TW201605811A - Pyrazolopyrimidin-2-yl derivatives as JAK inhibitors - Google Patents

Abstract

New pyrazolopyridmiin-2-yl derivatives 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

Pyrazolopyrimidine-2-yl derivative as a JAK inhibitor

The present invention relates to a pyrazolopyrimidine-2-yl derivative as a JAK inhibitor

Cytokines have key functions in regulating multiple aspects of immunity and inflammation, which are within the range of inhibition of immune cell development and differentiation to immune response. Type I and Type II cytokine receptors lack the intrinsic enzymatic activity that mediates signal transduction and therefore require association with a tyrosine kinase for this purpose. The JAK family of kinases contains four distinct members, JAK1, JAK2, JAK3, and TYK2, which bind to type I and type II cytokine receptors for control of signal transduction (Murray PJ, (2007). The JAK -STAT signalling pathway: input and output integration. J Immunol , 178: 2623). Each JAK kinase is selective for receptors of certain cytokines. In this regard, JAK-deficient cell lines and mice have demonstrated the fundamental role of each JAK protein in receptor signaling: class II cytokine receptors (IFN and IL-10 family), consensus gp130 chain (IL-6 family) And JAK1 in the receptors of 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); hematopoietic factor (Epo, Tpo, GM-CSF, IL-3, IL-5) and JAK2 in type II IFN (Parganas et al, (1998). JAK2 is essential for signalling through a variety of cytokine receptors. Cell , 93: 385); JAK3 in the receptor for the gamma chain (IL-2 family) (Park et al., (1995). Developmen Tatric defects of lymphoid cells in JAK3 kinase-deficient mice. Immunity, 3:771; Thomis et al., (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Science , 270:794; Russell et al. (1995). Mutation of JAK3 in a partient with SCID: Essential role of JAK3 in lymphoid development. Science , 270: 797); and in the receptors of IL-12, IL-23, IL-13 and type I IFN Tyk2 (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity , 13: 549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, after it is required for IL -12-mediated T cell function. Immunity, 13:561; Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25: 745).

Receptor stimulation sequentially leads to JAK activation by phosphorylation, receptor phosphorylation, STAT protein recruitment, and STAT activation and dimerization. The STAT dimer acts as a transcription factor that translocates to the nucleus and activates transcription of multiple reactive genes. There are seven identified STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. Each specific cytokine receptor preferentially associates with a particular STAT protein. Some associations are independent of cell type (eg, IFNg-STAT1), while other associations are cell type dependent (Murray PJ, (2007). The JAK-STAT signaling pathway: input and output integration. J Immunol , 178 :2623).

The lack of a mouse phenotype has provided insight into the function of each JAK and cytokine receptor signaling through each JAK. JAK3 exclusively associates with a common gamma chain for receptors of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. Due to this exclusive association, JAK3 knockout mice and common gamma chain deficient mice have the same phenotype (Thomis et al., (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Science , 270:794 DiSanto et al. (1995). Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. PNAS , 92:377). Furthermore, this phenotype is largely shared by SCID patients who maintain mutations/defects in the common gamma chain or JAK3 gene (O'Shea et al., (2004). JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol , 41:727). JAK3-deficient mice are growable, but exhibit abnormal lymphocyte proliferation, which results in reduced thymus size (10-100 fold less than wild-type). JAK3 deficiency peripheral T cells and no reaction with the activated / memory phenotype (Baird et al., (1998) .T cell development and activation in JAK3-deficient mice J.Leuk.Biol 63:.. 669). Thymic defects in these mice are strongly similar to those seen in IL-7 and IL-7 receptor knockout mice, suggesting that the absence of IL-7 signaling causes 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). Like SCID humans, these mice do not have NK cells, which may be due to the absence of IL-15 signaling, a survival factor for these cells. Unlike SCID patients, JAK3 knockout mice show a lack of B cell lymphocyte proliferation, whereas in human patients, B cells are present in the circulation but do not respond, resulting in hypoglobulinemia (O'Shea 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 cell 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 loss of JAK3 in the T cell compartment drives the expansion of the myeloid lineage, resulting in dysregulated bone marrow tissue formation.

JAK2-deficient mice are lethal to embryos due to the absence of directional red blood cell production. Bone marrow progenitor cells are unable to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are unaffected. JAK2 is not required for the production, expansion or functional differentiation of lymphoid progenitor cells (Parganas et al., (1998). JAK2 is essential for signaling through a variety of cytokine receptors. Cell , 93:385).

JAK1 deficiency mice die during the birth period due to nursing defects. JAK1 exclusively binds to the gp130 chain shared by the IL-6 cytokine family (ie, LIF, CNTF, OSM, CT-1) and together with JAK3, shares a common gamma chain by binding to non-consensus receptor subunits. The basic component of the receptor. In this regard, JAK1-deficient mice show a hematopoietic defect similar to JAK3-deficient mice. In addition, it shows a defective response to neurotrophins and to all interferons (class II cytokine receptors) (Rodri et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in Cytokine-induced biological response. Cell , 93: 373).

Finally, Tyk2-deficient mice showed impaired responses to IL-12 and IL-23 and only partial damage to IFN-α (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity , 13: 549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, after it is required for IL-12-mediated T cell function. Immunity , 13:561). However, human Tyk2 deficiency confirms that Tyk2 is involved in the signaling of IFN-α, IL-6, IL-10, IL-12 and IL-23 (Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles In multiple cytokine signals involved in innate and acquired immunity. Immunity , 25:745).

The role of JAK kinase in transducing signals from a variety of cytokines makes it a potential target for the treatment of diseases in which cytokines have a pathogenic effect, such as inflammatory diseases including but not limited to allergies and asthma ), chronic obstructive pulmonary disease (COPD), psoriasis, autoimmune diseases (such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, uveitis, transplant rejection) and physical and hematological malignancies ( Such as myeloproliferative disorders, leukemias and lymphomas.

Inhibition of JAK kinases (especially JAK1 and JAK3) may result in potent immunosuppression, which may be therapeutically used to prevent transplant rejection. In this regard, the JAK inhibitor CP-690, 550 (tofacitinib, previously tasocitinib) has been transplanted in several animal models (here the heart transplant, planted in the subject mouse) Efficacy was demonstrated by prolonging the mean survival time of the graft in heart allografts in the mouse ears, kidney allografts in cynomolgus monkeys, aorta and tracheal transplantation in rats (West K (2009) ) CP-690, 550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr . Op . Invest . Drugs 10: 491).

In rheumatoid joints, an imbalance between pro-inflammatory cytokine activity and anti-inflammatory cytokine activity facilitates induction of autoimmune, which in turn induces chronic inflammation and tissue destruction. In this regard, the pathogenic role of IL-6 in rheumatoid arthritis (RA) has been clinically validated by the use of the anti-IL-6R antibody tocilizumab. IL-6 activates the transcription factor STAT3 by using JAK1 that binds to the gp130 receptor chain (Heinrich et al., (2003). Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem J. 374:1 ). Constitutive STAT3 mediates abnormal growth and survival characteristics of RA synovial cells (Ivashkiv and Hu (2003). The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arth & Rheum. 48:2092). Other cytokines already involved in the pathogenesis of arthritis include IL-12 and IL-23 (involved in Th1 and Th17 cell proliferation, respectively); IL-15 and GM-CSF (McInnes and Schett, (2007). Cytokines In the pathogenesis of rheumatoid arthritis. Nature Rew Immunol. 7: 429.). Receptors for these cytokines also utilize JAK proteins for signal transduction, making JAK inhibitors a potential pleiotropic drug in this pathology. Therefore, administration of several JAK inhibitors in animal models of murine collagen-induced arthritis and rat adjuvant-induced arthritis has been shown to reduce inflammation and tissue destruction (Milici et al., (2008). Cartilage conservation by Inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arth. Res. 10: R14).

Inflammatory bowel disease (IBD) contains two major forms of intestinal inflammation: ulcerative colitis and Crohn's disease. Increasingly, many cytokines, including interleukins and interferons, have been implicated in the pathogenesis of IBD (Strober et al., (2002). The immunology of mucosal models of inflammation. Annu Rev Immunol. 20: 495). Activation of the IL-6/STAT3 cascade in lamina propria T cells has been shown to induce prolonged survival of pathogenic T cells (Atreya et al., (2000). Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation : Evidence in Crohn's disease and experimental colitis in vivo. Nature Med. 6: 583). In particular, STAT3 has been shown to be constitutively active in intestinal T cells of patients with Crohn's disease and JAK inhibitors have been shown to block constitutive activation of STAT3 in these cells (Lovato et al., (2003). Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. J Biol Chem. 278:16777). These observations indicate that the JAK-STAT pathway plays a pathogenic role in IBD and that the JAK inhibitor may be therapeutic in this setting.

Multiple sclerosis is an autoimmune demyelinating disease characterized by the formation of plaques in the white matter. The role of cytokines in the production of multiple sclerosis has long been known. Potential blocking therapy includes IFN-g, IL-6, IL-12 and IL-23 (Steinman L. (2008 ) .Nuanced roles of cytokines in three major human brain disorders J Clin Invest 118:.. 3557), by JAK- The cytokine of the STAT pathway signaling. The use of tyrosine phosphorylation inhibitors (JAK inhibitors) has been shown to inhibit IL-12-induced STAT3 phosphorylation and reduce the incidence and severity of active and passive experimental autoimmune encephalitis (EAE) (Bright et al. (1999) Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol. 162:6255). Another multi-kinase inhibitor CEP701 has been shown to reduce the secretion of TNF-α, IL-6 and IL-23 in peripheral DCs of mice with EAE and the levels of phospho-STAT1, STAT3 and STAT5, significantly improving EAE in mice. Clinical process (Skarica et al, (2009). Signal transduction inhibition of APCs diminishes Th17 and Th1 responses in experimental autoimmune encephalomyelitis. J. Immunol. 182: 4192.).

Psoriasis is an inflammatory disease of the skin that involves the process of infiltration and activation of immune cells that achieve epithelial remodeling. The current theory following the etiology of psoriasis states the existence of a network of cytokines that manages the interaction between immune cells and epithelial cells (Nickoloff BJ. (2007). Cracking the cytokine code in psoriasis, Nat Med , 13: 242). In this regard, IL-23 produced by dendritic cells was found to increase in the psoriasis skin along with IL-12. IL-23 induces the formation of Th17 cells, which in turn produce IL-17 and IL-22, which cause epidermal thickening. IL-23 and IL-22 induce STAT-3 phosphorylation and a large amount of STAT-3 is found in psoriasis skin. JAK inhibitors can therefore be therapeutic in this setting. Accordingly, the JAK1/3 inhibitor R348 has been found to impair psoriasis-like skin inflammation in a spontaneous T cell-dependent mouse model of psoriasis (Chang et al., (2009). JAK3 inhibition significant attenuates psoriasiform skin inflammation on CD18 mutant PL/J Mice. J Immunol. 183:2183).

Th2 cytokine-driven diseases such as allergies and asthma may also be targets for JAK inhibitors. IL-4 promotes Th2 differentiation, regulates B cell function and immunoglobulin class switching, regulates eosinophil chemokine production, induces IgE receptor and MHC II expression on B cells, and stimulates mast cells. Other Th2 cytokines such as IL-5 and IL-13 may also contribute to the recruitment of eosinophils in bronchoalveolar lavage by stimulating eosinophil chemokine production. The pharmacological inhibition of JAK has been shown to reduce IgE receptor and MHCII expression induced by IL-4 stimulation on B cells (Kudlacz et al., (2008). The JAK3 inhibitor CP-690, 550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. European J. Pharm. 582:154). In addition, JAK3-deficient mice exhibited poor eosinophil recruitment and mucus secretion in the tracheal lumen during OVA challenge, as compared to wild-type mice (Malaviya et al., (2000). Treatment of allergic asthma by targeting Janus kinase 3 -dependent leukotriene synthesis in mast cells with 4-(3',5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97). JPET 295:912.). In this regard, systemic administration of CP-690, 550 JAK inhibitors in mice has been shown to reduce eosinophil counts in BAL and eosinophil chemotactic factors and IL13 in a murine model of pulmonary eosinophilia. Content (Kudlacz et al, (2008). The JAK3 inhibitor CP-690, 550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia . European J. Pharm. 582: 154).

There are increasing indications that cytokines play a pathogenic role in eye inflammatory diseases such as uveitis or dry eye. Some cytokines involved in experimental autoimmune uveitis will be subject to JAK inhibition, such as IL-2, IL-6, IL-12 and IFNg (Vallochi et al., (2007). The role of cytokines in the regulation Of ocular autoimmune inflammation. Cytok Growth Factors Rev. 18:135). In this regard, drugs or biological agents that interfere with IL-2 signaling, such as cyclosporine or anti-IL-2 receptor antibodies (dalizumab), have been treated in the treatment of keratoconjunctivitis sicca and refractory uveitis, respectively. Show efficacy (Lim et al, (2006). Biologic therapies for inflammatory eye disease. Clin Exp Opht 34: 365). Similarly, allergic conjunctivitis, a common allergic eye disease characterized by conjunctival hyperemia, mast cell activation, and eosinophil infiltration, may benefit from JAK inhibition. STAT6-deficient mice show a reduced TH2-mediated immune response, usually triggered by IL-4, and do not develop classical early and late responses, suggesting that abolishing the IL-4 pathway by JAK inhibition can be therapeutic in this setting ( Ozaki et al., (2005). The control of allergic conjunctivitis by suppression of cytokine signaling (SOCS) 3 and SOCS5 in a murine model. J Immunol , 175: 5489).

There are increasing indications that STAT3 activity plays a key role in processes involved in tumorigenesis, such as cell cycle disorders, promoting uncontrolled growth, inducing survival factors, and inhibiting apoptosis (Siddiquee et al., (2008) .STAT3 as a target for inducing apoptosis in solid and haematological tumors. Cell Res. 18:254). Antagonism of STAT3 by means of dominant negative mutants or antisense oligonucleotides has been shown to promote apoptosis, angiogenesis inhibition and host immune competence upregulation in cancer cells. Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors may provide a therapeutic option for the treatment of this disease. In this regard, the use of JAK inhibitor tyrosine phosphorylation inhibitors has been shown to induce apoptosis in malignant cells and to inhibit cell proliferation in vitro and in vivo (Meydan et al., (1996). Inhibition of acute lymphoblastic leukemia by a JAK-2 inhibitor. Nature , 379:645).

Hematological malignancies with a dysregulated JAK-STAT pathway can benefit from JAK inhibition. Recent studies have been implicated in chromosomal translocations and mutations in pseudokinase domains in a variety of myeloproliferative disorders (IhIe and Gililand, 2007), including polycythemia vera, myelofibrosis, and essential thrombocythemia (such as The JAK2V617F mutation) dysregulates JAK2 kinase activity. In this regard, several JAK inhibitors of JAK2 are effectively blocked, such as TG-101209 (Pardanani et al., (2007). TG101209, a small molecular JAK2-selective inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations Leukemia .21:1658-68), TG101348 (Wernig et al, (2008). Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell , 13: 311), CEP701 ( Hexner et al. (2008). Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood , 111: 5663), CP-690, 550 (Manshouri et al. (2008). The JAK kinase inhibitor CP-690, 550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Sci , 99: 1265) and CYT387 (Pardanani et al, (2009). CYT387, a selective JAK1/JAK2 inhibitor :invitro assessment of kinase selectivity and preclinical studies using c Leukemia , 23: 1441) has been proposed for the treatment of myeloproliferative diseases based on its anti-proliferative activity against cells carrying the JAK2V617F mutation. Similarly, T cell leukemia due to human T cell leukemia virus (HTLV-1) transformation is constitutively activated with JAK3 and STAT5 (Migone et al., (1995). Constitutively activated JAK-STAT pathway in T cells transformed with HTLV-I Science, 269:79) related and JAK inhibitors can be therapeutic in this setting (Tomita et al., (2006). Inhibition of constitutively active JAK-STAT pathway suppresses cell growth of human T-cell leukemia virus type I -infected T cell lines and primary adult T-cell leukemia cells. Retrovirology , 3:22). JAK1 activating mutations have also been identified in adult acute lymphoblastic leukemia of T cell origin (Flex et al, (2008). Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205: 751-8) , indicating that this kinase is a target for the development of novel anti-leukemia drugs.

The conditions in which the JAK pathway is targeted or the JAK kinase is regulated (especially JAK1, JAK2 and JAK3 kinases) are expected to be therapeutically suitable for the treatment or prevention of diseases include: neoplastic diseases (eg leukemia, lymphoma, solid tumors); transplant rejection, Bone marrow transplantation applications (eg, graft versus host disease); autoimmune diseases (eg, diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease); respiratory inflammatory diseases (eg, asthma, chronic obstructive pulmonary disease), Inflammation-related eye diseases or allergic eye diseases (such as dry eye, glaucoma, uveitis, diabetic retinopathy, allergic conjunctivitis or age-related macular degeneration) and skin inflammatory diseases (such as atopic dermatitis or psoriasis).

Given the many benefits expected to benefit from treatments involving modulation of the JAK pathway or JAK kinase, it is apparent that new compounds that modulate the JAK pathway and the use of such compounds should provide substantial therapeutic benefit to multiple patients.

Provided herein are novel pyrazolopyrimidin-2-yl derivatives for use in the treatment of a condition in which the JAK pathway is targeted or in which the JAK kinase is therapeutically applicable.

The compounds described in the present invention are simultaneously effective JAK1, JAK2 and JAK3 inhibitors, i.e., pan-JAK inhibitors. This property makes it suitable for the treatment or prevention of pathological conditions or diseases, such as myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphoma and solid tumors; bone marrow and Organ transplant rejection; Immune-mediated diseases and inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), inflammation-related eye diseases or allergic eye diseases (such as dry Eye, uveitis or allergic conjunctivitis), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD) and skin inflammatory diseases (eg atopic dermatitis or psoriasis).

Certain pyrazolopyrimidin-2-yl derivatives have been found to be novel and potent JAK inhibitors and can therefore be used to treat or prevent such diseases.

Accordingly, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative:

Wherein X is selected from the group consisting of -N- and -CR ^c - groups, and G ₁ is selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, and at least one selected from the group consisting of a monocyclic 5-8 membered heteroaryl group of a hetero atom of O, S and N and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the group group, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, C _1-4 alkyl, C ₁ - ₄ thioalkyl, C Substituted by a substituent of a _1-2 hydroxyalkyl group, a bis-(C _1-2 alkyl)amino-C _1-4 alkyl group and a -NR'-SO ₂ -R" group, the L ₁ group is selected from - ( CH ₂ ) _(0-1) -, -O-, -NR ^x -(CH ₂ ) _(0-1) - a group consisting of groups wherein R ^x is selected from a hydrogen atom and optionally via - (CH) ₂ ) _{(0-2) a} group of C _1-2 alkyl groups substituted with a NR'R"- group, and L ₂ is selected from -(CH ₂ ) _p -, -(CH ₂ )-NR-, - _{NR- (CH 2) -, -} O- (CH 2) (0-2), -C (O) O -, - S- and the group consisting of -NR- group, wherein R represents a hydrogen atom or an optionally required by the selected -NR'R "- group and a phenyl group substituted with C _1-4 alkyl, wherein the phenyl is optionally substituted with hydroxy, R ¹ Selected from the group consisting of a hydrogen atom, the optionally substituted -NR'R "group is a straight-chain or branched C _1-4 alkyl, C _5-8 monocyclic aryl, monocyclic C _3-8 cycloalkyl group, containing at least a monocyclic or bicyclic 5-14 membered heteroaryl group selected from hetero atoms of O, S and N and a monocyclic or bicyclic 5-14 membered heterocyclic group containing at least one hetero atom selected from O, S and N a group wherein the aryl, cycloalkyl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, straight chains or branches Chain C _1-6 alkyl, straight or branched C _1-6 hydroxyalkyl, straight or branched C _1-4 alkoxy, -(O) _(0-1) (CH ₂ ) _{(0- 3) a} -NR'R" group, a -CO-OR ^d group, a -CH ₂ -R ^e group, a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N And a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, wherein the heterocyclic group and the heteroaryl group are independently selected from one or more selected from C _1-2 alkane a substituent substituted with a group consisting of a -C(O)-(C _1-2 alkyl) group and a -NR'R'group; the R ² is selected from a hydrogen atom, a halogen atom, and The group consisting of C _1-4 alkyl, R ³ selected from the group consisting of a hydrogen atom, C _1-4 alkyl and _{- (CH 2) (2-4)} NR'R "- the group consisting of the group, G ₂ Is selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N and containing at least one selected a group consisting of a monocyclic 5-8 membered heterocyclic group of a hetero atom of O, S and N wherein the aryl, cycloalkyl, heteroaryl and heterocyclic group are unsubstituted or substituted by one or more Substituted, the substituents are selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-2 hydroxyalkyl group, a -NR'R" group, and a formula (a) Group:

Wherein L ₃ represents a direct bond, a -CO- group or a -C(O)O- group, and R ⁴ is selected from a hydroxyl group, a -(CH ₂ ) _(0-1) -CN group, a -CF ₃ group a straight, branched or branched C _1-4 alkyl group, a straight or branched C _1-4 alkoxy group, a linear or branched C _1-4 hydroxyalkyl group and a C _1-4 alkylamino group. a group wherein the alkyl group and the hydroxyalkyl group are optionally substituted by one or more methyl groups, and R ^a and R ^{b are} independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 3-5 membered heterocyclic group containing at least one hetero atom selected from N, O and S, and R ⁵ is selected from the group consisting of hydrogen a group consisting of an atom and a linear or branched C _1-4 alkyl group, and R ^c is selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _5-8 aryl group, and at least a group consisting of a 5-8 membered heteroaryl group of a hetero atom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally selected from a halogen atom and C by one or more straight alkyl groups substituted with _1-4 substituents of the group, R ^d represents optionally substituted with one or more groups selected from phenyl, methyl and -NR'R "substituents of Or branched C _1-4 alkyl, or R ^d represents an optionally substituted C _1-2 alkyl groups of 5-8 membered monocyclic heterocycle containing at least one group selected from O, S and N of hetero atoms, R ^{The e} is selected from the group consisting of a monocyclic C _5-8 aryl group and a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, which are required to pass one or more Substituted from a substituent of a hydroxy, straight or branched C _1-4 alkyl group and a -CF ₃ group, R' and R" independently represent a hydrogen atom, a C _1-4 alkyl group or a C _3-6 cycloalkane a group, or R' and R", together with the nitrogen atom to which they are attached, form a 4-6 member, optionally containing one or more additional heteroatoms selected from N, S and O, and optionally substituted with a dimethylamino group. The N-containing heterocyclic group, n, m and q independently have a value of 0 or 1, and p has a value of 0, 1, or 2.

The invention further provides synthetic methods and intermediates described herein which are suitable for use in the preparation of such compounds.

The invention also relates to a compound of the invention as described herein for use in the treatment of a human or animal body by therapy.

The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

The invention also relates to a compound of the invention as described herein for use in the treatment of a pathological condition or disease which is readily ameliorated by inhibition of Janus kinase (JAK), in particular wherein the pathological condition or disease is selected from Myeloproliferative disorders, leukemias, lymphoid malignancies, and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more specifically, the pathological condition or disease is selected from rheumatoid arthritis, Multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

The invention also relates to the use of a compound of the invention as described herein for the manufacture of a medicament for the treatment of a pathological condition or disease which is readily ameliorated by inhibition of Janus kinase (JAK), in particular wherein the pathology The condition or disease is selected from the group consisting of myeloproliferative disorders, leukemia, lymphoid malignancies, and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more specifically, the pathological condition or disease selection Rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibition of Janus kinase (JAK), in particular wherein the pathological condition or disease line is selected from myeloproliferative Conditions, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; Immune-mediated diseases and inflammatory diseases, more specifically, the pathological conditions or diseases are selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergies Conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis; the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.

In another embodiment of the invention, the pathological condition or disease is selected from the group consisting of a respiratory disease; an allergic disease; inflammatory or autoimmune mediated; a functional disorder and a neurological disorder; a cardiovascular disease; a viral infection; Endocrine disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelodysplastic syndrome; myeloproliferative disorders (MPD); cancer and hematological malignancies, leukemia, lymphoma and solid tumors.

In a preferred embodiment, the pathological condition or disease is selected from the group consisting of leukemia, lymphoma and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, Ulcerative colitis, systemic lupus erythematosus, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering disease (including but not limited to) pemphigus vulgaris , bullous pemphigoid and bullous epidermis relaxation, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoma-like disease, allergic rhinitis , atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and actinic keratosis.

The invention also provides a combination product comprising (i) a compound of the invention as described herein; and (ii) one or more additional active substances, It is suitable for the treatment of myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammation A disease, more specifically, wherein the pathological condition or disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), dry eye syndrome , uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.

The term C ₁ -C ₆ alkyl, as used herein, encompasses a straight or branched chain group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isethyl Base, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methyl Pentyl, 3-methylpentyl and isohexyl.

The term C ₁ -C ₆ hydroxyalkyl, as used herein, encompasses a straight or branched alkyl group having from 1 to 6 carbon atoms, any of which may be substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl.

The term C ₁ -C ₄ thioalkyl, as used herein, encompasses a group containing a straight or branched alkyl group attached to one to four carbon atoms of a divalent-S- group.

Preferably, the substituted sulfanyl group includes a thiomethyl group, a thioethyl group, a n-thiopropyl group, an isothiopropyl group, a n-thiobutyl group, a second thiobutyl group, and a third thiobutyl group.

The term (C ₁ -C ₄ )alkylamino as used herein encompasses a group containing a straight or branched alkyl group attached to the divalent —NH— group as desired 1-4 carbon atoms. . Preferred (C ₁ -C ₄ )alkylamino groups include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, t-butylamino and Tributylamine group.

As used herein, the term di(C ₁ -C ₂ )alkylamine group encompasses a group containing a trivalent nitrogen atom having two straight or branched alkyl groups, each having from 1 to 2 carbon atoms. Preferred bis(C ₁ -C ₂ )alkylamino groups include dimethylamino, diethylamino and methyl(ethyl)amine groups.

As used herein, the term C ₁ -C ₄ alkoxy (or alkyloxy) encompasses a straight or branched chain oxygen-containing group, each having an alkyl moiety of from 1 to 4 carbon atoms. Examples of the C ₁ -C ₄ alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a second butoxy group or a third butoxy group.

As used herein, the term C ₃ -C ₈ cycloalkyl encompasses saturated monocyclic carbocyclic groups having from 3 to 8 carbon atoms, preferably from 3 to 7 carbon atoms. Examples of the monocyclic cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

As used herein, the term C ₅ -C ₈ aryl typically encompasses C ₅ -C ₈ , preferably C ₅ -C ₆ monocyclic aryl, such as phenyl.

As used herein, the term 5-14 membered heteroaryl typically encompasses a 5-14 member ring system, preferably a 5-10 member ring system, and more preferably a 5-6 member ring system. It contains at least one heteroaromatic ring and contains at least one hetero atom selected from the group consisting of O, S and N. The 5-14 membered heteroaryl group may be a single ring or two or more fused rings, at least one of which contains a hetero atom.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl ( Isoxazolyl), benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, carbazolyl, fluorenyl, Quinolinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, Cinnolinyl, triazolyl, indolizinyl, porphyrinyl, isoindolyl, isodecyl, imidazolidinyl, acridinyl, thienyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl and various pyrrolopyridinyl groups.

As used herein, the term 5-14 membered heterocyclic group typically cover a non-aromatic saturated or unsaturated C ₅ -C ₁₄ carbocyclic ring system, preferably C ₅ -C ₁₀ carbocyclic ring system, more preferably C ₅ -C _{A 6} carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 carbon atoms, preferably 1 or 2 carbon atoms, are replaced by a hetero atom selected from the group consisting of N, O and S. The heterocyclic group may be a single ring or two or more fused rings, at least one of which contains a hetero atom.

Examples of the 5-14 membered heterocyclic group include piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pyrazolidinyl. Quinuclidinyl, Triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, cyclothiaethane, aziridine, oxetanyl, sulfanyl, aza Cyclobutane, 4,5-dihydro-oxazolyl, 2-benzofuran-1(3H)-one, 1,3-dioxol-2-one, tetrahydrofuranyl, 3-nitrogen Hetero-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropentanyl, tetrahydrothiopyranyl, 1,4-azetidinyl, oxetanyl, thiephthyl (thiephanyl) ), azepanyl, 1,4-dioxanyl, 1,4-oxathiamethylene, 1,4-oxazacycloheptyl, 1,4-di Thiothane, 1,4-thiazepine, 1,4-diazepanyl, decyl, (1S,5R)-3-aza-bicyclo[3.1. 0]hexyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 2,3-hydrobenzofuranyl, 1,2, 3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, isoindolyl and porphyrin.

As used herein, the term bicyclic (which is a monocyclic C ₆ -C ₉ aryl or 5-9 membered heteroaryl fused to a 5-9 membered cycloalkyl or heterocyclyl) is typically meant to contain a monocyclic C. _a moiety of a bond shared between a _6- C ₉ aryl or a 5-9 membered heteroaryl group and a 5-9 membered cycloalkyl or heterocyclic group, wherein the heteroaryl or heterocyclic group contains at least one member selected from the group consisting of O, Heteroatoms of S and N. Typically, the bicyclic group is a phenyl or a 5 or 6 membered heteroaryl fused to 5 or 6 members, preferably 6 members of a cycloalkyl or heterocyclic group. Typically, the heteroaryl or heterocyclic group contains 1, 2 or 3, preferably 1 or 2, for example 1 hetero atom selected from O, S and N. Examples include alkyl or 1,2,3,4-tetrahydronaphthyl.

As used herein, some of the atoms, groups, moieties, chains and rings present in the general structure of the invention are "optionally substituted". This means that the atoms, groups, moieties, chains and rings may be unsubstituted or in any The position is substituted with one or more, for example 1, 2, 3 or 4 substituents, whereby the hydrogen atom bonded to the unsubstituted atom, group, moiety, chain and ring is a chemically acceptable atom, group Group, part, chain and ring replacement.

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

Compounds containing one or more palmitic centers can be used in enantiomeric or diastereomeric forms, as a mixture of racemates, and as a mixture in one or more stereoisomers. The scope of the invention as set forth and claimed encompasses racemic forms as well as individual enantiomers, diastereomers and stereoisomerically enriched mixtures of such compounds.

Conventional techniques for the preparation/isolation of individual enantiomers include the resolution of the racemate from a suitable optically pure precursor to the palm synthesis or using, for example, palmitic high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be an acid or base, such as tartaric acid or 1-benzene, with a suitable optically active compound, such as an alcohol, or where the compound contains an acidic or basic moiety. Ethylethylamine) reaction. The resulting mixture of diastereomers can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure by methods well known to those skilled in the art. Enantiomer. The antagonistic compound of the invention (and its antagonistic precursor) may have from 0-50% isopropanol (typically 2-20%) and 0-5% alkylamine (typically 0.1% di An asymmetric resin consisting of a mobile phase consisting of a hydrocarbon of diethylamine (typically heptane or hexane) is obtained in an enantiomerically enriched form using chromatography (typically HPLC). The eluate is concentrated to provide a concentrated mixture. Stereoisomer The knots can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds", Ernest L. Elie I (Wiley, New York, 1994).

As used herein, the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid that is acceptable for administration to a patient (eg, a mammal). The salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid and nitric acid; and organic acids such as citric acid, fumaric acid, gluconic acid, glutamic acid , lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, ascorbic acid, oxalic acid, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, xinafoic (1-hydroxy-2-naphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like.

Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, Zinc salts and their analogues.

Salts derived from pharmaceutically acceptable organic bases include the following salts: primary amines, secondary amines, and tertiary amines, including alkyl amines, arylalkylamines, heterocyclic amines, cyclic amines, naturally occurring amines, and Analogs thereof, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino Ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, Hydrabamine, isopropylamine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, Trimethylamine, tripropylamine, tromethamine and the like.

Other salts according to the invention are quaternary ammonium compounds in which one equivalent of anion (X ^- ) is combined with a positive charge of the N atom. X ^- may be an anion of various inorganic acids, such as chloride, bromide, iodide, sulfate, nitrate, phosphate; or an anion of an organic acid such as acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate.

As used herein, N-oxides are formed using a convenient oxidizing agent from a basic tertiary amine or imine present in the molecule.

The compounds of the invention may exist in unfused and fused 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 solvent molecules. When the solvent is water, the term hydrate is employed. Examples of solvate forms include, but are not limited to, in combination with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl hydrazine (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. A compound of the invention. It is specifically contemplated that in the present invention, a solvent molecule can be combined with a molecule of the compound 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 combined with one molecule of the compound of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention, less than one solvent molecule can be combined with one molecule of a compound of the invention, such as a hemihydrate. In addition, pre The solvates of the present invention are solvates of the compounds of the invention which retain the bioavailability of the unsolvated forms of such compounds.

The invention also includes isotopically labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number but differing in atomic mass or mass number from atomic mass or mass number as is common in nature. Examples of suitable included in the compounds of the invention of isotopes include isotopes of the following composition of: hydrogen, such as ² H and ³ H; carbon, such as ¹¹ C, ¹³ C and ¹⁴ C; chlorine, such as ³⁶ CI; fluorine, such as ¹⁸ F; iodine, such as ¹²³ I and ¹²⁵ I; nitrogen, such as ¹³ N and ¹⁵ N; oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O; phosphorus, such as ³² P; and sulfur, such as ³⁵ S. Certain isotopically-labeled compounds of the invention (e.g., compounds of the invention incorporating a radioisotope) are useful in drug and/or matrix tissue distribution studies. The radioactive isotopes ³ ( ³ H) and carbon-14 ( ¹⁴ C) are particularly suitable for this purpose in view of their ease of incorporation and ease of detection. With heavier isotopes such as deuterium, ² H obtain the substituted a certain therapeutic advantages of greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence in some cases may be preferred. Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be applied to Positron Emission Topography (PET) studies for examining matrix receptor occupancy.

Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using the appropriate isotopically labeled reagents in place of the otherwise employed unlabeled reagents.

Preferred isotopically labeled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative encompasses a compound of the invention wherein at least one hydrogen atom in a particular position is replaced by deuterium. Ruthenium (D or ² H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 mol%.

Hydroquinone exchange (incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. The exchange (incorporation) reaction can be complete or partial.

Typically, a deuterated derivative of a compound of the invention has an isotope enrichment factor (the ratio between the isotope abundance and the natural abundance of the isotope) of the hydrazine present at the site designated as the potential deuteration site on the compound, That is, it is incorporated into a predetermined position in the molecule to replace the percentage of hydrogen hydride, which is at least 3500 (52.5% 氘 incorporation).

In a preferred embodiment, the isotope enrichment factor is at least 5000 (75% 氘). In a more preferred embodiment, the isotope enrichment factor is at least 6333.3 (95% hydrazine incorporation). In a preferred embodiment, the isotope enrichment factor is at least 6633.3 (99.5% 氘 incorporation). It should be understood that the isotope enrichment factors of each sputum present at the site designated as the deuterated site are independent of other deuterated sites.

The isotope enrichment factor can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

Prodrugs of the compounds described herein are also within the scope of the invention. Thus, certain derivatives of the compounds of the invention, which may themselves have little or no pharmacological activity, can be converted to the desired activity, for example by hydrolytic cleavage, when administered to the body or on the body. Compound. These derivatives are called "prodrugs". Additional information on prodrug use can be found in Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (eds. EB Roche, American Pharmaceutical Association).

Prodrugs according to the present invention may be replaced, for example, by certain portions known to those skilled in the art as "pro-moiety" (e.g., as described in Design of Prodrugs, H. Bundgaard (Elsevier, 1985). It is produced by the appropriate functional groups present in the compounds of the invention.

Where the compound is a solid, it will be understood by those skilled in the art that the compounds and salts of the present invention may exist in different crystalline or polycrystalline forms or in amorphous form, all of which are intended to be within the scope of the invention.

Typically, the compounds of the invention have the formula:

Wherein X is selected from the group consisting of -N- and -CR ^c - groups, and G ₁ is selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, and at least one selected from the group consisting of a monocyclic 5-8 membered heteroaryl group of a hetero atom of O, S and N and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the group a group, a cycloalkyl group, a heteroaryl group and a heterocyclic group are unsubstituted or one or more selected from the group consisting of a halogen atom, a hydroxyl group, a -CHO group, a C _1-4 alkyl group, a C _1-2 hydroxyalkyl group, two Substituted by a substituent of the (C _1-2 alkyl)amino-C _1-4 alkyl group and the -NR'-SO ₂ -R" group, the L ₁ group is selected from -(CH ₂ ) _(0-1) - a group of -O-, -NR ^x -(CH ₂ ) _(0-1) - groups, wherein R ^x is selected from a hydrogen atom and optionally via -(CH ₂ ) _(0-2) NR' a group of C _1-2 alkyl groups substituted by a R"- group, and L ₂ is selected from -(CH ₂ ) _p -, -(CH ₂ )-NR-, -O-(CH ₂ ) _{(0- 2) a} group consisting of -S- and -NR- groups, wherein R represents a hydrogen atom or a C _1-4 alkyl group optionally substituted with a group selected from a -NR'R"- group and a phenyl group wherein the phenyl is optionally substituted with hydroxy, R ¹ selected from the group consisting of a hydrogen atom, an optionally -NR'R " The group substituted straight-chain or branched C _1-4 alkyl, C _5-8 monocyclic aryl, monocyclic C _3-8 cycloalkyl group, containing at least one heteroatom selected from O, S and N atoms of the monocyclic hetero Or a bicyclic 5-14 membered heteroaryl group and a monocyclic or bicyclic 5-14 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the aryl group, cycloalkyl group, hetero The aryl group and the heterocyclic group are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C _1-6 alkyl group, a straight chain or a branched chain C _1-6 hydroxyalkyl, straight or branched C _1-4 alkoxy, -(O) _(0-1) (CH ₂ ) _(0-3) -NR'R" group, -CO-OR ^{a d} group, a -CH ₂ -R ^e group, a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, and a hetero atom containing at least one selected from the group consisting of O, S and N Monocyclic 5-8 membered heteroaryl, wherein the heterocyclyl and heteroaryl are, independently, optionally, one or more selected from the group consisting of a C _1-2 alkyl group and a -NR'R' group. a substituent substituted; R ² is selected from the group consisting of a hydrogen atom, a halogen atom, and a C _1-4 alkyl group, and R ³ is selected from a hydrogen atom, a C _1-4 alkyl group, and -(C) H ₂ ) _{(2-4) a} group of NR'R"-groups, the G ₂ group being selected from a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, containing at least one selected from the group consisting of O a monocyclic 5-8 membered heteroaryl group of a hetero atom of S and N and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the aryl group And the cycloalkyl, heteroaryl and heterocyclic groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group. , C _1-2 hydroxyalkyl, -NR'R" group and group of formula (a):

Wherein L ₃ represents a direct bond, a -CO- group or a -C(O)O- group, and R ⁴ is selected from a hydroxyl group, a -(CH ₂ ) _(0-1) -CN group, a -CF ₃ group a straight, branched or branched C _1-4 alkyl group, a straight or branched C _1-4 alkoxy group, a linear or branched C _1-4 hydroxyalkyl group and a C _1-4 alkylamino group. a group wherein the alkyl group and the hydroxyalkyl group are optionally substituted by one or more methyl groups, and R ^a and R ^{b are} independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group, or R ^a and R ^b together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or a 3-5 membered heterocyclic group containing at least one hetero atom selected from N, O and S, and R ⁵ is selected from the group consisting of hydrogen a group consisting of an atom and a linear or branched C _1-4 alkyl group, and R ^c is selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _5-8 aryl group, and at least a group consisting of a 5-8 membered heteroaryl group of a hetero atom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally selected from a halogen atom and C by one or more straight alkyl groups substituted with _1-4 substituents of the group, R ^d represents optionally substituted with one or more groups selected from phenyl, methyl and -NR'R "substituents of Or branched C _1-4 alkyl group, R ^e group selected from the group consisting of C _5-8 monocyclic aryl group and containing at least one heteroatom selected from O, S and N heteroatom of 5-8 membered monocyclic heteroaryl groups of a group, wherein the ring is optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched C _1-4 alkyl group and a -CF ₃ group, and R' and R" independently represent a hydrogen atom, C _{1 -4} alkyl or C _3-6 cycloalkyl, or R' and R" together with the nitrogen atom to which they are attached, form, as desired, one or more additional heteroatoms selected from N, S and O and optionally The 4-6 member substituted with a dimethylamino group contains an N heterocyclic group, and n, m and q independently have a value of 0 or 1, and p has a value of 0, 1, or 2.

Typically, X represents a -CR ^c - group, wherein R ^c is selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a phenyl group, and at least one selected from the group consisting of O, S, and N. a group consisting of a heteroatom 5-8 membered heteroaryl group and a -NR'R" group, wherein the heteroaryl group is optionally subjected to one or more groups selected from the group consisting of a halogen atom and a C _1-4 alkyl group. a substituent substituted, and R' and R" independently represent a hydrogen atom or a C _1-4 alkyl group, preferably R ^c is selected from a hydrogen atom, a C _1-2 alkyl group, a C _1-2 alkoxy group, a group consisting of a phenyl group and a -NR'R" group, wherein R' and R" independently represent a hydrogen atom or a C _1-2 alkyl group, and more preferably R ^c is selected from the group consisting of a hydrogen atom and a methyl group. Group, the best is a hydrogen atom.

Typically, G ₁ is selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, and containing at least one selected from the group consisting of O, S and a group consisting of a heterocyclic monocyclic 5-8 membered heterocyclic group of N wherein the aryl, heteroaryl and heterocyclic group are unsubstituted or one or two selected from a halogen atom, a hydroxyl group, C _1- Substituted by a substituent of a _4- alkyl group, a C _1-2 hydroxyalkyl group, and a -NR'-SO ₂ -R" group.

In a preferred embodiment, G ₁ is selected from the group consisting of a phenyl group, a pyridyl group, and a monocyclic 6-membered heterocyclic group containing at least one hetero atom selected from O and N, wherein the phenyl group, pyridyl group And the heterocyclic group is unsubstituted or substituted with one or two substituents selected from a halogen atom and a C _1-2 alkyl group, and more preferably the G _{1 group} is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group. .

Typically, L ₁ is selected from the group consisting of -(CH ₂ ) _(0-1) -, -NR ^x -(CH ₂ ) ₍₁₎ - groups, wherein R ^x is selected from a hydrogen atom and optionally a group consisting of C _1-2 alkyl groups substituted with a -(CH ₂ ) _(0-2) NR'R"- group, wherein R' and R" independently represent a hydrogen atom or a methyl group, preferably L ₁ is selected from the group consisting of a direct bond and a -NR ^x -(CH ₂ ) ₍₁₎ - group, wherein R ^x is selected from the group consisting of a hydrogen atom and a methyl group, and more preferably L ₁ represents a direct bond. .

Typically, the L ₂ is selected from the group consisting of -(CH ₂ ) _p -, -O-(CH ₂ ) _(0-2) - and -NR- groups, wherein R represents a hydrogen atom or optionally a C _1-2 alkyl group substituted with a NR'R"- group, wherein p has a value of 0 or 1 and wherein R' and R" independently represent a hydrogen atom or a methyl group, preferably L ₂ is selected from - ( CH ₂ ) a group of _p -, -O-(CH ₂ ) ₂ -, wherein p has a value of 0 or 1. More preferably, L ₂ represents a -CH ₂ - group.

Typically, R ¹ is selected from the group consisting of a C _1-2 alkyl group substituted by a hydrogen atom, optionally substituted with a —NR′R′ group, a monocyclic C _5-8 aryl group, and a single atom containing at least one hetero atom selected from N a group consisting of a cyclic or bicyclic 5-14 membered heteroaryl group and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from N, wherein the aryl, heteroaryl and heterocyclic groups are unsubstituted Or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a linear or branched C _1-5 alkyl group, a linear C _1-2 alkoxy group, -(O) _{(0- 1)} (CH ₂ ) _{(0-3) a} group consisting of a -NR'R" group, a -CO-OR ^d group, and a -CH ₂ -R ^e group, wherein R ^d represents one or more as needed a linear or branched C _1-4 alkyl group substituted with a substituent selected from methyl and -NR'R", and R ^e is selected from a monocyclic C _5-8 aryl group and containing at least one selected from the group consisting of N a group consisting of a monocyclic 5-8 membered heteroaryl group of an atom which is optionally substituted with one or more substituents selected from a linear or branched C _1-4 alkyl group and a -CF ₃ group, R 'and R' independently denotes a hydrogen atom or a methyl group, or R' and R" together with the nitrogen atom to which they are attached form one or more as needed Selected from N, S and O, the additional hetero atoms and optionally substituted 4-6 membered of dimethylamino N-containing heterocyclic group.

In a preferred embodiment, R ¹ is selected from the group consisting of a hydrogen atom, a monocyclic C _5-8 aryl group, and a monocyclic 5-7 membered heterocyclic group containing one or two nitrogen atoms as a hetero atom. Wherein the aryl and heterocyclic groups are unsubstituted or one or more selected from the group consisting of a linear or branched C _1-5 alkyl group, a linear C _1-2 alkoxy group, -(O)(CH ₂ ) Substituent substitution of a group of _2- NR'R" groups and -NR'R"-groups, wherein R' and R" independently represent a hydrogen atom or a methyl group, preferably R ¹ is selected from benzene a group consisting of a monocyclic 6-7 membered heterocyclic group containing one or two nitrogen atoms as a hetero atom, wherein the phenyl and heterocyclic groups are selected from a methyl group, -(O)(CH _{2 )} Substituted by a substituent of the group consisting of a ₂ -NR'R" group and a -NR'R"- group, wherein R' and R" both represent a methyl group. More preferably, R ¹ is selected from the group consisting of a phenyl group and a monocyclic 6-7 membered heterocyclic group containing one or two nitrogen atoms as a hetero atom, wherein the phenyl group and the heterocyclic group have a substituent. -(O)(CH ₂ ) ₂ -NR'R" group substituted, wherein R' and R" each represent a methyl group and q has a value of 1.

Typically, q has a value of one.

In a preferred embodiment of the invention, the compound of formula (I) is wherein L ₂ represents a -CH ₂ - group and R ¹ is selected from a phenyl group and a single ring 6 containing one or two nitrogen atoms as a hetero atom. a group of -7 membered heterocyclic groups wherein the phenyl and heterocyclic groups are substituted with a substituent -(O)(CH ₂ ) ₂ -NR'R" group, wherein R' and R" are both represented Methyl and q have a value of 1.

Typically, R ² is selected from the group consisting of a hydrogen atom and a halogen atom, preferably a halogen atom, more preferably a fluorine atom.

Typically, R ³ is selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a --(CH ₂ ) _(2-4) NR'R"- group, wherein R' and R" are as defined in the technical scheme. Preferably, R ³ is selected from the group consisting of a hydrogen atom and a methyl group, and more preferably R ³ represents a hydrogen atom.

Typically, R ⁵ is selected from the group consisting of a hydrogen atom and a methyl group, preferably a hydrogen atom.

In a preferred embodiment, the G ₂ is selected from the group consisting of a monocyclic N 6-8 membered heteroaryl group and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N. a group wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a methyl group, a methoxy group, and a -NR'R" group. And the group of formula (a):

Wherein L ₃ represents a -CO- group or a -C(O)O- group, and R ⁴ is selected from the group consisting of a hydroxyl group, a cyano group, a -CF ₃ group, a methyl group, and R ^a and R ^{b are} independently Is selected from the group consisting of a hydrogen atom, a hydroxyl group, a methyl group, or R ^a and R ^b together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group or an O 4 -containing heterocyclic group, m having 0 Or a value of 1.

More preferably, the G ₂ is selected from the group consisting of pyridyl and monocyclic N 6 -membered heterocyclic groups wherein the pyridyl and heterocyclic groups are substituted by one or more substituents selected from the group consisting of a halogen atom and a group of the formula (a):

Wherein L ₃ represents a -CO- group, R ⁴ is selected from the group consisting of a hydroxyl group and a cyano group, and both R ^a and R ^b represent a hydrogen atom, and m has a value of 1.

In still a preferred embodiment, G ₂ represents a monocyclic N 6 membered heterocyclic group substituted with a group of formula (a):

Wherein L ₃ , R ⁴ , R ^a , R ^b and m are as defined above.

In another embodiment, the invention relates to a compound of formula (I), wherein X represents a -CR ^c - group, wherein Rc represents a hydrogen atom and G ₁ is selected from the group consisting of phenyl, pyridyl and piperazinyl. Group, L ₁ represents a direct bond, and L ₂ is selected from the group consisting of -(CH ₂ ) _p -, -O-(CH ₂ ) ₂ -, wherein p has a value of 0 or 1, and R ¹ is selected from a group consisting of a phenyl group and a monocyclic 6-7 membered heterocyclic group containing one or two nitrogen atoms as a hetero atom, wherein the phenyl group and the heterocyclic group are selected from a methyl group, -(O)(CH) ₂ ) Substituted by a substituent of the group consisting of a ₂ -NR'R" group and a -NR'R"- group, wherein R' and R" both represent a methyl group.

R ² is a fluorine atom, R ³ represents a hydrogen atom, R ⁵ represents a hydrogen atom, and G ₂ represents a monocyclic N 6 membered heterocyclic group which is substituted with a group of the formula (a):

Wherein L ₃ represents a -CO- group, R ⁴ is selected from the group consisting of a hydroxyl group and a cyano group, and both R ^a and R ^b represent a hydrogen atom, and m has a value of 1.

In another embodiment, the invention relates to a compound of formula (I), wherein X is selected from the group consisting of -N- and -CR ^c - groups, wherein R ^c is selected from the group consisting of a hydrogen atom and a methyl group a group of G ₁ selected from the group consisting of a phenyl group, a monocyclic N 6 membered heteroaryl group, and a monocyclic 6 membered heterocyclic group containing at least one hetero atom selected from O and N, wherein the benzene group a heteroaryl group and a heterocyclic group are unsubstituted or one or two selected from the group consisting of a fluorine atom, a hydroxyl group, a -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino group-C _1-2 alkyl group, and Substituted by a substituent of the -NR'-SO ₂ -R" group, the L ₁ is selected from the group consisting of a direct bond and a -NH-(CH ₂ )- group, and the L ₂ is selected from -(CH ₂ ) _p a group consisting of -, -O-(CH ₂ ) _(0-2) and -NR- groups, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group, and R ¹ is selected from a hydrogen atom. a C _1-2 alkyl group substituted with a -NR'R" group, a phenyl group, a monocyclic or bicyclic 5-9 membered heteroaryl group containing at least one nitrogen atom as a hetero atom, and containing at least one nitrogen atom as a hetero atom a group consisting of a monocyclic or bicyclic 5-9 membered heterocyclic group wherein the phenyl, heteroaryl and The heterocyclic group is unsubstituted or substituted by one or more substituents selected from the group consisting of a hydroxyl group, a methyl group, an ethyl group, a branched C _4-5 alkyl group, a C _1-3 hydroxyalkyl group, a methoxy group. , -(O) _(0-1) (CH ₂ ) _(2-3) -NR'R" group, -NR'R" group, -CO-OR ^d group, -CH ₂ -R ^e group And a group comprising a monocyclic 6-membered heteroaryl group selected from the group consisting of a hetero atom of N, wherein the heteroaryl group is optionally one or two selected from the group consisting of a methyl group and a -NR'R" group. Substituted substituents; R ² is selected from the group consisting of a fluorine atom and a methyl group, and R ³ is selected from the group consisting of a hydrogen atom and a -(CH ₂ ) ₂ NR'R"- group, G ₂ system A group consisting of a pyridyl group substituted with a fluorine atom and a piperidinyl group substituted with a group of the formula (a):

Wherein L ₃ represents a direct bond, a -CO- group or a -C(O)O- group, and R ⁴ is selected from a hydroxyl group, a -(CH ₂ ) _(0-1) -CN, a -CF ₃ group, a group consisting of methyl, ethyl, methoxy, hydroxypropyl, hydroxymethyl optionally substituted by one or two methyl groups, R ^a and R ^b are each a hydrogen atom or R ^a and R ^b together with The carbon atoms to be joined together form a 4-membered heterocyclic group containing an oxygen atom as a hetero atom, R ⁵ is selected from the group consisting of a hydrogen atom and a methyl group, and R ^d represents a third butyl group, optionally selected from the group consisting of a linear C _1-2 alkyl group substituted with a substituent of phenyl and -NR'R", and R ^e is selected from a phenyl group optionally substituted by a CF ₃ group or a third butyl group and containing one or two a nitrogen atom as a group consisting of a monocyclic 5-6 membered heteroaryl group of a hetero atom, wherein the heteroaryl group is optionally selected from one or more selected from a linear or branched C _1-4 alkyl group and a -CF ₃ group. Substituted by a substituent of the group, R' and R" independently represent a hydrogen atom, a methyl group or a cyclopentyl group, or R' and R" together with the nitrogen atom to which they are attached are formed, optionally containing one or more selected from N and 5-6 of additional heteroatoms and optionally substituted with dimethylamine groups N-containing heterocyclic group, n, m and q independently have a value of 0 or 1.

p has a value of 0, 1, or 2.

