29 (m, 3H), 4.50 – 4.75 (m, 1H), 7.07 (s, 1H), 7.40 – 7.58 (m, 1H), 8.19 – 8.40 (m, 2H), 8.58 – 8.69 (m, 1H), 8.79 (s, 1H).

EXAMPLE 48 5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarboxamide To a on of ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinecarboxylate (Example 46d, 23 mg, 0.052 mmol) in a mixture of tetrahydrofurane (2 mL) and water (0.5 mL) were added a few drops of concentrated ammonia. The resulting solution was stirred overnight at room temperature and then partitioned between water and dichloromethane. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, ed and the solvent was removed to give 0.008 g (37% yield) of the title compound as a pale solid.

LRMS (m/z): 414 (M+1)+.

EXAMPLE 49 ){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2- trifluoroethoxy)pyrimidinyl]amino}piperidinyl)oxoethanol a)Tert-butyl(3R){[5-fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy) pyrimidinyl]amino}piperidinecarboxylate Obtained as an white solid (92%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and 2,2,2-trifluoroethanol following the experimental procedure described in Example LRMS (m/z): 511 (M+1)+. b)5-Fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinyl(2,2,2- trifluoroethoxy) pyrimidinamine Obtained as a solid ochloride salt (100%) from tert-butyl (3R){[5-fluoro pyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidinyl]amino}piperidine carboxylate (Example 49a) following the experimental procedure described in e 14b.

LRMS (m/z): 411 (M+1)+. c)2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy) pyrimidinyl]amino}piperidinyl)oxoethanol Obtained as a white solid (32%) from 5-fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5- a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidinamine (Example 49b) following the experimental procedure described in Preparation 7 followed by cation by flash chromatography (gradient from romethane to dichloromethane/methanol 95:5).

LRMS (m/z): 469 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.69 - 1.85 (m, 2H), 1.86 - 2.04 (m, 1H), 2.12 - 2.38 (m, 1H), 2.92 - 3.26 (m, 2H), 3.28 - 3.65 (m, 2H), 3.68 - 3.83 (m, 1H), 3.95 - 4.15 (m, 1H), 4.15 - 4.36 (m, 2H), 4.69 - 5.08 (m, 3H), 6.85 - 7.00 (m, 1H), 7.32 - 7.45 (m, 1H), 8.33 (d, 1H), 8.43 (d, 1H), 8.49 - 8.61 (m, 1H).

EXAMPLE 50 2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol a)Tert-butyl-(3R){[6-(2,2-difluoroethoxy)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained as a beige solid (99%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and 2,2-difluoroethanol following the experimental procedure described in Example 5.

LRMS (m/z): 493 (M+1)+. b)6-(2,2-Difluoroethoxy)fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinamine Obtained as a solid dihydrochloride salt (100%) from tert-butyl (3R){[6-(2,2- difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine carboxylate (Example 50a) following the experimental procedure as bed in Example 14b.

LRMS (m/z): 393 (M+1)+. c)2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinyl dinyl]amino}piperidinyl)oxoethanol Obtained as a white solid (40%) from 6-(2,2-difluoroethoxy)fluoro-N-[(3R)-piperidin- 3-yl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 50b) following the experimental procedure described in Preparation 7 ed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 451 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.64 - 1.85 (m, 2H), 1.84 - 2.05 (m, 1H), 2.12 - 2.35 (m, 1H), 2.94 - 3.29 (m, 2H), 3.29 - 3.61 (m, 2H), 3.66 - 3.79 (m, 1H), 3.93 - 4.10 (m, 1H), 4.16 - 4.37 (m, 2H), 4.58 - 4.96 (m, 3H), 6.24 (t, 1H), 6.84 - 7.00 (m, 1H), 7.32 - 7.45 (m, 1H), 8.35 (d, 1H), 8.44 (d, 1H), 8.50 - 8.61 (m, 1H).

EXAMPLE 51 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol a)Tert-butyl-(3R)[(5-fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)amino]piperidinecarboxylate Obtained as an orange oil (92%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and isopropanol following the mental procedure described in Example 15a.

LRMS (m/z): 471 (M+1)+. b)5-Fluoroisopropoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a solid dihydrochloride salt (86%) from tert-butyl (3R)[(5-fluoro isopropoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 51a) following the experimental procedure bed in Example 14b.

LRMS (m/z): 371 (M+1)+. c) 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol Obtained as a light yellow solid (29%) from 5-fluoroisopropoxy-N-[(3R)-piperidin yl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 51b) ing the experimental procedure bed in Preparation 7 followed by purification by flash chromatography (gradient from dichloromethane to methanol 95:5).

LRMS (m/z): 429 (M+1)+. 1H-NMR  (300 MHz, CDCl 3): 1.47 (d, 6H), 1.65 - 1.80 (m, 2H), 1.82 - 1.94 (m, 1H), 2.09 - 2.28 (m, 1H), 2.87 - 3.25 (m, 2H), 3.25 - 3.57 (m, 2H), 3.67 - 3.79 (m, 1H), 3.93 - 4.08 (m, 1H), 4.11 - 4.30 (m, 2H), 4.61 - 4.85 (m, 1H), 5.42 - .64 (m, 1H), 6.74 - 6.95 (m, 1H), 7.28-7.33 (m, 1H), 8.28 - 8.58 (m, 3H).

EXAMPLE 52 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol a) 3-(4-Chlorofluoromorpholinylpyrimidinyl)pyrazolo[1,5-a]pyridine To a solution of 3-(4,6-dichlorofluoropyrimidinyl)pyrazolo[1,5-a]pyridine (Preparation 1d, 0.500 g, 1.77 mmol) in a mixture of ethanol (20 mL) and ydrofurane (10 mL) were added morpholine (0.183 mL, 2.11 mmol) and triethylamine (0.295 mL, 2.12 mmol). The resulting mixture was stirred for 3 hours and then the les were removed under reduced pressure. The residue was partitioned between water and dichloromethane, the organic layer was ted and washed with water, diluted hydrochloric acid and brine, dried over magnesium sulfate, filtered and the t was removed to give 0.575 g (98% yield) of the title compound as a pale solid.

LRMS (m/z): 334 (M+1)+. b)Tert-butyl-(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]piperidinecarboxylate To a solution of tert-butyl (3R)hydroxypiperidinecarboxylate (0.975 g, 4.84 mmol) in dioxane (10 mL) was added potassium tert-butoxide (0.370 g, 3.30 mmol). It was stirred at room temperature for 15 s and then 3-(4-chlorofluoromorpholin ylpyrimidinyl)pyrazolo[1,5-a]pyridine (Example 52a, 0.275 g, 0.82 mmol) were added. The resulting mixture was heated to 90 ºC overnight and then it was allowed to cool to room temperature and diluted with ethyl acetate, washed with water (x3) and brine, dried over magnesium sulfate, filtered and the ts were removed. The crude product was purified first by flash chromatography (dichloromethane to dichloromethane/methanol 94:6) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to yield the title compound (0.362 g, 88% yield) as a white solid.

LRMS (m/z): 499 (M+1)+. c)3-{5-Fluoromorpholinyl[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo [1,5-a]pyridine Obtained as a pale white solid (95%) from tert-butyl (3R)[(5-fluoromorpholinyl- zolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate le 52b) following the experimental procedure as described in Example 20b.

LRMS (m/z): 399 . d)2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol Obtained as a white solid (74%) from 3-{5-fluoromorpholinyl[(3R)-piperidin yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 52c) following the experimental procedure as bed in Preparation 7. The crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 457 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.70 – 2.27 (m, 4H), 3.18 – 3.76 (m, 4H), 3.76 – 3.92 (m, 7H), 3.94 – 4.33 (m, 2H), 5.20 – 5.35 (m, 1H), 6.81 – 6.93 (m, 1H), 7.27 – 7.36 (m, 1H), 8.26 – 8.40 (m, 1H), 8.47 – 8.63 (m, 2H).

EXAMPLE 53 3-{(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile Obtained as a white solid (80%) from 3-{5-fluoromorpholinyl[(3R)-piperidin pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 52c, 0.135 mg, 0.34 mmol) following the experimental ure as described in Preparation 6b. The crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 466 (M+1)+. 1H-NMR  (400 MHz, CDCl 3): 1.63 – 2.33 (m, 4H), 3.12 – 3.29 (m, 1H), 3.41 – 3.71 (m, 4H), 3.82 (m, 8H), 4.02 – 4.25 (m, 1H), 5.25 – 5.40 (m, 1H), 6.82 – 6.94 (m, 1H), 7.29 – 7.38 (m, 1H), 8.27 – 8.39 (m, 1H), 8.46 – 8.60 (m, 2H).

EXAMPLE 54 -((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile A mixture of ((5-fluoro(piperidinylamino)(pyrazolo[1,5-a]pyridin yl)pyrimidinyl)oxy)ethanol dihydrochloride (Example 40b, 0.050 g, 0.13 mmol), 2- chlorocyanopyrazine (0.025 g, 0.18 mmol) and triethylamine (0.056 mL, 0.4 mmol) in N,N-dimethylformamide (1.0 mL) was heated in a microwave at 120 °C for 2 hours.

The reaction mixture was cooled to ambient temperature and ethyl acetate (10 mL) was added. The solution was washed with water (10 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under d pressure. The residue was taken up in dichloromethane (5 mL), the suspension was filtered and dried in vacuo to give the title compound (0.012 g, 19%) as a solid.

LRMS (m/z): 476 (M+1)+. 1H-NMR  (300 MHz, DMSO-d 6): 1.50 - 1.98 (m, 4H), 2.00 - 2.17 (m, 1H), 3.02 (dd, 2H), 3.68 - 3.87 (m, 2H), 4.14 (br. s., 1H), 4.42 (d, 1H), 4.50 (d, 2H), 4.75 (br. s., 1H), 4.93 (d, 1H), 6.94 - 7.10 (m, 1H), 7.30 (dd, 2H), 8.32 (d, 1H), 8.46 (d, 1H), 8.58 (s, 1H), 8.80 (d, 1H).

EXAMPLE 55 (5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}pyrazinyl)methanol A e of (R)fluoromethoxy-N-(piperidinyl)(pyrazolo[1,5-a]pyridin yl)pyrimidinamine dihydrochloride (Example 42b, 0.040 g, 0.12 mmol), (5- pyrazinyl)methanol (0.017 g, 0.12 mmol) and diethylisopropylamine (0.061 mL, 0.35 mmol) in N-Methylpyrrolidone (1.0 mL) was heated in a microwave at 120 °C for 19 hours. The on mixture was cooled to ambient temperature and ethyl acetate (10 mL) was added. The solution was washed with water (10 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography (dichloromethane to 95:5 dichloromethane/ethanol) gave the title compound (0.007 mg, 13%) as a solid.

LRMS (m/z): 446 (M+1)+. 1H-NMR  (300 MHz, CDCl3): 1.52 - 2.02 (m, 3H), 2.12 - 2.27 (m, 1H), 3.16 - 3.51 (m, 2H), 4.01 (dd, 1H), 4.15 (s, 3H), 4.25 - 4.40 (m, 1H), 4.45 (dd, 1H), 4.70 (s, 2H), 4.95 (d, 1H), 6.75 - 6.95 (m, 1H), 7.13 - 7.26 (m, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.39 - 8.56 (m, 2H), 8.64 (s, 1H).

E 56 -{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinecarbonitrile A mixture of (R)fluoromethoxy-N-(piperidinyl)(pyrazolo[1,5-a]pyridin yl)pyrimidinamine dihydrochloride (Example 42b, 0.054 g, 0.13 mmol), 2-chloro cyanopyrazine (0.054 g, 0.38 mmol) and potassium carbonate (0.090 g, 0.65 mmol) in N,N-dimethylformamide (1.0 mL) was heated in a microwave at 120 °C for 1 hours.

The on mixture was cooled to ambient temperature and ethyl acetate (10 mL) was added. The on was washed with water (10 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was taken up in dichloromethane (5 mL), the suspension was filtered and dried in vacuo to give the title compound (0.012 g, 19%) as a pale yellow solid.

LRMS (m/z): 446 (M+1)+. 1H-NMR  (300 MHz, DMSO-d 6): 1.61 - 1.96 (m, 4H), 2.02 - 2.16 (m, 1H), 2.98 - 3.22 (m, 2H), 4.07 (s, 3H), 4.10 - 4.24 (m, 1H), 4.42 (d, 1H), 4.74 (br. s., 1H), 7.04 (d, 1H), 7.30 (dd, 2H), 8.37 (d, 1H), 8.47 (d, 1H), 8.60 (s, 1H), 8.81 (d, 1H).

EXAMPLE 57 2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)pyrimidinecarbonitrile A mixture of (R)((5-fluoro(piperidinylamino)(pyrazolo[1,5-a]pyridin yl)pyrimidinyl)oxy)ethanol dihydrochloride le 40b, 0.060 g, 0.16 mmol), 2- chloropyrimidinecarbonitrile (0.033 g, 0.24 mmol) and triethylamine (0.070 mL, 0.50 mmol) in N,N-dimethylformamide (1.0 mL) was heated in a microwave at 120 °C for 2 hours. The reaction mixture was cooled to ambient temperature and ethyl acetate (10 mL) was added. The solution was washed with water (10 mL) and brine (20 mL). The organic layer was separated, dried over ous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was taken up in dichloromethane (7 mL), the suspension was filtered and dried in vacuo to give the title compound (0.025 g, 33%) as a solid.

LRMS (m/z): 476 (M+1)+. 1H-NMR  (300 MHz, DMSO-d6): 1.44 - 1.96 (m, 4H), 2.00 - 2.22 (m, 1H), 2.84 - 3.15 (m, 2H), 3.67 - 3.85 (m, 2H), 4.06 (d, 1H), 4.50 (d, 2H), 4.68 (d, 1H), 4.93 (d, 1H) 5.07 (dd, 1H), 6.94 - 7.09 (m, 1H), 7.22 - 7.38 (m, 2H), 8.33 (d, 1H), 8.63 (s, 1H), 8.80 (d, 2H).

E 58 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin- rimidinyl}amino)piperidinyl]oxoethanol a) Tert-butyl (3R)({5-fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5- a]pyridinylpyrimidinyl}amino)piperidinecarboxylate Obtained as an oil (72%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5- a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and (2S) methoxypropanol following the experimental procedure described in Example 15a.

LRMS (m/z): 501 (M+1)+. b) 5-Fluoro[(1S)methoxymethylethoxy]-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine Obtained as a solid dihydrochloride salt (98%) from tert-butyl (3R)({5-fluoro[(1S)- 2-methoxymethylethoxy]pyrazolo[1,5-a]pyridinylpyrimidin yl}amino)piperidinecarboxylate (Example 58a) following the experimental procedure described in Example 14b.

