WO2015086693A1 - Pyrazolopyrimidin-2-yl derivatives as jak inhibitors - Google Patents

Pyrazolopyrimidin-2-yl derivatives as jak inhibitors Download PDF

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WO2015086693A1
WO2015086693A1 PCT/EP2014/077255 EP2014077255W WO2015086693A1 WO 2015086693 A1 WO2015086693 A1 WO 2015086693A1 EP 2014077255 W EP2014077255 W EP 2014077255W WO 2015086693 A1 WO2015086693 A1 WO 2015086693A1
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piperidin
pyridin
amino
pyrazolo
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French (fr)
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Jordi Bach Taña
Daniel Perez Crespo
Oriol Llera Soldevila
Cristina Esteve Trias
Lorena Taboada Martinez
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Almirall, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • Cytokines have critical functions in regulating many aspects of immunity and inflammation, ranging from the development and differentiation of immune cells to the suppression of immune responses.
  • Type I and type II cytokine receptors lack intrinsic enzymatic activity capable of mediating signal transduction, and thus require association with tyrosine kinases for this purpose.
  • the JAK family of kinases comprises four different members, namely JAK1 , JAK2, JAK3 and TYK2, which bind to type I and type II cytokine receptors for controlling signal transduction (Murray PJ, (2007).
  • the JAK-STAT signalling pathway input and output integration. J Immunol, 178: 2623).
  • Each of the JAK kinases is selective for the receptors of certain cytokines.
  • JAK-deficient cell lines and mice have validated the essential role of each JAK protein in receptor signalling: JAK1 in class II cytokine receptors (I FN and IL-10 family), those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21 ) (Rodig et al. (1998). Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373; Guschin et al. (1995).
  • JAK1 protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.
  • Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state.
  • JAK2 is essential for signalling through a variety of cytokine receptors.
  • JAK3 in receptors sharing the common gamma chain (IL-2 family)
  • IL-2 family common gamma chain
  • Park et al. (1995). Developmental defects of lymphoid cells in JAK3 kinase-deficient mice. Immunity, 3:771 ; Thomis et al., (1995). Defects in B lymphocyte maturation and T 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.
  • Receptor stimulation leads sequentially to JAK activation by phosphorylation, receptor phosphorylation, STAT protein recruitment and STAT activation and dimerization.
  • the STAT dimer then functions as a transcription factor, translocating to the nucleus and activating the transcription of multiple response genes.
  • STAT1 STAT2
  • STAT3, STAT4 STAT5a
  • STAT5b STAT6
  • Each particular cytokine receptor associates preferentially with a particular STAT protein.
  • Some associations are independent of cell type (ex: IFNg- STAT1 ) while others may be cell type dependent (Murray PJ, (2007).
  • the JAK-STAT signaling pathway input and output integration. J Immunol, 178: 2623).
  • JAK3 associates exclusively with the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines.
  • JAK3 knock out mice and common gamma chain deficient mice have an identical phenotype (Thomis et al., (1995).
  • JAK3-deficient mice are viable but display abnormal lymphopoiesis which leads to a reduced thymus size (10-100 fold smaller than wild type). JAK3-deficient peripheral T cells are unresponsive and have an activated/memory cell phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice. J. Leuk. Biol. 63: 669).
  • Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant Cytokine. J Exp Med, 181 :1519; Peschon et al, (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These mice, like SCID humans, have no NK cells, probably due to the absence of IL-15 signaling, a survival factor for these cells. JAK3 knockout mice, unlike SCID patients, show deficient B cell lymphopoiesis while in human patients, B cells are present in circulation but are not responsive leading to hypoglobulinemia (O'Shea et al., (2004).
  • JAK2 -deficient mice are embrionically lethal, due to the absence of definitive erythropoiesis.
  • Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are not affected.
  • JAK2 is not required for the generation, amplification or functional differentiation of lymphoid progenitors (Parganas et al., (1998). JAK2 is essential for signaling through a variety of cytokine receptors. Cell, 93:385).
  • JAK1 -deficient mice die perinatally due to a nursing defect.
  • JAK1 binds exclusively to the gp130 chain shared by the IL-6 cytokine family (i.e. LIF, CNTF, OSM, CT-1 ) and along with JAK3, is an essential component of the receptors sharing the common gamma chain, by binding to the non-shared receptor subunit.
  • JAK1 - deficient mice show similar hematopoiesis defects as JAK3-deficient mice. In addition, they show defective responses to neurotrophic factors and to all interferons (class II cytokine receptors) (Rodig et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373).
  • Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function. Immunity, 13:561 ). However, human Tyk2 deficiency demonstrates that Tyk2 is involved in the signaling from IFN-a, 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).
  • JAK kinases in transducing the signal from a myriad of cytokines makes them potential targets for the treatment of diseases in which cytokines have a pathogenic role, 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, as well as in solid and hematologic malignancies such as myeloproliferative disorders, leukemia and lymphomas.
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • autoimmune diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis
  • uveitis uveitis
  • transplant rejection as well as in solid and hematologic malignancies such as myeloproliferative disorders, le
  • JAK inhibitor CP-690,550 tofacitinib, formerly tasocitinib
  • CP-690,550 has shown efficacy in several animal models of transplantation (heretopic heart transplantation in mice, cardiac allografts implanted in the ear of mice, renal allotransplantation in cynomolgous monkeys, aorta and tracheal transplantation in rats) by prolonging the mean survival time of grafts (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 ).
  • IL-6 rheumatoid arthritis
  • RA rheumatoid arthritis
  • IL-6 activates the transcription factor STAT3, through the use of JAK1 binding to the gp130 receptor chain (Heinrich et al., (2003). Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem J. 374: 1 ).
  • JAK inhibitors for signal transduction, making JAK inhibitors potential pleiotropic drugs in this pathology. Consequently, administration of several JAK inhibitors in animal models of murine collagen-induced arthritis and rat adjuvant- induced arthritis has shown to reduce inflammation, and tissue destruction (Milici et al., (2008). Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arth. Res. 10:R14).
  • IBD Inflammatory bowel disease
  • cytokines including interleukins and interferons
  • Activation of the IL-6/STAT3 cascade in lamina propia 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).
  • STAT3 has been shown to be constitutively active in intestinal T cells of Crohn's disease patients and a JAK inhibitor has been shown to block the 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).
  • Multiple sclerosis is an autoimmune demyelinating disease characterized by the formation of plaques in the white matter.
  • cytokines include blockade of 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. 1 18:3557), cytokines that signal through the JAK- STAT pathways.
  • Use of tyrphostin, a JAK inhibitor has been shown to inhibit IL-12- induced phosphorylation of STAT3, and to 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 multikinase inhibitor, CEP701 has been shown to reduce secretion of TNF- alpha, IL-6 and IL-23 as well as the levels of phospho-STAT1 , STAT3, and STAT5 in peripheral DCs of mice with EAE, significantly improving the clinical course of EAE in mice (Skarica et al, (2009). Signal transduction inhibition of APCs diminishes Th17 and Th1 responses in experimental autoimmune encephalomyelitis. J. Immunol.
  • Psoriasis is a skin inflammatory disease which involves a process of immune cell infiltration and activation that culminates in epithelial remodeling.
  • the current theory behind the cause of psoriasis states the existence of a cytokine network that governs the interaction between immune and epithelial cells (Nickoloff BJ. (2007). Cracking the cytokine code in psoriasis, Nat Med, 13:242).
  • IL-23 produced by dendritic cells is found elevated in psoriatic skin, along with IL-12.
  • IL-23 induces the formation of Th17 cells which in turn produce IL-17 and IL-22, the last one being responsible for epidermis thickening.
  • IL-23 and IL-22 induce the phosphorylation of STAT-3, which is found abundantly in psoriatic skin. JAK inhibitors may thus be therapeutic in this setting.
  • a JAK1/3 inhibitor, R348 has been found to attenuate psoriasiform skin inflammation in a spontaneous T cell-dependent mouse model of psoriasis (Chang et al., (2009). JAK3 inhibition significantly attenuates psoriasiform skin inflammation on CD18 mutant PL/J mice. J Immunol. 183:2183).
  • Th2 cytokine-driven diseases such as allergy and asthma could also be a target of JAK inhibitors.
  • IL-4 promotes Th2 differentiation, regulates B-cell function and
  • immunoglobulin class switching regulates eotaxin production, induces expression of IgE receptor and MHC II on B cells, and stimulates mast cells.
  • Other Th2 cytokines like IL-5 and IL-13 can also contribute to eosinophil recruitment in bronchoalveolar lavage by stimulating eotaxin production.
  • Pharmacological inhibition of JAK has been shown to reduce the expression of IgE receptor and MHCII 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).
  • JAK3-deficient mice display poor eosinophil recruitment and mucus secretion to the airway lumen upon 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). JP£7295:912.).
  • cytokines play a pathogenetic role in ocular inflammatory disease such as uveitis or dry eye syndrome.
  • JAK inhibition vallochi et al, (2007).
  • drugs or biologicals that interfere with IL-2 signaling such as cyclosporine or anti-IL-2 receptor antibody (daclizumab) have shown efficacy in the treatment of keratoconjuctivitis sicca and refractory uveitis, respectively (Lim et al, (2006). Biologic therapies for inflammatory eye disease. Clin Exp Opht 34:365).
  • allergic conjunctivitis a common allergic eye disease characterized by conjuctival congestion, mast cell activation and eosinophil infiltration, could benefit from JAK inhibition.
  • 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 shown to promote apoptosis of cancer cells, inhibition of angiogenesis and up-regulation of host immunocompetence.
  • Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors may provide a therapeutic option to the treatment of this disease.
  • the use of the JAK inhibitor tyrphostin has been shown to induce apoptosis of malignant cells and inhibit cell proliferation in vitro and in vivo (Meydan et al., (1996).
  • JAK-2 inhibitor Inhibition of acute lymphoblastic leukemia by a JAK-2 inhibitor. Nature, 379:645). Hematological malignancies with dysregulated JAK-STAT pathways may benefit from JAK inhibition. Recent studies have implicated dysregulation of JAK2 kinase activity by chromosomal translocations and mutations within the pseudokinase domain (such as the JAK2V617F mutation) in a spectrum of myeloproliferative diseases (Ihle and Gililand, 2007), including polycythemia vera, myelofibrosis and essential
  • JAK inhibitors that tackle JAK2 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.
  • CEP701 is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with
  • JAK inhibitors may 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) pointing to this kinase as a target for the development of novel antileukemic drugs.
  • Conditions in which targeting of the JAK pathway or modulation of the JAK kinases, particularly JAK1 , JAK2 and JAK3 kinases, are contemplated to be therapeutically useful for the treatment or prevention of diseases include: neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g. diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease); respiratory inflammation diseases (e.g. asthma, chronic obstructive pulmonary disease), inflammation-linked ocular diseases or allergic eye diseases (e.g.
  • neoplastic diseases e.g. leukemia, lymphomas, solid tumors
  • transplant rejection e.g., bone marrow transplant applications (e.g., graft- versus-host disease)
  • autoimmune diseases e.g. diabetes, multiple sclerosis, rheumatoid arthritis
  • dry eye dry eye, glaucoma, uveitis, diabetic retinopathy, allergic conjunctivitis or age-related macular degeneration
  • skin inflammatory diseases e.g., atopic dermatitis or psoriasis
  • novel pyrazolopyrimidin-2-yl derivatives for use in the treatment of conditions in which targeting of the JAK pathway or inhibition of JAK kinases can be therapeutically useful.
  • the compounds described in the present invention are simultaneously potent JAK1 , JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphomas 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-linked ocular 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 (such as atopic dermatitis or psoriasis).
  • rheumatoid arthritis multiple sclerosis
  • inflammatory bowel disease such as ulcerative colitis or Crohn's disease
  • inflammation-linked ocular diseases or allergic eye diseases such as dry eye, uveitis, or allergic conjunctivitis
  • allergic rhinitis asthma,
  • X is selected from the group consisting of -N- and -CR C - group
  • Gi is selected from the group consisting of a monocyclic C 5- 8 aryl group, a monocyclic C 3 -8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci -4 alkyl group, a Ci -4 thioalkyl group, a Ci -2 hydroxyalkyl group, a di-(Ci- 2 alkyl)amino-Ci -4 alkyl group and a -NR'-S0 2 -R" group,
  • U is selected from the group consisting of a
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -(CH 2 )-NR-, -NR-(CH 2 )-, -O- (CH 2 )(o-2)> -C(0)0-, -S- and -NR- group, wherein R represents a hydrogen atom or a C-i-4 alkyl group optionally substituted with a group selected from -NR'R"- group and a phenyl group wherein said phenyl group is optionally substituted with a hydroxyl group,
  • R 1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci -4 alkyl group optionally substituted with a -NR'R" group, a monocyclic C 5- 8 aryl group, a monocyclic C 3 - 8 cycloalkyl group, a mono- or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from O, S and N and a mono- or bicyclic 5- to 14-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups 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 Ci -6 alkyl group, a linear or branched Ci -6 hydroxyalkyl group, a linear or branched Ci -4 alkoxy group,
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen atom and a Ci -4 alkyl group,
  • R 3 is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group and a -(CH 2 ) (2-4) NR'R"- 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- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a Ci -4 alkyl group, a Ci -4 alkoxy group, a Ci -2 hydroxyalkyl group, -NR'R" group and a group of formula (a):
  • L 3 represents a direct bond, -CO- group, or a -C(0)0- group
  • R 4 is selected from the group consisting of a hydroxyl group, a -(CH 2 )(o-i)-CN group, a -CF 3 group, a linear or branched Ci -4 alkyl group, a linear or branched
  • R a and R b are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci -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- to 5-membered heterocyclic group containing at least one heteroatom selected from N, O and S
  • R 5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group
  • R c is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group, a Ci -4 alkoxy group, a C 5- 8 aryl group, a 5- to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci -4 alkyl group,
  • R d represents a linear or branched Ci -4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a-NR'R" or R d represents a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N optionally substituted with a Ci -2 alkyl group,
  • R e is selected from the group consisting of a monocyclic C 5 - 8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic rings are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci -4 alkyl group and a -CF 3 group, R' and R" independently represent a hydrogen atom, a Ci -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 a 4- to 6-membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino 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 processes and intermediates described herein
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to
  • JAK Janus Kinases
  • the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and inflammatory diseases; more in particular wherein 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.