Specific individual compounds of the invention include: 3-{(3 R )-3-[[2-(dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazole) And [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[( 5-fluoro-6-{4-[(1-methyl-1 H -imidazol-2-yl)methyl]piperazin-1-yl}-2-pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({6-[4-(1 H -benzene) And imidazol-2-ylmethyl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidine- 1-yl]-3-oxooxypropionitrile; 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[ 4-(pyridin-2-ylmethyl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R ) -3-{[6-(4-{[4-(Dimethylamino)pyridin-2-yl]methyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxooxypropionitrile; 3-{(3 R )-3-[(5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-yl-6-{4-[(4-pyrrolidin-1-ylpyridin-2-yl)methyl]piperazin-1-yl}pyrimidine 4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 3-[(3 R )-3-({5-fluoro-6-[4-( 4-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3 - pendant oxypropionitrile; 4-{[4-(5-fluoro-6-{[(3 R )-1-(3-hydroxy-3-methylbutanyl)piperidin-3-yl]amino} -2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol; 4-{[4-(5-fluoro-6-{ [(3 R )-1-Glycolhydrazinopiperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazine- 1-yl]methyl}phenol; 3-[(3 R )-3-({5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1-yl]-2- Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-[(3 R )-3- ({5-Fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl} Amino)piperidin-1-yl]-3-oxooxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)) Oxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1- Benzyloxypropionitrile; 2-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperidin Pyrazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2 - pendant oxyethanol; 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-1-(methoxyethenyl)piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine; 6-(4-{4 -[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl- N -[(3 R )-1-(3,3,3-trifluoropropenyl)piperidin-3-yl]pyrimidin-4-amine; [3-((3 R )-3-{[6- (4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl]amino}piperidin-1-yl)oxetan-3-yl]acetonitrile; ( 2S )-1-((3 R )-3-{[6- (4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-1-oxopropan-2-ol; ( R )-1-(( R )-3-((6-(4) -(4-(2-(Dimethylamino)ethoxy)benzyl)piperazin-1-yl)-5-fluoro-2-(pyrazolo[1,5-a]pyridine-3 -yl)pyrimidin-4-yl)amino)piperidin-1-yl)-1-oxobutan-2-ol and ( S )-1-(( R )-3-((6-(4) -(4-(2-(Dimethylamino)ethoxy)benzyl)piperazin-1-yl)-5-fluoro-2-(pyrazolo[1,5-a]pyridine-3 -based pyrimidine 4-yl)amino)piperidin-1-yl)-1-oxobutan-2-ol; 3-((3 R )-3-{[6-(4-{3-[2- (Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl] Amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)) Oxy]benzyl}piperazin-1-yl)-5-fluoro-2-(5-methylpyrazolo[1,5- a ]pyridin-3-yl)pyrimidin-4-yl]amino "piperidin-1-yl)-3-oxopropiononitrile; 3-((3 R )-3-{[6-(4-{4-[3-(dimethylamino)propoxy) Benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl) 3-oxooxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[4-(2-piperidin-1-ylethoxy)benzyl] Piperazin-1-yl}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 3-{(3 R )-3-[(5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-{4-[4-(2-pyrrolidin-1-) Ethyloxy)benzyl]piperazin-1-yl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropiononitrile; 3-((3 R )-3 -{[6-((3 R ,5 S )-4-{4-[2-(dimethylamino)ethoxy]benzyl}-3,5-dimethylpiperazin-1- Base)-5-fluoro-2- Pyrazolo [1,5-a] pyridin-3-yl-pyrimidin-4-yl] amino} piperidin-1-yl) -3-oxo-propanenitrile; 3 - ((3 R) -3- { [6-(4-{4-[2-(Dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazin-1-yl}-5-fluoro-2-pyridyl Zizo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-((3 R )-3-{ [6-(4-{4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazin-1-yl)-5-fluoro-2-pyridyl Zizo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-[(3 R )-3-( {6-[4-(2-{4-[2-(Dimethylamino)ethoxy]phenyl}ethyl)piperazin-1-yl]-5-fluoro-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 4-{[4-(6-{[(3R)) 1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazine 1-(dimethylamino)ethyl ester of -1-yl]methyl}benzoate; 4-{[4-(6-{[(3R)-1-(cyanoethinyl))piperidine-3 -amino]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}piperidine-1-carboxylic acid tert-butyl ester; 3 - [(3 R) -3 - ({5- fluoro-6- [4- (piperidin-4-ylmethyl) piperazin-1-yl] -2- pyridine And [1,5-a] pyridin-3-yl} pyrimidin-4-yl amino) piperidin-1-yl] -3-oxo-propanenitrile; 3 - [(3 R) -3 - ({ 5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-({1-[4-(trifluoromethyl)benzyl]piperidin-4-yl }methyl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-[(3 R )-3-({5- Fluoro-6-[4-({1-[(1-methyl-1H-imidazol-2-yl)methyl]piperidin-4-yl}methyl)piperazin-1-yl]-2-pyridinium Zizo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{ [6-(4-{[1-(2,2-Dimethylpropyl)piperidin-4-yl]methyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1 , 5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-((3 R )-3-{[5-fluoro -2-pyrazolo[1,5-a]pyridin-3-yl-6-(4-{[1-(pyridin-2-ylmethyl)piperidin-4-yl]methyl}piperazine- 1-yl)pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )-3-({6-[4-(2,6) - dimethylpyridin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine -1-yl]-3-sided oxypropionitrile; 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6- [4-(2-pyrrolidin-1-ylpyridine-4 -yl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-{(3 R )-3-[(6-{ 4-[2-(Dimethylamino)pyridin-4-yl]piperazin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4 -amino)piperidin-1-yl}-3-oxopropiononitrile; 3-{(3 R )-3-[(6-{4-[4-(dimethylamino)pyridine) -2-yl]piperazin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl} 3-oxooxypropionitrile; 3-((3 R )-3-{[5-fluoro-6-(4-piperidin-4-ylpiperazin-1-yl)-2-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

3-[(3 R )-3-({6-[4-(1-Benzylpiperidin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 5-fluoro- N -[(1 S )-1-(5 -fluoropyridin-2-yl)ethyl]-6-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-pyrazolo[1,5- a ]pyridine 3-ylpyrimidin-4-amine; 3-{(3 R )-3-[(6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5- Fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R -3({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl] Pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-[(3 R )-3-({6-[4-(1,3-dihydro-) 2 H -isoindol-2-ylmethyl)piperidin-1-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino Piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy) Phenylmethyl}piperidin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl) 3-oxooxypropionitrile; 3-{(3 R )-3-[(6-{4-[[2-(dimethylamino)ethyl](methyl)amino]]piperidine- 1-yl}-5-fluoro-2-pyridyl And [1,5-a] pyridin-3-yl-pyrimidin-4-yl) amino] piperidin-1-oxo-yl} propanenitrile; 3 - [(3 R) -3 - ({5- fluoro -6-[4-(7-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)piperidine-1 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-{( 3 R )-3-[(6-{4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-yloxypropionitrile; 3-{(3 R )-3-[( 6-{4-[(2,6-Dimethylpyridin-4-yl)amino]piperidin-1-yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridine-3 -pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropiononitrile; 4-{[1-(6-{[(3R)-1-(cyanoethyl) Piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piper Benzene-1-carboxylate; 3-[(3 R )-3-({5-fluoro-6-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-2- Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; ( R )-3-{3-[ (6-{4-[(4-Benzylpiperazin-1-yl)methyl]piperidin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridine-3 -pyrimidin-4-yl)amino] 1-yl} -3-oxo-propanenitrile; 3 - [(3 R) -3 - ({6- [4 - ({4- [4- ( dimethylamino) -6- Pyridin-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4- Amino)piperidin-1-yl]-3-oxopropiononitrile; 3-[(3 R )-3-({5-fluoro-6-[(4-piperazin-1-ylbenzene) Methyl)amino]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; -[(3 R )-3-({5-fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 2-[(3 R )-3-({5-fluoro-6-[4-( 4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-2 - oxoethanol; 1-benzyl-4-[4-(6-{[(3R)-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methylpiperazine-1-indole bromide; 1-(4-t-butylbenzene Methyl)-4-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methylpiperazine-1-indole bromide; 3-((3 R )-3-{[6-(4-{ 4-[3-(two Amino)propyl]piperazin-1-yl}phenyl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidine -1-yl)-3-sided oxypropionitrile; 3-[(3 R )-3-([2-(dimethylamino)ethyl]{5-fluoro-6-[4-(4 -methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3- Side oxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(1-methylpiperidin-4-yl)phenyl]-2-pyrazolo[1 , 5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-[(3 R )-3-({5-fluorine) -2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)phenyl]pyrimidin-4-yl}amino)piperidine-1 -yl]-3-oxomethoxypropionitrile; 3-[(3 R )-3-({5-methyl-2-pyrazolo[1,5- a ]pyridin-3-yl-6-[ 4-(pyrrolidin-1-ylmethyl)phenyl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxooxypropionitrile; 3-[(3 R )-3- ({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}methyl)phenyl]-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )- 3-{[6-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazolo[1,5-a] Pyridine 3-pyrimidin-4-yl] amino} piperidin-1-yl) -3-oxo-propanenitrile; 3 - ((3 R) -3 - {[6- (4 - {[4- (Dimethylamino)piperidin-1-yl]methyl}-2-fluorophenyl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4- Amino]piperidin-1-yl)-3-oxopropiononitrile; 3-((3 R )-3-{[6-(3-{[4-(dimethylamino))piperidin Pyridin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl) 3-oxooxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[(4-methyl-1,4-diazepane-1-) Methyl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile ;3-{(3 R )-3-[(5-fluoro-6-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl} -2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R -3({6-[4-({4-[2-(dimethylamino)ethoxy)piperidin-1-yl}methyl)phenyl]-5-fluoro-2-pyridyl) Zizo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-{(3 R )-3-[ (6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl )amine ] Piperidin-1-yl} -3-oxo-propanenitrile; 3 - ((3 R) -3 - {(6- {4- [2- ( dimethylamino) ethoxy] phenyl }-5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl]amino}piperidin-1- Benzyloxypropionitrile; [(3 R )-3-({5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-yl-6-[4-(2) -pyrrolidin-1-ylethoxy)phenyl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{ [6-(4-{2-[4-(Dimethylamino)piperidin-1-yl]ethoxy}phenyl)-5-fluoro-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; ( R )-3-(3-((5-fluoro-6-(4-) (piperidin-4-yloxy)phenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)- 3-Rethoxypropionitrile; ( R )-3-(3-((6-(4-((1-ethylpiperidin-4-yl)oxy)phenyl)-5-fluoro-2- (pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; ( R )-3-(3 -((5-fluoro-6-(4-((1-(3-(piperidin-1-yl)propyl)piperidin-4-yl)oxy)phenyl)-2-(pyrazole) [1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )-3-({ 5-fluoro-6-[2-(4- Piperazin-1-yl)pyridin-4-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3 - pendant oxypropionitrile; 3-((3 R )-3-{[5-fluoro-6-(2-piperazin-1-ylpyridin-4-yl)-2-pyrazolo[1,5 -a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6-(2- {4-[3-(Dimethylamino)propyl]piperazin-1-yl}pyridin-4-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridine-3- Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[2-(4- Methyl-1,4-diazepan-1-yl)pyridin-4-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino Piperidin-1-yl]-3-oxopropiononitrile; 3-{(3 R )-3-[(5-fluoro-6-{2-[4-(2-hydroxyethyl)-1 ,4-diazepan-1-yl]pyridin-4-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidine- 1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[(6-{2-[4-(dimethylamino)piperidin-1-yl]pyridine-4 -yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 2-{(3 R )-3-[(6-{2-[4-(dimethylamino)piperidin-1-yl]pyridin-4-yl}-5-fluoro-2-pyrazole [1,5 - a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol; 3-((3 R )-3-{[6-(6-{ [4-(Dimethylamino)piperidin-1-yl]methyl}pyridin-3-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl]amino}piperidin-1-yl-3-oxooxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[6-(4-methyl-) 1,4-diazepan-1-yl)pyridin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidine -1-yl]-3-oxooxypropionitrile; 3-{(3 R )-3-[(6-{6-[4-(dimethylamino)piperidin-1-yl]pyridine- 3-yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile ;3-{(3 R )-3-[(6-{4-[4-(2-Aminoethoxy)benzyl]piperazin-1-yl}-5-fluoro-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[( 5-fluoro-6-{4-[1-(3-hydroxybenzyl)piperidin-4-yl]piperazin-1-yl}-2-pyrazolo[1,5- a ]pyridine-3 -pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 3-[(3 R )-3-([2-(dimethylamino)ethyl) {5-Fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-((3 R )-3-{[5-fluoro-6-(4-{4-[2- (Methylamino)ethoxy]benzyl}piperazin-1-yl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine -1-yl)-3-oxopropiononitrile; N -[(3 R )-1-(3-aminopropionyl)piperidin-3-yl]-5-fluoro-6-[4- (4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine; 3-[(3 R )-3-( [2-(Dimethylamino)ethyl]{5-fluoro-6-[3-hydroxy-5-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1 , 5-( a )pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-(6-{[2-(dimethylamino) Ethyl][(3 R )-1-ethanehydrazinopiperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine 4-yl)-5-(4-methylpiperazin-1-yl)phenol; 3-((3 R )-3-{[6-(4-{[4-(dimethylamino)) Piperidin-1-yl]methyl}-3-hydroxyphenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine -1-yl)-3-oxomethoxypropionitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-5-{[(1-methylpiperidin-4) - yl) amino] methyl} phenyl) -2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl] amino} piperidine-1 ) -3-oxo-propionitrile,; 3 - ((3 R) -3 - {[5- fluoro-6- (4 - {(3-hydroxybenzyl) [(1-methyl-piperidin-4- -yl)methyl]amino}piperidin-1-yl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl) -3-Sideoxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[3-hydroxy-5-({[1-(3-piperidin-1-ylpropyl) Piperidin-4-yl]amino}methyl)phenyl]2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl] 3-oxooxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{6-[4-(methylamino)piperidin-1-yl]pyridine-3- }}-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-(5-fluoro-6-{[(3 R )-1-ethylene-hydrazinopiperidin-3-yl]amino}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5-{[(1 -methylpiperidin-4-yl)amino]methyl}phenol; 3-{(3 R )-3-[(5-fluoro-6-{4-[3-hydroxy-5-(1-A) Isopiperidin-4-yl)benzyl]piperazin-1-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin Pyridin-1-yl}-3-oxopropanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[4-(3-piperidin-1) -propyl)piperazin-1-yl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}- 3-sided oxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[(3-hydroxybenzyl)(3-piperidin-1-ylpropyl)) Amino]piperidin-1-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-yloxy Propionitrile; 3-((3 R )-3-{[6-(3-{[4-(cyclopentylamino)piperidin-1-yl]methyl}-5-hydroxyphenyl)-5 -fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[methyl(1-methylpiperidin-4-yl)amino]methyl}phenyl)-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-{(3 R )-3-[( 5-fluoro-6-{3-hydroxy-4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}-2-pyrazolo[1, 5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({6-[2 -(1,4-diazepan-1-yl)pyridin-4-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl }Amino)piperidin-1-yl]-3-oxopropiononitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-5-{[methyl ( 1-methylpiperidin-4-yl)amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine- 1-yl)-3-oxooxypropionitrile; 3-{(3 R )-3-[[5-fluoro-6-(3-hydroxy-5-{[(1-methylpiperidin-4-) Amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl](methyl)amino]piperidin-1-yl}- 3-sided oxypropionitrile; 3-{(3 R )-3-[(6-{3-[(cyclopentylamino)methyl]-5-hydroxyphenyl}-5-fluoro-2- Pyrazolo[1,5- a ]pyridine e-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3 -({6-[3-(1,4-diazepan-1-ylmethyl)-5-hydroxyphenyl]-5-fluoro-2-pyrazolo[1,5- a ] Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6-(3-{6- [4-(Dimethylamino)piperidin-1-yl]pyridin-3-yl}-5-hydroxyphenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridine-3 -pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile; 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy- 5-[(4-Methyl-1,4-diazepan-1-yl)methyl]phenyl}-2-pyrazolo[1,5- a ]pyridine-3 -pyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-hydroxy- 3-[(4-Methyl-1,4-diazepan-1-yl)methyl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 1-[4-(6-{[(3R)-1-(cyanoethenyl)piperidine-3 -amino]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]piperidine-4-carboxylic acid 1-methylpiperidine 4-yl ester; 3-{(3 R )-3-[(6-{6-[4-(cyclopentylamino)piperidin-1-yl]pyridin-3-yl}-5-fluoro -2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 3-((3 R ) -3-{[6-(3-{[4-(Dimethylamino)piperidin-1-yl]methyl}-4-hydroxyphenyl)-5-fluoro-2-pyrazolo[1 , 5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-[(3 R )-3-({5-fluorine) -6-[3-hydroxy-4-(piperazin-1-ylmethyl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino) Piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[(1-methylpiperidine) 4-yl) amino] methyl} phenyl) -2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl] amino} piperidine -1-yl)-3-oxopropanonitrile; 1'-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5 -Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]-4-methyl-1,4'-bipiperidine-4-carboxylic acid ethyl ester ;3-[(3 R )-3-({5-fluoro-6-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]-3- (methylthio)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxypropane Nitrile; 3-[(3 R )-3-({5-fluoro-6-[3-[(4-methyl-1,4-diazepan-1-yl)methyl]-4) -(Methylthio)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxy Propionitrile; 3-[(3 R )-3-({6-[4-({2-[4-(dimethylamino)piperidin-1-yl]ethyl}thio)phenyl] -5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-{ (3 R )-3-[(6-{6-[4-(Dimethylamino)piperidin-1-yl]-5-hydroxypyridin-3-yl}-5-fluoro-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({ 5-fluoro-6-[2-(4-isopropyl-1,4-diazepan-1-yl)pyridin-4-yl]-2-pyrazolo[1,5- a ] Pyridine-3- Pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-{(3 R )-3-[(6-{4-[(cyclopentylamino) )methyl]-3-hydroxyphenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}- 3-sided oxypropionitrile; 3-{(3 R )-3-[(6-{3-[(cyclopentylamino)methyl]-4-hydroxyphenyl}-5-fluoro-2- Pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 4-(6-{[(3R) 1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)benzoic acid Piperidin-4-yl ester; 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-4-[(methylamino)methyl]phenyl}-2-pyridyl) Zizo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanonitrile; 4-(6-{[(3R)- 1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)benzoic acid 1 '-Methyl-1,4'-bipiperidin-4-yl ester; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[methyl(pyridine) 4-yl)amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3 - oxo propionitrile; 3 - {(3 R) -3 - [(5- fluoro-6- {4 - [(5-fluoro-2-hydroxybenzamide ) Amino] piperidin-1-yl} -2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxo-side 3-propiononitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-hydroxy-3-[(methylamino)methyl]phenyl}-2-pyrazolo[1 , 5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 3-{[4-(cyclopentylamino)piperidine -1-yl]methyl}-5-(5-fluoro-6-{[(3 R )-1-ethanehydrazinopiperidin-3-yl]amino}-2-pyrazolo[1 , 5- a ]pyridin-3-ylpyrimidin-4-yl)phenol; 3-((3 R )-3-{{5-fluoro-6-[4-(3-hydroxybenzyl)piperazine- 1-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}[2-(methylamino)ethyl]amino}piperidin-1-yl) -3-Sideoxypropionitrile; 3-{[4-(5-fluoro-6-{[(3 R )-1-ethane-hydrazinopiperidin-3-yl][2-(methylamine) Ethyl)amino}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol; 3-[(3 R )-3-({6-[4-(1,4'-bipiperidin-1'-ylmethyl)-3-hydroxyphenyl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 2-((3 R )-3-{[5-fluoro-6- (4-{4-[2-(Methylamino)ethoxy]benzyl}piperazin-1-yl)-2-pyrazolo[1,5- a ] Pyridyl-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol; or a pharmaceutically acceptable salt or solvate thereof or N-oxide or stereoisomer Or a deuterated derivative.

Most interesting are: 3-{(3 R )-3-[[2-(dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazole[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[(5- Fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-{4-[(4-pyrrolidin-1-ylpyridin-2-yl)methyl]piperazin-1-yl Pyrimidine-4-yl)amino]piperidin-1-yl}-3-oxopropiononitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(4- Hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3- side Oxypropionitrile; 4-{[4-(5-fluoro-6-{[(3 R )-1-(3-hydroxy-3-methylbutyryl)piperidin-3-yl]amino}-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol; 3-((3 R )-3-{[6-(4 -{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridine-3- Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile; 2-((3 R )-3-{[6-(4-{4-[2-( Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amine Benzylpiperidin-1-yl)-2-oxoethanol; 6-(4-{4-[2-(dimethylamino)ethoxy]benzene } Piperazin-1-yl) -5-fluoro - N - [(3 R) -1- ( methoxy-acetyl) piperidin-3-yl] -2-pyrazolo [1,5- a Pyridyl-3-ylpyrimidin-4-amine; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]benzyl} Piperazin-1-yl)-5-fluoro-2-(5-methylpyrazolo[1,5- a ]pyridin-3-yl)pyrimidin-4-yl]amino}piperidin-1-yl 3-oxooxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]-3,5-di Methylbenzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl 3-oxooxypropionitrile; 4-{[4-(6-{[(3R)-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}piperidine-1-carboxylic acid tert-butyl ester; 3-[(3 R ) -3-({6-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-{(3 R )-3-[(6-{4-[4-(two Methylamino)pyridin-2-yl]piperazin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin Pyridin-1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[(6-{4-[3-(dimethylamino)propyl]piperazine-1- Base}-5- Fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(7-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine) -3-yl)piperidin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3- side Oxypropionitrile; 4-{[1-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1-carboxylic acid benzyl ester; ( R )-3-{3-[(6- {4-[(4-Benzylpiperazin-1-yl)methyl]piperidin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(4-methyl) Piperazine-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxy Propiononitrile; 1-(4-t-butylbenzyl)-4-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino} 5-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methylpiperazine-1-indole bromide; 3-[(3 R )-3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}methyl)phenyl] -5-fluoro-2-pyrazole [1,5-a] pyridine-3-yl} pyrimidin-4-yl amino) piperidin-1-yl] -3-oxo-propanenitrile; 3 - ((3 R) -3 - {[6 -(3-{[4-(Dimethylamino)piperidin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-yl Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )-3-({6-[4-({4-[2-( Dimethylamino)ethoxy]piperidin-1-yl}methyl)phenyl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl Amino)piperidin-1-yl]-3-oxopropanonitrile; 3-[(3 R )-3-({5-fluoro-6-[2-(4-methylpiperazine-1) -yl)pyridin-4-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxypropane Nitrile; 3-{(3 R )-3-[(6-{2-[4-(dimethylamino)piperidin-1-yl]pyridin-4-yl}-5-fluoro-2-pyridyl Zizo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanonitrile; 3-[(3 R )-3-( {5-Fluoro-6-[6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]-2-pyrazolo[1,5- a ] Pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; or a pharmaceutically acceptable salt or solvate thereof or N-oxide or stereoiso A construct or a deuterated derivative.

General synthesis program

The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It should be understood that other process conditions may be used in giving typical or preferred process conditions (i.e., reaction temperature, time, reactant molar ratio, solvent, pressure, etc.) unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents employed, but such conditions can be determined by those skilled in the art by conventional optimization procedures.

In addition, it will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for a particular functional group and suitable conditions for protecting and removing the protecting group are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999 and references cited therein.

The process for preparing the compounds of the invention is provided as a further embodiment of the invention and is illustrated by the following procedure.

According to one embodiment of the invention, the compound of formula (I) can be prepared by the following synthetic route, as illustrated in Scheme 1.

Treating the dichloropyrimidine of formula (II) with an amine of formula (III) in the presence of a base such as triethylamine or sodium bicarbonate in a solvent such as methanol or ethanol at a temperature ranging from ambient to reflux. A compound of formula (IV) is produced.

In the specific case where L ₁ is a direct bond and G ₁ is an aryl or heteroaryl ring, the compound of formula (I) can be obtained from the chloropyrimidine of formula (IV) by the formula (V) under the Suzuki-Miyaura reaction conditions. The compound (wherein Y is an acid or an acid ester) is obtained by reaction (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457). These reactions may be carried out by a suitable palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride methylene chloride complex or ruthenium (triphenylphosphine)palladium ( 0)) in a solvent such as toluene, 1,4-dioxane or 1,2-dimethoxyethane in the presence of a base such as cesium carbonate or sodium carbonate at 80 Catalyzed with or without microwave irradiation at temperatures in the range of °C-110 °C.

An acid or acid ester of the formula (V) wherein L ₁ is a direct bond, G ₁ is an aryl or heteroaryl ring and Y is an acid or an acid ester, or may be a halogen derivative according to the formula (V) Wherein Y is a bromine atom or a chlorine atom) by using a suitable boron reagent (such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1, 3,2-dioxaborolan)) using a palladium catalyst such as bis(diphenylphosphino)ferrocene]palladium(II) chloride complex or bis(dibenzylideneacetone) Palladium (0)) in a solvent such as 1,4-dioxane or 1,2-dimethoxyethane in the presence or absence of a ligand such as tricyclohexylphosphine in a base such as potassium acetate It is prepared in the presence of a temperature in the range of 80-150 ° C with or without microwave irradiation.

In another specific case where L ₁ is a direct bond and G ₁ is a heterocyclic group attached to the pyrimidine ring via a nitrogen atom, the compound of formula (I) can be derived from a chloro derivative of formula (IV) with formula (V) a heterocyclic amine (wherein Y is a hydrogen atom) in the absence of a solvent such as N,N' -dimethyl in the presence of a base such as sodium hydrogencarbonate or N -ethyl- N -isopropylpropan-2-amine The solvent of acetamide or 1-methylpyrrolidin-2-one is prepared by reacting at a temperature in the range of 80-130 ° C with or without microwave irradiation.

In still another specific case where L ₁ is a -NR ^x -(CH ₂ )- group, the compound of formula (I) may be a chloropyrimidine of formula (IV) and an amine of formula (V) wherein Y is hydrogen The atom is obtained by a reaction using microwave irradiation at 140 ° C in a solvent such as N -methylpyrrolidone.

The compound of formula (II) can be prepared as described in Scheme 2: Ethyl propiolate and N -aminopyridinium of formula (VII) (in the particular case where X = CR ^c ) or N -aminopyrazinium salt (in the particular case where X = N) For example, in the presence of a base of potassium carbonate, the reaction is carried out in a solvent such as N,N' -dimethylformamide at a temperature ranging from 0 ° C to ambient temperature to provide an ester of formula (VIII). N -aminopyridinium and N -aminopyrazinium salts of the formula (VII) are commercially available or may be obtained by the corresponding pyridine of the formula (VI) (in the specific case where X = CR ^c ) or pyrazine (in the specific case where X=N) is prepared by reacting O- (mesitylsulfonyl)hydroxylamine in a suitable solvent such as dichloromethane at a temperature ranging from 0 ° C to ambient temperature. . Treatment of the ester of formula (VIII) with a mixture of trimethylaluminum and ammonium chloride in a solvent such as toluene at 80 ° C provides the oxime intermediate of formula (IX). The oxime of formula (IX) can be reacted with a malonate of formula (X) to form a dihydroxypyrimidine of formula (XI). These reactions can be carried out in the presence of a suitable base such as sodium methoxide in a solvent such as methanol at a temperature ranging from 0 ° C to ambient temperature. The dihydroxypyrimidine of formula (XI) can be converted to the dichloropyrimidine of formula (II) by treatment with a suitable chlorinating agent such as phosphorus oxychloride (V) at a temperature ranging from 25 ° C to reflux. .

In the particular case where L ₁ is a direct bond and G ₁ is an aryl or heteroaryl ring, the compound of formula (I) can also be prepared by an alternative synthetic method, as shown in Scheme 3: Treatment of the trichloropyrimidine of formula (XII) with an amine of formula (III) in the presence of a base such as triethylamine or sodium bicarbonate in a solvent such as ethanol at -20 °C yields a compound of formula (XIII).

In the particular case where L ₁ is a direct bond and G ₁ is an aryl or heteroaryl ring, the compound of formula (XIV) can be derived from formula (XIII) Pyrimidines are obtained by reaction with a compound of formula (V) wherein Y is an acid or an acid ester under Suzuki-Miyaura reaction conditions. These reactions can be catalyzed by a suitable palladium catalyst such as ruthenium (triphenylphosphine)palladium(0) in a solvent such as 1,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 °C. Formula (XIV) Pyrimidine is reacted with a stannane of formula (XV) in the presence of a palladium catalyst such as ruthenium (triphenylphosphine)palladium(0) in a solvent such as 1,4-dioxane at 100 ° C to provide formula (I) ) compound.

In another specific case, the compound of formula (I) wherein R ³ is a hydrogen atom may be further added to a solvent such as N,N' -dimethylformamide in a suitable base such as sodium hydride, followed by the addition of, for example, iodine An alkylating agent of methane or (2-chloroethyl)dimethylamine hydrochloride, which is reacted at a temperature ranging from ambient temperature to 80 ° C to provide a compound of formula (I) wherein R ³ is now A Base or -(CH ₂ ) ₂ -NMe ₂ group).

In yet another particular case, the compound of formula (I) wherein the residue at G ₁ , G ₂ or R ¹ is functionalized with a suitable protecting group such as benzyl (Bn) or methoxy (OMe) The alcohol, phenol or carboxylic acid moiety can be removed under standard conditions at the alcohol, phenol or carboxylic acid moiety ( Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). In the particular case of the primary alcohol, the free alcohol portion can then be oxidized under standard conditions to form the corresponding aldehyde.

In still another specific aspect, the compound of formula (I) and the compound of formula (XIV) wherein the residue at G ₁ contains an aldehyde moiety can be further reacted with a primary or secondary amine such as sodium triethoxy borohydride. a reducing agent in the presence of a solvent such as dichloromethane at ambient temperature the reaction formula (I) and a compound of formula (XIV) (wherein in the residue of G ₁ is now the secondary or tertiary amine).

In still another particular embodiment, the compound of formula (I) wherein the residue at G ₁ , G ₂ or R ¹ contains a suitable moiety such as a third butoxycarbonyl (BOC) or a benzyloxycarbonyl (CBZ) The protecting group functionalized amine moiety can be removed at the amine moiety under standard conditions ( Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). The corresponding free amine can then be further functionalized under standard conditions to yield the corresponding guanamine, urethane and N -alkylated amine.

Starting compounds are commercially available or can be obtained according to conventional synthetic methods known in the art.

Instance

The synthesis of the compounds of the present invention and the intermediates therefor are illustrated by the following Examples (1-139), including Preparation Examples (Preparation 1-117), and are provided to provide the skilled artisan with sufficient clarity of the present invention. It is fully explained, but should not be construed as limiting the basic aspects of the subject matter as set forth in the previous section of this specification.

preparation Preparation 1 Pyrazolo[1,5- a ]pyridine-3-carboxamidine a) Pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester

Potassium 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 dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and chloroform. The organic phase was separated, EtOAc m m m m m m

LRMS (m/z): 191 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.4 (t, 3H), 4.4 (q, 2H), 7.0 (td, 1H), 7.4 (ddd, 1H), 8.2 (d, 1H), 8.4 (s , 1H), 8.6 (dt, 1H).

b) pyrazolo[1,5- a ]pyridine-3-carboxamidine

A 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 118.29 mmol) was added dropwise to ammonium chloride (5.90 g, 118.29) at 0 °C. Methyl) in a stirred suspension in toluene (100 mL). The reaction mixture was stirred at room temperature for 1 hour. A solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (preparation 1a, 7.50 g, 39.43 mmol) in toluene (20 mL) was then added and the mixture was stirred overnight at 80 °C. Further, a 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 118.29 mmol) and toluene (100 mL) containing ammonium chloride (5.90 g, 118.29 mmol) were added and the reaction mixture was further stirred at 80 ° C for 24 hours. After cooling to 0 ° C 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 dry. The residue was purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 161 (M+1) ⁺ .

Preparation 2 5-methylpyrazolo[1,5-a]pyridine-3-carboxamidine a) 2,4,6-trimethylbenzenesulfonic acid 1-amino-4-methylpyridine-1-pyrene

A solution of O-(mesitylsulfonyl)hydroxylamine (23.11 g, 107.4 mmol) in dichloromethane (272 mL) was added dropwise to 4-methylpyridine (10.0 g, 107.4 mmol) in dichloromethane The cooled (0 ° C) solution in (136 mL) and the resulting mixture was stirred at room temperature for 2 hr. The solvent was partially evaporated and diethyl ether was added to precipitate an oil. The reaction mixture was cooled to 0 ° C and the solvent was decanted. The oil was dried <RTI ID=0.0>

LRMS (m/z): 109 (M) ⁺ .

¹ H-NMR δ (300MHz, 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]pyridine-3-carboxylate

A solid was obtained from 2,4,6-trimethylbenzenesulfonic acid 1-amino-4-methylpyridin-1-indole (Preparation 2a) and ethyl propiolate according to the experimental procedure as described in Preparation 1a ( 54%), the crude product was purified by flash chromatography (hexane / ethyl acetate).

LRMS (m/z): 205 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, 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]pyridine-3-carboxamidine

Toluene (62 mL, 124 mmol) containing 2.0 M trimethylaluminum solution was added dropwise to a cooled (0 ° C) suspension of ammonium chloride (6.18 g, 115.6 mmol) in toluene (133 mL) and the mixture was stirred until A gas is formed again. Then a solution of ethyl 5-methylpyrazolo[1,5-a]pyridine-3-carboxylate (preparation 2b, 7.87 g, 38.53 mmol) in toluene (25 mL) was added dropwise and the reaction mixture was at 80 ° C Stir overnight. Ammonium chloride (6.18 g, 115.6 mmol) and toluene (62 mL, 124 mmol) containing a 2.0 M trimethylaluminum solution were added and the suspension was stirred at 80 ° C overnight and stirred at room temperature over the weekend. The reaction mixture was cooled at 0 ° C and methanol (30 mL) was added dropwise. The suspension was filtered through diatomaceous earth (Celite ^©) and the solid was washed with methanol. The organic phases were combined, the solvent was partially evaporated (up to 100 mL solution) and dichloromethane (100 mL) was added. The solid formed was filtered and the solvent was evaporated to dryness. The residue was purified by EtOAcqqqqqq

LRMS (m/z): 175 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, 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).

Preparation 3 3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)pyrazolo[1,5- a ]pyridine a) 5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4,6-diol

Pyrazolo[1,5- a ]pyridine-3-carboxamidine (Preparation 1b, 4.75 g, 29.47 mmol) was added portionwise to sodium (1.63 g, 71.02 mmol) in methanol (120 mL). In solution. Diethyl 2-fluoromalonate (7.0 mL, 44.20 mmol) was then added and the mixture was stirred from 0 ° C to room temperature overnight. The solvent was evaporated to dryness crystals crystals crystals crystals

LRMS(m/z): 247(M+1) ⁺

¹ H-NMR δ (300MHz, DMSO-d ₆ ): 7.2 (t, 1H), 7.5-7.7 (m, 1H), 8.7 (d, 1H), 8.8-8.9 (m, 2H), 11.8 (bs, 1H), 12.7 (bs, 1H).

b) 3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)pyrazolo[1,5- a ]pyridine

5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4,6-diol (preparation 3a, 7.00 g, 28.43 mmol) and phosphorus oxychloride (V) (55 mL, The mixture of 589 mmol) was stirred at 110 ° C 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 sulfate and evaporated The title compound (5.3 g, 65%).

LRMS(m/z): 283(M+1) ⁺

¹ H-NMR δ (300 MHz, CDCl ₃ ): 7.0 (td, 1H), 7.4 (ddd, 1H), 8.6 (dd, 2H), 8.7 (s, 1H).

Preparation 4 3-(4,6-Dichloro-5-methylpyrimidin-2-yl)pyrazolo[1,5-a]pyridine a) 5-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4,6-diol

Pyrazolo[1,5-a]pyridine-3-carboxamidine (Preparation 1b, 2.89 g, 18.05 mmol) and diethyl methylmalonate (6.44 mL, 37.45 mmol) were added portionwise to 0 °C A solution of sodium (1.24 g, 53.91 mmol) in MeOH (14 mL). The solvent was evaporated to dryness and the residue was dissolved in water and acidified to pH = 1 using 6N hydrochloric acid. The precipitate was filtered, washed with EtOAc EtOAcjjjjjjj

LRMS (m/z): 243 (M + 1) ⁺ .

¹ H-NMR δ (400MHz, DMSO- d ₆ ): 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-Dichloro-5-methylpyrimidin-2-yl)pyrazolo[1,5-a]pyridine

According to the experimental procedure as described in Preparation 3b, 5-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4,6-diol (Preparation 4a) and trichloro Phosphorus oxide (V) gave a solid (30%), which was then purified by flash chromatography (hexane/ethyl acetate 1:4).

LRMS (m/z): 279 (M + 1) ⁺ .

¹ H-NMR δ (400MHz, 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).

Preparation 5 3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)-5-methylpyrazolo[1,5-a]pyridine a) 5-fluoro-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4,6-diol

A yellow solid was obtained from 5-methylpyrazolo[1,5-a]pyridine-3-carboxamidine (Preparation 2c) and diethyl 2-fluoromalonate according to the procedure described in Preparation 4a. %).

LRMS (m/z): 261 (M + 1) ⁺ .

^{1 H-NMR δ (400MHz,} 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).

b) 3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)-5-methylpyrazolo[1,5-a]pyridine

5-fluoro-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4,6-diol (Preparation 5a, 1.19 g, 4.57 mmol) and phosphorus oxychloride A mixture of (V) (9.3 mL, 99.6 mmol) was stirred at 110 ° C for 75 min. The solvent was removed under reduced pressure and water was added. Filter the precipitate, wash it with water and be true The title compound (1.08 g, 79%).

LRMS (m/z): 297 (M + 1) ⁺ .

¹ H-NMR δ (400MHz, 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) .

Preparation 6 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -yl-3-oxoxypropionitrile a) (3R)-3-[(6-Chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid Third butyl ester

( R )-3-Aminopiperidine-1-carboxylic acid tert-butyl ester (2.97 g, 14.83 mmol) was added to 3-(4,6-dichloro-5-fluoropyrimidin-2-yl)pyrazole [ 1,5- a ]pyridine (preparation 3b, 3.50 g, 12.36 mmol) and triethylamine (2.0 mL, 15.08 mmol) in EtOAc (EtOAc) After cooling to room temperature, the solvent was evaporated under reduced pressure and water was added. The precipitate was filtered and dried <RTI ID=0.0>

LRMS (m/z): 447 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 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).

b) 6-Chloro-5-fluoro- N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine

1,4-Dioxane (31.4 mL, 125.6 mmol) containing 4.0 M hydrogen chloride solution was added to (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 6a, 5.61 g, 12.55 mmol) in 1,4-dioxane (150 mL) The resulting mixture was stirred at room temperature overnight. The resulting precipitate was filtered, washed with EtOAc EtOAcjjjjjjj

LRMS (m/z): 347 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 1.7-2.2 (m, 5H), 2.9-3.1 (m, 2H), 3.4 (t, 1H), 3.6-3.7 (m, 1H), 4.4-4.7 (m, 1H), 7.1 (td, 1H), 7.5 (ddd, 1H), 8.5 (d, 1H), 8.6 (dd, 2H).

c) 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidine -1-yl}-3-sided oxypropionitrile

3-[(2,5-Di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile (prepared as described in BE 875054 (A1), 3.58 g, 19.66 mmol) was added to 6-Chloro-5-fluoro- N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-yl-pyrimidine-4-amine (Preparation 6b , 5.5 g, 13.10 mmol) and a solution of triethylamine (9.1 mL, 65.7 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature overnight. Further 3-[(2,5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile (0.80 g, 4.39 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours . The solvent was evaporated under reduced pressure and water was added. The resulting precipitate was filtered, washed with EtOAcjjjjjjjjj

LRMS (m/z): 414 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.7-2.0 (m, 4H), 2.2 (t, 1H), 3.3-3.5 (m, 2H), 3.6-3.7 (m, 1H), 3.9 (dd, 1H), 4.3 (bs, 1H), 4.6 (d, 1H), 5.0 (d, 1H), 6.91 (dt, 1H), 7.39 (ddd, 1H), 8.4-8.6 (m, 2H), 8.7 (s , 1H).

Preparation 7 ( S )-6-Chloro-5-fluoro- N- (1-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1,5-a]pyridin-3-yl) Pyrimidine-4-amine

3- (4,6-dichloro-5-fluoro-2-yl) pyrazolo [1,5- a] pyridine (Preparation 3b, 1.00g, 3.53mmol), ( 1 S) -1- (5 A mixture of fluoropyridin-2-yl)ethylamine dihydrochloride (0.85 g, 6.06 mmol) and sodium bicarbonate (1.40 g, 16.66 mmol) The solvent was evaporated and the residue was crystallisjjjjjjjjjj

LRMS (m/z): 387 (M + 1) ⁺ .

Preparation 8 ( R )-3-(3-((6-chloro-5-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine -1-yl)-3-oxopropiononitrile a) ( R )-3-((6-chloro-5-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine- 1-butyl formate

3 - (4, 6 - dichloro --5-- methyl-pyrimidin - 2 - yl) pyrazolo [1,5-a] pyridine (Preparation 4b, 1.11g, 3.98mmol), ( R) -3- amino A mixture of piperidine-1-carboxylic acid tert-butyl ester (0.93 g, 4.65 mmol) and diisopropylethylamine (1.04 mL, 5.97 mmol) in ethanol (12 mL) was evaporated. N,N' -dimethylacetamide (9 mL) was then added and the reaction mixture was stirred at 100 ° C for additional 68 hours. The ethanol was evaporated and excess water was added. The precipitate was filtered, washed with water and dried then evaporated

LRMS (m/z): 443 (M + 1) ⁺ .

b) ( R )-6-Chloro-5-methyl- N- (piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4-amine

A 4M solution of hydrogen chloride in 1,4-dioxane (16 mL) was added to ( R )-3-((6-chloro-5-methyl-2-(pyrazolo[1,5-a]pyridine- 3-ter)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (preparation 8a, 1.49 g, 3.37 mmol) in 1,4-dioxane (20 mL) The reaction mixture was stirred at room temperature overnight. Dichloromethane (160 mL) was then added and the suspension was stirred at room temperature for 24 h. The solvent was evaporated in vacuo <RTI ID=0.0>

LRMS (m/z): 343 (M + 1) ⁺ .

c) ( R )-3-(3-((6-chloro-5-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino) Piperidin-1-yl)-3-oxopropiononitrile

( R )-6-Chloro-5-methyl- N- (piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4-amine (Preparation 8b, 0.97g, 2.55mmol), 3-[(2,5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile (0.76g, 4.16mmol) and triethylamine (1.57mL, 11.29mmol) in N, N '- dimethylformamide (9mL) in the solution was stirred overnight at rt. The reaction mixture was diluted with water and the precipitate was filtered. The title compound (0.7 g, 67%).

LRMS (m/z): 410 (M + 1) ⁺ .

^{1 H-NMR δ (400MHz,} DMSO- d 6): 1.51-1.82 (m, 3H), 2.00-2.11 (m, 1H), 2.13 (s, 3H), 2.54-2.74 (m, 1H), 2.96- 3.09 (m, 1H), 3.62-3.76 (dd, 1H), 3.85-4.35 (m, 4H), 4.67-4.70 (d, 1H), 6.77-6.81 (m, 1H), 7.02-7.06 (t, 1H) ), 7.43-7.49 (m, 1H), 8.37-8.40 (d, 1H), 8.61-8.66 (d, 1H), 8.76-8.80 (m, 1H).

Preparation 9 ( R )-3-(3-((6-Chloro-5-fluoro-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)) Piperidin-1-yl)-3-oxopropiononitrile a) ( R )-3-((6-chloro-5-fluoro-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino) Piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 6a from 3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-5-methylpyrazolo[1,5-a]pyridine (Preparation 5b) and (R) -3- amino-piperidin-1-carboxylic acid tert-butyl ester obtained as a solid (100%).

LRMS (m/z): 461 (M+1) ⁺ .

¹ H-NMR δ (400MHz, CDCl ₃ ): 1.42 (bs, 9H), 1.62 (m, 2H), 1.75-1.94 (m, 2H), 1.99-2.08 (m, 1H), 2.46 (s, 3H) , 3.45-3.53 (m, 3H), 3.73-3.86 (m, 1H), 4.24-4.33 (m, 1H), 5.10-5.29 (bs, 1H), 6.69-6.71 (d, 1H), 8.23 (s, 1H), 8.37-8.39 (d, 1H), 8.57 (s, 1H).

b) (R) -6- chloro-5-fluoro-2- (5-methyl-pyrazolo [1,5-a] pyridin-3-yl) - N - (piperidin-3-yl) pyrimidin - 4-amine

A 4M solution of hydrogen chloride in 1,4-dioxane (23 mL) was added to ( R )-3-((6-chloro-5-fluoro-2-(5-methylpyrazolo[1,5-a a solution of tert-butyl pyridin-3-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate (preparation 9a, 2.07 g, 4.49 mmol) in 1,4-dioxane (35 mL) The resulting solution was stirred at room temperature for 2 hours. An excess of diethyl ether was added and the residue was purified eluting elut elut elut elut elut elut elut elut

LRMS (m/z): 361 (M + 1) ⁺ .

^{1 H-NMR δ (400MHz,} DMSO- d 6): 1.59-1.72 (m, 1H), 1.80-2.00 (m, 2H), 2.08-2.13 (m, 1H), 2.50 (s, 3H), 2.89- 2.92 (m, 2H), 3.21-3.30 (d, 1H), 3.31-3.48 (d, 1H), 4.54 (bs, 2H), 6.91-6.94 (d, 1H), 8.01-8.03 (d, 1H), 8.12 (s, 1H), 8.63 (s, 1H), 8.69-8.71 (d, 1H), 9.22 (bs, 1H), 9.38 (bs, 1H).

c) ( R )-3-(3-((6-Chloro-5-fluoro-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl) Amino)piperidin-1-yl)-3-oxopropanenitrile

8c prepared according to the experimental procedure of the (R) -6- chloro-5-fluoro-2- (5-methyl-pyrazolo [1,5-a] pyridin-3-yl) - N - ( Piperidin-3-yl)pyrimidine-4-amine (Preparation 9b) and 3-[(2,5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile to give a solid ( 83%), and the crude product was purified by flash chromatography (hexane/ethyl acetate).

LRMS (m/z): 428 (M+1) ⁺ .

¹ H-NMR δ (400 MHz, DMSO- d ₆ ): 1.44-1.75 (m, 2H), 1.78-1.88 (m, 1H), 2.02-2.15 (m, 1H), 2.41 (s, 3H), 2.62 ( t,1H), 2.76(t,1H), 2.96-3.13(d,1H), 3.16-3.18(d,1H),3.62-3.78(dd,1H),3.87-4.30(m,4H),4.60- 4.68 (dd, 1H), 6.90-6.92 (d, 1H), 7.83-7.93 (dd, 1H), 8.07-8.11 (d, 1H), 8.52-8.57 (d, 1H), 8.66-8.70 (dd, 1H) ). .

Preparation 10 ( R ) -N 1-(5-Fluoro-6-morpholinyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl) -N 2, N 2- Dimethyl- N 1-(piperidin-3-yl)ethane-1,2-diamine a) (3 R )-3-[(5-fluoro-6-morpholin-4-yl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino] Piperidine-1-carboxylic acid tert-butyl ester

(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid A mixture of tributyl ester (preparation 6a, 0.15 g, 0.34 mmol) and morpholine (0.14 g, 1.68 mmol) in 1-methylpyrrolidin-2-one (1.5 mL) was placed in a microwave container at 130 Microwave irradiation was carried out at ° C for 2 hours. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The organic phase was separated, EtOAcjjjjjjjjjjj

LRMS (m/z): 498 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.55 (s, 9H), 1.60 (m, 2H), 1.70-1.85 (m, 2H), 3.25-3.60 (bd, 3H), 3.67-3.89 (dt, 8H), 4.17-4.30 (m, 1H), 4.76 (bs, 1H), 6.82 (td, 1H), 7.24-7.32 (m, 1H), 8.40-8.50 (dd, 2H), 8.55 (s, 1H) .

b) (3 R )-3-[[2-(Dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1,5-a]pyridine 3-butylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 0.041g, 1.03mmol) was added portionwise to the (3 R) -3 - [( 5- fluoro-2-morpholin-4-pyrazolo [1 , 5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 10a, 0.17 g, 0.34 mmol) and (2-chloroethyl) dimethyl A suspension of the amine hydrochloride (0.074 g, 0.51 mmol) in N, N' -dimethylformamide (2 mL) and mixture was stirred overnight at 55 °C. Further, (2-chloroethyl)dimethylamine hydrochloride (0.074 g, 0.51 mmol) and sodium hydride (0.041 g, 1.03 mmol) were added and the mixture was stirred at 65 ° C for further 72 hours. 2-Chloroethyl)dimethylamine hydrochloride (0.074 g, 0.51 mmol) and sodium hydride (0.041 g, 1.03 mmol) were added and the reaction mixture was stirred at 65 ° C for 24 hours. Water (6 mL) was added and EtOAc m.

LRMS (m/z): 570 (M+2) ⁺ .

c)( R ) -N 1-(5-fluoro-6-morpholinyl-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl) -N 2, N 2-dimethyl- N 1-(piperidin-3-yl)ethane-1,2-diamine

Of hydrogen chloride in 1,4-dioxane (1.6 mL of) was added to 4.0M in the (3 R) -3 - [[ 2- ( dimethylamino) ethyl] (5-fluoro-6-morpholino 3-butyl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 10b, 0.18 g, 0.32 mmol ) in a solution of methanol (4 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the title compound wasjjjjjjjjjjjjj

LRMS (m/z): 469 (M + 1) ⁺ .

Preparation 11 1-[(1-methyl-1H-imidazol-2-yl)methyl]piperazine a) 4-[(1-methyl-1H-imidazol-2-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester

Tri-butyl 1-piperazinecarboxylate (0.5 g, 2.68 mmol), 2-(chloromethyl)-1-methyl-1 H -imidazole hydrochloride (0.45 g, 2.68 mmol) and triethylamine (0.79) A solution of mL, 5.67 mmol) in acetonitrile (20 mL) was stirred at <RTIgt; The solvent was evaporated and the crude material was partitioned eluted with ethyl acetate. The organic phase was separated, EtOAcjjjjjjjjj

LRMS (m/z): 281 (M + 1) ⁺ .

b) 1-[(1-Methyl-1H-imidazol-2-yl)methyl]piperazine

4-[(1-Methyl-1H-imidazol-2-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester (preparation 11a, 0.59 g, 2.10 mmol) and ethanol (1.25 mL) containing 1.25 M hydrogen chloride solution The mixture was stirred at room temperature for 8 hours. The solvent was evaporated and the~~~~~~~~~~~~~~~~~~~~

LRMS (m/z): 181 (M + 1) ⁺ .

Preparation 12 5-fluoro-6-{4-[(1-methyl-1 H -imidazol-2-yl)methyl]piperazin-1-yl}- N -[(3 R )-piperidin-3-yl ]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine a) (3 R )-3-[(5-fluoro-6-{4-[(1-methyl-1 H -imidazol-2-yl)methyl]piperidin Triazin-1-yl}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid Tributyl ester (preparation 6a, 0.1g, 0, 22mmol), 1-[(1-methyl-1H-imidazol-2-yl)methyl]piperazine (preparation 11b, 0.098g, 0,34mmol) and carbonic acid A suspension of sodium hydrogen (0.17 g, 2,02 mmol) in N,N' -dimethylacetamide (0.6 mL) was stirred at &lt Excess water was added and the precipitate formed was filtered, washed with water and dried. The solid was purified by flash chromatography eluting EtOAc

LRMS (m/z): 592 (M+2) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.30-1.54 (m, 6H), 1.67-1.88 (m, 3H), 1.93-2.13 (m, 1H), 2.50-2.70 (m, 3H), 3.16- 3.45 (m, 2H), 3.45-3.61 (m, 1H), 3.62-3.81 (m, 6H), 4.15-4.30 (m, 1H), 4.68-4.81 (m, 1H), 6.77-6.86 (m, 1H) ), 6.86-6.92 (d, 1H), 6.92-7.00 (d, 1H), 7.26-7.32 (m, 1H), 8.36-8.64 (m, 1H).

b) 5-Fluoro-6-{4-[(1-methyl-1 H -imidazol-2-yl)methyl]piperazin-1-yl}- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine

Of hydrogen chloride in 1,4-dioxane (2mL) was added to 4.0M in the (3 R) -3 - [( 5- fluoro-6- {4 - [(1-methyl -1 H - imidazol-2 -yl)methyl]piperazin-1-yl}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (Preparation 12a, 0.087 g, 0.15 mmol) <RTI ID=0.0> The solvent was evaporated and EtOAc EtOAc m.

LRMS (m/z): 492 (M+2) ⁺ .

Preparation 13 2-(piperazin-1-ylmethyl)-1H-benzimidazole a) 4-(1H-benzimidazol-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester

Tri-butyl 1-piperazinecarboxylate (1.0 g, 5.37 mmol), 2-(chloromethyl)-1 H -benzimidazole (0.89 g, 5.34 mmol) and potassium carbonate (0.82gr, 5.93 mmol) in acetonitrile The mixture in (20 mL) was stirred at room temperature overnight. The solvent was evaporated and the crude material obtained was suspended in water and filtered. The title compound (0.8 g, 45%) was obtained eluted

LRMS (m/z): 317 (M+1) ⁺ .

b) 2-(piperazin-1-ylmethyl)-1 H -benzimidazole

Add 4.0 M solution of hydrogen chloride in 1,4-dioxane (5 mL) to 4-(1H-benzimidazol-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (Preparation 13a, 0.8 g , 2.53 mmol) in a solution of methanol (6 mL) and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated and the residue was crystallised eluted eluted eluted The title compound (0.15 g, 24%).

LRMS (m/z): 217 (M + 1) ⁺ .

Preparation 14 6-[4-(1 H -benzimidazol-2-ylmethyl)piperazin-1-yl]-5-fluoro- N -[(3 R )-piperidin-3-yl]-2-pyridyl Oxazo[1,5-a]pyridin-3-ylpyrimidin-4-amine a) (3 R) -3 - ({6- [4- (1 H - benzimidazol-2-ylmethyl) piperazin-1-yl] -5-fluoro-2-pyrazolo [1, 3-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester

(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid Tributyl ester (preparation 6a, 0.1 g, 0.22 mmol), 2-(piperazin-1-ylmethyl)-1H-benzimidazole (preparation 13b, 0.063 g, 0.29 mmol) and sodium bicarbonate (0.056 g, A mixture of 0.67 mmol) in N,N' -dimethylacetamide (1 mL) was stirred at 130 ° C for 12 h. Further, 2-(piperazin-1-ylmethyl)-1H-benzimidazole (20 mg) was added and the mixture was further stirred at 130 ° C for 4 hours. After cooling to room temperature, water (6 mL) was evaporated.

LRMS (m/z): 628 (M+2) ⁺ .

b) 6-[4-(1 H -Benzimidazol-2-ylmethyl)piperazin-1-yl]-5-fluoro- N -[(3 R )-piperidin-3-yl]-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine

Of hydrogen chloride in 1,4-dioxane (1 mL) was added to 4.0M in the (3 R) -3 - ({ 6- [4- (1 H - benzimidazol-2-yl-methyl) piperazine - 1-butyl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 14a, 0.128 g, 0.2 mmol) in a solution of MeOH (3 mL). The solvent was evaporated and the residue was crystallisjjjjjjjjjjjj

LRMS (m/z): 528 (M+2) ⁺ .

Preparation 15 N,N -dimethyl-2-(piperazin-1-ylmethyl)pyridin-4-amine a) 4-[(4-bromopyridin-2-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester

Sodium triethoxy borohydride (0.85 g, 4.01 mmol) was added to 4-bromopyridinecarboxaldehyde (0.25 g, 1.34 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.28 g, 1.48 mmol) and acetic acid ( 0.02 mL, 0.4 mmol) in dichloromethane (5 mL) EtOAc. The solvent was then evaporated and the residue was triturated with diethyl ether filtered and evaporated in vacuo. The residue was purified by flash chromatography eluting elut elut elut

LRMS (m/z): 356/358 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.46 (s, 9H), 2.46 (t, 4H), 3.46 (t, 4H), 3.64 (s, 2H), 7.62 (d, 1H), 8.37 (d) , 1H).

b) N,N -dimethyl-2-(piperazin-1-ylmethyl)pyridin-4-amine

4-[(4-Bromopyridin-2-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester (preparation 15a, 0.1 g, 0.28 mmol) and 40% aqueous dimethylamine (0.18 mL, 1.42 mmol) The mixture was stirred overnight at 155 ° C in a sealed tube. The solvent was evaporated and the residue was washed with ethyl acetate. The resulting material was triturated with EtOAc (EtOAc)

LRMS (m/z): 221 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 2.77 (s, 4H), 3.17-3.33 (m, 10H), 3.77 (s, 2H), 6.83-6.98 (m, 2H), 8.05 (d, 1H) ).

Preparation 16 1-[(4-pyrrolidin-1-ylpyridin-2-yl)methyl]piperazine a) 4-[(4-pyrrolidin-1-ylpyridin-2-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester

4-[(4-Bromopyridin-2-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester (preparation 15a, 0.10 g, 0.28 mmol) and pyrrolidine (0.12 mL, 1.40 mmol) in ethanol (1 mL The solution in the solution was stirred overnight at 80 °C. Pyrrolidine (0.12 mL, 1.40 mmol) was added and the mixture was stirred at 80 ° C overnight. The solvent and excess pyrrolidine were evaporated to dryness and the residue was partitioned between water and dichloromethane. The title compound (86 mg, 88%).

LRMS (m/z): 347 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.45 (s, 9H), 2.02 (m, 4H), 2.46 (m, 4H), 3.31 (m, 4H), 3.45 (m, 4H), 3.53 (s) , 2H), 6.27 (dd, 1H), 6.48 (d, 1H), 8.15 (d, 1H).

b) 1-[(4-Pyrrolidin-1-ylpyridin-2-yl)methyl]piperazine

Add 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.65 mL, 2.60 mmol) to 4-[(4-pyrrolidin-1-ylpyridin-2-yl)methyl]piperazine-1-carboxylic acid A stirred solution of the third butyl ester (Preparation 16a, 0.09 g, 0.25 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at room temperature for 3 hours and then a solution of hydrogen chloride in EtOAc (EtOAc) After stirring overnight, the precipitate formed was filtered and dried in vacuo to give crystals crystals crystals

LRMS (m/z): 247 (M + 1) ⁺ .

Preparation 17 4-[(4-{5-fluoro-6-[(3 R )-piperidin-3-ylamino]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4- Peptazin-1-yl)methyl]phenol a) (3 R )-3-({5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a] Pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester

(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid Tributyl ester (preparation 6a, 2.20g, 4.92mmol), 1-(4-methoxybenzyl)piperazine (1.5g, 7.27mmol) and sodium bicarbonate (3.80g, 45.23mmol) in N,N The mixture in dimethyl acetamide (10 mL) was stirred at 130 ° C overnight. After cooling to rt, EtOAc (EtOAc m.