LRMS (m/z): 401 (M+1)+. c) 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a] pyridinylpyrimidinyl}amino)piperidinyl]oxoethanol ed as a white solid (24%) from 5-fluoro[(1S)methoxymethylethoxy]- N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine ochloride salt (Example 58b) following the experimental procedure described in Preparation 7 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 459 (M+1)+. 1H NMR (300 MHz, CDCl 3): δ 1.24 – 1.33 (m, 3H), 1.45 – 1.52 (m, 3H), 1.69 – 1.81 (m, 2H), 1.90 (s, 1H), 2.15 – 2.28 (m, 1H), 2.92 – 3.23 (m, 2H), 3.26 – 3.40 (m, 1H), 3.46 (s, 3H), 3.52 – 3.81 (m, 2H), 3.96 – 4.12 (m, 1H), 4.18 – 4.31 (m, 1H), 4.65 – 4.83 (m, 1H), 5.52 – 5.67 (m, 1H), 6.81 – 6.98 (m, 1H), 7.30 – 7.37 (m, 1H), 8.30 – 8.70 (m, 3H).

EXAMPLE 59 (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propanol To a 0 ºC cooled on of 2-[(3R)({5-fluoro[(1S)methoxymethylethoxy] pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)piperidinyl]oxoethanol (Example 58c, 0.053 g, 0.12 mmol) in dichloromethane (1 mL), a 1M solution of boron tribromide in dichloromethane (0.24 mL, 0.24 mmol) was added. The mixture was stirred at 0ºC for 1.5 hours and concentrated to dryness. A mixture of ol and 7N ammonia in ol (1:1) (2 mL) was added and the resulting suspension was concentrated to dryness. The crude was ed by preparative HPLC (gradient from water to methanol) to yield the pure title compound (0.021 g, 41%) as a white solid.

LRMS (m/z): 445 (M+1)+. 1H NMR (300 MHz, CDCl 3): δ 1.23 – 1.33 (m, 2H), 1.42 – 1.51 (m, 3H), 1.70 – 2.30 (m, 4H), 2.95 – 3.24 (m, 2H), 3.30 – 4.12 (m, 4H), 4.23 (d, 1H), 4.77 (m, 1H), 5.48 (m, 1H), 6.89 (m, 1H), 7.27 – 7.41 (m, 3H), 8.26 – 8.68 (m, 3H).

EXAMPLE 60 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxoethanol a) Tert-butyl (3R)({5-fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5- a]pyridinylpyrimidinyl}amino)piperidinecarboxylate Obtained as a colorless oil (72%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and (2R)methoxypropanol ing the experimental procedure described in Example 15a.

LRMS (m/z): 501 (M+1)+. b) 5-Fluoro[(1R)methoxymethylethoxy]-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine Obtained as a yellow oil (100%) from tert-butyl (3R)({5-fluoro[(1R)methoxy methylethoxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)piperidine carboxylate (Example 60a) following the experimental procedure described in Example 20b.

LRMS (m/z): 401 (M+1)+. c) 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5- a]pyridinylpyrimidinyl}amino)piperidinyl]oxoethanol ed as a white solid (46%) from 5-fluoro[(1R)methoxymethylethoxy]- N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 60b) following the experimental procedure described in Preparation 7 ed by purification by reverse phase chromatography (C-18 silica from ®, water/methanol as eluents 0% to 100%).

LRMS (m/z): 459 (M+1)+. 1H NMR (400 MHz, CDCl 3): δ 1.36 – 1.50 (m, 3H), 1.71 (m, 2H), 1.82 – 1.94 (m, 1H), 2.17 (s, 1H), 2.92 – 3.39 (m, 3H), 3.43 (s, 3H), 3.48 – 3.61 (m, 2H), 3.67 – 3.76 (m, 2H), 3.95 – 4.05 (m, 1H), 4.16 – 4.25 (m, 2H), 4.66 – 4.77 (m, 1H), .47 – 5.63 (m, 1H), 6.76 – 6.91 (m, 1H), 7.26 – 7.36 (m, 1H), 8.31 – 8.66 (m, 3H).

EXAMPLE 61 (2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propanol Obtained as a white solid (90%) from 2-[(3R)({5-fluoro[(1R)methoxy methylethoxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)piperidinyl] oxoethanol (Example 60c) following the experimental ure described in Example LRMS (m/z): 445 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 1.45 (dd, 3H), 1.68 – 1.79 (m, 2H), 1.85 – 1.92 (m, 1H), 2.16 – 2.24 (m, 1H), 2.83 – 3.22 (m, 3H), 3.35 – 3.56 (m, 2H), 3.66 – 3.76 (m, 1H), 3.83 – 3.89 (m, 2H), 3.99 (dd, 4.2 Hz, 1H), 4.14 – 4.27 (m, 2H), 4.66 – 4.81 (m, 1H), 5.41 – 5.52 (m, 1H), 6.82 – 6.92 (m, 1H), 7.27 – 7.37 (m, 1H), 8.29 – 8.63 (m, 3H).

EXAMPLE 62 2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin yl)amino]piperidinyl}oxoethanol Obtained as a yellow solid (18%) from 3-{(3R)[(6-chlorofluoropyrazolo[1,5-a] pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 7b) following the experimental procedure described in Example 17 followed by purification by flash chromatography ent from dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 448 (M+1)+. 1H NMR (400 MHz, : δ 1.69 – 2.01 (m, 3H), 2.21 (d, 1H), 3.13 – 3.51 (m, 4H), 3.77 (d, 1H), 3.92 – 4.08 (m, 1H), 4.19 – 4.40 (m, 3H), 4.66 (d, 1H), 5.13 (s, 1H), 6.80 – 6.95 (m, 1H), 7.29 – 7.41 (m, 1H), 7.41 – 7.56 (m, 1H), 8.38 – 8.82 (m, 5H), 9.37 (s, 1H).

E 63 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol a) Tert-butyl (3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinecarboxylate Metal sodium (0.031 g, 1.34 mmol) was added to methanol (8 mL) and the mixture was stirred at room temperature until metal sodium was consumed. Tert-butyl (3R)[(6- chlorofluoropyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Preparation 9, 0.300 g, 0.67 mmol) was added, the reaction mixture was stirred overnight at room temperature. The solid that had formed was filtered and the clean solution was concentrated in vacuo to yield 0.297 g (100% yield) of the title compound, which was used without further purification in the next synthetic step.

LRMS (m/z): 444 (M+1)+. b) 3-{5-Fluoromethoxy[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo[1,5- a]pyridine Obtained as a pale white solid (55%) from utyl (3R)[(5-fluoromethoxy pyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Example 63a) following the experimental ure as bed in Example 20b.

LRMS (m/z): 344 (M+1)+. c) 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol Obtained as a white solid (38%) from luoromethoxy[(3R)-piperidin yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 63b) following the experimental procedure as described in Preparation 7. The crude was purified first by flash chromatography (dichloromethane to 95:5 dichloromethane/methanol) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 402 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.89 - 2.33 (m, 4H), 3.16 - 3.69 (m, 4H), 3.77 - 4.44 (m, 6H), 5.29 (dt, 1H), 6.82 - 6.99 (m, 1H), 7.29 - 7.43 (m, 1H), 8.35 - 8.47 (m, 1H), 8.49 – 8.68 (m, 2H).

EXAMPLE 64 3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile Obtained as a white solid (43%) from 3-{5-fluoromethoxy[(3R)-piperidin yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 63b) following the experimental procedure as described in Preparation 6b. The crude was purified first by flash tography (gradient from dichloromethane to dichloromethane/methanol 85:15) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 411 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.72 – 2.29 (m, 4H), 3.28 – 3.64 (m, 4H), 3.64 – 3.89 (m, 2H), 4.17 (d, 3H), 5.27 – 5.43 (m, 1H), 6.85 – 6.98 (m, 1H), 7.32 – 7.45 (m, 1H), 8.33 – 8.48 (m, 1H), 8.48 – 8.66 (m, 2H).

EXAMPLE 65 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxoethanol a) Tert-butyl -{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinecarboxylate A mixture of utyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.250 g, 0.56 mmol) and cesium de (0.42 g, 2.77 mmol) in dimethyl sulfoxide (10 mL) was stirred at 80 ºC for 2 hours. Then it was allowed to cool to room temperature and ethylene glycol (0.310 mL, .56 mmol) was added. The solution was stirred at 80 ºC for one hour and at room temperature for 16 hours, then it was partitioned between water and ethyl acetate. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, ed and the solvents were removed in vacuo. The crude was ed by flash chromatography (gradient from dichloromethane to romethane/methanol 95:5) to give the title nd (87% yield) as a white solid LRMS (m/z): 474 (M+1)+. b) 2-({5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin yl}oxy)ethanol To a solution of tert-butyl (3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5- a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 65a, 0.229 g, 0.48 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.37 mL) and the resulting mixture was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure and the residue was treated with a saturated aqueous solution of sodium bicarbonate (30 mL) and stirred vigorously for 1 hour. Then the product was extracted with dichloromethane (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness to yield the title compound (0.174 g, 96%) as a white solid.

LRMS (m/z): 374 (M+1)+. c) 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol A mixture of 2-({5-fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)ethanol le 65b, 0.087 g, 0.23 mmol), 2-hydroxyacetic acid (0.021 g, 0.28 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridiniumoxide hexafluorophosphate (0.106 g, 1.20 mmol) and triethylamine (0.097 mL, 0.70 mmol) in N,N-dimethylformamide (2 mL) was stirred at room ature for 64 hours. The resulting mixture was partitioned between s saturated solution of sodium bicarbonate and ethyl e, the organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The res ulting crude was purified by flash chromatography ent from dichloromethane to dichloromethane/methanol 92:8) to yield the title compound (0.048 g, 48%) as a white solid.

LRMS (m/z): 432 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.92 – 2.33 (m, 4H), 3.17 – 3.75 (m, 4H), 3.81 – 4.40 (m, 5H), 4.61 – 4.73 (m, 2H), 5.23 – 5.37 (m, 1H), 6.84 – 6.97 (m, 1H), 7.29 – 7.42 (m, 1H), 8.35 (dd, 1H), 8.46 – 8.66 (m, 2H).

EXAMPLE 66 3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile 3-[(2,5-Dioxopyrrolidinyl)oxy]oxopropanenitrile (prepared as described in BE875054(A1), 0.051 g, 0.28 mmol) was added to a solution of 2-({5-fluoro[(3R)- piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)ethanol (Example 65b, 0.087 g, 0.23 mmol) and triethylamine (0.065 mL, 0.47 mmol) in dichloromethane (3 mL). The resulting mixture was stirred at room temperature for 68 hours. A saturated aqueous solution of sodium bicarbonate (20 mL) was added and the mixture was stirred vigorously for 30 minutes. Then methylene chloride was added, the organic layer was separated and the s phase was ted twice with more methylene chloride. The combined organic layers were washed with water, brine, dried over ium sulfate and concentrated in vacuo. The resulting crude was purified first by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 92:8) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as s [0.1% v/v ammonium formate buffered] 0% to 100%) to yield the title compound (0.049 g, 48%) as a white solid.

LRMS (m/z): 441 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.85 – 2.31 (m, 4H), 3.19 – 3.92 (m, 5H), 3.95 – 4.18 (m, 3H), 4.63 – 4.74 (m, 2H), 5.26 – 5.44 (m, 1H), 6.85 – 6.98 (m, 1H), 7.33 – 7.45 (m, 1H), 8.28 – 8.43 (m, 1H), 8.48 – 8.64 (m, 2H).

EXAMPLE 67 2-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol a) Tert-butyl (3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin- rimidinyl]oxy}piperidinecarboxylate A mixture of utyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.250 g, 0.56 mmol) and 1- piperazine (0.224 g, 2.23 mmol) in tetrahydrofurane (2 mL) was stirred at reflux temperature overnight. Then the reaction e was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (0.285 g, 100%) as an oil.

LRMS (m/z): 512 (M+1)+. b) 3-{5-Fluoro(4-methylpiperazinyl)[(3R)-piperidinyloxy]pyrimidin yl}pyrazolo[1,5-a]pyridine To a solution of tert-butyl (3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5- a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 67a, 0.285 g, 0.56 mmol) in dioxane (3 mL) was added a 4 M solution of hydrochloric acid (2.6 mL) and the resulting mixture was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure to give the title compound as a dichlorohydrate (0.270 g, 100%) as a brownish solid.

LRMS (m/z): 412 (M+1)+. c) ){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol A mixture of 2-hydroxyacetic acid (0.040 g, 0.53 mmol) and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridiniumoxide hexafluorophosphate (0.220 g, 0.58 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 30 s. A solution of 3-{5-fluoro(4- methylpiperazinyl)[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine dichlorohydrate salt (Example 67b, 0.198 g, 0.48 mmol) and triethylamine (0.335 mL, 2.4 mmol) in N,N-dimethylformamide (1.5 mL) was added and the resulting mixture was stirred at room temperature overnight. Then water was added and the t was ted with methylene chloride (x3). The ed c layers were washed with water, brine, dried over magnesium e and concentrated in vacuo. The resulting crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title compound (0.062 g, 27%) as a white solid.

LRMS (m/z): 470 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.90 – 2.26 (m, 4H), 2.27 – 2.52 (m, 3H), 2.66 (s, 4H), 3.12 – 4.38 (m, 11H), 5.28 (s, 1H), 6.81 – 6.96 (m, 1H), 7.28 – 7.38 (m, 1H), 8.34 (dd, 1H), 8.45 – 8.62 (m, 2H).

EXAMPLE 68 3-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile 3-[(2,5-Dioxopyrrolidinyl)oxy]oxopropanenitrile (prepared as bed in BE875054(A1), 0.175 g, 0.96 mmol) was added to a solution of 3-{5-fluoro(4- methylpiperazinyl)[(3R)-piperidinyloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine dichlorohydrate salt (Example 67b, 0.198 g, 0.48 mmol) and triethylamine (0.335 mL, 2.41 mmol) in romethane (25 mL). The ing mixture was stirred overnight at room temperature and then it was diluted with methylene chloride. The solution was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo.

The resulting crude was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title compound (0.018 g, 8%) as a white solid.

LRMS (m/z): 479 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.85 – 2.31 (m, 4H), 2.47 (d, 7H), 3.09 – 3.96 (m, 9H), 4.01 – 4.27 (m, 1H), 5.31 (s, 1H), 6.75 – 6.98 (m, 1H), 7.29 – 7.42 (m, 1H), 8.20 – 8.42 (m, 1H), 8.42 – 8.63 (m, 2H).

EXAMPLE 69 2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin midinyl}oxy)piperidinyl]oxoethanol a) Tert-butyl (3R)({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}oxy)piperidinecarboxylate A solution of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.250 g, 0.56 mmol) and 2- aminoethanol (0.340 g, 5.58 mmol) in dioxane (2 mL) was stirred at reflux temperature ght. Then the reaction mixture was partitioned between water and ethyl acetate, the organic layer was separated and the s phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and trated in vacuo to yield the title compound (0.264 g, 100%) as an oil.