  • COPD chronic obstructive pulmonary disease
  • the invention is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more in particular wherein 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.
  • JAK Janus Kinases
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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; comprising administering a therapeutically effective amount of the compounds of the invention or a pharmaceutical composition of the invention to a subject in need of such treatment.
  • JK Janus Kinases
  • the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome;
  • MPDs myeloproliferative disorders
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and
  • COPD chronic
  • the invention also provides a combination product comprising (i) the compounds of the invention as described herein; and (ii) 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 mielofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, 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.
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia or mielofibrosis
  • CrC 6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, isopentyl, 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-methylpentyl, 3-methylpentyl and iso-hexyl radicals
  • Ci-C 6 hydroxyalkyi embraces linear or branched alkyl radicals having 1 to 6 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxy methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxylhexyl.
  • Ci-C 4 thioalkyl embraces radicals containing a linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -S- radical.
  • Preferred optionally substituted thioalkyl radicals include thiomethyl, thioethyl, n- thiopropyl, i-thiopropyl, n-thiobutyl, sec-thiobutyl and t-thiobutyl.
  • (Ci-C 4 )alkylamino embraces radicals containing an optionally substituted, linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -NH- radical.
  • Preferred (Ci-C 4 )alkylamino radicals include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, sec-butylamino and t- butylamino.
  • di-(Ci-C 2 )alkylamino embraces radicals containing a trivalent nitrogen atom with two linear or branched alkyl radicals of 1 to 2 carbon atoms in each alkyl radical.
  • Preferred di-(Ci-C 2 )alkylamino radicals include dimethylamino, diethylamino and methyl(ethyl)amino.
  • Ci-C 4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • Examples of C C 4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy or t-butoxy.
  • C 3 -C 8 cycloalkyl embraces saturated monocyclic carbocyclic radicals having from 3 to 8 carbon atoms, preferably from 3 to 7 carbon atoms.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 5 -C 8 aryl radical embraces typically a C 5 -C 8 , preferably C 5 -C 6 monocyclic aryl radical such as phenyl.
  • 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10-membered ring system, more preferably a 5- to 6-membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
  • a 5- to 14- membered heteroaryl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2
  • the term 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C 5 -Ci 4 carbocyclic ring system, preferably C 5 - C-io carbocyclic ring system, more preferably C 5 -C 6 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • a heterocyclyl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • Examples of 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1 (3H)-one, 1 ,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyrany
  • bicyclyl group which is a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group typically refers to a moiety containing a bond which is shared between a monocyclic C 6 -C 9 aryl or 5- to 9- membered heteroaryl group and a 5- to 9- membered cycloalkyi or heterocyclyl group, wherein said heteroaryl or heterocyclyl group contains at least one heteroatom selected from O, S and N.
  • said bicyclyl group is a phenyl or 5- or 6- membered heteroaryl group fused to a 5- or 6-, preferably 6-, membered cycloalkyi or heterocyclyl group.
  • said heteroaryl or heterocyclyl group contains 1 , 2 or 3, preferably 1 or 2, for example 1 , heteroatom selected from O, S and N. Examples include chromanyl groups or 1 ,2,3,4-tetrahydronaphthalenyl groups..
  • halogen atom embraces chlorine, fluorine, bromine and iodine atoms.
  • a halogen atom is typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • the resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
  • the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid) and the like.
  • inorganic acids for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid
  • organic acids for example citric, fumaric,
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the
  • salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X " ) is associated with the positive charge of the N atom.
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • 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.
  • hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
  • less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non- solvate form of the compounds.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes 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 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labeled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon- 14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
  • a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
  • isotopic enrichment factor ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen
  • the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.
  • the isotopic enrichment factor can be determined using conventional analytical methods known to an ordinary skilled 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.
  • certain derivatives of the compounds of the present invention which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of the present invention.
  • X is selected from the group consisting of -N- and -CR C - group
  • Gi is selected from the group consisting of a monocyclic C 5- 8 aryl group, a monocyclic C 3 -8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci -4 alkyl group, a Ci -2 hydroxyalkyl group, a di (Ci -2 alkyl)amino- Ci -4 alkyl group and -NR'-S0 2 -R" group,
  • U is selected from the group consisting of a -(CH 2 )(o-i)-, -0-
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen atom and a Ci -4 alkyl group
  • R 3 is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group and a -(CH 2 ) (2-4) NR'R"- 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- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a Ci -4 alkyl group, a Ci -4 alkoxy group, a Ci -2 hydroxyalkyl group., -NR'R" group and a group of formula (a):
  • L 3 represents a direct bond, -CO- group, or a -C(0)0- group
  • R 4 is selected from the group consisting of a hydroxyl group, a -(CH 2 )(o-i)-CN group, a -CF 3 group, a linear or branched Ci -4 alkyl group, a linear or branched Ci -4 alkoxy group, a linear or branched Ci -4 hydroxyalkyl group and a Ci -4 alkylamino group wherein the alkyl and the hydroxyalkyl groups are optionally substituted with one or more methyl groups,
  • R a and R b are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci -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- to 5-membered heterocyclic group containing at least one heteroatom selected from N, O and S,
  • R 5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group,
  • R c is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group, a Ci -4 alkoxy group, a C 5- 8 aryl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci -4 alkyl group,
  • R d represents a linear or branched Ci -4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a-NR'R",
  • R e is selected from the group consisting of a monocyclic C 5 - 8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic ring are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci -4 alkyl group and a -CF 3 group, R' and R" independently represents a hydrogen atom, a Ci -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 a 4 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 ,
  • p has a value of 0, 1 or 2.
  • X represents a -CR c -group, wherein R c is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group, a Ci -4 alkoxy group, a phenyl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci -4 alkyl group, and R' and R" independently represents a hydrogen atom or a Ci -4 alkyl group, preferably, R c is selected from the group consisting of a hydrogen atom, a Ci -2 alkyl group, a Ci -2 alkoxy group, a phenyl group and a -NR'R" group, wherein R' and R" independently represents a hydrogen atom or a Ci -2 alkyl group, more
  • d is selected from the group consisting of a monocyclic C 5- 8 aryl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, a hydroxyl group, a Ci -4 alkyl group, a Ci -2 hydroxyalkyl group and -NR'-S0 2 -R" group.
  • d is selected from the group consisting of a phenyl group, a pyridyl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, pyridyl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, and a Ci -2 alkyl group, more preferably G- ⁇ is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group.
  • U is selected from the group consisting of a -(CH 2 )(o-i)-, -NR x -(CH 2 )(i)- group, wherein R x is selected from a the group consisting of a hydrogen atom and a Ci -2 alkyl group optionally substituted with -(CH 2 )(o-2 ) NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L-i is selected from the group consisting of direct bond and -NR X -(CH 2 ) (1) - group, wherein R x is selected from a the group consisting of a hydrogen atom and a methyl group, more preferably, U represents a direct bond.
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -O-(CH 2 ) (0 - 2) - and -NR- group, wherein R represents a hydrogen atom or a Ci -2 alkyl group optionally substituted with a -NR'R"- group, wherein p has a value of 0 or 1 and wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L 2 is selected from the group consisting of a -(CH 2 ) P -, -0-(CH 2 ) 2 -, wherein p has a value of 0 or 1 . More preferably, L 2 represents -CH 2 - group.
  • R 1 is selected from the group consisting of a hydrogen atom, a Ci -2 alkyl group optionally substituted with a -NR'R" group, a monocyclic C 5- 8 aryl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from N, wherein the aryl, heteroaryl and heterocyclyl groups 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 Ci -5 alkyl group, a linear Ci -2 alkoxy group, a -(0)(o-i)(CH 2 ) ( o-3 ) -NR'R" group, a -CO-0-R d group, a -CH 2 -R e group, wherein
  • ⁇ R d represents a linear or branched Ci -4 alkyl group optionally substituted with one or more substituents selected from a methyl group and a-NR'R",
  • R e is selected from the group consisting of a monocyclic C 5 - 8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from N, which cyclic ring are optionally substituted with one or more substituents selected from a linear or branched Ci -4 alkyl group and a -CF 3 group,
  • R' and R" independently represents a hydrogen atom or a methyl group or R' and R" together with the nitrogen atom to which they are attached form a 4 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group.
  • R 1 is selected from the group consisting of a hydrogen atom, a monocyclic C 5 - 8 aryl group and a monocyclic 5- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the aryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a a linear or branched Ci -5 alkyl group, a linear C-i-2 alkoxy group, a -(0)(CH 2 )2-NR'R" group and a -NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, R 1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent selected from the group consist
  • R 1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent wich is -(0)(CH 2 )2-NR'R" group, wherein both R' and R" represents a methyl group and q has a value of 1 .
  • q has a value of 1.
  • the compounds of formula (I) are wherein L 2 represents -CH 2 - group and R 1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent which is -(0)(CH 2 ) 2 -NR'R" group, wherein both R' and R" represents a methyl group and q has a value of 1.
  • 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.
  • R 3 is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group and a— (CH 2 ) (2-4) NR'R"- group, wherein R' and R" are as defined in claim 1 , preferably, R 3 is selected from a hydrogen atom and a -methyl group, more preferably R 3 represents a hydrogen atom.
  • R 5 is selected from the group consisting of a hydrogen atom and a methyl group, preferably a hydrogen atom.
  • G 2 is selected from the group consisting of a monocyclic N- containing 6- to 8- membered heteroaryl group and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a methyl group, a methoxy, -NR'R" group and a group of formula (a):
  • L 3 represents -CO- group, or a -C(0)0- group
  • R 4 is selected from the group consisting of a hydroxyl group, a cyano group, a - CF 3 group, a methyl group,
  • R a and R b are independently selected from the group consisting of a hydrogen atom, a hydroxyl, 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-containing 4- membered heterocyclic group,
  • G 2 is selected from the group consisting of a pyridyl group and a monocyclic N-containing 6- membered heterocyclyl group, wherein the pyridyl and heterocyclyl groups are substituted by one or more substituents selected from a halogen atom and a group of formula (a):
  • R 4 is selected from the group consisting of a hydroxyl group and a cyano group
  • G 2 represents a monocyclic N-containing 6- membered heterocyclyl group which is substituted by a group of formula (a):
  • X represents a -CR c -group, wherein Rc represents a hydrogen atom
  • Gi is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group,
  • ⁇ U represents a direct bond
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -0-(CH 2 )2-, wherein p has a value of 0 or 1 ,
  • R 1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH 2 )2- NR'R" group and a -NR'R"- group, wherein both R' and R" represents a methyl group.
  • R 2 is a fluorine atom
  • ⁇ R 3 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • G 2 represents a monocyclic N-containing 6- membered heterocyclyl group
  • o L 3 represents -CO- group
  • o R 4 is selected from the group consisting of a hydroxyl group and a cyano group
  • R a and R b represent a hydrogen atom
  • m has a value of 1 .
  • the present invention is related to compounds of formula (I), wherein X is selected from the group consisting of -N- and -CR C - group, wherein R c is selected from the group consisting of a hydrogen atom and a methyl group, Gi is selected from the group consisting of a phenyl group, a monocyclic N-containing 6-membered heteroaryl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a fluorine atom, a hydroxyl group, -SCH 3 group, -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino-Ci-2 alkyl group and - NR'-S0 2 -R" group,
  • L-i is selected from the group consisting of a direct bond and -NH-(CH 2 )- group
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -(CH 2 )-NR-, -O-(CH 2 ) (0 - 2) , -C(0)0- , and -NR- group, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group,
  • R 1 is selected from the group consisting of a hydrogen atom, a Ci -2 alkyl group, which alkyl group is substituted with a -NR'R" group, a phenyl group, a mono- or bicylic 5- to 9-membered heteroaryl group containing at least one nitrogen atom as heteroatom and a mono- or bicyclic 5- to 9-membered heterocyclyl group containing at least one nitrogen atom as heteroatom, wherein the phenyl, heteroaryl and heterocyclyl groups are 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 C4-5 alkyl group, a Ci -3 hydroxyalkyl group, a methoxy group, a -(0) ( o-i ) (CH 2 ) (2-3) -NR'R" group, - NR'R” group, a -C(0)-
  • R 2 is selected from the group consisting of a fluorine atom and a methyl group
  • R 3 is selected from the group consisting of a hydrogen atom and a -(CH 2 ) 2 NR'R" group,
  • G 2 is selected from the group consisting of a pyridyl group substituted with a fluorine atom and a piperidinyl substituted with a group of formula (a):
  • L 3 represents a direct bond, -CO- group, or a -C(0)0- group
  • R 4 is selected from the group consisting of a hydroxyl group, -(CH 2 )(o-i)-CN, a - CF 3 group, a methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups, and a Ci -2 aminoalkyl group, both R a and R b are a hydrogen atom or R a and R b together with the carbon atom to which they are attached form a 4-membered heterocyclic group containing oxygen atom as heteroatom, R 5 is selected from the group consisting of a hydrogen atom and a methyl group,
  • R d represents a t-butyl group, a linear Ci -2 alkyl group optionally substituted with one substituent selected from a phenyl group and a -NR'R
  • R e is selected from the group consisting of a phenyl group optionally substituted with a CF 3 group or with a t-butyl group, and a monocyclic 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as heteroatom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF 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 form a 5 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 , and p has a value of 0, 1 or 2.