LRMS (m/z): 618 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.54-1.85 (m, 13H), 2.49-2.64 (m, 4H), 2.98 (m, 4H), 3.50 (s, 2H), 3.67-3.78 (m, 6H), 3.81 (s, 3H), 4.21 (m, 1H), 4.72 (m, 1H), 6.77-6.92 (m, 3H), 7.26 (m, 3H), 8.46 (m, 2H), 8.55 (s) , 1H).

b) 5-Fluoro-6-[4-(4-methoxybenzyl)piperazin-1-yl] -N -[(3 R )-piperidin-3-yl]-2-pyrazole [1,5-a]pyridin-3-ylpyrimidin-4-amine

Trifluoroacetic acid (1.80mL, 23.37mmol) was added dropwise to (3 R) -3 - ({ 5- fluoro-6- [4- (4-methoxybenzyl) piperazin-1-yl] - T-butyl 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylate (Preparation 17a, 2.86 g, 4.64 mmol) in dichloromethane The solution in (80 mL) was stirred at room temperature overnight. Additional trifluoroacetic acid (1.80 mL, 23.37 mmol) was added and after stirring for additional 4 hours, water was added and mixture was basified with 4% aqueous sodium bicarbonate. The organic layer was separated by EtOAc EtOAc (EtOAc)

LRMS (m/z): 518 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.53-1.88 (m, 4H), 2.52-2.61 (m, 4H), 2.64-2.84 (m, 2H), 2.85-2.98 (m, 2H), 3.28 ( Dd,1H), 3.50 (s, 2H), 3.68-3.78 (m, 4H), 3.81 (s, 3H), 4.23 (m, 1H), 4.97 (m, 1H), 6.81 (td, 1H), 6.85 -6.91 (m, 2H), 7.20 - 7.31 (m, 3H), 8.40 - 8.54 (m, 3H).

c) 4-[(4-{5-fluoro-6-[(3 R )-piperidin-3-ylamino]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl}piperazin-1-yl)methyl]phenol

A 1.0 M solution of boron tribromide in dichloromethane (2.5 mL, 2.5 mmol) was added dropwise to 5-fluoro-6-[4-(4-methoxybenzyl)piperazine at 0 °C. 1-yl] -N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 17b, 0.32 g, 0.62 mmol) in a solution of dichloromethane (30 mL). The reaction mixture was allowed to warm to rt and stirred overnight. Methanol (10 mL) was added dropwise and the mixture was stirred 10 min then evaporated. The title compound (310 mg, 100%) was obtained eluted eluted eluted eluted eluted

LRMS (m/z): 503 (M + 1) ⁺ .

Preparation 18 N,N -dimethyl-2-(4-(piperazin-1-ylmethyl)phenoxy)ethylamine a) 4-[2-(Dimethylamino)ethoxy]benzaldehyde

4-hydroxybenzaldehyde (6.0 g, 49.1 mmol), 2-chloro- N,N -dimethylethylamine hydrochloride (10.61 g, 73.70 mmol) and potassium carbonate (20.37 g, 147.4 mmol) in N, N The mixture in dimethylformamide (60 mL) was stirred at 90 ° C overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 194 (M + 1) ⁺ .

b) N, N - dimethyl-2- (4- (piperazin-1-ylmethyl) phenoxy) ethanamine

4-[2-(Dimethylamino)ethoxy]benzaldehyde (preparation 18a, 7.25 g, 37.5 mmol), piperazine-1-carboxylic acid tert-butyl ester (6.98 g, 37.5 mmol) and triethyl hydrazine A mixture of sodium oxyborohydride (9.54 g, 45.0 mmol) in dichloromethane (30 mL) The reaction mixture was washed with aq. The solvent was evaporated to dryness. EtOAc (EtOAc m. The solvent was evaporated and EtOAc EtOAc m.

LRMS (m/z): 264 (M + 1) ⁺ .

¹ H-NMR δ (300 MHz, CD ₃ OD): 3.0 (s, 6H), 3.6 (s, 10H), 4.3-4.5 (m, 4H), 7.2 (d, 2H), 7.6 (d, 2H).

Preparation 19 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine a) (3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 17a from ( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl Amino] piperidine-1-carboxylic acid tert-butyl ester (preparation 6a) and N,N -dimethyl-2-[4-(piperazin-1-ylmethyl)phenoxy]ethylamine (preparation) 18b) A solid (60%) was obtained, which was then purified by flash chromatography.

LRMS (m/z): 674 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.40 (bs, 9H), 1.70-1.80 (m, 4H), 1.94-2.07 (m, 2H), 2.33 (s, 6H), 2.50-2.60 (m, 4H), 3.67-3.77 (m, 4H), 4.06 (t, 2H), 4.20 (m, 1H), 4.71 (d, 1H), 6.80 (m, 1H), 6.85-6.93 (m, 2H), 7.24 (m, 3H), 8.35-8.58 (m, 3H).

b) 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine -3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine

Of hydrogen chloride in 1,4-dioxane (3.70mL, 14.80mmol) was added to 4.0M in the (3 R) -3 - {[ 6- (4- {4- [2- ( dimethylamino) Ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 - a solution of tert-butyl formate (preparation 19a, 0.99 g, 1.46 mmol) in 1,4-dioxane (10 mL). The reaction crude material was filtered and the obtained solid was suspended in 1,4-dioxane and basified with a 2.0 M solution of ammonia in ethanol. The resulting suspension was filtered and the filtrate was evaporated in vacuo. The residue was purified by EtOAcqqqqqq

LRMS (m / z): 575 (M + 2) +.

Preparation 20 N, N - dimethyl-2- [3- (piperazin-1-ylmethyl) phenoxy] ethanamine a) 3-[2-(Dimethylamino)ethoxy]benzaldehyde

3-hydroxybenzaldehyde (0.20 g, 1.64 mmol), 2-chloro- N,N -dimethylethylamine hydrochloride (0.36 g, 2.64 mmol) and potassium carbonate (0.9 g, 6.51 mmol) in acetonitrile (6 mL) The mixture was stirred at 70 ° C overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate The crude material was purified by EtOAcjjjjjjjjj

LRMS (m/z): 194 (M + 1) ⁺ .

b) N,N -dimethyl-2-[3-(piperazin-1-ylmethyl)phenoxy]ethylamine

3-[2-(Dimethylamino)ethoxy]benzaldehyde (Preparation 20a, 0.12 g, 0.61 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.61 mmol) and triethyl hydrazine A mixture of sodium oxyborohydride (0.15 g, 0.7 mmol) in dichloromethane (5 mL) Reaction mixture Wash with 2N aqueous sodium hydroxide solution and 0.1 N aqueous hydrogen chloride solution. The organic layer was separated, dried over magnesium sulfate and evaporated. A 5N aqueous hydrogen chloride solution (5 mL) was added to the residue and the mixture was stirred at room temperature for one hour. The solvent was evaporated and the residue was partitioned between dichloromethane and 2N aqueous sodium hydroxide. The title compound (92 mg, 52%) eluted elute

LRMS (m/z): 264 (M + 1) ⁺ .

Preparation 21 N,N -dimethyl-3-(4-(piperazin-1-ylmethyl)phenoxy)propan-1-amine a) 4-(3-(Dimethylamino)propoxy)benzaldehyde

3-Chloro- N,N -dimethylpropan-1-amine dihydrochloride (3.10 g, 19.60 mmol) was added to 4-hydroxybenzaldehyde (2.00 g, 16.40 mmol), cesium carbonate (13.30 g, 41.00 mmol) And a suspension of potassium iodide (0.10 g, 0.61 mmol) in N,N -dimethylformamide (40 mL) and the mixture was stirred at 80 ° C for 2 hr. After cooling to room temperature, the solid was filtered and washed with ethyl acetate. The combined filtrate and washings were washed with EtOAcq.

LRMS (m/z): 208 (M + 1) ⁺ .

¹ H-NMR δ (400MHz, CDCl ₃ ): 1.98 (dd, 2H), 2.25 (s, 6H), 2.45 (t, 2H), 4.10 (t, 2H), 7.00 (d, 2H), 7.81 (d) , 2H), 9.87 (s, 1H).

b) tert-butyl 4-(4-(3-(dimethylamino)propoxy)benzyl)piperazine-1-carboxylate

4-[3-(Dimethylamino)propoxy]benzaldehyde (Preparation 21a, 2.00 g, 9.65 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.59 g, 19.3 mmol) in methanol (76 mL) The mixture was stirred at room temperature for 30 minutes. Sodium triethoxysulfonate (0.73 g, 11.6 mmol) was added and the acetic acid was catalyzed and the mixture was stirred at room temperature for additional 90 min. The solvent was evaporated and the residue was partitioned between dichloromethane and sat. The organic layer was separated and washed with aq. The residue was purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 378 (M + 1) ⁺ .

¹ H-NMR δ (400MHz, CDCl ₃ ): 1.44 (s, 9H), 1.97 (dd, 2H), 2.29 (s, 6H), 2.34 - 2.35 (m, 4H), 2.49 (t, 2H), 3.39 -3.43 (m, 6H), 4.00 (t, 2H), 6.82 - 6.86 (m, 2H), 7.18 - 7.20 (m, 2H).

c) N,N -dimethyl-3-(4-(piperazin-1-ylmethyl)phenoxy)propan-1-amine

Add 4.0 M solution of hydrogen chloride in 1,4-dioxane (17 mL, 68.2 mmol) to 4-(4-(3-(dimethylamino)propoxy)benzyl)piperazine-1- To a stirred solution of 1,4-dioxane (22 mL) and water (0.10 mL), EtOAc. The solvent was evaporated and EtOAc EtOAc m.

LRMS (m/z): 278 (M+1) ⁺ .

^{1 H-NMR δ (400MHz,} D 2 O): 2.26 (m, 2H), 2.96 (s, 6H), 3.94 (t, 2H), 3.61 (bs, 8H), 4.22 (m, 2H), 4.44 ( s, 2H), 7.11 - 7.13 (d, 2H), 7.49 - 7.51 (d, 2H).

Preparation 22 1-[4-(2-piperidin-1-ylethoxy)benzyl]piperazine a) tert-butyl 4-(4-hydroxybenzyl)piperazine-1-carboxylate

Sodium triethoxy borohydride (0.63 g, 2.95 mmol) was added to 4-hydroxybenzaldehyde (0.30 g, 2.47 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 2.70 mmol) and acetic acid ( 0.042 mL, 0.74 mmol) in dichloromethane (10 mL) EtOAc. The reaction mixture was partitioned between diethyl ether and water. The organic phase was separated, dried EtOAcjjjjjjjjj

LRMS (m/z): 293 (M + 1) ⁺ .

b) tert-butyl 4-[4-(2-piperidin-1-ylethoxy)benzyl]piperazine-1-carboxylate

T-butyl 4-(4-hydroxybenzyl)piperazine-1-carboxylate (preparation 22a, 0.55 g, 1.88 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.420 g, 2.28) A suspension of potassium acetate (0.786 g, 5.69 mmol) in N,N' -dimethylformamide (4 mL) was stirred at 50 ° C overnight. The reaction mixture was filtered and the filtrate evaporated to dry. The resulting oil was partitioned between diethyl ether and 1N aqueous sodium hydroxide. The organic layer was separated, EtOAcjjjjjjjjj

LRMS (m/z): 404 (M + 1) ⁺ .

c) 1-[4-(2-piperidin-1-ylethoxy)benzyl]piperazine

Add 4.0 M solution of hydrogen chloride in 1,4-dioxane (6 mL) to 4-[4-(2-piperidin-1-ylethoxy)benzyl]piperazine-1-carboxylic acid tert-butyl The ester (preparation 22b, 0.488 g, 1.19 mmol) eluted elute The solvent was evaporated and the residue was crystalljjjjjjjjjjjjjjj

LRMS (m/z): 304 (M + 1) ⁺ .

Preparation 23 1-(4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)piperazine a) 4-(2-(pyrrolidin-1-yl)ethoxy)benzaldehyde

Barium carbonate (10 g, 30.7 mmol), (1-(2-chloroethyl)pyrrolidine hydrochloride (2.5 g, 14.7 mmol) and a catalytic amount of potassium iodide were added portionwise to 4-hydroxybenzaldehyde (1.50 g, 12.3). Methyl) in a solution of N,N' -dimethylformamide (30 mL) and the resulting suspension was stirred at 60 ° C for 2 h and at 80 ° C for 1 h. The reaction mixture was filtered and solid The organic layer was washed with water (100 mL). EtOAc (EtOAc)EtOAc. The solvent was evaporated to give the title compound (1.

LRMS (m/z): 220 (M + 1) ⁺ .

¹ H-NMR δ (400 MHz, CDCl ₃ ): 1.80-1.83 (m, 4H), 2.61-2.64 (m, 4H), 2.91-2.94 (t, 2H), 4.17 - 4.20 (t, 2H), 7.00- 7.03 (d, 2H), 7.81 - 7.83 (d, 2H), 9.87 (s, 1H).

b) 4-(4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)piperazine-1-carboxylic acid Third butyl ester

Piperazine-1-carboxylic acid tert-butyl ester (3.16 g, 16.96 mmol) was added to 4-(2-(pyrrolidin-1-yl)ethoxy)benzaldehyde (Preparation 23a, 1.86 g, 8.48 mmol) in methanol The solution in (74 mL) and the resulting mixture was stirred at room temperature for 10 min. Sodium cyanoborohydride (0.64 g, 10.2 mmol) was then added and the pH of the solution was adjusted to 5 by the addition of acetic acid. After stirring at room temperature for 1.5 hours, the solvent was evaporated mjjjjjjjjjjj The organic phase was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 390 (M + 1) ⁺ .

¹ H-NMR δ (400 MHz, CDCl ₃ ): 1.44 (s, 9H), 1.80-1.82 (m, 4H), 2.34 - 2.36 (m, 4H), 2.65 (s, 4H), 2.90 - 2.93 (t, 2H), 3.39-3.43 (m, 6H), 4.09-4.12 (t, 2H), 6.85-6.87 (d, 2H), 7.19-7.21 (d, 2H).

c) 1-(4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)piperazine

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (13.2 mL, 52.8 mmol) was added to 4-(4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)piperazine- A solution of 1-butylic acid tert-butyl ester (preparation 23b, 1.03 g, 2.65 mmol) in 1,4-dioxane (20 mL). An excess of diethyl ether was added and the suspension was filtered and washed with diethyl ether toiel

LRMS (m/z): 290 (M + 1) ⁺ .

¹ H-NMR δ (400MHz, D ₂ O): 2.04-2.10 (m, 2H), 2.17-2.23 (m, 2H), 2.65 (m, 2H), 2.90-2.93 (t, 2H), 3.61 (bs) , 6H), 3.70 (m, 4H), 3.76 (m, 1H), 4.42-4.44 (m, 4H), 7.14 - 7.16 (d, 2H), 7.51 - 7.53 (d, 2H).

Preparation 24 [2-(4-{[(2 R ,6 S )-2,6-Dimethylpiperazin-1-yl]methyl}phenoxy)ethyl]dimethylamine

Sodium triethoxy borohydride (0.32 g, 1.51 mmol) was added to (3 R , 5 S )-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.28 g, 1.30 mmol) and A solution of 4-[2-(dimethylamino)ethoxy]benzaldehyde (Preparation 18a, 0.25 g, 1.29 mmol) in dichloromethane (10 mL). The reaction mixture was washed with EtOAc EtOAc. A 4 M solution of hydrochloric acid in 1,4-dioxane was added to the residue and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated to dryness to give crystals crystals crystals

LRMS (m/z): 292 (M + 1) ⁺ .

Preparation 25 {2-[2,6-Dimethyl-4-(piperazin-1-ylmethyl)phenoxy]ethyl}dimethylamine a) 4-[2-(Dimethylamino)ethoxy]-3,5-dimethylbenzaldehyde

A mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (1.00 g, 6.66 mmol) and potassium carbonate (2.76 g, 20 mmol) in EtOAc (40 mL) The reaction was cooled to room temperature and add potassium iodide (0.06g, 0.33mmol) and 2-chloro - N, N - dimethyl-amine (1.08g, 7.46mmol) and the mixture was stirred overnight at 50 ℃. The reaction mixture was cooled to room temperature, filtered and evaporated to dryness. The residue was partitioned between water and ethyl acetate. The organic layer was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 222 (M + 1) ⁺ .

b) 4-{4-[2-(Dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazine-1-carboxylic acid tert-butyl ester

4-[2-(Dimethylamino)ethoxy]-3,5-dimethylbenzaldehyde (Preparation 25a, 0.98 g, 4.43 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.99 g) A mixture of 5.31 mmol) in methanol (40 mL) was stirred at room temperature for 1 hour. Acetic acid (0.51 mL, 8.86 mmol) and sodium cyanoborohydride (0.33 mg, 5.31 mmol) were added and the mixture was stirred at room temperature for one hour. The solvent was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with aq. The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m / z): 392 (M + 1) +.

c) {2-[2,6-Dimethyl-4-(piperazin-1-ylmethyl)phenoxy]ethyl}dimethylamine

4-{4-[2-(Dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazine-1-carboxylic acid tert-butyl ester (Preparation 25b, 0.63 g, 1.60 mmol ) A mixture of hydrogen chloride in 4.0 M solution of 1,4-dioxane (8 mL, 32 mmol) was stirred at room temperature for 1 hour. The reaction mixture was filtered and EtOAcjjjjjjjjjj

LRMS (m/z): 292 (M + 1) ⁺ .

^{1 H-NMR δ (400MHz,} D 2 O): 2.35 (s, 6H), 3.09 (s, 6H), 3.53-3.65 (m, 8H), 3.66-3.71 (m, 2H), 4.17-4.28 (m , 2H), 4.38 (s, 2H), 7.26 (s, 2H).

Preparation 26 {2-[3,5-Dimethyl-4-(piperazin-1-ylmethyl)phenoxy]ethyl}dimethylamine a) 4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzaldehyde

According to the experimental procedure as described in 25a was prepared from 4-hydroxy-2,6-dimethylbenzaldehyde and 2-chloro - N, N - dimethyl-amine as a solid (50%).

LRMS (m/z): 222 (M + 1) ⁺ .

b) 4-{4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 25b, 4-[2-(dimethylamino)ethoxy]-2,6-dimethylbenzaldehyde (Preparation 26a) and piperazine-1-carboxylic acid The tributyl ester obtained a solid (48%), which was then purified by flash chromatography (dichloromethane to dichloromethane / methanol 9:1).

LRMS (m/z): 392 (M + 1) ⁺ .

c) {2-[3,5-Dimethyl-4-(piperazin-1-ylmethyl)phenoxy]ethyl}di Methylamine

According to the experimental procedure as described in Preparation 25c, the third procedure consists of 4-{4-[2-(dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazine-1-carboxylic acid. Butyl ester (Preparation 26b) gave the solid hydrochloride (100%).

LRMS (m/z): 292 (M + 1) ⁺ .

^{1 H-NMR δ (400MHz,} D 2 O): 2.32 (s, 6H), 2.84 (s, 6H), 3.43-3.52 (m, 8H), 3.53-3.62 (m, 2H), 4.23-4.28 (m , 2H), 4.41 (s, 2H), 6.74 (s, 2H).

Preparation 27 c) N,N -dimethyl-2-[4-(2-piperazin-1-ylethyl)phenoxy]ethylamine a) 4-[2-(4-hydroxyphenyl)ethyl]piperazine-1-carboxylic acid tert-butyl ester

4-(2-Bromoethyl)phenol (0.9 g, 4.48 mmol), 1-butyl piperazinecarboxylic acid tert-butyl ester (1.0 g, 5.37 mmol) and N -ethyl- N -isopropyl-2-propylamine ( A mixture of 1.56 mL, 8.95 mmol) in acetonitrile (18 mL) was stirred at <RTI ID=0.0> The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, EtOAc mjjjjjjjjj

LRMS (m/z): 307 (M + 1) ⁺ .

b) 4-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)piperazine-1-carboxylic acid tert-butyl ester

4- [2- (4-hydroxyphenyl) ethyl] piperazine-1-carboxylic acid tert-butyl ester (Preparation 27a, 1.13g, 3.70mmol), 2- chloro - N, N - dimethylethylamine salt A mixture of the acid salt (0.64 g, 4.40 mmol), potassium iodide (0.06 g, 0.37 mmol) and potassium carbonate (1.53 g, 11.0 mmol) in acetone (20 mL) was warmed at 60 ° C for 20 hours. After cooling to room temperature, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulfate The residue was purified by EtOAcqqqqq

LRMS (m/z): 378 (M + 1) ⁺ .

c) N,N -dimethyl-2-[4-(2-piperazin-1-ylethyl)phenoxy]ethylamine

According to the experimental procedure as described in Preparation 25c, tert-butyl 4-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)piperazine-1-carboxylate ( Preparation 27b) Obtained the solid hydrochloride (99%).

LRMS (m / z): 278 (M + 1) +.

¹ H-NMR δ (300MHz, DMSO- d ₆ ): 2.8 (s, 6H), 3.0 (dd, 2H), 3.2-3.6 (m, 12H), 4.3 (t, 2H), 7.0 (d, 2H) , 7.2 (d, 2H).

Preparation 28 3-{(3 R )-3-[(5-fluoro-6-piperazin-1-yl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amine Piperidin-1-yl}-3-oxopropiononitrile a) 4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a] Pyridin-3-ylpyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -yl}-3-oxopropanenitrile (preparation 6c, 0.20 g, 0.48 mmol), 1-piperazinecarboxylic acid tert-butyl ester (0.108 g, 0.58 mmol) and sodium bicarbonate (0.131 g, 1.56 mmol) The suspension in N,N' -dimethylacetamide (0.8 mL) was stirred at 100 ° C for 56 hours. After cooling to room temperature, excess water was added and the residue was filtered,jjjjjjjjjjj

LRMS (m/z): 565 (M+2) ⁺ .

b) 3-{(3 R )-3-[(5-fluoro-6-piperazin-1-yl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl) Amino]piperidin-1-yl}-3-oxopropiononitrile

A 4M solution of hydrogen chloride in 1,4-dioxane (2.13 mL) was added to 4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino} -5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (preparation 28a, 0.24 g, 0.43 mmol) in ethanol The solution in (4 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue was takenqqqq eluted The title compound (0.078 g, 38%).

LRMS (m/z): 464 (M+1) ⁺ .

Preparation 29 4-(dimethylamino)ethyl 4-methylmercaptobenzoate a) 2-(Dimethylamino)ethyl 4-(hydroxymethyl)benzoate

A mixture of methyl 4-(hydroxymethyl)benzoate (1.0 g, 6 mmol) and 2-(dimethylamino)ethanol (10 g, 112 mmol) was stirred at 100 ° C overnight. The reaction mixture was partitioned between diethyl ether and water. The organic layer was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 224 (M+l) ⁺ .

b) 2-(dimethylamino)ethyl 4-methylmercaptobenzoate

Manganese dioxide (0.674 g, 7.75 mmol) was added to 2-(dimethylamino)ethyl 4-(hydroxymethyl)benzoate (preparation 29a, 0.172 g, 0.77 mmol) in chloroform (1.7 mL) The resulting suspension was stirred at 45 ° C for 48 hours. The suspension was diluted with dichloromethane and filtered through diatomaceous earth (Celite ^®). The filtrate was evaporated to dryness crystals crystals crystals crystals

LRMS (m/z): 222 (M + 1) ⁺ .

Preparation 30 4-(piperazin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester a) 4-{[1-(Tertoxycarbonyl)piperidin-4-yl]methyl}piperazine-1-carboxylic acid benzyl ester

4-Methylmercaptopiperidine-1-carboxylic acid tert-butyl ester (0.98 g, 4.60 mmol), piperazine-1-carboxylic acid benzyl ester (1.02 g, 4.61 mmol) and sodium triethoxy borohydride (1.01) A mixture of g, 4.76 mmol) in dichloromethane (30 mL) The title compound (1.68 g, 87%) eluted elute

LRMS (m/z): 418 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.20-1.35 (m, 3H), 1.45 (s, 9H), 1.80-2.20 (m, 3H), 2.60-2.90 (m, 6H), 3.50 (s, 2H), 3.77-4.58 (m, 6H), 5.15 (s, 2H), 7.32-7.40 (m, 5H).

b) tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate

Add 10% palladium on carbon (0.10 g, 0.97 mmol) to 4-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}piperazine-1-carboxylic acid benzyl ester (Preparation 30a) , 0.80 g, 2.31 mmol) in a suspension in ethanol (15 mL) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diatomaceous earth (Celite ^®), and the filtrate was evaporated. The residue was filtered through a pad of EtOAc (EtOAc) eluting with EtOAc. The solvent was evaporated to dryness crystals crystals

LRMS (m/z): 284 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 0.94-1.13 (m, 2H), 1.45 (s, 9H), 1.51-1.76 (m 3H), 2.25 (d, 2H), 2.56-2.79 (m, 8H) ), 3.20 (m, 4H), 4.14 (bs, 1H).

Preparation 31 1-(2,6-dimethylpyridin-4-yl)piperazine a) tert-butyl 4-(2,6-dimethylpyridin-4-yl)piperazine-1-carboxylate

To the Schlenk tube, piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.62 mmol), 4-bromo-2,6-lutidine (0.15 g, 0.81 mmol), and third butanol were fed. Sodium (0.09 g, 0.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.01 g, 0.02 mmol) and toluene (4 mL). The Schlenk tube was subjected to three vacuum-backfill cycles with argon followed by the addition of bis(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred overnight at 90 °C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth (Celite ^®) and washed with water. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc.

LRMS (m/z): 292 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.48 (s, 9H), 2.43 (s, 6H), 3.25-3.32 (m, 4H), 3.51-3.58 (m, 4H), 6.38 (s, 2H) .

b) 1-(2,6-dimethylpyridin-4-yl)piperazine

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.70 mL, 6.80 mmol) was added to the tert-butyl 4-(2,6-dimethylpyridin-4-yl)piperazine-1-carboxylate ( A stirred solution of 31a, 0.20 g, EtOAc (EtOAc) The solvent was evaporated and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and basified by the addition of 4% aqueous sodium bicarbonate. The water was evaporated to dryness and dichloromethane was added. After stirring vigorously for 30 minutes, the solid was filtered and evaporatedjjjjjjjjj

LRMS (m/z): 192 (M + 1) ⁺ .

^{1 H-NMR δ (300MHz,} CDCl 3): 2.43 (s, 6H), 2.92-3.03 (m, 4H), 3.24-3.30 (m, 4H), 6.39 (s, 2H).

Preparation 32 1-(2-pyrrolidin-1-ylpyridin-4-yl)piperazine a) 4-butyl 2-(2-chloropyridin-4-yl)piperazine-1-carboxylate

To the Schlenk tube was fed piperazine-1-carboxylic acid tert-butyl ester (1.74 g, 9.34 mmol), 4-bromo-2-chloropyridine (1.35 g, 7.02 mmol), and sodium butoxide (1.35 g). , 14.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.32 g, 0.55 mmol) and toluene (45 mL). The Schlenk tube was subjected to three evacuation cycles with argon backfill followed by the addition of bis(dibenzylideneacetone)dipalladium (0.17 g, 0.19 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 90 °C for 4 hours. After cooling to room temperature, the reaction mixture was diatomaceous earth (Celite ^®) was filtered and washed with ethyl acetate. The filtrate and washings were combined and the solvent was evaporated to dryness. The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 298 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.49 (s, 9H), 3.30-3.37 (m, 4H), 3.53-3.60 (m, 4H), 6.57 (dd, 1H), 6.65 (d, 1H) , 8.04 (d, 1H).

b) 4-(2-pyrrolidin-1-ylpyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

To the Schlenk tube was added tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (preparation 32a, 0.30 g, 1.01 mmol), pyrrolidine (0.21 mL, 2.52 mmol) ), sodium butoxide (0.29 g, 3.02 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.03 g, 0.05 mmol) in toluene (3 mL). The Schlenk tube was subjected to three vacuum-backfill cycles with argon followed by the addition of palladium acetate (0.01 g, 0.05 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred overnight at 80 °C. After cooling to room temperature, the reaction mixture was diatomaceous earth (Celite ^®) was filtered and washed with ethyl acetate. The filtrate and washings were combined and the solvent was evaporated to dryness. The residue was purified by EtOAc EtOAc EtOAc EtOAc

LRMS (m/z): 192 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 2.00-2.11 (m, 4H), 3.40-3.48 (m, 4H), 3.53 (m, 4H), 3.57-3.63 (m, 4H), 6.22 (dd, 1H), 7.95 (d, 1H), 8.52 (s, 1H).

c) 1-(2-pyrrolidin-1-ylpyridin-4-yl)piperazine

Add 4.0 M solution of hydrogen chloride to 1,4-dioxane (1.12 mL, 4.48 mmol) to 4-(2-pyrrolidin-1-ylpyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Preparation 32b, 0.15 g, 0.45 mmol) EtOAc m. The reaction mixture was filtered and EtOAc EtOAcjjjjjjjj

LRMS (m/z): 233 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 2.07-2.17 (m, 4H), 3.33 - 3.43 (m, 4H), 3.47-3.57 (m, 4H), 3.80-3.92 (m, 4H), 5.99 (s, 1H), 6.65 (d, 1H), 7.62 (d, 1H).

Preparation 33 N,N -dimethyl-4-piperazin-1-ylpyridin-2-amine a) 4-[2-(Dimethylamino)pyridin-4-yl]piperazine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 32b, 3-butyl 2-(2-chloropyridin-4-yl)piperazine-1-carboxylate (Preparation 32a) and dimethylamine salt The acid salt was obtained as a colorless oil (yield: 39%).

LRMS (m/z): 307 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.48 (s, 9H), 3.06 (s, 6H), 3.24 - 3.31 (m, 4H), 3.51-3.60 (m, 4H), 5.79 (d, 1H) , 6.12 (dd, 1H), 7.94 (d, 1H).

b) N,N -dimethyl-4-piperazin-1-ylpyridin-2-amine

The solid hydrochloride salt was obtained from 4-[2-(dimethylamino)pyridin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (preparation 33a) according to the procedure procedure as described in Preparation 32c. %).

LRMS (m/z): 207 (M + 1) ⁺ .

Preparation 34 N,N -dimethyl-2-piperazin-1-ylpyridin-4-amine a) 2-Chloro- N,N -dimethylpyridin-4-amine

A colorless oil (70%) was obtained from 4-bromo-2-chloropyridine and dimethylamine hydrochloride, and then crude material was purified by flash chromatography.

LRMS (m/z): 157/159 (M+1) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 3.01 (s, 6H), 6.42 (dd, 1H), 6.49 (d, 1H), 7.78 (d, 1H).

b) 4-[4-(Dimethylamino)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester

Colorless oil was obtained from 2-chloro- N,N -dimethylpyridin-4-amine (preparation 34a) and piperazine-1-carboxylic acid tert-butyl ester (54%) according to the procedure The crude product was then purified by flash chromatography (hexane to diethyl ether).

LRMS (m/z): 307 (M + 1) ⁺ .

c) N,N -dimethyl-2-piperazin-1-ylpyridin-4-amine

Solid hydrochloride salt (91) was obtained from 4-[4-(dimethylamino)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (preparation 34b) according to the procedure procedure %).

LRMS (m/z): 207 (M + 1) ⁺ .

Preparation 35 4-[4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 12a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-piperazin-1-ylpiperidine-1-carboxylic acid tert-butyl ester afforded solid (51% The crude product was then purified by flash chromatography (dichloromethane to dichloromethane / methanol 9:1).

LRMS (m/z): 647 (M + 1) ⁺ .

Preparation 36 2-(piperidin-4-ylmethyl)isoporphyrin a) tert-butyl 4-(1,3-dihydro-2H-isoindol-2-ylmethyl)piperidine-1-carboxylate

Sodium triethoxy borohydride (0.47 g, 2.22 mmol) was added to isoporphyrin (0.22 g, 1.85 mmol), 4-methylmercapto-1-piperidinecarboxylic acid A solution of the third butyl ester (0.40 g, 1.88 mmol) and acetic acid (0.033 mL, 0.58 mmol) in dichloromethane (10 mL). The reaction mixture was partitioned between excess diethyl ether and water. The organic phase was separated, washed with EtOAc EtOAcjjjjjjj

LRMS (m/z): 317 (M + 1) +.

b) 2-(piperidin-4-ylmethyl)isoporphyrin

Add 4.0 M solution of hydrogen chloride in 1,4-dioxane (13 mL) to 4-(1,3-dihydro-2H-isoindol-2-ylmethyl)piperidine-1-carboxylic acid tert-butyl The ester (preparation 36a, 0.610 g, 1.93 mmol) in MeOH (10 mL). Diethyl ether was added until the blue solid completely precipitated. The solid was filtered and washed with EtOAcqqqqqqqq

LRMS (m/z): 217 (M + 1) ⁺ .

Preparation 37 N,N -dimethyl-2-(4-(piperidin-4-ylmethyl)phenoxy)ethylamine a) tert-butyl 4-(4-hydroxybenzyl)piperidine-1-carboxylate

4-(4-Hydroxybenzyl)piperidine hydrochloride (0.38 g, 1.67 mmol), dibutyl succinate (0.37 g, 1.69 mmol) and sodium hydrogencarbonate (1.4 g, 16.70 mmol) A mixture of 4-dioxane and water in a 1:1 mixture (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water and brine then dried over sodium sulfate. By flash chromatography (n-hexane to positive The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 292 (M + 1) ⁺ .

b) tert-butyl 4-{4-[2-(dimethylamino)ethoxy]benzyl}piperidine-1-carboxylate

T-butyl 4-(4-hydroxybenzyl)piperidine-1-carboxylate (preparation 37a, 0.20 g, 0.70 mmol), 2-chloro- N,N -dimethylethylamine hydrochloride (0.12 g A mixture of 0.8 mmol) and cesium carbonate (0.91 g, 2.79 mmol) in tetrahydrofuran (4 mL) was heated at 130 ° C for 20 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, EtOAc m m m m m m

LRMS (m/z): 363 (M+1) ⁺ .

c) N,N -dimethyl-2-(4-(piperidin-4-ylmethyl)phenoxy)ethylamine

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.50 mL, 5.46 mmol) was added to 4-{4-[2-(dimethylamino)ethoxy]benzyl}piperidine-1 A stirred solution of the toluene butyrate (preparation 37b, 0.20 g, 0.55 mmol) in 1,4-dioxane (3 mL) and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated and the residue was crystalljjjjjjjjjjjj

LRMS (m/z): 263 (M + 1) ⁺ .

^{1 H-NMR δ (300MHz,} DMSO-d 6): 1.3-1.4 (m, 4H), 1.7 (d, 2H), 2.8 (s, 6H), 3.2 (d, 3H), 3.6-3.8 (m, 3H), 4.2-4.3 (m, 2H), 4.3-4.4 (m, 2H), 6.9 (d, 2H), 7.1 (d, 2H).

Preparation 38 2,6-Dimethyl- N -piperidin-4-ylpyridin-4-amine a) 4-[(2,6-dimethylpyridin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

To the Schlenk tube was fed 4-aminopiperidine-1-carboxylic acid tert-butyl ester (0.249 g, 1.24 mmol), 4-bromo-2,6-lutidine (0.193 g, 1.04 mmol), Potassium tert-butoxide (0.290 g, 2.58 mmol) and toluene (5 mL). The Schlenk tube was subjected to three vacuum-backfill cycles with argon followed by the addition of bis(dibenzylideneacetone)dipalladium (76 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2 ' , 4 ' , 6 ' -triisopropylbiphenyl (10 mg, 0.02 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered through Celite ^® diatomaceous earth and the filtrate was concentrated to dryness. The crude residue was purified by EtOAcqqqqqq

LRMS (m/z): 306 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.34 (td, 2H), 1.47 (s, 9H), 2.01 (dd, 2H), 2.39 (s, 6H), 2.93 (t, 2H), 3.39-3.54 (m, 1H), 3.92 (d, 1H), 4.06 (d, 2H), 6.15 (s, 2H).

b) 2,6-Dimethyl- N -piperidin-4-ylpyridin-4-amine

Solid hydrochloride salt was obtained from 4-[(2,6-dimethylpyridin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 38a) according to the procedure described in Preparation 37c (100%).

LRMS (m/z): 206 (M + 1) ⁺ .

Preparation 39 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid benzyl ester

Add 4.0 μM solution of hydrogen chloride in 1,4-dioxane (15 mL, 60 mmol) to 4-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}piperate at 0 °C A solution of benzyl azine-formate benzyl ester (preparation 30a, 0.86 g, 2.06 mmol) in methanol (15 mL). The solvent was evaporated and the residue was filtered thru EtOAc (EtOAc) eluting with EtOAc (EtOAc) The solvent was evaporated to dryness crystals crystals

LRMS (m/z): 318 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.50-1.62 (m, 5H), 1.95-2.05 (m, 2H), 2.20-2.27 (m, 2H), 2.28-2.42 (m, 4H), 2.77- 2.87 (m, 2H), 3.44 - 3.48 (m, 6H), 5.12 (s, 2H), 7.27-7.37 (m, 5H).

Preparation 40 N,N ,2-trimethyl-6-[1-(piperidin-4-ylmethyl)piperidin-4-yl]pyridin-4-amine a) 4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}methyl)piperidine-1-carboxylic acid tert-butyl ester

Sodium triethoxy borohydride (0.24 g, 1.13 mmol) was added to N,N ,2-trimethyl-6-piperidin-4-ylpyridin-4-amine dihydrochloride (0.28 g, 0.96 mmol , a solution of tert-butyl 4-methylmercapto-1-piperidinecarboxylate (0.20 g, 0.94 mmol) and triethylamine (0.25 mL, 1.79 mmol) in dichloromethane (4 mL) Stir overnight at room temperature. The crude material was partitioned between excess diethyl ether and water. The organic phase was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 417 (M + 1) ⁺ .

b) N,N ,2-trimethyl-6-[1-(piperidin-4-ylmethyl)piperidin-4-yl]pyridin-4-amine

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (4 mL) was added to 4-({4-[4-(dimethylamino)-6-methylpyridin-2-yl]piperidine-1 A solution of -3 -methyl)piperidine-l-carboxylic acid tert-butyl ester (preparation 40a, 0.308 g, 0.74 mmol) in EtOAc (10 mL). The solvent was evaporated and the residue was crystalljjjjjjjjjjjjjjj

LRMS (m/z): 317 (M+1) ⁺ .

Preparation 41 ( R )-4-(4-((6-((1-(2-cyanoethyl))piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

Feeding a microwave reactor with 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl) Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c, 0.15 g, 0.36 mmol) and 4-[4-(aminomethyl)phenyl]piperazine-1-carboxylic acid Third butyl ester (0.42 g, 1.45 mmol) of N -methylpyrrolidone (1.5 mL). The reaction mixture was subjected to microwave irradiation at 140 ° C for 2 hours, followed by pouring into water. The precipitate was filtered, washed with EtOAc EtOAcjjjjjjjj

LRMS (m/z): 669 (M + 1) ⁺ .

Preparation 42 ( R )-5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenyl)-N-(piperidin-3-yl)-2-(pyrazolo[1,5 -a]pyridin-3-yl)pyrimidine-4-amine a) ( R )-3-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyrazolo[1,5-a]pyridine- 3-butyl)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Fed to the Schlenk tube (3 R) -3 - [( 6- chloro-5-fluoro-2-pyrazolo [1,5-a] pyridin-3-yl-pyrimidin-4-yl) amine Piperidine-1-carboxylic acid tert-butyl ester (preparation 6a, 0.30 g, 0.67 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)phenyl]piperazine (0.253 g, 0.84 mmol), 2M aqueous hydrazine carbonate (1.0 mL, 2.0 mmol), and 1,4-dioxane (1 mL). The Schlenk tube is subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex. (0.075 g, 0.09 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 90 °C and heated overnight. The residue was diluted with water and extracted with a mixture of diethyl ether / pentane 1:1. The organic layer was washed with EtOAc EtOAc m.

LRMS (m/z): 588 (M+2) ⁺ .

b) 5-Fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl] -N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine

Of hydrogen chloride in 1,4-dioxane (1.9 mL) was added to 4.0M in the (3 R) -3 - ({ 5- fluoro-6- [4- (4-methylpiperazin-1-yl) Phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 42a, 0.222 g, 0.38 mmol) The solution was stirred in methanol (2.5 mL) and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated and the residue was taken diethyl ether. The resulting yellow solid was filtered and washed with EtOAc (EtOAc)

LRMS (m/z): 597 (M+2) ⁺ .

Preparation 43 1-Benzyl-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Piperazine-1-pyrene

(Bromomethyl)benzene (0.786 mL, 0.66 mmol) was added to 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane) A stirred solution of pent-2-yl)phenyl]piperazine (0.2 g, 0.66 mmol) in THF (1 mL) The title compound (0.185 g, 57%) was obtained.

LRMS (m/z): 393 (M) ⁺ .

Preparation 44 1-(4-Tertibutylbenzyl)-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron bromide) Cyclopent-2-yl)phenyl]piperazine-1-anthracene

1-(Bromomethyl)-4-t-butylbenzene (0.150 g, 0.66 mmol) was added to 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3) , a solution of 2-dioxaborolan-2-yl)phenyl]piperazine (0.2 g, 0.66 mmol) in tetrahydrofuran (2 mL). Further, 1-(bromomethyl)-4-t-butylbenzene (0.02 g) was added and the reaction mixture was further stirred at room temperature for 24 hours. The solvent was evaporated and the residue was taken with hexanes and filtered. The white solid was washed with EtOAc (EtOAc)

LRMS (m/z): 449 (M) ⁺ .

Preparation 45 3-((3 R )-3-{[5-fluoro-6-(4-piperazin-1-ylphenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile a) 4-[4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5 -a]pyridin-3-ylpyrimidin-4-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester

Feeding 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl) into a Schlenk tube Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c, 0.20 g, 0.48 mmol), 4-[4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 0.61 mmol), 2 M aqueous cesium carbonate solution (0.73 mL, 1.45 mmol) and 1 , 4-dioxane (5 mL). The Schlenk tube is subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex. (0.04 g, 0.05 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was removed and the residue was crystallisjjjjjjjjj

LRMS (m/z): 640 (M + 1) ⁺ .

b) 3-((3 R )-3-{[5-fluoro-6-(4-piperazin-1-ylphenyl)-2-pyrazolo[1,5- a ]pyridin-3-yl Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.57 mL, 2.27 mmol) was added to 4-[4-(6-{[(3 R )-1-(cyanoethinyl)piperidine- 3-butyl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (preparation 45a, 0.15 g, 0.23 mmol) in EtOAc (EtOAc m. A 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.50 mL, 1.98 mmol) was then added and the mixture was stirred at room temperature overnight. The precipitate was filtered and washed with EtOAc (EtOAc)

LRMS (m/z): 540 (M + 1) ⁺ .

Preparation 46 ( R )- N ¹ -(5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4- Base) -N ² , N ² -dimethyl- N ¹ -(piperidin-3-yl)ethane-1,2-diamine a) ( R )-3-((2-(Dimethylamino)ethyl)(5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenyl)-2- (pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 0.081g, 2.03mmol) was added portionwise to the (3 R) -3 - ({ 5- fluoro-6- [4- (4-methyl-piperazin-1-yl Benzyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester (preparation 42a, 0.4 g, 0.68 mmol) And a suspension of (2-chloroethyl)dimethylamine hydrochloride (0.15 g, 1.04 mmol) in N,N' -dimethylformamide (2 mL) and the mixture obtained at 55 ° C Stir overnight. (2-Chloroethyl)dimethylamine hydrochloride (0.15 g, 1.04 mmol) and sodium hydride (60% dispersion in mineral oil, 0.081 g, 2.03 mmol) and the reaction mixture at 55 Stir at °C for 3 days. After cooling to room temperature, water was added and the precipitate formed was filtered, washed with water and dried under vacuum. The title compound (0.272 g, 45%)

LRMS (m/z): 659 (M+2) ⁺ .

b)( R )- N ¹ -(5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4- Base) -N ² , N ² -dimethyl- N ¹ -(piperidin-3-yl)ethane-1,2-diamine

Of hydrogen chloride in 1,4-dioxane (1.5mL) was added to 4.0M in the (3 R) -3 - ([ 2- ( dimethylamino) ethyl] {5-fluoro-6- [4 -(4-Methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid A solution of tributyl ester (preparation 46a, 0.272 g, 0.30 mmol) in MeOH (15 mL). The solvent was evaporated and the title compound was crystalljjjjjjjjj The title compound (0.07 g, 31%).

LRMS (m/z): 559 (M+2) ⁺ .

Preparation 47 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Phenyl) piperidine

4-(4-bromophenyl)-1-methylpiperidine (0.50 g, 1.97 mmol), 4,4,4',4',5,5,5',5 were fed into the Schlenk tube. '-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (0.75 g, 2.95 mmol), potassium acetate (0.58 g, 5.91 mmol) and 1,4- Dioxane (4 mL). The Schlenk tube is subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex. (0.08 g, 0.1 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 80 °C and heated overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The organic phase was separated, diluted with EtOAc (EtOAc)EtOAc. The residue was treated with pentane and filtered. The filtrate was evaporated in vacuo to give crystallite crystallite

LRMS (m/z): 302 (M + 1) ⁺ .

Preparation 48 3-((3 R )-3-{[5-fluoro-6-(4-methylnonylphenyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl Amino}piperidin-1-yl)-3-oxopropiononitrile a) 3-[(3 R )-3-({5-fluoro-6-[4-(hydroxymethyl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine -4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

Feeding 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl) into a Schlenk tube Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c, 1.00 g, 2.42 mmol), 4-hydroxymethylphenyl acid (0.55 g, 3.62 mmol), 2.0 M sodium carbonate Aqueous solution (1.21 mL, 2.42 mmol) and 1,2-dimethoxyethane (15 mL). The Schlenk tube was subjected to three vacuum-backfill cycles with argon and then ruthenium (triphenylphosphine)palladium(0) (279 mg, 0.24 mmol) was added. After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 80 °C and heated overnight. The solvent was removed and the~~~~~~~~~~~~

LRMS (m/z): 486 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.7-1.9 (m, 2H), 2.1-2.3 (m, 2H), 3.2-3.5 (m, 4H), 3.6-3.7 (m, 1H), 3.9 ( Dd,1H),4.3(bs,2H),4,6(dd,1H),4.8(t,2H),5.1(bs,1H),6.9(dt,1H),7.3-7.4(m,1H) , 7.5-7.6 (m, 2H), 8.1 (d, 2H), 8.5-8.6 (m, 2H), 8.7 (s, 1H).

b) 3-((3 R )-3-{[5-fluoro-6-(4-methylnonylphenyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4 -amino]piperidin-1-yl)-3-oxopropiononitrile

According to the experimental procedure as described in Preparation 29b, 3-[(3 R )-3-({5-fluoro-6-[4-(hydroxymethyl)phenyl]-2-pyrazolo[1,5- a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Preparation 48a) gave a white solid (33%). The crude product was purified by hexane to ethyl acetate.

LRMS (m/z): 484 (M+1) ⁺ .

Preparation 49 [4-(pyrrolidin-1-ylmethyl)phenyl] acid

Sodium triethoxysulfonium borohydride (8.49 g, 40.05 mmol) was added to pyrrolidine (1.1 g, 15.5 mmol), 4-methylmercaptophenyl acid (2.0 g, 13.34 mmol) and a solution of acetic acid (0.23 mL, 4 mmol) in dichloromethane (40 mL). The solvent was evaporated and the residue was crystalljjjjjjjjj

LRMS (m/z): 206 (M + 1) ⁺ .

Preparation 50 3-((3 R )-3-{[6-(4-Methylphenyl)-5-methyl-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4- Amino}piperidin-1-yl)-3-oxopropiononitrile a) 3-[(3 R )-3-({6-[4-(hydroxymethyl)phenyl]-5-methyl-2-pyrazolo[1,5- a ]pyridin-3-yl Pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

Feeding 3-{(3 R )-3-[(6-chloro-5-methyl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4- to the Schrank tube Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 8c, 0.35 g, 0.85 mmol), 4-hydroxymethylphenyl acid (0.19 g, 1.28 mmol), 2.0 M carbonate A sodium aqueous solution (0.64 mL, 1.28 mmol) and 1,2-dimethoxyethane (4 mL). The Schlenk tube was subjected to three vacuum-backfill cycles with argon and then ruthenium (triphenylphosphine)palladium(0) (99 mg, 0.09 mmol) was added. After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 80 °C and heated overnight. The solvent was removed and the~~~~~jjjjjjjjjjj

LRMS (m/z): 482 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 1.57-1.92 (m, 4H), 1.97 (s, 3H), 2.75 (m, 1H), 2.88 (m, 1H), 3.15 (d, 1H), 3.69 (d,1H), 3.84(d,1H),4.12-4.41(m,2H),4.50(s,2H),4.61(s,2H),6.79-6.98(m,1H),7.23-7.51 ( m, 5H), 8.39-8.62 (m, 3H).

b) 3-((3 R )-3-{[6-(4-Methylphenyl)-5-methyl-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 29b, 3-[(3 R )-3-({6-[4-(hydroxymethyl)phenyl]-5-methyl-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (preparation 50a) and manganese (IV) oxide gave a solid (85%).

LRMS (m/z): 480 (M + 1) ⁺ .

Preparation 51 [4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}methyl)phenyl] acid

Sodium triethoxy borohydride (1.0 g, 4.72 mmol) was added to N,N ,2-trimethyl-6-piperidin-4-ylpyridin-4-amine dihydrochloride (0.49 g, 1.69 mmol , a solution of (4-carbamidophenyl) acid (0.25 g, 1.67 mmol) and triethylamine (0.47 mL, 3.34 mmol) in dichloromethane (8 mL). hour. The reaction mixture was partitioned between diethyl ether and dilute aqueous potassium carbonate. The title compound (0.32 g, 48%) was obtained as a white solid.

LRMS (m/z): 354 (M + 1) ⁺ .

Preparation 52 3-((3 R )-3-{[5-fluoro-6-(2-fluoro-4-carboxyphenyl)-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile a) 3-[(3 R )-3-({5-fluoro-6-[2-fluoro-4-(hydroxymethyl)phenyl]-2-pyrazolo[1,5- a ]pyridine- 3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (2-fluoro-4-(hydroxymethyl)phenyl) acid gave a white solid (54%) The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol 95:5).

LRMS (m/z): 504 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.73-2.08 (m, 4H), 2.12-2.36 (m, 1H), 3.31-3.44 (m, 2H), 3.49 (dd, 2H), 3.58-3.79 ( m, 1H), 3.88-4.09 (m, 1H), 4.24 - 4.42 (m, 1H), 4.77-4.93 (m, 2H), 5.10 (d, 1H), 6.82-6.96 (m, 1H), 7.20- 7.30 (m, 1H), 7.30-7.40 (m, 2H), 7.79 (t, 1H), 8.44 - 8.56 (m, 2H), 8.65 (d, 1H).

b) 3-((3 R )-3-{[5-fluoro-6-(2-fluoro-4-carboxyphenyl)-2-pyrazolo[1,5- a ]pyridine-3- Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile

According to the experimental procedure as described in Preparation 29b, 3-[(3 R )-3-({5-fluoro-6-[2-fluoro-4-(hydroxymethyl)phenyl]-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Preparation 52a) and Manganese Oxide (IV) gave a white solid ( 68%).

LRMS (m/z): 502 (M + 1) ⁺ .

Preparation 53 3-((3 R )-3-{[5-fluoro-6-(3-methylnonylphenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl Amino}piperidin-1-yl)-3-oxopropiononitrile a) 3-[(3 R )-3-({5-fluoro-6-[3-(hydroxymethyl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine -4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (Preparation 6c) and 3-hydroxymethylphenyl acid afforded a white solid (76%). The crude product was purified from hexane to ethyl acetate.

LRMS (m/z): 486 (M + 1) ⁺ .

b) 3-((3 R )-3-{[5-fluoro-6-(3-methylnonylphenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4 -amino]piperidin-1-yl)-3-oxopropiononitrile

According to the experimental procedure as described in Preparation 29b, 3-[(3 R )-3-({5-fluoro-6-[3-(hydroxymethyl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Preparation 53a) and manganese (IV) oxide afforded a white solid (44%). The crude product was purified by flash chromatography (methylene chloride to dichloromethane / methanol gradient: 95).

LRMS (m/z): 484 (M+1) ⁺ .

Preparation 54 3 - {(3 R) -3 - [(2- chloro-5-fluoro-6- {4 - [(4-methyl-1,4-diazepan-1-yl) methyl] Phenyl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile a) (3 R )-3-[(2,6-Dichloro-5-fluoropyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

A solution of 2,4,6-trichloro-5-fluoropyrimidine (0.05 g, 2.48 mmol) in ethanol (10 mL) at -20 °C was added dropwise to ( 3R )-3-aminopiperidine-1 a stirred solution of tert-butyl formate (0.55 g, 2.73 mmol) in ethanol (10 mL). The resulting mixture was stirred at -20 ° C for 1 hour and then partitioned between water and chloroform. The organic phase was separated, dried over sodium sulfate and evaporated EtOAc. The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 365/367 (M + 1) ⁺ .

b) (3 R )-3-({2-chloro-5-fluoro-6-[4-(hydroxymethyl)phenyl]pyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester

Prepared according to the procedure described in Experiment 50a of a (3 R) -3 - [( 2,6- dichloro-5-fluoro-pyrimidin-4-yl) amino] piperidine-1-carboxylic acid tert-butyl ester ( Preparation 54a) and 4-(hydroxymethyl)phenyl acid gave a white solid (23%).

LRMS (m/z): 437 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.43 (s, 9H), 1.50-1.80 (m, 5H), 3.30-3.60 (m, 4H), 4.18 (bs, 1H), 4.75 (s, 2H) , 5.40 (s, 1H), 7.45 (d, 2H), 7.96 (dd, 2H).

c) (3 R )-3-{[2-chloro-5-fluoro-6-(4-methylnonylphenyl)pyrimidin-4-yl]amino}piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 29b from ( 3R )-3-({2-chloro-5-fluoro-6-[4-(hydroxymethyl)phenyl]pyrimidin-4-yl}amino) Piperidine-1-carboxylic acid tert-butyl ester (preparation 54b) and manganese (IV) oxide afforded a colorless oil (61%), followed by flash chromatography (hexane tohexane/ethyl acetate 6:4) The crude product was purified by gradient.

LRMS (m/z): 435 (M + 1) ⁺ .

d) (3 R )-3-[(2-chloro-5-fluoro-6-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]benzene Tert-butyl pyridin-4-yl)amino]piperidine-1-carboxylic acid

Three acetyl group with sodium borohydride (262mg, 1.24mmol) was added to (3 R) -3 - {[ 2- chloro-5-fluoro-6- (4-acyl phenyl) pyrimidin-4-yl] Amino} piperidine-1-carboxylic acid tert-butyl ester (preparation 54c, 336 mg, 0.77 mmol), 1-methyl-1,4-diazepane (132 mg, 1.15 mmol) in dichloromethane (10 mL) The solution in the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with EtOAcq.

LRMS (m/z): 534 (M + 1) ⁺ .

e) 2-Chloro-5-fluoro-6-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}- N -[(3 R )-piperidin-3-yl]pyrimidine-4-amine

Of hydrogen chloride in 1,4-dioxane (0.42mL, 1.7mmol) was added to a solution of 4.0M of (3 R) -3 - [( 2- chloro-5-fluoro-6- {4 - [(4- Tert-butyl 1,4- diazepan-1-yl)methyl]phenyl}pyrimidin-4-yl)amino]piperidine-1-carboxylate (preparation 54d, 90mg, 0.17mmol The stirred solution in 1,4-dioxane (2 mL) and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated and the residue was crystalljjjjjjjjjj

LRMS (m / z): 434 (M + 1) +.

f) 3-{(3 R )-3-[(2-chloro-5-fluoro-6-{4-[(4-methyl-1,4-diaza) Heptan-1-yl)methyl]phenyl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

3-[(2,5-Di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile (42 mg, 0.25 mmol) was added to 2-chloro-5-fluoro-6-{4 -[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}- N -[(3 R )-piperidin-3-yl]pyrimidine-4-amine (Preparation 54e, 90 mg, 0.21 mmol) and EtOAc (EtOAc) The reaction mixture was washed with water, dried over sodium sulfate and evaporated The residue was purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 501 (M + 1) ⁺ .

Preparation 55 N,N -Dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethylamine

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.22 g, 1.00 mmol), 2-chloro- N,N- A mixture of dimethylethylamine hydrochloride (0.17 g, 1.15 mmol) and cesium carbonate (1.3 g, 4.40 mmol) in tetrahydrofuran (4 mL) was heated at 130 ° C for 2 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, EtOAc m m m m m m

LRMS (m/z): 291 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.3 (s, 12H), 2.3 (s, 6H), 2.7 (t, 2H), 4.1 (t, 2H), 6.8-7.0 (d, 2H), 7.6 -7.9 (d, 2H).