LRMS (m/z): 473 (M+1)+. b) 2-({5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin yl}amino)ethanol Prepared from tert-butyl (3R)({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5- a]pyridinylpyrimidinyl}oxy)piperidinecarboxylate (Example 69a, 0.263 g, 0.56 mmol) following the experimental procedure as described in Example 67b to give the title compound (100% yield) as the dichlorohydrate salt.

LRMS (m/z): 373 (M+1)+. c) 2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxoethanol ed from fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)ethanol dichlorohydrate salt (Example 69b, 0.156 g, 0.42 mmol) following the experimental ure as described in Example 67c. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title compound (0.072 g, 39%) as a white solid.

LRMS (m/z): 431 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.89 – 2.27 (m, 4H), 3.17 – 4.01 (m, 9H), 4.01 – 4.39 (m, 2H), 5.21 – 5.40 (m, 2H), 6.81 – 6.95 (m, 1H), 7.28 – 7.38 (m, 1H), 8.30 – 8.44 (m, 1H), 8.45 – 8.66 (m, 2H).

EXAMPLE 70 3-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile ed as a light yellow solid (42%) from fluoro[(3R)-piperidinyloxy] pyrazolo[1,5-a]pyridinylpyrimidinyl}amino)ethanol dichlorohydrate salt (Example 69b) following the experimental procedure as bed in Preparation 6b. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%).

LRMS (m/z): 440 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.86 – 2.34 (m, 4H), 3.14 – 4.23 (m, 11H), 5.20 – .47 (m, 2H), 6.77 – 6.98 (m, 1H), 7.26 – 7.43 (m, 1H), 8.27 – 8.46 (m, 1H), 8.46 – 8.65 (m, 2H).

EXAMPLE 71 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol a) utyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinecarboxylate Obtained as a light yellow solid (95%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Preparation 9, 0.300 g, 0.67 mmol) and (2-methylpyridinyl)boronic acid following the experimental procedure as described in Example 34 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 85:15).

LRMS (m/z): 505 (M+1)+. b) 3-{5-Fluoro(2-methylpyridinyl)[(3R)-piperidinyloxy]pyrimidin yl}pyrazolo[1,5-a]pyridine Prepared from tert-butyl (3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5- a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 71a, 0.326 g, 0.65 mmol) following the experimental procedure as described in Example 67b to give the title compound (100% yield) as the rohydrate salt.

LRMS (m/z): 405 (M+1)+. c) 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol Prepared from luoro(2-methylpyridinyl)[(3R)-piperidinyloxy]pyrimidin yl}pyrazolo[1,5-a]pyridine dichlorohydrate salt (Example 71b, 0.179 g, 0.44 mmol) following the mental procedure as described in Example 67c. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) followed by stirring in a mixture of methanol (5 mL), water (1 mL) and a few drops of a 2 M solution of sodium hydroxide for 3 hours. Then the t was extracted with methylene chloride (x3) and the organic solution washed with water and brine, dried over magnesium e, filtered and the ts removed in vacuo to yield the pure title compound (0.082 g, 40%) as a white solid.

LRMS (m/z): 463 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.93 – 2.34 (m, 4H), 2.74 (s, 3H), 3.21 – 4.46 (m, 7H), 5.43 (s, 1H), 6.86 – 7.01 (m, 1H), 7.31 – 7.49 (m, 1H), 7.80 – 8.00 (m, 2H), 8.48 (t, 1H), 8.53 – 8.60 (m, 1H), 8.61 – 8.77 (m, 2H).

EXAMPLE 72 3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile Obtained as a light yellow solid (49%) from 3-{5-fluoro(2-methylpyridinyl)[(3R)- dinyloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine dichlorohydrate salt le 71b) following the experimental procedure as described in Preparation 6b. The crude t was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 85:15).

LRMS (m/z): 472 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.89 – 2.42 (m, 4H), 2.73 (s, 3H), 3.21 – 4.30 (m, 6H), 5.49 (s, 1H), 6.84 – 7.04 (m, 1H), 7.41 (s, 1H), 7.77 – 8.00 (m, 2H), 8.42 – 8.52 (m, 1H), 8.52 – 8.60 (m, 1H), 8.60 – 8.80 (m, 2H).

EXAMPLE 73 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile a) Tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H- pyranyloxy)methyl]pyridinyl}pyrimidinyl)oxy]piperidinecarboxylate ed as a pale solid (90%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate (Preparation 9, 0.150 g, 0.34 mmol) and 2-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)pyridine (Example 37b) following the experimental procedure as described in Example 20a followed by cation by flash chromatography (gradient from hexane to hexane/ethyl acetate 30:70).

LRMS (m/z): 606 (M+1)+. b) (4-{5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin yl}pyridinyl)methanol To a solution of tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2- [(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidinyl)oxy]piperidine carboxylate (Example 73a, 0.182 g, 0.30 mmol) in tetrahydrofurane (2 mL) was added 2 M hydrochloric acid (0.45 mL). The resulting solution was d at 60 ºC for 5 hours and at room temperature for 16 hours. Then it was diluted with water, basified with 2 M sodium hydroxide solution and extracted with methylene chloride (x3). The combined organic layer was washed with brine, dried over magnesium e, filtered and the solvent was removed to yield the title compound (0.126 g, 100%) as a pale solid.

LRMS (m/z): 421 (M+1)+. c) 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile Obtained as a white solid (34%) from (4-{5-fluoro[(3R)-piperidinyloxy] lo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 73b) following the experimental procedure as described in Preparation 6b. The crude was purified by flash chromatography (dichloromethane to 90:10 dichloromethane/methanol).

LRMS (m/z): 488 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.92 – 2.38 (m, 3H), 3.02 – 4.37 (m, 7H), 4.92 (s, 2H), 5.34 – 5.57 (m, 1H), 6.86 – 7.05 (m, 1H), 7.33 – 7.51 (m, 1H), 7.97 (s, 1H), 8.00 (s, 1H), 8.44 – 8.53 (m, 1H), 8.53 – 8.61 (m, 1H), 8.62 – 8.75 (m, 1H), 8.75 – 8.84 (m, 1H).

E 74 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxoethanol Obtained as a light yellow solid (58%) from (4-{5-Fluoro[(3R)-piperidinyloxy] pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 73b) following the experimental procedure as described in Preparation 7. The crude product was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 90:10).

LRMS (m/z): 479 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.78 – 2.43 (m, 4H), 3.24 – 4.24 (m, 7H), 4.94 (s, 2H), 5.42 – 5.57 (m, 1H), 6.89 – 7.03 (m, 1H), 7.37 – 7.49 (m, 1H), 7.90 – 8.12 (m, 2H), 8.40 – 8.51 (m, 1H), 8.57 (t, 1H), 8.62 – 8.73 (m, 1H), 8.78 (t, 1H).

EXAMPLE 75 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinol a) Tert-butyl (3R){[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl]oxy}piperidinecarboxylate A mixture of tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)oxy]piperidinecarboxylate (Preparation 9, 0.300 g, 0.67 mmol) and piperidinol (0.271 g, 2.68 mmol) in dimethylacetamide (2 mL) was stirred at 110 ºC for 1 hour.

Then the on e was partitioned between water and ethyl acetate, the organic layer was ted and the s phase was extracted twice with ethyl acetate.

The ed organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (0.332 g, 100%) as an oil.

LRMS (m/z): 513 (M+1)+. b) luoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidin yl}piperidinol Prepared from tert-butyl (3R){[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5- a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 75a, 0.332 g, 0.65 mmol) following the experimental procedure as described in Example 67b to give the title nd (100% yield) as the dichlorohydrate salt.

LRMS (m/z): 413 (M+1)+. c) 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin midinyl)piperidinol Prepared from 1-{5-fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin midinyl}piperidinol dichlorohydrate salt le 75b, 0.133 g, 0.32 mmol) following the experimental procedure as described in Example 67c. The crude product was purified by flash chromatography (gradient from 100% dichloromethane to 100% ol) to yield the pure title compound (0.106 g, 70%) as a white solid.

LRMS (m/z): 471 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 – 2.15 (m, 10H), 2.91 – 3.11 (m, 2H), 3.53 – 4.34 (m, 6H), 4.38 – 4.63 (m, 1H), 4.78 (s, 1H), 5.00 – 5.36 (m, 1H), 6.91 – 7.12 (m, 1H), 7.34 – 7.60 (m, 1H), 8.23 – 8.42 (m, 1H), 8.48 – 8.66 (m, 1H), 8.69 – 8.86 (m, 1H).

EXAMPLE 76 3-((3R){[5-Fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile Obtained as a white solid (62%) from 1-{5-Fluoro[(3R)-piperidinyloxy] pyrazolo[1,5-a]pyridinylpyrimidinyl}piperidinol dichlorohydrate (Example 75b) following the experimental procedure as described in Preparation 6b. The crude was purified first by flash chromatography (dichloromethane to 90:10 dichloromethane/methanol) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%).

LRMS (m/z): 488 (M+1)+. 1H-NMR (400 MHz, CDCl3): δ 1.62 – 2.35 (m, 8H), 3.12 – 4.33 (m, 12H), 5.31 (s, 1H), 6.79 – 6.96 (m, 1H), 7.28 – 7.39 (m, 1H), 8.27 – 8.44 (m, 1H), 8.45 – 8.61 (m, 2H).

E 77 2-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl](methyl)amino]piperidinyl}oxoethanol A mixture of 2-hydroxyacetic acid (0.016 g, 0.21 mmol) and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridiniumoxide hexafluorophosphate (0.082 g, 0.22 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 15 s. 5-fluoro-N-methyl(2-methylpyridinyl)- N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 21b, 0.075 g, 0.18 mmol) and triethylamine (0.150 mL, 1.1 mmol) were added and the resulting mixture was d at room temperature for 2 hours. Then water (50 mL) and a 2 M sodium hydroxide aqueous solution (5 mL) were added and the resulting solution was d for 30 minutes. Then the product was extracted with ethyl acetate (x3), the combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane to 92:8 dichloromethane/methanol) to yield the title compound (0.055 g, 64%) as a white solid.

LRMS (m/z): 476 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.62 – 2.25 (m, 4H), 2.50 – 3.34 (m, 8H), 3.41 – 3.78 (m, 2H), 4.03 – 4.35 (m, 2H), 4.41 – 4.61 (m, 1H), 4.61 – 5.03 (m, 1H), 6.80 – 6.95 (m, 1H), 7.31 (q, 1H), 7.73 – 7.98 (m, 2H), 8.45 (d, 1H), 8.49 – 8.59 (m, 1H), 8.59 – 8.74 (m, 2H).

EXAMPLE 78 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile a) Tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{2-[(tetrahydro-2H- pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinecarboxylate ed as a pale solid (90%) from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5- a]pyridinylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5, 0.250 g, 0.56 mmol) and 2-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)pyridine (Example 37b, 0.268 g, 0.84 mmol) following the mental procedure as described in Example 20a.

LRMS (m/z): 605 (M+1)+. b) (4-{5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}pyridinyl)methanol Obtained as a white solid (99%) from tert-butyl (3R)[(5-fluoropyrazolo[1,5- a]pyridinyl{2-[(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidin yl)amino]piperidinecarboxylate (Example 78a) following the experimental ure as described in Example 73b.

LRMS (m/z): 420 (M+1)+. c) 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile Obtained as a white solid (31%) from (4-{5-fluoro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 78b) following the experimental procedure as described in Preparation 6b. The crude was purified by flash tography (dichloromethane to 92:8 dichloromethane/methanol).

LRMS (m/z): 487 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.74 – 2.33 (m, 4H), 3.18 – 4.60 (m, 8H), 4.82 – 4.98 (m, 2H), 5.19 (s, 1H), 6.77 – 7.05 (m, 1H), 7.39 (s, 1H), 7.79 – 8.07 (m, 2H), 8.36 – 8.86 (m, 4H).

EXAMPLE 79 5-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin midinyl)pyridinecarboxylic acid To a solution of ethyl luoro{[(3R)glycoloylpiperidinyl]amino} pyrazolo[1,5-a]pyridinylpyrimidinyl)pyridinecarboxylate (Example 38c, 0.120 g, 0.23 mmol) in a mixture of tetrahydrofurane (3 mL) and water (3 mL) was added a 2 M aqueous solution of sodium hydroxide (0.580 mL) and the resulting solution was stirred at room temperature overnight. Then the reaction mixture was diluted with water and acidified to pH = 5 and directly injected for purification by reverse phase chromatography (C-18 silica from Waters®, water/1:1 itrile-methanol as s [0.1% v/v ammonium formate buffered] 0% to 100%) to yield the title compound (0.039 g, 34%) as a white solid.

LRMS (m/z): 492 (M+1)+.

EXAMPLE 80 2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin yl)amino]piperidinyl}oxoethanol Obtained as a dark yellow solid (79%) from 3-{(3R)[(6-chlorofluoro lo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl}oxopropanenitrile (Preparation 7b) following the experimental procedure bed in Example 20a.

LRMS (m/z): 448 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.67 – 2.04 (m, 3H), 2.11 – 2.29 (m, 1H), 3.10 – 3.34 (m, 2H), 3.39 – 3.56 (m, 2H), 3.64 – 3.83 (m, 1H), 3.95 – 4.12 (m, 1H), 4.32 (d, 1H), 4.58 – 4.76 (m, 1H), 5.08 – 5.22 (m, 1H), 6.85 – 6.94 (m, 1H), 7.30 – 7.42 (m, 1H), 8.00 (d, 2H), 8.53 (dt 2H), 8.61 – 8.84 (m, 3H).

EXAMPLE 81 2-[(3R)({6-[6-(Dimethylamino)pyridinyl]fluoropyrazolo[1,5-a]pyridin midinyl}amino)piperidinyl]oxoethanol Obtained from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.098 g, 0.24 mmol) and N,N- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridinamine (prepared as described in Example 37b from 5-bromo-N,N-dimethylpyridinamine) following the experimental procedure as described in Example 20a. The crude product was purified first by flash chromatography (dichloromethane to dichloromethane/methanol 98:2) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium e buffered] 0% to 100%) to yield the title compound (0.040 g, 34%) as a white solid.

LRMS (m/z): 491 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.67 – 2.38 (m, 4H), 3.06 – 3.29 (m, 6H), 3.33 – 5.09 (m, 9H), 6.53 – 6.71 (m, 1H), 6.79 – 6.97 (m, 1H), 7.28 – 7.39 (m, 1H), 8.28 (d, 1H), 8.45 – 8.79 (m, 3H), 9.04 (s, 1H).

EXAMPLE 82 2-{(3R)[(5-Fluoro-2'-methylpyrazolo[1,5-a]pyridinyl-4,5'-bipyrimidin yl)amino]piperidinyl}oxoethanol Obtained from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.098 g, 0.24 mmol) and 2- methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrimidine (prepared as bed in Example 37b from 5-bromomethylpyrimidine) following the experimental procedure as described in Example 20a. The crude product was purified first by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) and then by e phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v ammonium formate buffered] 0% to 100%) to yield the title compound (0.049 g, 44%) as a white solid.