  • the present invention is related to compounds of formula (I), wherein
  • X is selected from the group consisting of -N- and -CR C - group, wherein R c is selected from the group consisting of a hydrogen atom and a methyl group,
  • Gi is selected from the group consisting of a phenyl group, a monocyclic N- containing 6- membered heteroaryl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a fluorine atom, a hydroxyl group, -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino-Ci- 2 alkyl group and -NR'-S0 2 -R" group, ⁇ L-i is selected from the group consisting of a direct bond and -NH-(CH 2 )- group,
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -O-(CH 2 ) (0 - 2 ) and -NR- group, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group,
  • R 1 is selected from the group consisting of a hydrogen atom, a Ci -2 alkyl group substituted with a -NR'R" group, a phenyl group, a mono- or bicylic 5-9 membered heteroaryl group containing at least one nitrogen atom as heteroatom and a mono- or bicyclic 5- to 9- membered heterocyclyl group containing at least one nitrogen atom as heteroatom, wherein the phenyl, heteroaryl and heterocyclyl groups are 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 C4-5 alkyl group, a Ci -3 hydroxyalkyl group, a methoxy group, a -(0)(o-i)(CH 2 )( 2-3 )-NR'R" group, -NR'R" group, a -CO-0-R d group, a -CH 2
  • R 2 is selected from the group consisting of a fluorine atom and a methyl group
  • R 3 is selected from the group consisting of a hydrogen atom and a -(Ch ⁇ NR'R"- group
  • G 2 is selected from the group consisting of a pyridyl group substituted with a
  • o L 3 represents a direct bond, -CO- group, or a -C(0)0- group
  • o R 4 is selected from the group consisting of a hydroxyl group, -(CH 2 )(o-i)-CN, a - CF 3 group, an methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups,
  • both R a and R b are a hydrogen atom or R a and R b together with the carbon atom to which they are attached form a 4-membered heterocyclic group containing oxygen atom as heteroatom,
  • R 5 is selected from the group consisting of a hydrogen atom and a methyl group
  • R d represents a t-butyl group, a linear Ci -2 alkyl group optionally substituted with one substituent selected from a phenyl group and a-NR'R",
  • R e is selected from the group consisting of a phenyl group optionally substituted with a CF 3 group or with a t-butyl group, and a monocyclic 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as heteroatom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from a linear or branched Ci -4 alkyl group and a -CF 3 group,
  • R' and R" independently represents a hydrogen atom, a methyl group or a
  • cyclopentyl group or R' and R" together with the nitrogen atom to which they are attached form a 5- to 6-membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a dimethylamino group,
  • • n, m and q independently have a value of 0 or 1 .
  • • p has a value of 0, 1 or 2.
  • Particular individual compounds of the invention include:
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, 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, Third Edition, Wiley, New York, 1999, and references cited therein.
  • compounds of general formula (I) may be prepared by the following synthetic route as illustrated in Scheme 1 :
  • compounds of formula (I) may be obtained from chloropyrimidines of formula (IV) by reaction with compounds of formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or tetrakis(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 temperatures ranging from 80 °C to 1 10 °C with or without the use of microwave irradiation.
  • a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or tetrakis(triphenylphosphine)palladium(0) in a solvent such as toluene, 1 ,4- dioxane or 1 ,
  • Boronic acids or boronates of formula (V) where L-i is a direct bond, Gi is an aryl or heteroaryl ring and Y is a boronic acid or boronate ester may be commercially available or may be prepared from the corresponding haloderivatives of formula (V), where Y is a bromine atom or a chlorine atom, by treatment with an appropriate boron reagent such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) with a palladium catalyst such as bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or bis(dibenzylideneacetone)palladium(0), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane, with or without the presence of a ligand such as tricyclohex
  • compounds of formula (I) may be prepared by reaction of chloroderivatives of formula (IV) with heterocyclic amines of formula (V), where Y is an hydrogen atom, in the presence of a base such as sodium hydrogencarbonate or /V-ethyl-/V-isopropylpropan-2-amine without the use of a solvent or in a solvent such as ⁇ /, ⁇ /'-dimethylacetamide or 1 -methylpyrrolidin-2-one at temperatures ranging from 80-130 °C with or without the use of microwave irradiation.
  • a base such as sodium hydrogencarbonate or /V-ethyl-/V-isopropylpropan-2-amine
  • compounds of formula (I) may be obtained by reaction of chloropyrimidines of formula (IV) with amines of formula (V), where Y is an hydrogen atom, in a solvent such as /V-methylpyrrolidone at 140 °C with the use of microwave irradiation.
  • a suitable solvent such as dichloromethane at temperatures ranging from 0 °C to ambient temperature.
  • esters of formula (VIII) with a mixture of trimethylaluminum and ammonium chloride in a solvent such as toluene at 80 °C provides amidine intermediates of formula (IX).
  • Amidines of formula (IX) may be reacted with malonate esters of formula (X) to give dihydroxypirimidines of formula (XI). Such reactions may be carried out in the presence of a suitable base such as sodium methoxide in a solvent such as methanol at temperatures ranging from 0 °C to ambient temperature. Dihydroxypirimidines of formula (XI) may be converted to dichloropyrimidines of formula (II) by treatment with a suitable chlorinating agent, for example phosphorus(V) oxychloride, at temperatures ranging from 25 °C to reflux.
  • a suitable chlorinating agent for example phosphorus(V) oxychloride
  • compounds of formula (XIV) may be obtained from dichloropyrimidines of formula (XIII) by reaction with compounds of formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions.
  • Such reactions may be catalysed by a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as 1 ,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 °C.
  • compounds of formula (I), where R 3 is an hydrogen atom may undergo further reaction with a suitable base, such as sodium hydride, in a solvent such as ⁇ /, ⁇ /'-dimethylformamide, followed by the addition of an alkylating agent, such as methyl iodide or (2-chloroethyl)dimethylamine hydrochloride at temperatures ranging from ambient temperature to 80 °C, to furnish compounds of formula (I), where R 3 is now a methyl or a -(CH 2 )2-N Me2 group.
  • a suitable base such as sodium hydride
  • a solvent such as ⁇ /, ⁇ /'-dimethylformamide
  • an alkylating agent such as methyl iodide or (2-chloroethyl)dimethylamine hydrochloride
  • compounds of formula (I), in which the residue at G-i, G 2 or R 1 contains an alcohol, phenol or carboxylic acid moiety functionalized with an appropriate protecting group such as benzyl (Bn) or methoxy (OMe), may be deprotected at the alcohol, phenol or carboxylic acid moiety under standard conditions ⁇ Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540).
  • an appropriate protecting group such as benzyl (Bn) or methoxy (OMe
  • the free alcohol moiety may then be oxidized under standard conditions to give the corresponding aldehyde.
  • compounds of formula (I) and compounds of formula (XIV) in which the residue at d contains an aldehyde moiety may be further reacted with a primary or secondary amine in the presence of a reductive agent, such as sodium triacetoxyborohydride, in a solvent such as dichloromethane at ambient temperature to give compounds of formula (I) and compounds of formula (XIV) in which the residue at Gi is now a secondary or tertiary amine.
  • a reductive agent such as sodium triacetoxyborohydride
  • compounds of formula (I), in which the residue at Gi, G 2 or R 1 contains an amine moiety functionalized with an appropriate protecting group such as ie f-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), may be deprotected at the amine moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540).
  • the corresponding free amine may then be further functionalized under standard conditions to give the corresponding amides, carbamates and /V-alkylated amines.
  • Starting compounds are commercially available or may be obtained following the conventional synthetic methods already known in the art.
  • Trimethylaluminium solution in toluene (62 mL, 124 mmol) was added dropwise to a cooled (0 °C) suspension of ammonium chloride (6.18 g, 1 15.6 mmol) in toluene (133 mL) and the resulting mixture was stirred until no more gas was formed.
  • Trifluoroacetic acid (1 .80 mL, 23.37 mmol) was added dropwise to a solution of tert- butyl (3R)-3-( ⁇ 5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1 -yl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl ⁇ amino)piperidine-1 -carboxylate (Preparation 17a, 2.86 g, 4.64 mmol) in dichloromethane (80 mL) and the resulting mixture was stirred overnight at room temperature.
  • 3-Chloro-/V,/V-dimethylpropan-1 -amine dihydrochloride (3.10 g, 19.60 mmol) was added to a suspension of 4-hydroxybenzaldehyde (2.00 g, 16.40 mmol), cesium carbonate (13.30 g, 41.00 mmol) and potassium iodide (0.10 g, 0.61 mmol) in N,N- dimethylformamide (40 mL) and the resulting mixture was stirred at 80 °C for 2 hours.
  • the aqueous phase was extracted with ethyl acetate (x3) and the organic fractions were combined and washed with 2.0 N aqueous sodium hydroxide solution, water and brine.
  • the organic phase was separated, dried over magnesium sulfate and the solvent was evaporated to give the title compound (1 .93 g, 72%).
  • reaction mixture was washed with 2M aqueous solution of sodium hydroxide and the organic layer was separated, dried over magnesium sulfate and the solvent evaporated to dryness.
  • 4M Solution of hydrochloric acid in 1 ,4-dioxane was added to the residue and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness to yield the hydrochloride salt of the title compound (299 mg, 45%) as a solid.
  • a Schlenk tube was charged with ie f-butyl piperazine-1 -carboxylate (0.12 g, 0.62 mmol), 4-bromo-2,6-dimethylpyridine (0.15 g, 0.81 mmol), sodium ie/f-butoxide (0.09 g, 0.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 g, 0.02 mmol) and toluene (4 mL).
  • the Schlenk tube was subjected to three cycles of evacuation- backfilling with argon and then tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol) was added.
  • the Schlenk 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 ethyl acetate (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title compound (198 mg, 100%) as an oil.
  • diatomaceous earth Celite ®
  • x3 ethyl acetate
  • a Schlenk tube was charged with ie f-butyl piperazine-1 -carboxylate (1 .74 g, 9.34 mmol), 4-bromo-2-chloropyridine (1 .35 g, 7.02 mmol), sodium ie/f-butoxide (1 .35 g, 14.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.32 g, 0.55 mmol) and toluene (45 mL).
  • the Schlenk tube was subjected to three cycles of evacuation- backfilling with argon and then tris(dibenzylideneacetone)dipalladium (0.17 g, 0.19 mmol) was added.
  • the Schlenk tube was sealed and the mixture was stirred at 90 °C for 4 hours.
  • the reaction mixture was filtered through diatomaceous earth (Celite ® ) and washed with ethyl acetate. The filtrate and washings were combined and the solvents were evaporated to dryness. The residue was purified by flash chromatography (hexanes to 3:7 hexanes/ethyl acetate) to yield the title compound (1 .34 g, 64%) as a yellow solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then palladium acetate (0.01 g, 0.05 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 80 °C. After cooling to room emperature, the reaction mixture was filtered through diatomaceous earth (Celite ® ) and washed with ethyl acetate. The filtrate and washings were combined and the solvents were evaporated to dryness. The residue was purified by reverse phase chromatography (water/acetonitrile/methanol as eluents) to yield the title compound (320 mg, 96%) as an oil.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tris(dibenzylideneacetone) dipalladium (76 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (10 mg, 0.02 mmol) were added. After three further cycles of evacuation- backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth Celite ® and the filtrate was concentrated to dryness. The crude residue was purified by reverse phase chromatography (gradient from water to methanol) to yield the title compound (188 mg, 60%).
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride dichloromethane complex (0.075 g, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 90 °C overnight. The residue was diluted with water and extracted with a mixture of diethyl ether/pentane 1 :1 . The organic layer was washed with water, dried over magnesium sulfate and the solvents were evaporated to yield the title compound (0.4 g, 87%) as a gum.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino) ferrocene]palladium(ll) dichloride dichloromethane complex (0.04 g, 0.05 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was removed and the residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 93:7) to yield the title compound (145 mg, 46%) as a solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis (diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (0.08 g, 0.1 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The reaction mixture cooled to room temperature and partitioned between dichloromethane and water. The organic phase was separated, diluted with pentane, washed with diluted aqueous sodium hydroxide solution, dried over magnesium sulfate and the solvents were evaporated to dryness. The residue was treated with pentane and filtered. The filtrate was evaporated under vacuum to give the title compound (0.45 g, 67%) as a brown solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (279 mg, 0.24 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The solvent was removed and the residue was purified by flash chromatography (hexanes to hexanes/ethyl acetate 1 :9) to yield the title compound (915 mg, 77%) as a white solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The solvent was removed and the residue was purified by flash chromatography (hexane/ethyl acetate from 50% to 100%) to yield the title compound (0.27 g, 64%) as a white solid.
  • reaction mixture was washed with water, dried over sodium sulfate and the solvent was evaporated to dryness.
  • the residue was purified by flash chromatography (chloroform to chloroform/methanol /ammonia 40:2:0.2) to yield the title compound (42 mg, 40%) as a yellow solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (73 mg, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was evaporated and the residue was purified by flash chromatography (hexanes to ethyl acetate) to yield the title compound (0.34 g, 64%) as a white solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride complex with dichloromethane (0.10 g, 0.12 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C for 4 hours. The mixture was cooled, filtered thorugh diatomaceous earth (Celite ® ) and the solvent was concentrated to dryness. The residue was treated with petroleum ether, filtered and the solvent was evaporated to dryness to yield the title compound (0.5 g, 86%) as a yellow oil.
  • Lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 20 mL, 20 mmol) was added to a suspension of 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-tetraza-1 -phospha bicyclo ⁇ 3.3.3 ⁇ undecane (0.04 g, 0.17 mmol) in toluene (32 mL) and the reaction mixture was subjected to three cycles of evacuation-backfilling with argon.
  • a microwave reactor was charged 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'-bi-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 cycles of evacuation- backfilling with argon and then tricyclohexylphosphine (0.15 g, 0.53 mmol) and bis(dibenzylideneacetone)palladium(0) (0.08 g, 0.14 mmol) were added.
  • the reaction mixture was subjected to microwave irradiation for 2 hours at 150 °C, filtered through diatomaceous earth (Celite ® ) and the solvent was evaporated to dryness. The residue was treated with diethyl ether and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 90:10) to yield the title compound (0.83, 58%) as a solid.
  • the aqueous phase was separated, acidified by addition of concentrated hydrochloric acid solution and extracted with a 1 :1 mixture of diethyl ether/hexane.
  • the organic layer was separated, dried over magnesium sulfate and the solvent was partially evaporated.
  • the precipitate formed was filtered and dried to yield the title compound (0.75 g, 77%) as a white solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (0.15 g, 0.18 mmol) was added. After three further cycles of evacuation- backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The organic phase was separated, diluted with pentane, washed with diluted aqueous sodium hydroxide solution, dried over magnesium sulfate and the solvents were evaporated to dryness. The residue was treated with hexane and filtered to yield the title compound (0.35 g, 36%).