Preparation 56 N- (6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4 -yl) -N' , N' -dimethyl-N-[(3 R )-piperidin-3-yl]ethane-1,2-diamine a) (3 R) -3 - [(6- {4- [2- ( dimethylamino) ethoxy] phenyl} -5-fluoro-2-pyrazolo [1,5-a] Pyridyl-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

Fed to the Schlenk tube (3 R) -3 - [( 6- chloro-5-fluoro-2-pyrazolo [1,5-a] pyridin-3-yl-pyrimidin-4-yl) amine Piperidine-1-carboxylic acid tert-butyl ester (preparation 6a, 0.40 g, 0.9 mmol), N,N -dimethyl-2-(4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)phenoxy)ethylamine (preparation 55, 0.39 g, 1.3 mmol), 2.0 M aqueous cesium carbonate (0.89 g, 2.7 mmol) and 1,2- Dimethoxyethane (3 mL). The Schlenk tube was subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex ( 73 mg, 0.09 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was evaporated and purified EtOAcjjjjjjjjjj

LRMS (m/z): 577 (M + 1) ⁺ .

b) (3 R )-3-{(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5-a] Pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl] Amino} piperidine-1-carboxylic acid tert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 50mg, 1.96mmol) was added portionwise to the (3 R) -3 - [( 6- {4- [2- ( dimethylamino) ethoxy] phenyl }-5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (Preparation 56a, 0.34 g, 0.6 Methyl) and a suspension of 2-chloro- N,N -dimethylethylamine hydrochloride (0.13 g, 1.17 mmol) in N,N -dimethylformamide (10 mL) Heat at °C for 18 hours. Water was added and the precipitate formed was filtered, washed with water and dried then evaporated

LRMS (m/z): 648 (M + 1) ⁺ .

c) N- (6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine 4-yl) -N' , N' -dimethyl- N -[(3 R )-piperidin-3-yl]ethane-1,2-diamine

Of hydrogen chloride in 1,4-dioxane (1.5mL, 5.86mmol) was added to a solution of 4.0M of (3 R) -3 - {( 6- {4- [2- ( dimethylamino) ethoxy Phenyl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl]amino}piperidine A stirred solution of 1-butylic acid tert-butyl ester (preparation 56b, 0.35 g, 0.54 mmol) in 1,4-dioxane (5 mL). The solvent was evaporated and the residue was crystalljjjjjjjjjjj

LRMS (m/z): 548 (M + 1) ⁺ .

Preparation 57 1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenoxy]ethyl}pyrrolidine

According to the experimental procedure as described in Preparation 55, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 1-(2) The chloroethyl)pyrrolidine was obtained as a brown oil (yield: 84%).

LRMS (m/z): 318 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.3 (s, 12H), 1.8-1.9 (m, 4H), 2.6 (t, 4H), 2.9 (t, 2H), 4.1 (t, 2H), 6.7 (d, 2H), 6.9 (d, 2H).

Preparation 58 N,N -Dimethyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy Ethyl}piperidin-4-amine

According to the experimental procedure as described in Preparation 55, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 1-(2) -Chloroethyl) -N,N -dimethylpiperidin-4-amine was obtained as a brown oil (50%) elute elute Crude product.

LRMS (m/z): 375 (M + 1) ⁺ .

Preparation 59 ( R )-4-(4-(6-((1-(2-Cyanoethyl))piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo[1,5 -a]pyridin-3-yl)pyrimidin-4-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-(4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester gave solid (87%), which was purified by flash chromatography (hexane to ethyl acetate) product.

LRMS (m/z): 656 (M+2) ⁺ .

¹ H-NMR δ (400MHz, CDCl ₃ ): 1.60-1.66m, 1H), 1.75-1.85 (m, 3H), 1.92-2.05 (m, 3H), 2.18-2.60 (m, 1H), 3.32-3.48 (m, 6H), 3.59 (s, 1H), 3.69-3.77 (m, 2H), 3.84-3.98 (m, 1H), 4.26-4.35 (m, 1H), 4.58-4.61 (m, 1H), 5.05 (bs, 1H), 6.82-6.92 (m, 1H), 7.10-7.40 (m, 2H), 7.33-7.38 (m, 1H), 8.11 (d, 2H), 8.49-8.60 (m, 2H), 8.61 -8.73 (d, 1H).

Preparation 60 4-[4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a Pyridyl-3-ylpyrimidin-4-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-[4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester obtained as a solid (46%), followed by flash chromatography (dichloromethane to dichloromethane /Methanol 93:7) The crude product was purified.

LRMS (m/z): 642 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.39-1.65 (m, 7H), 1.77-1.90 (m, 2H), 2.22 (m, 2H), 3.35-3.47 (m, 4H), 3.52-3.70 ( m,6H), 3.92 (m, 2H), 4.25-4.40 (m, 2H), 5.08 (m, 1H), 6.74-6.84 (m, 1H), 6.92 (m, 1H), 7.35 (m, 2H) , 8.14 - 8.78 (m, 4H).

Preparation 61 (2-(4-methyl-1,4-diazepan-1-yl)pyridin-4-yl) acid a) 1-(4-bromopyridin-2-yl)-4-methyl-1,4-diazepane

4-bromo-2-fluoropyridine (4.25 g, 24.15 mmol), 1-methyl-1,4-diazepane (3.6 mL, 29 mmol) and potassium carbonate (10.0 g, 72.3 mmol) in dimethyl The mixture in the hydrazine (30 mL) was heated overnight at 100 °C. The reaction mixture was poured into water and extracted with diethyl ether (x3). The combined organic layers were washed with EtOAc EtOAc m.

LRMS (m / z): 270,272 (M, M + 2) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.92-2.09 (m, 2H), 2.38 (s, 3H), 2.50-2.62 (m, 2H), 2.63-2.73 (m, 2H), 3.60 (t, 2H), 3.77-3.85 (m, 2H), 6.64 (d, 1H), 6.66-6.70 (m, 1H), 7.95 (d, 1H).

b) (2-(4-Methyl-1,4-diazepan-1-yl)pyridin-4-yl) acid

To the Schlenk tube was fed 1-(4-bromopyridin-2-yl)-4-methyl-1,4-diazepane (Preparation 61a, 0.67 g, 2.48 mmol), 4, 4 , 4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (0.76 g, 2.98 mmol) Potassium acetate (0.73 g, 7.44 mmol) and 1,4-dioxane (8 mL). The Schlenk tube is subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex. (0.10 g, 0.12 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 80 °C and heated for 4 hours. The mixture was cooled, dried diatomaceous earth (Celite ^®) was filtered, and the solvent was concentrated to dryness. The residue was taken from EtOAc EtOAc (EtOAc)

LRMS (m/z): 236 (M + 1) ⁺ .

Preparation 62 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1,4- Diazaheptan-1-yl)ethanol a) 2-(4-(4-bromopyridin-2-yl)-1,4-diazepan-1-yl)ethanol

An oil (55%) was obtained from 4-bromo-2-fluoropyridine and 2-(1,4-diazepan-1-yl)ethanol according to the procedure described in Preparation 61a.

LRMS (m/z): 300, 302 (M, M+2) ⁺ .

b) 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1, 4-diazepane-1-yl)ethanol

According to the experimental procedure as described in Preparation 61b from 2-[4-(4-bromopyridin-2-yl)-1,4-diazepan-1-yl]ethanol (Preparation 62a) and 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave a yellow solid (97% ).

LRMS (m/z): 266 (M + 1) ⁺ .

Preparation 63 (2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl) acid a) 1-(4-bromopyridin-2-yl) -N,N -dimethylpiperidin-4-amine

A yellow solid (90%) was obtained from 4-bromo-2-fluoropyridine and N,N -dimethylpiperidin-4-amine according to the procedure as described in Preparation 61a.

LRMS (m / z): 284,286 (M, M + 2) +.

b) (2-(4-(Dimethylamino)piperidin-1-yl)pyridin-4-yl) acid

According to the experimental procedure as described in Preparation 61b, 1-(4-bromopyridin-2-yl) -N,N -dimethylpiperidin-4-amine (Preparation 63a) and 4,4,4',4 ',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) afforded an orange oil (100%).

LRMS (m/z): 250 (M + 1) ⁺ .

Preparation 64 ( R )-1-(3-((6-chloro-5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine- 1-yl)-2-hydroxyethyl ketone

6-chloro-5-fluoro- N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine (Preparation 6b, 0.46 g, 1.10 mmol), 2-hydroxyacetic acid (0.10 g, 1.10 mmol), hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ a mixture of 4,5-b]pyridinium-3-oxide (0.54 g, 1.42 mmol) and triethylamine (0.53 mL, 3.82 mmol) in N,N -dimethylformamide (2 mL) Stir for 18 hours under temperature. Water was added and the reaction mixture was stirred for 30 minutes. The precipitate was filtered, washed with EtOAc EtOAcjjjjjjj

LRMS (m/z): 405 (M + 1) ⁺ .

Preparation 65 (6-{[4-(Dimethylamino)piperidin-1-yl]methyl}pyridin-3-yl) acid a) 1-((5-bromopyridin-2-yl)methyl) -N,N -dimethylpiperidin-4-amine

a mixture of 5-bromopyridine-2-carbaldehyde (0.30 g, 1.61 mmol) and N,N -dimethylpiperidin-4-amine (0.121 mg, 1.61 mmol) in dichloromethane (15 mL) Stir for 30 minutes. Sodium triethoxysulfonate (0.41 g, 1.93 mmol) was added and the acetic acid was catalyzed and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with aq. The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 298,300 (M, M+2) ⁺ .

b) (6-{[4-(Dimethylamino)piperidin-1-yl]methyl}pyridin-3-yl) acid

According to the experimental procedure as described in Preparation 61b from 1-[(5-bromopyridin-2-yl)methyl] -N,N -dimethylpiperidin-4-amine (Preparation 65a) and 4,4, 4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) obtained as an orange oil (82% ).

LRMS (m/z): 264 (M + 1) ⁺ .

Preparation 66 [6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl] acid a) 1-(5-bromopyridin-2-yl)-4-methyl-1,4-diazepane

An oil (90%) was obtained from 5-bromo-2-fluoropyridine and 1-methyl-1,4-diazepane according to the procedure described in Preparation 61a.

LRMS (m/z): 270, 272 (M, M + 2) ⁺ .

b) [6-(4-Methyl-1,4-diazepan-1-yl)pyridin-3-yl] acid

According to the experimental procedure as described in Preparation 61b from 1-(5-bromopyridin-2-yl)-4-methyl-1,4-diazepane (Preparation 66a) and 4,4,4' , 4',5,5,5',5'-octamethyl-2,2'-(1,3,2-dioxaborolane) afforded a brown oil (93%).

LRMS (m/z): 236 (M + 1) ⁺ .

Preparation 67 (6-(4-(Dimethylamino)piperidin-1-yl)pyridin-3-yl) acid a) 1-(5-bromopyridin-2-yl) -N,N -dimethylpiperidin-4-amine

An oil (88%) was obtained from 5-bromo-2-fluoropyridine and N,N -dimethylpiperidin-4-amine according to the procedure as described in Preparation 61a.

LRMS (m / z): 284,286 (M, M + 2) +.

b) (6-(4-(Dimethylamino)piperidin-1-yl)pyridin-3-yl) acid

According to the experimental procedure as described in Preparation 61b, 1-(5-bromopyridin-2-yl) -N,N -dimethylpiperidin-4-amine (Preparation 67a) and 4,4,4',4 ',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) afforded an orange oil (100%).

LRMS (m/z): 250 (M + 1) ⁺ .

Preparation 68 (2-(4-(Piperazine-1-ylmethyl)phenoxy)ethyl)carbamic acid tert-butyl ester a) 2-(Tertibutoxycarbonylamino)ethyl methanesulfonate

A solution of methanesulfonium chloride (1.44 mL, 18.60 mmol) in dichloromethane (15 mL) was added dropwise to a solution of &lt;RTI ID=0.0&gt; And a stirred solution of triethylamine (3.46 mL, 24.82 mmol) in dichloromethane (15 mL). Stirring at 0 ° C After 1.5 hours, the reaction mixture was partitioned between water and pentane. The organic phase was separated, washed with EtOAc EtOAcjjjjjjjj

LRMS (m/z): 240 (M + 1) +.

b) (2-(4-Methyl phenoxy)ethyl) carbamic acid tert-butyl ester

2-(Tertibutoxycarbonylamino)methanesulfonate (preparation 68a, 3.0g, 12.54mmol), 4-hydroxybenzaldehyde (1.53g, 12.54mmol) and potassium carbonate (5.21g) at 60 °C A mixture of 37.70 mmol) in N,N' -dimethylformamide (20 mL) was stirred overnight. The crude material was partitioned between diethyl ether and water. The organic phase was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 266 (M + 1) +.

c) 4-(4-(2-(t-butoxycarbonyl)amino)ethoxy)benzyl)piperazine-1-carboxylic acid benzyl ester

An oil was obtained from (3-(4-methylnonylphenoxy)ethyl)carbamic acid tert-butyl ester (preparation 68b) and piperazine-1-carboxylic acid benzyl ester according to the procedure described in Preparation 54d. (71%).

LRMS (m/z): 470 (M + 1) ⁺ .

d) (2-(4-(Piperazine-1-ylmethyl)phenoxy)ethyl)carbamic acid tert-butyl ester

Benzyl 4-(4-(2-(3-t-butoxycarbonyl)amino)ethoxy)benzyl)piperazine-1-carboxylate according to the experimental procedure as described in Preparation 30b 68c) Obtained an oil (75%).

LRMS (m/z): 336 (M + 1) ⁺ .

Preparation 69 ( R )-(2-(4-((4-(6-(2-(2-cyanoethyl))piperidin-3-yl)amino)-5-fluoro-2-(pyrazole) And [1,5-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)phenoxy)ethyl)carbamic acid tert-butyl ester

According to the experimental procedure as described in Preparation 17a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (2-(4-(piperazin-1ylmethyl)phenoxy)ethyl)amine The third butyl formate (preparation 68d) gave a white solid (51%).

LRMS (m/z): 713 (M + 1) ⁺ .

Preparation 70 3-{[4-(6-{[2-(dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol a) (3 R )-3-{(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamine) Tert-butyl]ethyl]amino}piperidine-1-carboxylic acid

Sodium hydride (60% dispersion in mineral oil, 0.125g, 3.13mmol) was added portionwise to the (3 R) -3 - [( 6- chloro-5-fluoro-2-pyrazolo [1,5-a] Pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 6a, 0.40 g, 0.90 mmol) in N,N -dimethylformamide (4 mL) The solution was stirred and the mixture was stirred at room temperature for 15 minutes. (2-Chloroethyl)dimethylamine hydrochloride (0.150 g, 1.04 mmol) was added and the mixture was stirred at <RTIgt; Water was added and the resulting precipitate was filtered, washed with water and dried. The title compound (0.18 g, 37%) eluted elute

LRMS (m/z): 519 (M+2) ⁺ .

b) (3 R )-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 17a from ( 3R )-3-{(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl [2-(Dimethylamino)ethyl]amino}piperidine-1-carboxylic acid tert-butyl ester (preparation 70a) and 3-(piperazin-1-ylmethyl)phenol gave a white solid (14 The crude product was purified by flash chromatography (methylene chloride to dichloromethane / methanol gradient: 95:5).

LRMS (m/z): 675 (M+2) ⁺ .

c) 3-{[4-(6-{[2-(Dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino}-5-fluoro-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol

According to the experimental procedure as described in Preparation 6b from ( 3R )-3-([2-(dimethylamino)ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl) Piperazine-1-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 70b) gave solid Hydrochloride (99%).

LRMS (m / z): 575 (M + 2) +.

Preparation 71 Methyl {2-[4-(piperazin-1-ylmethyl)phenoxy]ethyl}aminocarboxylic acid tert-butyl ester a) 4-(4-{2-[(Tertibutoxycarbonyl)(methyl)amino]ethoxy}benzyl)piperazine-1-carboxylic acid benzyl ester

Sodium hydride (60% dispersion in mineral oil, 0.115 g, 4.79 mmol) was added portionwise to 4-(4-{2-[(t-butoxycarbonyl)amino]ethoxy}benzene at 0 °C Methyl)piperazine-1-carboxylic acid benzyl ester (preparation 68c, 0.749 g, 1.60 mmol) in N,N' -dimethylformamide (4.5 mL) and the mixture was stirred at room temperature 1 hour. Methyl iodide was then added at 0 ° C and the reaction mixture was stirred at room temperature for 3 h then partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 485 (M+2) ⁺ .

b) methyl {2-[4-(piperazin-1-ylmethyl)phenoxy]ethyl}aminocarboxylic acid tert-butyl ester

10% palladium on carbon (0.050 g, 0.47 mmol) was added to 4-(4-{2-[(t-butoxycarbonyl)(methyl)amino]ethoxy}benzyl)piperazine-1 A solution of benzyl formate (preparation 71a, 0.55 g, 1.14 mmol) in methanol (25 mL). The reaction mixture was diatomaceous earth (Celite ^®), and the filtrate was evaporated to dryness. The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 351 (M+1) ⁺ .

Preparation 72 [2-(4-{[4-(6-{[(3 R )-1-(Cyanoethyl)piperidin-3-yl]amine) -5-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenoxy)ethyl]methylamine Tert-butyl carboxylic acid

According to the experimental procedure as described in Preparation 28a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (Preparation 6c) and methyl {2-[4-(piperazin-1-ylmethyl)phenoxy]B The third alkyl carbamic acid ester (preparation 71b) gave a solid (63%), which was then purified by flash chromatography (dichloromethane to dichloromethane/methanol / ammonia 85:15:0.2).

LRMS (m/z): 728 (M + 1) ⁺ .

Preparation 73 ( R )-(3-(3-((5-fluoropiperazin-1-yl)phenyl)-2-(pyrazolo[1,5-a]] Pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropyl)carboxylic acid tert-butyl ester

(R) -5- fluoro-6- (4- (4-methyl-piperazin-1-yl) phenyl) - N - (piperidin-3-yl) -2- (pyrazolo [1,5 -a]pyridin-3-yl)pyrimidine-4-amine (Preparation 42b, 68 mg, 0.14 mmol) was added to 3-((t-butoxycarbonyl)amino)propanoic acid (32 mg, 0.17 mmol), hexafluoro 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide (64 mg, 0.17 mmol) and two A solution of isopropylethylamine (0.039 mL, 0.22 mmol) in N,N' -dimethylcarbamide (1.5 mL) was obtained and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between excess diethyl ether and water. The organic phase was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 658 (M + 1) +.

Preparation 74 3-(6-{[2-(Dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1-yl)phenol a) 3-chloro-5-(4-methylpiperazin-1-yl)phenol

Lithium bis(trimethyldecyl) aminide (1 M solution in tetrahydrofuran, 20 mL, 20 mmol) was added to 3-bromo-5-chlorophenol (1.75 g, 8.44 mmol), 1-methylpiperazine (0.84 g, 8.44 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphinobicyclo{3.3.3}undecane (0.04 g, 0.17 mmol) in toluene (32 mL) The suspension in the reaction was subjected to three cycles of evacuation - backfilling with argon. Palladium(II) acetate (0.050 g, 0.22 mmol) was added and the mixture was again subjected to three vacuum-cycles backfilled with argon. The reaction mixture was heated at 80 deg.] C overnight, then cooled to room temperature, filtered through diatomaceous earth (Celite ^®), and the solvent was evaporated to dryness. The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m / z): 227,229 (M + 1, M + 3) +.

b) 3-(4-Methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol

The microwave reactor was fed with 3-chloro-5-(4-methylpiperazin-1-yl)phenol (preparation 74a, 1.00 g, 4.41 mmol), 4,4,4',4',5,5 , 5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (1.25 g, 4.92 mmol), potassium acetate (0.65 g, 6.62 mmol) And 1,2-dimethoxyethane (12 mL). The reactor was subjected to three evacuation cycles with argon backfill followed by the addition of tricyclohexylphosphine (0.15 g, 0.53 mmol) and bis(dibenzylideneacetone)palladium(0) (0.08 g, 0.14 mmol). In a further three evacuation - backfilled with argon after cycling, the reaction mixture was subjected to microwave irradiation at 150 deg.] C for 2 hours, filtered through diatomaceous earth (Celite ^®) and the solvent evaporated to dryness. The residue was taken up in diethyl ether and filtered. The filtrate was concentrated and purified with EtOAc EtOAcjjjjjjj

LRMS (m/z): 319 (M + 1) ⁺ .

c) (3 R )-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[3-hydroxy-5-(4-methylpiperazin-1-yl)benzene yl] -2-pyrazolo [1,5- a] pyridin-3-yl} pyrimidin-4-ylamino) piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 50a, ( 3R )-3-{(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl [2-(Dimethylamino)ethyl]amino}piperidine-1-carboxylic acid tert-butyl ester (preparation 70a) and 3-(4-methylpiperazin-1-yl)-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 74b) gave solid (77%), followed by flash chromatography (2) The crude product was purified by a gradient of chloromethane to dichloromethane / methanol / ammonia 100: 8:1.

LRMS (m / z): 675 (M + 2) +.

d) 3-(6-{[2-(Dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1, 5- a ]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1-yl)phenol

According to the experimental procedure as described in Preparation 6b from ( 3R )-3-([2-(dimethylamino)ethyl]{5-fluoro-6-[3-hydroxy-5-(4-A Tetbutylpyrazine-1-yl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylic acid tert-butyl ester 74c) Obtained the solid hydrochloride (100%).

LRMS (m / z): 575 (M + 2) +.

Preparation 75 2-(hydroxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol a) 5-bromo-2-(hydroxymethyl)phenol

The borane-dimethylsulfide complex (1.1 mL, 11.58 mmol) was added dropwise to a solution of 4-bromo-2-hydroxybenzoic acid (1.0 g, 4.64 mmol) in tetrahydrofuran (15 mL). The mixture was stirred overnight at room temperature. After cooling to 0 °C, 0.5N hydrochloric acid (5 mL) was added dropwise and then water (2mL). The reaction mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated to dry. The residue was partitioned between dilute aqueous sodium hydroxide and 1:1 mixture of diethyl ether/hexane. The aqueous phase was separated, acidified by addition of concentrated aqueous hydrochloric acid and extracted with diethyl ether/hexanes 1:1 mixture. The organic layer was separated, dried over magnesium sulfate and evaporated. The resulting precipitate was filtered and dried to give crystall

LRMS (m/z): 204 (M + 1) +.

b) 2-(Hydroxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

Feeding 5-bromo-2-(hydroxymethyl)phenol into the Schlenk tube (Preparation 75a, 0.75g, 3.69mmol), 4,4,4',4',5,5,5',5' - octamethyl-2,2'-bi-(1,3,2-dioxaborolane) (1.41 g, 5.55 mmol), potassium acetate (1.09 g, 11.11 mmol) and 1,4-di Oxane (7.5 mL). Schrank The tube was subjected to three vacuum-backfill cycles with argon and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (0.15 g) , 0.18 mmol). After three additional vacuum-backfill cycles with argon, the Schlank tube was sealed and the mixture was stirred at 80 °C and heated overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The organic phase was separated, diluted with EtOAc (EtOAc)EtOAc. The residue was taken from EtOAc (EtOAc)

LRMS (m/z): 251 (M + 1) +.

Preparation 76 ( R )-3-(3-((5-fluoro-6-(4-carbamido-3-hydroxyphenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)) Pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile a) ( R )-3-(3-((5-fluoro-6-(3-hydroxy-4-(hydroxymethyl)phenyl)-2-(pyrazolo[1,5-a]pyridine- 3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-(hydroxymethyl)-5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)phenol (Preparation 75b) gave a white solid (46%).

LRMS (m/z): 502 (M + 1) +.

b) ( R )-3-(3-((5-fluoro-6-(4-carbamido-3-hydroxyphenyl)-2-(pyrazole) And [1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

Manganese dioxide (0.126 g, 1.45 mmol) was added to ( R )-3-(3-((5-fluoro-6-(3-hydroxy-4-(hydroxymethyl)phenyl)-2-)pyrazole And [1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (preparation 76a, 0.146 g, 0.29 mmol) in tetrahydrofuran The solution in (3 mL) was stirred at 45 ° C for 5 hours. Further added manganese dioxide (0.126 g, 1.45 mmol) and the suspension was stirred at 45 ° C overnight and stirred at room temperature over the weekend. Manganese dioxide (0.126 g, 1.45 mmol) was added a third time and the suspension was stirred overnight at 45 ° C, then diluted with tetrahydrofuran and filtered over Celite ^® . The filtrate was evaporated to dryness crystals crystals crystals crystals

LRMS (m/z): 500 (M + 1) +.

Preparation 77 3-{[(1-methylpiperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Pent-2-yl)phenol a) 3-chloro-5-{[(1-methylpiperidin-4-yl)amino]methyl}phenol

A mixture of 3-chloro-5-hydroxybenzaldehyde (0.540 g, 3.46 mmol) and 1-methylpiperidin-4-amine (0.434 mL, 3.46 mmol) in dichloromethane (20 mL) minute. Sodium triethoxysulfonium borohydride (1.46 g, 6.91 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine, dried By flash chromatography (dichloromethane to dichloromethane / methanol / ammonia The title compound (0.85 g, 97%)

LRMS (m/z): 255 (M + 1) ⁺ .

b) 3-{[(1-Methylpiperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopent-2-yl)phenol

To the microwave reactor was fed 3-chloro-5-{[(1-methylpiperidin-4-yl)amino]methyl}phenol (Preparation 77a, 0.85 g, 3.34 mmol), 4, 4, 4 ',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (0.934 g, 3.68 mmol), acetic acid Potassium (0.492 g, 5.01 mmol) and 1,2-dimethoxyethane (5 mL). The reactor was subjected to three vacuum-backfill cycles with argon followed by the addition of tricyclohexylphosphine (0.113 g, 0.12 mmol) and bis(dibenzylideneacetone)palladium(0) (0.058 g, 0.30 mmol). In a further three evacuation - backfilled with argon after cycling, the reaction mixture was subjected to microwave irradiation at 150 deg.] C for 2 hours, filtered through diatomaceous earth (Celite ^®) and the solvent evaporated to dryness. The residue was taken-~~~~~~~~~~~~~~~~~~~~~~

LRMS (m/z): 347 (M + 1) ⁺ .

Preparation 78 3-{[[(1-methylpiperidin-4-yl)methyl](piperidin-4-yl)amino]methyl}phenol a) 4-[(3-hydroxybenzyl)amino]piperidine-1-carboxylic acid tert-butyl ester

Sodium borohydride (0.50 g, 13.22 mmol) was added portionwise to 3-hydroxybenzaldehyde (1.50 g, 12.28 mmol) and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (2.50 g, 12.48 mmol) in ethanol (15 mL) in solution and mixed The mixture was stirred at room temperature for 2 hours. After cooling to 0 ° C, aq. aq. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated The residue was purified by flash chromatography eluting elut elut elut elut elut elut

LRMS (m/z): 307 (M + 1) ⁺ .

b) 4-{(3-hydroxybenzyl)[(1-methylpiperidin-4-yl)methyl]amino}piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 54d, from 3-[(3-hydroxybenzyl)amino]piperidine-1-carboxylic acid tert-butyl ester (Preparation 78a) and 1-methylpiperidine-4-carbaldehyde A solid (61%) was obtained which was purified by flash chromatography (dichloromethane to dichloromethane/methanol/methanol: 100: 8:1 gradient).

LRMS (m/z): 419 (M+2) ⁺ .

c) 3-{[[(1-methylpiperidin-4-yl)methyl](piperidin-4-yl)amino]methyl}phenol

According to the experimental procedure as described in Preparation 6b, 3-{(3-hydroxybenzyl)[(1-methylpiperidin-4-yl)methyl]amino}piperidin-1-carboxylic acid tert-butyl Ester (Preparation 78b) gave solid trihydrochloride (100%).

LRMS (m/z): 319 (M+2) ⁺ .

Preparation 79 3-({[1-(3-piperidin-1-ylpropyl)piperidin-4-yl]amino}methyl)-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenol a) [1-(3-piperidin-1-ylpropyl)piperidin-4-yl]carbamic acid tert-butyl ester

Piperidine-4-ylaminocarbamic acid tert-butyl ester (1.19 g, 5.94 a solution of 1-(3-chloropropyl)piperidine (1.295 g, 6.54 mmol) and N,N-diisopropylethylamine (2.28 mL, 13.09 mmol) in chloroform (50 mL) Stir for 18 hours. Further, 1-(3-chloropropyl)piperidine (0.350 g, 1.60 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.267 mmol) were added and the mixture was stirred at 62 ° C for 3 hours. The solvent was evaporated and the~~~~~~~~~~~~~~~~~~~~~~~

b) 1-(3-piperidin-1-ylpropyl)piperidin-4-amine

Obtained (99%) from [1-(3-piperidin-1-ylpropyl)piperidin-4-yl]carbamic acid tert-butyl ester (preparation 79a) according to the experimental procedure as described in Preparation 6b. This was followed by cation exchange chromatography (dissolved with 2N ammonia solution in methanol).

c) 3-chloro-5-({[1-(3-piperidin-1-ylpropyl)piperidin-4-yl]amino}methyl)phenol

Obtained from 1-(3-piperidin-1-ylpropyl)piperidin-4-amine (Preparation 79b) and 3-chloro-5-hydroxybenzaldehyde according to the procedure described in Preparation 77a (80%) .

LRMS (m/z): 366 (M+1) ⁺ .

d) 3-({[1-(3-piperidin-1-ylpropyl)piperidin-4-yl]amino}methyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenol

Prepared from 3-chloro-5-({[1-(3-piperidin-1-ylpropyl)piperidin-4-yl]amino}methyl)phenol according to the experimental procedure as described in Preparation 77b 79c) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) Oil (69%).

LRMS (m/z): 376 (M + 1) ⁺ .

Preparation 80 (6-{4-[(Tertibutoxycarbonyl)(methyl)amino]piperidin-1-yl}pyridin-3-yl) acid a) [1-(5-Bromopyridin-2-yl)piperidin-4-yl]methylcarbamic acid tert-butyl ester

An oil (92%) was obtained from 5-bromo-2-fluoropyridine and <RTI ID=0.0>#</RTI> </RTI> <RTIgt;

LRMS (m/z): 370, 372 (M, M + 2) ⁺ .

b) (6-{4-[(Tertibutoxycarbonyl)(methyl)amino]piperidin-1-yl}pyridin-3-yl) acid

From [1-(5-bromopyridin-2-yl)piperidin-4-yl]methylcarbamic acid tert-butyl ester (preparation 80a) and 4,4,4 according to the experimental procedure as described in Preparation 61b ',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) gave a solid (40%).

LRMS (m/z): 336 (M + 1) ⁺ .

Preparation 81 {1-[5-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}methylaminocarbamic acid tert-butyl ester

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (6-{4-[(t-butoxycarbonyl)(methyl)amino]piperidin The pyridine-1-yl}pyridin-3-yl) acid (Preparation 80b) gave a solid (31%).

LRMS (m/z): 670 (M+2) ⁺ .

Preparation 82 3-[(4-Pyrrolidin-1-ylpiperidin-1-yl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Pent-2-yl)phenol a) 3-chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenol

A mixture of 3-chloro-5-hydroxybenzaldehyde (1.50 g, 9.58 mmol) and 4-pyrrolidin-1-ylpiperidine (1.63 g, 10.54 mmol) in dichloromethane (30 mL) minute. Sodium triethoxyhydride borohydride (3.05 g, 14.37 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine, dried The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 296 (M+1) ⁺ .

b) 3-[(4-Pyrrolidin-1-ylpiperidin-1-yl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopent-2-yl)phenol

The microwave reactor was fed with 3-chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenol (Preparation 82a, 2.25 g, 7.63 mmol), 4, 4, 4 ',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (2.13 g, 8.39 mmol), acetic acid Potassium (1.12 g, 11.45 mmol) and 1,2-dimethoxyethane (10 mL). The reactor was subjected to three evacuation cycles with argon backfill followed by the addition of tricyclohexylphosphine (0.26 g, 0.92 mmol) and bis(dibenzylideneacetone)palladium(0) (0.13 g, 0.23 mmol). In a further three evacuation - backfilled with argon after cycling, the reaction mixture was subjected to microwave irradiation at 150 deg.] C for 2 hours, filtered through diatomaceous earth (Celite ^®) and the solvent evaporated to dryness. The residue was taken from EtOAc EtOAc m.

LRMS (m/z): 387 (M + 1) ⁺ .

Preparation 83 3-(1-methylpiperidin-4-yl)-5-(piperazin-1-ylmethyl)phenol a) tert-butyl 4-(3-bromo-5-hydroxybenzyl)piperazine-1-carboxylate

A white solid (90%) was obtained from 3-bromo-5-hydroxybenzaldehyde and piperazine-1-carboxylic acid tert-butyl ester according to the procedure as described in Preparation 82a.

LRMS (m/z): 371, 373 (M, M+2) ⁺ .

b) 4-[3-hydroxy-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 45a, tert-butyl 4-(3-bromo-5-hydroxybenzyl)piperazine-1-carboxylate (Preparation 83a) and 1-methyl-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine affords a solid (74%), then The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 388 (M + 1) ⁺ .

c) 4-[3-hydroxy-5-(1-methylpiperidin-4-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester

4-[3-Hydroxy-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester (preparation 83b, 0.50 g, 1.29mmol) in ethanol (24 mL of) in a solution of H-Cube ^® continuous flow hydrogenation reactor using 10% Pd / C MicroCatCart ^® deg.] C and hydrogenated at 50 atm. The resulting solution was concentrated to give the title compound (j.

LRMS (m/z): 390 (M + 1) ⁺ .

d) 3-(1-methylpiperidin-4-yl)-5-(piperazin-1-ylmethyl)phenol

According to the experimental procedure as described in Preparation 6b, 4-[3-hydroxy-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzyl]piperazine-1 - tert-butyl formate (preparation 83c) gave solid trihydrochloride (100%).

LRMS (m/z): 290 (M + 1) ⁺ .

Preparation 84 3-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopent-2-yl)phenol a) 1-(Benzyloxy)-3,5-dichlorobenzene

(Bromomethyl)benzene (3.03 g, 17.73 mmol) was added to 3,5-dichlorophenol (2.89 g, 17.73 mmol) and cesium carbonate (8.66 g, 26.60 mmol) in N,N -dimethylformamide The suspension in (50 mL) was stirred at room temperature for 4 hours. Water was added and the reaction mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate The title compound (4.12 g, 90%) eluted

LRMS (m/z): 253, 255 (M, M + 2) ⁺ .

b) 4-[3-(Benzyloxy)-5-chlorophenyl]piperazine-1-carboxylic acid tert-butyl ester

1-(Benzyloxy)-3,5-dichlorobenzene (preparation 84a, 2.00 g, 7.90 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.21 g, 11.85 mmol) and tert-butanol The mixture of sodium (1.14 g, 11.85 mmol) in toluene (20 mL) was subjected to three vacuum-cycles with argon backfill. Bis(dibenzylideneacetone)palladium(0) (0.72 g, 0.79 mmol) and 2-(di-tert-butylphosphino)biphenyl (0.47 g, 1.58 mmol) were added. After three additional vacuum-backfill cycles with argon, the reactor was sealed and the reaction mixture was heated at 90 °C overnight. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth (Celite ^®), and the solvent was evaporated to dryness. The title compound (1.49 g, 46%)

LRMS (m/z): 403, 405 (M, M + 2) ⁺ .

c) 1-[3-(Benzyloxy)-5-chlorophenyl]piperazine

Obtaining a white solid hydrochloride salt from 4-[3-(phenylmethyloxy)-5-chlorophenyl]piperazine-1-carboxylic acid tert-butyl ester (preparation 84b) according to the procedure of procedure (99%).

LRMS (m/z): 303, 305 (M, M + 2) ⁺ .

d) 1-[3-(Benzyloxy)-5-chlorophenyl]-4-(3-piperidin-1-ylpropyl)piperazine

Yellow was obtained from 1-[3-(phenylmethyloxy)-5-chlorophenyl]piperazine (preparation 84c) and 1-(3-chloropropyl)piperidine according to the procedure described in Preparation 79a. Oil (85%).

LRMS (m/z): 428, 430 (M, M + 2) ⁺ .

e) 3-chloro-5-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]phenol

1-[3-(Benzyloxy)-5-chlorophenyl]-4-(3-piperidin-1-ylpropyl)piperazine according to the experimental procedure as described in Preparation 30b 84d) was obtained (84%) then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 339, 341 (M, M+2) ⁺ .

f) 3-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 3-chloro-5-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]phenol (Preparation 84e) and 4,4,4 ',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave a brown solid (44%).

LRMS (m/z): 430 (M + 1) ⁺ .

Preparation 85 3-{[piperidin-4-yl(3-piperidin-1-ylpropyl)amino]methyl}phenol a) 4-[(3-piperidin-1-ylpropyl)amino]piperidine-1-carboxylic acid tert-butyl ester

Sodium triethoxy borohydride (1.27 g, 5.99 mmol) was added to 4-butyloxypiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 5.02 mmol), (3-piperidin-1-ylpropane) A solution of the amine (1.27 g, 8.93 mmol) and acetic acid (0.1 mL) in dichloroethane (5 mL) and mixture was stirred at 50 ° C for 5 hr. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane and 1N aqueous sodium hydroxide. The organic layer was separated, washed with brine, dried over magnesium sulfate The title compound (1.04 g, 58%) eluted elute

LRMS (m/z): 326 (M + 1) ⁺ .

b) 4-[(3-Hydroxybenzyl)(3-piperidin-1-ylpropyl)amino]piperidin-1- Tert-butyl formate

Obtained from 4-((3-piperidin-1-ylpropyl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 85a) and 3-hydroxybenzaldehyde according to the experimental procedure as described in Preparation 82a Solid (34%).

LRMS (m/z): 432 (M + 1) ⁺ .

c) 3-{[piperidin-4-yl(3-piperidin-1-ylpropyl)amino]methyl}phenol

Preparation of tert-butyl 4-[(3-hydroxybenzyl)(3-piperidin-1-ylpropyl)amino]piperidine-1-carboxylate according to the experimental procedure as described in Preparation 6b (Preparation 85b ) A solid trihydrochloride salt (100%) was obtained.

LRMS (m/z): 332 (M+1) ⁺ .

Preparation 86 3-{[4-(cyclopentylamino)piperidin-1-yl]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentan-2-yl)phenol a) [1-(3-Chloro-5-hydroxybenzyl)piperidin-4-yl]carbamic acid tert-butyl ester

According to the experimental procedure as described in Preparation 82a, 3-chloro-5- Hydroxybenzaldehyde and piperidin-4-ylaminocarbamic acid tert-butyl ester gave a solid (63%).

LRMS (m/z): 341 (M+1) ⁺ .

b) 3-[(4-Aminopiperidin-1-yl)methyl]-5-chlorophenol

Solid dihydrochloride salt was obtained from [1-(3-chloro-5-hydroxybenzyl)piperidin-4-yl]carbamic acid tert-butyl ester (preparation 86a) according to the procedure described in Preparation 6b (100%).

LRMS (m/z): 241 (M + 1) ⁺ .

c) 3-chloro-5-{[4-(cyclopentylamino)piperidin-1-yl]methyl}phenol

An oil (47%) was obtained from 3-[(4-aminopiperidin-1-yl)methyl]-5-chlorophenol (preparation 86b) and cyclopentanone according to an experimental procedure as described in Preparation 82a. .

LRMS (m/z): 309 (M + 1) ⁺ .

d) 3-{[4-(Cyclopentylamino)piperidin-1-yl]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Boron-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 3-chloro-5-{[4-(cyclopentylamino)piperidin-1-yl]methyl}phenol (Preparation 86c) and 4,4,4' , 4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) gave a solid (57%).

LRMS (m/z): 401 (M + 1) ⁺ .

Preparation 87 2-[(4-Methyl-1,4-diazepan-1-yl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenol a) 5-Chloro-2-[(4-methyl-1,4-diazepan-1-yl)methyl]phenol

Obtained (89%) from 4-chloro-2-hydroxybenzaldehyde and 1-methyl-1,4-diazepane according to the experimental procedure as described in Preparation 77a.

LRMS (m/z): 255 (M + 1) ⁺ .

b) 2-[(4-Methyl-1,4-diazepan-1-yl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 77b, 5-chloro-2-[(4-methyl-1,4-diazepan-1-yl)methyl]phenol (Preparation 87a) and 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) Obtained an oil (60%).

LRMS (m/z): 347 (M + 1) ⁺ .

Preparation 88 {2-[4-(Tertibutoxycarbonyl)-1,4-diazepan-1-yl]pyridin-4-yl} acid a) 4-(4-bromopyridin-2-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

A white solid (70%) was obtained from 4-bromo-2-fluoropyridine and &lt;RTI ID=0.0&gt;&gt;

LRMS (m / z): 356,358 (M, M + 2) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.73-2.07 (m, 6H), 2.11-2.32 (m, 1H), 2.79-3.01 (m, 2H), 3.05-3.18 (m, 2H), 3.20- 3.34 (m, 1H), 3.36-3.54 (m, 3H), 3.56-3.73 (m, 1H), 3.79-3.90 (m, 4H), 3.91-4.61 (m, 1H), 4.26-4.44 (m, 1H) ), 4.97-5.20 (m, 1H), 6.84-7.00 (m, 1H), 7.09-7.22 (m, 1H), 7.30-7.43 (m, 2H), 8.24-8.39 (m, 1H), 8.46-8.76 (m, 3H).

b) {2-[4-(Tertibutoxycarbonyl)-1,4-diazepan-1-yl]pyridin-4-yl} acid

From the 4-(4-bromopyridin-2-yl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (preparation 88a) and 4,4 according to the experimental procedure as described in Preparation 61b , 4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) obtained as a brown oil (100 %).

LRMS (m/z): 322 (M + 1) ⁺ .

Preparation 89 4-[4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a Pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 45a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and {2-[4-(t-butoxycarbonyl)-1,4-diazacyclocycle Heptan-1-yl]pyridin-4-yl} acid (Preparation 88b) gave a solid (60%), which was purified by flash chromatography (dichloromethane to dichloromethane/methanol gradient: 95:5) .

LRMS (m/z): 655 (M + 1) ⁺ .

Preparation 90 3-{[methyl(1-methylpiperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopent-2-yl)phenol a) 3-chloro-5-{[methyl(1-methylpiperidin-4-yl)amino]methyl}phenol

Obtained (62%) from 3-chloro-5-hydroxybenzaldehyde and N ,1-dimethylpiperidin-4-amine according to the procedure described in Preparation 77a.

LRMS (m/z): 269 (M+1) ⁺ .

b) 3-{[Methyl(1-methylpiperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 77b, 3-chloro-5-{[methyl(1-methylpiperidin-4-yl)amino]methyl}phenol (Preparation 90a) and 4,4,4 ',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave an oil (70%).

LRMS (m/z): 361 (M + 1) ⁺ .

Preparation 91 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)(methyl)amino] Piperidin-1-yl}-3-oxopropiononitrile a) (3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)(methyl)amino]piperider Pyridin-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 71a from ( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl Amino] piperidine-1-carboxylic acid tert-butyl ester (preparation 6a) and methyl iodide gave a solid (59%).

LRMS (m/z): 461 (M+1) ⁺ .

b) 6-Chloro-5-fluoro- N -methyl- N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-amine

According to the experimental procedure as described in Preparation 6b from ( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl (Methyl)amino]piperidine-1-carboxylic acid tert-butyl ester (Preparation 91a) gave the solid hydrochloride (100%).

LRMS (m/z): 361 (M + 1) ⁺ .

c) 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)(methyl)amine Peptidin-1-yl}-3-oxopropiononitrile

According to the experimental procedure as described in Preparation 6c, 6-chloro-5-fluoro- N -methyl- N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5- a] pyridin-3-ylpyrimidin-4-amine (preparation 91b) and 3-[(2,5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile to give a solid ( 83%).

LRMS (m/z): 428 (M+1) ⁺ .

Preparation 92 3-[(cyclopentylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol a) 3-chloro-5-[(cyclopentylamino)methyl]phenol

A solid (50%) was obtained from 3-chloro-5-hydroxybenzaldehyde and cyclopentylamine according to the procedure as described in Preparation 82a.

LRMS (m/z): 226 (M + 1) ⁺ .

b) 3-[(Cyclopentylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 3-chloro-5-[(cyclopentylamino)methyl]phenol (Preparation 92a) and 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave an oil (70%).

LRMS (m/z): 318 (M + 1) ⁺ .

Preparation 93 4-[3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1,4-di Azacycloheptane-1-carboxylic acid tert-butyl ester a) 4-(3-chloro-5-hydroxybenzyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester

Obtained (84%) from 3-chloro-5-hydroxybenzaldehyde and 1,4-diazepane-1-carboxylic acid tert-butyl ester according to the procedure described in Preparation 77a.

LRMS (m/z): 341 (M+1) ⁺ .

b) 4-[3-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1,4 -Diazepane-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 77b, 3-butyl 3-(3-chloro-5-hydroxybenzyl)-1,4-diazepane-1-carboxylate (Preparation 93a) and 4 , 4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) obtained an oil ( 67%).

LRMS (m/z): 433 (M + 1) ⁺ .

Preparation 94 4-[3-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5-hydroxybenzyl]-1,4-diazepane-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-[3-hydroxy-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)benzyl]-1,4-diazepane-1-carboxylic acid tert-butyl ester (Preparation 93b) gave solid (73%) The crude product was then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 85: 15: 0.5).

LRMS (m/z): 684 (M + 1) ⁺ .

Preparation 95 3-{6-[4-(Dimethylamino)piperidin-1-yl]pyridin-3-yl}-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)phenol a) 3-chloro-5-{6-[4-(dimethylamino)piperidin-1-yl]pyridin-3-yl}phenol

According to the experimental procedure as described in Preparation 45a, (6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl) acid (Preparation 67b) and 3-bromo-5-chloro The phenol was obtained as a solid (50%), then the crude material was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8:1).

LRMS (m/z): 332 (M+1) ⁺ .

b) 3-{6-[4-(Dimethylamino)piperidin-1-yl]pyridin-3-yl}-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 3-chloro-5-{6-[4-(dimethylamino)piperidin-1-yl]pyridin-3-yl}phenol (Preparation 95a) and 4 , 4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) obtained solid (96% ).

LRMS (m/z): 424 (M + 1) ⁺ .

Preparation 96 2-[(4-Methyl-1,4-diazepan-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenol a) 4-Chloro-2-[(4-methyl-1,4-diazepan-1-yl)methyl]phenol

Obtained (89%) from 5-chloro-2-hydroxybenzaldehyde and 1-methyl-1,4-diazepane according to the procedure described in Preparation 77a.

LRMS (m/z): 255 (M + 1) ⁺ .

b) 2-[(4-Methyl-1,4-diazepan-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 77b, 4-chloro-2-[(4-methyl-1,4-diazepan-1-yl)methyl]phenol (Preparation 96a) and 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) Obtained an oil (61%).

LRMS (m/z): 347 (M + 1) ⁺ .

Preparation 97 Piperidine-4-carboxylic acid 1-methylpiperidin-4-yl ester a) Piperidine-1,4-dicarboxylic acid 1-t-butyl 4-(1-methylpiperidin-4-yl) ester

N,N' -carbonyldiimidazole (0.18 g, 1.11 mmol) was added to a solution of 1-(t-butoxycarbonyl)piperidine-4-carboxylic acid (0.17 g, 0.74 mmol) in tetrahydrofuran (6 mL) The resulting solution was stirred at room temperature for 4 hours. Further, N,N' -carbonyldiimidazole (0.12 g, 0.7 mmol) was added and the solution was further stirred at room temperature for 2 hr. Then 1-methylpiperidin-4-ol (0.15 g, 1.30 mmol) was added and the solution was stirred at room temperature overnight. The solvent was evaporated under vacuum and the crude material was partitioned between diethyl ether and water. The organic phase was separated, washed with aq. sodium hydrogen sulfate, dried over sodium sulfate and evaporated. The crude material obtained was dissolved in diethyl ether and hexane was added until a precipitate formed. Filter the solids. Additional hexane was added to the filtrate until the oil precipitated and the oil was discarded. The combined organic layers were concentrated to give the title compound (jjjjjjj

LRMS (m/z): 327 (M + 1) +.

b) Piperidine-4-carboxylic acid 1-methylpiperidin-4-yl ester

A 4 M solution of hydrogen chloride in dioxane (1.7 mL) was added to piperidine-1,4-dicarboxylic acid 1-t-butyl 4-(1-methylpiperidin-4-yl) ester (Preparation 97a, 0.2 g, 0.65 mmol) in a solution of propan-2-ol (4 mL) and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated and the residue was purified eluted eluted elut The hydrochloride salt of the compound (0.15 g, 69%).

LRMS (m/z): 227 (M + 1) +.

Preparation 98 (6-{4-[(Tertibutoxycarbonyl)(cyclopentyl)amino]piperidin-1-yl}pyridin-3-yl) acid a) 1-Benzyl- N -cyclopentylpiperidin-4-amine

An oil (68%) was obtained from 1-phenylmethylpiperidin-4-one and cyclopentylamine according to the procedure described in Preparation 49.

LRMS (m/z): 259 (M + 1) ⁺ .

b) (1-Benzylpiperidin-4-yl)cyclopentylaminocarboxylic acid tert-butyl ester

Water (15 mL) containing potassium carbonate (1.20 g, 8.68 mmol) and 1,4-dioxane (15 mL) containing ditributyl dicarbonate (1.74 g, 7.97 mmol) were added to 1-benzyl- N -Cyclopentylpiperidin-4-amine (Preparation 98a, 1.87 g, 7.24 mmol) in EtOAc (EtOAc) The solvent was concentrated in vacuo and the residue was partitioned between water and pentane. The organic layer was separated and the aqueous layer was extracted with pentane. The combined organic layers were washed with EtOAc EtOAc m.

LRMS (m / z): 359 (M + 1) +.

c) tert-butyl cyclopentyl (piperidin-4-yl)carbamate

10% palladium on carbon (0.45 g, 4.28 mmol) and ammonium formate (1.35 g, 21.4 mmol) were added to (1-phenylmethylpiperidin-4-yl)cyclopentylaminocarboxylic acid tert-butyl ester (Preparation 98b) , 1.53 g, 4.27 mmol) in methanol (22 mL) and the reaction mixture was stirred at 60 ° C for 3 h and then cooled to Room temperature. The catalyst was filtered, washed with methanol and the combined filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was separated. The aqueous layer was extracted with EtOAc (EtOAc m.

LRMS (m/z): 269 (M+1) ⁺ .

d) [1-(5-Bromopyridin-2-yl)piperidin-4-yl]cyclopentylaminocarboxylic acid tert-butyl ester

An orange oil was obtained from tributyl butyl cyclopentyl (piperidin-4-yl)carbamate (preparation 98c) and 5-bromo-2-fluoropyridine according to the procedure described in Preparation 61a (100%) ).

LRMS (m / z): 424,426 (M, M + 2) +.

e) (6-{4-[(Tertibutoxycarbonyl)(cyclopentyl)amino]piperidin-1-yl}pyridin-3-yl) acid

According to the experimental procedure as described in Preparation 61b from [1-(5-bromopyridin-2-yl)piperidin-4-yl]cyclopentylaminocarboxylic acid tert-butyl ester (preparation 98d) and 4,4, 4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) gave a solid (92%).

LRMS (m/z): 390 (M + 1) ⁺ .

Preparation 99 {1-[5-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}cyclopentylaminocarboxylic acid tert-butyl ester

Feeding the microwave reactor with 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl) Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c, 0.20 g, 0.48 mmol), {1-[5-(6-{[(3 R )-1-(cyano) Ethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidine -4 yl}cyclobutylaminocarbamic acid tert-butyl ester (preparation 98e, 0.66 g, 1.70 mmol), 2M aqueous hydrazine carbonate (0.73 mL, 1.75 mmol) and 1,4-dioxane (4 mL). The reactor was subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex (0.024). g, 0.03 mmol). In a further three evacuation - backfilled with argon after cycling, the reactor was sealed and the reaction mixture was subjected to microwave irradiation at 140 deg.] C for 2 h, filtered through diatomaceous earth (Celite ^®) and evaporated to dryness. The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 724 (M+2) ⁺ .

Preparation 100 2-{[4-(Dimethylamino)piperidin-1-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentan-2-yl)phenol a) 4-Chloro-2-{[4-(dimethylamino)piperidin-1-yl]methyl}phenol

Obtaining a solid (86%) from 5-chloro-2-hydroxybenzaldehyde and N,N -dimethylpiperidin-4-amine according to the procedure described in Preparation 82a, followed by flash chromatography (dichloro The crude product was purified from methane to dichloromethane / methanol / ammonia 40: 8:1.

LRMS (m/z): 269 (M+1) ⁺ .

b) 2-{[4-(Dimethylamino)piperidin-1-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boron-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 4-chloro-2-{[4-(dimethylamino)piperidin-1-yl]methyl}phenol (Preparation 100a) and 4,4,4' , 4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) gave a solid (99%).

LRMS (m/z): 361 (M + 1) ⁺ .

Preparation 101 4-[2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine-1-carboxylic acid Third butyl ester a) tert-butyl 4-(4-chloro-2-hydroxybenzyl)piperazine-1-carboxylate

A yellow oil (86%) was obtained from 4-chloro-2-hydroxybenzaldehyde and piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Preparation 82a, followed by flash chromatography (dichloro The crude product was purified from methane to dichloromethane / methanol 95:5).

LRMS (m/z): 327 (M + 1) ⁺ .

b) 4-[2-Hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine-1 -T-butyl formate

According to the experimental procedure as described in Preparation 82b, 3-butyl 4-(4-chloro-2-hydroxybenzyl)piperazine-1-carboxylate (Preparation 101a) and 4,4,4',4', 5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) afforded a white solid (35%), followed by flash chromatography The crude product was purified (methylene chloride to dichloromethane / methanol gradient: 95).

LRMS (m/z): 419 (M+1) ⁺ .

Preparation 102 4-[4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl)-2-hydroxybenzyl]piperazine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 99, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-[2-hydroxy-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester (Preparation 101b) gave solid (74%), followed by flash chromatography (2) The crude product was purified by gradient from chloromethane to dichloromethane / methanol 95:5.

LRMS (m/z): 670 (M + 1) ⁺ .

Preparation 103 (3-hydroxy-4-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl) acid a) 5-Chloro-2-{[(1-methylpiperidin-4-yl)amino]methyl}phenol

(91%) was obtained from 4-chloro-2-hydroxybenzaldehyde and 1-methylpiperidin-4-amine according to the procedure described in Preparation 77a.

LRMS (m/z): 255 (M + 1) ⁺ .

b) (3-hydroxy-4-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl) acid

According to the experimental procedure as described in Preparation 77b, 5-chloro-2-{[(1-methylpiperidin-4-yl)amino]methyl}phenol (Preparation 103a) and 4,4,4', 4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) obtained (47%), followed by reverse phase The crude product was purified by chromatography (water to methanol).

LRMS (m/z): 265 (M + 1) ⁺ .

Preparation 104 Ethyl 4-methyl-[1,4'-bipiperidine]-4-carboxylate a) ethyl 4-methylpiperidine-4-carboxylate

Add 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) to 4-methylpiperidine-1,4-dicarboxylic acid 1-t-butyl 4-ethyl ester (0.34 g, 1.25 mmol) in ethanol The solution in (4 mL) was stirred at room temperature for 6 hours. The solvent was evaporated and the~~~~~~~~~~~~~~~

LRMS (m/z): 172 (M + 1) +.

b) 4-methyl-[1,4'-bipiperidinyl]-1',4-dicarboxylic acid 1'-tert-butyl 4-ethyl ester

4-methylpiperidine-4-carboxylic acid ethyl ester hydrochloride (preparation 104a, 0.30 g, 1.44 mmol), 4-butyloxypiperidine-1-carboxylic acid tert-butyl ester (0.32 g, 1.59 mmol), three A mixture of sodium acetoxyborohydride (0.37 g, 1.73 mmol) and triethylamine (0.20 mL, 1.45 mmol) in dichloromethane (5 mL) Acetic acid (4 drops) was added and the reaction mixture was stirred at room temperature for a further 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried over magnesium sulfate The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 355 (M + 1) +.

c) ethyl 4-methyl-[1,4'-bipiperidine]-4-carboxylate

Add 4M solution of hydrogen chloride in 1,4-dioxane (3.2 mL) to 4-methyl-[1,4'-bipiperidine]-1',4-dicarboxylic acid 1'-t-butyl 4 Ethyl ester (preparation 104b, 0.23 g, 0.65 mmol) in EtOAc (EtOAc) The solvent was evaporated and the residue was crystalljjjjjjjjjjjjjj

LRMS (m/z): 255 (M + 1) +.