LRMS (m/z): 463 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.68 – 2.40 (m, 4H), 2.85 (s, 3H), 3.09 – 4.75 (m, 8H), 5.06 – 5.31 (m, 1H), 6.79 – 6.98 (m, 1H), 7.26 – 7.42 (m, 1H), 8.32 – 8.86 (m, 3H), 9.39 (s, 2H).

EXAMPLE 83 2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol a) Tert-butyl (3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridin midinyl]oxy}piperidinecarboxylate Obtained as a colorless solid (63%) from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and 2-ethoxyethanol following the experimental procedure described in Example 15a.

LRMS (m/z): 501 (M+1)+. b) 3-{4-(2-Ethoxyethoxy)fluoro[(3R)-piperidinyloxy]pyrimidin yl}pyrazolo[1,5-a]pyridine Obtained as an oil (100%) from tert-butyl (3R){[6-(2-ethoxyethoxy)fluoro pyrazolo[1,5-a]pyridinylpyrimidinyl]oxy}piperidinecarboxylate (Example 83a) following the experimental procedure bed in e 20b.

LRMS (m/z): 401 (M+1)+. c) ){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol Obtained as a white solid (51%) from 2-ethoxyethoxy)fluoro[(3R)-piperidin- 3-yloxy]pyrimidinyl}pyrazolo[1,5-a]pyridine (Example 83b) following the experimental procedure described in Preparation 7 followed by purification by reverse phase chromatography (C-18 silica from Waters®, water/methanol as eluents 0% to 100%).

LRMS (m/z): 459 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.20 – 1.29 (m, 3H), 1.65 – 1.94 (m, 3H), 2.17 (s, 1H), 2.92 – 3.20 (m, 2H), 3.29 – 3.66 (m, 3H), 3.66 – 3.78 (m, 1H), 3.81 – 3.90 (m, 2H), 3.95 – 4.04 (m, 1H), 4.14 – 4.32 (m, 2H), 4.60 – 4.78 (m, 3H), 6.85 (q, 1H), 7.26 – 7.36 (m, 1H), 8.28 – 8.70 (m, 3H).

EXAMPLE 84 2-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol a) utyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{6-[(tetrahydro-2H- pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5, 0.250 g, 0.56 mmol) and 2-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (prepared as described in Example 37a and 37b from (5-bromopyrimidin- 2-yl)methanol) following the experimental procedure as described in Example 20a. The crude t was ed by flash tography (hexane to hexane/ethyl acetate :80) to yield the title compound (0.237 g, 70%) as a white solid.

LRMS (m/z): 605 (M+1)+. b) Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}pyridinyl)methanol Obtained as a white solid (100%) from tert-butyl (3R)[(5-fluoropyrazolo[1,5- a]pyridinyl{6-[(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidin yl)amino]piperidinecarboxylate (Example 84a) following the experimental procedure as described in Example 73b.

LRMS (m/z): 420 (M+1)+. c) 2-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxoethanol Prepared from (5-{5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}pyridinyl)methanol (Example 84b, 0.065 g, 0.16 mmol) following the experimental ure as described in Example 67c. The crude product was ed first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile- methanol as eluents 0% to 100%) and then by preparative HPLC (gradient from water to methanol) to yield the pure title compound (0.005 g, 7%) as a white solid.

LRMS (m/z): 478 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.68 – 2.30 (m, 3H), 2.98 – 4.95 (m, 11H), 5.01 – 5.23 (m, 1H), 6.82 – 6.98 (m, 1H), 7.29 – 7.57 (m, 2H), 8.39 – 8.60 (m, 2H), 8.60 – 8.80 (m, 1H), 9.32 (s, 1H).

EXAMPLE 85 3-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile Obtained as a pale solid (23%) from (5-{5-fluoro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 84b, 0.023 g, 0.06 mmol) following the experimental procedure as bed in Preparation 6b. The crude was purified by flash tography (dichloromethane to 90:10 dichloromethane/methanol).

LRMS (m/z): 487 . 1H-NMR (400 MHz, CDCl 3): δ 2.13 – 2.40 (m, 2H), 3.08 – 4.97 (m, 9H), 6.77 – 7.02 (m, 1H), 7.31 – 7.43 (m, 1H), 7.43 – 7.58 (m, 1H), 8.34 – 8.83 (m, 3H), 9.25 (d, 1H).

EXAMPLE 86 2-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol Obtained from 2-{(3R)[(6-chlorofluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol (Preparation 7, 0.098 g, 0.24 mmol) and 2,6- dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine (prepared as described in Example 37b from 4-bromo-2,6-dimethylpyridine) following the experimental procedure as described in Example 20a. The crude product was purified first by flash chromatography oromethane to dichloromethane/methanol 98:2) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents [0.1% v/v ammonium e buffered] 0% to 100%) to yield the title compound (0.014 g, 12%) as a white solid.

LRMS (m/z): 476 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.76 – 2.32 (m, 4H), 2.65 (s, 6H), 2.96 – 5.39 (m, 9H), 6.76 – 6.99 (m, 1H), 7.35 (q, 1H), 7.64 (d, 2H), 8.41 – 8.61 (m, 2H), 8.70 (m, 1H).

EXAMPLE 87 3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile a) Tert-butyl (3R){[6-(2,6-dimethylpyridinyl)fluoropyrazolo[1,5- a]pyridinylpyrimidinyl]amino}piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl) amino]piperidinecarboxylate (Preparation 5, 0.300 g, 0.67 mmol) and 2,6-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine red as described in Example 37b from o-2,6-dimethylpyridine) following the experimental procedure as described in Example 20a. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents 0% to 100%) to yield the title compound (0.149 g, 43%) as a white solid.

LRMS (m/z): 519 (M+1)+. b) 6-(2,6-Dimethylpyridinyl)fluoro-N-[(3R)-piperidinyl]pyrazolo[1,5- a]pyridinylpyrimidinamine To a solution of tert-butyl (3R){[6-(2,6-dimethylpyridinyl)fluoropyrazolo[1,5- a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 87a, 0.149 g, 0.29 mmol) in dioxane (2 mL) was added a 4 M solution of hydrochloric acid in dioxane (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour and then the volatiles were removed under reduced pressure to give 0.141 g (100% yield) of the title compound as a dichlorohydrate salt.

LRMS (m/z): 418 . c) 3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile Obtained as a light yellow solid (77%) from 6-(2,6-Dimethylpyridinyl)fluoro-N- [(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine le 87b) following the mental ure as described in Preparation 6b. The crude product was purified by flash chromatography (dichloromethane to romethane/methanol 90:10).

LRMS (m/z): 485 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.74 – 2.33 (m, 4H), 2.67 (s, 6H), 2.99 – 5.28 (m, 8H), 6.80 – 7.03 (m, 1H), 7.31 – 7.47 (m, 1H), 7.58 – 7.76 (m, 2H), 8.39 – 8.60 (m, 2H), 8.60 – 8.78 (m, 1H).

EXAMPLE 88 )({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol a) Tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{5-[(tetrahydro-2H- pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chlorofluoropyrazolo[1,5-a]pyridin ylpyrimidinyl) amino]piperidinecarboxylate ration 5, 0.335 g, 0.56 mmol) and 3-[(tetrahydro-2H-pyranyloxy)methyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (prepared as described in Example 37a and 37b from (5-bromopyridin yl)methanol) following the experimental procedure as described in Example 20a. The crude product was purified by flash chromatography (hexane to hexane/ethyl acetate :80) to yield the title compound (0.335 g, 99%) as a white solid.

LRMS (m/z): 605 (M+1)+. b) (5-{5-Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}pyridinyl)methanol To a solution of tert-butyl (3R)[(5-fluoropyrazolo[1,5-a]pyridinyl{5- [(tetrahydro-2H-pyranyloxy)methyl]pyridinyl}pyrimidinyl)amino]piperidine carboxylate (Example 88a, 0.335 g, 0.56 mmol) in tetrahydrofuran (2 mL), 1N hydrochloric acid (1.70 mL) was added. The on mixture was d at room temperature for 1 hour and then at 60 ºC for 3 hours, then water (15 mL) and a 2M solution of sodium hydroxide (1 mL) were added. The product was extracted with dichloromethane (x3), the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title nd (0.209 g, 90%) as a pale solid.

LRMS (m/z): 420 (M+1)+. c) 2-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxoethanol Prepared from Fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}pyridinyl)methanol (Example 88b, 0.104 g, 0.25 mmol) following the experimental procedure as described in Example 67c. The crude t was treated with a mixture of methanol (15 mL), water (15 mL) and a few drops of a 2 M on of sodium hydroxide for 1 hour and then purified by flash chromatography (dichloromethane to 85:15 dichloromethane/methanol) to yield the title compound (0.041 g, 35%) as a white solid.

LRMS (m/z): 478 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.58 – 2.32 (m, 5H), 3.04 – 4.43 (m, 7H), 4.55 – 4.70 (m, 1H), 4.79 (s, 2H), 6.77 – 6.97 (m, 1H), 7.27 – 7.39 (m, 1H), 8.38 – 8.53 (m, 2H), 8.53 – 8.73 (m, 3H), 9.17 (s, 1H).

EXAMPLE 89 3-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile Obtained as a light yellow solid (51%) from (5-{5-fluoro[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinyl)methanol (Example 88b) following the experimental procedure as described in Preparation 6b. The crude product was ed by flash chromatography (dichloromethane to dichloromethane/methanol 90:10).

LRMS (m/z): 487 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.61 – 2.29 (m, 4H), 2.99 – 4.18 (m, 6H), 4.17 – 4.36 (m, 1H), 4.46 – 4.63 (m, 1H), 4.80 (s, 2H), 6.79 – 6.97 (m, 1H), 7.30 – 7.44 (m, 1H), 8.28 – 8.54 (m, 2H), 8.54 – 8.76 (m, 2H), 9.06 – 9.28 (m, 1H).

EXAMPLE 90 (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol a) Tert-butyl -[(5-fluoro{[(2S)hydroxypropyl]oxy}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]piperidinecarboxylate Obtained as a (1.8:1) mixture of the title compound and tert-butyl (3R)({5-fluoro [(1S)hydroxymethylethoxy]pyrazolo[1,5-a]pyridinylpyrimidin )piperidinecarboxylate from tert-butyl (3R)[(6-chlorofluoro pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 5) and (2S)methoxypropanol following the experimental procedure described in Example 15a.

LRMS (m/z): 488 (M+1)+. b) (2S)({5-Fluoro[(3R)-piperidinyloxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)propanol Obtained as a (2:1) mixture of the title compound and (2S)({5-fluoro[(3R)- piperidinyloxy]pyrazolo[1,5-a]pyridinylpyrimidinyl}oxy)propanol (71%) from the mixture obtained in Example 90a, following the experimental procedure described in Example 20a.

LRMS (m/z): 388 (M+1)+. c) (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propanol Obtained as a white solid (16%) from the mixture obtained in Example 90b, following the experimental procedure described in Preparation 7 followed by purification by reverse phase chromatography (C-18 silica from Waters®, water/methanol as eluents 0% to 100%).

LRMS (m/z): 445 (M+1)+. 1H NMR (400 MHz, CDCl 3): δ 1.29 – 1.39 (m, 3H), 1.66 – 1.96 (m, 3H), 2.13 – 2.25 (m, 1H), 2.98 – 3.79 (m, 5H), 3.93 – 4.81 (m, 7H), 6.82 – 6.94 (m, 1H), 7.28 – 7.39 (m, 1H), 8.32 – 8.47 (m, 1H), 8.61 (s, 2H).

EXAMPLE 91 -[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile Obtained as a pale yellow solid (47%) from 5-fluoro[(1R)methoxy methylethoxy]-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidinamine le 60b) following the experimental ure bed in Example 54 followed by purification by flash chromatography (gradient from hexane to ethyl acetate).

LRMS (m/z): 504 . 1H NMR (300 MHz, DMSO-d6): δ 1.31 – 1.39 (m, 3H), 1.54 – 2.16 (m, 5H), 2.91 – 3.21 (m, 3H), 3.48 – 3.73 (m, 2H), 4.74 (s, 5H), 5.54 (td, 1H), 6.94 – 7.07 (m, 1H), 7.20 – 7.37 (m, 2H), 8.23 – 8.35 (m, 1H), 8.39 – 8.49 (m, 1H), 8.56 (s, 1H), 8.75 – 8.83 (m, 1H).

E 92 Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinecarboxylate a) Isopropyl 6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinecarboxylate A mixture of 6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro pyrazolo[1,5-a]pyridinylpyrimidinecarboxylic acid (Example 46b, 0.093 g, 0.18 mmol), cesium carbonate (0.115 g, 0.35 mmol) and propane (0.027 mL, 1.50 mmol) in N,N-dimethylformamide (2.5 mL) was d at 60 ºC for 1 hour. Then the reaction mixture was partitioned between water and ethyl e and the organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvents were evaporated in vacuo. The product w as purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) to give the title compound (0.085 g, 90%) as an oil.

LRMS (m/z): 499 (M+1)+. b) Isopropyl 5-fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin ylpyrimidinecarboxylate To a solution of isopropyl 6-{[(3R)(tert-butoxycarbonyl)piperidinyl]amino}fluoro- 2-pyrazolo[1,5-a]pyridinylpyrimidinecarboxylate (Example 92a, 0.085 g, 0.17 mmol) in dichloromethane (3 mL), trifluoroacetic acid (0.302 mL) was added. The mixture was stirred at room temperature for 30 minutes, the volatiles were removed in vacuo and the residue was redissolved in water. The pH was adjusted to 9 with a saturated sodium bicarbonate solution and the product was extracted with dichloromethane (x3). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvents were ated in vacuo to give the title nd (0.068 g, 100%) as an oil.

LRMS (m/z): 399 (M+1)+. c) Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinecarboxylate Prepared from isopropyl 5-fluoro[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinecarboxylate (Example 92b, 0.068 g, 0.17 mmol) following the mental procedure as described in Example 67c. The crude product was purified by flash chromatography (dichloromethane to 95:5 dichloromethane/methanol) to yield the title compound (0.015 g, 19%) as a pale yellow solid.

LRMS (m/z): 457 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.37 – 1.47 (m, 6H), 1.69 – 2.27 (m, 4H), 3.09 – 4.67 (m, 8H), 5.19 (s, 1H), 5.28 – 5.45 (m, 1H), 6.82 – 6.92 (m, 1H), 7.29 – 7.41 (m, 1H), 8.46 – 8.55 (m, 1H), 8.55 – 8.78 (m, 2H).

EXAMPLE 93 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}oxoethanol a) utyl (3R)[(6-methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)amino]piperidinecarboxylate Obtained as an oil (31%) from (R)-tert-butyl 3-((6-chloromethyl(pyrazolo[1,5- a]pyridinyl)pyrimidinyl)amino)piperidinecarboxylate (Preparation 8c) following the experimental procedure bed in e 42c.