  • PREPARATION 76 ( ?)-3-(3-((5-Fluoro-6-(4-formyl-3-hydroxyphenyl)-2-(pyrazolo[1 ,5-a]pyridin-3-yl) pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropanenitrile
  • a microwave reactor was charged with 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'- bi-1 ,3,2-dioxaborolane (0.934 g, 3.68 mmol), potassium acetate (0.492 g, 5.01 mmol) and 1 ,2-dimethoxyethane (5 mL).
  • the reactor was subjected to three cycles of evacuation-backfilling with argon and then tricyclohexylphosphine (0.1 13 g, 0.12 mmol) and bis(dibenzylideneacetone)palladium(0) (0.058 g, 0.30 mmol) were added.
  • the reaction mixture was subjected to microwave irradiation for 2 hours at 150 °C, filtered through diatomaceous earth (Celite ® ) and the solvent was evaporated to dryness. The residue was treated with diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried to yield the title compound (0.592 g, 43%) as a white solid.

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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

PYRAZOLOPYRIMIDIN-2-YL DERIVATIVES AS JAK INHIBITORS
Cytokines have critical functions in regulating many aspects of immunity and inflammation, ranging from the development and differentiation of immune cells to the suppression of immune responses. Type I and type II cytokine receptors lack intrinsic enzymatic activity capable of mediating signal transduction, and thus require association with tyrosine kinases for this purpose. The JAK family of kinases comprises four different members, namely JAK1 , JAK2, JAK3 and TYK2, which bind to type I and type II cytokine receptors for controlling signal transduction (Murray PJ, (2007). The JAK-STAT signalling pathway: input and output integration. J Immunol, 178: 2623). Each of the JAK kinases is selective for the receptors of certain cytokines. In this regard, JAK-deficient cell lines and mice have validated the essential role of each JAK protein in receptor signalling: JAK1 in class II cytokine receptors (I FN and IL-10 family), those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21 ) (Rodig et al. (1998). Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373; Guschin et al. (1995). A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 14: 1421 ; Briscoe et al. (1996). Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state. EMBO J. 15:799); JAK2 in hematopoietic factors (Epo, Tpo, GM-CSF, IL-3, IL-5) and type II IFNs (Parganas et al., (1998). JAK2 is essential for signalling through a variety of cytokine receptors. Cell, 93:385); JAK3 in receptors sharing the common gamma chain (IL-2 family) (Park et al., (1995). Developmental defects of lymphoid cells in JAK3 kinase-deficient mice. Immunity, 3:771 ; Thomis et al., (1995). Defects in B lymphocyte maturation and T 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 Tyk2 in the receptors of IL- 12, IL-23, IL-13 and type I IFNs (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, although 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 leads sequentially to JAK activation by phosphorylation, receptor phosphorylation, STAT protein recruitment and STAT activation and dimerization. The STAT dimer then functions as a transcription factor, translocating to the nucleus and activating the transcription of multiple response genes. There are seven STAT proteins identified: STAT1 , STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Each particular cytokine receptor associates preferentially with a particular STAT protein. Some associations are independent of cell type (ex: IFNg- STAT1 ) while others may be cell type dependent (Murray PJ, (2007). The JAK-STAT signaling pathway: input and output integration. J Immunol, 178: 2623).
The phenotype of deficient mice has provided insights on the function of each JAK and the cytokine receptors signaling through them. JAK3 associates exclusively with the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. By virtue of this exclusive association, JAK3 knock out mice and common gamma chain deficient mice have an identical phenotype (Thomis et al., (1995).
Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Science, 270:794; DiSanto et al., (1995). Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. PNAS, 92:377). Moreover, this phenotype is shared to a great extent with SCID patients that hold
mutations/defects in the common gamma chain or JAK3 genes (O'Shea et al., (2004). JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41 : 727). JAK3-deficient mice are viable but display abnormal lymphopoiesis which leads to a reduced thymus size (10-100 fold smaller than wild type). JAK3-deficient peripheral T cells are unresponsive and have an activated/memory cell phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice. J. Leuk. Biol. 63: 669). The thymic defect in these mice strongly resembles that seen in IL-7 and IL-7 receptor knockout mice, suggesting that the absence of IL-7 signaling accounts for this defect in JAK3 -/-mice (von Freeden-Jeffry et al., (1995). Lymphopenia in
Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant Cytokine. J Exp Med, 181 :1519; Peschon et al, (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These mice, like SCID humans, have no NK cells, probably due to the absence of IL-15 signaling, a survival factor for these cells. JAK3 knockout mice, unlike SCID patients, show deficient B cell lymphopoiesis while in human patients, B cells are present in circulation but are not responsive leading to 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 and T cell development in mice and humans. On the other hand, Grossman et al. (1999. Dysregulated myelopoiesis in mice lacking JAK3. Blood, 94:932:939) have shown that the loss of JAK3 in the T-cell compartment drives the expansion of the myeloid lineages leading to dysregulated myelopoiesis.
JAK2 -deficient mice are embrionically lethal, due to the absence of definitive erythropoiesis. Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are not affected. JAK2 is not required for the generation, amplification or functional differentiation of lymphoid progenitors (Parganas et al., (1998). JAK2 is essential for signaling through a variety of cytokine receptors. Cell, 93:385).
JAK1 -deficient mice die perinatally due to a nursing defect. JAK1 binds exclusively to the gp130 chain shared by the IL-6 cytokine family (i.e. LIF, CNTF, OSM, CT-1 ) and along with JAK3, is an essential component of the receptors sharing the common gamma chain, by binding to the non-shared receptor subunit. In this regard, JAK1 - deficient mice show similar hematopoiesis defects as JAK3-deficient mice. In addition, they show defective responses to neurotrophic factors and to all interferons (class II cytokine receptors) (Rodig et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373).
Finally, Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function. Immunity, 13:561 ). However, human Tyk2 deficiency demonstrates that Tyk2 is involved in the signaling from IFN-a, 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 kinases in transducing the signal from a myriad of cytokines makes them potential targets for the treatment of diseases in which cytokines have a pathogenic role, 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, as well as in solid and hematologic malignancies such as myeloproliferative disorders, leukemia and lymphomas. Inhibition of JAK kinases, especially JAK1 and JAK3, could give rise to potent immunosuppression which could be used therapeutically to prevent transplant rejection. In this regard, the JAK inhibitor CP-690,550 (tofacitinib, formerly tasocitinib) has shown efficacy in several animal models of transplantation (heretopic heart transplantation in mice, cardiac allografts implanted in the ear of mice, renal allotransplantation in cynomolgous monkeys, aorta and tracheal transplantation in rats) by prolonging the mean survival time of grafts (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 and anti-inflammatory cytokine activities favours the induction of autoimmunity, followed by chronic inflammation and tissue destruction. In this regard, the pathogenic role of IL-6 in rheumatoid arthritis (RA) has been validated clinically by the use of the anti-IL-6R antibody tocilizumab. IL-6 activates the transcription factor STAT3, through the use of JAK1 binding 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 the abnormal growth and survival properties of RA synoviocytes (Ivashkiv and Hu (2003). The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arth & Rheum. 48:2092). Other cytokines that have been implicated in the pathogenesis of arthritis include IL-12 and IL-23, implicated in Th1 and Th17 cell proliferation, respectively; IL-15, and GM-CSF (Mclnnes and Schett, (2007). Cytokines in the pathogenesis of rheumatoid arthritis. Nature Rew Immunol. 7:429.). The receptors for these cytokines also utilize JAK proteins for signal transduction, making JAK inhibitors potential pleiotropic drugs in this pathology. Consequently, administration of several JAK inhibitors in animal models of murine collagen-induced arthritis and rat adjuvant- induced arthritis has shown to reduce inflammation, and tissue destruction (Milici et al., (2008). Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arth. Res. 10:R14).
Inflammatory bowel disease (IBD) encloses two major forms of intestinal inflammation: ulcerative colitis and Crohn's disease. Growing evidence has shown that multiple cytokines, including interleukins and interferons, are involved 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 propia 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). Specifically, STAT3 has been shown to be constitutively active in intestinal T cells of Crohn's disease patients and a JAK inhibitor has been shown to block the 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 a JAK inhibitor could 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 generation of multiple sclerosis has long been known. Potential therapies include blockade of 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. 1 18:3557), cytokines that signal through the JAK- STAT pathways. Use of tyrphostin, a JAK inhibitor, has been shown to inhibit IL-12- induced phosphorylation of STAT3, and to 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 multikinase inhibitor, CEP701 , has been shown to reduce secretion of TNF- alpha, IL-6 and IL-23 as well as the levels of phospho-STAT1 , STAT3, and STAT5 in peripheral DCs of mice with EAE, significantly improving the clinical course of EAE in mice (Skarica et al, (2009). Signal transduction inhibition of APCs diminishes Th17 and Th1 responses in experimental autoimmune encephalomyelitis. J. Immunol.
182:4192.). Psoriasis is a skin inflammatory disease which involves a process of immune cell infiltration and activation that culminates in epithelial remodeling. The current theory behind the cause of psoriasis states the existence of a cytokine network that governs the interaction between immune 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 is found elevated in psoriatic skin, along with IL-12. IL-23 induces the formation of Th17 cells which in turn produce IL-17 and IL-22, the last one being responsible for epidermis thickening. IL-23 and IL-22 induce the phosphorylation of STAT-3, which is found abundantly in psoriatic skin. JAK inhibitors may thus be therapeutic in this setting. In accordance, a JAK1/3 inhibitor, R348, has been found to attenuate psoriasiform skin inflammation in a spontaneous T cell-dependent mouse model of psoriasis (Chang et al., (2009). JAK3 inhibition significantly attenuates psoriasiform skin inflammation on CD18 mutant PL/J mice. J Immunol. 183:2183). Th2 cytokine-driven diseases such as allergy and asthma could also be a target of JAK inhibitors. IL-4 promotes Th2 differentiation, regulates B-cell function and
immunoglobulin class switching, regulates eotaxin production, induces expression of IgE receptor and MHC II on B cells, and stimulates mast cells. Other Th2 cytokines like IL-5 and IL-13 can also contribute to eosinophil recruitment in bronchoalveolar lavage by stimulating eotaxin production. Pharmacological inhibition of JAK has been shown to reduce the expression of IgE receptor and MHCII 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). Furthermore, JAK3-deficient mice display poor eosinophil recruitment and mucus secretion to the airway lumen upon 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). JP£7295:912.). In this regard, systemic administration of the CP-690,550 JAK inhibitor in mice has been shown to reduce the eosinophil count as well as the levels of eotaxin and IL13 in BAL in a murine model of pulmonary eosinophilia (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 is increasing evidence that cytokines play a pathogenetic role in ocular inflammatory disease such as uveitis or dry eye syndrome. Some cytokines implicated in experimental autoimmune uveitis, such as IL-2, IL-6, IL-12 and IFNg, would be amenable to JAK inhibition (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 biologicals that interfere with IL-2 signaling such as cyclosporine or anti-IL-2 receptor antibody (daclizumab) have shown efficacy in the treatment of keratoconjuctivitis sicca and refractory uveitis, respectively (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 conjuctival congestion, mast cell activation and eosinophil infiltration, could benefit from JAK inhibition. STAT6- deficient mice, showing decreased TH2-mediated immune responses which are normally triggered by IL-4, do not develop the classical early and late phase responses, suggesting that IL-4 pathway abrogation through JAK inhibition may 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 is growing evidence of the critical role of STAT3 activity in processes involved in tumorigenesis like cell cycle dysregulation, promotion of uncontrolled growth, induction of survival factors and inhibition of 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 shown to promote apoptosis of cancer cells, inhibition of angiogenesis and up-regulation of host immunocompetence. Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors may provide a therapeutic option to the treatment of this disease. In this regard, the use of the JAK inhibitor tyrphostin has been shown to induce apoptosis of malignant cells and 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 dysregulated JAK-STAT pathways may benefit from JAK inhibition. Recent studies have implicated dysregulation of JAK2 kinase activity by chromosomal translocations and mutations within the pseudokinase domain (such as the JAK2V617F mutation) in a spectrum of myeloproliferative diseases (Ihle and Gililand, 2007), including polycythemia vera, myelofibrosis and essential
thrombocythemia. In this regard, several JAK inhibitors that tackle JAK2 potently, 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: 31 1 ), 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, 1 1 1 : 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 cell lines and primary cells from polycythemia vera patients. Leukemia, 23:1441 ) have been proposed for treating myeloproliferative diseases on the basis of their antiproliferative activity on cells carrying the JAK2V617F mutation. Similarly, T-cell leukemia due to human T-cell leukemia virus (HTLV-1 ) transformation is associated with JAK3 and STAT5 constitutive activation (Migone et al, (1995). Constitutively activated JAK-STAT pathway in T cells transformed with HTLV-I. Science, 269: 79) and JAK inhibitors may 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) pointing to this kinase as a target for the development of novel antileukemic drugs. Conditions in which targeting of the JAK pathway or modulation of the JAK kinases, particularly JAK1 , JAK2 and JAK3 kinases, are contemplated to be therapeutically useful for the treatment or prevention of diseases include: neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g. diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease); respiratory inflammation diseases (e.g. asthma, chronic obstructive pulmonary disease), inflammation-linked ocular diseases or allergic eye diseases (e.g. dry eye, glaucoma, uveitis, diabetic retinopathy, allergic conjunctivitis or age-related macular degeneration) and skin inflammatory diseases (e.g., atopic dermatitis or psoriasis).
In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of the JAK pathway or of the JAK Kinases it is immediately apparent that new compounds that modulate JAK pathways and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients.
Provided herein are novel pyrazolopyrimidin-2-yl derivatives for use in the treatment of conditions in which targeting of the JAK pathway or inhibition of JAK kinases can be therapeutically useful.
The compounds described in the present invention are simultaneously potent JAK1 , JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as
myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphomas 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-linked ocular 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 (such as atopic dermatitis or psoriasis).