Preparation 105 1-methyl-4-[2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl]-1,4-diazepane a) 1-[4-Bromo-2-(methylthio)benzyl]-4-methyl-1,4-diazepane

Colorless oil (62%) obtained from 4-bromo-2-(methylthio)benzaldehyde and 1-methyl-1,4-diazepane according to the procedure described in Preparation 82a. The crude product was then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 100: 8:1).

LRMS (m / z): 329,331 (M, M + 2) +.

b) 1-Methyl-4-[2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Phenylmethyl]-1,4-diazepane

From 1-[4-bromo-2-(methylthio)benzyl]-4-methyl-1,4-diazepane (Preparation 105a) according to the experimental procedure as described in Preparation 61b And 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) to obtain a yellow oil (79%).

LRMS (m/z): 377 (M + 1) ⁺ .

Preparation 106 1-methyl-4-[2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl]-1,4-diazepane a) 1-[5-Bromo-2-(methylthio)benzyl]-4-methyl-1,4-diazepane

A solid (96%) was obtained from 5-bromo-2-(methylthio)benzaldehyde and 1-methyl-1,4-diazepane according to the experimental procedure as described in Preparation 82a. The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8:1).

LRMS (m / z): 329,331 (M, M + 2) +.

b) 1-Methyl-4-[2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Phenylmethyl]-1,4-diazepane

According to the experimental procedure as described in Preparation 61b from 1-[5-bromo-2-(methylthio)benzyl]-4-methyl-1,4-diazepane (Preparation 106a) And 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) to obtain a solid ( 92%).

LRMS (m/z): 377 (M + 1) ⁺ .

Preparation 107 [4-({2-[4-(Dimethylamino)piperidin-1-yl]ethyl}thio)phenyl]acid a) 1-(2-chloroethyl)- N , N -dimethylpiperidin-4-amine

1-Bromo-2-chloroethane (1.95 mL, 23.43 mmol) was added to N,N -dimethylpiperidin-4-amine (2.0 g, 15.60 mmol) and potassium carbonate (4.31 g, 31.20 mmol) in acetone The solution in (10 mL) was stirred at room temperature for 18 h. The solid was filtered and the filtrate was evaporated eluting mjjjjjjjjjj

LRMS (m/z): 191 (M+1) ⁺ .

b) [4-({2-[4-(Dimethylamino)piperidin-1-yl]ethyl}thio)phenyl] acid

1-(2-Chloroethyl) -N,N -dimethylpiperidin-4-amine (Preparation 107a, 0.399 g, 2.09 mmol), (4-nonylphenyl) acid (0.129 g, 0.84 mmol) A mixture of cesium carbonate (1.09 g, 3.35 mmol) in tetrahydrofuran (3 mL) was placed in a microwave vessel and subjected to microwave irradiation at 130 ° C for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic phase was separated, washed with water and brine, dried over sodium sulfate The title compound (0.136 g, m.

LRMS (m/z): 309 (M + 1) ⁺ .

Preparation 108 {6-[4-(Dimethylamino)piperidin-1-yl]-5-hydroxypyridin-3-yl} acid a) 5-bromo-2-fluoro-3-{[2-(trimethyldecyl)ethoxy]methoxy}pyridine

Diisopropylethylamine (0.41 mL, 2.34 mmol) and [2-(chloromethoxy)ethyl](trimethyl)decane (0.32 mL, 1.80 mmol) were added to 5-bromo-2 at 0 °C. A solution of fluoropyridin-3-ol (0.30 g, 1.56 mmol) in dichloromethane (8 mL). The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. Minute The organic layer was washed with brine, dried over magnesium sulfate and evaporated The crude material was purified by flash chromatography eluting elut elut elut elut

b) 1-(5-Bromo-3-{[2-(trimethyldecyl)ethoxy]methoxy}pyridin-2-yl) -N , N -dimethylpiperidin-4-amine

According to the experimental procedure as described in Preparation 61a, 5-bromo-2-fluoro-3-{[2-(trimethyldecyl)ethoxy]methoxy}pyridine (Preparation 108a) and N,N - Dimethylpiperidin-4-amine gave an oil (39%).

LRMS (m/z): 430, 432 (M, M + 2) ⁺ .

c) 5-bromo-2-[4-(dimethylamino)piperidin-1-yl]pyridin-3-ol

1-(5-Bromo-3-{[2-(trimethyldecyl)ethoxy]methoxy}pyridin-2-yl) -N , N -dimethylpiperidin-4-amine (Preparation A solution of 108b, 0.23 g (0.53 mmol) in trifluoroacetic acid (2.20 mL) was stirred at room temperature for 30 min. The solvent was evaporated to dryness. The aqueous layer was separated, basified with 2N aqueous sodium hydroxide and ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m.

LRMS (m/z): 300, 302 (M, M+2) ⁺ .

d) {6-[4-(Dimethylamino)piperidin-1-yl]-5-hydroxypyridin-3-yl} acid

According to the experimental procedure as described in Preparation 61b from 5-bromo-2-[4-(dimethylamino)piperidin-1-yl]pyridin-3-ol (Preparation 108c) and 4,4,4' , 4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) gave an oil (92%).

LRMS (m/z): 266 (M + 1) ⁺ .

Preparation 109 2-[(cyclopentylamino)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol a) 4-chloro-2-[(cyclopentylamino)methyl]phenol

A white solid (100%) was obtained from 5-chloro-2-hydroxybenzaldehyde and cyclopentylamine according to an experimental procedure as described in Preparation 82a.

LRMS (m/z): 226 (M + 1) ⁺ .

b) 2-[(cyclopentylamino)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 4-chloro-2-[(cyclopentylamino)methyl]phenol (Preparation 109a) and 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave a solid (33%).

LRMS (m/z): 318 (M + 1) ⁺ .

Preparation 110 2-[(cyclopentylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol a) 5-Chloro-2-[(cyclopentylamino)methyl]phenol

A white solid (100%) was obtained from 4-chloro-2-hydroxybenzaldehyde and cyclopentylamine according to the procedure as described in Preparation 82a.

LRMS (m/z): 226 (M + 1) ⁺ .

b) 2-[(cyclopentylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 82b, 5-chloro -2-[(cyclopentylamino)methyl]phenol (Preparation 110a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-Dioxaborolane) gave a solid (29%).

LRMS (m/z): 318 (M + 1) ⁺ .

Preparation 111 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)oxypiperidine-1-carboxylic acid Third butyl ester a) 4-((4-bromobenzylidene)oxy)piperidine-1-carboxylic acid tert-butyl ester

Triethylamine (0.76 mL, 5.48 mmol) and 4-butylpiperidine-1-carboxylic acid tert-butyl ester (0.54 g, 2.68 mmol) were added to 4-bromobenzylidene chloride (0.6 g, 2.73 mmol) in tetrahydrofuran ( The solution in 3 mL) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between diethyl ether and water. The organic phase was separated, washed with aq. The crude material was taken from EtOAc EtOAc EtOAc.

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

b) 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)oxypiperidine-1 -T-butyl formate

To the Schlenk tube, a third butyl 4-((4-bromobenzylidinyl)oxy)piperidine-1-carboxylate (preparation 111a, 0.93 g, 2.42 mmol), 4, 4, 4' , 4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (0.92 g, 3.62 mmol), potassium acetate (0.71 g, 7.23 mmol) and 1,4-dioxane (5 mL). The Schlenk tube is subjected to three vacuum-backfill cycles with argon followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride complex. (0.10 g, 0.12 mmol). In the other three vacuum - use After the argon backfill cycle, the Schlenk tube was sealed and the mixture was stirred at 80 ° C and heated for 4 hours. The reaction mixture was cooled to room temperature, diluted with excess diethyl ether and filtered. The solvent was evaporated to dryness, taken up with hexanes and filtered. The filtrate was diluted with aq. MeOH / EtOAc (EtOAc)EtOAc.

LRMS (m/z): 432 (M + 1) +.

Preparation 112 ( R )-4-((4-(6-((1-(2-cyanoethyl))piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo[1, 3-a]pyridin-3-yl)pyrimidin-4-yl)benzylidene)oxy)piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Preparation 56a, ( R )-3-(3-((6-chloro-5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine) 4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (preparation 6c) and 4-((4-(4,4,5,5-tetramethyl-1,3) ,2-dioxaborolan-2-yl)benzylidene)oxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 111b) gave a brown gum. </RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt;

LRMS (m/z): 683 (M + 1) +.

Preparation 113 2-[(Methylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol a) 5-Chloro-2-[(methylamino)methyl]phenol

A mixture of 4-chloro-2-hydroxybenzaldehyde (0.412 g, 2.63 mmol) and methylamine (40% in water, 4.6 mL, 52.72 mmol) Sodium borohydride (0.199 g, 5.26 mmol) was added portionwise at 0 ° C and the mixture was stirred at room temperature for 18 h. The solvent was removed and the crude material was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water and brine, dried The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 172 (M + 1) ⁺ .

b) 2-[(Methylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

According to the experimental procedure as described in Preparation 77b, 5-chloro-2-[(methylamino)methyl]phenol (Preparation 113a) and 4,4,4',4',5,5,5', 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave a solid (38%).

LRMS (m/z): 264 (M + 1) ⁺ .

Preparation 114 2-{[methyl(pyridin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)phenol a) 5-Chloro-2-{[methyl(pyridin-4-yl)amino]methyl}phenol

5-chloro-2-[(methylamino)methyl]phenol (preparation 113a, 0.579 g, 3.37 mmol), 4-chloropyridine (0.506 g, 3.37 mmol) and 4-methylmorpholine (0.473 mL, 3.71 mmol) of the solution in N -methyl-2-pyrrolidone (4.5 mL) was stirred at 120 ° C for 18 hours in a sealed tube. The solvent was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

LRMS (m/z): 249 (M + 1) ⁺ .

b) 2-{[Methyl(pyridin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenol

According to the experimental procedure as described in Preparation 77b, 5-chloro-2-{[methyl(pyridin-4-yl)amino]methyl}phenol (Preparation 114a) and 4,4,4',4', 5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) gave a solid (37%).

LRMS (m/z): 341 (M+1) ⁺ .

Preparation 115 4-fluoro-2-((piperidin-4-ylamino)methyl)phenol a) tert-butyl 4-((5-fluoro-2-hydroxybenzyl)amino)piperidine-1-carboxylate

a solution of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (0.2 g, 1 mmol) and 5-fluoro-2-hydroxybenzaldehyde (0.14 g, 1 mmol) in dichloromethane (1 mL) at room temperature Stir overnight. Sodium cyanoborohydride (0.13 g, 2.07 mmol) was added portionwise and the mixture was stirred at room temperature for 24 hr then partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The residue was taken from EtOAc (EtOAc)

LRMS (m/z): 325 (M + 1) +.

b) 4-fluoro-2-((piperidin-4-ylamino)methyl)phenol

3-((5-fluoro-2-hydroxybenzyl)amino)piperidine-1-carboxylic acid tert-butyl ester (preparation 115a, 0.22 g, 0.68 mmol) and ethanol (4 mL) containing 1.25 M hydrogen chloride solution The mixture was stirred overnight at room temperature. Evaporation solvent The residue was taken from EtOAc (EtOAc m.

LRMS (m/z): 225 (M + 1) +.

Preparation 116 [2-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]methylaminocarboxylic acid tert-butyl ester a) 4-chloro-2-[(methylamino)methyl]phenol

Obtained (79%) from 5-chloro-2-hydroxybenzaldehyde and water containing 40% methylamine solution according to the experimental procedure as described in Preparation 113a.

LRMS (m/z): 172 (M + 1) ⁺ .

b) (5-chloro-2-hydroxybenzyl)methylaminocarbamic acid tert-butyl ester

a mixture of 4-chloro-2-[(methylamino)methyl]phenol (preparation 116a, 0.30 g, 1.75 mmol) and di-tert-butyl dicarbonate (0.458 g, 2.10 mmol) in tetrahydrofuran (5 mL) Stir at room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, EtOAc m m m m m m

LRMS (m/z): 272 (M + 1) ⁺ .

c) [2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]methylaminocarboxylic acid Tributyl ester

According to the experimental procedure as described in Preparation 77b, (5-chloro-2-hydroxybenzyl)methylcarbamic acid tert-butyl ester (preparation 116b) and 4,4,4',4',5,5 , 5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) gave an oil (61%).

LRMS (m/z): 347 (M + 1) ⁺ .

Preparation 117 [5-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridine -3-ylpyrimidin-4-yl)-2-hydroxybenzyl]methylaminocarbamic acid tert-butyl ester

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and [2-hydroxy-5-(4,4,5,5-tetramethyl-1,3 , tert-butyl 2-dioxaborolan-2-yl)benzyl]methylcarbamate (preparation 116c) afforded solid (45%), followed by flash chromatography (hexane to acetic acid Ethyl ester) The crude product was purified.

LRMS (m/z): 615 (M + 1) ⁺ .

Instance Example 1 3-{(3 R )-3-[[2-(dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1,5- a ] Pyridyl-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

N- (5-fluoro-6-morpholin-4-yl-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl) -N',N' -dimethyl- N -[(3 R )-piperidin-3-yl]ethane-1,2-diamine tetrahydrochloride (preparation 10c, 0.18 g, 0.29 mmol), 3-[(2,5-di-side oxygen) Pyrrrolidin-1-yl)oxy]-3-oxopropanenitrile (0.080 g, 0.44 mmol) and triethylamine (0.224 mL, 1.76 mmol) in N,N' -dimethylformamide The solution in (2 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (6 mL) and the formed precipitate was filtered. The title compound (0.057 g, 35%) was obtained.

LRMS (m/z): 537 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.87-2.18 (m, 4H), 2.18-2.42 (s, 6H), 2.45-2.70 (m, 3H), 2.84-3.01 (dd, 1H), 3.03- 3.23 (dd, 1H), 3.27-3.48 (m, 2H), 3.48-3.81 (m, 8H), 3.81-3.98 (m, 4H), 4.07-4.42 (m, 2H), 4.57-4.88 (dd, 2H) ), 6.78-6.94 (m, 1H), 7.27-7.38 (m, 2H), 8.21 - 8.44 (m, 1H), 8.44 - 8.61 (m, 1H).

Example 2 3-{(3 R )-3-[(5-fluoro-6-{4-[(1-methyl-1 H -imidazol-2-yl)methyl]piperazin-1-yl}-2- Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

5-fluoro-6-{4-[(1-methyl-1H-imidazol-2-yl)methyl]piperazin-1-yl} -N -[(3 R )-piperidin-3-yl] 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (preparation 12b, 0.082 g, 0.12 mmol), 3-[(2,5-di- oxypyrrolidine-1 -Alkyloxypropionitrile (0.033 g, 0.18 mmol) and triethylamine (0.12 mL, 0.85 mmol) in N,N' -dimethylformamide (1 mL) Stir overnight at room temperature. The reaction mixture was diluted with excess water and extracted with EtOAc. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated The residue was purified by flash chromatography eluting elut elut elut

LRMS (m/z): 559 (M+2) ⁺ .

¹ H-NMR δ (400 MHz, CDCl ₃ ): 1.17-1.45 (m, 6H), 1.71-1.82 (m, 2H), 2.08-2.23 (m, 1H), 2.53-2.69 (m, 2H), 3.06 - 3.16 (m, 1H), 3.30-3.43 (m, 1H), 3.43-3.62 (m, 2H), 3.62-3.69 (m, 1H), 3.69-3.85 (m, 4H), 4.12-4.29 (m, 1H) ), 4.48-4.70 (m, 1H), 6.75-7.04 (m, 3H), 7.04-7.16 (m, 1H), 7.27-7.39 (m, 1H), 8.28-8.61 (m, 3H).

Example 3 3-[(3 R )-3-({6-[4-(1 H -benzimidazol-2-ylmethyl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1] ,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropiononitrile

According to the experimental procedure as described in Example 1, 6-[4-( 1H -benzimidazol-2-ylmethyl)piperazin-1-yl]-5-fluoro- N -[( 3R )- Piperidin-3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine pentahydrochloride (preparation 14b) and 3-[(2,5-di-side oxygen) The pyridyl-1-yloxy]-3-oxo-propanenitrile gave a yellow solid (45%), which was purified by flash chromatography.

LRMS (m / z): 595 (M + 2) +.

^{1 H-NMR δ (300MHz,} CDCl 3): 1.04-1.39 (m, 1H), 1.72-1.99 (m, 2H), 2.07-2.28 (m, 1H), 2.56-2.88 (m, 4H), 3.05- 3.21 (m, 1H), 3.24-3.68 (m, 3H), 3.68-4.04 (m, 4H), 4.07-4.34 (m, 1H), 4.45-4.77 (m, 1H), 6.73-6.99 (m, 1H) ), 7.38-7.90 (m, 2H), 8.21 - 8.68 (m, 3H), 9.50-9.89 (m, 1H).

Example 4 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyridin-2-ylmethyl)piperazine) -1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -yl}-3-oxopropanenitrile (preparation 6c, 0.05 g, 0.12 mmol), 1-(pyridin-2-ylmethyl)piperazine (0.03 g, 0.18 mmol) and sodium bicarbonate (0.09 g, A mixture of 1.10 mmol) in N,N -dimethylacetamide (0.5 mL) was stirred at 90 ° C overnight. Water was added and the precipitate formed was filtered. The title compound (40 mg, 58%) eluted elute

LRMS (m/z): 555 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.68-1.78 (m, 4H), 2.63 (m, 4H), 3.40 (d, 2H), 3.45-3.48 (m, 2H), 3.56 (bs, 1H) , 3.72 (s, 2H), 3.75-3.85 (m, 6H), 4.20 (m, 1H), 4.50-4.65 (m, 1H), 6.83 (m, 1H), 7.14-7.23 (m, 1H), 7.24 -7.33 (m, 1H), 7.44 (d, 1H), 7.68 (m, 1H), 8.33 (d, 1H), 8.40 - 8.52 (m, 2H), 8.54 - 8.62 (m, 1H).

Example 5 3-((3 R )-3-{[6-(4-{[4-(Dimethylamino)pyridin-2-yl]methyl}piperazin-1-yl)-5-fluoro-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-(piperazin-1-ylmethyl)pyridine-4 -Amine (Preparation 15b) gave a brown solid (30%).

LRMS (m/z): 599 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.65-2.23 (m, 4H), 2.66 (m, 4H), 3.02 (s, 6H), 3.36-3.57 (m, 4H), 3.61 (s, 2H) , 3.74-3.86 (m, 6H), 4.19 (m, 1H), 4.61 (m, 1H), 6.41 (dd, 1H), 6.67 (d, 1H), 6.84 (m, 1H), 7.27-7.33 (dd , 1H), 8.20 (d, 1H), 8.30-8.58 (m, 3H).

Example 6 3-{(3 R )-3-[(5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-{4-[(4-pyrrolidin-1-ylpyridine) -2-yl)methyl]piperazin-1-yl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-[(4-pyrrolidin-1-ylpyridin-2-yl)methyl]piperazine (Preparation 16b) Obtained solid (40%).

LRMS (m/z): 624 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.70-1.84 (m, 4H), 2.00-2.07 (m, 4H), 2.65-2.70 (m, 4H), 3.30-3.43 (m, 6H), 3.44 3.64 (m, 4H), 3.73-3.85 (m, 6H), 4.20 (m, 1H), 4.60 (m, 1H), 6.30 (d, 1H), 6.54 (s, 1H), 6.86 (m, 1H) , 7.30 (d, 1H), 8.19 (d, 1H), 8.30-8.58 (m, 3H).

Example 7 3-[(3 R )-3-({5-fluoro-6-[4-(4-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

3-[(2,5-Di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanonitrile (108 mg, 0.59 mmol) was added to 4-[(4-{5-fluoro-6) -[(3 R )-piperidin-3-ylamino]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}piperazin-1-yl)methyl] A stirred solution of phenol (Preparation 17c, 0.20 g, 0.30 mmol) Water was added and the organic layer was separated, washed with brine, dried over magnesium sulfate The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 570 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.74-1.95 (m, 4H), 2.51-2.66 (m, 4H), 3.39 (d, 1H), 3.44 - 3.60 (m, 4H), 3.67-3.87 ( m, 6H), 4.17 (m, 1H), 4.47-4.67 (m, 1H), 6.73-6.90 (m, 3H), 7.15-7.22 (m, 2H), 7.25-7.34 (m, 1H), 8.34 ( Dd, 1H), 8.40-8.60 (m, 2H).

Example 8 4-{[4-(5-fluoro-6-{[(3 R )-1-(3-hydroxy-3-methylbutanyl)piperidin-3-yl]amino}-2-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol

4-[(4-{5-fluoro-6-[(3 R )-piperidin-3-ylamino]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4- }}piperazin-1-yl)methyl]phenol (preparation 17c, 0.10 g, 0.20 mmol), 3-hydroxy-3-methylbutyric acid (0.04 mL, 0.30 mmol), hexafluorophosphate 1-[double ( Dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5-b]pyridinium-3-oxide (0.11 g, 0.30 mmol) and diisopropyl B amine (0.28mL, 1.62mmol) in N, N - dimethylformamide mixture (1 mL) are stirred at the room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane. The residue was purified by flash chromatography eluting elut elut elut elut elut elut

LRMS (m/z): 604 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.13 (d, 6H), 1.75-1.90 (m, 4H), 2.32-2.47 (m, 2H), 2.56-2.71 (m, 4H), 3.19-3.37 ( m, 2H), 3.55 (s, 2H), 3.71-3.85 (m, 4H), 3.90-4.01 (m, 1H), 4.60-4.75 (m, 1H), 5.40 (bs, 1H), 6.81 (m, 3H), 7.26 (m, 3H), 8.33 - 8.56 (m, 3H).

Example 9 4-{[4-(5-fluoro-6-{[(3 R )-1-ethanehydrazinopiperidin-3-yl]amino}-2-pyrazolo[1,5-a] Pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol

Hexafluorophosphoric acid (benzotriazol-1-yloxy) ginseng (dimethylamino) hydrazine (0.079 g, 0.21 mmol) was added to 4-[(4-{5-fluoro-6-[(3 R) -piperidin-3-ylamino]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}piperazin-1-yl)methyl]phenol (Preparation 17c, 0.080g, 0.16mmol), a solution of glycolic acid (0.015g, 0.20mmol) and triethylamine (0.031mL, 0.22mmol) in N,N' -dimethylformamide (0.6mL) and the resulting mixture Stir at room temperature for 16 hours. Excess water was added and the precipitate was filtered, washed with EtOAc EtOAcjjjjjjj

LRMS (m/z): 562 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.22-1.38 (m, 1H), 1.52 -2.08 (m, 5H), 2.09-2.24 (m, 1H), 2.51-2.69 (bs, 3H), 3.04- 3.17 (m, 1H), 3.17-3.28 (m, 1H), 3.35-3.61 (m, 2H), 3.61-3.71 (m, 1H), 3.71-3.84 (bs, 1H), 3.84-3.94 (m, 1H) ), 3.95-4.06 (d, 1H), 4.11-4.30 (m, 2H), 4.55-4.70 (m, 1H), 6.72-6.92 (m, 3H), 7.12-7.23 (d, 2H), 8.28-8.67 (m, 3H).

Example 10 3-[(3 R )-3-({5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

3-[(2,5-Di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile (0.03 g, 0.14 mmol) was added to 5-fluoro-6-[4-(4 -Methoxybenzyl)piperazin-1-yl] -N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine 4-Amine (Preparation 17b, 0.05 g, 0.09 mmol) and EtOAc (EtOAc) Water was added and the organic layer was separated, washed with brine, dried over magnesium sulfate The residue was purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 585 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.69-1.81 (m, 4H), 2.52-2.62 (m, 4H), 3.39 (d, 2H), 3.42-3.58 (m, 4H), 3.72-3.85 ( m, 6H), 4.18 (m, 1H), 4.49-4.65 (m, 1H), 6.77-6.93 (m, 3H), 7.19-7.31 (m, 1H), 8.34 (m, 1H), 8.40-8.59 ( m, 2H).

Example 11 3-[(3 R )-3-({5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-(piperazin-1-ylmethyl)phenol gave a pale yellow solid (51%). The crude product was purified by flash chromatography (hexane toEtOAc).

LRMS (m/z): 571 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.59-1.94 (m, 4H), 2.58 (m, 4H), 3.44 (d, 2H), 3.45-3.53 (m, 4H), 3.57 (s, 1H) , 3.65-3.84 (m, 6H), 4.12-4.24 (m, 1H), 4.65-4.75 (m, 1H), 6.75 (dd, 1H), 6.80-6.89 (m, 3H), 7.17 (td, 1H) , 7.23 - 7.34 (m, 1H), 8.27 - 8.61 (m, 3H).

Example 12 3-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-(4-(piperazin-1-ylmethyl) Phenyloxy)ethylamine (Preparation 18b) gave a white solid (64%), which was then purified by reverse phase chromatography (using water/methanol as solvent).

LRMS (m/z): 641 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.7-1.9 (m, 4H), 2.1-2.2 (m, 1H), 2.3 (s, 6H), 2.5-2.6 (m, 4H), 2.7 (t, 2H), 3.4 (d, 1H), 3.4-3.6 (m, 4H), 3.7-3.9 (m, 5H), 4.1 (t, 2H), 4.2 (s, 1H), 4.4-4.7 (m, 2H) , 6.8-6.9 (m, 1H), 6.9 (d, 2H), 7.2 (d, 2H), 7.2-7.3 (m, 1H), 8.3-8.6 (m, 3H).

Example 13 2-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol

6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (preparation 19b, 0.11 g, 0.19 mmol), 2-hydroxyacetic acid (0.02 g, 0.24 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide fluorophosphate (0.11 g, 0.30 mmol) and triethylamine (0.04mL, 0.24mmol) in N, N - dimethylformamide mixture (2mL) in the stirred at room temperature for 1 hour. The solvent was evaporated and purified EtOAcqqqqqqqq

LRMS (m/z): 632 (M + 1) ⁺ .

Example 14 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-1-(A Oxidyl)piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine

Triethylamine (0.034 mL, 0.24 mmol) was added to hexafluorophosphoric acid (benzotriazol-1-yloxy) gin (dimethylamino) hydrazine (0.069 g, 0.18 mmol) and methoxyacetic acid (0.016) g, 0.18 mmol) in a mixture of chloroform (0.5 mL) and the mixture was stirred at room temperature for 5 min. Next, 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine was added. a solution of -3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 19b, 0.087 g, 0.15 mmol) in chloroform (1.5 mL) Stir overnight at room temperature. The reaction mixture was partitioned between dichloromethane and dilute aqueous sodium hydroxide. The precipitated precipitate formed was separated and dissolved in methanol and excess diethyl ether. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 647 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.75-1.94 (m, 3H), 1.99-2.14 (m, 2H), 2.30-2.38 (s, 6H), 2.50-2.61 (m, 4H), 2.69- 2.78(t,2H),3.24-3.34(s,2H),3.34-3.44(m,1H),3.45-3.52(ds,3H),3.52-3.61(m,1H),3.63-3.81(m,5H ), 3.81-3.85 (d, 2H), 3.97-4.02 (m, 1H), 4.03-4.10 (t, 2H), 4.10-4.34 (m, 3H), 4.66-4.77 (m, 1H), 4.84-4.94 (d, 1H), 6.74-6.86 (m, 1H), 6.86-6.94 (d, 2H), 7.20-7.30 (m, 3H), 8.33 - 8.59 (m, 3H).

Example 15 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a] Pyridin-3-yl- N -[(3 R )-1-(3,3,3-trifluoropropenyl) Piperidin-3-yl]pyrimidine-4-amine

6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (preparation 19b, 0.10 g, 0.18 mmol), 3,3,3-trifluoropropionic acid (0.03 mL) , 0.27 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate ( A mixture of 0.14 g, 0.36 mmol) and diisopropylethylamine (0.06 mL, 0.35 mmol) in N,N -dimethylformamide (2 mL) was stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with dichloromethane (x3). The combined organic layers were washed with water (x3), dried by a phase separator and evaporated to dryness. The residue was purified by EtOAcqqqqq

LRMS (m/z): 684 (M + 1) ⁺ .

Example 16 [3-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro -2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)oxetan-3-yl]acetonitrile

6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (preparation 19b, 0.10 g, 0.17 mmol) and oxetane-3-ylidene acetonitrile (0.15 A mixture of g, 1.58 mmol) in acetonitrile (2 mL) was stirred at <RTIgt; Additional oxetane-3-ylideneacetonitrile was added over 24 hours (0.15 g, 1.58 mmol) and 48 hours (0.30 g, 3.16 mmol) and the reaction mixture was stirred for a further 72 hours. The solvent was evaporated and the residue was purifiedjjjjjjjjjj

LRMS (m/z): 670 (M+2) ⁺ .

Example 17 (2 S )-1-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl) -5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-1-oxopropan-2-ol

6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (preparation 19b, 0.11 g, 0.18 mmol), (S)-2-ethoxypropoxypropionic acid ( 0.03 mL, 0.21 mmol), hexafluorophosphoric acid (benzotriazol-1-yloxy) ginseng (dimethylamino) hydrazine (0.10 g, 0.21 mmol) and triethylamine (0.05 mL, 0.34 mmol) The mixture in dichloromethane (2 mL) was stirred at room temperature for 3 h. Then dichloromethane was added and the reaction mixture was washed with water, dried by a phase separator and the solvent evaporated to produce a residue was purified by flash The residue form acetic acid (1 S) -2 - (( 3 R) - 3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-1-methyl-2-oxoethyl ester (108 mg, 67%).

LRMS (m/z): 689 (M+2) ⁺ .

Acetic acid (1S)-2-((3R)-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1-yl)- 5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-1-methyl-2-oxoethyl ester A mixture of (108 mg, 0.16 mmol) and EtOAc (EtOAc m. The solvent was evaporated and the crude material was triturated with dichloromethane. The solid formed was filtered through diatomaceous earth (Celite ^®) and the filtrate was evaporated to produce a residue by flash chromatography (dichloromethane to dichloromethane / ethanol 8: 2) to give the residue, to yield the title compound (45mg , 36%).

LRMS (m/z): 647 (M+2) ⁺ .

Example 18 ( R )-1-(( R )-3-((6-(4-(4-(2-(dimethylamino)ethoxy)benzyl)piperazin-1-yl)-5 -fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-1-oxobutan-2-ol and ( S )-1-(( R )-3-((6-(4-(4-(2-(dimethylamino)ethoxy)benzyl)piperazin-1-yl)-5 -fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-1-oxobutan-2-ol

6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- N -[(3 R )-piperidine-3 -yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (preparation 19b, 0.07 g, 0.12 mmol), sodium 2-hydroxybutyrate (0.02 g, 0.14 mmol) , hexafluorophosphoric acid (benzotriazol-1-yloxy) ginseng (dimethylamino) hydrazine (0.06 g, 0.14 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dichloromethane (1 mL) The mixture was stirred at room temperature for 3 hours and at 40 ° C overnight. Additional methylene chloride was added and the reaction mixture was washed with water, and the residue was crystallised eluted eluted eluted The title compound (26 mg, 32%).

LRMS (m/z): 661 (M+2) ⁺ .

Example 19 3-((3 R )-3-{[6-(4-{3-[2-(dimethylamino)ethoxy]benzyl} Piperazine-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-side oxygen Propiononitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-[3-(piperazin-1-ylmethyl) Phenoxy]ethylamine (Preparation 20b) gave a solid (38%), which was then purified by reverse phase chromatography using water/methanol as solvent.

LRMS (m/z): 641 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 2.10-2.25 (m, 4H), 2.43 (s, 6H), 2.58 (m, 4H), 3.39 (d, 2H), 3.45-3.55 (m, 4H) , 3.70-3.85 (m, 6H), 4.12-4.25 (m, 3H), 4.50-4.65 (m, 1H), 6.79-6.89 (m, 2H), 6.92-6.99 (m, 2H), 7.19 (m, 2H), 7.19-7.33 (m, 2H), 8.30-8.59 (m, 3H).

Example 20 3-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro- 2-(5-Methylpyrazolo[1,5- a ]pyridin-3-yl)pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, ( R )-3-(3-((6-chloro-5-fluoro-2-(5-methylpyrazolo[1,5-a]pyridine-3) -yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (preparation 9c) and N,N -dimethyl-2-(4-(piperazine)-1 -Methylmethyl)phenoxy)ethylamine (Preparation 18b) gave a solid (33%), which was purified by flash chromatography (dichloromethane and methanol as solvent).

^{1 H-NMR δ (400MHz,} DMSO- d 6): 0.81 (m, 1H), 1.02-1.49 (m, 1H), 1.62-1.69 (m, 2H), 1.71-1.84 (m, 2H), 1.93- 2.09 (m, 2H), 2.31 (s, 6H), 2.36 (s, 3H), 2.62-2.80 (m, 3H), 2.91-3.05 (m, 2H), 3.43 (s, 3H), 3.53-3.75 ( Bs, 4H), 3.77-4.25 (m, 6H), 4.53-4.65 (m, 6H), 6.71-6.94 (m, 4H), 7.18-7.29 (d, 2H), 8.06-8.15 (d, 1H), 8.44-8.51 (d, 1H), 8.57-8.66 (m, 1H).

Example 21 3-((3 R )-3-{[6-(4-{4-[3-(Dimethylamino)propoxy]benzyl}piperazin-1-yl)-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-3-(4-(piperazin-1-ylmethyl) Phenoxy)propan-1-amine (Preparation 21c) gave a solid (34%).

LRMS (m/z): 656 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.60-1.83 (m, 4H), 1.92-2.02 (m, 2H), 2.08-2.21 (m, 2H), 2.28 (s, 6H), 2.45-2.60 ( m, 6H), 3.39 (d, 1H), 3.45-3.60 (m, 4H), 3.70-3.84 (m, 6H), 4.07 (t, 2H), 4.20 (bs, 1H), 4.50-4.64 (m, 1H), 6.80-6.90 (m, 3H), 7.21-7.32 (m, 3H), 8.31 - 8.58 (m, 3H).

Example 22 3-{(3 R )-3-[(5-fluoro-6-{4-[4-(2-piperidin-1-ylethoxy)benzyl] Piperazine-1-yl}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-[4-(2-piperidin-1-ylethoxy)benzyl]piperidin The crude product was purified by flash chromatography (chloroform to 2% methanol / chloroform).

LRMS (m/z): 682 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.38-1.51 (m, 1H), 1.54-1.67 (m, 2H), 1.67-2.01 (m, 3H), 2.05-2.24 (m, 1H), 2.44- 2.64 (m, 4H), 2.72-2.83 (t, 2H), 3.03-3.17 (dd, 1H), 3.24 - 3.66 (m, 4H), 3.67-3.87 (m, 3H), 4.06-4.15 (t, 2H) ), 4.15-4.29 (bs, 1H), 4.47-4.67 (m, 1H), 6.76-6.94 (m, 3H), 7.22-7.33 (m, 3H), 8.28-8.60 (m, 3H).

Example 23 3-{(3 R )-3-[(5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-{4-[4-(2-pyrrolidin-1-) Ethyloxy)benzyl]piperazin-1-yl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-[4-(2-pyrrolidin-1-ylethoxy)benzyl]piperidin The crude product was purified by flash chromatography (dichloromethane / methanol / ammonia 40: 4: 0.2).

LRMS (m/z): 668 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 0.71-0.95 (m, 1H), 1.49-1.65 (m, 2H), 1.78-1.91 (s, 3H), 2.09-2.22 (m, 1H), 2.36- 2.46 (m, 1H), 2.47-2.74 (m, 4H), 2.84-2.98 (m, 2H), 3.29-3.42 (m, 1H), 3.42-3.61 (m, 2H), 3.69-3.87 (m, 2H) ), 4.02-4.16 (m, 1H), 4.16-4.38 (m, 1H), 4.48-4.70 (m, 1H), 6.74-6.95 (m, 3H), 7.05-7.17 (dd, 1H), 7.30-7.41 (m, 1H), 7.46-7.59 (m, 2H), 8.28-8.62 (m, 3H).

Example 24 3-((3 R )-3-{[6-((3 R ,5 S )-4-{4-[2-(dimethylamino)ethoxy]benzyl}-3,5 -Dimethylpiperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)- 3-sided oxypropionitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-(4-{[(2 R ,6 S )-2,6-dimethylperidine Pyrazin-1-yl]methyl}phenoxy)ethyl]dimethylamine (Preparation 24) gave a pale-yellow solid (8%), followed by flash chromatography (dichloromethane to dichloromethane/methanol 9 : 1) Purification of the crude product.

LRMS (m/z): 670 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.16 (dd, 6H), 1.55-1.80 (4H), 2.35 (s, 6H), 2.68-2.75 (m, 4H), 2.85-3.10 (m, 2H) , 3.30-3.60 (m, 4H), 3.75-3.85 (m, 4H), 4.06 (t, 2H), 4.15-4.31 (m, 3H), 4.50-4.68 (m, 1H), 6.80-6.88 (m, 3H), 7.25-7.32 (m, 3H), 8.30-8.55 (m, 3H).

Example 25 3-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazine-1 -yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and {2-[2,6-dimethyl-4-(piperazin-1-ylmethyl) Phenoxy]ethyl}dimethylamine (Preparation 25c) gave a solid (45%), which was purified by flash chromatography (dichloromethane to dichloromethane / methanol 9:1).

LRMS (m/z): 670 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.68-1.95 (m, 4H), 2.10-2.20 (m, 2H), 2.33 (d, 12H), 2.52-2.61 (m, 4H), 2.75 (t, 2H), 3.37-3.52 (m, 3H), 3.71 (s, 2H), 3.74-3.85 (m, 5H), 3.88 (t, 2H), 4.15-4.25 (m, 1H), 4.50-4.65 (m, 1H), 6.78-6.86 (m, 1H), 6.98 (s, 2H), 7.27-7.35 (m, 1H), 8.33 - 8.58 (m, 3H).

Example 26 3-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazine-1 -yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-[3,5-dimethyl-4-(piperazin-1-ylmethyl) Phenoxy]ethyl}dimethylamine (Preparation 26c) gave a solid (48%).

LRMS (m/z): 670 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.68-1.95 (m, 4H), 2.10-2.20 (m, 2H), 2.33 (d, 12H), 2.52-2.61 (m, 4H), 2.75 (t, 2H), 3.42-3.56 (m, 4H), 3.65-3.74 (m, 4H), 3.75-3.82 (m, 2H), 4.02-4.08 (m, 2H), 4.16-4.24 (m, 1H), 4.50- 4.65 (m, 1H), 6.61 (s, 2H), 6.78-6.86 (m, 1H), 7.25-7.32 (m, 1H), 8.33 - 8.58 (m, 3H).

Example 27 3-[(3 R )-3-({6-[4-(2-{4-[2-(dimethylamino)ethoxy]phenyl)ethyl)piperazin-1-yl] -5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-[4-(2-piperazin-1-ylethyl) The phenyloxy]ethylamine (Preparation 27c) gave a brown solid (yield: 51%), which was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5).

LRMS (m/z): 656 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.1-1.5 (m, 4H), 1.5-1.9 (m, 5H), 2.1-2.2 (m, 2H), 2.35 (s, 6H), 2.5-2.9 ( m,8H), 3.3-3.6(m,3H),3.7-3.9(m,3H),4.1(t,2H),4.2(bs,1H),6.8-6.9(m,3H),7.1(d, 2H), 7.3-7.4 (m, 1H), 8.2-8.7 (m, 3H).

Example 28 4-{[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a 2-pyridyl-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}benzoic acid 2-(dimethylamino)ethyl ester

Sodium triethoxy borohydride (0.043 g, 0.20 mmol) was added to 3-{(3 R )-3-[(5-fluoro-6-piperazin-1-yl-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 28b, 0.078 g, 0.17 mmol) and 4-methylmercaptobenzene A solution of 2-(dimethylamino)ethyl formate (preparation 29b, 0.037 g, 0.17 mmol) in dichloromethane (2 mL) Further, 2-(dimethylamino)ethyl 4-methylmercaptobenzoate (0.055 g) and sodium triethoxysulfonium borohydride (0.020 g) were added and the solution was stirred for additional 24 hours. The reaction mixture was partitioned between tetrahydrofuran and brine. The organic phase was separated, dried over magnesium sulfate and evaporated to dry. The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 670 (M+2) ⁺ .

Example 29 4-{[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}piperidine-1-carboxylic acid tert-butyl ester

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate ( Preparation 30b) gave a brown solid (88%).

LRMS (m/z): 662 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.11 (m, 2H), 1.65-1.90 (m, 7H), 2.54 (m, 4H), 2.71 (m, 2H), 2.98 (d, 2H), 3.37 (m, 2H), 3.47-3.61 (m, 2H), 3.77 (s, 6H), 4.05-4.24 (m, 3H), 4.49-4.65 (m, 1H), 6.80-6.90 (m, 1H), 7.27 -7.34 (m, 1H), 8.36 (d, 1H), 8.41 - 8.60 (m, 2H).

Example 30 3-[(3 R )-3-({5-fluoro-6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-2-pyrazolo[1,5-a Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.30 mL, 5.20 mmol) was added to 4-{[4-(6-{[(3 R )-1-(cyanoethenyl)piperidine) 3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}piperidine-1 - a solution of the toluene butyrate (Example 29, 0.17 g, 0.26 mmol) in 1,4-dioxane (5 mL) and the mixture was stirred at room temperature for 2 hr. Then diethyl ether was added and the resulting precipitate was filtered and washed with ethyl acetate and ethyl acetate toield of the title compound (150 mg, 92%).

LRMS (m/z): 562 (M+2) ⁺ .

Example 31 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl) -6-[4-({1-[4-(Trifluoromethyl)benzyl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin Pyridin-1-yl-3-oxopropiononitrile

3-[(3 R )-3-({5-fluoro-6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-2-pyrazolo[1,5-a Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 30, 0.07 g, 0.12 mmol), 1-(bromomethyl)-4 a mixture of -(trifluoromethyl)benzene (0.03 g, 0.10 mmol) and sodium bicarbonate (0.08 g, 0.94 mmol) in N,N -dimethylacetamide (0.5 mL) was stirred overnight at 90 ° C . Water was added and the suspension was filtered. The title compound (53 mg, 70%) eluted elute

LRMS (m/z): 720 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.27 (m, 3H, 1.54 (m, 1H), 1.70-1.80 (m, 5H), 2.00 (td, 2H), 2.20-2.29 (m, 2H), 2.45-2.60 (m, 4H), 2.87 (d, 2H), 3.39 (d, 2H), 3.45-3.55 (m, 4H), 3.70-3.82 (m, 6H), 4.18 (m, 1H), 4.46- 4.66 (m, 2H), 6.85 (m, 1H), 7.28 (m, 1H), 7.44 (d, 2H), 7.57 (d, 2H), 8.36 (d, 1H), 8.40-8.59 (m, 2H) .

Example 32 3-[(3 R )-3-({5-fluoro-6-[4-({1-[(1-methyl-1H-imidazol-2-yl)methyl]piperidin-4-yl}) Methyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxy Propiononitrile

3-[(3 R )-3-({5-fluoro-6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-2-pyrazolo[1,5-a Pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 30, 0.06 g, 0.11 mmol), 2-(chloromethyl)-1 a mixture of -methyl- 1H -imidazole (0.02 g, 0.09 mmol) and sodium hydrogencarbonate (0.07 g, 0.84 mmol) in N,N -dimethylacetamide (1.5 mL) was stirred at 90 ° C. hour. The title compound (17 mg, EtOAc)

LRMS (m/z): 655 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.08-1.28 (m, 5H), 1.70-1.90 (m, 4H), 2.05 (t, 2H), 2.20 (m, 2H), 2.52 (m, 4H) , 2.81 (d, 2H), 3.39 (d, 2H), 3.58 (m, 2H), 3.67-3.85 (m, 9H, 4.20 (m, 1H), 4.55 - 4.65 (m, 1H), 6.76 - 6.89 ( m, 2H), 6.92 (d, 1H), 7.30 (m, 1H), 8.35 (d, 1H), 8.42 - 8.60 (m, 2H).

Example 33 3-((3 R )-3-{[6-(4-{[1-(2,2-dimethylpropyl)piperidin-4-yl]methyl}piperazin-1-yl)- 5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

3-[(3 R )-3-({5-fluoro-6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-2-pyrazolo[1,5-a Pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 30, 0.04 g, 0.08 mmol), pivalaldehyde (0.01 mL, 0.08 mmol) A mixture of sodium triethoxysulfonium borohydride (0.02 g, 0.09 mmol) in dichloromethane (0.5 mL) was stirred at room temperature overnight. The reaction mixture was washed with aq. The organic layer was separated, dried over magnesium sulfate and evaporated The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 632 (M+2) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 0.92 (s, 9H), 1.17-1.43 (m, 4H), 1.61-1.99 (m, 4H), 2.20 (m, 6H), 2.46-2.60 (m, 4H), 3.40 (d, 2H), 3.44 - 3.60 (m, 2H), 3.69-3.87 (m, 6H), 4.21 (m, 1H), 4.48-4.69 (m, 1H), 6.85 (m, 1H) , 7.31 (m, 1H), 8.36 (d, 1H), 8.42 - 8.58 (m, 2H).

Example 34 3-((3 R )-3-{[5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-(4-{[1-(pyridin-2-yl) Piperidin-4-yl]methyl}piperazin-1-yl)pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

3-[(3 R )-3-({5-fluoro-6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-2-pyrazolo[1,5-a Pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 30, 0.05 g, 0.09 mmol), 2-(bromomethyl)pyridine ( A mixture of 0.02 g, 0.08 mmol) and sodium bicarbonate (0.06 g, 0.80 mmol) in N,N -dimethylacetamide (1 mL) was stirred at 90 ° C overnight. Water was added and the resulting suspension was filtered. The title compound (17 mg, 33%) eluted elute

LRMS (m/z): 653 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 0.85 (m, 1H), 1.16-1.45 (m, 3H), 1.70-1.90 (m, 4H), 2.11 (m, 2H), 2.24 (d, 2H) , 2.54 (m, 4H), 2.94 (d, 2H), 3.39 (d, 2H), 3.43-3.59 (m, 2H), 3.73 (m, 8H), 4.20 (m, 1H), 4.47-4.68 (m) , 1H), 6.72-6.92 (m, 1H), 7.17 (m, 1H), 7.23-7.34 (m, 1H), 7.43 (d, 1H), 7.65 (m, 1H), 8.35 (d, 1H), 8.39-8.61 (m, 3H).

Example 35 3-[(3 R )-3-({6-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropiononitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-(2,6-dimethylpyridin-4-yl)piperazine (preparation 31b) were obtained. The crude product was purified by flash chromatography (EtOAc/hexane gradient).

LRMS (m/z): 570 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.70-1.85 (m, 2H), 2.05-2.22 (m, 2H), 2.44 (s, 6H), 3.35-3.55 (m, 8H), 3.72-3.82 ( m, 2H), 3.83-3.95 (m, 4H), 4.22 (m, 1H), 4.69 (td, 1H), 6.42 (s, 2H), 6.80-6.92 (m, 1H), 7.32 (m, 1H) , 8.35 (d, 1H), 8.42 - 8.55 (m, 2H).

Example 36 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(2-pyrrolidin-1-ylpyridine)- 4-yl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (Preparation 6c) and 1-(2-pyrrolidin-1-ylpyridin-4-yl)piperazine (Preparation 32c) A solid (23%) was obtained which was then purified by flash chromatography.

LRMS (m/z): 610 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.18-1.31 (m, 2H), 1.70-1.83 (m, 4H), 2.17 (m, 2H), 3.40-3.50 (m, 9H), 3.68-3.83 ( m, 4H), 3.85-3.95 (m, 5H), 4.22 (m, 1H), 4.62-4.73 (m, 1H), 5.69 (d, 1H), 6.15 (dd, 1H), 6.80-6.93 (m, 1H), 7.33 (m, 1H), 7.94 (d, 1H), 8.30-8.60 (m, 3H).

Example 37 3-{(3 R )-3-[(6-{4-[2-(dimethylamino)pyridin-4-yl]piperazin-1-yl}-5-fluoro-2-pyrazole [1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-4-piperazin-1-ylpyridin-2-amine (preparation 32b) A solid (38%) was obtained, which was then purified by flash chromatography.

LRMS (m/z): 585 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.65-1.95 (m, 4H), 3.08 (s, 6H), 3.28-3.62 (m, 8H), 3.72-3.95 (m, 4H), 4.23 (m, 1H), 4.67 (m, 1H), 5.85 (d, 1H), 6.18 (dd, 1H), 6.79-6.93 (m, 1H), 7.33 (m, 1H), 7.96 (d, 1H), 8.30-8.63 (m, 3H).

Example 38 3-{(3 R )-3-[(6-{4-[4-(dimethylamino)pyridin-2-yl]piperazin-1-yl}-5-fluoro-2-pyrazole [1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-piperazin-1-ylpyridin-4-amine (preparation 34c) A solid (36%) was obtained, which was then purified by reverse phase chromatography using water and ethanol as solvent.

LRMS (m/z): 584 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.76-1.83 (m, 2H), 2.15-2.22 (m, 2H), 3.01 (s, 6H), 3.40 (d, 2H), 3.48 (m, 2H) , 3.62-3.71 (m, 4H), 3.85-3.96 (m, 4H), 4.21 (m, 1H), 4.63-4.70 (m, 1H), 5.80 (d, 1H), 6.11 (dd, 1H), 6.86 (m, 1H), 7.32 (m, 1H), 7.94 (d, 1H), 8.33 - 8.63 (m, 3H).

Example 39 3-((3 R )-3-{[5-fluoro-6-(4-piperidin-4-ylpiperazin-1-yl)-2-pyrazolo[1,5-a]pyridine-3 -pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added to 4-[4-(6-{[(3 R )-1-(cyanoethenyl)piperidine- 3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]piperidine-1-carboxylic acid third A stirred solution of butyl ester (preparation 35, 0.206 g, 0.32 mmol) in 1,4-dioxane (5 mL). The solvent was evaporated to dryness EtOAc (mjqqqqq

LRMS (m/z): 547 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.45 (d, 2H), 1.69-1.96 (m, 5H), 2.16 (m, 1H), 2.41 (m, 1H), 2.62 (m, 5H), 3.17 (d, 2H), 3.30-3.62 (m, 4H), 3.78 (bs, 4H), 4.21 (bs, 1 H), 4.46-4.71 (m, 2H), 6.87 (m, 1H), 7.28-7.35 ( m, 1H), 8.31 - 8.63 (m, 3H).

Example 40 3-[(3 R )-3-({6-[4-(1-Benzylpiperidin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1, 5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 33, 3-((3 R )-3-{[5-fluoro-6-(4-piperidin-4-ylpiperazin-1-yl)-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (Example 39) and benzaldehyde afforded solid (56%) The crude product was then purified by reverse phase chromatography (water to methanol gradient).

LRMS (m/z): 637 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.65 (m., 4H), 1.82 (m, 3H), 1.99 (t, 2H), 2.16 (d, 1H), 2.32 (t, 1H), 2.70 ( Br.s.,4H), 2.97(d,2H), 3.29-3.61(m,5H),3.77(bs,5H), 4.20(bs,1H),4.47-4.68(m,2H),6.77-6.92 (m, 1H), 7.29-7.38 (m, 6H), 8.31 - 8.62 (m, 3H).

Example 41 5-fluoro- N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]-6-[4-(1-methylpiperidin-4-yl)piperazine-1- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine

6-chloro-5-fluoro- N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine 4-Amine (preparation 7, 0.16 g, 0.41 mmol), 1-(1-methylpiperidin-4-yl)piperazine (0.11 g, 0.60 mmol) and sodium bicarbonate (0.14 g, 1.67 mmol) The mixture in N , ' N -dimethylacetamide (3 mL) was heated at 90 ° C overnight. The reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The organic layer was separated, washed with water and brine, dried The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 534 (M + 1) ⁺ .

1H-NMR δ (300MHz, CDCl ₃ ): 1.49-1.76 (m, 6H), 1.84 (d, 2H), 1.96 (t, 2H), 2.28 (s, 3H), 2.60-2.79 (m, 4H), 2.93 (d, 2H), 3.69-3.84 (m, 4H), 5.32-5.51 (m, 1H), 5.59 (dd, 1H), 6.63-6.88 (m, 1H), 7.11-7.28 (m, 1H), 7.31-7.50 (m, 2H), 8.28 (d, 1H), 8.40-8.58 (m, 3H).

Example 42 3-{(3 R )-3-[(6-{4-[3-(Dimethylamino)propyl]piperazin-1-yl}-5-fluoro-2-pyrazolo[1, 5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-3-piperazin-1-ylpropan-1-amine obtained shallow Orange solid (70 mg, 26%).

LRMS (m/z): 549 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.68-1.84 (m, 4H), 2.09-2.21 (m, 1H), 2.25 (s, 6H), 2.30-2.38 (m, 2H), 2.40-2.48 ( m, 2H), 2.52-2.70 (m, 4H), 3.26-3.62 (m, 3H), 3.79 (s, 4H), 4.12-4.33 (m, 5H), 4.46-4.73 (m, 1H), 6.79- 6.95 (m, 1H), 7.30-7.39 (m, 1H), 8.27-8.60 (m, 3H).

Example 43 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)perylene) Pyridin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-(1-pyrrolidylmethyl)piperidine dihydrochloride afforded solid (46%) The crude product was purified by flash chromatography (chloroform to chloroform / methanol 9:1).

LRMS (m/z): 547 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.21-1.45 (m, 3H), 1.71-2.00 (m, 5H), 2.07-2.25 (m, 1H), 2.31-2.47 (m, 1H), 2.47- 2.71 (bs, 2H), 2.89-3.18 (m, 2H), 3.26-3.68 (m, 3H), 3.72-3.87 (m, 1H), 4.10-4.29 (bs, 1H), 4.37-4.71 (m, 2H) ), 6.75-6.93 (m, 1H), 7.28-7.39 (m, 1H), 8.30-8.65 (m, 3H).

Example 44 3-[(3 R )-3-({6-[4-(1,3-Dihydro-2 H -isoindol-2-ylmethyl)piperidin-1-yl]-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -yl}-3-oxopropanenitrile (preparation 6c, 0.07 g, 0.17 mmol), 2-(piperidin-4-ylmethyl)isoindoline dihydrochloride (preparation 36b, 0.073 g, 0.25 A suspension of mmol) and sodium bicarbonate (0.142 g, 1.69 mmol) in N,N' -dimethylacetamide (0.5 mL) was stirred at 90 ° C overnight. Excess water was added and the precipitate was filtered and washed with water. The precipitate was purified by reverse phase chromatography to give the title compound, mjjjjjjjjj g, 21%).

LRMS (m / z): 595 (M + 2) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.08-1.25 (m, 1H), 1.25-1.48 (m, 1H), 1.48-1.87 (m, 2H), 1.87-2.10 (m, 2H), 2.10- 2.28(m,1H),2.91-3.14(m,2H),3.81-4.24(m,2H),4.24-4.46(m,1H),4.46-4.72(m,1H),4.77-4.98(m,1H) ), 6.64-6.90 (m, 1H), 6.92-7.10 (m, 1H), 7.20-7.54 (m, 3H), 8.26-8.48 (m, 1H), 8.48-8.66 (m, 1H), 8.66-8.86 (m, 1H), 10.71-11.06 (m, 2H).

Example 45 3-((3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperidin-1-yl)-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-(4-(piperidin-4-ylmethyl) Phenyloxy)ethylamine (Preparation 37c) gave a brown solid (20%), which was then purified by reverse phase chromatography (water to water / methanol 2:8).

LRMS (m/z): 641 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.2-1.5 (m, 4H), 1.7-1.8 (m, 4H), 2.3 (s, 6H), 2.5 (d, 2H), 2.7 (t, 2H) , 2.8-3.0 (m, 2H), 3.4 (ddd, 4H), 3.8 (d, 2H), 4.0 (t, 2H), 4.2 (s, 1H), 4.4-4.7 (m, 4H), 6.9 (d , 3H), 7.1 (d, 2H), 7.2-7.3 (m, 1H), 8.3-8.6 (m, 3H).

Example 46 3-{(3 R )-3-[(6-{4-[[2-(dimethylamino)ethyl](methyl)amino]piperidin-1-yl}-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl} pendant oxypropionitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (Preparation 6c) and N,N,N' -trimethyl- N' -piperidin-4-ylethane- The 1,2-diamine gave a solid (14%) which was then purified by reverse phase chromatography (water to methanol gradient).