LRMS (m/z): 439 (M+1)+. b) 6-Methoxymethyl-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a solid dihydrochloride salt (99%) from tert-butyl (3R)[(6-methoxy methylpyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 93a) following the experimental procedure described in Example 14b.

LRMS (m/z): 339 (M+1)+. c) 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol Obtained as a white solid (41%) from 6-methoxymethyl-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 93b) following the experimental procedure described in Example 67c followed by purification by reverse phase chromatography (C-18 silica from Waters®, water/methanol as eluents 0% to 100%).

LRMS (m/z): 396 (M+1)+. 1H NMR (400 MHz, CDCl 3): δ 1.59 – 1.86 (m, 6H), 2.06 – 2.15 (m, 1H), 3.02 – 3.93 (m, 6H), 4.01 (d, 3H), 4.09 – 4.35 (m, 3H), 6.75 – 6.86 (m, 1H), 7.21 (s, 1H), 8.39 – 8.72 (m, 3H).

EXAMPLE 94 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin- 1-yl}oxoethanol a) Tert-butyl (3R)[(6-methoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate Obtained as a white solid (74%) from tert-butyl (3R)[(6-chloropyrazolo[1,5- a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Preparation 10c, 0.300 g, 0.70 mmol) following the experimental procedure as described in Example 42a. Excess solution of sodium methoxide in methanol was added until the on was completed.

LRMS (m/z): 425 (M+1)+. b) 6-Methoxy-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridinylpyrimidin amine Obtained as a pale white solid (80%) from tert-butyl (3R)[(6-methoxypyrazolo[1,5- a]pyridinylpyrimidinyl)amino]piperidinecarboxylate (Example 94a) following the experimental procedure as described in Example 20b.

LRMS (m/z): 343 (M+1)+. c) 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}oxoethanol Obtained as a white solid (80%) from 6-methoxy-N-[(3R)-piperidinyl]pyrazolo[1,5- a]pyridinylpyrimidinamine (Example 94b) following the experimental procedure as described in Preparation 7. The crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 91:9).

LRMS (m/z): 383 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.65 – 2.23 (m, 4H), 3.01 – 3.18 (m, 1H), 3.31 – 3.92 (m, 4H), 3.92 – 4.10 (m, 3H), 4.10 – 4.93 (m, 3H), 5.43 – 5.64 (m, 1H), 6.77 – 6.94 (m, 1H), 7.28 – 7.42 (m, 1H), 8.39 – 8.60 (m, 2H), 8.60 – 8.78 (m, 1H).

EXAMPLE 95 3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin- 3-oxopropanenitrile Obtained as a white solid (93%) from 6-methoxy-N-[(3R)-piperidinyl]pyrazolo[1,5- dinylpyrimidinamine (Example 94b) following the experimental procedure as described in Preparation 6b. The crude was purified by flash tography (gradient from dichloromethane to dichloromethane/methanol 80:20).

LRMS (m/z): 383 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.66 – 2.25 (m, 4H), 3.23 – 3.91 (m, 5H), 3.93 – 4.15 (m, 3H), 4.18 – 4.86 (m, 2H), 5.57 (d, 1H), 6.88 (dt, 1H), 7.28 – 7.42 (m, 1H), 8.46 – 8.59 (m, 2H), 8.59 – 8.75 (m, 1H).

EXAMPLE 96 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol a) Tert-butyl (3R){[6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinecarboxylate A solution of 2-methoxyethanol (0.55 mL, 7.0 mmol) and potassium tert-butanol (0.236 g, 2.1 mmol) in dioxane (3 mL) was stirred at room temperature for 30 minutes. Then tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidine- 1-carboxylate (Preparation 10c, 0.300 g, 0.70 mmol) was added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and ioned n water and ethyl acetate. The c layer was separated and the aqueous layer was extracted with ethyl acetate. The combined c layers were washed with brine, dried over ium e and concentrated in vacuo. The resulting crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title nd (0.188 g, 57%) as a solid.

LRMS (m/z): 469 (M+1)+. b) 6-(2-Methoxyethoxy)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a pale white solid (86%) from tert-butyl (3R){[6-(2-methoxyethoxy) pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 96a) following the experimental procedure as described in Example 20b.

LRMS (m/z): 369 (M+1)+. c) 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol Obtained as a white solid (20%) from 6-(2-methoxyethoxy)-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 96b) following the experimental procedure as described in Preparation 6b. The crude was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%), then by flash chromatography (dichloromethane to dichloromethane/methanol 85:15) and finally by preparative HPLC (gradient from water to methanol).

LRMS (m/z): 427 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.63 – 2.25 (m, 4H), 3.01 – 3.25 (m, 2H), 3.25 – 4.30 (m, 9H), 4.37 – 4.81 (m, 3H), 5.47 – 5.70 (m, 1H), 6.79 – 6.96 (m, 1H), 7.27 – 7.37 (m, 1H), 8.40 – 8.57 (m, 2H), 8.57 – 8.71 (m, 1H).

EXAMPLE 97 3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile Obtained as a white solid (25%) from 6-(2-methoxyethoxy)-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 96b) following the experimental ure as described in Preparation 6b. The crude was purified first by flash chromatography (dichloromethane to dichloromethane/methanol 85:15), then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents 0% to 100%) and finally by preparative HPLC (gradient from water to methanol).

LRMS (m/z): 436 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.64 – 2.25 (m, 4H), 2.87 – 4.17 (m, 11H), 4.34 – 4.81 (m, 3H), 5.53 – 5.67 (m, 1H), 7.28 – 7.40 (m, 1H), 8.41 – 8.58 (m, 2H), 8.58 – 8.70 (m, 1H) EXAMPLE 98 2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxoethanol a) utyl (3R){[6-(2-methoxypyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate (Preparation 10c, 0.300 g, 0.70 mmol) ing the mental procedure as described in Example 20a. The crude product was purified by reverse phase tography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents 0% to 100%) to yield the title compound (0.153 g, 38%) as a white solid.

LRMS (m/z): 502 (M+1)+. b) ethoxypyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained as a pale white solid (57%) from tert-butyl (3R){[6-(2-methoxypyridinyl)- 2-pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (Example 98a) following the experimental procedure as bed in Example 20b.

LRMS (m/z): 402 . c) 2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol Obtained as a white solid (29%) from 6-(2-methoxypyridinyl)-N-[(3R)-piperidinyl]- 2-pyrazolo[1,5-a]pyridinylpyrimidinamine (Example 98b) ing the experimental procedure as described in Preparation 7. The crude was purified first by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 91:9), then by reverse phase tography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) and finally by preparative HPLC (gradient from water to methanol).

LRMS (m/z): 460 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.65 – 2.32 (m, 4H), 3.08 – 3.90 (m, 5H), 4.02 (s, 3H), 4.09 – 5.03 (m, 3H), 6.57 (m, 1H), 6.90 (m, 1H), 7.31 – 7.48 (m, 2H), 7.53 (m, 1H), 8.31 (d, 1H), 8.54 (t, 1H), 8.63 (dd, 1H), 8.75 (m, 1H).

EXAMPLE 99 2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol a) Tert-butyl (3R){[6-(6-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate (Preparation 10c, 0.300 g, 0.70 mmol) following the experimental ure as described in Example 20a. The crude product was purified first by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 85:15) and then by reverse phase chromatography (C-18 silica from Waters®, 1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title compound (0.128 g, 41%) as a white solid.

LRMS (m/z): 486 (M+1)+. b) 6-(6-Methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine Obtained from tert-butyl -{[6-(6-methylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate (Example 99a) ing the experimental procedure as described in Example 67b to give the title compound (93% yield) as the dichlorohydrate salt.

LRMS (m/z): 386 . c) 2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxoethanol Prepared from 6-(6-methylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinamine dichlorohydrate salt (Example 99b, 0.085 g, 0.18 mmol) following the experimental procedure as described in Example 67c. The crude product was ed first by flash chromatography (dichloromethane to 85:15 dichloromethane/methanol) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) to yield the title compound (0.082 g, 50%) as a pale solid.

LRMS (m/z): 444 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 1.38 – 2.10 (m, 4H), 2.55 (s, 3H), 2.60 – 3.15 (m, 2H), 3.57 – 4.80 (m, 4H), 6.67 – 6.89 (m, 1H), 7.04 (s, 1H), 7.27 – 7.58 (m, 2H), 8.18 – 9.30 (m, 4H).

EXAMPLE 100 3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile Obtained as a white solid (48%) from 6-(6-methylpyridinyl)-N-[(3R)-piperidinyl] pyrazolo[1,5-a]pyridinylpyrimidinamine dichlorohydrate salt (Example 99b) following the experimental procedure as described in Preparation 6b. The crude was ed first by flash chromatography (dichloromethane to dichloromethane/methanol 85:15) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%).

LRMS (m/z): 453 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.68 – 2.30 (m, 4H), 2.65 (s, 3H), 3.06 – 3.93 (m, 5H), 4.03 – 4.55 (m, 2H), 4.81 – 5.04 (m, 1H), 6.48 – 6.69 (m, 1H), 6.80 – 7.02 (m, 1H), 7.28 – 7.44 (m, 2H), 8.29 (d, 1H), 8.47 – 8.82 (m, 3H), 9.23 (s, 1H).

EXAMPLE 101 2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol a) Tert-butyl -{[6-(2,6-dimethylpyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate ration 10c, 0.276 g, 0.64 mmol) following the experimental procedure as described in Example 20a. The crude product was purified by flash chromatography (gradient from dichloromethane to romethane/methanol 85:15) to yield the title compound as a white solid.

LRMS (m/z): 500 (M+1)+. b) 6-(2,6-Dimethylpyridinyl)-N-[(3R)-piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinamine ed as a solid dihydrochloride salt (52%) from utyl (3R){[6-(2,6- dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine carboxylate (Example 101a) following the experimental procedure described in Example 14b.

LRMS (m/z): 400 (M+1)+. c) 2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol Obtained as a white solid (55%) from 6-(2,6-dimethylpyridinyl)-N-[(3R)-piperidin- 3-yl]pyrazolo[1,5-a]pyridinylpyrimidinamine dihydrochloride salt (Example 101b) following the experimental procedure described in Preparation 7. The crude was ed first by flash chromatography (dichloromethane to dichloromethane/methanol 85:15) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%).

LRMS (m/z): 458 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.65 – 2.29 (m, 4H), 2.65 (s, 6H), 3.01 – 5.07 (m, 9H), 6.43 – 6.73 (m, 1H), 6.77 – 7.06 (m, 1H), 7.31 – 7.46 (m, 1H), 7.52 – 7.75 (m, 2H), 8.45 – 8.86 (m, 3H).

EXAMPLE 102 3-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile Obtained as a white solid (54%) from 6-(2,6-dimethylpyridinyl)-N-[(3R)-piperidin yl]pyrazolo[1,5-a]pyridinylpyrimidinamine dihydrochloride salt (Example 101b) following the experimental ure as described in Preparation 6b. The crude was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents 0% to 100%) and then by flash tography (chloroform to chloroform/methanol 95:5).

LRMS (m/z): 467 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.69 – 2.30 (m, 4H), 2.65 (s, 6H), 3.19 – 4.53 (m, 7H), 4.76 – 5.12 (m, 1H), 6.63 (d, 1H), 6.82 – 7.03 (m, 1H), 7.32 – 7.49 (m, 1H), 7.56 – 7.71 (m, 2H), 8.45 – 8.70 (m, 2H), 8.70 – 8.85 (m, 1H).

EXAMPLE 103 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile a) utyl (3R){[6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinecarboxylate To a solution of potassium tert-butoxide (0.523 g, 4.7 mmol) in dioxane (3 mL), ethylene glycol (2 mL) was added and the resulting solution was stirred at room temperature for 30 minutes. Then tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)amino]piperidinecarboxylate ration 10c, 0.400 g, 0.93 mmol) was added and the mixture was heated at 85 ºC ght. Excess ts were added and the mixture was heated at reflux until the starting material was consumed. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents 0% to 100%) to yield the title compound (0.324 g, 76%) as a yellowish oil.

LRMS (m/z): 455 (M+1)+. b) 2-({6-[(3R)-Piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin yl}oxy)ethanol Obtained as a solid ochloride salt (100%) from tert-butyl (3R){[6-(2- hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidine carboxylate (Example 103a) following the experimental procedure described in Example 14b.

LRMS (m/z): 355 (M+1)+. c) 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile Obtained as a pale solid (61%) from [(3R)-piperidinylamino]pyrazolo[1,5- a]pyridinylpyrimidinyl}oxy)ethanol dihydrochloride salt (Example 103b) following the mental procedure as bed in ation 6b. The crude was purified by flash chromatography (dichloromethane to dichloromethane/methanol 85:15).

LRMS (m/z): 422 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.67 – 2.23 (m, 4H), 2.91 – 4.18 (m, 10H), 4.36 – 4.92 (m, 3H), 5.62 (s, 1H), 6.77 – 6.99 (m, 1H), 7.28 – 7.44 (m, 1H), 8.41 – 8.57 (m, 2H), 8.57 – 8.68 (m, 1H).

EXAMPLE 104 -((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile A suspension of 2-({6-[(3R)-piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl}oxy)ethanol dihydrochloride salt (Example 103b, 0.292 g, 0.82 mmol), 5- chloropyrazinecarbonitrile (0.126 g, 0.91 mmol) and potassium carbonate (0.182 g, 1.32 mmol) in N,N-dimethylformamide (8 mL) was heated at 120 ºC for 1 hour under microwave irradiation. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under d pressure. The crude product was purified first by flash chromatography (100% hexane to 100% ethyl acetate) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrilemethanol as eluents 0% to 100%) to yield the title compound (0.068 g, 18%) as a solid.

LRMS (m/z): 458 (M+1)+. 1H-NMR (400 MHz, CDCl 3): δ 1.65 – 2.30 (m, 4H), 3.10 – 3.52 (m, 3H), 3.87 – 4.15 (m, 4H), 4.44 – 4.68 (m, 3H), 4.78 (s, 1H), 5.60 (s, 1H), 6.77 – 6.96 (m, 1H), 7.19 – 7.25 (m, 1H), 8.11 – 8.21 (m, 1H), 8.34 (d, 1H), 8.40 – 8.48 (m, 1H), 8.48 – 8.56 (m, 1H), 8.64 (s, 1H).

EXAMPLE 105 -(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin midinyl)pyridinol a) Tert-butyl (3R){[6-(5-hydroxypyridinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinecarboxylate Obtained from tert-butyl (3R)[(6-chloropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate (Preparation 10c, 0.400 g, 0.93 mmol) following the experimental procedure as described in Example 20a. The crude product was used without further purification in the next step.