It has now been found that certain pyrazolopyrimidin-2-yl derivatives are novel and potent JAK inhibitors and can therefore be used in the treatment or prevention of these diseases. Thus the present invention is directed to compounds of formula (I), or a
pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof:
Figure imgf000010_0001
Formula (I)
wherein
X is selected from the group consisting of -N- and -CRC- group,
Gi is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci-4 alkyl group, a Ci-4 thioalkyl group, a Ci-2 hydroxyalkyl group, a di-(Ci-2 alkyl)amino-Ci-4 alkyl group and a -NR'-S02-R" group, U is selected from the group consisting of a -(CH2)(o-i)-, -0-, -NRx-(CH2)(o-i)- group, wherein Rx is selected from the group consisting of a hydrogen atom and a Ci-2 alkyl group optionally substituted with a -(CH2)(o-2)NR'R"- group,
L2 is selected from the group consisting of a -(CH2)P-, -(CH2)-NR-, -NR-(CH2)-, -O- (CH2)(o-2)> -C(0)0-, -S- and -NR- group, wherein R represents a hydrogen atom or a C-i-4 alkyl group optionally substituted with a group selected from -NR'R"- group and a phenyl group wherein said phenyl group is optionally substituted with a hydroxyl group,
R1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci-4 alkyl group optionally substituted with a -NR'R" group, a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a mono- or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from O, S and N and a mono- or bicyclic 5- to 14-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups 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 Ci-6 alkyl group, a linear or branched Ci-6 hydroxyalkyl group, a linear or branched Ci-4 alkoxy group, a -(0)(o-i)(CH2)(o-3)-NR'R" group, a -CO-0-Rd group, a -CH2-Re group, a monocyclic 5-to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5-to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N wherein said heterocyclyl and heteroaryl group independently are optionally substituted with one or more substituents selected from the group consisting of a Ci-2 alkyl group, -C(0)-(Ci-2 alkyl) group and a -NR'R" group;
R2 is selected from the group consisting of a hydrogen atom, a halogen atom and a Ci-4 alkyl group,
R3 is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group and a -(CH2)(2-4)NR'R"- group,
G2 is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci-4 alkoxy group, a Ci-2 hydroxyalkyl group, -NR'R" group and a group of formula (a):
Figure imgf000012_0001
L3 represents a direct bond, -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, a -(CH2)(o-i)-CN group, a -CF3 group, a linear or branched Ci-4 alkyl group, a linear or branched
Ci-4 alkoxy group, a linear or branched Ci-4 hydroxyalkyl group and a Ci-4 alkylamino group wherein the alkyl and the hydroxyalkyl groups are optionally substituted with one or more methyl groups, Ra and Rb are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci-4 alkyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 3- to 5-membered heterocyclic group containing at least one heteroatom selected from N, O and S, R5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group,
Rc is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, a C5-8 aryl group, a 5- to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci-4 alkyl group,
Rd represents a linear or branched Ci-4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a-NR'R" or Rd represents a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N optionally substituted with a Ci-2 alkyl group,
Re is selected from the group consisting of a monocyclic C5-8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic rings are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci-4 alkyl group and a -CF3 group, R' and R" independently represent a hydrogen atom, a Ci-4 alkyl group or a C3-6 cycloalkyl group, or R' and R" together with the nitrogen atom to which they are attached form a 4- to 6-membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino 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 processes and intermediates described herein, which are useful for preparing said compounds.
The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
The invention also provides a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier.
The invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to
amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and inflammatory diseases; more in particular wherein 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 is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more in particular wherein 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 provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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; comprising administering a therapeutically effective amount of the compounds of the invention or a pharmaceutical composition of the invention to a subject in need of such treatment.
In another embodiment of the present invention, the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome;
myeloproliferative disorders (MPDs); cancer and hematologic malignancies, leukemia, lymphomas and solid tumors.
In a preferred embodiment, the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, 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) the compounds of the invention as described herein; and (ii) 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 mielofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, 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. As used herein the term CrC6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, isopentyl, 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-methylpentyl, 3-methylpentyl and iso-hexyl radicals.
As used herein, the term Ci-C6 hydroxyalkyi embraces linear or branched alkyl radicals having 1 to 6 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxy methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxylhexyl.
As used herein, the term Ci-C4 thioalkyl embraces radicals containing a linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -S- radical. Preferred optionally substituted thioalkyl radicals include thiomethyl, thioethyl, n- thiopropyl, i-thiopropyl, n-thiobutyl, sec-thiobutyl and t-thiobutyl.
As used herein, the term (Ci-C4)alkylamino embraces radicals containing an optionally substituted, linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -NH- radical. Preferred (Ci-C4)alkylamino radicals include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, sec-butylamino and t- butylamino.
As used herein, the term di-(Ci-C2)alkylamino embraces radicals containing a trivalent nitrogen atom with two linear or branched alkyl radicals of 1 to 2 carbon atoms in each alkyl radical. Preferred di-(Ci-C2)alkylamino radicals include dimethylamino, diethylamino and methyl(ethyl)amino.
As used herein, the term Ci-C4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms. Examples of C C4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy or t-butoxy.
As used herein, the term C3-C8 cycloalkyl embraces saturated monocyclic carbocyclic radicals having from 3 to 8 carbon atoms, preferably from 3 to 7 carbon atoms.
Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, the term C5-C8 aryl radical embraces typically a C5-C8, preferably C5-C6 monocyclic aryl radical such as phenyl.
As used herein, the term 5- to 14-membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10-membered ring system, more preferably a 5- to 6-membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N. A 5- to 14- membered heteroaryl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d] pyrimidinyl and the various pyrrolopyridyl radicals. As used herein, the term 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-Ci4 carbocyclic ring system, preferably C5- C-io carbocyclic ring system, more preferably C5-C6 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S. A heterocyclyl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
Examples of 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1 (3H)-one, 1 ,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1 ,4-azathianyl, oxepanyl, thiephanyl, azepanyl, 1 ,4-dioxepnayl, 1 ,4-oxathiepanyl, 1 ,4-oxaazepanyl, 1 ,4-dithiepanyl, 1 ,4- thiezepanyl, 1 ,4-diazepanyl, tropanyl, (1 S,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- tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, isoindolinyl and indolinyl. As used herein, the term bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyi or heterocyclyl group typically refers to a moiety containing a bond which is shared between a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group and a 5- to 9- membered cycloalkyi or heterocyclyl group, wherein said heteroaryl or heterocyclyl group contains at least one heteroatom selected from O, S and N. Typically said bicyclyl group is a phenyl or 5- or 6- membered heteroaryl group fused to a 5- or 6-, preferably 6-, membered cycloalkyi or heterocyclyl group. Typically said heteroaryl or heterocyclyl group contains 1 , 2 or 3, preferably 1 or 2, for example 1 , heteroatom selected from O, S and N. Examples include chromanyl groups or 1 ,2,3,4-tetrahydronaphthalenyl groups..
As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
As used herein, the term halogen atom embraces chlorine, fluorine, bromine and iodine atoms. A halogen atom is typically a fluorine, chlorine or bromine atom. The term halo when used as a prefix has the same meaning.
Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine. The resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
As used herein, the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic 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, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Other salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X") is associated with the positive charge of the N atom. X" may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. As used herein, an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate.
Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non- solvate form of the compounds. The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon- 14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
Typically, a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
In a preferred embodiment, the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites. The isotopic enrichment factor can be determined using conventional analytical methods known to an ordinary skilled 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 present invention, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
In the case of compounds that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of the present invention.
Typically, compounds of the present invention have the following formula:
Figure imgf000022_0001
Formula (I)
wherein
X is selected from the group consisting of -N- and -CRC- group,
Gi is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci-4 alkyl group, a Ci-2 hydroxyalkyl group, a di (Ci-2 alkyl)amino- Ci-4 alkyl group and -NR'-S02-R" group, U is selected from the group consisting of a -(CH2)(o-i)-, -0-, -NRx-(CH2)(o-i)- group, wherein Rx is selected from a the group consisting of a hydrogen atom and a Ci-2 alkyl group optionally substituted with -(CH2)(o-2)NR'R"- group, L2 is selected from the group consisting of a -(CH2)P-, -(CH2)-NR-, -O-(CH2)(0-2), -S- and -NR- group, wherein R represents a hydrogen atom or a Ci-4 alkyl group optionally substituted with a group selected from -NR'R"- group and a phenyl group wherein said phenyl group is optionally substituted with a hydroxyl group, R1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci-4 alkyl group optionally substituted with a -NR'R" group, a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a mono- or bicyclic 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups 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 Ci-6 alkyl group, a linear or branched Ci-6 hydroxyalkyl group, a linear or branched Ci-4 alkoxy group, a -(0)(o-i)(CH2)(o-3)-NR'R" group, a -CO-0-Rd group, a -CH2-Re group, a monocyclic 5-to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5-to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N wherein said heterocyclyl and heteroaryl group independently are optionally substituted with one or more substituents selected from the group consisting of a Ci-2 alkyl group and a -NR'R" group;
R2 is selected from the group consisting of a hydrogen atom, a halogen atom and a Ci-4 alkyl group, R3 is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group and a -(CH2)(2-4)NR'R"- group,
G2 is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci-4 alkoxy group, a Ci-2 hydroxyalkyl group., -NR'R" group and a group of formula (a):
Figure imgf000024_0001
wherein
L3 represents a direct bond, -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, a -(CH2)(o-i)-CN group, a -CF3 group, a linear or branched Ci-4 alkyl group, a linear or branched Ci-4 alkoxy group, a linear or branched Ci-4 hydroxyalkyl group and a Ci-4 alkylamino group wherein the alkyl and the hydroxyalkyl groups are optionally substituted with one or more methyl groups,
Ra and Rb are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci-4 alkyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 3- to 5-membered heterocyclic group containing at least one heteroatom selected from N, O and S,
R5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group,
Rc is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, a C5-8 aryl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci-4 alkyl group,
Rd represents a linear or branched Ci-4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a-NR'R",
Re is selected from the group consisting of a monocyclic C5-8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic ring are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci-4 alkyl group and a -CF3 group, R' and R" independently represents a hydrogen atom, a Ci-4 alkyl group or a C3-6 cycloalkyl group, or R' and R" together with the nitrogen atom to which they are attached form a 4 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 ,
p has a value of 0, 1 or 2.
Typically, X represents a -CRc-group, wherein Rc is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, a phenyl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci-4 alkyl group, and R' and R" independently represents a hydrogen atom or a Ci-4 alkyl group, preferably, Rc is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group, a Ci-2 alkoxy group, a phenyl group and a -NR'R" group, wherein R' and R" independently represents a hydrogen atom or a Ci-2 alkyl group, more preferably Rc is selected from the group consisting of a hydrogen atom and a methyl group, being most preferably, a hydrogen atom.
Typically, d is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci-2 hydroxyalkyl group and -NR'-S02-R" group.
In a preferred embodiment, d is selected from the group consisting of a phenyl group, a pyridyl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, pyridyl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, and a Ci-2 alkyl group, more preferably G-\ is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group. Typically, U is selected from the group consisting of a -(CH2)(o-i)-, -NRx-(CH2)(i)- group, wherein Rx is selected from a the group consisting of a hydrogen atom and a Ci-2 alkyl group optionally substituted with -(CH2)(o-2)NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L-i is selected from the group consisting of direct bond and -NRX-(CH2)(1)- group, wherein Rx is selected from a the group consisting of a hydrogen atom and a methyl group, more preferably, U represents a direct bond.
Typicaly, L2 is selected from the group consisting of a -(CH2)P-, -O-(CH2)(0-2)- and -NR- group, wherein R represents a hydrogen atom or a Ci-2 alkyl group optionally substituted with a -NR'R"- group, wherein p has a value of 0 or 1 and wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L2 is selected from the group consisting of a -(CH2)P-, -0-(CH2)2-, wherein p has a value of 0 or 1 . More preferably, L2 represents -CH2- group.
Typically, R1 is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group optionally substituted with a -NR'R" group, a monocyclic C5-8 aryl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from N, wherein the aryl, heteroaryl and heterocyclyl groups 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 Ci-5 alkyl group, a linear Ci-2 alkoxy group, a -(0)(o-i)(CH2)(o-3)-NR'R" group, a -CO-0-Rd group, a -CH2-Re group, wherein
· Rd represents a linear or branched Ci-4 alkyl group optionally substituted with one or more substituents selected from a methyl group and a-NR'R",
• Re is selected from the group consisting of a monocyclic C5-8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from N, which cyclic ring are optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF3 group,
• R' and R" independently represents a hydrogen atom or a methyl group or R' and R" together with the nitrogen atom to which they are attached form a 4 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group. In a preferred embodiment, R1 is selected from the group consisting of a hydrogen atom, a monocyclic C5-8 aryl group and a monocyclic 5- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the aryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a a linear or branched Ci-5 alkyl group, a linear C-i-2 alkoxy group, a -(0)(CH2)2-NR'R" group and a -NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, R1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH2)2-NR'R" group and a -NR'R"- group, wherein both R' and R" represents a methyl group. More preferably, R1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent wich is -(0)(CH2)2-NR'R" group, wherein both R' and R" represents a methyl group and q has a value of 1 .
Typically, q has a value of 1.
In a preferred embodiment of the present invention, the compounds of formula (I) are wherein L2 represents -CH2- group and R1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent which is -(0)(CH2)2-NR'R" group, wherein both R' and R" represents a methyl group and q has a value of 1.
Typically, R2 is selected from the group consisting of a hydrogen atom and a halogen atom, preferably a halogen atom, more preferably, a fluorine atom.
Typically, R3 is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group and a— (CH2)(2-4)NR'R"- group, wherein R' and R" are as defined in claim 1 , preferably, R3 is selected from a hydrogen atom and a -methyl group, more preferably R3 represents a hydrogen atom.
Typically, R5 is selected from the group consisting of a hydrogen atom and a methyl group, preferably a hydrogen atom. In a preferred embodiment, G2 is selected from the group consisting of a monocyclic N- containing 6- to 8- membered heteroaryl group and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a methyl group, a methoxy, -NR'R" group and a group of formula (a):
Figure imgf000028_0001
wherein
• L3 represents -CO- group, or a -C(0)0- group,
• R4 is selected from the group consisting of a hydroxyl group, a cyano group, a - CF3 group, a methyl group,
• Ra and Rb are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a methyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or an O-containing 4- membered heterocyclic group,
• m has a value of 0 or 1.