LRMS (m/z): 563 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.57-1.77 (m, 4H), 1.72-1.90 (m, 4H), 2.25 (s, 6H), 2.31 (s, 3H), 2.38-2.43 (m, 2H), 2.53-2.73 (m, 3H), 2.33-8.88 (m, 2H), 3.40 (d, 1H), 3.43-3.53 (m, 1H), 3.77-3.83 (m, 2 H) 4.14 - 4.25 ( m, 2H), 4.50-4.64 (m, 3H), 6.86 (td, 1H), 7.30 (m, 1H), 8.32 - 8.62 (m, 3H).

Example 47 3-[(3 R )-3-({5-fluoro-6-[4-(7-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4, 3-a]pyrazin-3-yl)piperidin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1- 3-oxyloxypropionitrile

3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -yl}-3-oxopropanenitrile (preparation 6c, 0.07 g, 0.17 mmol), 7-methyl-3-piperidin-4-yl-5,6,7,8-tetrahydro[1,2 , 4] Triazolo[4,3-a]pyrazine dihydrochloride (0.077 g, 0.26 mmol) and sodium hydrogencarbonate (0.085 g, 1.02 mmol) in N,N' -dimethylacetamide ( The suspension in 0.5 mL) was stirred at 90 ° C for 48 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over magnesium sulfate and evaporated to dry. The title compound (0.030 g, 26%).

LRMS (m/z): 599 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.72-1.93 (m, 1H), 1.97-2.27 (m, 4H), 2.45-2.60 (s, 2H), 2.76-2.91 (s, 2H), 2.91 3.07 (m, 2H), 3.07-3.31 (m, 2H), 3.31-3.70 (m, 4H), 3.70-3.89 (m, 3H), 3.91-4.06 (m, 2H), 4.12-4.33 (bs, 1H) ), 4.43-4.61 (m, 2H), 4.61-4.75 (m, 1H), 6.74-6.94 (m, 1H), 7.26-7.37 (m, 1H), 8.27-8.68 (m, 3H).

Example 48 3-{(3 R )-3-[(6-{4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N,2 -trimethyl-6-(piperidin-4-yl)pyridine-4 The amine dihydrochloride salt was obtained as a solid (24%), then the crude material was purified by flash chromatography (chloroform to chloroform/methanol 100:5).

LRMS (m/z): 597 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 0.70-0.88 (m, 2H), 1.09-1.33 (m, 3H), 1.41-1.93 (m, 8H), 1.95-2.21 (m, 2H), 2.36- 2.54 (s, 3H), 2.89-2.99 (s, 6H), 2.99-3.19 (m, 2H), 3.28-3.37 (d, 1H), 3.41-3.60 (m, 2H), 3.60-3.77 (m, 2H) ), 4.07-4.27 (bs, 1H), 4.40-4.68 (m, 2H), 6.13-6.23 (m, 2H), 6.70-6.87 (m, 1H), 7.20-7.30 (m, 1H), 8.26-8.55 (m, 3H).

Example 49 3-{(3 R )-3-[(6-{4-[(2,6-dimethylpyridin-4-yl)amino]piperidin-1-yl}-5-fluoro-2-pyridyl Zoxa[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2,6-dimethyl- N -piperidin-4-ylpyridin-4-amine (preparation 38b) A solid (59%) was obtained, which was then purified by reverse phase chromatography (water to methanol gradient).

LRMS (m/z): 535 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.48-1.92 (m, 3H), 2.09-2.25 (m, 3H), 2.40 (s, 6H), 3.09-3.29 (m, 2H), 3.38 (s, 1H), 3.46-3.84 (m, 5H), 4.06 (bs, 1H), 4.22 (bs, 1H), 4.34 - 4.57 (m, 3H), 4.64 (m, 1H), 6.19 (s, 2H), 6.87 (dd, 1H), 7.30 (t, 1H), 8.29-8.61 (m, 3H).

Example 50 4-{[1-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a Pyridine-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1-carboxylic acid benzyl ester

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid benzyl ester (preparation The crude product was purified by flash chromatography (hexane toEtOAc).

LRMS (m/z): 696 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.22-1.35 (m, 5H), 1.70-1.90 (m, 4H), 2.18 (s, 1H), 2.22 (bs, 2H), 2.39 (m, 3H) , 2.92-3.03 (m, 3H), 3.39 (d, 2H), 3.47-3.58 (m, 6H), 3.73-3.81 (m, 1H), 4.22 (m, 1H), 4.45-4.52 (m, 2H) , 4.59 (m, 1H), 5.14 (s, 2H), 6.87 (m, 1H), 7.23 - 7.42 (m, 6H), 8.37 (d, 1H), 8.45 - 8.60 (m, 2H).

Example 51 3-[(3 R )-3-({5-fluoro-6-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-2-pyrazolo[1,5-a Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

10% palladium on carbon (0.02 g, 0.17 mmol) was added to 4-{[1-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}- 5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1-carboxylic acid benzyl ester (Example 50, 0.24 g, 0.35 mmol) in a suspension in ethanol (15 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hr. The reaction mixture was diatomaceous earth (Celite ^®), and the filtrate was evaporated to dryness. The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 562 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.22-1.35 (m, 5H), 1.70-1.90 (m, 4H), 2.15-2.22 (m, 3H), 2.41 (m, 3H), 2.90-3.03 ( m,7H), 3.39 (d, 2H), 3.47-3.58 (m, 2H), 3.77-3.81 (m, 1H), 4.19 (m, 1H), 4.45-4.52 (m, 2H), 4.59 (bs, 1H), 6.80-6.88 (m, 1H), 7.27-7.33 (m, 1H), 8.37 (d, 1H), 8.45-8.60 (m, 2H).

Example 52 ( R )-3-{3-[(6-{4-[(4-Benzylpiperazin-1-yl)methyl]piperidin-1-yl}-5-fluoro-2-pyrazole [1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 33, 3-[(3 R )-3-({5-fluoro-6-[4-(piperazin-1-ylmethyl)piperidin-1-yl]- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 51) and benzaldehyde obtained white The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol 9:1).

LRMS (m/z): 652 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.22-1.35 (m, 5H), 1.70 - 1.90 (m, 4H), 2.12 - 2.24 (m, 3H), 2.39 (bs, 3H), 2.90-3.05 ( m,3H), 3.40 (d, 2H), 3.47-3.58 (m, 6H), 3.73-3.81 (m, 1H), 4.22 (m, 1H), 4.40-4.52 (m, 2H), 4.55-4.62 ( m, 1H), 6.80-6.90 (m, 1H), 7.22-7.35 (m, 5H), 8.37 (d, 1H), 8.44 - 8.58 (m, 2H).

Example 53 3-[(3 R )-3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}) Piperidin-1-yl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3- Side oxypropionitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (Preparation 6c) and N,N,2 -trimethyl-6-[1-(piperidin-4-yl) The hydrazin-4-yl]pyridin-4-amine trihydrochloride (preparation 40b) gave a yellow solid (37%).

LRMS (m/z): 687 (M + 1) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.20-1.45 (m, 2H), 1.63-2.32 (m, 12H), 2.39-2.51 (s, 2H), 2.57-2.74 (m, 1H), 2.90- 3.08(s,6H), 3.25-3.68(m,3H),3.73-3.86(d,1H),4.11-4.29(bs,1H),4.39-4.67(m,3H),6.21-6.31(d,2H ), 6.77-6.92 (m, 1H), 7.27-7.37 (m, 1H), 8.34-8.63 (m, 3H).

Example 54 3-[(3 R )-3-({5-fluoro-6-[(4-piperazin-1-ylbenzyl)amino]-2-pyrazolo[1,5- a ]pyridine- 3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxypropane Nitrile

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.42 mL, 1.68 mmol) was added to ( R )-4-(4-((6-((1-(2-cyanoethyl))) Piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)methyl)phenyl)per A solution of the pyridine-carboxylic acid tert-butyl ester (preparation 41, 77 mg, 0.11 mmol) in 1,4-dioxane (2 mL). The solvent was evaporated to dryness EtOAcqqqqqm

LRMS (m/z): 569 (M + 1) ⁺ .

Example 55 3-[(3 R )-3-({5-fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-methyl-4-[4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)phenyl]piperazine afforded solid (37%), then flash chromatography (dichloromethane to dichloromethane / methanol 93:7) The crude product was purified.

LRMS (m/z): 554 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.75-1.90 (m, 3H), 2.20 (s, 1H), 2.29 (s, 2H), 2.95 (s, 3H), 3.45-3.60 (m, 10H) , 3.85-3.98(t,2H), 4.30(m,1H),5.00(s,1H),6.82-6.95(m,1H), 7.04(m,2H),7.35(t,1H),8.11(d , 2H), 8.42 - 8.76 (m, 3H).

Example 56 2-[(3 R )-3-({5-fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-2-oxoethanol

Hexafluorophosphoric acid (benzotriazol-1-yloxy) ginseng (dimethylamino) hydrazine (0.075 g, 0.21 mmol) was added to 5-fluoro-6-[4-(4-methylpiperazine- 1-yl)phenyl] -N -[(3 R )-piperidin-3-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 42b, 0.09g, 0.15mmol), a solution of glycolic acid (0.016g, 0.22mmol) and triethylamine (0.105mL, 0.76mmol) in N,N' -dimethylformamide (0.7mL) and the resulting mixture Stir at room temperature for 3 hours. The solvent was evaporated and purified EtOAcqqqqqqqq

LRMS (m/z): 546 (M+2) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.71-1.97 (m, H), 2.34-2.41 (s, 1H), 2.55-2.65 (dd, 1H), 3.09-3.29 (m, 2H), 3.30- 3.50 (m, 4H), 3.50-3.58 (m, 1H), 3.72-3.85 (dd, 1H), 3.94-4.10 (m, 2H), 4.18-4.39 (m, 3H), 4.61-4.74 (dd, 1H) ), 4.95-5.08 (m, 1H), 6.78-6.94 (m, 1H), 6.98-7.09 (d, 2H), 7.13-7.25 (m, 1H), 7.28-7.37 (m, 1H), 8.06-8.15 (d, 2H), 8.46-8.79 (m, 3H).

Example 57 1-Benzyl-4-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methyl Piperazine-1-indole bromide

According to the experimental procedure as described in Preparation 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-benzyl-1-methyl-4-[4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-indole bromide (Preparation 43) gave a yellow solid (27%), The crude product was purified by flash chromatography.

LRMS (m/z): 645 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 0.78-1.01 (m, 1H), 1.21-1.46 (m, 5H), 1.51-2.04 (m, 2H), 2.12-2.27 (m, 1H), 2.69 -2.88 (m, 1H), 2.88-3.04 (m, 1H), 3.04-3.28 (m, 2H), 3.42-3.68 (m, 2H), 3.68-4.39 (m, 4H), 4.70-4.79 (m, 1H), 6.89-7.04 (m, 1H), 7.04-7.30 (m, 2H), 7.33-7.51 (m, 2H), 7.52-7.76 (m, 4H), 7.95-8.15 (m, 2H), 8.44 8.73 (m, 3H).

Example 58 1-(4-Tertibutylbenzyl)-4-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5- Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methylpiperazine-1-indole bromide

According to the experimental procedure as described in Preparation 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-(4-t-butylbenzyl)-1-methyl-4-[4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-indole bromide (Preparation 44) gave a white solid (28%), then the crude product was purified by flash chromatography.

LRMS (m/z): 701 (M+2) ⁺ .

¹ H-NMR δ (300MHz, DMSO- d ₆ ): 1.24-1.37 (s, 9H), 1.47-1.88 (m, 4H), 2.01-2.15 (bs, 1H), 2.17-2.31 (m, 1H), 2.61-2.87 (m, 2H), 3.00-3.15 (m, 3H), 3.28-3.31 (m, 2H), 3.43-3.72 (m, 5H), 3.73-3.84 (m, 1H), 3.84-4.38 (m) ,5H),4.64-4.76(s,2H),7.01-7.09(m,1H),7.15-7.25(d,2H),7.42-7.62(m,5H),8.00-8.11(d,2H),8.47 -8.56 (d, 1H), 8.66-8.84 (m, 2H).

Example 59 3-((3 R )-3-{[6-(4-{4-[3-(Dimethylamino)propyl]piperazin-1-yl}phenyl)-5-fluoro-2- Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

3-((3 R )-3-{[5-fluoro-6-(4-piperazin-1-ylphenyl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (preparation 45b, 0.12 g, 0.22 mmol), 3-chloro- N,N -dimethylpropan-1-amine ( A mixture of 0.04 g, 0.22 mmol) and sodium bicarbonate (0.06 g, 0.67 mmol) in N,N -dimethylacetamide (2 mL) was stirred at 100 ° C for 48 hours. The reaction mixture was purified by EtOAc EtOAcqqqqq

LRMS (m/z): 626 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.67-2.00 (m, 6H), 2.40-2.66 (m, 14H), 3.13 (m, 2H), 3.33 (m, 2H), 3.57-3.67 (m, 2H), 3.82-3.94 (m, 2H), 4.26 (m, 2H), 4.55 (d, 1H), 6.87 (m, 1H), 7.01 (dd, 1H), 7.34 (m, 1H), 8.07 (d) , 2H), 8.43 - 8.61 (m, 3H).

Example 60 3-[(3 R )-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl]- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

N- {5-fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl }- N',N' -dimethyl- N -[(3 R )-piperidin-3-yl]ethane-1,2-diamine (preparation 46b, 0.07 g, 0.13 mmol), 3-[ (2,5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanonitrile (0.027 g, 0.15 mmol)) and triethylamine (0.21 mL, 0.15 mmol) in dichloromethane The solution in (3 mL) was stirred at room temperature for 1 hour. Excess ethyl acetate was added and the reaction mixture was washed with water. The organic phase was dried over sodium sulfate and the solvent evaporated to dry. The residue was purified by flash chromatography eluting elut elut elut

LRMS (m/z): 626 (M+2) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.91-2.22 (m, 5H), 2.24-2.31 (m, 1H), 2.31-2.36 (s, 6H), 2.36-2.40 (s, 3H), 2.50- 2.71 (m, 8H), 2.92-3.05 (m, 1H), 3.09-3.25 (m, 1H), 3.26-3.51 (m, 7H), 3.51-3.59 (d, 1H), 3.59-3.86 (m, 4H) ), 4.32-4.50 (m, 2H), 4.63-4.74 (m, 1H), 4.77-4.87 (m, 1H), 6.80-6.93 (m, 1H), 6.98-7.08 (d, 2H), 7.27-7.37 (m, 1H), 7.99-8.08 (d, 2H), 8.46-8.66 (m, 3H).

Example 61 3-[(3 R )-3-({5-fluoro-6-[4-(1-methylpiperidin-4-yl)phenyl]-2-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-methyl-4-[4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)phenyl]piperidine (Preparation 47) gave solid (30%), which was subsequently purified by flash chromatography.

LRMS (m/z): 554 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.74-1.99 (m, 9H), 2.03-2.17 (m, 3H), 2.18-2.29 (m, 2H), 2.30-2.40 (s, 3H), 2.49- 2.67 (m, 2H), 2.94-3.08 (d, 2H), 3.15-3.27 (dd, 1H), 3.32-3.54 (m, 4H), 3.56-3.72 (m, 2H), 3.87-4.04 (m, 2H) ), 4.24-4.41 (m, 2H), 4.54-4.66 (dd, 1H), 4.99-5.11 (m, 1H), 6.82-6.96 (m, 1H), 7.30-7.46 (m, 3H), 8.03-8.11 (d, 2H), 8.47-8.76 (m, 3H).

Example 62 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)benzene A pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 4-(1-pyrrolidinylmethyl)phenyl acid (preparation 49) gave solid (13% The crude product was then purified by flash chromatography.

LRMS (m/z): 540 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.74-2.03 (m, 5H), 2.15-2.30 (m, 1H), 2.47-2.67 (bs, 3H), 3.15-3.28 (m, 1H), 3.34 3.54 (m, 2H), 3.55-3.71 (m, 2H), 3.71-3.77 (m, 1H), 3.86-4.05 (m, 1H), 4.24-4.40 (bs, 1H), 4.52-4.64 (dd, 1H) ), 5.01-5.14 (bs, 1H), 6.82-6.96 (m, 1H), 7.30-7.41 (m, 1H), 7.46-7.57 (m, 2H), 8.05-8.13 (d, 2H), 8.48-8.76 (m, 3H).

Example 63 3-[(3 R )-3-({5-methyl-2-pyrazolo[1,5- a ]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)) Phenyl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 33, 3-((3 R )-3-{[6-(4-carbamidophenyl)-5-methyl-2-pyrazolo[1,5- a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (preparation 50b) and pyrrolidine to give a solid (19%), followed by reverse phase The crude product was purified by chromatography (water to methanol gradient).

LRMS (m/z): 535 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.84 (bs, 5H), 2.14 (s, 3H), 2.60 (bs, 3H), 3.39 (d, 1H), 3.50 (dd, 2H), 3.58 (d) , 1H), 3.72 (s, 2H), 3.91 (dd, 1H), 4.25-4.49 (m, 2H), 4.58 (d, 1H), 4.74 (d, 1H), 6.85 (dt, 2H), 7.30 ( m, 1H), 7.41 - 7.53 (m, 2H), 7.55 - 7.63 (m, 2H), 8.43 - 8.77 (m, 3H).

Example 64 3-[(3 R )-3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}) Phenyl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxypropane Nitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and [4-({4-[4-(dimethylamino))-6-methylpyridine 2-yl]piperidin-1-yl}methyl)phenyl] acid (Preparation 51) gave a yellow solid (14%) elute elute The crude product was purified.

LRMS (m/z): 695 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.20-1.39 (m, 2H), 1.67-2.05 (m, 7H), 2.05-2.30 (m, 3H), 2.40-2.52 (s, 2H), 2.62 2.79 (m, 1H), 2.95-3.02 (s, 6H), 3.02-3.11 (m, 1H), 3.16-3.27 (dd, 1H), 3.33-3.55 (m, 2H), 3.55-3.70 (m, 2H) ), 3.86-4.03 (m, 1H), 4.25-4.40 (bs, 1H), 4.54-4.64 (dd, 1H), 5.04-5.15 (m, 1H), 6.21-6.31 (m, 2H), 6.82-6.95 (m, 1H), 7.28-7.42 (m, 2H), 7.47-7.58 (m, 2H), 8.04-8.13 (d, 2H), 8.48-8.76 (m, 3H).

Example 65 3-((3 R )-3-{[6-(4-{[4-(Dimethylamino)piperidin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, 3-((3R)-3-{[5-fluoro-6-(4-carbamidophenyl)-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (preparation 48b) and N,N -dimethylpiperidin-4-amine afforded a solid ( 26%). The crude product was purified by reverse phase chromatography (a gradient of 40% water to methanol with a 0.1% hydrochloric acid solution) and then eluted via a exchange cartridge (using 2N ammonia solution/methanol as a solvent) to give the title compound as a free base. .

LRMS (m/z): 597 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 1.7-1.8 (m, 2H), 1.9-2.1 (m, 3H), 2.2-2.4 (m, 3H), 2.9 (s, 6H), 3.4-3.7 (m, 5H), 3.8 (d, 2H), 3.9-4.1 (m, 3H), 4.3 (bs, 5H), 7.0-7.1 (m, 1H), 7.4-7.5 (m, 1H), 7.7 (m) , 2H), 8.2 (d, 2H), 8.6-8.7 (m, 3H).

Example 66 3-((3 R )-3-{[6-(4-{[4-(Dimethylamino)piperidin-1-yl]methyl}-2-fluorophenyl)-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, 3-(( 3R )-3-{[5-fluoro-6-(2-fluoro-4-carboxyphenyl)-2-pyrazolo[1] , 5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (Preparation 52b) and N,N -Dimethylpiperidine-4 - The amine obtained a solid (20%). The crude product was purified by reverse phase chromatography (with a gradient of 40% water from EtOAc (MeOH) to MeOH).

LRMS (m/z): 614 (M + 1) ⁺ .

^{1 H-NMR δ (300MHz,} CDCl 3): 1.74-1.87 (m, 3H), 1.87-2.01 (m, 3H), 2.00-2.13 (m, 3H), 2.18-2.31 (m, 1H), 2.44 ( s, 6H), 3.02 (d, 2H), 3.29-3.53 (m, 4H), 3.58 (d, 3H), 3.66-3.78 (m, 1H), 3.89-4.13 (m, 1H), 4.27-4.45 ( m, 1H), 5.10 (d, 1H), 6.71-7.05 (m, 1H), 7.15-7.45 (m, 3H), 7.74 (t, 1H), 8.35-8.79 (m, 3H).

Example 67 3-((3 R )-3-{[6-(3-{[4-(Dimethylamino)piperidin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, 3-((3 R )-3-{[5-fluoro-6-(3-methylnonylphenyl)-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (Preparation 53b) and N,N -dimethylpiperidin-4-amine gave solid (14%), then the crude product was purified by reverse phase chromatography (yield with a gradient of &lt

LRMS (m/z): 596 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.46-1.66 (m, 4H), 1.97-2.13 (m, 4H), 2.15-2.25 (m, 2H), 2.31 (s, 6H), 3.01 (d, 2H), 3.33-3.54 (m, 3H), 3.56-3.75 (m, 5H), 3.95 (t, 1H), 4.25-4.44 (m, 1H), 4.99-5.19 (m, 1H), 6.85-6.97 ( m, 1H), 7.37 (t, 1H), 7.42 - 7.59 (m, 2H), 7.91 - 8.15 (m, 2H), 8.46 - 8.61 (m, 2H), 8.62 - 8.79 (m, 1H).

Example 68 3-{(3 R )-3-[(5-fluoro-6-{4-[(4-methyl-1,4-diazepane-1-) Methyl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, 3-((3R)-3-{[5-fluoro-6-(4-carbamidophenyl)-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (preparation 48b) and 1-methyl-1,4-diazepane obtained The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 582 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.74-2.05 (m, 6H), 2.15-2.30 (m, 1H), 2.39 (s, 3H), 2.57-2.93 (m, 8H), 3.28-3.54 ( m,3H),3.59(s,1H),3.74(s,2H),3.84-4.04(m,1H), 4.20-4.44(m,1H),4.93-5.17(m,1H),6.81-7.04( m, 1H), 7.37 (t, 1 H), 7.47-7.58 (m, 2H), 8.09 (d, 2H), 8.48-8.79 (m, 3H).

Example 69 3-{(3 R )-3-[(5-fluoro-6-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}- 2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

3-{(3 R )-3-[(2-chloro-5-fluoro-6-{4-[(4-methyl-1,4-diazepan-1-yl)methyl] Phenyl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 54f, 42 mg, 0.08 mmol), 3-(tributylstannyl)pyrazolo[1 , 5-a]pyrazine (prepared as described in WO2011157397, 52mg, 0.13mmol) and hydrazine (triphenylphosphane) palladium (0) (10mg, 0.01mmol) in 1,4-dioxane (1mL The mixture was heated at 100 ° C for 18 hours. The title compound (21 mg, 41%) eluted elute

LRMS (m/z): 584 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 0.9 (t, 2H), 1.3 (dd, 2H), 1.6-1.8 (m, 4H), 1.8-1.9 (m, 3H), 2.40 (s, 3H) , 2.7-2.8 (m, 5H), 2.9 (d, 1H), 3.3-3.5 (m, 4H), 4.47 (d, 1H), 5.19 (s, 2H), 7.4-7.5 (m, 2H), 7.9 (dd, 1H), 8.08 (d, 2H), 8.4-8.5 (m, 1H), 8.7-8.8 (m, 1H), 10.0 (d, 1H).

Example 70 3-[(3 R )-3-({6-[4-({4-[2-(Dimethylamino)ethoxy)piperidin-1-yl}methyl)phenyl]-5 -fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 33, 3-((3R)-3-{[5-fluoro-6-(4-carbamidophenyl)-2-pyrazolo[1,5-a] Pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (preparation 48b) and N,N -dimethyl-2-(piperidin-4- The ethoxy group of ethylamine (prepared as described in PCT2009093032) gave a brown solid (16%), which was then purified by reverse phase chromatography (water to water/methanol (4:6) gradient).

LRMS (m/z): 640 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.6-2.2 (m, 15H), 2.26 (s, 5H), 2.8 (d, 2H), 3.2-3.5 (m, 5H), 3.9 (d, 1H) , 4.3 (s, 2H), 5.0-5.2 (m, 2H), 6.9 (dd, 1H), 7.3-7.4 (m, 1H), 7.4 - 7.5 (m, 2H), 8.1 (d, 2H), 8.5 -8.6 (m, 2H), 8.6-8.8 (m, 2H).

Example 71 3-{(3 R )-3-[(6-{4-[2-(dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-2-(4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethylamine (Preparation 55) gave a yellow solid (66%). The crude product was purified by methanol/ammonia 40:2:0.2).

LRMS (m/z): 543 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.6-2.0 (m, 4H), 2.2 (d, 1H), 2.4 (s, 6H), 2.8 (dd, 2H), 3.3-3.5 (m, 2H) , 3.6-3.7 (m, 1H), 3.8-4.0 (m, 1H), 4.2 (dd, 2H), 4.3 (bs, 1H), 4.6 (dd, 1H), 5.0 (bs, 1H), 6.8-7.0 (m, 1H), 7.1 (dd, 2H), 7.3-7.5 (m, 2H), 8.1 (dd, 2H), 8.5-8.7 (m, 2H).

Example 72 3-((3 R )-3-{(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5-a Pyridyl-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 10, N- (6-{4-[2-(dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5 -a]pyridin-3-ylpyrimidin-4-yl) -N',N' -dimethyl- N -[(3 R )-piperidin-3-yl]ethane-1,2-diamine ( Preparation of 56c) and 3-[(2,5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile afforded a yellow solid (54%). The crude product was purified to chloroform / methanol / ammonia 40:2:0.2).

LRMS (m/z): 615 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 2.0-2.2 (m, 4H), 2.3-2.5 (m, 12H), 2.6-2.7 (m, 2H), 2.82 (t, 2H), 3.4-3.6 ( m, 2H), 3.7-3.9 (m, 3H), 4.2 (t, 2H), 4.4 (bs, 2H), 4.7 (d, 1H), 4.79 (d, 1H), 6.8-6.9 (m, 1H) , 7.0-7.1 (m, 2H), 7.3-7.4 (m, 1H), 8.0 (dd, 2H), 8.5-8.6 (m, 3H).

Example 73 [(3 R )-3-({5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-yl-6-[4-(2-pyrrolidin-1-ylethoxy)) Phenyl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-{2-[4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)phenoxy]ethyl}pyrrolidine (Preparation 57) gave a yellow solid (42%) elute elute The crude product was purified by ammonia 40:2:0.2).

LRMS (m/z): 569 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.6-1.9 (m, 9H), 2.7 (s, 4H), 3.0 (t, 2H), 3.4-3.5 (m, 2H), 3.6 (s, 1H) , 3.9-4.0 (m, 1H), 4.2 (t, 2H), 4.3 (bs, 1H), 4.6 (dd, 1H), 5.0 (bs, 1H), 6.8-7.0 (m, 1H), 7.1 (dd , 2H), 7.3-7.4 (m, 1H), 8.1 (d, 2H), 8.5-8.7 (m, 2H), 8.7 (s, 1H).

Example 74 3-((3 R )-3-{[6-(4-{2-[4-(Dimethylamino)piperidin-1-yl]ethoxy}phenyl)-5-fluoro-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and N,N -dimethyl-1-{2-[4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}piperidin-4-amine (Preparation 58) gave a yellow solid (60%). The crude product was purified by flash chromatography (chloroform to chloroform / methanol / ammonia 40:2:0.2).

LRMS (m/z): 627 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.59 (dt, 2H), 1.80-1.90 (m, 7H), 2.10-2.20 (m, 4H), 2.30 (s, 6H), 2.84 (t, 2H) , 3.08 (d, 2H), 3.40-3.50 (m, 2H), 3.58 (s, 1H), 3.90 (d, 1H), 4.19 (t, 2H), 4.30 (bs, 1H), 5.05 (bs, 1H) ), 6.80-6.90 (m, 1H), 7.04 (dd, 2H), 7.3-7.4 (m, 1H), 8.11 (d, 2H), 8.50-8.70 (m, 3H).

Example 75 ( R )-3-(3-((5-fluoro-6-(4-(piperidin-4-yloxy)phenyl)-2-(pyrazolo[1,5-a]pyridine-3) -yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropiononitrile

A 4.0 N solution of hydrogen chloride in 1,4-dioxane (3.30 mL, 1.4 mmol) was added dropwise to ( R )-4-(4-(6-((1-(2-cyanoethyl))) Piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)phenoxy)piperidine-1-carboxylic acid A solution of the third butyl ester (preparation 59, 0.44 g, 0.67 mmol) in 1,4-dioxane (7 mL) was obtained. Diethyl ether was added and the residue was crystallised eluted eluted elut elut elut elut elut elut elut elut

LRMS (m/z): 555 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.58-1.85 (m, 4H), 2.02-2.12 (m, 2H), 2.19-2.22 (m, 2H), 2.77-2.80 (m, 2H), 3.13 3.20 (m, 2H), 3.36-3.45 (m, 4H), 3.56-3.64 (m, 1H), 3.87-3.98 (m, 1H), 4.31 (bs, 1H), 4.47-4.53 (m, 1H), 5.02 (bs, 1H), 6.84-6.92 (m, 1H), 7.02-7.08 (m, 2H), 7.32-7.38 (m, 1H), 8.11 (d, 2H), 8.49-8.59 (m, 2H), 8.62-8.72 (d, 1H).

Example 76 ( R )-3-(3-((6-(4-()-ethylpiperidin-4-yl)oxy)phenyl)-5-fluoro-2-(pyrazolo[1,5 -a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 21b, ( R )-3-(3-((5-fluoro-6-(4-(piperidin-4-yloxy)phenyl)-2-)pyrazole And [1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (Example 75) and acetaldehyde afforded solid (76% The crude product was then purified by reverse phase chromatography using water and acetonitrile as solvent.

LRMS (m/z): 583 (M + 1) ⁺ .

^{1 H-NMR δ (400MHz,} DMSO- d 6): 1.01 (t, 3H), 1.62-1.84 (m, 4H), 1.98-2.10 (m, 2H), 2.16-2.22 (m, 2H), 2.67- 2.75 (m, 4H), 3.64-4.84 (m, 2H), 4.05-4.60 (m, 2H), 4.17-4.23 (m, 2H), 4.26-4.34 (bs, 1H), 4.45-4.54 (m, 2H) ), 4.70-4.76 (m, 1H), 7.04 (t, 1H), 7.16-7.19 (m, 1H), 7.43-7.51 (m, 2H), 8.04 (d, 2H), 8.51 (d, 1H), 8.69-8.74 (d, 1H), 8.78-8.82 (m, 1H).

Example 77 ( R )-3-(3-((5-fluoro-6-(4-((1-(3-(piperidin-1-yl)propyl)piperidin-4-yl)oxy)phenyl) -2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

( R )-3-(3-((5-fluoro-6-(4-(piperidin-4-yloxy)phenyl)-2-(pyrazolo[1,5-a]pyridine-3) -yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (Example 75, 0.07 g, 0.11 mmol), 1-(3-chloropropyl)piperidine ( A mixture of 0.03 g, 0.13 mmol) and sodium bicarbonate (0.08 g, 0.99 mmol) in N,N -dimethylacetamide (1.5 mL) was stirred at 90 ° C overnight. Water was added and the precipitate formed was filtered, washed with water and dried. The title compound (24 mg, 32%) was obtained eluted

LRMS (m/z): 681 (M+2) ⁺ .

¹ H-NMR δ (400 MHz, DMSO- d ₆ ): 1.31-1.40 (m, 1H), 1.45-1.51 (m, 2H), 1.52-1.58 (m, 1H), 1.64-1.71 (m, 2H), 1.78-1.84 (m, 1H), 1.95-2.10 (m, 2H), 2.18-2.42 (m, 5H), 2.65-2.77 (m, 2H), 3.05-3.16 (m, 3H), 3.66 (d, 2H) ), 3.76- 3.82 (m, 1H), 3.96-4.06 (m, 6H), 4.09-4.16 (m, 2H), 4.18-4.23 (m, 2H), 4.30 (bs, 1H), 4.45-4.53 (m , 2H), 4.69-4.76 (m, 1H), 7.04 (t, 1H), 7.16-7.18 (m, 1H), 7.48-7.56 (m, 2H), 8.03 (d, 2H), 8.51 (d, 1H) ), 8.69-8.74 (d, 1H), 8.78-8.82 (m, 1H).

Example 78 3-[(3 R )-3-({5-fluoro-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-2-pyrazolo[1,5- a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-methyl-4-[4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)pyridin-2-yl]piperazine gave solid (81%), which was subsequently purified by flash chromatography (dichloromethane to dichloromethane/methanol 9 : 1) Purification of the crude product.

LRMS (m/z): 555 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.72-2.02 (m, 4H), 2.38 (s, 3H), 2.60 (dd, 4H), 3.34-3.51 (m, 3H), 3.60-3.72 (m, 6H), 3.84-4.01 (m, 1H), 4.32 (m, 1H), 4.54 (dd, 1H), 6.83-6.95 (m, 1H), 7.27 (m, 1H), 7.35 (dd, 1H), 7.41 (s, 1H), 8.35 (t, 1H), 8.53 (dd, 2H), 8.66 (d, 1H).

Example 79 3-((3 R )-3-{[5-fluoro-6-(2-piperazin-1-ylpyridin-4-yl)-2-pyrazolo[1,5-a]pyridine-3- Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropiononitrile

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.57 mL, 2.26 mmol) was added to 4-[4-(6-{[(3 R )-1-(cyanoethenyl)piperidine- 3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl The ester (preparation 60, 0.17 g, 0.23 mmol) in EtOAc (EtOAc) Further, a 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.57 mL, 2.26 mmol) was added and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated and the residue was partitioned between dichloromethane and water. A 4% aqueous solution of sodium hydrogencarbonate was added until the pH was basic and then the organic layer was separated by a phase separator and solvent evaporated to dryness. The residue was purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 541 (M + 1) ⁺ .

^{1 H-NMR δ (300MHz,} DMSO- d 6): 1.65-1.87 (m, 4H), 2.55-2.90 (m, 4H), 3.75-3.90 (m, 4H), 3.95-4.25 (m, 6H), 4.27-4.37(m,1H),4.69(d,1H),7.07(td,1H),7.31(d,1H), 7.49(m,1H),7.77(t,1H),8.36(dd,1H) , 8.49 (d, 1H), 8.78-8.95 (m, 2H).

Example 80 3-((3 R )-3-{[6-(2-{4-[3-(Dimethylamino)propyl]piperazin-1-yl}pyridin-4-yl)-5-fluoro -2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

3-((3 R )-3-{[5-fluoro-6-(2-piperazin-1-ylpyridin-4-yl)-2-pyrazolo[1,5-a]pyridine-3- Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (Example 79, 0.13 g, 0.23 mmol), 3-chloro- N,N -dimethylpropan-1 A mixture of the amine hydrochloride (0.04 g, 0.33 mmol) and sodium bicarbonate (0.06 g, 0.71 mmol) in N,N -dimethylacetamide (2 mL) was stirred at 90 ° C for 25 hours. The crude material was purified by reverse phase chromatography (water/methanol eluting solvent) to afford residue, which was purified by flash chromatography (dichloromethane to dichloromethane / hexane 6:4) Compound (24 mg, 16%).

LRMS (m/z): 626 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CD ₃ OD): 1.26-1.35 (m, 3H), 1.75-1.87 (m, 3H), 2.15-2.25 (m, 2H), 2.40 (s, 6H), 2.45-2.60 (m, 4H), 2.66 (t, 2H), 2.81 (t, 2H), 3.21-3.35 (m, 6H), 3.60-3.70 (m, 4H), 4.20-4.27 (m, 1H), 4.60 (m) , 2H), 7.02 (m, 1H), 7.32 (d, 1H), 7.48 (m, 2H), 8.27 (s, 1H), 8.55-8.70 (m, 3H).

Example 81 3-[(3 R )-3-({5-fluoro-6-[2-(4-methyl-1,4-diazepan-1-yl)pyridin-4-yl]-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 50a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (2-(4-methyl-1,4-diazepan-1-yl) Pyridin-4-yl) acid (Preparation 61b) gave a solid (25%), which was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8:1).

LRMS (m/z): 569 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.72-1.99 (m, 3H), 2.02 -2.19 (m, 3H), 2.19-2.29 (m, 1H), 2.42 (s, 3H), 2.54-2.67 ( m, 2H), 2.71-2.86 (m, 2H), 3.40-3.54 (m, 3H), 3.60 (s, 1H), 3.76 (t, 2H), 3.86-4.01 (m, 3H), 4.18-4.43 ( m, 1H), 4.94-5.30 (m, 1H), 6.80-7.03 (m, 1H), 7.23-7.26 (m, 2H), 7.36 (dd, 1H), 8.31 (t, 1H), 8.48-8.77 ( m, 3H).

Example 82 3-{(3 R )-3-[(5-fluoro-6-{2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]pyridine-4 -yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-(4-(4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)pyridin-2-yl)-1,4-diazepan-1-yl)ethanol (Preparation 62b) gave a light brown solid (20% The crude product was then purified by reverse phase chromatography (water to methanol).

LRMS (m/z): 599 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.75-1.97 (m, 3H), 1.98-2.13 (m, 3H), 2.18-2.32 (m, 1H), 2.62-2.81 (m, 4H), 2.86- 3.00 (m, 3H), 3.36-3.54 (m, 3H), 3.55-3.66 (m, 3H), 3.78 (t, 2H), 3.84-3.99 (m, 3H), 4.23-4.44 (m, 1H), 4.96-5.30 (m, 1H), 6.82-7.00 (m, 1H), 7.19 (d, 1H), 7.24-7.31 (m, 1H), 7.31-7.44 (m, 1H), 8.32 (t, 1H), 8.47-8.78 (m, 3H).

Example 83 3-{(3 R )-3-[(6-{2-[4-(dimethylamino)piperidin-1-yl]pyridine-4- 5-B-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4 -yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (2-(4-(dimethylamino)piperidin-1-yl)pyridine-4- The acid (preparation 63b) gave an orange solid (35%), which was then purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5 and dichloromethane/methanol/methanol 100:8:1) product.

LRMS (m/z): 583 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.47-1.72 (m, 3H), 1.76-2.08 (m, 6H), 2.16-2.29 (m, 1H), 2.34 (s, 6H), 2.39-2.54 ( m,1H), 2.95(t,2H),3.34-3.54(m,2H),3.56-3.76(m,1H),3.85-4.03(m,1H), 4.25-4.41(m,1H), 4.40 -4.62 (m, 2H), 4.95-5.21 (m, 1H), 6.78-7.02 (m, 1H), 7.16-7.30 (m, 1H), 7.31-7.42 (m, 1H), 7.44 (s, 1H) , 8.35 (t, 1H), 8.48-8.78 (m, 3H).

Example 84 2-{(3 R )-3-[(6-{2-[4-(dimethylamino)piperidin-1-yl]pyridin-4-yl}-5-fluoro-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol

According to the procedure described for the preparation of 45a, 2-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4- Amino]piperidin-1-yl}-2-oxoethanol (preparation 64) and {2-[4-(dimethylamino)piperidin-1-yl]pyridin-4-yl} The acid (preparation 63b) gave a solid (30%), which was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5 and dichloromethane/methanol/methanol 100:8:1).

LRMS (m/z): 574 (M+1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.48-1.68 (m, 3H), 1.85-2.03 (m, 4H), 2.15-2.28 (m, 2H), 2.33 (s, 6H), 2.38-2.53 ( m,1H), 2.94(t,2H),3.14-3.34(m,2H), 3.36-3.55(m,1H),3.94-4.12(m,1H),4.19-4.38(m,3H),4.46( d, 2H), 5.14 (t, 1H), 6.74-6.98 (m, 1H), 7.17-7.27 (m, 1H), 7.29-7.39 (m, 1H), 7.43 (s, 1H), 8.34 (dd, 1H), 8.49-8.85 (m, 3H).

Example 85 3-((3 R )-3-{[6-(6-{[4-(Dimethylamino)piperidin-1-yl]methyl}pyridin-3-yl)-5-fluoro-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the procedure described for the preparation of 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4- Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (6-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridine The -3-yl) acid (Preparation 65b) gave a solid (8%), which was then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 100: 8:1).

LRMS (m/z): 597 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.45-1.72 (m, 3H), 1.77-1.94 (m, 5H), 2.10-2.27 (m, 5H), 2.32 (s, 6H), 2.94 - 3.13 ( m, 2H), 3.37-3.53 (m, 3H), 3.60-3.73 (m, 2H), 3.85-4.01 (m, 1H), 4.21-4.44 (m, 1H), 5.13 (s, 1H), 6.79- 7.04 (m, 1H), 7.35-7.45 (m, 1H), 7.55-7.66 (m, 1H), 8.41 (d, 1H), 8.48-8.79 (m, 3H), 9.34 (d, 1H).

Example 86 3-[(3 R )-3-({5-fluoro-6-[6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the procedure described for the preparation of 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4- Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and [6-(4-methyl-1,4-diazepan-1-yl)pyridine The -3-yl] acid (Preparation 66b) gave a solid (34%), which was then purified by reverse phase chromatography (water to methanol).

LRMS (m/z): 569 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.50-1.73 (m, 1H), 1.74-1.92 (m, 2H), 1.98-2.15 (m, 2H), 2.17-2.31 (m, 1H), 2.41 ( s, 3H), 2.56-2.67 (m, 2H), 2.74-2.86 (m, 2H), 3.40-3.62 (m, 5H), 3.69-3.82 (m, 2H), 3.90-4.04 (m, 3H), 4.21-4.42 (m, 1H), 4.87-5.12 (m, 1H), 6.56-6.71 (m, 1H), 6.79-6.99 (m, 1H), 7.33-7.45 (m, 1H), 8.29 (dd, 1H) ), 8.45-8.80 (m, 3H), 8.90-9.11 (m, 1H).

Example 87 3-{(3 R )-3-[(6-{6-[4-(dimethylamino)piperidin-1-yl]pyridin-3-yl}-5-fluoro-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the procedure described for the preparation of 50a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4- Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and {6-[4-(dimethylamino)piperidin-1-yl]pyridin-3-yl The acid (preparation 67b) was obtained as a brown solid (28%), then purified by flash chromatography (dichloromethane to dichloromethane / methanol 95:5, then dichloromethane / methanol / ammonia 100: 8:1) product.

LRMS (m/z): 583 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.75-1.87 (m, 2H), 1.87-2.07 (m, 4H), 2.24 (d, 2H), 2.33 (s, 6H), 2.38-2.56 (m, 1H), 2.89-3.06 (m, 2H), 3.34-3.52 (m, 3H), 3.59 (s, 1H), 3.74-4.06 (m, 1H), 4.18-4.42 (m, 2H), 4.44 - 4.57 ( m, 2H), 5.03 (s, 1H), 6.76 (dd, 1H), 6.84-6.97 (m, 1H), 7.32-7.41 (m, 1H), 8.29 (d, 1H), 8.47-8.58 (m, 2H), 8.60 (s, 1H), 9.04 (s, 1H).

Example 88 3-{(3 R )-3-[(6-{4-[4-(2-Aminoethoxy)benzyl]piperazin-1-yl}-5-fluoro-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the procedure as described in Preparation 39, ( R )-(2-(4-((4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-)-)- yl) -5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)phenoxy)ethyl)aminocarboxylic acid The third butyl ester (Preparation 69) gave a solid (64%).

LRMS (m/z): 613 (M + 1) ⁺ .

^{1 H-NMR δ (300MHz,} DMSO- d 6): 1.41-1.69 (m, 2H), 1.69-1.84 (bs, 1H), 1.87-2.08 (bs, 1H), 2.35-2.63 (m, 6H), 2.64-2.79 (m, 1H), 2.80-2.91 (dd, 2H), 2.91-3.39 (m, 6H), 3.41-3.50 (s, 2H), 3.51-3.77 (m, 5H), 3.77-4.01 (m , 3H), 4.03-4.23 (m, 2H), 4.58-4.73 (d, 1H), 6.74-6.83 (m, 1H), 6.83-6.93 (d, 2H), 6.93-7.02 (m, 1H), 7.15 - 7.26 (d, 2H), 7.32 - 7.48 (m, 1H), 8.29 - 8.42 (m, 1H), 8.52 - 8.64 (m, 1H), 8.68 - 8.80 (m, 1H).

Example 89 3-{(3 R )-3-[(5-fluoro-6-{4-[1-(3-hydroxybenzyl)piperidin-4-yl]piperazin-1-yl}-2-pyridinium Zoxa[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, 3-((3 R )-3-{[5-fluoro-6-(4-piperidin-4-ylpiperazin-1-yl)-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile (Example 39) and 3-hydroxybenzaldehyde afforded a solid ( 40%) followed by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:1).

LRMS (m/z): 654 (M + 1) ⁺ .

^{1 H NMR δ (300MHz, DMSO} ): 1.28-2.07 (m, 6H), 2.35-2.45 (m, 3H), 3.15 (d, 2H), 3.30-3.50 (m, 4H), 3.54-3.75 (m, 6H), 3.93 (d, 1H), 4.01 (br.s, 2H), 4.05-4.20 (m, 5H), 4.63 (d, 1H), 6.55-6.88 (m, 3H), 6.95-7.12 (m, 2H), 7.33-7.48 (m, 1H), 8.37 (d, 1H), 8.52-8.61 (m, 1H), 8.74 (t, 1H).

Example 90 3-[(3 R )-3-([2-(dimethylamino)ethyl]{5-fluoro-6-[4-(3-hydroxybenzene) Methyl)piperazin-1-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxy Propiononitrile

According to the experimental procedure as described in Preparation 8c, 3-{[4-(6-{[2-(dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino} 5-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol (Preparation 70c) and 3-[(2, 5-Bisoxypyrrolidin-1-yl)oxy]-3-yloxypropanenitrile gave a light brown solid (38%).

LRMS (m/z): 642 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.90-2.13 (m, 5H), 2.27-2.45 (m, 5H), 2.51-2.74 (m, 7H), 2.89 (s, 1H), 2.96 (s, 1H), 3.27-3.50 (m, 1H), 3.54 (s, 3H), 3.60-3.88 (m, 8H), 4.39-5.06 (m, 1H), 6.71-6.80 (m, 1H), 6.81-6.96 ( m, 3H), 7.16-7.36 (m, 2H), 8.32 - 8.54 (m, 3H).

Example 91 3-((3 R )-3-{[5-fluoro-6-(4-{4-[2-(methylamino)ethoxy]benzyl}piperazin-1-yl)-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 6b from [2-(4-{[4-(6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino)} -5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenoxy)ethyl]methylaminocarboxylic acid The third butyl ester (Preparation 72) gave a solid (77%) which was then taken to flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 80: 20:1).

LRMS (m/z): 628 (M + 1) ⁺ .

^{1 H NMR δ (300MHz, CDCl} 3): 2.57 (bs, 6H), 3.06 (t, 1H), 3.39 (d, 1H), 3.43-3.54 (m, 3H), 3.56 (s, 1H), 3.69- 3.83 (m, 5H), 4.14 (t, 1H), 4.19 (br.s., 1H), 4.48-4.66 (m, 2H), 6.78-6.93 (m, 3H), 7.27-7.33 (m, 2H) , 8.34 (d, 1H), 8.39-8.58 (m, 3H).

Example 92 N -[(3 R )-1-(3-Aminopropyl)piperidin-3-yl]-5-fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl ]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine

Add 4 M solution of hydrogen chloride in 1,4-dioxane (0.4 mL) to ( R )-(3-(3-((5-fluoro-6-(4-(4-methylpiperazin-1-) Phenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropyl) A solution of the third butyl carbamate (preparation 73, 53 mg, 0.08 mmol) in MeOH (4 mL). The solvent was evaporated and EtOAc EtOAcqqqqqqqqq

LRMS (m/z): 558 (M + 1) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 0.70-0.99 (m, 2H), 1.00-1.38 (m, 4H), 1.99-2.28 (m, 2H), 2.28-2.50 (m, 3H), 2.50- 2.83(m,4H),2.88-3.20(m,3H),3.23-3.54(m,4H),3.90-4.19(m,2H),4.21-4.49(m,2H),5.12-5.46(m,3H ), 6.73-6.95 (m, 2H), 6.96-7.13 (m, 2H), 7.94-8.30 (m, 3H), 8.44 - 8.83 (m, 3H).

Example 93 3-[(3 R )-3-([2-(dimethylamino)ethyl]{5-fluoro-6-[3-hydroxyl 5-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1- 3-oxyloxypropionitrile

According to the experimental procedure as described in Preparation 8c, 3-(6-{[2-(dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino}-5-fluoro -2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1-yl)phenol (Preparation 74d) and 3-[(2 , 5-di-oxypyrrolidin-1-yl)oxy]-3-oxo-propanenitrile afforded a solid (33%), followed by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia The crude product was purified by a gradient of 100:8:1.

LRMS (m/z): 641 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.31-1.55 (m, 3H), 1.86-2.20 (m, 4H), 2.24-2.48 (m, 7H), 2.52-2.79 (m, 5H), 2.83 3.32 (m, 4H), 3.32-3.60 (m, 3H), 3.62-3.88 (m, 3H), 4.21-4.49 (m, 2H), 4.55-4.90 (m, 2H), 5.80-6.27 (m, 2H) ), 6.56 (s, 1H), 6.78-6.98 (m, 2H), 7.20 (s, 1H), 8.39-8.67 (m, 2H).

Example 94 3-(6-{[2-(Dimethylamino)ethyl][(3 R )-1-ethanehydrazinopiperidin-3-yl]amino}-5-fluoro-2-pyridyl Zoxa[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1-yl)phenol

According to the experimental procedure as described in Preparation 64, 3-(6-{[2-(dimethylamino)ethyl][(3 R )-piperidin-3-yl]amino}-5-fluoro 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1-yl)phenol (Preparation 74d) and 2-hydroxyacetic acid were obtained. The solid (30%) was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 633 (M+2) ⁺ .

^{1 H-NMR δ (300MHz,} DMSO- d 6): 1.01-1.43 (m, 1H), 1.70-2.08 (m, 2H), 2.20-2.40 (m, 7H), 2.47-2.53 (m, 6H), 2.62-3.07(m,3H), 3.16(d,4H), 3.63-3.85(m,3H), 4.00-4.23(m,3H), 4.27-4.46(m,2H),4.50-4.69(m,2H ), 6.48 (s, 1 H), 6.84 (d, 1H), 6.96-7.11 (m, 2H), 7.44 (dd, 1H), 8.48 (t, 1H), 8.55-8.66 (m, 1H), 8.80 (d, 1H), 9.48 (s, 1H).

Example 95 3-((3 R )-3-{[6-(4-{[4-(Dimethylamino)piperidin-1-yl]methyl}-3-hydroxyphenyl)-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, ( R )-3-(3-((5-fluoro-6-(4-carbamido-3-hydroxyphenyl)-2-(pyrazolo[1] , 5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (preparation 76b) and N,N -dimethylpiperidine- The 4-amine gave a yellow solid (14%), which was purified by flash chromatography (dichloromethane/methanol/methanol 40:4.0:0.2).

LRMS (m/z): 612 (M + 1) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.52-1.71 (m, 3H), 1.71-2.04 (m, 8H), 2.08-2.27 (m, 5H), 2.27-2.34 (s, 6H), 3.03- 3.23 (m, 3H), 3.30-3.51 (m, 3H), 3.56-3.61 (s, 1H), 3.61-3.71 (m, 1H), 3.73-3.81 (s, 2H), 3.87-4.05 (m, 2H) ), 4.24-4.37 (m, 2H), 4.56-4.67 (dd, 5H), 4.89-4.95 (d, 1H), 5.04-5.17 (d, 1H), 6.82-6.95 (m, 1H), 7.07-7.15 (m, 1H), 7.32 - 7.41 (m, 1H), 7.51 - 7.61 (m, 2H), 8.45 - 8.67 (m, 3H), 8.67 - 8.77 (s, 1H).

Example 96 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-5-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl)-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (Preparation 6c) and 3-{[(1-methylpiperidin-4-yl)amino]methyl}- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 77b) gave a solid (87%), then a flash layer The crude product was purified (dichloromethane to dichloromethane / methanol / ammonia: 85: 15: 0.5).

LRMS (m/z): 599 (M + 1) ⁺ .

¹ H NMR δ (300 MHz, DMSO): 1.20-1.39 (m, 3H), 1.50-1.95 (m, 5H), 2.05 (d, 1H), 2.11 (s, 3H), 2.22-2.46 (m, 2H) , 2.53-2.79 (m, 3H), 3.04 (dd, 1H), 3.69-3.81 (m, 3H), 3.93-4.23 (m, 3H), 4.73 (dd, 1H), 6.67-6.77 (m, 1H) , 6.90 (s, 1H), 7.0-7.10 (m, 1H), 7.34 (s, 1H), 7.40-7.63 (m, 2H), 8.52 (d, 1H), 8.65-8.87 (m, 2H), 9.61 (d, 1H).

Example 97 3-((3 R )-3-{[5-fluoro-6-(4-{(3-hydroxybenzyl)[(1-methylpiperidin-4-yl)methyl]amino}perylene Pyridin-1-yl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 4, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-{[[(1-methylpiperidin-4-yl)methyl](piperidine) -4-yl)amino]methyl}phenol (Preparation 78c) gave a solid (5%), which was then purified by flash chromatography (dichloromethane to dichloromethane/methanol/methanol: 100:8:1 gradient) The crude product was purified by reverse phase chromatography (water to methanol gradient).

LRMS (m/z): 696 (M+2) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.16-1.53 (m, 6H), 1.62-2.16 (m, 6H), 2.27 (s, 3H), 2.57 (t, 4H), 2.78-3.25 (m, 8H), 3.41-3.68 (m, 3H), 3.69-4.02 (m, 3H), 4.07-4.34 (m, 2H), 4.34-4.53 (m, 2H), 4.59-4.80 (m, 1H), 6.49 ( d, 1H), 6.60-6.66 (m, 1H), 6.74 (d, 1H), 6.79-6.94 (m, 1H), 7.06-7.23 (m, 1H), 7.28-7.43 (m, 1H), 8.33 8.69 (m, 3H).

Example 98 3-[(3 R )-3-({5-fluoro-6-[3-hydroxy-5-({[1-(3-piperidin-1-ylpropyl)piperidin-4-yl]amine) Methyl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-({[1-(3-piperidin-1-ylpropyl)piperidin-4 -yl]amino}methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 79d) gave solid (8%), then the crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8: 0.5).

LRMS (m/z): 710 (M + 1) ⁺ .

¹ H NMR δ (300 MHz, DMSO): 1.21-1.36 (m, 6-7H), 1.36-1.50 (m, 4H), 1.65-2.10 (m, 11H), 2.14-2.60 (m, 7H), 2.77- 2.83 (m, 3H), 3.69-3.81 (m, 3H), 3.93-4.23 (m, 3H), 4.73 (dd, 1H), 6.72-6.93 (m, 3H), 7.45-7.56 (m, 2H), 7.34 (s, 1H), 7.40-7.63 (m, 2H), 8.52-8.72 (m, 3H).

Example 99 3-{(3 R )-3-[(5-fluoro-6-{6-[4-(methylamino)piperidin-1-yl]pyridin-3-yl}-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

A 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.36 mL, 1.44 mmol) was added to {1-[5-(6-{[(3 R )-1-(cyanoethenyl)piperidine) 3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}A A solution of tert-butyl carbamic acid (preparation 81, 80 mg, 0.12 mmol) in 1,4-dioxane (3 mL). The solvent was evaporated to dryness and the residue was partitioned between dichloromethane and 4% aqueous sodium hydrogen carbonate. The organic layer was separated, EtOAcjjjjjjjjjj

LRMS (m/z): 570 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.33-1.51 (m, 2H), 1.73-1.96 (m, 2H), 1.98-2.10 (m, 2H), 2.16-2.30 (m, 1H), 2.51 ( s, 3H), 2.62-2.78 (m, 1H), 2.98-3.26 (m, 2H), 3.33-3.52 (m, 2H), 3.62-3.68 (m, 1H), 3.71 (s, 4H), 3.85- 4.04 (m, 1H), 4.26-4.67 (m, 3H), 4.95-5.07 (m, 1H), 6.80 (dd, 1H), 6.84-6.96 (m, 1H), 7.30-7.44 (m, 1H), 8.29 (d, 1H), 8.49-8.58 (m, 2H), 8.66 (d, 1H), 9.04 (br.s., 1H).

Example 100 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and pyrrolidin-1-ylpiperidin-1-yl)methyl]-5-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 82b) gave a solid (39%). The crude product was purified by a gradient of dichloromethane / methanol / ammonia 100: 8:1.