LRMS (m/z): 488 (M+1)+. b) 5-{6-[(3R)-Piperidinylamino]pyrazolo[1,5-a]pyridinylpyrimidin yl}pyridinol Obtained as a solid dihydrochloride salt from tert-butyl (3R){[6-(5-hydroxypyridin yl)pyrazolo[1,5-a]pyridinylpyrimidinyl]amino}piperidinecarboxylate (crude product obtained in Example 105a) following the experimental procedure described in Example 14b.

LRMS (m/z): 388 (M+1)+. c) 5-(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)pyridinol Obtained as a white solid (0.031 g, 27%) from 5-{6-[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinol dihydrochloride salt (Example 105b) following the mental procedure described in Preparation 7. The crude was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 itrile-methanol as s 0% to 100%) and then by ative HPLC (gradient from water to ol).

LRMS (m/z): 446 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ 1.45 – 2.15 (m, 4H), 2.60 – 3.21 (m, 3H), 3.49 – 4.81 (m, 6H), 6.76 (s, 1H), 7.04 (s, 1H), 7.33 – 7.62 (m, 2H), 7.82 (s, 1H), 8.14 – 8.35 (m, 1H), 8.49 – 8.94 (m, 3H), 10.19 (s, 1H).

EXAMPLE 106 3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile Obtained as a pale solid (0.030 g, 26%) from 5-{6-[(3R)-piperidinylamino] pyrazolo[1,5-a]pyridinylpyrimidinyl}pyridinol dihydrochloride salt (Example 105b) following the experimental procedure as described in Preparation 6b. The crude was purified by preparative HPLC (gradient from water to methanol).

LRMS (m/z): 455 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ 1.38 – 1.83 (m, 4H), 2.59 – 3.19 (m, 5H), 3.45 – 4.43 (m, 4H), 6.66 – 6.94 (m, 1H), 6.95 – 7.19 (m, 1H), 7.31 – 7.68 (m, 2H), 7.82 (s, 1H), 8.23 (s, 1H), 8.45 – 8.94 (m, 3H), 10.19 (s, 1H).

EXAMPLE 107 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)(methyl)amino]piperidinyl}oxoethanol PHARMACOLOGICAL ACTIVITY In vitro JAK kinase Assays Compounds were ed for their ability to inhibit JAK1, JAK2 and JAK3 using the assays as indicated below.

The catalytic domains of human JAK1 (aa 54), JAK2 (aa 826-1132), JAK3 (aa 795-1124) and Tyk2 (aa 871-1187) were expressed as inal GST-fusion proteins using a baculovirus expression system and were purchased from Carna Biosciences.

The enzymatic activity was d using as substrate a biotinylated peptide, poly (GT)-Biotin (CisBio). The e concentration in the reactions was 60 nM for JAK1, 20 nM for JAK2, 140 nM for JAK3 and 50 nM for Tyk2. The degree of phosphorylation was detected by TR-FRET (time-resolved fluorescence energy transfer).

IC50s of compounds were measured for each kinase in a reaction mixture containing the enzyme, ATP and the peptide in 8 mM MOPS (pH 7.0), 10 mM MgCl2, 0.05% βmercaptoethanol , 0.45 mg/ml BSA. The ATP concentration in the reactions was 3 µM for JAK1, 0.2 µM for JAK2, 0.6 µM for JAK3 and 1.8 µM for Tyk2. The enzymatic reactions took place for 30 minutes at room temperature. Then, the reactions were d with 20 µL of quench detection buffer (50 mM HEPES, 0.5 M KF, EDTA 0.25 M, 0.1% (w/v) BSA, pH 7.5) ning 0.115 µg/mL of anti-phosphoTyr (PT66)- Cryptate (CisBio) and a variable concentration of SA-XL665 (CisBio) to keep the SA-B ratio constant. Incubate for 3 h and read on Victor 2V spectrofluorometer (PerkinElmer) set to read fluorescence resonance energy transfer.

Some of the acronyms used above have the following meaning: AA: aminoacids GST: glutathione-S-transferase MOPS: 3-(N-morpholino)propane sulfonic acid BSA: bovine serum n ATP: adenosine tri-phosphate EDTA: nediaminetetraacetic acid HEPES: 4-(2-hydroxyethyl)piperazineethanesulfonic acid SA-XL665: Streptavidin (biotin-binding tetrameric protein isolated from Streptomyces avidinii) XL665 Table 1 depicts IC50 values for certain exemplary compounds described herein.

Table 1 Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1 (nM) (nM) (nM) 1 3 0.5 12 2 4 1 82 3 4 0.8 150 4 4 1 220 2 0.5 9 6 3 0.7 15 7 2 0.5 10 8 10 0.7 16 9 3 0.7 85 0.7 0.5 32 11 3 1 40 12 4 0.5 4 13 4 1 4 14 1 0.5 1 2 1 13 16 1 0.7 4 e No. IC50 JAK3 IC50 JAK2 IC50 JAK1 (nM) (nM) (nM) 17 1 0.6 2 18 2 0.6 1 19 2 0.3 2 1 0.5 1 21 11 1 6 22 4 0.7 7 23 5 1 8 24 6 1 17 2 0.6 22 26 30 4 26 27 3 0.7 19 28 3 0.8 5 29 10 4 27 2 0.6 4 31 2 0.4 1 32 4 0.6 2 33 2 0.6 6 34 4 0.2 2 2 2 7 36 2 0.5 2 37 7 1 2 38 6 2 4 39 3 0.8 11 40 2 0.8 4 41 3 1 8 42 1 1 13 43 1 0.7 4 44 140 74 970 45 3 1 4 46 4 3 10 47 12 4 10 48 5 2 13 49 14 10 35 e No. IC50 JAK3 IC50 JAK2 IC50 JAK1 (nM) (nM) (nM) 50 9 3 15 51 3 2 36 52 11 1 11 53 3 0.5 2 54 2 2 7 55 33 12 170 56 8 7 43 57 2 2 19 58 7 2 66 59 4 3 29 60 16 7 110 61 8 10 58 62 7 1 4 63 9 3 127 64 4 3 28 65 9 2 38 66 4 0.3 10 67 23 5 139 68 6 1 48 69 11 3 37 70 8 3 28 71 26 2 35 72 6 1 6 73 27 2 13 74 4 1 3 75 26 4 29 76 5 1 9 77 23 2 3 e No. IC50 JAK3 IC50 JAK2 IC50 JAK1 (nM) (nM) (nM) 78 1 0.5 2 79 6 1 2 80 4 1 2 81 2 1 3 82 8 2 9 83 4 2 32 84 5 1 2 85 4 1 1 86 1 3 1 87 3 1 10 88 4 1 14 89 3 1 5 90 4 1 14 91 5 2 114 92 4 1 12 93 6 3 23 94 7 1 7 95 7 3 3 96 2 1 6 97 1 1 2 98 5 2 3 99 7 9 2 100 2 2 0.5 101 1 1 2 102 5 2 1 Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1 (nM) (nM) (nM) 103 1 1 1 104 1 3 4 105 5 5 2 106 1 1 1 It can be seen from Table 1 that the compounds of formula (I) are potent inhibitors of JAK1, JAK2 and JAK3 kinases. red compounds of the invention possess an IC50 value for the inhibition of JAK1, JAK2 and JAK3 kinases (determined as defined above) of less than 1 µM (1000 nM), preferably of less than 0.5 µM (500 nM), more preferably of less than 0.2 µM (200 nM) for each Janus Kinase.

The compounds of this invention have been shown to display an improved profile in the Ames genotoxicity screen.

The invention is also directed to a nd of the invention as bed herein for use in the treatment of the human or animal body by therapy. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by s such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

COMBINATIONS The 2-(pyrazolopyridinyl)pyrimidine derivatives of the present invention may also be combined with other active compounds in the treatment of a pathological condition or e susceptible to amelioration by inhibition of Janus Kinases.

The combinations described can optionally se one or more additional active substances which are known to be useful in the treatment of dermatological diseases, a respiratory diseases, allergic diseases, inflammatory or mune-mediated es, function disorders, neurological disorders, cardiovascular diseases, viral infections, lism/endocrine function disorders, neurological disorders, pain, bone marrow and organ transplant rejections, myelo-dysplastic syndromes, myeloproliferative disorder (MPDs), cancer, hematologic malignancies, leukemia, lymphoma and solid tumors; more in particular n the pathological ion or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell oma, squamous cell carcinoma, c keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive ary disease (COPD), cystic fibrosis, iectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca, such as a) Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone nate, hydrocortisone, methylprednisolone, sone furoate, prednicarbate, prednisolone or prednisone; b) ofolate reductase inhibitors, such as methotrexate or pralatrexate; c) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS186323; d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; e) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; f) Calcineurin inhibitors, such as cyclosporine A, imus, pimecrolimus or voclosporin; g) e-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, rin or mizoribine; h) c acid , such as dimethyl fumarate; i) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; j) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; k) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal dies, such as infliximab, adalimumab, certolizumab pegol or golimumab; l) Soluble Tumor necrosis -alpha (TNF-alpha) receptors such as etanercept or CC-11050; m) Anti-Interleukin 6 Receptor ) antibody, such as zumab, sarilumab, SA-237 or ALX-0061; n) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) antibody, such as ustekinumab; o) nterleukin 17 Receptor (IL-17R) antibody, such as umab; p) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, uzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; q) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab; r) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab; s) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; t) Anti-Interleukin 4 or ) / Interleukin 13 or (IL-13R) antibody, such as dupilumab; u) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab; v) Anti-Interleukin 1 Receptor (IL-1R) antibody w) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab; x) -cell activating factor (BAFF), such as belimumab or atacicept; y) Anti-CD19 (B lymphocyte protein) onal antibody, such as blinatumomab, MEDI-551 or MOR-208; z) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or ; aa) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; bb) Dihydropteroate synthase tors, such as dapsone or sulfadoxine; cc) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine, desloratadine, hazine, mizolastine or cetirizine; dd) nyl riene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast, masilukast; ee) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipripant; ff) Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.

The compounds of formula (I) and the combinations described may be used in the treatment of dermatological diseases, a respiratory es, ic diseases, inflammatory or autoimmune-mediated diseases, function disorders, neurological disorders, cardiovascular diseases, viral infections, metabolism/endocrine function disorders, neurological disorders, pain, bone marrow and organ transplant rejections, myelo-dysplastic syndromes, myeloproliferative disorder (MPDs), cancer, logic malignancies, ia, lymphoma and solid tumors; more in particular wherein the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, ma gangrenosum, lichen planus, ring diseases ing but not limited to pemphigus vulgaris, bullous goid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus matosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic is, inflammatory bowel e, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic ctivitis and keratoconjuntivitis sicca; ably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo.

In a preferred embodiment the compounds of formula (I) and the combinations bed may be used in the treatment of dermatological diseases.

The active compounds in the combination product may be administered together in the same pharmaceutical ition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

It is plated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered together at the same time.

Preferably, at least two, and more preferably all actives would be administered as an admixture.

Also described is a combination product of the 2-(pyrazolopyridinyl)pyrimidine tives of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease tible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is ed from atopic dermatitis, psoriasis, contact itis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell oma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases ing but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune tic anemia, type I diabetes, , chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic is, inflammatory bowel disease, ulcerative colitis, Crohn’s e, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic itis, psoriasis, chronic hand , cutaneous lupus, alopecia areata and vitiligo.

The invention also encompasses the use of a combination of the compounds of the invention er with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases.

Also described is a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, ous vasculitits, dermatomyositis, cutaneous T-cell ma, Sézary syndrome, ma nosum, lichen planus, blistering diseases including but not limited to gus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, mas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic , type I diabetes, asthma, chronic obstructive pulmonary disease , cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo, comprising administering a therapeutically effective amount of a combination of the 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention together with one or more other therapeutic agents.

The active compounds in the combinations described may be administered by any suitable route, depending on the nature of the er to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, lled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, s, nasal sprays or aerosols, etc) or by injection (subcutaneous, intradermic, intramuscular, enous, etc).

The active compounds in the combination, i.e. the 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different itions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

One execution described consists of a kit of parts comprising a 2-(pyrazolopyridin yl)pyrimidine derivative of the invention together with instructions for aneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, cutaneous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, ring es ing but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, ic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and Another ion described consists of a package comprising a azolopyridin yl)pyrimidine tive of the invention and another active compound useful in the treatment of atopic dermatitis, psoriasis, t dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, c keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, omyositis, ous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases including but not d to gus vulgaris, bullous pemphigoid and epidermolysis a, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosis, autoimmune hemolytic , type I diabetes, asthma, chronic obstructive ary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, tive colitis, Crohn’s e, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo.

PHARMACEUTICAL COMPOSITIONS Pharmaceutical compositions ing to the present invention comprise the 2- (pyrazolopyridinyl)pyrimidine derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier.

As used herein, the term pharmaceutical composition refers to a mixture of one or more of the 2-(pyrazolopyridinyl)pyrimidine derivatives described herein, or physiologically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers, deuterated derivatives thereof or prodrugs thereof, with other chemical ents, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a ceutical ition is to facilitate administration of a compound to an organism.

As used herein, a physiologically/pharmaceutically able diluent or r refers to a r or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

Further described are pharmaceutical compositions comprising the 2-(pyrazolopyridin- 3-yl)pyrimidine derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), such as the ones previously described.

The invention is also directed to pharmaceutical compositions of the ion for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular atopic dermatitis, psoriasis, t itis, eczema, c hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous itits, dermatomyositis, cutaneous T-cell lymphoma, Sézary me, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis a, leukemia, mas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, ic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; preferably in the treatment of atopic dermatitis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo.

Also described is the use of a pharmaceutical ition of the invention for the manufacture of a medicament for treating these diseases.

Also described is a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia , cutaneous lupus erythematosus, cutaneous vasculitits, dermatomyositis, ous T-cell lymphoma, Sézary me, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sis, amyotrophic lateral sclerosis, systemic lupus erythematosis, mune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic ary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel e, ulcerative colitis, Crohn’s disease, dry eye, uveitis, allergic conjunctivitis and keratoconjuntivitis sicca; ably in the treatment of atopic dermatitis, sis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo, comprising administering a therapeutically ive amount of a pharmaceutical composition of the invention.

The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a 2-(pyrazolopyridinyl)pyrimidine derivative which is a compound of formula (I) or a ceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or ated derivative f in ation with a pharmaceutically acceptable excipient such as a carrier or diluent. Preferably the compositions are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration. The compounds of the present invention show physicochemical properties (such as solubility water and in a range of ilic and hydrophilic solvents, melting point and stability), which make them specially suitable for topical administration.

In a preferred embodiment, the compositions are made up in a form suitable for topical administration.

Pharmaceutical compositions suitable for the ry of 2-(pyrazolopyridin yl)pyrimidine derivatives of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001. i) l stration The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, s, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Other means of topical administration e delivery by oporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection. ations for topical administration may be formulated to be immediate and/or modified release. Modified e formulations e delayed-, sustained-, pulsed-, controlled-, targeted and programmed e. ii) Oral Administration The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (GI) tract.

Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as es, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art. The active ingredient may also be presented as a bolus, electuary or paste. iii) Oral mucosal administration The 2-(pyrazolopyridinyl)pyrimidine tives of the invention can also be administered via the oral l. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.

Pharmaceutical products to be administered via the oral l can be designed using hesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers and/or oral mucosal permeation ers. iv) Inhaled administration The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention can also be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an l spray from a pressurized container, pump, spray, er (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or t the use of a suitable lant. v) Nasal mucosal administration The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may also be administered via the nasal mucosal.

Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert e such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents. vi) Parenteral Administration The 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may also be administered directly into the blood stream, into , or into an internal organ.

Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, ranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including eedle) injectors, needle-free injectors and infusion ques.

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 eous 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 lyophilization, may y be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate ation techniques, such as the incorporation of solubility-enhancing agents. vii) /lntravaginal Administration 2-(pyrazolopyridinyl)pyrimidine derivatives 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 atives may be used as appropriate. Formulations for /vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, ned-, -, controlled-, targeted and programmed release. viii) Ocular Administration 2-(pyrazolopyridinyl)pyrimidine derivatives of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include nts, biodegradable {e.g. able gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. Such formulations may also be delivered by iontophoresis.

Formulations for /aural stration may be ated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

The amount of the active 2-(pyrazolopyridinyl)pyrimidine derivative administered will be dependent on the subject being d, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01- 3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.

Preferably, the the pharmaceutical compositions of the invention are made up in a form suitable for oral or topical administration, being ularly preferred topical administration.

The amount of each active which is ed to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular er or disease being treated.

The following preparations forms are cited as formulation es: Formulation Examples Formulation Example 1 (Oral suspension) Ingredient Amount Active Compound 3 mg Citric acid 0,5 g Sodium chloride 2,0 g Methyl paraben 0,1 g Granulated sugar 25 g Sorbitol (70% solution) 11 g Veegum K 1,0 g Flavoring 0,02 g Dye 0,5 mg Distilled water q.s. to 100 mL Formulation Example 2 (Hard gelatine capsule for oral administration) Ingredient Amount Active Compound 1 mg Lactose 150 mg Magnesium stearate 3 mg Formulation e 3 (O/W emulsion) Ingredient Amount Active compound 1% Cetyl alcohol 3% Stearyl alcohol 4% yl monostearate 4% Sorbitan monostearate 0.8% Sorbitan monostearate POE 0.8% Liquid vaseline 5% Methylparaben 0.18% Propylparaben 0.02% Glycerine 15% Purified water csp. 100% ation Example 4 (O/W emulsion) Ingredient Amount Active compound 1% ic/Carpic ceride 5% Cetyl alcohol 7% Gliceryl monostearate 3.5% Sorbitan monostearate 0.8% Sorbitan monostearate POE 0.7% White petrolatum 10% Stearoxytrimethysilane 5% EDTA 0.1% Methylparaben 0.18% Propylparaben 0.02% Glycerine 20% Purified water csp. 100% Formulation Example 5 (O/W emulsion) Ingredient Amount Active compound 1% Octyldodecanol 5% Cetyl alcohol 4% Gliceryl monostearate 6% Ceteareth-12 1.5% Ceteareth-20 1.5% an monostearate POE 0.7% White petrolatum 3% Dimethicole 1.5% Benzyl alcohol 2% Glycerine 20% Propilenglycol 10% Purified water csp. 100% Modifications, which do not affect, alter, change or modify the essential aspects of the 2-(pyrazolopyridinyl)pyrimidine derivatives, combinations or pharmaceutical compositions described, are ed within the scope of the present invention. 142 142 The following numbered paragraphs define particular aspects of the present invention: 1. A 2-(pyrazolopyridinyl)pyrimidine derivative for use in the treatment of the human or animal body, which 2-(pyrazolopyridinyl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or ated derivative thereof: Formula (I) wherein • X represents –O- or –NR3- group, • R1 and R2 are independently ed from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or branched C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine group; • G1 is selected from the group consisting of –CN group, -CO-Ra group, a –O-R6 group, a -(CHR7)m-NR’R’’ group, a phenyl group, a clic C5-7 cycloalkyl group, a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom ed from O, S and N and a monocyclic 5- to 6- membered cyclyl group containing at least one heteroatom selected from O, S and N, wherein the phenyl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a - (CH2)0-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra represents a en atom, a yl group, a linear or branched C1-3 alkyl group, a linear or ed C1-3 alkoxy group or an amino group, • Q is selected from the group consisting of: wherein o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - CO(CH2)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6- membered heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, wherein the heterocyclyl and heteroaryl group independently are unsubstituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 yalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 represents a phenyl group, a pyrimidine group or a pyridine group, wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents selected from a n atom, a linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or ed (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or branched C1-6 alkyl group wherein said linear or ed C1-6 alkyl group is unsubstituted or substituted with one or more substituents ed from a halogen atom, a hydroxyl group and –NR’R” group, • R7 represents a hydrogen atom, a hydroxyl or a C1-2 alkyl group, • R’ and R’’ independently represents a hydrogen atom, a linear or ed C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m independently has a value from 0 to 3, wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a] nylpyrimidinyl)amino]piperidinyl}oxopropanenitrile • 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxetanyl)acetonitrile • Ethyl -[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate • 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxoethanol • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile or • 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile. 2. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 1 wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • )[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • 3-[(3R)({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a] pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a] pyridinyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile • (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl) pyrimidinyl)amino)piperidinyl)oxopropanenitrile 3. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraphs 1 or 2 wherein R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, preferably a fluorine atom, a hydrogen atom or a methyl group. 4. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any one of the ing paragraphs wherein R2 represents a hydrogen atom or a ne atom, preferably a en atom.

. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any preceding paragraph wherein X represents a –O- or –NR3- group. 6. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 5 wherein R3 represents a hydrogen atom. 7. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any preceding paragraph wherein Q represents Qa. 8. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraph 7 n R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; preferably R4 represents a –C(O)CH2OH group or a -C(O)CH2CN group. 9. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any preceding paragraph wherein G1 ents a –O-R6 group, a CN group or a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N and being unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or ed C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy group.

. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 9 wherein R6 represents a linear or branched (C1-6 )-(C1-6 alkyl) group or a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group. 11. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraph 1 wherein • R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, preferably a fluorine atom, a hydrogen atom or a methyl group; • R2 represents a hydrogen atom or a fluorine atom, preferably a hydrogen atom; • X represents a –O- or –NR3- group; • R3 ents a hydrogen atom; • Q represents Qa; • R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; preferably R4 ents a –C(O)CH2OH group or a -C(O)CH2CN group; • G1 represents a –O-R6 group, a CN group or a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from O, S and N and being unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-4 alkyl group, a linear or branched C1-2 hydroxyalkyl group or a linear or branched C1-4 alkoxy group; and • R6 represents a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group or a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more tuents selected from a halogen atom and a hydroxyl group. 12. A 2-(pyrazolopyridinyl)pyrimidine derivative for use ing to paragraph 1 wherein • X represents –O- or –NR3- group, • R1 and R2 are independently ed from the group consisting of a en atom, a fluorine atom and a methyl group; • R3 is selected from the group consisting of a hydrogen atom and a methyl group; • G1 is ed from the group consisting of –CN group, a –CONH2 group, a - CO2Et group, a –CO2iPr group, a –O-R6 group, a –NHCH2CH2OH group, a phenyl group, a pyridinyl group, a pyrazolyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, wherein the phenyl, pyridinyl, pyrazolyl, piperidinyl, piperazinyl and morpholinyl groups are unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a methyl group, a - CH2OH group, a –CH2-C(OH)(CH3)2 group, a methoxy group, an amino group, a )2 group, a –COOH group and a –CO2Et group; • R4 is selected from the group consisting of a -CO(CH2)-OH group; 2)- CN group, a pyrazinyl group and a pyrimidinyl group, wherein the pyrazinyl and pyrimidinyl groups independently are unsubstituted or substituted with a CN group or a –-CH2OH group; • R5 represents a N group; • G2 represents a pyrimidine group or a pyridine group, wherein the pyrimidine and pyridine groups are tituted or substituted by a fluorine atom; and • R6 is selected from the group consisting of a hydrogen atom, a -CH2CO2CH2Ph group, a –(CH2)2OCH3 group, a –(CH2)2OCH2CH3 group, a 3)CH2OCH3 group, a methyl group, an ethyl group, a butyl group, a –CH2CF3 group, a – CH2CHF2 group, a CH(CH3)2 group, a –(CH2)2OH group, a –(CH2)2-3N(CH3)2 group, a -CH(CH3)-CH2OH group, a –CH2CH(OH)CH2OH group. 13. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to paragraph 1 which is one of (Trans{[5-fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}cyclohexyl)acetonitrile; (Trans{[6-(4-aminopiperidinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}cyclohexyl)acetonitrile; {Trans[(5-fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]cyclohexyl}acetonitrile; [Trans({6-[4-(dimethylamino)piperidinyl]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; (Trans{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}cyclohexyl)acetonitrile; {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; {Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; [Trans({5-fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl}amino)cyclohexyl]acetonitrile; [trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; [Trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; 6-(4-Aminopiperidinyl)fluoro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazolo [1,5-a]pyridinylpyrimidinamine; 2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]etanol; (2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propane-1,2-diol; 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxopropanenitrile; 3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; )({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitril; 3-((3R){[6-(6-Aminopyridinyl)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-((3R){[5-fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile; 3-((3R){[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-{(3R)[[5-fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl](methyl)amino]piperidinyl}oxopropanenitrile; 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinol; 2-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; )({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 2-((3R){[5-fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-Methylmorpholinylpyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}oxoethanol; 2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; Ethyl 1-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)methylpiperidinecarboxylate; 2-((3R){[5-Fluoro(5-methylpyrazolo[1,5-a]pyridinyl)morpholin ylpyrimidinyl]amino}piperidinyl)oxoethanol; Ethyl 1-(6-{[(3R)(cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5- a]pyridinylpyrimidinyl)piperidinecarboxylate; 1-(6-{[(3R)(Cyanoacetyl)piperidinyl]amino}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)piperidinecarboxylic acid; 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(1H-pyrazolyl)pyrimidin yl]amino}piperidinyl)oxoethanol; 1-[4-(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)-1H-pyrazolyl]methylpropanol; 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(6-methoxypyridinyl)pyrazolo[1,5-a]pyridin midinyl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(6-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; Ethyl 5-(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)pyridinecarboxylate; 2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino] piperidinyl}oxoethanol; ro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinol; Benzyl [(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]acetate; )[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; Ethyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarboxylate; -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarbonitrile; -Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinecarboxamide; 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin ]piperidinyl}oxoethanol; 3-{(3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile; 5-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; (5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}pyrazinyl)methanol; -{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinecarbonitrile; 2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrimidinecarbonitrile; 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin ]piperidinyl}oxoethanol; 3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxopropanenitrile; 2-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(4-methylpiperazinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile; 2-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxoethanol; 3-[(3R)({5-Fluoro[(2-hydroxyethyl)amino]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile; 2-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- xy}piperidinyl)oxopropanenitrile; 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxopropanenitrile; 2-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}oxy)piperidinyl]oxoethanol; 1-(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin midinyl)piperidinol; ){[5-Fluoro(4-hydroxypiperidinyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]oxy}piperidinyl)oxopropanenitrile; 2-{(3R)[[5-Fluoro(2-methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl](methyl)amino]piperidinyl}oxoethanol; 3-[(3R)({5-Fluoro[2-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile; -(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)pyridinecarboxylic acid; 2-{(3R)[(5-Fluoropyrazolo[1,5-a]pyridinylpyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-[(3R)({6-[6-(Dimethylamino)pyridinyl]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 2-{(3R)[(5-Fluoro-2'-methylpyrazolo[1,5-a]pyridinyl-4,5'-bipyrimidin yl)amino]piperidinyl}oxoethanol; 2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 3-[(3R)({5-Fluoro[6-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile; 2-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2,6-Dimethylpyridinyl)fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile; 2-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxoethanol; 3-[(3R)({5-Fluoro[5-(hydroxymethyl)pyridinyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; )({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile; Isopropyl 5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinecarboxylate; )[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin yl}oxoethanol; 3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin yl}oxopropanenitrile; 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Methoxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxoethanol; 2-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(6-Methylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2,6-Dimethylpyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; -((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; -(6-{[(3R)Glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin yl)pyridinol; 3-((3R){[6-(5-Hydroxypyridinyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)(methyl)amino]piperidinyl}oxoethanol; or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated tive f. 14. A 2-(pyrazolopyridinyl)pyrimidine derivative as d in any one of paragraphs 1 to 13, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases.

. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to any one of paragraphs 1 to 14, wherein the treatment is of a pathological condition or disease selected from atopic dermatitis, psoriasis, contact dermatitis, eczema, chronic hand eczema, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma, vitiligo, alopecia areata, cutaneous lupus erythematosus, cutaneous vasculitits, omyositis, ous T-cell lymphoma, Sézary syndrome, pyoderma gangrenosum, lichen planus, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, ia, lymphomas and solid tumors, rheumatoid arthritis, multiple sis, amyotrophic lateral sclerosis, ic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, thic pulmonary fibrosis, sarcoidosis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, dry eye, uveitis, ic conjunctivitis and keratoconjuntivitis sicca; preferably from atopic dermatitis, psoriasis, chronic hand eczema, ous lupus, alopecia areata and vitiligo. 16. A pharmaceutical composition comprising a 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of paragraphs 1 to 13 in association with a pharmaceutically acceptable diluent or carrier. 17. Use of a 2-(pyrazolopyridinyl)pyrimidine tive as defined in any one of paragraphs 1 to 13, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in aph 14 or 15. 18. A method for treating a subject afflicted with a ogical condition or disease as defined in paragraph 14 or 15, which comprises administering to said subject a therapeutically effective amount of a 2-(pyrazolopyridinyl)pyrimidine derivative as d in any one of paragraphs 1 to 13, or a ceutical composition as defined in aph 16. 19. A combination t sing (i) at least one 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of paragraphs 1 to 13, and (ii) one or more active ingredients selected from: gg) Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, nide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, sone furoate, prednicarbate, prednisolone or prednisone; hh) Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate; ii) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS186323; jj) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine; kk) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine; ll) Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; mm) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as enolate mophetyl, ribavirin or mizoribine; nn) Fumaric acid esters, such as dimethyl fumarate; oo) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol; pp) Retinoids, such as tazarotene, alitretinoin, acitretin or isotretinoin; qq) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) onal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab; rr) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC-11050; ss) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061; tt) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor R) antibody, such as numab; uu) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab; vv) Anti-CD20 (B lymphocyte protein) antibody, such as mab, ofatumumab, uzumab, ocrelizumab, ublituximab, veltuzumab, ocaratuzumab; ww) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab; xx) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab; yy) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab; zz) Anti-Interleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab; aaa) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, umab or bimekizumab; bbb) Anti-Interleukin 1 or (IL-1R) antibody ccc) Anti-Inmunoglobuline E (IgE) antibody, such as omalizumab or umab; ddd) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept; eee) Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI-551 or MOR-208; fff) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or ; ggg) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant; hhh) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine; iii) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine; jjj) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, ukast, tipelukast, kast; kkk) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or ipant; lll) Topical anti-septics, such as triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths.