More preferably, G2 is selected from the group consisting of a pyridyl group and a monocyclic N-containing 6- membered heterocyclyl group, wherein the pyridyl and heterocyclyl groups are substituted by one or more substituents selected from a halogen atom and a group of formula (a):
Figure imgf000028_0002
wherein
• L3 represents -CO- group,
• R4 is selected from the group consisting of a hydroxyl group and a cyano group,
• both Ra and Rb represent a hydrogen atom, and m has a value of 1
In a still preferred embodiment, G2 represents a monocyclic N-containing 6- membered heterocyclyl group which is substituted by a group of formula (a):
Figure imgf000029_0001
wherein
L3 , R4, Ra, Rb and m are as defined above. In another embodiment, the present invention related to compounds of formula (I), wherein
• X represents a -CRc-group, wherein Rc represents a hydrogen atom,
• Gi is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group,
· U represents a direct bond,
• L2 is selected from the group consisting of a -(CH2)P-, -0-(CH2)2-, wherein p has a value of 0 or 1 ,
• R1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH2)2- NR'R" group and a -NR'R"- group, wherein both R' and R" represents a methyl group.
• R2 is a fluorine atom,
· R3 represents a hydrogen atom,
• R5 represents a hydrogen atom,
• G2 represents a monocyclic N-containing 6- membered heterocyclyl group
which is substituted by a group of formula (a):
Figure imgf000029_0002
wherein
o L3 represents -CO- group,
o R4 is selected from the group consisting of a hydroxyl group and a cyano group,
o both Ra and Rb represent a hydrogen atom, and m has a value of 1 .
In another embodiment, the present invention is related to compounds of formula (I), wherein X is selected from the group consisting of -N- and -CRC- group, wherein Rc is selected from the group consisting of a hydrogen atom and a methyl group, Gi is selected from the group consisting of a phenyl group, a monocyclic N-containing 6-membered heteroaryl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a fluorine atom, a hydroxyl group, -SCH3 group, -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino-Ci-2 alkyl group and - NR'-S02-R" group,
L-i is selected from the group consisting of a direct bond and -NH-(CH2)- group, L2 is selected from the group consisting of a -(CH2)P-, -(CH2)-NR-, -O-(CH2)(0-2), -C(0)0- , and -NR- group, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group,
R1 is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group, which alkyl group is substituted with a -NR'R" group, a phenyl group, a mono- or bicylic 5- to 9-membered heteroaryl group containing at least one nitrogen atom as heteroatom and a mono- or bicyclic 5- to 9-membered heterocyclyl group containing at least one nitrogen atom as heteroatom, wherein the phenyl, heteroaryl and heterocyclyl groups are 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 C4-5 alkyl group, a Ci-3 hydroxyalkyl group, a methoxy group, a -(0)(o-i)(CH2)(2-3)-NR'R" group, - NR'R" group, a -C(0)-0-Rd group, a -CH2-Re group and a monocyclic 6-membered heteroaryl group containing one heteroatom selected from N, wherein said heteroaryl substituent on the R1 moiety is optionally further substituted with one or two further substituents selected from the group consisting of a methyl group and a -NR'R" group,
R2 is selected from the group consisting of a fluorine atom and a methyl group,
R3 is selected from the group consisting of a hydrogen atom and a -(CH2)2NR'R" group,
G2 is selected from the group consisting of a pyridyl group substituted with a fluorine atom and a piperidinyl substituted with a group of formula (a):
Figure imgf000031_0001
L3 represents a direct bond, -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, -(CH2)(o-i)-CN, a - CF3 group, a methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups, and a Ci-2 aminoalkyl group, both Ra and Rb are a hydrogen atom or Ra and Rb together with the carbon atom to which they are attached form a 4-membered heterocyclic group containing oxygen atom as heteroatom, R5 is selected from the group consisting of a hydrogen atom and a methyl group,
Rd represents a t-butyl group, a linear Ci-2 alkyl group optionally substituted with one substituent selected from a phenyl group and a -NR'R", Re is selected from the group consisting of a phenyl group optionally substituted with a CF3 group or with a t-butyl group, and a monocyclic 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as heteroatom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF3 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 form a 5 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 , and p has a value of 0, 1 or 2. In another embodiment, the present invention is related to compounds of formula (I), wherein
• X is selected from the group consisting of -N- and -CRC- group, wherein Rc is selected from the group consisting of a hydrogen atom and a methyl group,
• Gi is selected from the group consisting of a phenyl group, a monocyclic N- containing 6- membered heteroaryl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a fluorine atom, a hydroxyl group, -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino-Ci-2 alkyl group and -NR'-S02-R" group, · L-i is selected from the group consisting of a direct bond and -NH-(CH2)- group,
• L2 is selected from the group consisting of a -(CH2)P-, -O-(CH2)(0-2) and -NR- group, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group,
• R1 is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group substituted with a -NR'R" group, a phenyl group, a mono- or bicylic 5-9 membered heteroaryl group containing at least one nitrogen atom as heteroatom and a mono- or bicyclic 5- to 9- membered heterocyclyl group containing at least one nitrogen atom as heteroatom, wherein the phenyl, heteroaryl and heterocyclyl groups are 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 C4-5 alkyl group, a Ci-3 hydroxyalkyl group, a methoxy group, a -(0)(o-i)(CH2)(2-3)-NR'R" group, -NR'R" group, a -CO-0-Rd group, a -CH2-Re group and a monocyclic 6- membered heteroaryl group containing one heteroatom selected from N wherein said heteroaryl group is optionally substituted with one or two substituents selected from the group consisting of a methyl group and a -NR'R" group;
R2 is selected from the group consisting of a fluorine atom and a methyl group, • R3 is selected from the group consisting of a hydrogen atom and a -(Ch^NR'R"- group,
• G2 is selected from the group consisting of a pyridyl group substituted with a
fluorine atom and a piperidinyl substituted with a group of formula (a):
Figure imgf000033_0001
wherein
o L3 represents a direct bond, -CO- group, or a -C(0)0- group,
o R4 is selected from the group consisting of a hydroxyl group, -(CH2)(o-i)-CN, a - CF3 group, an methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups,
o both Ra and Rb are a hydrogen atom or Ra and Rb together with the carbon atom to which they are attached form a 4-membered heterocyclic group containing oxygen atom as heteroatom,
• R5 is selected from the group consisting of a hydrogen atom and a methyl group,
• Rd represents a t-butyl group, a linear Ci-2 alkyl group optionally substituted with one substituent selected from a phenyl group and a-NR'R",
• Re is selected from the group consisting of a phenyl group optionally substituted with a CF3 group or with a t-butyl group, and a monocyclic 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as heteroatom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF3 group,
• R' and R" independently represents a hydrogen atom, a methyl group or a
cyclopentyl group, or R' and R" together with the nitrogen atom to which they are attached form a 5- to 6-membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a dimethylamino group,
• n, m and q independently have a value of 0 or 1 . • p has a value of 0, 1 or 2.
Particular individual compounds of the invention include:
3-{(3R)-3-[[2-(Dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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
3-[(3R)-3-({6-[4-(1 /-/-Benzimidazol-2-ylmethyl)piperazin-1 -yl]-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile 3-[(3R)-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-oxopropanenitrile
3-((3/?)-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-oxopropanenitrile
3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-{4-[(4-pyrrolidin-1 -ylpyridin-2- yl)methyl]piperazin-1 -yl}pyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
4- {[4-(5-Fluoro-6-{[(3R)-1 -(3-hydroxy-3-methylbutanoyl)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/?)-1 -glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol
3-[(3R)-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-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-((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)-3-oxopropanenitrile
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)-2-oxoethanol 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)-1 - (methoxyacetyl)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-/V-[(3R)-1 -(3,3,3-trifluoropropanoyl)piperidin-3-yl]pyrimidin-4-ami [3-((3/?)-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
(2S)-1 -((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 -oxopropan-2-ol (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
3-((3/?)-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-oxopropanenitrile
3-((3/?)-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
3-((3/?)-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
3-{(3R)-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-{(3R)-3-[(5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-{4-[4-(2-pyrrolidin-1 -ylethoxy) benzyl]piperazin-1 -yl}pyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile 3-((3R)-3-{[6-((3R,5S)-4-{4-[2-(Dimethylamino)ethoxy]benzyl}-3,5-dimethyl piperazin-1 -yl)-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino} piperidin- 1 -yl)-3-oxopropanenitrile
3-((3R)-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazin-1 -yl)-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile 3-((3R)-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazin-1 -yl)-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
3-[(3/?)-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- oxopropanenitrile
2-(Dimethylamino)ethyl 4-{[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}benzoate
Terf-butyl 4-{[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}piperidine-1 -carboxylate
3- [(3R)-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
3-[(3R)-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]-^ oxopropanenitrile
3-[(3R)-3-({5-Fluoro-6-[4-({1 -[(1 -methyl-1 H-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-oxopropanenitrile
3-((3R)-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-((3R)-3-{[5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-(4-{[1 -(pyridin-2-ylmethyl) piperidin-4-yl]methyl}piperazin-1 -yl)pyrimidin-4-yl]amino}piperidin-1 -yl)-^
oxopropanenitrile 3-[(3R)-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-oxopropanenitrile
3-[(3R)-3-({5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-[4-(2-pyrrolidin-1 -ylpyridin-4- yl)piperazin-1 -yl]pyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitrile 3-{(3R)-3-[(6-{4-[4-(Dimethylamino)pyridin-2-yl]piperazin-1 -yl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-((3R)-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-[(3R)-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-oxopropanenitrile
5-Fluoro-/V-[(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/?)-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-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-[(3R)-3-({6-[4-(1 ,3-Dihydro-2H-isoindol-2-ylmethyl)piperidin-1 -yl]-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile 3-((3/?)-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
3-{(3R)-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} oxopropanenitrile
3-[(3 ?)-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 -yl]-3- oxopropanenitrile
3-{(3R)-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
3-{(3R)-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-oxopropanenitrile
Benzyl 4-{[1 -(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5- a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1 -carboxylate
3-[(3/?)-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 (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-oxopropanenitrile
3-[(3R)-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-ylpyrimidin-4-yl}amino) piperidin- 1 -yl]-3-oxopropanenitrile
3-[(3R)-3-({5-Fluoro-6-[(4-piperazin-1 -ylbenzyl)amino]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-[(3R)-3-({5-Fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile 2-[(3R)-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 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide
1 -(4-7e/f-Butylbenzyl)-4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide
3-((3/?)-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-[(3R)-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-oxopropanenitrile 3-[(3R)-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-oxopropanenitrile
3-[(3R)-3-({5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1 -ylmethyl) phenyl]pyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-[(3R)-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- oxopropanenitrile
3-((3/?)-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-oxopropanenitrile 3-((3/?)-3-{[6-(4-{[4-(Dimethylamino)piperidi^
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitri
3- ((3R)-3-{[6-(3-{[4-(Dimethylamino)piperidin-1 -yl]methyl}phenyl)-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile 3-{(3R)-3-[(5-Fluoro-6-{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
3-{(3R)-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/?)-3-({6-[4-({4-[2-(Dimethylamino)ethoxy
2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-{(3R)-3-[(6-{4-[2-(Dimethylamino)ethoxy]phenyl3-5-fluoro-2-pyrazolo[1 ,5-a]pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-((3R)-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 -yl)-3- oxopropanenitrile
[(3R)-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-oxopropanenitrile
3-((3R)-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-oxopropanenitrile (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-oxopropanenitrile
(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-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-((3/?)-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-oxopropanenitrile 3-((3/?)-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-[(3R)-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-oxopropanenitrile 3-{(3R)-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]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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}-3-oxopropanenitrile
2- {(3R)-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/?)-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
3-[(3R)-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-oxopropanenitrile 3-{(3R)-3-[(6-{6-[4-(Dimethylamino)piperidin-1 -yl]pyridin-3-yl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitrile
3-{(3R)-3-[(5-Fluoro-6-{4-[1 -(3-hydroxybenzyl)piperidin-4-yl]piperazin-1 -yl}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-[(3R)-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl]-
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3- ((3R)-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 Λ/-[(3/?)-1 -(3-Aminopropanoyl)piperidin-3-yl]-5-fluoro-6-[4-(4-methylpiperazin-1 - yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
3-[(3R)-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- oxopropanenitrile 3-(6-{[2-(Dimethylamino)ethyl][(3R)-1 -glycoloylpiperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1 -yl)phenol
3-((3/?)-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
3-((3R)-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-oxopropanenitri
3- ((3/?)-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- oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-{(3R)-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-{(3R)-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
3- (5-Fluoro-6-{[(3R)-1 -glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)-5-{[(1 -methylpiperidin-4-yl)amino]methyl}phenol 3-{(3R)-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- oxopropanenitrile
3-{(3R)-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
3-{(3R)-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- oxopropanenitrile
3-((3/?)-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 3-((3/?)-3-{[5-Fluoro-6-(3-hydroxy-4-{[methyl(1 -methylpiperidin-4-yl)amino]meth phenyl)-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
3-{(3R)-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
3-[(3R)-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
3-((3R)-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
3-{(3R)-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
3- {(3R)-3-[(6-{3-[(Cyclopentylamino)methyl]-5-hydroxyphenyl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridine-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-[(3/?)-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-oxopropanenitrile
3-((3/?)-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
3-{(3R)-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-{(3R)-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 1 -methylpiperidin-4-yl 1 -[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]piperidine-4-carboxylate
3-{(3R)-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-oxopropanenitrile 3-((3/?)-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
3-[(3/?)-3-({5-Fluoro-6-[3-hydroxy-4-(piperazin-1 -ylmethyl)phenyl]-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-((3/?)-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
Ethyl 1 '-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl)benzyl]-4-methyl-1 ,4'-bipiperidine-4-carboxylate 3-[(3R)-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- oxopropanenitrile
3- [(3R)-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- oxopropanenitrile
3-[(3/?)-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
3-{(3R)-3-[(6-{6-[4-(Dimethylamino)piperidin-1 -yl]-5-hydroxypyridin-3-yl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile 3-[(3R)-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-oxopropanenitrile
3-{(3R)-3-[(6-{4-[(Cyclopentylamino)methyl]-3-hydroxyphenyl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-3-[(6-{3-[(Cyclopentylamino)methyl]-4-hydroxyphenyl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Piperidin-4-yl 4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate
3-{(3R)-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 1 '-Methyl-1 ,4'-bipiperidin-4-yl 4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate
3-((3R)-3-{[5-Fluoro-6-(3-hydroxy-4-{[methyl(pyridin-4-yl)amino]methyl}phenyl)-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile 3-{(3R)-3-[(5-Fluoro-6-{4-[(5-fluoro-2-hydroxybenzyl)amino]piperidin-1 -yl}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitrile
3-{[4-(Cyclopentylamino)piperidin-1 -yl]methyl}-5-(5-fluoro-6-{[(3R)-1 - glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenol
3-((3/?)-3-{{5-Fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl]-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl}[2-(methylamino)ethyl]amino}piperidin-1 -yl)-3-oxopropanenitn
3-{[4-(5-Fluoro-6-{[(3R)-1 -glycoloylpiperidin-3-yl][2-(methylamino)ethyl]amino}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol 3-[(3R)-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-oxopropanenitrile
2- ((3R)-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 or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.