LRMS (m/z): 638 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.48-1.75 (m, 4H), 1.82-1.96 (m, 4H), 1.96-2.27 (m, 8H), 2.61 (m, 5H), 2.96 (d, 2H), 3.29-3.42 (m, 2H), 3.46 (d, 1H), 3.50 (s, 1H), 3.54 (m, 1H), 3.60 (m, 1H), 3.71-4.05 (m, 1H), 4.13 -4.37(m,1H),4.99-5.23(m,1H),6.74-7.01(m,2H), 7.29-7.38(m,1H),7.41-7.58(m,2H),8.38-8.56(m, 2H), 8.64 (d, 1H).

Example 101 3-(5-Fluoro-6-{[(3 R )-1-ethylene-hydrazinopiperidin-3-yl]amino}-2-pyrazolo[1,5- a ]pyridine-3- Pyrimidin-4-yl)-5-{[(1-methylpiperidin-4-yl)amino]methyl}phenol

According to the experimental procedure as described in Preparation 45a, 2-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-2-oxoethanol (preparation 64) and 3-{[(1-methylpiperidin-4-yl)amino]methyl}-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 77b) gave a solid (89%), followed by flash chromatography The crude product was purified (dichloromethane to dichloromethane / methanol / ammonia 40: 8: 0.5).

LRMS (m/z): 589 (M + 1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ): 1.47-1.64 (m, 2H), 1.67-2.21 (m, 9H), 2.30 (s, 3H), 2.55-2.63 (m, 1H), 2.89 (d, 2H) ), 3.07-3.26 (m, 2H), 3.34 - 3.46 (m, 2H), 3.49 (s, 2H), 3.84 (s, 2H), 4.15 - 4.30 (m, 2H), 5.07 - 5.20 (m, 1H) ), 6.79-6.89 (m, 1H), 6.93 (d, 1H), 7.41 - 7.56 (m, 2H), 8.45 - 8.56 (m, 2H), 8.59 - 8.74 (m, 1H).

Example 102 3-{(3 R )-3-[(5-fluoro-6-{4-[3-hydroxy-5-(1-methylpiperidin-4-yl)benzyl]piperazin-1-yl }-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

Feeding the microwave reactor with 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl) Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c, 0.075 g, 0.18 mmol), 3-(1-methylpiperidin-4-yl)-5-(piperazine- 1-Methylmethyl)phenol (preparation 83d, 0.216 g, 0.54 mmol) and N -methylpyrrolidone (1.5 mL). Diisopropylethylamine (0.315 mL, 1.81 mmol) was added and the reaction mixture was subjected to microwave irradiation at 130 ° C for 7 hours, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate The title compound (0.019 g, 15%) eluted elute

LRMS (m/z): 667 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.54-1.96 (m, 10H), 2.02-2.22 (m, 4H), 2.35 (s, 2H), 2.40-2.53 (m, 2H), 2.54-2.77 ( m, 4H), 2.94-3.21 (m, 2H), 3.30-3.66 (m, 5H), 3.72-3.95 (m, 4H), 4.11-4.33 (m, 1H), 4.46-4.73 (m, 1H), 6.62 (s, 1H), 6.74 (d, 2H), 6.80-6.98 (m, 1H), 7.21-7.40 (m, 1H), 8.25-8.62 (m, 3H).

Example 103 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]phenyl} -2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 84f) gave a solid (10%).

LRMS (m/z): 682 (M+2) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.26 (br.s., 2H), 1.40-1.57 (m, 4H), 1.61-2.00 (m, 4H), 2.14-2.30 (m, 2H), 2.35 -2.68 (m, 13H), 3.09-3.29 (m, 4H), 3.33-3.54 (m, 3H), 3.57-3.73 (m, 1H), 3.86-4.11 (m, 1H), 4.18-4.40 (m, 1H), 4.44-4.66 (m, 1H), 4.99-5.21 (m, 1H), 6.52 (br.s., 1H), 6.80- 6.96 (m, 1H), 7.07 (br.s., 1H), 7.20-7.36 (m, 2H), 8.39-8.74 (m, 3H).

Example 104 3-{(3 R )-3-[(5-fluoro-6-{4-[(3-hydroxybenzyl)(3-piperidin-1-ylpropyl)amino]piperidin-1- -2-}pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Example 102, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-{[piperidin-4-yl(3-piperidin-1-ylpropyl)amine The crude product was obtained by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 710 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.51-1.68 (m, 3H), 1.69-2.00 (m, 5H), 2.00-2.27 (m, 4H), 2.62-2.67 (m, 5H), 2.69- 2.96 (m, 5H), 3.00-3.22 (m, 3H), 3.32-3.45 (m, 2H), 3.54-3.82 (m, 6H), 3.54-3.65 (m, 3H), 4.10-4.31 (m, 1H) ), 4.41-4.75 (m, 3H), 6.64 (d, 1H), 6.78 (dd, 1H), 6.83-6.93 (m, 1H), 7.12 (t, 1H), 7.19-7.25 (m, 1H), 7.29-7.37 (m, 1H), 8.25-8.64 (m, 3H).

Example 105 3-((3 R )-3-{[6-(3-{[4-(cyclopentylamino)piperidin-1-yl]methyl}-5-hydroxyphenyl)-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-{[4-(cyclopentylamino)piperidin-1-yl]methyl} -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 86d) gave a solid (15%). The crude product was purified by chromatography (methylene chloride to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 652 (M + 1) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.16-1.74 (m, 10H), 1.97-2.16 (m, 10H), 2.58 (t, 1H), 2.76-3.02 (m, 2H), 3.17-3.31 ( m, 2H), 3.34-3.50 (m, 3H), 3.50-3.63 (m, 3H), 3.81-3.99 (m, 1H), 4.18-4.42 (m, 1H), 5.09 (d, 1H), 6.81 7.05 (m, 2H), 7.30-7.39 (m, 1H), 7.44 (d, 2H), 8.36-8.91 (m, 3H).

Example 106 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[methyl(1-methylpiperidin-4-yl)amino]methyl}phenyl) -2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 33, ( R )-3-(3-((5-fluoro-6-(4-carbamido-3-hydroxyphenyl)-2-(pyrazolo[1] , 5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (Preparation 76b) and N ,1-Dimethylpiperidine- The 4-amine gave a yellow solid (14%), which was purified by flash chromatography (dichloromethane/methanol/methanol 40:4.0:0.2).

LRMS (m/z): 612 (M + 1) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.69-1.91 (m, 7H), 1.96-2.11 (m, 4H), 2.14-2.28 (m, 2H), 2.29-2.33 (s, 3H), 2.33 2.37 (s, 3H), 2.46-2.69 (m, 4H), 2.70-2.95 (m, 4H), 2.96-3.08 (d, 3H), 3.11-3.25 (d, 1H), 3.28-3.49 (m, 3H) ), 3.51-3.61 (m, 1H), 3.61-3.76 (m, 2H), 3.84 - 3.93 (s, 2H), 3.93-4.05 (m, 1H), 4.24 - 4.39 (bs, 1H), 4.54-4.67 (dd, 1H), 5.01-5.11 (m, 1H), 6.81-6.95 (m, 1H), 7.05-7.16 (m, 1H), 7.29-7.41 (t, 1H), 7.49-7.59 (m, 2H) , 8.43 - 8.77 (m, 3H).

Example 107 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-4-[(4-methyl-1,4-diazepan-1-yl)methyl] Phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-[(4-methyl-1,4-diazepan-1-yl) )methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 87b) gave a solid (48%). The crude product was then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8: 0.5).

LRMS (m/z): 598 (M+1) ⁺ .

^{1 H NMR δ (300MHz, CDCl} 3): 1.71-2.02 (m, 4H), 2.09 (s, 3H), 2.37 (s, 2H), 2.49-2.76 (m, 4H), 2.85 (br.s,. 2H), 3.18 (d, 1H), 3.29-3.72 (m, 5H), 3.82-4.06 (m, 3H), 4.31 (t, 1H), 5.05 (br.s., 1H), 6.79-6.93 (m , 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.52-7.59 (m, 2H), 8.44 - 8.74 (m, 3H).

Example 108 3-[(3 R )-3-({6-[2-(1,4-diazepan-1-yl)pyridin-4-yl]-5-fluoro-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 99, 4-[4-(6-{[(3 R )-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]-1,4-diazepane-1-carboxylic acid tert-butyl ester (preparation The crude product was obtained by flash chromatography (methylene chloride to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 555 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.74-2.07 (m, 6H), 2.14-2.33 (m, 1H), 2.83-3.00 (m, 2H), 3.05-3.19 (m, 2H), 3.19- 3.34 (m, 1H), 3.36-3.54 (m, 3H), 3.56-3.73 (m, 1H), 3.78-4.01 (m, 4H), 4.28-4.66 (m, 2H), 5.13 (br.s., 1H), 6.82-6.99 (m, 1H), 7.13-7.23 (m, 1H), 7.27 (br.s., 1H), 7.31-7.44 (m, 1H), 8.31 (br.s., 1H), 8.46-8.79 (m, 3H).

Example 109 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-5-{[methyl(1-methylpiperidin-4-yl)amino]methyl}phenyl) -2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in 45a was prepared from 3 - {(3 R) -3 - [(6- chloro-5-fluoro-2-pyrazolo [1,5-a] pyridin-3-yl pyrimidine - 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-{[methyl(1-methylpiperidin-4-yl)amino]methyl }-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 90b) gave a solid (52%), The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8: 0.5).

LRMS (m/z): 612 (M + 1) ⁺ .

^{1 H NMR δ (300MHz, CDCl} 3): 1.64-1.91 (m, 6H), 1.97-2.04 (m, 3H), 2.27 (s, 3H), 2.30 (s, 3H), 2.49 (t, 1H), 2.97 (d, 2H), 3.19 (dd, 1H), 3.32-3.53 (m, 4H), 3.55-3.67 (m, 3H), 3.83-4.00 (m, 2H), 4.26 (d, 1H), 4.52 ( Dd,1H)5.08(t,1H),6.79-6.98(m,2H), 7.29-7.37(m,2H),7.46(d,1H),7.58(d,1H),8.44-8.72(m,4H ).

Example 110 3-{(3 R )-3-[[5-fluoro-6-(3-hydroxy-5-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl)-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl](methyl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)(methyl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 91c) and 3-{[(1-methylpiperidin-4-yl)amino] Methyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 77b) gave a solid (59%), then The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 80: 20: 0.2).

LRMS (m/z): 612 (M + 1) ⁺ .

¹ H NMR δ (300 MHz, CDCl ₃ ): 1.45-1.65 (m, 3H), 1.84-2.17 (m, 8H), 2.26-2.35 (m, 4H), 2.59 (d, 1H), 2.89 (dd, 2H) ), 3.17 (dd, 3H), 3.28 (d, 1H), 3.47-3.53 (m, 2H), 3.57 (d, 1H), 3.75 (s, 1H), 3.85 (s, 2H), 4.34 - 4.51 ( m,1H), 6.78-6.92 (m, 2H), 6.95 (d, 1H), 7.40 (d, 1H), 7.47 (br.s., 1H), 8.50 (dd, 2H), 8.63 (d, 1H) ).

Example 111 3-{(3 R )-3-[(6-{3-[(cyclopentylamino)methyl]-5-hydroxyphenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile

According to the experimental procedure as described in Preparation 45a, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 3-[(cyclopentylamino)methyl]-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 92b) gave solid (21%) elute /Methanol/ammonia 100:8:1 gradient) The crude product was purified.

LRMS (m/z): 569 (M + 1) ⁺ .

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.43-1.64 (m, 3H), 1.67-1.82 (m, 3H), 1.85-2.00 (m, 4H), 2.04-2.29 (m, 4H), 3.06- 3.29 (m, 2H), 3.33-3.42 (m, 1H), 3.50 (s, 2H), 3.55-3.67 (m, 1H), 3.82 (d, 2H), 3.88-4.56 (m, 1H), 4.22 ( s, 1H), 5.13 (br.s., 1H), 6.76-7.02 (m, 2H), 7.09-7.35 (m, 1H), 7.42 (d, 1H), 7.55 (d, 1H), 8.40-8.70 (m, 3H).

Example 112 3-[(3 R )-3-({6-[3-(1,4-diazepan-1-ylmethyl)-5-hydroxyphenyl]-5-fluoro-2-pyridyl) Zoxa[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 6b, 4-[3-(6-{[(3 R )-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)-5-hydroxybenzyl]-1,4-diazepane-1-carboxylic acid tert-butyl ester (Preparation 94) A solid (77%) was obtained, then the crude material was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 80: 20:1).

LRMS (m/z): 584 (M+1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ): 1.77-1.86 (m, 6H), 2.12-2.26 (m, 1H), 2.73-2.77 (m, 3H), 2.95-3.04 (m, 3H), 3.14-3.27 (m, 1H), 3.31-3.44 (m, 2H), 3.46 (s, 2H), 3.63 (d, 1H), 3.70 (d, 2H), 3.87 (dd, 1H), 4.24 - 4.33 (m, 1H) ), 4.52 (dd, 1H), 6.88 (dd, 1H), 7.05 (d, 1H), 7.32 (d, 1H), 7.50 (d, 2H), 8.42 - 8.58 (m, 2H), 8.59 - 8.73 ( m, 1H).

Example 113 3-((3 R )-3-{[6-(3-{6-[4-(Dimethylamino)piperidin-1-yl]pyridin-3-yl}-5-hydroxyphenyl) -5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

Feeding the microwave reactor with 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl) Amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c, 0.070 g, 0.17 mmol), 3-{6-[4-(dimethylamino)piperidin-1-yl Pyridin-3-yl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 95b, 0.23 g, 0.43 Methyl) 2 M aqueous solution of cesium carbonate (0.25 mL, 0.50 mmol) and 1,4-dioxane (3 mL). The reactor was subjected to three vacuum-backfill cycles with argon and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (0.01) g, 0.01 mmol). In a further three evacuation - backfilled with argon after cycling, the reactor was sealed and the reaction mixture was subjected to microwave irradiation at 140 deg.] C for 2 h, filtered through diatomaceous earth (Celite ^®) and evaporated to dryness. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut

LRMS (m/z): 675 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.48-1.66 (m, 3H), 1.70-1.87 (m, 3H), 1.96 (d, 4H), 2.15-2.27 (m, 1H), 2.35 (s, 6H), 2.39-2.52 (m, 1H), 3.11-3.43 (m, 2H), 3.47 (d, 1H), 3.60 (s, 1H), 3.82-4.09 (m, 1H), 4.18-4.63 (m, 4H), 5.09-5.25 (m, 1H), 6.72 (d, 1H), 6.78-6.94 (m, 1H), 7.10 (d, 1H), 7.30-7.38 (m, 1H), 7.52 (br.s. , 1H), 7.66-7.85 (m, 2H), 8.42 - 8.57 (m, 3H), 8.66 (d, 1H).

Example 114 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[(4-methyl-1,4-diazepan-1-yl)methyl] Phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

3-[(3 R )-3-({6-[3-(1,4-diazepan-1-ylmethyl)-5-hydroxyphenyl]-5-fluoro-2-pyridyl) Zoxa[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 112, 0.03 g, 0.05 mmol), EtOAc A mixture of (0.008 mL, 0.11 mmol) and acetic acid (0.05 mL) in THF (0.20 mL) was stirred at room temperature for one hour. Sodium triethoxysulfonium borohydride (0.033 g, 0.16 mmol) was added and the mixture was stirred at room temperature for 3 hr then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water and brine, dried The residue was purified by EtOAc EtOAcjjjjjjj

LRMS (m/z): 598 (M+1) ⁺ .

^{1 H NMR δ (300MHz, CDCl} 3): 1.73-2.06 (m, 6H), 2.08 (s, 3H), 2.55 (s, 2H), 2.73-2.85 (m, 3H), 2.92 (d, 1H), 2.98 (d, 1H), 3.20-3.30 (m, 1H), 3.32-3.47 (m, 2H), 3.49 (s, 2H), 3.59 (s, 1H), 3.70 (d, 1H), 3.92 (t, 1H), 4.22-4.36 (m, 1H), 4.44-4.56 (m, 1H), 5.12 (d, 1H), 6.86 (dd, 1H), 7.08-7.18 (m, 2H), 7.30-7.39 (m, 1H), 7.51 (s, 1H), 8.48-8.57 (m, 2H), 8.59-8.72 (m, 1H).

Example 115 3-{(3 R )-3-[(5-fluoro-6-{4-hydroxy-3-[(4-methyl-1,4-diazepan-1-yl)methyl] Phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-[(4-methyl-1,4-diazepan-1-yl) )methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 96b) gave a solid (40%). Flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5) was then carried out.

LRMS (m/z): 598 (M+1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ): 1.73-2.00 (m, 6H), 2.10 (d, 2H), 2.35-2.38 (m, 5H), 2.49-2.73 (m, 7H), 2.86-2.90 (m , 3H), 3.36-3.75 (m, 7H), 3.84-4.00 (m, 3H), 4.26-4.35 (m, 1H), 4.56 (dd, 1H), 5.00-5.05 (m, 1H), 6.69-7.00 (m, 3H), 7.37 (d, 1H), 7.82 (s, 1H), 8.01 (d, 1H), 8.49-8.58 (m, 2H), 8.61 - 8.73 (m, 1H).

Example 116 1-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl)benzyl]piperidine-4-carboxylic acid 1-methylpiperidin-4-yl ester

According to the experimental procedure as described in Preparation 40a, ( R )-3-(3-((5-fluoro-6-(4-carbamido-3-hydroxyphenyl)-2-(pyrazolo[1] ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (preparation 48b) and piperidine-4-carboxylic acid 1-methyl The piperidin-4-yl ester (Preparation 97b) gave a green solid (32%).

LRMS (m/z): 694 (M + 1) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.65-1.77 (m, 2H), 1.77-1.98 (m, 6H), 2.00-2.14 (t, 2H), 2.16-2.38 (m, 5H), 2.49- 2.69 (bs, 2H), 2.81-2.98 (d, 2H), 3.15-3.29 (dd, 1H), 3.32-3.52 (m, 2H), 3.54-3.61 (s, 2H), 3.61-3.77 (m, 2H) ), 3.85-4.04 (m, 1H), 4.24-4.40 (bs, 1H), 4.51-4.63 (dd, 2H), 4.72-4.87 (m, 2H), 5.00-5.12 (bs, 2H), 6.80-6.97 (m, 1H), 7.30-7.42 (t, 1H), 7.42-7.55 (t, 2H), 8.02-8.13 (d, 2H), 8.46-8.78 (m, 3H).

Example 117 3-{(3 R )-3-[(6-{6-[4-(cyclopentylamino)piperidin-1-yl]pyridin-3-yl}-5-fluoro-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 99, {1-[5-(6-{[(3R)-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro- T-butyl 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}cyclopentylaminocarbamate (Preparation 99) A solid (16%) was obtained, which was purified by flash chromatography (dichloromethane to dichloromethane/methanol/methanol.

LRMS (m/z): 623 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.25-1.49 (m, 3H), 1.68-1.81 (m, 5H), 1.83-1.98 (m, 4H), 1.99-2.12 (m, 3H), 2.17- 2.31(m,1H), 2.72-2.94(m,1H), 2.95-3.12(m,2H),3.13-3.35(m,2H), 3.38-3.74(m,5H),3.84-4.05(m,1H ), 4.19-4.52 (m, 3H), 4.90-5.10 (m, 1H), 6.75-6.83 (m, 1H), 6.83-6.96 (m, 1H), 7.30-7.43 (m, 1H), 8.28 (d) , 1H), 8.46-8.58 (m, 2H), 8.66 (d, 1H), 8.92-9.09 (m, 1H).

Example 118 3-((3 R )-3-{[6-(3-{[4-(Dimethylamino)piperidin-1-yl]methyl}-4- Hydroxyphenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Example 113, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-{[4-(dimethylamino)piperidin-1-yl]methyl} 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 100b) gave a solid (26%), then The crude product was purified by chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 612 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.52-1.72 (m, 5H), 1.75-1.99 (m, 5H), 2.09-2.38 (m, 4H), 2.99-3.29 (m, 3H), 3.35- 3.59 (m, 4H), 3.66-3.77 (m, 2H), 3.80-4.02 (m, 3H), 4.23-4.40 (m, 1H), 4.58 (dd, 1H), 5.03 (t, 1H), 6.76- 7.02 (m, 3H), 7.32-7.42 (m, 1H), 7.85 (s, 1H), 7.96-8.06 (m, 1H), 8.47-8.62 (m, 2H), 8.68 (d, 1H).

Example 119 3-[(3 R )-3-({5-fluoro-6-[3-hydroxy-4-(piperazin-1-ylmethyl)phenyl]-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 99, 4-[4-(6-{[(3 R )-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro- T-butyl 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-2-hydroxybenzyl]piperazine-1-carboxylate (Preparation 102) gave a solid (43% The crude product was then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 570 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.46-2.09 (m, 7H), 2.15-2.37 (m, 1H), 2.51-2.77 (m, 3H), 2.99 (s, 3H), 3.32-3.50 ( m, 4H), 3.57-3.74 (m, 1H), 3.80 (d, 2H), 3.88-4.10 (m, 1H), 4.21-4.44 (m, 1H), 5.08 (d, 1H), 6.82-6.96 ( m, 1H), 7.11-7.21 (m, 1H), 7.32-7.44 (m, 1H), 7.49-7.64 (m, 2H), 8.46-8.61 (m, 2H), 8.61 - 8.77 (m, 1H).

Example 120 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[(1-methylpiperidin-4-yl)amino]methyl}phenyl)-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and (3-hydroxy-4-{[(1-methylpiperidin-4-yl)amine [Methyl}phenyl) acid (Preparation 103b) gave a solid (75%), which was then purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40:8:0.5).

LRMS (m/z): 598 (M+1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ): 1.43-1.61 (m, 3H), 1.74-1.88 (m, 3H), 2.01-2.09 (m, 4H), 2.30 (s, 3H) 2.61 (d, 1H) , 2.86 (d, 2H), 3.17 (dd, 1H), 3.31-3.51 (m, 3H), 3.59 (s, 1H) 3.62-3.71 (m, 1H), 3.87-4.05 (m, 1H), 4.12 ( d, 2H), 4.29 (bs, 1H), 4.61 (dd, 1H), 5.06 (d, 1H), 6.89 (dd, 1H), 7.14 (dd, 1H), 7.31-7.40 (m, 1H), 7.54 - 7.60 (m, 2H) 8.49-8.58 (m, 2H), 8.59 - 8.75 (m, 1H).

Example 121 1'-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a Pyridine-3-ylpyrimidin-4-yl)benzyl]-4-methyl-1,4'-bipiperidine-4-carboxylic acid ethyl ester

According to the experimental procedure as described in Preparation 40a, ( R )-3-(3-((5-fluoro-6-(4-carbamido-3-hydroxyphenyl)-2-(pyrazolo[1] , 5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (preparation 48b) and 4-methyl-[1,4' -bipiperidine]-4-carboxylic acid ethyl ester dihydrochloride (preparation 104c) gave a green solid (31%), which was purified by flash chromatography (dichloromethane / methanol / ammonia 40:4:0.2) .

LRMS (m/z): 722 (M + 1) +.

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.10-1.21 (s, 3H), 1.21-1.31 (t, 3H), 1.40-1.92 (m, 12H), 1.92-2.08 (m, 2H), 2.08- 2.44 (m, 6H), 2.63-2.87 (bs, 2H), 2.90-3.06 (d, 2H), 3.14-3.29 (dd, 1H), 3.32-3.51 (m, 3H), 3.51-3.73 (m, 3H) ), 3.85-4.03 (m, 1H), 4.07-4.23 (q, 2H), 4.23-4.41 (bs, 1H), 4.51-4.64 (d, 1H), 4.99-5.15 (m, 2H), 6.80-6.98 (m, 1H), 7.31 - 7.42 (t, 1H), 7.42 - 7.53 (t, 2H), 8.00 - 8.13 (d, 2H), 8.47 - 8.80 (m, 3H).

Example 122 3-[(3 R )-3-({5-fluoro-6-[4-[(4-methyl-1,4-diazepane-1-) Methyl]-3-(methylthio)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl 3-oxyloxypropionitrile

According to the experimental procedure as described in Example 113, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-methyl-4-[2-(methylthio)-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1,4-diazepane (Preparation 105b) afforded a light brown solid (37%), the crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia gradient: 100: 8:1).

LRMS (m/z): 628 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.75-2.05 (m, 5H), 2.17-2.31 (m, 1H), 2.41 (s, 3H), 2.58 (s, 3H), 2.64-2.91 (m, 8H), 3.35-3.69 (m, 5H), 3.74 (s, 2H), 3.87-4.01 (m, 1H), 4.21-4.44 (m, 1H), 4.98-5.17 (m, 1H), 6.83-6.97 ( m, 1H), 7.32-7.40 (m, 1H), 7.51 (t, 1H), 7.86 (d, 1H), 8.06 (s, 1H), 8.45 - 8.80 (m, 3H).

Example 123 3-[(3 R )-3-({5-fluoro-6-[3-[(4-methyl-1,4-diazepan-1-yl)methyl]-4-( Methylthio)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

According to the experimental procedure as described in Example 113, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 1-methyl-4-[2-(methylthio)-5-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1,4-diazepane (Preparation 106b) afforded solid (26 The crude product was purified by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40: 8:1 gradient).

LRMS (m/z): 628 (M + 1) ⁺ .

Example 124 3-[(3 R )-3-({6-[4-({2-[4-(Dimethylamino)piperidin-1-yl]ethyl}thio)phenyl]-5- Fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and [4-({2-[4-(dimethylamino)piperidin-1-yl) [Ethyl}thio)phenyl] acid (Preparation 107b) afforded a solid (17%), followed by flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 40:8:1) and reverse phase layer The crude product was purified (water to methanol).

LRMS (m/z): 642 (M + 1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ): 1.58 (td, 3H), 1.82 (d, 4H), 2.05 (t, 2H), 2.12 - 2.26 (m, 2H), 2.30 (s, 6H), 2.64 2.72 (m, 1H), 3.02 (d, 2H), 3.12-3.17 (m, 2H), 3.24 (dd, 1H), 3.34-3.52 (m, 3H), 3.59 (s, 1H), 3.61-3.70 ( m,1H), 3.91(d,1H), 4.32(br.s.,1H), 4.56(dd,1H),5.07(td,1H),6.82-6.95(m,1H),7.32-7.40(m , 1H) 7.45 (dd, 2H), 8.07 (d, 2H), 8.50-8.59 (m, 2H), 8.60-8.74 (m, 1H).

Example 125 3-{(3 R )-3-[(6-{6-[4-(dimethylamino)piperidin-1-yl]-5-hydroxypyridyl Pyridin-3-yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-yloxy Propiononitrile

According to the experimental procedure as described in Example 113, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and {6-[4-(dimethylamino)piperidin-1-yl]-5- The hydroxypyridin-3-yl} acid (Preparation 108d) gave a solid (11%), which was then purified by flash chromatography (dichloromethane to methylene chloride/methanol/methanol: 100:8:1).

LRMS (m/z): 599 (M+2) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.67-1.90 (m, 4H), 1.95-2.12 (m, 3H), 2.13-2.28 (m, 3H), 2.39 (s, 6H), 2.90 (t, 2H), 3.11-3.52 (m, 3H), 3.57-3.71 (m, 1H), 3.71-4.04 (m, 3H), 4.23-4.43 (m, 1H), 5.12 (d, 1H), 6.82-6.96 ( m, 1H), 7.29-7.42 (m, 1H), 7.88 (s, 1H), 8.44 - 8.76 (m, 4H).

Example 126 3-[(3 R )-3-({5-fluoro-6-[2-(4-isopropyl-1,4-diazepan-1-yl)pyridin-4-yl]- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

3-[(3 R )-3-({6-[2-(1,4-diazepan-1-yl)pyridin-4-yl]-5-fluoro-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile (Example 108, 0.075 g, 0.14 mmol) and prop-2- A solution of the ketone (0.012 mL, 0.16 mmol) in dichloromethane (0.70 mL) was stirred at room temperature for 30 min. Sodium triethoxysilane borohydride (0.045 g, 0.21 mmol) was added and the mixture was stirred at room temperature overnight. Further, propan-2-one (0.012 mL, 0.16 mmol) and sodium triethoxysulfonylborohydride (0.045 g, 0.21 mmol) were added and the mixture was stirred overnight at room temperature. The solvent was concentrated in EtOAc (mjqqqqqq

LRMS (m/z): 597 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.04 (d, 6H), 1.76-2.11 (m, 5H), 2.16-2.31 (m, 1H), 2.57-2.71 (m, 2H), 2.76-2.90 ( m, 2H), 2.91-3.08 (m, 1H), 3.19-3.54 (m, 3H), 3.56-3.71 (m, 2H), 3.73-4.02 (m, 5H), 4.27-4.62 (m, 1H), 5.03-5.20(m,1H),6.84-6.98(m,1H),7.11-7.20(m,1H), 7.27(s,1H),7.35(t,1H),8.31(t,1H),8.49- 8.77 (m, 3H).

Example 127 3-{(3 R )-3-[(6-{4-[(cyclopentylamino)methyl]-3-hydroxyphenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile

According to the experimental procedure as described in Example 113, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-[(cyclopentylamino)methyl]-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 110b) gave solid (11%), then flash chromatography (dichloromethane to dichloromethane /Methanol/ammonia 100:8:1 gradient) The crude product was purified.

LRMS (m/z): 569 (M + 1) ⁺ .

^{1 H-NMR δ (300MHz,} CDCl 3): 1.37-2.05 (m, 13H), 2.12-2.32 (m, 1H), 3.08-3.27 (m, 1H), 3.32-3.64 (m, 5H), 3.87- 4.04(m,1H),4.07(d,2H), 4.25-4.42(m,1H),5.05(dd,1H),6.81-6.97(m,1H),7.09-7.22(m,1H),7.32- 7.42 (m, 1H), 7.52-7.64 (m, 2H), 8.45-8.76 (m, 3H).

Example 128 3-{(3 R )-3-[(6-{3-[(cyclopentylamino)methyl]-4-hydroxyphenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile

According to the experimental procedure as described in Example 113, 3-{( 3R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-[(cyclopentylamino)methyl]-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 109b) gave solid (11%) elute /Methanol/ammonia 100:8:1 gradient) The crude product was purified.

LRMS (m/z): 569 (M + 1) ⁺ .

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.41-1.66 (m, 4H), 1.70-1.87 (m, 5H), 1.86-2.03 (m, 5H), 2.13-2.33 (m, 1H), 3.13 3.28 (m, 1H), 3.32-3.52 (m, 3H), 3.54-3.74 (m, 1H), 3.85-4.00 (m, 1H), 4.12 (s, 2H), 4.25-4.43 (m, 1H), 4.93-5.11(m,1H),6.82-7.03(m,2H),7.33-7.42(m,1H),7.86(s,1H),7.92-8.06(m,1H),8.49-8.61(m,2H ), 8.68 (d, 1H).

Example 129 4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridine-3 -Pyrylpyrimidin-4-yl)piperidin-4-ylbenzoate

A 4M solution of hydrogen chloride in 1,4-dioxane (3.37 mL) was added to ( R )-4-((4-(6-((1-(2-cyanoethyl))piperidin-3- Amino)-5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)benzylidene)oxy)piperidine-1-carboxylic acid Tributyl ester (preparation 112, 0.46 g, 0.67 mmol) in EtOAc (10 mL)EtOAc. The solvent was evaporated and the residue was crystallisjjjjjjjjjj The solid was dissolved in water and the aqueous solution was basified by the addition of solid sodium hydrogencarbonate. The resulting precipitate was filtered and purified by flash chromatography eluting elut elut elut elut elut

LRMS (m/z): 583 (M + 1) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.56-1.99 (m, 3H), 1.99-2.15 (m, 2H), 2.15-2.31 (m, 1H), 2.37-2.53 (bs, 1H), 2.79- 2.97 (m, 2H), 3.12-3.33 (m, 2H), 3.33-3.55 (m, 2H), 3.55-3.74 (m, 2H), 3.86-4.06 (m, 1H), 4.25-4.43 (bs, 2H) ), 4.50-4.65 (d, 1H), 5.04-5.26 (m, 2H), 6.80-6.99 (m, 1H), 7.32-7.45 (t, 1H), 8.08-8.31 (s, 4H), 8.45-8.80 (m, 3H).

Example 130 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-4-[(methylamino)methyl]phenyl}-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and [2-[(methylamino)methyl]-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 113b) gave solid (9%), then flash chromatography (dichloromethane to dichloromethane /Methanol/Ammonia 85:15:1) The crude product was purified.

LRMS (m/z): 515 (M + 1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ): 1.69-2.04 (m, 6H), 2.14-2.31 (m, 2H), 2.43-2.59 (m, 3H), 3.16 (d, 1H), 3.30-3.74 (m) , 5H), 4.06 (d, 2H), 4.30 (br.s., 1H), 4.62 (d, 1H), 4.98-5.10 (m, 1H), 6.82-6.94 (m, 1H), 7.08-7.21 ( m, 1H), 7.35 (d, 1H), 7.52-7.61 (m, 2H), 8.47-8.74 (m, 3H).

Example 131 4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridine-3 -Pyrylpyrimidin-4-yl)benzoic acid 1'-methyl-1,4'-bipiperidin-4-yl ester

According to the experimental procedure as described in Example 33, 4-(6-{[(3 R )-1-(cyanoethinyl)piperidin-3-yl]amino}-5-fluoro-2-pyridyl Zyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)benzoic acid piperidin-4-yl ester (Example 129) and 1-methylpiperidin-4-one afforded a white solid (46% The crude product was then purified by flash chromatography (dichloromethane / methanol / ammonia 40: 4.0: 0.2).

LRMS (m/z): 480 (M + 1) +.

¹ H-NMR δ (300MHz, CDCl ₃ ): 1.55-2.15 (m, 12H), 2.16-2.41 (m, 4H), 2.43-2.61 (m, 2H), 2.80-3.01 (m, 3H), 3.19- 3.31 (dd, 2H), 3.32-3.55 (m, 2H), 3.55-3.75 (m, 2H), 3.85-4.06 (m, 1H), 4.24-4.43 (bs, 1H), 4.51-4.64 (d, 1H) ), 4.68-4.78(s,1H), 4.98-5.23(m,2H),6.82-7.00(m,1H),7.32-7.45(t,1H),8.03-8.34(s,4H),8.40-8.78 (m, 3H)

Example 132 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[methyl(pyridin-4-yl)amino]methyl}phenyl)-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile

According to the experimental procedure as described in Preparation 45a, 3-{(3 R )-3-[(6-chloro-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (preparation 6c) and 2-{[methyl(pyridin-4-yl)amino]methyl}-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 114b) gave solid (7%), followed by flash chromatography (2) The crude product was purified from methyl chloride to dichloromethane / methanol / ammonia 85: 15:1).

LRMS (m/z): 592 (M + 1) ⁺ .

¹ H NMR δ (300MHz, CDCl ₃ ) 1.66-2.03 (m, 4H), 2.08-2.26 (m, 1H), 3.09 (s, 3H), 3.30-3.53 (m, 2H), 3.54-3.73 (m, 2H), 3.85 (dd, 1H), 4.30 (br.s., 1H), 4.50 (d, 1H), 4.65 (br.s., 2H), 6.59-6.64 (m, 2H), 6.86 (dd, 1H), 7.06 (dd, 1H), 7.28-7.37 (m, 1H), 7.44-7.68 (m, 2H), 8.16 (br.s., 2H), 8.41-8.69 (m, 3H).

Example 133 3-{(3 R )-3-[(5-fluoro-6-{4-[(5-fluoro-2-hydroxybenzyl)amino]piperidin-1-yl}-2-pyrazole [1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

( R )-3-(3-((6-chloro-5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine- 1-yl)-3-oxopropanenitrile (preparation 6c, 0.1 g, 0.24 mmol), 4-fluoro-2-((piperidin-4-ylamino)methyl)phenol dihydrochloride (preparation A suspension of 115b, 0.14 g, 0.47 mmol) and sodium bicarbonate (0.1 g, 1.19 mmol) in N, N' -dimethylacetamide (1 mL) was stirred at 80 ° C for 24 hours. Further sodium hydrogencarbonate (0.1 g) was added and the suspension was further stirred at 80 ° C for 24 hours. An excess of water was added and the resulting residue was crystallised eluted eluted elut elut elut elut elut elut elut elut elut

LRMS (m/z): 602 (M + 1) +.

¹ H-NMR δ (300 MHz, CDCl ₃ ): 1.36-1.69 (m, 3H), 1.69-1.99 (m, 4H), 2.02-2.23 (m, 3H), 2.74-2.92 (m, 1H), 2.95- 3.20 (m, 2H), 3.28-3.44 (m, 2H), 3.44 - 3.70 (m, 3H), 3.70-3.86 (m, 2H), 4.00-4.09 (s, 2H), 4.14-4.30 (bs, 1H) ), 4.34-4.53 (m, 2H), 4.57-4.73 (m, 1H), 6.65-6.80 (m, 2H), 6.80-6.94 (m, 2H), 7.29-7.37 (m, 1H), 8.29-8.62 (m, 3H).

Example 134 3-{(3 R )-3-[(5-fluoro-6-{4-hydroxy-3-[(methylamino)methyl]phenyl}-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoxypropanenitrile

According to the experimental procedure as described in Preparation 6b from [5-(6-{[(3R)-1-(cyanoethinyl)piperidin-3-yl]amino}-5-fluoro-2-pyridyl T-butyl oxazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)-2-hydroxybenzyl]methylcarbamic acid (Preparation 117) afforded a solid (75%). Flash chromatography (dichloromethane to dichloromethane / methanol / ammonia 80: 20:1).

LRMS (m/z): 515 (M + 1) ⁺ .

¹ H NMR δ (300MHz, CDCl3): 1.72-1.98 (m, 3H), 2.21 (t, 1H), 2.54 (s, 3H), 3.15-3.26 (m, 1H), 3.38-3.50 (m, 3H) , 3.59 (s, 1H), 3.65 (d, 1H), 3.87--3.97 (m, 1H), 4.11 (s, 1H), 4.31 (br.s., 1H), 4.51-4.62 (m, 1H) , 5.01(d,1H),6.84-6.89(m,2H),7.33-7.39(m,1H),7.86(s,1H),7.95-8.04(m,1H),8.47-8.61(m,2H) , 8.61-8.75 (m, 1H).

Example 135 3-{[4-(cyclopentylamino)piperidin-1-yl]methyl}-5-(5-fluoro-6-{[(3 R )-1-ethanehydrazinopiperidine- 3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)phenol Example 136 3-((3 R )-3-{{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridine -3-ylpyrimidin-4-yl}[2-(methylamino)ethyl]amino}piperidin-1-yl)-3-oxopropanenitrile Example 137 3-{[4-(5-fluoro-6-{[(3 R )-1-ethanecarbamimidyl-3-yl][2-(methylamino)ethyl]amino}- 2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol Example 138 3-[(3 R )-3-({6-[4-(1,4'-bipiperidin-1'-ylmethyl)-3-hydroxyphenyl]-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile Example 139 2-((3 R )-3-{[5-fluoro-6-(4-{4-[2-(methylamino)ethoxy]benzyl}piperazin-1-yl)-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidine -1-yl)-2-oxoethanol Pharmacological activity In vitro JAK kinase analysis

Compounds were screened for their ability to inhibit JAKl, JAK2 and JAK3 using assays as indicated below.

The catalytic domains of human JAK1 (aa 850-1154), JAK2 (aa 826-1132), JAK3 (aa 795-1124), and Tyk2 (aa 871-1187) are expressed as N-terminal GST-fusion proteins using a baculovirus expression system and Purchased from Carna Biosciences.

The biotinylated peptide poly(GT)-biotin (CisBio) was used as a substrate to analyze the enzyme activity. The peptide concentration in the reaction 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 Difference Fluorescence Energy Transfer).

The IC ₅₀ for the compound containing the enzyme, ATP and peptide at _{8mM MOPS (pH 7.0), 2} , 0.05% β- mercaptoethanol, 0.45mg / ml BSA in the reaction mixture of each 10mM MgCl kinases are measured. The ATP concentration in the reaction was 3 μM with respect to JAK1, 0.2 μM for JAK2, 0.6 μM for JAK3 and 1.8 μM for Tyk2. The enzyme reaction was carried out for 30 minutes at room temperature. Next, the reaction was carried out with 20 μL of quenching detection buffer (50 mM HEPES, containing 0.115 μg/mL anti-phospho Tyr(PT66)-Cryptate (CisBio) and variable concentration of SA-XL665 (CisBio) to maintain a constant SA-B ratio. 0.5 M KF, EDTA 0.25 M, 0.1% (w/v) BSA, pH 7.5) stopped. Incubate for 3 hours and read on a Victor 2V fluorometer (PerkinElmer) device to read the fluorescence resonance energy transfer.

Some of the above words have the following meanings: AA: Amino acids

GST: glutathione-S-transferase

MOPS: 3-(N-morpholinyl)propane sulfonic acid

BSA: Bovine Serum Albumin

ATP: adenosine triphosphate

EDTA: ethylenediaminetetraacetic acid

HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

SA-XL665: streptavidin (biotin-binding tetrameric protein isolated from streptavidin ( Streptomyces avidinii )) XL665

Table 1 depicts the present invention in certain embodiments of the IC ₅₀ values shown compound. In Table 1, "A" represents ₅₀ value of less than 0.1μM (100nM) of the IC, "B" represents the range of IC (1000 nM) value of ₅₀ 0.1μM (100nM) to [mu] M, and C represents than 1μM (1000nM ) IC ₅₀ value.

As can be seen from Table 1, the compound of formula (I) is a potent inhibitor of JAK1, JAK2 and JAK3 kinase. Preferred compounds of the present invention has less than 1μM (1000nM) for each of the Janus kinase, preferably less than 0.5μM (500nM), more preferably less than 0.2μM (200nM) ₅₀ on the inhibition values of JAK1, JAK2 and JAK3 kinase of the IC (as The definition of the text is determined).

The invention also relates to a compound of the invention as described herein for use in the treatment of a human or animal body by therapy. The compounds of the invention intended for pharmaceutical use may be in the form of crystalline or amorphous products or mixtures thereof versus. It can be obtained, for example, in the form of a solid plug, powder or film by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

combination

The compounds of the invention may also be combined with other active compounds for the treatment of pathological conditions or diseases which are readily ameliorated by inhibition of Janus kinase.

Combinations of the invention may optionally comprise one or more additional active substances which are known to be useful in the treatment of myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphoid malignancies and solid tumors. Bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye Symptoms, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis, such as (a) dihydrofolate reductase inhibitors such as methotrexate (Methotrexate) Or CH-1504; (b) Dihydroorotate dehydrogenase (DHODH) inhibitors, such as Leflunomide, terifIunomide or International Patent Application No. WO 2008/077639 and a compound as described in WO2009/021696; (c) an immunomodulator such as Glatirameracetate (Copaxone), Laquinimod or Imiquimod (d)DNA And repair inhibitors, such as Mitoxantrone or Cladribine; (e) immunosuppressive agents, such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP); f) an anti-α4 integrin antibody, such as Natalizumab (Tysabri); (g) an α4 integrin antagonist, such as R-1295, TBC-4746, CDP-323, ELND-002, non-rass (Firategrast) or TMC-2003; (h) corticoid and glucocorticoid, such as prednisone or methylprednisolone, fluticasone, mometasone (mometasone), budesonide, ciclesonide or beta-metasone; (i) fumarate, such as BG-12; (j) anti-tumor necrosis Factor-α (anti-TNF-α), such as Infliximab, Adalimumab or Certolizumab pegol; (k) Soluble Tumor Necrosis Factor-α (TNF-α) Receptors, such as etanercept; (1) anti-CD20 (lymphocyte protein) monoclonal antibodies, such as rituximab (Rituximab), okuximab (Ocr) Elizumab), Ofatumumab or TRU-015; (m) anti-CD52 (lymphocyte protein) monoclonal antibodies, such as alemtuzumab; (n) anti-CD25 (lymphocyte protein), Such as daclizumab; (o) anti-CD88 (lymphocyte protein), such as eculizumab or pexilizumab; (p) anti-interleukin 6 receptor ( IL-6R), such as tocilizumab; (q) anti-interleukin 12 receptor (IL-12R) / interleukin 23 receptor (IL-23R), such as utek monoclonal antibody ( Ustekinumab); (r) Calcineurin inhibitors, such as cyclosporine A or tacrolimus; (s) inosine monophosphate dehydrogenase (IMPDH) inhibition Agents, such as mycophenolate mophetyl, ribavirin, mizoribine or mycophenolic acid; (t) cannabinoid receptor agonists, such as Sativex; (u) chemokine CCR1 antagonists, such as MLN-3897 or PS-031291; (v) chemokine CCR2 antagonists, such as INCB-8696; (w) necrosis factor-κB (NF-κB or NFKB) activation inhibition Agent, such as sulfasalazine (Sulf Asalazine), Iguratimod or MLN-0415; (x) adenosine A _2A agonist, such as ATL-313, ATL-146e, CGS-21680, Regadenoson or UK-432,097 (y) sphingosine-1 (S1P) phosphate receptor agonist, such as fingolimod, BAF-312 or ACT128800; (z) sphingosine-1 (S1P) lyase Inhibitors, such as LX2931; (aa) spleen tyrosine kinase (Syk) inhibitors, such as R-112; (bb) protein kinase inhibitor (PKC) inhibitors, such as NVP-AEB071; (cc) anticholinergic Inducing agents, such as tiotropium or aclidinium; (dd) beta adrenergic agonists, such as formoterol, indacaterol or argon Abediterol (LAS100977); (ee) a compound having a bifunctional muscarinic antagonist-β2 agonist activity (MABA); (ff) a histamine 1 (H1) receptor antagonist, such as a nitrogen Azelastine or ebastine; (gg) inhibitors of chemoattractant receptor homologs (CRTH2) expressed on TH ₂ cells, such as OC-459, AZD-1981, ACT-129968 , QAV-680; (hh) vitamin D derivatives, such as calcipotriol (calcipotriol) (Daivonex); (ii) anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors, such as aceclofenac, diclofenac ( Diclofenac), ibuprofen, naproxen, apribicoxib, celecoxib, cimicoxib, deracoxib, Etoricoxib, Iumiracoxib, parecoxib sodium, rofecoxib, serenocoxib-1 or valdecoxib ( Valdecoxib); (jj) anti-allergic agent; (kk) antiviral agent; (ll) phosphodiesterase (PDE) III inhibitor; (mm) phosphodiesterase (PDE) IV inhibitor, such as AN2728, E- 6005, DRM02, roflumilast or GRC-4039; (nn) dual phosphodiesterase (PDE) III/IV inhibitor; (oo) xanthine derivatives such as theophylline or cocoa beans Theobromine; (pp) p38 mitogen-activated protein kinase (p38 MAPK) inhibitor, such as ARRY-797; (qq) mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, such as ARRY-14 2886 or ARRY-438162; (rr) phosphoinositide 3-kinase (PI3K) inhibitor; (ss) interferon, including interferon beta 1a, such as Avonex from Biogen Idec, CinnoVex from CinnaGen, and Rebif from EMD Serono, And interferon beta 1b, such as Betaferon from Schering and Betaseron from Berlex; (tt) interferon alpha, such as Sumiferon MP; (uu) TrkA (NGF receptor) inhibitor, such as CT-327; (vv) T cell activity Inhibitors such as GSK2894512 (Benvitimod, WBI-1001); and (ww) iNOS inhibitors such as HL-009.

The compounds of formula (I) and combinations according to the invention are useful for the treatment of myeloproliferative disorders, leukemias, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, wherein intended use JAK inhibitors have beneficial effects such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), dry eye, uveitis, allergic conjunctivitis, Allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis, preferably asthma or chronic obstructive pulmonary disease (COPD).

The active compounds in the combination may be administered together in the form of the same pharmaceutical composition or as separate compositions which are intended to be administered separately, simultaneously, concomitantly or sequentially by the same or different routes.

All active agents are expected to be administered at the same time or in close proximity. Alternatively, one or two active agents may be administered in the morning and other active agents may be administered later in the day. Or in another instance, one or two active agents may be administered twice a day and the other active agents are administered once a day, either as one of the two doses administered one day, either simultaneously or separately. Preferably, at least two and more preferably all of the active agents will be administered together at the same time. Preferably, at least two and more preferably all of the active agents will be administered as a blend.

The invention also relates to a combination of a compound of the invention, together with one or more other therapeutic agents, for the treatment of pathological conditions or diseases which are readily ameliorated by inhibition of Janus kinase (JAK), in particular the pathological condition Or the disease is selected from the group consisting of a myeloproliferative disorder, leukemia, a lymphoid malignant disease, and a solid tumor; bone marrow and organ transplant rejection; an immune-mediated disease and an inflammatory disease; more specifically, the pathological condition or disease is selected from the group consisting of Rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

The invention also encompasses the use of a compound of the invention in combination with one or more other therapeutic agents for the manufacture of a formulation or medicament for the treatment of such diseases.

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibition of Janus kinase (JAK), wherein the pathological condition or disease is selected from the group consisting of myeloproliferative disorders, leukemia, lymphoid malignancy Diseases and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, the pathological conditions or diseases are selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease , dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis; the method comprising administering a therapeutically effective amount of a compound of the invention in one or more A combination of other therapeutic agents.

The active compound of the combination of the invention may be administered by any suitable route, depending on the nature of the condition to be treated, for example, orally (in the form of a syrup, lozenge, capsule, buccal, controlled release formulation, fast dissolving formulation, etc.) ); by surface (in the form of a cream, ointment, lotion, nasal spray or aerosol); by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, solution, In the form of a dispersion or the like, preferably by inhalation.

The active compound in the combination (i.e., the pyrazolopyrimidin-2-yl derivative of the present invention) and other optional active compounds may be used together with the same pharmaceutical composition or by the same or different routes, separately, simultaneously, Co-administered in the form of different compositions that are accompanied or sequentially administered.

An embodiment of the invention consists of a kit of sub-packages comprising a pyrazolopyrimidin-2-yl derivative of the invention, together with simultaneous, parallel, separate or sequential use in combination with another active compound In the specification, the other active compound is suitable for the treatment of myeloproliferative disorders, leukemia, lymphoid malignant diseases and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically for the treatment of rheumatoid joints Inflammation, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

Another embodiment of the invention consists of a package comprising a pyrazolopyrimidin-2-yl derivative of the invention and another active compound, which is useful for the treatment of myeloproliferative disorders, leukemia, lymph Malignant diseases and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveal Inflammation, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

Pharmaceutical composition

Pharmaceutical compositions according to the invention comprise a compound of the invention together with a pharmaceutically acceptable diluent or carrier.

The term pharmaceutical composition, as used herein, refers to one or more compounds described herein or a physiologically/pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, deuterated derivative thereof or Prodrugs and other chemical components (such as physiologically/pharmaceutically acceptable carriers and excipients) mixture. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

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

The invention further provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier in association with one or more other therapeutic agents for the treatment of pathological conditions which are readily ameliorated by inhibition of Janus kinase (JAK) A disease or disease, such as a disease as described previously.

The invention also relates to a pharmaceutical composition of the invention for use in the treatment of a pathological condition or disease which is readily ameliorated by inhibition of Janus kinase (JAK), in particular wherein the pathological condition or disease line is selected from the group consisting of myelosynthesis Sexual disorders, leukemias, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more specifically, the pathological conditions or diseases are selected from rheumatoid arthritis, multiple Sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis. The invention also encompasses the use of the pharmaceutical compositions of the invention for the manufacture of a medicament for the treatment of such diseases.

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibition of Janus kinase (JAK), wherein the pathological condition or disease is selected from the group consisting of myeloproliferative disorders, leukemia, lymphoid malignancy Diseases and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, the pathological conditions or diseases are selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease , Dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis; the method comprises administering a therapeutically effective amount of a pharmaceutical composition of the invention.

The invention also provides a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, as the active ingredient together with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise from 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition, depending on the nature of the formulation and whether further dilution is desired prior to application. Preferably, the compositions are prepared in a form suitable for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation will be 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 Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

The pharmaceutically acceptable excipients which are admixed with the active compounds or salts of such compounds to form the compositions of the invention are well known per se, and the excipients which are employed in particular depend in particular on the intended method of administration of such compositions. Examples of excipients, without limitation, include calcium carbonate, calcium phosphate, various sugar and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Additional suitable carriers for formulations of the compounds of the invention can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

i) Oral investment

The compounds of the invention can be administered orally (administered orally; per os (Latin)). Oral administration involves swallowing such that the compound is absorbed from the intestine and delivered to the liver via the portal circulation (hepatic first pass metabolism) and eventually into the gastrointestinal (GI) tract.

The composition for oral administration may take the form of a lozenge, a delayed lozenge, a sublingual lozenge, a capsule, an inhalation aerosol, an inhalation solution, a dry powder inhalation or a liquid preparation such as a mixture, a solution, an elixir, a syrup or a suspension. The liquids all contain the compounds of the invention; such formulations can be made by methods well known in the art. The active ingredient can also be presented in the form of a bolus, elixirs or paste.

When the composition is in the form of a lozenge, any of the pharmaceutical carriers conventionally used in the preparation of solid formulations can be employed. Examples of such carriers include magnesium stearate, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.

The lozenge can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be compressed in a free-flowing form (eg, powder or granules) by mixing in a suitable machine, if necessary, in admixture with binders, lubricants, inert diluents, lubricants, surfactants or dispersing agents. The active ingredient is prepared.

Molded lozenges can be made by molding in a suitable machine a mixture of powdered compound moistened with an inert liquid diluent. The lozenge may optionally be coated or scored and may be formulated such that a slow or controlled release of the active ingredient therein is provided.

For lozenge dosage forms, the dosage may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form, depending on the dosage. In addition to the drug, the tablet usually also contains a disintegrant. Examples of the disintegrant include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crosslinked povidone, polyvinylpyrrolidone, methylcellulose. Microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% to 25% by weight of the dosage form, preferably from 5% to 20% by weight.

Adhesives are generally used to impart cohesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Prime. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystals Cellulose, starch and calcium hydrogen phosphate dihydrate. Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80; and glidants such as ceria and talc. When present, the amount of surfactant is typically from 0.2% to 5% by weight of the tablet, and the glidant is typically from 0.2% to 1% by weight of the tablet.

Tablets also typically contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant is usually present in an amount of from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking Agent.

Exemplary lozenges contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to About 10% by weight of the lubricant. The tablet blend can be compressed directly or by roller to form a tablet. The portion of the tablet blend or blend may alternatively be wet granulated, dry granulated or melt granulated prior to tableting; melt condensed; or extruded. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

Tablet formulations are discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", H. Lieberman and L. Lachman, Marcel Dekker, N. Y., 1980.

When the composition is in the form of a capsule, any conventional encapsulation is suitable, such as the use of the carriers mentioned above in hard gelatin capsules. When the composition is in the form of a soft gelatin capsule, any conventional pharmaceutical carrier for preparing a dispersion or suspension, such as an aqueous jelly, cellulose, citrate or oil, may be considered and incorporated into a soft gelatin capsule. .

Solid formulations for oral administration can be formulated for immediate release and/or modified release. Modulated release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release.

Suitable modulating release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release techniques, such as high energy dispersion and permeability and coated particles, can be found in Verma et al. Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing ingots to achieve controlled release is described in WO 00/35298. The disclosures of these references are hereby incorporated by reference in their entirety.

Liquid formulations include suspensions, solutions, syrups and elixirs. The formulations may be used as a filler in soft or hard capsules, and typically include a carrier (eg, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more Emulsifiers and / or suspensions. The solution can be a soluble salt or other derivative of the active compound and an aqueous solution such as sucrose (to form a syrup). The suspension may comprise the insoluble active compound of the invention or a pharmaceutically acceptable salt thereof and water, together with a suspending or flavouring agent. Liquid formulations can also be prepared by reconstitution of a solid (eg, a sachet).

Ii) oral mucosal administration

The compounds of the invention may also be administered via the oral mucosa. In the oral mucosal cavity, drug delivery is categorized into three categories: (a) sublingual delivery, which is the systemic delivery of the drug as a mucosa lining the mouth, and (b) buccal delivery, which is the drug as a cheek The lining of the mucosa (buccal mucosa) is administered, and (c) the local delivery, which is the delivery of the drug into the oral cavity.

Pharmaceutical products intended for administration via the oral mucosa may be designed using mucoadhesives, fast dissolving lozenges, and solid mouth lozenge formulations using one or more mucoadhesive (bioadhesive) polymers (such as hydroxyl groups). Propylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal penetration Enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulfate, and others) are formulated.