. A 2-(pyrazolopyridinyl)pyrimidine tive, which 2-(pyrazolopyridin yl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or ated derivative thereof: Formula (I) wherein • X represents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or ed C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a –(CH2)1pyrrolidine group; • G1 is selected from the group consisting of –CN group, -CO-Ra group, a –O-R6 group, a -(CHR7)m-NR’R’’ group, a phenyl group, a monocyclic C5-7 cycloalkyl group, a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 6- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the phenyl, cycloalkyl, heteroaryl and cyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a yl group, a linear or branched C1-4 alkyl group, a linear or branched C1hydroxyalkyl group, a linear or branched C1-4 alkoxy group, a - (CH2)0-2NR’R’’ group, -(CH2)0-2CN group and -CO-Ra group, wherein Ra represents a en atom, a yl group, a linear or branched C1-3 alkyl group, a linear or branched C1-3 alkoxy group or an amino group, • Q is selected from the group consisting of: wherein o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - )1CF3 group, a cyanothiazole group, a monocyclic 4- to 6- ed heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 6- membered heteroaryl group containing at least one atom selected from O, S and N, wherein the heterocyclyl and heteroaryl group independently are unsubstituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 hydroxyalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 represents a phenyl group, a pyrimidine group or a pyridine group, wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents ed from a n atom, a linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group and –NR’R” group, • R7 represents a hydrogen atom, a yl or a C1-2 alkyl group, • R’ and R’’ independently represents a hydrogen atom, a linear or ed C1-3 alkyl group, a linear or ed C1-3 hydroxyalkyl group, a linear or branched C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m independently has a value from 0 to 3, wherein the 2-(pyrazolopyridinyl)pyrimidine derivative is not: • 3-{(3R)[[2-(Dimethylamino)ethyl](5-fluoromorpholinylpyrazolo[1,5-a] nylpyrimidinyl)amino]piperidinyl}oxopropanenitrile • 3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • (3-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl) amino]piperidinyl}oxetanyl)acetonitrile • Ethyl (3R)[(5-fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinecarboxylate • 2-{(3R)[(5-Fluoromorpholinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxoethanol • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)piperidinyl]pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-[(3R)({5-Fluoro[4-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(4-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoropiperazinylpyrazolo[1,5-a]pyridinylpyrimidinyl) amino]piperidinyl}oxopropanenitrile • )({6-[4-(Hydroxymethyl)phenyl]methylpyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[6-(4-Formylphenyl)methylpyrazolo[1,5-a]pyridinylpyrimidin- 4-yl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[2-fluoro(hydroxymethyl)phenyl]pyrazolo[1,5-a] pyridinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(2-fluoroformylphenyl)pyrazolo[1,5-a]pyridin ylpyrimidinyl]amino}piperidinyl)oxopropanenitrile • 3-[(3R)({5-Fluoro[3-(hydroxymethyl)phenyl]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]oxopropanenitrile • 3-((3R){[5-Fluoro(3-formylphenyl)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile • 3-{(3R)[(5-Fluoro{3-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • 3-{(3R)[(5-Fluoro{4-hydroxy[(methylamino)methyl]phenyl} pyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidinyl} oxopropanenitrile • (R)(3-((5-Fluoro(3-hydroxy(hydroxymethyl)phenyl)(pyrazolo[1,5-a] nyl)pyrimidinyl)amino)piperidinyl)oxopropanenitrile • (R)(3-((5-Fluoro(4-formylhydroxyphenyl)(pyrazolo[1,5-a]pyridinyl) dinyl)amino)piperidinyl)oxopropanenitrile 21. A 2-(pyrazolopyridinyl)pyrimidine derivative according to paragraph 20, which 2- (pyrazolopyridinyl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or e, or stereoisomer or deuterated derivative thereof, as defined in any one of paragraphs 3 to 13.

Claims (26)

Claims

1. A 2-(pyrazolopyridinyl)pyrimidine derivative, which 2-(pyrazolopyridin yl)pyrimidine derivative is a compound of formula (I), or a pharmaceutically able 5 salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: Formula (I) wherein 10 • X represents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a hydrogen atom, a halogen atom, a linear or branched C1-4 alkyl, a linear or ed C1-4 alkoxy group and -CN group; • R3 is selected from the group consisting of a hydrogen atom, a linear or 15 branched C1-4 alkyl group, a -(CH2)1-3NR’R’’ group and a 1pyrrolidine group; • G1 is a –O-R6 group, • Q is selected from the group consisting of: 20 n o R4 is selected from the group consisting of a linear or branched C1-4 alkyl group, -CO-R’ group, -CO(CH2)1OH group; -CO(CH2)1CN group, - CO(CH2)1CF3 group, a cyanothiazole group, a monocyclic 4- to 6- membered heterocyclyl group containing at least one heteroatom 25 selected from O, S and N and a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from O, S and N, n the heterocyclyl and heteroaryl group independently are unsubstituted or substituted with one or more substituents selected from –(CH2)m-CN group and a C1-2 hydroxyalkyl group, o R5 represents a –(CH2)m-CN group or a –(CH2)m-OH group; o G2 represents a phenyl group, a pyrimidine group or a pyridine group, 5 wherein the phenyl, pyrimidine and pyridine groups are unsubstituted or substituted by one or more substituents selected from a n atom, a linear or branched C1-4 alkyl group, a hydroxyl group, a –CN group, • R6 is selected from the group consisting of a hydrogen atom, -(CH2)(1-2)-CO-O- R”’ group, a linear or branched (C1-6 alkoxy)-(C1-6 alkyl) group and a linear or 10 branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group and –NR’R” group, • R’ and R’’ independently represents a hydrogen atom, a linear or branched C1-3 alkyl group, a linear or branched C1-3 hydroxyalkyl group, a linear or branched 15 C1-3 alkoxy group, • R”’ represents a C1-2 alkyl group or a benzyl group, and • m independently has a value from 0 to 3.

2. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 wherein R1 20 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group,

3. A azolopyridinyl)pyrimidine derivative according to claim 2, wherein R1 ents a fluorine atom, a hydrogen atom or a methyl group. 25

4. A 2-(pyrazolopyridinyl)pyrimidine derivative according to any one of the preceding claims wherein R2 represents a hydrogen atom or a fluorine atom,

5. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 4, wherein R2 represents a hydrogen atom.

6. A 2-(pyrazolopyridinyl)pyrimidine derivative according to any one of the preceding claims wherein X represents a –O- or –NR3- group.

7. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 6 n R3 35 represents a hydrogen atom.

8. A 2-(pyrazolopyridinyl)pyrimidine derivative according to any one of the preceding claims wherein Q represents Qa.

9. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 8 wherein R4 5 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group

10. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 9, n R4 represents a –C(O)-CH2OH group or a –C(O)CH2CN group. 10

11. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 wherein • R1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, • R2 represents a hydrogen atom or a fluorine atom ; • X represents a –O- or –NR3- group; 15 • R3 ents a hydrogen atom; • Q represents Qa; • R4 represents a -CO(CH2)1OH group or a -CO(CH2)1CN group; • G1 represents a –O-R6 group; and • R6 represents a linear or branched (C1-6 )-(C1-6 alkyl) group or a linear or 20 branched C1-6 alkyl group wherein said linear or branched C1-6 alkyl group is unsubstituted or substituted with one or more substituents ed from a halogen atom and a hydroxyl group.

12. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 11, wherein 25 • R1 represents a fluorine atom, a hydrogen atom or a methyl group. • R2 represents a hydrogen atom • R4 represents a –C(O)CH2OH group or a –C(O)CH2CN group.

13. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 wherein 30 • X ents –O- or –NR3- group, • R1 and R2 are independently selected from the group consisting of a en atom, a fluorine atom and a methyl group; • R3 is selected from the group consisting of a hydrogen atom and a methyl group; 35 • G1 is a –O-R6 group; • R4 is selected from the group consisting of a -CO(CH2)-OH group; -CO(CH2)-CN group, a nyl group and a pyrimidinyl group, wherein the pyrazinyl and pyrimidinyl groups independently are unsubstituted or substituted with a CN group or a –-CH2OH group; 5 • R5 represents a –CH2-CN group; • G2 represents a pyrimidine group or a pyridine group, wherein the pyrimidine and ne groups are unsubstituted or substituted by a fluorine atom; and • R6 is selected from the group consisting of a hydrogen atom, a -CH2CO2CH2Ph group, a –(CH2)2OCH3 group, a 2OCH2CH3 group, a –CH(CH3)CH2OCH3 10 group, a methyl group, an ethyl group, a butyl group, a –CH2CF3 group, a – CH2CHF2 group, a )2 group, a –(CH2)2OH group, a –(CH2)2-3N(CH3)2 group, a -CH(CH3)-CH2OH group, a –CH2CH(OH)CH2OH group.

14. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1 which is one of (Trans{[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin 15 yl]amino}cyclohexyl)acetonitrile; {Trans[(6-{[(2S)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; {Trans[(6-{[(2R)-2,3-dihydroxypropyl]oxy}fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl)amino]cyclohexyl}acetonitrile; 20 [trans({6-[2-(dimethylamino)ethoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; [Trans({6-[2-(dimethylamino)propoxy]fluoropyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)cyclohexyl]acetonitrile; 2-[(5-Fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5-a]pyridin- 25 3-ylpyrimidinyl)oxy]ethanol; (2S)[(5-fluoro{[(1S)(5-fluoropyrimidinyl)ethyl]amino}pyrazolo[1,5- a]pyridinylpyrimidinyl)oxy]propane-1,2-diol; 3-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile; 30 3-{(3R)[(6-butoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxopropanenitrile; 3-((3R){[6-(2-ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Methoxyethoxy)methylpyrazolo[1,5-a]pyridinylpyrimidin 35 yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 5 3-[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; )[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino] dinyl}oxoethanol; 5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin 10 ylpyrimidinol; Benzyl [(5-fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]acetate; 2-{(3R)[(6-Ethoxyfluoropyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 15 2-((3R){[5-Fluoropyrazolo[1,5-a]pyridinyl(2,2,2-trifluoroethoxy)pyrimidin- 4-yl]amino}piperidinyl)oxoethanol; 2-((3R){[6-(2,2-Difluoroethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 2-{(3R)[(5-Fluoroisopropoxypyrazolo[1,5-a]pyridinylpyrimidin 20 no]piperidinyl}oxoethanol; 5-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; (5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinyl)methanol; 25 5-{(3R)[(5-fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}pyrazinecarbonitrile; 2-((3R){[5-fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrimidinecarbonitrile; 2-[(3R)({5-Fluoro[(1S)methoxymethylethoxy]pyrazolo[1,5-a]pyridin 30 ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin 35 ylpyrimidinyl}amino)piperidinyl]oxoethanol; (2R)[(5-Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridin- 3-ylpyrimidinyl)oxy]propanol; 2-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxoethanol; 3-{(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin yl)oxy]piperidinyl}oxopropanenitrile; 5 2-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxoethanol; 3-((3R){[5-Fluoro(2-hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]oxy}piperidinyl)oxopropanenitrile; 2-((3R){[6-(2-Ethoxyethoxy)fluoropyrazolo[1,5-a]pyridinylpyrimidin 10 yl]amino}piperidinyl)oxoethanol; (2S)[(5-Fluoro{[(3R)glycoloylpiperidinyl]oxy}pyrazolo[1,5-a]pyridin ylpyrimidinyl)oxy]propanol; 5-[(3R)({5-Fluoro[(1R)methoxymethylethoxy]pyrazolo[1,5-a]pyridin ylpyrimidinyl}amino)piperidinyl]pyrazinecarbonitrile; 15 2-{(3R)[(6-Methoxymethylpyrazolo[1,5-a]pyridinylpyrimidin yl)amino]piperidinyl}oxoethanol; 2-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin yl}oxoethanol; 3-{(3R)[(6-Methoxypyrazolo[1,5-a]pyridinylpyrimidinyl)amino]piperidin 20 yl}oxopropanenitrile; 2-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxoethanol; 3-((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile; 25 3-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile; 5-((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)pyrazinecarbonitrile; or a pharmaceutically acceptable salt, N-oxide, e, isomer or deuterated 30 derivative thereof.

15. A 2-(pyrazolopyridinyl)pyrimidine tive according to claim 1, which is 3-[(5- Fluoro{[(3R)glycoloylpiperidinyl]amino}pyrazolo[1,5-a]pyridinylpyrimidin- 4-yl)oxy]propanol, or a pharmaceutically acceptable salt, N-oxide, solvate, 35 stereoisomer or deuterated derivative thereof.

16. A 2 -(pyrazolopyridinyl)pyrimidine tive according to claim 1, which is 2- {(3R)[(5-Fluoromethoxypyrazolo[1,5-a]pyridinylpyrimidin no]piperidinyl}oxoethanol, or a pharmaceutically acceptable salt, N-oxide, solvate, stereoisomer or deuterated derivative thereof.

17. A 2 -(pyrazolopyridinyl)pyrimidine derivative according to claim 1, which is 3- ((3R){[6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin no}piperidinyl)oxopropanenitrile, or a pharmaceutically acceptable salt, N- oxide, solvate, stereoisomer or deuterated derivative thereof.

18. A 2-(pyrazolopyridinyl)pyrimidine derivative according to claim 1, which is 3- ((3R){[6-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridinylpyrimidin yl]amino}piperidinyl)oxopropanenitrile, or a pharmaceutically acceptable salt, N- oxide, solvate, stereoisomer or ated derivative f.

19. A 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 18, for use in the treatment of the human or animal body.

20. A 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 20 18, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases.

21. A 2-(pyrazolopyridinyl)pyrimidine derivative for use according to claim 20, wherein the treatment is of a pathological condition or disease selected from atopic 25 itis, psoriasis, chronic hand eczema, cutaneous lupus, alopecia areata and vitiligo.

22. A pharmaceutical composition sing a 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 18, in association with a 30 pharmaceutically acceptable diluent or carrier.

23. Use of a 2-(pyrazolopyridinyl)pyrimidine derivative as defined in any one of claims 1 to 18, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claim 20 or 21.

24. A 2-(pyrazolopyridinyl)pyrimidine tive, which 2-(pyrazolopyridin yl)pyrimidine derivative is a compound of formula (I) as claimed in any one of claims 1 to 21, substantially as herein described with reference to any example thereof. 5

25. A pharmaceutical composition as claimed in claim 22, substantially as herein described with reference to any example f.

26. A use as claimed in claim 23, substantially as herein described with reference to any example thereof.