Of outstanding interest are:
3- {(3R)-3-[[2-(Dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile 3-{(3R)-3-[(5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-{4-[(4-pyrrolidin-1 -ylpyridin-2- yl)methyl]piperazin-1 -yl}pyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
4- {[4-(5-Fluoro-6-{[(3R)-1 -(3-hydroxy-3-methylbutanoyl)piperidin-3-yl]amino}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol 3-((3/?)-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-oxopropanenitri
2- ((3/?)-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-/V-[(3R)-1 -
(methoxyacetyl)piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
3- ((3/?)-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 3-((3R)-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazin-1 -yl)-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Terf-butyl 4-{[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}piperidine-1 -carboxylate 3-[(3R)-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-oxopropanenitrile
3-{(3R)-3-[(6-{4-[4-(Dimethylamino)pyridin-2-yl]piperazin-1 -yl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3/?)-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-oxopropanenitrile
3-[(3 ?)-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 -yl]-3- oxopropanenitrile
Benzyl 4-{[1 -(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5- a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1 -carboxylate
(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-oxopropanenitrile
3-[(3/?)-3-({5-Fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile 1 - (4-7e/f-Butylbenzyl)-4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide
3-[(3R)-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- oxopropanenitrile
3-((3/?)-3-{[6-(3-{[4-(Dimethylamino)piperidin-1 -yl]methyl}phenyl)-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
3-[(3/?)-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-oxopropanenitrile 3-[(3R)-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-oxopropanenitrile
3- {(3R)-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}-3-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.
GENERAL SYNTHETIC PROCEDURES
The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, 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, Third Edition, Wiley, New York, 1999, and references cited therein.
Processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.
According to one embodiment of the present invention, compounds of general formula (I) may be prepared by the following synthetic route as illustrated in Scheme 1 :
Figure imgf000047_0001
Scheme 1
Treatment of dichloropyrimidines of formula (II) with amines of formula (III) in the presence of a base such as triethylamine or sodium hydrogencarbonate in a solvent such as methanol or ethanol at temperatures ranging from ambient temperature to reflux gives rise to compounds of formula (IV).
In the particular case where L-i is a direct bond and Gi is an aryl or heteroaryl ring, compounds of formula (I) may be obtained from chloropyrimidines of formula (IV) by reaction with compounds of formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457). Such reactions may be catalysed by a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or tetrakis(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 temperatures ranging from 80 °C to 1 10 °C with or without the use of microwave irradiation.
Boronic acids or boronates of formula (V) where L-i is a direct bond, Gi is an aryl or heteroaryl ring and Y is a boronic acid or boronate ester may be commercially available or may be prepared from the corresponding haloderivatives of formula (V), where Y is a bromine atom or a chlorine atom, by treatment with an appropriate boron reagent such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) with a palladium catalyst such as bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or bis(dibenzylideneacetone)palladium(0), in a solvent such as 1 ,4-dioxane or 1 ,2-dimethoxyethane, with or without the presence of a ligand such as tricyclohexylphosphine, in the presence of a base such as potassium acetate at temperatures ranging from 80-150 °C with or without the use of microwave irradiation.
In another particular case where L-i is a direct bond and Gi is an heterocyclyl group attached to the pyrimidine ring through a nitrogen atom, compounds of formula (I) may be prepared by reaction of chloroderivatives of formula (IV) with heterocyclic amines of formula (V), where Y is an hydrogen atom, in the presence of a base such as sodium hydrogencarbonate or /V-ethyl-/V-isopropylpropan-2-amine without the use of a solvent or in a solvent such as Λ/,Λ/'-dimethylacetamide or 1 -methylpyrrolidin-2-one at temperatures ranging from 80-130 °C with or without the use of microwave irradiation.
In yet another particular case where L-i is a -NRX-(CH2)- group, compounds of formula (I) may be obtained by reaction of chloropyrimidines of formula (IV) with amines of formula (V), where Y is an hydrogen atom, in a solvent such as /V-methylpyrrolidone at 140 °C with the use of microwave irradiation.
Compounds of formula (II) may be prepared as illustrated in Scheme
Figure imgf000048_0001
(VI) (VII) (VI II) (IX)
Figure imgf000048_0002
(XI)
Scheme 2 Reaction of ethyl propiolate with /V-aminopyridinium (in the particular case where X = CRC) or /V-aminopyrazinium salts (in the particular case where X = N) of formula (VII) in the presence of a base, for example potassium carbonate, in a solvent such as Ν,Ν'- dimethylformamide at temperatures ranging from 0 °C to ambient temperature, furnishes esters of formula (VIII). /V-aminopyridinium and /V-aminopyrazinium salts of formula (VII) may be commercially available or may be prepared by reaction of the corresponding pyridines (in the particular case where X = CRC) or pyrazine (in the particular case where X = N) of formula (VI) with 0-(mesitylsulfonyl)hydroxylamine in a suitable solvent such as dichloromethane at temperatures ranging from 0 °C to ambient temperature. Treatment of esters of formula (VIII) with a mixture of trimethylaluminum and ammonium chloride in a solvent such as toluene at 80 °C provides amidine intermediates of formula (IX). Amidines of formula (IX) may be reacted with malonate esters of formula (X) to give dihydroxypirimidines of formula (XI). Such reactions may be carried out in the presence of a suitable base such as sodium methoxide in a solvent such as methanol at temperatures ranging from 0 °C to ambient temperature. Dihydroxypirimidines of formula (XI) may be converted to dichloropyrimidines of formula (II) by treatment with a suitable chlorinating agent, for example phosphorus(V) oxychloride, at temperatures ranging from 25 °C to reflux. In the particular case where L-i is a direct bond and Gi is an aryl or heteroaryl ring, compounds of general formula (I) may also be prepared by an alternative synthetic approach as shown in Scheme 3:
Figure imgf000050_0001
Scheme 3
Treatment of trichloropyrimidines of formula (XII) with amines of formula (III) in the presence of a base such as triethylamine or sodium hydrogencarbonate in a solvent such as ethanol at -20 °C gives rise to compounds of formula (XIII).
In the particular case where L-i is a direct bond and Gi is an aryl or heteroaryl ring, compounds of formula (XIV) may be obtained from dichloropyrimidines of formula (XIII) by reaction with compounds of formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions. Such reactions may be catalysed by a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as 1 ,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 °C. Reaction of chloropyrimidines of formula (XIV) with stannanes of formula (XV) in the presence of a palladium catalyst such as tetrakis (triphenylphosphine)palladium(O) in a solvent such as 1 ,4-dioxane at 100 °C provides compounds of formula (I).
In another particular case, compounds of formula (I), where R3 is an hydrogen atom, may undergo further reaction with a suitable base, such as sodium hydride, in a solvent such as Λ/,Λ/'-dimethylformamide, followed by the addition of an alkylating agent, such as methyl iodide or (2-chloroethyl)dimethylamine hydrochloride at temperatures ranging from ambient temperature to 80 °C, to furnish compounds of formula (I), where R3 is now a methyl or a -(CH2)2-N Me2 group. In yet another particular case, compounds of formula (I), in which the residue at G-i, G2 or R1 contains an alcohol, phenol or carboxylic acid moiety functionalized with an appropriate protecting group such as benzyl (Bn) or methoxy (OMe), may be deprotected at the alcohol, phenol or carboxylic acid moiety under standard conditions {Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). In the particular case of primary alcohols, the free alcohol moiety may then be oxidized under standard conditions to give the corresponding aldehyde. In yet another particular case, compounds of formula (I) and compounds of formula (XIV) in which the residue at d contains an aldehyde moiety, may be further reacted with a primary or secondary amine in the presence of a reductive agent, such as sodium triacetoxyborohydride, in a solvent such as dichloromethane at ambient temperature to give compounds of formula (I) and compounds of formula (XIV) in which the residue at Gi is now a secondary or tertiary amine.
In yet another particular case, compounds of formula (I), in which the residue at Gi, G2 or R1 contains an amine moiety functionalized with an appropriate protecting group such as ie f-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), may be deprotected at the amine moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). The corresponding free amine may then be further functionalized under standard conditions to give the corresponding amides, carbamates and /V-alkylated amines. Starting compounds are commercially available or may be obtained following the conventional synthetic methods already known in the art.
EXAMPLES
The synthesis of the compounds of the invention and of the intermediates for use therein are illustrated by the following Examples (1 -139) (including Preparation Examples (Preparations 1 -1 17)) and are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description.
PREPARATIONS PREPARATION 1
Pyrazolo[1 ,5-a]pyridine-3-carboximidamide
a) Ethyl pyrazolo[1 ,5-a]pyridine-3-carboxylate
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 Λ/,/V-dimethylformamide (44 mL) at 0 °C. Ethyl propiolate (3 ml_, 29.7 mmol) was then added dropwise and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between water and chloroform. The organic phase was separated, washed with water and brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (5.51 g, 96%) as a red oil.
LRMS (m/z): 191 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .4 (t, 3H), 4.4 (q, 2H), 7.0 (td, 1 H), 7.4 (ddd, 1 H), 8.2 (d, 1 H), 8.4 (s, 1 H), 8.6 (dt, 1 H). b) Pyrazolo[1 ,5-a]pyridine-3-carboximidamide
A 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 1 18.29 mmol) was added dropwise to a stirred suspension of ammonium chloride (5.90 g, 1 18.29 mmol) in toluene (100 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. A solution of ethyl pyrazolo[1 ,5-a]pyridine-3-carboxylate (Preparation 1 a, 7.50 g, 39.43 mmol) in toluene (20 mL) was then added and the resulting mixture was stirred overnight at 80 °C. Additional 2.0 M solution of trimethylaluminum in toluene (58.9 mL, 1 18.29 mmol) and ammonium chloride (5.90 g, 1 18.29 mmol) in toluene (100 mL) were added and the reaction mixture was stirred at 80 °C for further 24h. 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 dryness. Purification of the residue by flash chromatography (dichloromethane to 7:3 dichloromethane/ethanol) gave the title compound (4.72 g, 74%) as a yellow solid.
LRMS (m/z): 161 (M+1 )+.
PREPARATION 2
5-Methylpyrazolo[1 ,5-a]pyridine-3-carboximidamide
a) 1 -Amino-4-methylpyridin-1 -ium 2,4,6-trimethylbenzenesulfonate
A solution of 0-(mesitylsulfonyl)hydroxylamine (23.1 1 g, 107.4 mmol) in dichloromethane (272 mL) was added dropwise to a cooled (0 °C) solution of 4- methylpyridine (10.0 g, 107.4 mmol) in dichloromethane (136 mL) and the resulting mixture was stirred for 2 hours at room temperature. The solvent was partially evaporated and diethyl ether was added to precipitate an oil. The reaction mixture was cooled to 0 °C and the solvents were decanted. The oil was dried under vacuum to yield the title compound (33.1 1 g, 99%).
LRMS (m/z): 109 (M)+.
1H-NMR δ (300 MHz, CDCI3): 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
Obtained as a solid (54%) from 1 -amino-4-methylpyridin-1 -ium 2,4,6-trimethylbenzene sulfonate (Preparation 2a) and ethyl propiolate following the experimental procedure as described in Preparation 1 a followed by purification of the crude product by flash chromatography (hexanes/ethyl acetate).
LRMS (m/z): 205 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .38 -1.42 (t, 3H), 2.46 (s, 3H), 4.34 - 4.40 (q, 2H), 6.75 - 6.77 (d, 1 H), 7.92 (s, 1 H), 8.33 (s, 1 H), 8.37 - 8.39 (d, 1 H). c) 5-Methylpyrazolo[1 ,5-a]pyridine-3-carboximidamide
2.0 M Trimethylaluminium solution in toluene (62 mL, 124 mmol) was added dropwise to a cooled (0 °C) suspension of ammonium chloride (6.18 g, 1 15.6 mmol) in toluene (133 mL) and the resulting mixture was stirred until no more gas was formed. 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 then added dropwise and the reaction mixture was stirred overnight at 80 °C. Additional ammonium chloride (6.18 g, 1 15.6 mmol) and 2.0 M trimethylaluminium solution in toluene (62 mL, 124 mmol) were added and the suspension was stirred overnight at 80 °C and a weekend at room temperature. The reaction mixture was cooled at 0 °C and methanol (30 mL) was added dropwise. The suspension was filtered over diatomaceous earth (Celite®) and the solid was washed with methanol. The organic phases were combined, solvents were partially evaporated (up to 100 mL of solution) and dichloromethane (100 mL) was added. The solid formed was filtered and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (dichloromethane/methanol) gave the title compound (6.7 g, 98%).
LRMS (m/z): 175 (M+1 )+.
1H-NMR δ (300 MHz, DMSO-d6): 2.50 (s, 3H), 7.08 - 7.10 (d, 1 H), 7.88 (s, 1 H), 8.65 (s, 1 H), 8.81 - 8.83 (d, 1 H), 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-carboximidamide (Preparation 1 b, 4.75 g, 29.47 mmol) was added portionwise to a stirred solution of sodium (1 .63 g, 71.02 mmol) in methanol (120 mL) at 0 °C. Diethyl 2-fluoromalonate (7.0 mL, 44.20 mmol) was then added and the reaction mixture was stirred from 0 °C to room temperature overnight. The solvent was evaporated to dryness to yield the title compound (7.25 g, 99%) as a solid that was used in the next synthetic step without further purification.