Iii) Inhalation administration

The compounds of the invention may also be inhaled, typically in the form of a dry powder from a dry powder inhaler (alone, in the form of a mixture, for example in the form of a dry blend with lactose, or in the form of a mixed component granule, for example with a phospholipid, such as Phospholipid choline) form or in the form of an aerosol spray from a pressurized container, pump, nebulizer, nebulizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist) or aerosolizer, using or It is not suitable for administration with a propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive such as polyglucosamine or cyclodextrin.

The dry powder composition for delivery to the lung via inhalation can be presented, for example, in the form of capsules and cartridges such as gelatin or in the form of a blister such as laminated aluminum foil for use in an inhaler or insufflator. Formulations typically contain a powder mix for inhalation of the compound of the present invention, and a suitable powder base (carrier material) such as lactose or starch. Lactose is preferably used. Each capsule or cartridge may generally contain from 0.001 to 50 mg, more preferably from 0.01 to 5 mg, of the active ingredient or an equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient can be presented without the need for excipients.

The formulation of the formulation may be suitable for unit dose or multiple dose delivery. In the case of multiple dose delivery, the formulation can be metered in or measured in use. Dry powder inhalers are therefore classified into three groups: (a) a single dose, (b) multiple unit doses, and (c) multiple dose devices.

For the first type of inhaler, a single dose has been weighed by the manufacturer into a small container, which is primarily a hard gelatin capsule. gum The balloon must be taken by a separate box or container and inserted into the region of the opening of the inhaler. Secondly, the capsule must be opened or perforated by a pin or cutting blade to allow a portion of the inspiratory flow to pass through the capsule for powder entrainment or to expel the powder from the capsule through such perforations during inhalation by means of centrifugal force. After inhalation, the empty capsule must be removed from the inhaler again. In general, the decomposition of the inhaler is necessary to insert and remove the capsule, which is a difficult and cumbersome operation for some patients.

Other disadvantages associated with the use of hard gelatin capsules for inhalation of powders are (a) poor protection against moisture absorption from the surrounding air, and (b) due to openings or perforations after the capsule has been previously exposed to extreme relative humidity. The problem is that it causes breaks or dents, and (c) possible inhalation of the capsule fragments. Furthermore, for a variety of capsule inhalers, incomplete drainage has been reported (e.g., Nielsen et al., 1997).

Some capsule inhalers have cartridges from which individual capsules can be transferred to a receiving chamber where perforation and evacuation occur as described in WO 92/03175. Other capsule inhalers have rotating cartridges having capsule chambers that are alignable with the air conduit for dose ejection (e.g., WO 91/02558 and GB 2242134). It comprises a plurality of unit dose inhalers, together with a type of inhaler, having a limited number of spare unit doses on the disc or strip.

The blister inhaler provides better moisture protection for the medicament than a capsule inhaler. The powder is accessed by perforating the closure and the bulb foil or by stripping the closure foil. When a blister strip is used instead of a disc, the number of doses can be increased, but this does not facilitate the patient to replace the empty strip. Therefore, the equipment The implant can typically be provided with an incorporated dosage system that includes techniques for transporting the strip and opening the blister pocket.

Multi-dose inhalers do not contain pre-measured amounts of powder formulations. It consists of a relatively large container and a dose measuring component that must be operated by the patient. The container contains a plurality of doses that are individually separated from the bulk powder by volumetric displacement. There are a variety of dose measuring components, including rotatable membranes (eg, EP0069715) or discs (eg, GB 2041763, EP 0424790, DE 4239402, and EP 0674533), rotatable cylinders (eg, EP 0166294, GB 2165159, and WO 92/09322) and Rotatable frustums (e.g., WO 92/00771) each have a chamber that must be filled with powder from the container. Other multi-dose devices have measurement sliders (eg, US 5201308 and WO 97/00703) or measurement plungers that have a volume of powder moved from the container to the delivery chamber or Partial grooves or peripheral grooves of an air duct (for example, EP 0505321, WO 92/04068 and WO 92/04928), or measuring sliders such as Genuair® (formerly known as Novolizer SD2FL), which are described in the following patent application Medium: WO97/000703, WO03/000325 and WO2006/008027.

Repeated dose measurement is a major problem for multi-dose inhaler devices.

Powder formulations must exhibit good and stable flow characteristics because the filling of the dose measuring cup or chamber is typically under the influence of gravity.

For pre-loaded single dose and multiple unit dose inhalers, the dose measurement accuracy and repeatability can be guaranteed by the manufacturer. Multi-dose inhalers, on the other hand, can contain a higher number of doses The number of treatments to start with is generally lower.

Since the inspiratory air flow in the multi-dose device typically passes directly through the dose measuring chamber, and since the bulky and robust dose measuring system of the multi-dose inhaler cannot be agitated by the inhaled air flow, the powder material is simply self-cavity The chamber is entrained and only a small amount of deagglomeration is produced during discharge.

Therefore, an independent disintegration member is necessary. However, in practice, it is not always part of the inhaler design. Due to the high number of doses in the multi-dose device, it is necessary to minimize the powder adhering to the inner walls of the air conduit and the depolymerization structure, and/or it is necessary to periodically clean these components so as not to affect the device. Residual dose in the middle. Some multi-dose inhalers have disposable drug containers that can be replaced after a prescribed number of doses have been taken (e.g., WO 97/000703). For such semi-permanent multi-dose inhalers with disposable drug containers, the requirements for preventing drug accumulation are particularly stringent.

In addition to the application via a dry powder inhaler, the compositions of the invention may be administered in the form of an aerosol which is operated via a propellant gas or by means of a so-called atomizer, whereby the solution of the pharmacologically active substance can be at a high pressure The lower spray is to obtain a mist of the inhalable particles. The advantage of these nebulizers is that the use of propellant gases is completely dispensed with. The nebulizer is described in, for example, PCT Patent Application No. WO 91/14468 and WO 97/12687, the disclosure of which is incorporated herein by reference.

The spray composition delivered to the lung by inhalation can be formulated, for example, as an aqueous solution or suspension or aerosol delivered by a pressurized pack (such as a metered dose inhaler) using a suitable liquefied propellant. Suitable for inhalation The aerosol composition can be a suspension or solution and usually contains the active ingredient and a suitable propellant, such as a fluorocarbon or a hydrogen-containing chlorofluorocarbon or a mixture thereof, especially a hydrofluorocarbon such as dichlorodifluoromethane, Trichlorofluoromethane, dichlorotetrafluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof. Carbon dioxide or a gas suitable gas can also be used as a propellant.

The aerosol composition can be excipient free or can optionally contain additional formulation excipients well known in the art, such as surfactants (such as oleic acid or lecithin) and cosolvents (e.g., ethanol). The pressurized formulation will typically be held in a canister (eg, an aluminum can) that is closed with a valve (eg, a metering valve) and assembled into an actuator that is provided with a mouthpiece.

The dosage of the administered drug by inhalation requires a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually from 1 to 10 μm, preferably from 2 to 5 μm. When inhaled into the small airway, particles larger than 20 μm are usually too large. To achieve these particle sizes, the particles of the active ingredient produced can be reduced in size by conventional means, such as by micronization. The desired portion can be separated by air classification or screening. Preferably, the particles will be crystalline.

It is difficult to achieve high dose repetition with micronized powder because the micronized powder has poor fluidity and tends to coalesce. In order to improve the efficiency of the dry powder composition, the particles should be large in the inhaler but should be small when discharged into the respiratory tract. Therefore, excipients such as lactose or glucose are usually used. In the present invention, the particle size of the excipient will generally be much larger than the inhaled medicament. When the excipient is lactose, it will typically be studied The milled lactose is present, preferably crystalline alpha lactose monohydrate.

The pressurized aerosol composition will typically be filled into a canister having a valve, particularly a metering valve. The canister may optionally be coated with a plastic material such as the fluorocarbon polymer described in W096/32150. The canister will be fitted in an actuator adapted for buccal delivery.

Iv) nasal mucosal administration

The compounds of the invention may also be administered via the nasal mucosa.

Typical compositions for nasal mucosal administration are typically applied by metered, atomized jet pumps and in an inert medium combined with conventional excipients such as buffers, antimicrobials, tonicity modifiers and viscosity modifiers as needed. In the form of a solution or suspension in a reagent such as water.

v) parenteral administration

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

The parenteral formulation is typically an aqueous solution which may contain excipients such as salts, carbohydrates and buffers (preferably to a pH of from 3 to 9), but for some applications it may be more suitably formulated as sterile. An aqueous solution or a dry form intended to be combined with a suitable vehicle such as sterile, pyrogen free water.

Preparation of parenteral formulations can be readily accomplished under sterile conditions, for example by lyophilization, using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compound of the invention for preparing a parenteral solution can be It is increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancers.

Formulations for parenteral administration can be formulated for immediate release and/or modified release. Modulated release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release. Thus, the compounds of the invention can be formulated as solid, semi-solid or shaken liquids for administration as an implanted reservoir that provides controlled release of the active compound. Examples of such formulations include drug coated stents and PGLA microspheres.

Vi) surface casting

The compounds of the invention may also be administered topically to the skin or mucosa, i.e., transdermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, spreaders, dressings, foams, films, dermal patches, wafers, implants, sponges. , fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Infiltration enhancers can be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 Finnin, and Morgan (October 1999). Other means of surface administration include delivery by electroporation, iontophoresis, ultrasonic drug penetration therapy, ultrasonic electroosmosis, and microneedle or needle-free injection.

Formulations for topical administration can be formulated for immediate release and/or modified release. Modulated release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release.

Vii) rectal/vaginal administration

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary or enemas. Cocoa butter is a traditional suppository base. However, various alternatives can be used as appropriate. Formulations for rectal/vaginal administration can be formulated for immediate release and/or modified release. Modulated release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release.

Viii) eye cast

The compounds of the invention may also be administered directly to the eye or ear in the form of micron sized suspensions or drops of solution in isotonic pH adjusted sterile physiological saline. Other formulations suitable for ophthalmic and otic administration include ointments, biodegradable (eg, absorbable gel sponges, collagen), and non-biodegradable (eg, polyoxygenated) implants, wafers, lenses, and microparticles. Or a vesicle system (such as a vesicle or liposome). Polymers (such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose)) or heteropolysaccharide polymers (such as knotting Gum) can be incorporated with a preservative such as benzalkonium chloride. The formulations can also be delivered by iontophoresis.

Formulations for eye/ear administration can be formulated for immediate release and/or modified release. Modulatory release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, or stylized release.

Ix) Other technologies

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve the solubility, dissolution rate, taste masking of the compounds used in any of the above modes of administration, Biological availability and/or stability.

The amount of active compound administered will depend on the condition being treated The severity of the individual, disorder or condition, rate of administration, treatment of the compound, and judgment of the prescribing physician. However, the effective dose is typically in the range of from 0.01 to 3000 mg, more preferably from 0.5 to 1000 mg, of the active ingredient per day or an equivalent amount of its pharmaceutically acceptable salt. The daily dose can be administered in one or more treatments per day, preferably from 1 to 4 treatments.

Preferably, the pharmaceutical compositions of the invention are formulated in a form suitable for oral, inhalation or topical administration, especially preferably in the form of oral or inhalation administration.

The pharmaceutical formulation is preferably presented in unit dosage form and may be prepared by any methods known in the art of pharmacy.

Preferably, the composition is in unit dosage form, such as a lozenge, capsule or metered aerosol dose, such that the patient can administer a single dose.

Of course, the amount of each active substance that is required to achieve a therapeutic effect will vary depending on the particular active substance, the route of administration, the individual being treated, and the particular condition or disease being treated.

The following preparation forms are cited as examples of formulations:

Formulation instance

Formulation Example 1 (oral suspension)

Formulation Example 2 (hard gelatin capsule for oral administration)

Formulation Example 3 (gelatin cartridge for inhalation)

Formulation Example 4 (Formulation for DPI inhalation)

Formulation Example 5 (for MDI formulation)

Modifications that do not affect, modify, alter or modify the basic aspects of the described compounds, combinations or pharmaceutical compositions are included in the scope of the invention Inside.

Claims (27)

a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof or an N-oxide or a stereoisomer or a deuterated derivative, Wherein X is selected from the group consisting of -N- and -CR ^c - groups, and G ₁ is selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, and at least one selected from the group consisting of a monocyclic 5-8 membered heteroaryl group of a hetero atom of O, S and N and a group of monocyclic 5-8 membered heterocyclic groups containing at least one hetero atom selected from O, S and N, wherein The aryl, cycloalkyl, heteroaryl and heterocyclic groups are unsubstituted or one or more selected from the group consisting of a halogen atom, a hydroxyl group, a -CHO group, a C _1-4 alkyl group, a C _1-4 sulfanyl group Substituting a substituent of a C _1-2 hydroxyalkyl group, a di(C _1-2 alkyl)amino-C _1-4 alkyl group and a -NR'-SO ₂ -R" group, and the L ₁ group is selected from - (CH ₂ ) _(0-1) -, -O-, -NR ^x -(CH ₂ ) _(0-1) - a group consisting of groups wherein R ^x is selected from a hydrogen atom and optionally - CH ₂ ) _{(0-2) a} group of C _1-2 alkyl groups substituted by a group of NR'R"- groups, and L ₂ is selected from -(CH ₂ ) _p -, -(CH ₂ )-NR-, a group consisting of -NR-(CH ₂ )-, -O-(CH ₂ ) _(0-2) , -C(O)O-, -S-, and -NR- groups, wherein R represents a hydrogen atom or an optionally selected -NR'R "group and a phenyl group substituted with C _1-4 alkyl, wherein the phenyl group optionally taken based hydroxy , R ¹ selected from the group consisting of a hydrogen atom, an optionally substituted -NR'R "group of a straight-chain or branched C _1-4 alkyl, C _5-8 monocyclic aryl, monocyclic C _3-8 cycloalkyl An alkyl group, a monocyclic or bicyclic 5-14 membered heteroaryl group containing at least one hetero atom selected from O, S and N, and a monocyclic or bicyclic ring containing at least one hetero atom selected from O, S and N a group of 14 membered heterocyclic groups, wherein the aryl, cycloalkyl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: a halogen atom, a hydroxyl group, a C _1-6 alkyl group of a straight or branched chain, a C _1-6 hydroxyalkyl group of a straight or branched chain, a C _1-4 alkoxy group of a straight or branched chain, an (O) _(0-1) (CH ₂ ) _(0-3) -NR'R" group, -CO-OR ^d group, -CH ₂ -R ^e group, containing at least one selected from the group consisting of O, S and N a heterocyclic monocyclic 5-8 membered heterocyclic group and a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, wherein the heterocyclic group and the heteroaryl group are independently regarded Substituting one or more substituents selected from the group consisting of a C _1-2 alkyl group, a —C(O)—(C _1-2 alkyl) group, and a —NR′R′ group; R ² is selected from the group consisting of a hydrogen atom, a halogen atom and a C _1-4 alkyl group, and R ³ is selected from a hydrogen atom, a C _1-4 alkyl group, and --(CH ₂ ) _(2-4) NR'. a group of R"-groups, the G ₂ group being selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, a single ring containing at least one hetero atom selected from O, S and N a group of 5-8 membered heteroaryl groups and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the aryl group, cycloalkyl group, heteroaryl group and The heterocyclic group is unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-2 hydroxyalkyl group. , -NR'R" group and group of formula (a): Wherein L ₃ represents a direct bond, a -CO- group or a -C(O)O- group, and R ⁴ is selected from a hydroxyl group, a -(CH ₂ ) _(0-1) -CN group, a -CF ₃ group a C _1-4 alkyl group of a group, a straight chain or a branched chain, a C _1-4 alkoxy group of a straight or branched chain, a C _1-4 hydroxyalkyl group of a straight or branched chain, and a C _1-4 alkylamine a group consisting of a group wherein the alkyl group and the hydroxyalkyl group are optionally substituted by one or more methyl groups, and R ^a and R ^{b are} independently selected from the group consisting of a hydrogen atom, a hydroxyl group, and a C _1-4 alkyl group. a group, or R ^a and R ^b together with the carbon atom to which they are attached, form a C _3-6 cycloalkyl group or a 3-5 membered heterocyclic group containing at least one hetero atom selected from N, O and S, R ⁵ It is selected from the group consisting of a hydrogen atom and a linear or branched C _1-4 alkyl group, and R ^c is selected from a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, and a C _5-8 group. a group consisting of an aryl group, a 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, and a -NR'R" group, wherein the heteroaryl group is optionally subjected to one or more Substituted by a substituent of a group consisting of a halogen atom and a C _1-4 alkyl group, R ^d represents one or more selected from phenyl, methyl and -NR'R, as needed. a substituted or substituted C _1-4 alkyl group, or R ^d represents a monocyclic ring containing at least one hetero atom selected from O, S and N, optionally substituted by a C _1-2 alkyl group. a 5- to 8-membered heterocyclic group, the R ^{e being} selected from the group consisting of a monocyclic C _5-8 aryl group and a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, The cyclic rings are optionally substituted by one or more substituents selected from the group consisting of a C _1-4 alkyl group of a hydroxyl group, a straight chain or a branched chain, and a -CF ₃ group, and R' and R" independently represent a hydrogen atom. , C _1-4 alkyl or C _3-6 cycloalkyl, or R' and R" together with the nitrogen atom to which they are attached, form, as desired, one or more additional heteroatoms selected from N, S and O and The 4-6 member-containing N heterocyclic group substituted with a dimethylamino group as needed, n, m and q independently have a value of 0 or 1, and p has a value of 0, 1, or 2. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein the X is selected from the group consisting of -N- and -CR ^a group of ^c -groups, the G ₁ group being selected from the group consisting of a monocyclic C _5-8 aryl group, a monocyclic C _3-8 cycloalkyl group, a monocyclic ring containing at least one hetero atom selected from O, S and N a group of -8 membered heteroaryl groups and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the aryl group, cycloalkyl group, heteroaryl group and hetero group The ring group is unsubstituted or one or more selected from the group consisting of a halogen atom, a hydroxyl group, a -CHO group, a C _1-4 alkyl group, a C _1-2 hydroxyalkyl group, a di(C _1-2 alkyl)amino group. Substituted by a substituent of -C _1-4 alkyl and -NR'-SO ₂ -R" groups, L ₁ is selected from -(CH ₂ ) _(0-1) -, -O-, -NR ^x -( CH ₂ ) _(0-1) - a group consisting of groups wherein R ^x is selected from C _1- substituted by a hydrogen atom and optionally a -(CH ₂ ) _(0-2) NR'R"- group alkyl group consisting of _2, L ₂ selected from the group consisting of _{- (CH 2) p -,} - (CH 2) -NR -, - O- (CH 2) (0-2), -S- and -NR- a group consisting of groups wherein R represents a hydrogen atom or optionally selected from -NR'R" a C _1-4 alkyl group substituted with a group and a phenyl group, wherein the phenyl group is optionally substituted by a hydroxyl group, and R ¹ is selected from a linear chain substituted with a hydrogen atom and optionally substituted by a -NR'R" group Or a branched chain C _1-4 alkyl, monocyclic C _5-8 aryl, monocyclic C _3-8 cycloalkyl, monocyclic or bicyclic 5 containing at least one hetero atom selected from O, S and N a 14-membered heteroaryl group and a group consisting of a monocyclic or bicyclic 5-14 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the aryl group, cycloalkyl group, heteroaryl group And the heterocyclic group are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C _1-6 alkyl group, a straight chain or a branched chain. C _1-6 hydroxyalkyl, straight or branched C _1-4 alkoxy, -(O) _(0-1) (CH ₂ ) _(0-3) -NR'R" group, - a CO-OR ^d group, a -CH ₂ -R ^e group, a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N and containing at least one selected from the group consisting of O, S and N a heterocyclic monocyclic 5-8 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group are independently selected from one or more selected from C _1- Substituted by a substituent of a group consisting of ₂ alkyl groups and -NR'R'groups; R ² is selected from the group consisting of a hydrogen atom, a halogen atom and a C _1-4 alkyl group, and R ³ is selected from a hydrogen atom, a group consisting of C _1-4 alkyl and --(CH ₂ ) _(2-4) NR'R"- groups, G ₂ is selected from monocyclic C _5-8 aryl, monocyclic C _3-8 a cycloalkyl group, a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, and a monocyclic 5-8 membered heterocyclic ring containing at least one hetero atom selected from O, S and N a group of radical groups wherein the aryl, cycloalkyl, heteroaryl and heterocyclic groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, C _{1 -4} alkyl, C _1-4 alkoxy, C _1-2 hydroxyalkyl, -NR'R" groups and groups of formula (a): Wherein L ₃ represents a direct bond, a -CO- group or a -C(O)O- group, and R ⁴ is selected from a hydroxyl group, a -(CH ₂ ) _(0-1) -CN group, a -CF ₃ group a C _1-4 alkyl group of a group, a straight chain or a branched chain, a C _1-4 alkoxy group of a straight or branched chain, a C _1-4 hydroxyalkyl group of a straight or branched chain, and a C _1-4 alkyl alkane a group consisting of a group wherein the alkyl group and the hydroxyalkyl group are optionally substituted by one or more methyl groups, and R ^a and R ^b are independently selected from the group consisting of a hydrogen atom, a hydroxyl group, and a C _1-4 alkyl group. a group, or R ^a and R ^b together with the carbon atom to which they are attached, form a C _3-6 cycloalkyl group or a 3-5 membered heterocyclic group containing at least one hetero atom selected from N, O and S, R ⁵ is selected from the group consisting of a hydrogen atom and a linear or branched C _1-4 alkyl group, and R ^c is selected from a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _{5 - 8} aryl group, containing at least one selected from the group consisting of O, S and N heteroatom of 5-8 membered heteroaryl and -NR'R "group, wherein the heteroaryl group is optionally substituted by one or more lines One selected from the group consisting of a halogen atom and a C _1-4 alkyl group, and R ^d represents one or more selected from phenyl, methyl and -N, as desired. R'R "substituents of straight or branched C _1-4 alkyl, R ^e selected from the group consisting of C _5-8 monocyclic aryl group and containing at least one heteroatom selected from O, S and N heteroatom of a group of monocyclic 5-8 membered heteroaryl groups which are optionally subjected to one or more C _1-4 alkyl groups and -CF ₃ groups selected from hydroxyl, straight or branched chains. Substituent substituent, R' and R" independently represent a hydrogen atom, a C _1-4 alkyl group or a C _3-6 cycloalkyl group, or R' and R" together with the nitrogen atom to which they are attached form one or a plurality of 4-6 member-containing N heterocyclic groups selected from the group consisting of additional heteroatoms selected from N, S and O and optionally substituted with a dimethylamino group, n, m and q independently having a value of 0 or 1, p Has a value of 0, 1, or 2. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein X represents a -CR ^c - group, wherein R ^c is selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a phenyl group, a 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, and -NR' a group consisting of R" groups, wherein the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of a halogen atom and a C _1-4 alkyl group, and R' and R" are independently Represents a hydrogen atom or a C _1-4 alkyl group, preferably R ^c is selected from the group consisting of a hydrogen atom, a C _1-2 alkyl group, a C _1-2 alkoxy group, a phenyl group, and a —NR′R′ group. Group, wherein R' and R" independently represent a hydrogen atom or a C _1-2 alkyl group. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein R ^c is selected from the group consisting of a hydrogen atom and a methyl group. The group is preferably a hydrogen atom. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative thereof, wherein G ₁ is selected from the group consisting of a single ring a C _5-8 aryl group, a monocyclic 5-8 membered heteroaryl group containing at least one hetero atom selected from O, S and N, and a monocyclic ring 5-8 containing at least one hetero atom selected from O, S and N a group consisting of heterocyclic groups in which the aryl, heteroaryl and heterocyclic groups are unsubstituted or one or two selected from a halogen atom, a hydroxyl group, a C _1-4 alkyl group, C _1-2 Substituted by a hydroxyalkyl group and a substituent of the -NR'-SO ₂ -R" group. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein G ₁ is selected from the group consisting of phenyl, pyridyl and a group consisting of at least one monocyclic 6-membered heterocyclic group selected from the group consisting of O and N hetero atoms, wherein the phenyl, pyridyl and heterocyclic groups are unsubstituted or one or two selected from halogen atoms And a substituent of a C _1-2 alkyl group. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein G ₁ is selected from the group consisting of phenyl, pyridyl and Group of piperazinyl groups. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative thereof, wherein L ₁ is selected from the group consisting of - ( CH ₂ ) _(0-1) -, -NR ^x -(CH ₂ ) ₍₁₎ - a group consisting of groups wherein R ^x is selected from a hydrogen atom and optionally via -(CH ₂ ) _{(0-2 a} group of C _1-2 alkyl groups substituted with a NR'R"- group, wherein R' and R" independently represent a hydrogen atom or a methyl group, preferably L ₁ is selected from a direct bond and -NR ^x -(CH ₂ ) ₍₁₎ - a group consisting of groups wherein R ^x is selected from the group consisting of a hydrogen atom and a methyl group. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein L ₁ represents a direct bond. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, according to any one of the preceding claims, wherein L ₂ is selected from - ( a group of CH ₂ ) _p -, -O-(CH ₂ ) _(0-2) - and -NR- groups, wherein R represents a hydrogen atom or, if desired, a C substituted with a -NR'R"- group _{a 1-2} alkyl group, wherein p has a value of 0 or 1, and wherein R' and R" independently represent a hydrogen atom or a methyl group, preferably L ₂ is selected from -(CH ₂ ) _p -, -O-( CH ₂ ) ₂ - a group of constituents, where p has a value of 0 or 1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, according to any of the preceding claims, wherein R ¹ is selected from a hydrogen atom a C _1-2 alkyl group substituted with a -NR'R" group, a monocyclic C _5-8 aryl group, and a 5- or 14-membered heteroaryl group containing at least one heterocyclic ring selected from N. a group consisting of a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from N, wherein the aryl, heteroaryl and heterocyclic groups are unsubstituted or substituted by one or more Substituted, the substituents are selected from a C _1-5 alkyl group having a halogen atom, a hydroxyl group, a linear or branched chain, a linear C _1-2 alkoxy group, -(O) _(0-1) (CH ₂ ) _{(0-3) a} group consisting of a -NR'R" group, a -CO-OR ^d group, and a -CH ₂ -R ^e group, wherein R ^d represents one or more selected from a methyl group and optionally -NR'R "substituents of straight or branched C _1-4 alkyl, R ^e selected from the group consisting of C _5-8 monocyclic aryl group and containing at least one heteroatom selected from N atoms of a monocyclic 5 a group of -8 membered heteroaryl groups, which are optionally selected from one or more selected from straight chain or divided Chain C _1-4 alkyl, and -CF ₃ group of substituents, R 'and R "are independently represents a hydrogen atom or a methyl group, or R' and R" together with the nitrogen atom to which they are attached form an optionally together with A 4-6 member-containing N heterocyclic group containing one or more additional heteroatoms selected from N, S and O and optionally substituted with a dimethylamino group. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein R ¹ is selected from a hydrogen atom, a monocyclic C _a group consisting of a _5-8 aryl group and a monocyclic 5-7 membered heterocyclic group containing one or two nitrogen atoms as a hetero atom, wherein the aryl and heterocyclic groups are unsubstituted or one or more Selecting a straight or branched C _1-5 alkyl group, a linear C _1-2 alkoxy group, a -(O)(CH ₂ ) ₂ -NR'R" group, and a -NR'R"- group Substituents of the constituent groups are substituted, wherein R' and R" independently represent a hydrogen atom or a methyl group. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein R ¹ is selected from the group consisting of phenyl and one or a group of two nitrogen atoms as a monocyclic 6-7 membered heterocyclic group of a hetero atom, wherein the phenyl and heterocyclic groups are selected from a group consisting of methyl, -(O)(CH ₂ ) ₂ -NR The substituent of the group consisting of the 'R' group and the -NR'R"- group is substituted, wherein R' and R" both represent a methyl group. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative thereof, wherein R ² is selected from a hydrogen atom, or a pharmaceutically acceptable salt or oxime derivative thereof. And a group consisting of halogen atoms, preferably a halogen atom, more preferably a fluorine atom. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein R ³ is selected from a hydrogen atom, or a pharmaceutically acceptable salt or solvate thereof. a group of C _1-4 alkyl and -(CH ₂ ) _(2-4) NR'R"- groups, wherein R' and R" are as defined in claim 1 or 2, preferably R ³ is selected from a hydrogen atom and a -methyl group, and more preferably R ³ represents a hydrogen atom. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein R ⁵ is selected from a hydrogen atom, or a pharmaceutically acceptable salt or solvate thereof. And a group of methyl groups, preferably a hydrogen atom. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative thereof, wherein G ₂ is selected from the group consisting of a single ring a group comprising a N 6-8 membered heteroaryl group and a monocyclic 5-8 membered heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the aryl and heteroaryl groups are not Substituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a methyl group, a methoxy group, a -NR'R" group, and a group of formula (a): Wherein L ₃ represents a -CO- group or a -C(O)O- group, and R ⁴ is selected from the group consisting of a hydroxyl group, a cyano group, a -CF ₃ group and a methyl group, and R ^a and R ^{b are} independently the group consisting of selected from a hydrogen atom, a hydroxyl group, a methyl group, or R ^a and R ^b together with the carbon atoms they are attached form a C _3-6 cycloalkyl group or an O 4-membered heterocyclic group, m is 0 having Or a value of 1. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein the G ₂ is selected from the group consisting of pyridyl and monocyclic a group of N 6 membered heterocyclic groups wherein the pyridyl and heterocyclic groups are substituted by one or more substituents selected from the group consisting of a halogen atom and a group of formula (a): Wherein L ₃ represents a -CO- group, R ⁴ is selected from the group consisting of a hydroxyl group and a cyano group, and both R ^a and R ^b represent a hydrogen atom, and m has a value of 1. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein G ₂ represents a monocyclic N 6 -membered heterocyclic ring a group substituted by a group of formula (a): Wherein L ₃ , R ⁴ , R ^a , R ^b and m are as defined in claim 17. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, according to any of the preceding claims, wherein X represents -CR ^c - a group wherein R ^c represents a hydrogen atom, G ₁ is selected from the group consisting of phenyl, pyridyl and piperazinyl, L ₁ represents a direct bond, and L ₂ is selected from -(CH ₂ ) _p -, -O a group of -(CH ₂ ) ₂ - wherein p has a value of 0 or 1, and R ¹ is selected from the group consisting of a phenyl group and a monocyclic 6-7 membered heterocyclic group containing one or two nitrogen atoms as a hetero atom a group wherein the phenyl and heterocyclic groups are selected from the group consisting of a methyl group, a -(O)(CH ₂ ) ₂ -NR'R" group, and a -NR'R"- group Substituted by a substituent wherein R' and R" both represent a methyl group, R ² is a fluorine atom, R ³ represents a hydrogen atom, R ⁵ represents a hydrogen atom, and G ₂ represents a monocyclic N 6 membered heterocyclic group, which is a Substitution of formula (a): Wherein L ₃ represents a -CO- group, R ⁴ is selected from the group consisting of a hydroxyl group and a cyano group, and both R ^a and R ^b represent a hydrogen atom, and m has a value of 1. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, wherein the X is selected from the group consisting of -N- and a group of -CR ^c - groups, wherein R ^c is selected from the group consisting of a hydrogen atom and a methyl group, and G ₁ is selected from the group consisting of a phenyl group, a monocyclic N 6 membered heteroaryl group, and at least one selected from the group consisting of a group consisting of a monocyclic 6-membered heterocyclic group of a hetero atom of O and N, wherein the phenyl, heteroaryl and heterocyclic groups are unsubstituted or substituted by one or more substituents, such substituents Selected from a fluorine atom, a hydroxyl group, a -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino group-C _1-2 alkyl group, and a -NR'-SO ₂ -R" group, and the L ₁ group is selected from the group consisting of a group consisting of a bond and a -NH-(CH ₂ )- group, the L ₂ group being selected from the group consisting of -(CH ₂ ) _p -, -O-(CH ₂ ) _(0-2) and -NR- groups a group wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group, and R ¹ is selected from a C _1-2 alkyl group substituted with a hydrogen atom, substituted with a —NR′R′ group, a phenyl group, a monocyclic or bicyclic 5-9 membered heteroaryl group having at least one nitrogen atom as a hetero atom and containing at least one nitrogen atom a group consisting of a monocyclic or bicyclic 5-9 membered heterocyclic group of a hetero atom, wherein the phenyl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents, The substituent is selected from the group consisting of hydroxyl, methyl, ethyl, branched C _4-5 alkyl, C _1-3 hydroxyalkyl, methoxy, -(O) _(0-1) (CH ₂ ) _{(2-3 a} -NR'R" group, a -NR'R" group, a -CO-OR ^d group, a -CH ₂ -R ^e group, and a monocyclic 6-membered heteroaryl group containing a hetero atom selected from N a group consisting of the heteroaryl group optionally substituted with one or two substituents selected from the group consisting of methyl and -NR'R"groups; R ² is selected from a fluorine atom And a group of methyl groups, R ³ is selected from the group consisting of a hydrogen atom and a -(CH ₂ ) ₂ NR'R" group, and the G ₂ is selected from a pyridyl group substituted by a fluorine atom and a formula (a) Group of substituted piperidinyl groups of groups: Wherein L ₃ represents a direct bond, a -CO- group or a -C(O)O- group, and R ⁴ is selected from a hydroxyl group, a -(CH ₂ ) _(0-1) -CN, a -CF ₃ group, a group consisting of a methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups, and R ^a and R ^b are each a hydrogen atom or R ^a and R ^b together with The carbon atoms to be joined together form a 4-membered heterocyclic group containing an oxygen atom as a hetero atom, R ⁵ is selected from the group consisting of a hydrogen atom and a methyl group, and R ^d represents a third butyl group, optionally selected from the group consisting of a linear C _1-2 alkyl group substituted with a substituent of phenyl and -NR'R", and R ^e is selected from a phenyl group optionally substituted by a CF ₃ group or a third butyl group and containing one or two a nitrogen atom as a group of monocyclic 5-6 membered heteroaryl groups of a hetero atom, wherein the heteroaryl group is optionally subjected to one or more C _1-4 alkyl groups and -CF selected from linear or branched chains. Substituted by a substituent of the ₃ group, R' and R" independently represent a hydrogen atom, a methyl group or a cyclopentyl group, or R' and R" together with the nitrogen atom to which they are attached are formed, optionally containing one or more selected from one or more Additional heteroatoms of N and O and optionally dimethyl The substituent groups 5-6 membered N-containing heterocyclic group, n and m independently has a value of 0 or 1, p has a value of 0, 1 or 2. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative, according to claim 1 or 2, which is one of the following: 3- {(3 R )-3-[[2-(Dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1,5- a ]pyridine- 3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[ (1-Methyl-1 H -imidazol-2-yl)methyl]piperazin-1-yl}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amine 3-piperidin-1-yl}-3-oxopropanenitrile; 3-[(3 R )-3-({6-[4-(1 H -benzimidazol-2-ylmethyl)piperidinyl Pyrazin-1-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxy Propionitrile; 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyridin-2-ylmethyl) Piperazine-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6-(4- {[4-(Dimethylamino)pyridin-2-yl]methyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine 4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-{(3 R )-3-[(5-fluoro-2-pyrazolo[1,5- a]pyridin-3-yl-6-{4-[(4-pyrrolidine) 1-ylpyridin-2-yl)methyl]piperazin-1-yl}pyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(4-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine 4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 4-{[4-(5-fluoro-6-{[(3 R )-1-(3-hydroxy) -3-methylbutyridyl)piperidin-3-yl]amino}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl }Phenol; 4-{[4-(5-fluoro-6-{[(3 R )-1-ethanehydrazinopiperidin-3-yl]amino}-2-pyrazolo[1,5 -a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}phenol; 3-[(3 R )-3-({5-fluoro-6-[4-(4- Methoxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3 - pendant oxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxypropionitrile; 3-((3 R )-3-{[6- (4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridine- 3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 2-((3 R )-3-{[6-(4-{4-[2 -( Methylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino "piperidin-1-yl)-2-oxoethanol; 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1-yl)- 5-fluoro- N -[(3 R )-1-(methoxyethenyl)piperidin-3-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4 -amine;6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5 -a]pyridin-3-yl- N -[(3 R )-1-(3,3,3-trifluoropropenyl)piperidin-3-yl]pyrimidin-4-amine; [3-(( 3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)oxetan-3-yl]acetonitrile; ( 2S )-1-(( 3 R )-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-1-oxopropan-2-ol; ( R )-1-(( R -3((6-(4-(4-(2-(dimethylamino)ethoxy)benzyl)piperazin-1-yl)-5-fluoro-2-(pyrazole) [1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-1-oxobutan-2-ol and ( S )- 1-(( R )-3-((6-(4-(4-(2-(dimethylamino))ethoxy)benzyl)piperazin-1-yl)-5-fluoro-2 -(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-1-oxobutan-2-ol; 3-(( 3 R )-3-{[6-(4-{3-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-((3 R )-3-{[ 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1-yl)-5-fluoro-2-(5-methylpyrazolo[1 , 5-( a )pyridin-3-yl)pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6- (4-{4-[3-(Dimethylamino)propoxy]benzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridine- 3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[ 4-(2-piperidin-1-ylethoxy)benzyl]piperazin-1-yl}-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl) Amino]piperidin-1-yl}-3-oxopropanonitrile; 3-{(3 R )-3-[(5-fluoro-2-pyrazolo[1,5-a]pyridine-3 -yl-6-{4-[4-(2-pyrrolidin-1-ylethoxy)benzyl]piperazin-1-yl}pyrimidin-4-yl)amino]piperidin-1-yl }-3-sideoxy Carbonitrile; 3 - ((3 R) -3 - {[6 - ((3 R, 5 S) -4- {4- [2- ( dimethylamino) ethoxy] benzyl} -3 ,5-Dimethylpiperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl 3-oxooxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]-3,5-di Methylbenzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl 3-oxooxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]-2,6-di Methylbenzyl}piperazin-1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl 3-oxooxypropionitrile; 3-[(3 R )-3-({6-[4-(2-{4-[2-(dimethylamino)ethoxy]phenyl) Ethyl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3 - pendant oxypropionitrile; 4-{[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl}benzoic acid 2-(dimethylamino)ethyl ester; 4-{[4-( 6-{[(3 R )-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl Pyrimidine-4- Tert-butyl peptazin-1-yl]methyl}piperidine-1-carboxylate; 3-[(3 R )-3-({5-fluoro-6-[4-(piperidin-4-) Methyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo 3-propiononitrile; 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-({1-[4- (trifluoromethyl)benzyl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-yloxypropane Nitrile; 3-[(3 R )-3-({5-fluoro-6-[4-({1-[(1-methyl-1H-imidazol-2-yl)methyl]piperidin-4- Methyl)methyl)piperazin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3- side Oxypropionitrile; 3-((3 R )-3-{[6-(4-{[1-(2,2-dimethylpropyl)piperidin-4-yl]methyl}piperazine- 1-yl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile 3-((3 R )-3-{[5-fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-(4-{[1-(pyridin-2-yl) Methyl)piperidin-4-yl]methyl}piperazin-1-yl)pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile; 3-[(3 R )-3-({6-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl}amine 3-piperidin-1-yl]-3-oxopropiononitrile; 3-[(3 R )-3-({5-fluoro-2-pyrazolo[1,5-a]pyridine-3- -6-[4-(2-Pyrrolidin-1-ylpyridin-4-yl)piperazin-1-yl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxyloxy 3-propiononitrile 3-{(3 R )-3-[(6-{4-[2-(dimethylamino)pyridin-4-yl]piperazin-1-yl}-5-fluoro-2- Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3- [(6-{4-[4-(Dimethylamino)pyridin-2-yl]piperazin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridine-3 -pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropiononitrile; 3-((3 R )-3-{[5-fluoro-6-(4-piperidine) 4--4-piperazin-1-yl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-side oxygen 3-propiononitrile; 3-[(3 R )-3-({6-[4-(1-phenylmethylpiperidin-4-yl)piperazin-1-yl]-5-fluoro-2-pyrazole And [1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 5-fluoro- N -[(1 S )- 1-(5-fluoropyridin-2-yl)ethyl]-6-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-pyrazolo[1,5 - a ]pyridin-3-ylpyrimidin-4-amine; 3-{(3 R )-3-[(6-{4-[3-(dimethylamino)propyl]piperazin-1-yl }-5-fluoro-2-pyrazole[1, 5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({5-fluoro- 2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]pyrimidin-4-yl}amino)piperidin Pyridin-1-yl]-3-oxopropanenitrile; 3-[(3 R )-3-({6-[4-(1,3-dihydro-2 H -isoindol-2-yl) Methyl)piperidin-1-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3 - pendant oxypropionitrile; 3-((3 R )-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperidin-1- 5-)fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanonitrile; -{(3 R )-3-[(6-{4-[[2-(Dimethylamino)ethyl](methyl)amino]piperidin-1-yl}-5-fluoro-2 -pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl} pendant oxypropionitrile; 3-[(3 R )-3-({ 5-fluoro-6-[4-(7-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-3-yl)piperidin Pyridin-1-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxopropanenitrile; -{(3 R )-3-[(6-{4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}-5-fluoro-2 -pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropiononitrile; 3-{(3 R )-3-[(6-{4-[(2,6) - dimethylpyridin-4-yl)amino]piperidin-1-yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino Piperidin-1-yl}-3-oxopropanonitrile; 4-{[1-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino) }-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1-carboxylic acid benzyl ester; -[(3 R )-3-({5-fluoro-6-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-2-pyrazolo[1,5-a] Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; ( R )-3-{3-[(6-{4-[(4- Benzylpiperazin-1-yl)methyl]piperidin-1-yl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)amino Piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({6-[4-({4-[4-(dimethylamino))-6) -methylpyridin-2-yl]piperidin-1-yl}methyl)piperidin-1-yl]-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-[(3 R )-3-({5-fluoro-6-[(4-piperazin-1-) benzyl) amino] -2-pyrazolo [1,5- a] pyridin-3-yl} pyrimidin-4-yl amino) piperidin-1-yl] -3-oxo-propanenitrile 3 - [(3 R) -3 - ({5- fluoro-6- [4- (4-methyl-piperazin-1-yl) phenyl] -2-pyrazolo [1,5-a] pyridine -3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 2-[(3 R )-3-({5-fluoro-6-[4- (4-Methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]- 2-sided oxyethanol; 1-benzyl-4-[4-(6-{[(3R)-1-(cyanoethenyl)piperidin-3-yl]amino}-5-fluoro -2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methylpiperazine-1-indole bromide; 1-(4-t-butyl Benzyl)-4-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 , 5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1-methylpiperazine-1-indenyl bromide; 3-((3 R )-3-{[6-(4- {4-[3-(Dimethylamino)propyl]piperazin-1-yl}phenyl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine- 4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )-3-([2-(dimethylamino)ethyl]{5- Fluoro-6-[4-(4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin Pyridin-1-yl]-3-oxopropanenitrile; 3-[(3 R )-3-({5-fluoro-6-[4-(1-methylpiperidin-4-yl)phenyl) ]-2-pyrazole [1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-[(3 R )-3-({5 -Fluoro-2-pyrazolo[1,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1-ylmethyl)phenyl]pyrimidin-4-yl}amino)piperidine -1-yl]-3-sided oxypropionitrile; 3-[(3 R )-3-({5-methyl-2-pyrazolo[1,5- a ]pyridin-3-yl-6 -[4-(pyrrolidin-1-ylmethyl)phenyl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-[(3 R )- 3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1-yl}methyl)phenyl]-5- Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R -3{[6-(4-{[4-(Dimethylamino)piperidin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazolo[1,5- a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxooxypropionitrile; 3-((3 R )-3-{[6-(4-{ [4-(Dimethylamino)piperidin-1-yl]methyl}-2-fluorophenyl)-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine 4-yl]amino}piperidin-1-yl)-3-oxo-propanonitrile; 3-((3 R )-3-{[6-(3-{[4-(dimethylamine) Piperidin-1-yl]methyl}phenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 - ) -3-oxo-propanenitrile; 3 - {(3 R) -3 - [(5- fluoro-6- {4 - [(4-methyl-1,4-diazepane -1 -yl)methyl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropyl Nitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl }-2-pyrazolo[1,5-a]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({6-[4-({4-[2-(dimethylamino)ethoxy)piperidin-1-yl}methyl)phenyl]-5-fluoro-2- Pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-{(3 R )-3- [(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine-4- Amino]piperidin-1-yl}-3-oxopropiononitrile; 3-((3 R )-3-{(6-{4-[2-(dimethylamino)ethoxy) Phenyl}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl]amino} Acridine-1-yl)-3-oxopropanonitrile; [(3 R )-3-({5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-yl-6-[ 4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{[6-(4-{2-[4-(Dimethylamino)piperidin-1-yl]ethoxy}phenyl)-5-fluoro-2-pyrazolo[ 1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; ( R )-3-(3-((5-fluoro) -6-(4-(piperidin-4-yloxy)phenyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine -1-yl)-3-oxomethoxypropionitrile; ( R )-3-(3-((6-(4-((1-ethylpiperidin-4-yl)oxy)phenyl)-) 5-fluoro-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile; ( R -3(3-((5-fluoro-6-(4-((1-(3-(piperidin-1-yl)propyl)piperidin-4-yl)oxy)phenyl)- 2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R -3({5-fluoro-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-2-pyrazolo[1,5-a]pyridine-3- Pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-((3 R )-3-{[5-fluoro-6-(2-piperazine- 1-ylpyridin-4-yl)-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-acetoxypropyl Nitrile; 3-((3 R )-3-{[6-(2-{4-[3-(dimethylamino)propyl)piperazin-1-yl}pyridin-4-yl)-5 -fluoro-2-pyrazolo[1,5-a]pyridine-3- Pyrimidin-4-yl] amino} piperidin-1-yl) -3-oxo-propanenitrile; 3 - [(3 R) -3 - ({5- fluoro-6- [2- (4- -1,4-diazepan-1-yl)pyridin-4-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino) Piperidin-1-yl]-3-oxopropanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{2-[4-(2-hydroxyethyl)-1, 4-diazepane-1-yl]pyridin-4-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -yl}-3-oxopropanenitrile; 3-{( 3R )-3-[(6-{2-[4-(dimethylamino)piperidin-1-yl]pyridine-4- 5-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; -{(3 R )-3-[(6-{2-[4-(Dimethylamino)piperidin-1-yl]pyridin-4-yl}-5-fluoro-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-2-oxoethanol; 3-((3 R )-3-{[6-( 6-{[4-(Dimethylamino)piperidin-1-yl]methyl}pyridin-3-yl)-5-fluoro-2-pyrazolo[1,5- a ]pyridine-3- Pyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )-3-({5-fluoro-6-[6-(4- methyl-1,4-diazepan-l-yl) pyridin-3-yl] -2-pyrazolo [1,5- a] pyridin-3-yl} pyrimidin-4-yl Yl) piperidin-1-yl] -3-oxo-propanenitrile; 3 - {(3 R) -3 - [(6- {6- [4- ( dimethylamino) piperidine-1 Pyridyl-3-yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3- side Oxypropionitrile; 3-{(3 R )-3-[(6-{4-[4-(2-aminoethoxy)benzyl]piperazin-1-yl}-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanonitrile; 3-{(3 R )- 3-[(5-fluoro-6-{4-[1-(3-hydroxybenzyl)piperidin-4-yl]piperazin-1-yl}-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 3-[(3 R )-3-([2-(dimethylamine) Ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-((3 R )-3-{[5-fluoro-6-(4-{4-[2- (Methylamino)ethoxy]benzyl}piperazin-1-yl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine -1-yl)-3-oxopropiononitrile; N -[(3 R )-1-(3-aminopropionyl)piperidin-3-yl]-5-fluoro-6-[4- (4-methylpiperazin-1-yl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-amine; 3-[(3 R )-3-( [2-(Dimethylamino)ethyl]{5-fluoro-6-[3-hydroxy-5-(4-methylpiperazin-1-yl)phenyl]2-pyrazolo[1, 5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-(6-{[2-(dimethylamino)) Ethyl][(3 R )-1-ethanehydrazinopiperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-yl)-5-(4-methylpiperazin-1-yl)phenol; 3-((3 R )-3-{[6-(4-{[4-(dimethylamino))piperidin Pyridin-1-yl]methyl}-3-hydroxyphenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine- 1-yl)-3-oxooxypropionitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-5-{[(1-methylpiperidin-4-) Amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxo 3-propiononitrile; 3-((3 R )-3-{[5-fluoro-6-(4-{(3-hydroxybenzyl)[(1-methylpiperidin-4-yl)methyl] Amino}piperidin-1-yl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-yloxy Propiononitrile; 3-[(3 R )-3-({5-fluoro-6-[3-hydroxy-5-({[1-(3-piperidin-1-ylpropyl))piperidine-4- Amino]methyl)methyl]phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidine- 1-yl]-3-oxooxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{6-[4-(methylamino)piperidin-1-yl] Pyridin-3-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; -{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}-2- Pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-yloxypropionitrile; 3-(5-fluoro-6-{ [(3 R )-1-Glycolhydrazinopiperidin-3-yl]amino}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)-5- {[(1-Methylpiperidin-4-yl)amino]methyl}phenol; 3-{(3 R )-3-[(5-fluoro-6-{4-[3-hydroxy-5- (1-Methylpiperidin-4-yl)benzyl]piperazin-1-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino] Piperidin-1-yl}-3-sidedoxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-5-[4-(3-piperidine-)- 1-ylpropyl)piperazin-1-yl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl} 3-oxooxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[(3-hydroxybenzyl)(3-piperidin-1-ylpropyl) ) amino] piperidin-1-yl} -2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxo-side Propionitrile; 3 - ((3 R) -3 - {[6- (3 - {[4- ( cyclopentyl amino) piperidin-1-yl] methyl} -5-hydroxyphenyl) -5 -fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxopropanenitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-4-{[methyl(1-methylpiperidin-4-yl)amino]methyl}phenyl)-2-pyrazole And [1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-{(3 R )-3-[( 5-fluoro-6-{3-hydroxy-4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}-2-pyrazolo[1, 5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-[(3 R )-3-({6-[2 -(1,4-diazepan-1-yl)pyridin-4-yl]-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl }Amino)piperidin-1-yl]-3-oxopropiononitrile; 3-((3 R )-3-{[5-fluoro-6-(3-hydroxy-5-{[methyl ( 1-methylpiperidin-4-yl)amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine- 1-yl)-3-oxooxypropionitrile; 3-{(3 R )-3-[[5-fluoro-6-(3-hydroxy-5-{[(1-methylpiperidin-4-) yl) amino] methyl} phenyl) -2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl] (methyl) amino] piperidine 1-yl} -3-oxo-propanenitrile; 3 - {(3 R) -3 - [(6- {3 - [( cyclopentyl) methyl] -5-hydroxyphenyl} - 5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-yloxypropanenitrile; 3-[( 3 R )-3-({6-[3-(1,4-diazepan-1-ylmethyl)-5-hydroxyphenyl]-5-fluoro-2-pyrazolo[1 , 5-( a )pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxooxypropionitrile; 3-((3 R )-3-{[6-( 3-{6-[4-(Dimethylamino)piperidin-1-yl]pyridin-3-yl}-5-hydroxyphenyl)-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6- {3-hydroxy-5-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}-2-pyrazolo[1,5- a ]pyridine- 3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-hydroxyl) -3-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine 4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 1-[4-(6-{[(3R)-1-(cyanoethenyl)piperidine- 3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]piperidine-4-methyl 1-methylpiperidin-4-yl acid ester; 3-{(3 R )-3-[(6-{6-[4-(cyclopentylamino)piperidin-1-yl]pyridine-3 -yl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 3-((3 R )-3-{[6-(3-{[4-(Dimethylamino)piperidin-1-yl]methyl}-4-hydroxyphenyl)-5-fluoro- 2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-3-oxomethoxypropionitrile; 3-[(3 R )- 3-({5-fluoro-6-[3-hydroxy-4-(piperazin-1-ylmethyl)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidine- 4-(yl)amino)piperidin-1-yl]-3-oxo-propanonitrile; 3-(( 3R )-3-{[5-fluoro-6-(3-hydroxy-4-{[ (1-methylpiperidin-4-yl)amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidine -1-yl)-3-oxopropanonitrile; 1'-[4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5 -Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]-4-methyl-1,4'-bipiperidine-4-carboxylic acid ethyl ester ; 3-[(3 R )-3-({5-fluoro-6-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]-3- (methylthio) phenyl] -2-pyrazolo [1,5- a] pyridin-3-yl} pyrimidin-4-yl amino) piperidin-1-yl] -3-oxo-side Propionitrile; 3 - [(3 R) -3 - ({5- fluoro-6- [3 - [(4-methyl-1,4-diazepan-1-yl) methyl] - 4-(Methylthio)phenyl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-sideoxy 3-propiononitrile; 3-[(3 R )-3-({6-[4-({2-[4-(dimethylamino)piperidin-1-yl]ethyl}thio)phenyl) 5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxo-propanonitrile; 3- {(3 R )-3-[(6-{6-[4-(Dimethylamino)piperidin-1-yl]-5-hydroxypyridin-3-yl}-5-fluoro-2-pyridyl Zizo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanonitrile; 3-[(3 R )-3-( {5-Fluoro-6-[2-(4-isopropyl-1,4-diazepan-1-yl)pyridin-4-yl]-2-pyrazolo[1,5- a Pyridyl-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; 3-{(3 R )-3-[(6-{4-[( Cyclopentylamino)methyl]-3-hydroxyphenyl}-5-fluoro-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidine- 1-yl}-3-sided oxypropionitrile; 3-{(3 R )-3-[(6-{3-[(cyclopentylamino)methyl]-4-hydroxyphenyl}-5 - fluoro-2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxo-propionic 4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridine- 3-ylpyrimidin-4-yl)benzoic acid piperidin-4-yl ester; 3-{(3 R )-3-[(5-fluoro-6-{3-hydroxy-4-[(methylamino) Methyl]phenyl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 4-(6-{[(3R)-1-(cyanoethyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1,5-a]pyridine-3 -Pyrylpyrimidin-4-yl)benzoic acid 1'-methyl-1,4'-bipiperidin-4-yl ester; 3-((3 R )-3-{[5-fluoro-6-(3 -hydroxy-4-{[methyl(pyridin-4-yl)amino]methyl}phenyl)-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl]amine Benzylpiperidin-1-yl)-3-oxo-propanonitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-[(5-fluoro-2-hydroxybenzo) Amino]piperidin-1-yl}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3- side Oxypropionitrile; 3-{(3 R )-3-[(5-fluoro-6-{4-hydroxy-3-[(methylamino)methyl]phenyl}-2-pyrazolo[ 1,5- a ]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanonitrile; 3-{[4-(cyclopentylamino)per piperidin-1-yl] methyl} -5- (5-fluoro -6 - {[(3 R) -1- glycol acyl piperidin-3-yl] amine } -2-pyrazolo [1,5- a] pyridin-3-yl-pyrimidin-4-yl) phenol; 3 - ((3 R) -3 - {{5- fluoro-6- [4- (3 -hydroxybenzyl)piperazin-1-yl]-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}[2-(methylamino)ethyl]amine 3-piperidin-1-yl)-3-oxopropanonitrile; 3-{[4-(5-fluoro-6-{[(3 R )-1-ethanehydrazinopiperidin-3- [2-(methylamino)ethyl]amino}-2-pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl)piperazin-1-yl]methyl }phenol; 3-[(3 R )-3-({6-[4-(1,4'-bipiperidin-1'-ylmethyl)-3-hydroxyphenyl]-5-fluoro-2 -pyrazolo[1,5- a ]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1-yl]-3-oxomethoxypropionitrile; and 2-((3 R )- 3-{[5-fluoro-6-(4-{4-[2-(methylamino)ethoxy]benzyl}piperazin-1-yl)-2-pyrazolo[1,5 - a ]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1-yl)-2-oxoethanol. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative thereof, according to any one of claims 1 to 22, which is used by therapy For the treatment of human or animal body. A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or an N-oxide or a stereoisomer or a deuterated derivative thereof, according to any one of claims 1 to 22, which is useful for treatment A pathological condition or disease that is ameliorated by inhibition of Janus kinase. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 22 and a pharmaceutically acceptable diluent or carrier. Use of a compound as defined in any one of claims 1 to 22 for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claim 24. A method for treating an individual suffering from a pathological condition or disease as defined in claim 24, comprising administering to the individual a therapeutically effective amount of a compound as defined in any one of claims 1 to 22 or A pharmaceutical composition as defined in claim 25.