LRMS (m/z): 247 (M+1 )+
1H-NMR δ (300 MHz, DMSO-d6): 7.2 (t, 1 H), 7.5 - 7.7 (m, 1 H), 8.7 (d, 1 H), 8.8 -
8.9 (m, 2H), 1 1.8 (bs, 1 H), 12.7 (bs, 1 H). b) 3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine
A mixture of 5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidine-4,6-diol (Preparation 3a, 7.00 g, 28.43 mmol) and phosphorus(V) oxychloride (55 mL, 589 mmol) was stirred at 1 10 °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 the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (n- hexane to dichloromethane) to yield the title compound (5.3 g, 65%) as a yellow solid.
LRMS (m/z): 283 (M+1 )+
1H -NMR δ (300 MHz, CDCI3): 7.0 (td, 1 H), 7.4 (ddd, 1 H), 8.6 (ddt, 2H), 8.7 (s, 1 H). 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-carboximidamide (Preparation 1 b, 2.89 g, 18.05 mmol) and diethyl methylmalonate (6.44 mL, 37.45 mmol) were added portionwise to a solution of sodium (1.24 g, 53.91 mmol) in methanol (14 mL) at 0 °C and the resulting suspension was stirred at room temperature overnight. The solvent was evaporated to dryness and the residue was dissolved in water and acidified to pH=1 using a 6N hydrochloric acid solution. The precipitate was filtered, washed with water and dried under vacuum to yield the title compound (3.54 g, 81 %) as a yellow solid.
LRMS (m/z): 243 (M+1 )+.
1H-NMR δ (400 MHz, DMSO-d6): 1 .79 (s, 3H), 7.10 - 7.14 (t, 1 H), 7.52 - 7.56 (dd, 1 H), 8.73 - 8.75 (d, 1 H), 8.81 - 8.83 (d, 1 H), 8.91 (s, 1 H). b) 3-(4,6-Dichloro-5-methylpyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine
Obtained as a solid (30%) from 5-methyl-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidine-4,6- diol (Preparation 4a) and phosphorus(V) oxychloride following the experimental procedure as described in Preparation 3b followed by purification of the crude product by flash chromatography (hexanes/ ethyl acetate 1 :4).
LRMS (m/z): 279 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3): 2.47 (s, 3H), 6.93 - 6.97 (t, 1 H), 7.39 - 7.44 (dd, 1 H), 8.53 - 8.56 (m, 1 H), 8.71 (s, 1 H).
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
Obtained as a yellow solid (80%) from 5-methylpyrazolo[1 ,5-a]pyridine-3- carboximidamide (Preparation 2c) and diethyl 2-fluoromalonate following the experimental procedure as described in Preparation 4a.
LRMS (m/z): 261 (M+1 )+.
1H-NMR δ (400 MHz, DMSO-d6): 2.50 (s, 3H), 6.99 - 7.01 (d, 1 H), 8.47 (s, 1 H), 8.71 - 8.73 (d, 1 H), 8.82 (s, 1 H), 12.59 (bs, 1 H). b) 3-(4,6-Dichloro-5-fluoropyrimidin-2-yl)-5-methylpyrazolo[1 ,5-a]pyridine
A mixture of 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(V) oxychloride (9.3 mL, 99.6 mmol) was stirred at 1 10 °C for 75 minutes. The solvent was removed under reduced pressure and water was added. The precipitate was filtered, washed with water and dried under vacuum to yield the title compound (1.08 g, 79%) as a yellow solid.
LRMS (m/z): 297 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3): 2.51 (s, 3H), 6.78 - 6.80 (d, 1 H), 8.23 (s, 1 H), 8.41 - 8.43 (d, 1 H), 8.62 (s, 1 H).
PREPARATION 6
3-{(3 ?)-3-[(6-Chloro-5-fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino] piperidin-1 -yl}-3-oxopropanenitrile
a) Terf-butyl (3 ?)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl) amino]piperidine-1 -carboxylate
(R)-7e f-butyl 3-aminopiperidine-1 -carboxylate (2.97 g, 14.83 mmol) was added to a solution of 3-(4,6-dichloro-5-fluoropyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine (Preparation 3b, 3.50 g, 12.36 mmol) and triethylamine (2.0 ml_, 15.08 mmol) in ethanol (80 mL) and the resulting mixture was stirred at 80 °C for 48 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and water was added. The precipitate was filtered and dried in vacuo to give the title compound (5.60 g, 100%) as a white solid.
LRMS (m/z): 447 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .6 (s, 9H), 1 .7 - 1 .9 (m, 3H), 2.0 - 2.1 (m, 1 H),
3.5 (bs, 4H), 4.3 (d, 1 H), 5.2 (s, 1 H), 6.9 (t, 1 H), 7.3 - 7.4 (m, 1 H), 8.5 (t, 2H), 8.3 (s, 1 H). b) 6-Chloro-5-fluoro-W-[(3 ?)^iperidin-3-yl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin- 4-amine
4.0 M hydrogen chloride solution in 1 ,4-dioxane (31 .4 mL, 125.6 mmol) was added to a solution of ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl)amino]piperidine-1 -carboxylate (Preparation 6a, 5.61 g, 12.55 mmol) in 1 ,4-dioxane (150 mL) and the resulting mixture was stirred overnight at room temperature. The precipitate formed was filtered and washed with 1 ,4-dioxane and diethyl ether and dried in vacuo to give the hydrochloride salt of the title compound (5.50 g, 100%) as a white solid.
LRMS (m/z): 347 (M+1 )+.
1H-NMR δ (300 MHz, CD3OD): 1 .7 - 2.2 (m, 5H), 2.9 - 3.1 (m, 2H), 3.4 (t, 1 H),
3.6 - 3.7(m, 1 H), 4.4 - 4.7 (m, 1 H), 7.1 (td, 1 H), 7.5 (ddd, 1 H), 8.5 (d, 1 H), 8.6 (dd, 2H). c) 3-{(3 ?)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino] piperidin-1 -yl}-3-oxopropanenitrile
3-[(2,5-Dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile (prepared as described in BE875054(A1 ), 3.58 g, 19.66 mmol) was added to a solution of 6-chloro-5-fluoro-/V- [(3R)-piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-yl-pyrimidin-4-amine (Preparation 6b, 5.5 g, 13.10 mmol) and triethylamine (9.1 mL, 65.7 mmol) in dichloromethane (10 mL). The resulting mixture was stirred overnight at room temperature. Additional 3-[(2,5- dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile (0.80 g, 4.39 mmol) was added and the reaction mixture was stirred at room temperature for further 5 hours. The solvent was evaporated under reduced pressure and water was added. The precipitate formed was filtered, washed with water and dried in vacuo to give the title compound (5.03 g, 93%) as a white solid.
LRMS (m/z): 414 (M+1 )+. 1H-NMR δ (300 MHz, CDCI3): 1 .7 - 2.0 (m, 4H), 2.2 (t, 1 H), 3.3 - 3.5 (m, 2H), 3.6 - 3.7 (m, 1 H), 3.9 (dd, 1 H), 4.3 (bs, 1 H), 4.6 (d, 1 H), 5.0 (d, 1 H), 6.91 (dt, 1 H), 7.39 (ddd, 1 H), 8.4 - 8.6 (m, 2H), 8.7 (s, 1 H). PREPARATION 7
(S)-6-Chloro-5-fluoro-yV-(1 -(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[1 ,5-a]pyridin-3- yl)pyrimidin-4-amine
A mixture of 3-(4,6-dichloro-5-fluoropyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine (Preparation 3b, 1.00 g, 3.53 mmol), (1 S)-1 -(5-fluoropyridin-2-yl)ethanamine dihydrochloride (0.85 g, 6.06 mmol) and sodium hydrogencarbonate (1 .40 g, 16.66 mmol) in ethanol (20 mL) was heated at reflux overnight. The solvent was evaporated and the residue was crystallized from methanol to yield the title compound (1.25 g, 82%) as a solid.
LRMS (m/z): 387 (M+1 )+. PREPARATION 8
( ?)-3-(3-((6-Chloro-5-methyl-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino) piperidin-1 -yl)-3-oxopropanenitrile
a) (/?)-7erf-butyl 3-((6-chloro-5-methyl-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4- yl)amino)piperidine-1 -carboxylate
A mixture of 3-(4,6-dichloro-5-methylpyrimidin-2-yl)pyrazolo[1 ,5-a]pyridine (Preparation 4b, 1.1 1 g, 3.98 mmol), (R)-ieri-butyl 3-aminopiperidine-1 -carboxylate (0.93 g, 4.65 mmol) and diisopropylethylamine (1 .04 mL, 5.97 mmol) in ethanol (12 mL) was stirred 68 hours at 80 °C. Λ/,Λ/'-dimethylacetamide (9 mL) was then added and the reaction mixture was stirred at 100 °C for further 68 hours. The ethanol was evaporated and excess of water was added. The precipitate was filtered, washed with water and dried to give the title compound (1.49 g, 85%).
LRMS (m/z): 443 (M+1 )+. b) ( ?)-6-Chloro-5-methyl-yV-(piperidin-3-yl)-2-(pyrazolo[1 ,5-a]pyridin-3-yl) pyrimidin-4-amine
4M Solution of hydrogen chloride in 1 ,4-dioxane (16 mL) was added to a suspension of (R)-ieri-butyl 3-((6-chloro-5-methyl-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino) piperidine-1 -carboxylate (Preparation 8a, 1 .49 g, 3.37 mmol) in 1 ,4-dioxane (20 mL) and the reaction mixture was stirred overnight at room temperature. Dichloromethane was then added (160 mL) and the suspension was stirred 24 h at room temperature. The solvents were partially evaporated under vacuum and the solid was filtered to give the title compound as a dihydrochloride salt (0.97 g, 76%). LRMS (m/z): 343 (M+1 )+. c) ( ?)-3-(3-((6-Chloro-5-methyl-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl) amino)piperidin-1 -yl)-3-oxopropanenitrile
A solution of (/?)-6-chloro-5-methyl-/V-(piperidin-3-yl)-2-(pyrazolo[1 ,5-a]pyridin-3-yl) pyrimidin-4-amine (Preparation 8b, 0.97 g, 2.55 mmol), 3-[(2,5-dioxopyrrolidin-1 -yl)oxy] -3-oxopropanenitrile (0.76 g, 4.16 mmol) and triethylamine (1 .57 mL, 1 1 .29 mmol) in Λ/,Λ/'-dimethylformamide (9 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water and the precipitate was filtered. Purification of the precipitate by flash chromatography gave the title compound (0.7 g, 67%) as a white solid.
LRMS (m/z): 410 (M+1 )+.
1H-NMR δ (400 MHz, DMSO-d6): 1 .51 - 1 .82 (m, 3H), 2.00 - 2.1 1 (m, 1 H), 2.13 (s, 3H), 2.54 - 2.74 (m, 1 H), 2.96 - 3.09 (m, 1 H), 3.62 - 3.76 (dd, 1 H), 3.85 - 4.35 (m, 4H), 4.67 - 4.70 (d, 1 H), 6.77 - 6.81 (m, 1 H), 7.02 - 7.06 (t, 1 H), 7.43 -
7.49 (m, 1 H), 8.37 - 8.40 (d, 1 H), 8.61 - 8.66 (d, 1 H), 8.76 - 8.80 (m, 1 H).
PREPARATION 9
( ?)-3-(3-((6-Chloro-5-fluoro-2-(5-methylpyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl) amino)piperidin-1 -yl)-3-oxopropanenitrile
a) (/?)-7erf-butyl 3-((6-chloro-5-fluoro-2-(5-methylpyrazolo[1 ,5-a]pyridin-3-yl) pyrimidin-4-yl)amino)piperidine-1 -carboxylate
Obtained as a solid (100%) from 3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-5-methyl pyrazolo[1 ,5-a]pyridine (Preparation 5b) and (R)-ieri-butyl 3-aminopiperidine-1 - carboxylate following the experimental procedure as described in Preparation 6a.
LRMS (m/z): 461 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3): 1 .42 (bs, 9H), 1.62 (m, 2H), 1.75 - 1.94 (m, 2H), 1 .99 - 2.08 (m, 1 H), 2.46 (s, 3H), 3.45 - 3.53 (m, 3H), 3.73 - 3.86 ( m, 1 H), 4.24 - 4.33 (m, 1 H), 5.10 - 5.29 (bs, 1 H), 6.69 - 6.71 (d, 1 H), 8.23 (s, 1 H), 8.37 - 8.39 (d, 1 H), 8.57 (s, 1 H). b) ( ?)-6-Chloro-5-fluoro-2-(5-methylpyrazolo[1 ,5-a]pyridin-3-yl)-yV-(piperidin-3-yl) pyrimidin-4-amine
4M Solution of hydrogen chloride in 1 ,4-dioxane (23 mL) was added to a solution of (R)-ieri-butyl 3-((6-chloro-5-fluoro-2-(5-methylpyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl) amino)piperidine-1 -carboxylate (Preparation 9a, 2.07 g, 4.49 mmol) in 1 ,4-dioxane (35 mL) and the resulting solution was stirred 2 hours at room temperature. Excess of diethyl ether was added and the precipitate was filtered, washed with diethyl ether, ethyl acetate and finally acetonitrile to give the title compound as a dihydrochloride salt (1 .86 g, 95%).
LRMS (m/z): 361 (M+1 )+.
1H-NMR δ (400 MHz, DMSO-d6): 1.59 - 1 .72 (m, 1 H), 1 .80 - 2.00 (m, 2H), 2.08 -
2.13 (m, 1 H), 2.50 (s, 3H), 2.89 - 2.92 (m, 2H), 3.21 - 3.30 (d, 1 H), 3.31 - 3.48
(d, 1 H), 4.54 (bs, 2H), 6.91 - 6.94 (d, 1 H), 8.01 - 8.03 (d, 1 H), 8.12 (s, 1 H), 8.63
(s, 1 H), 8.69 - 8.71 (d, 1 H), 9.22 (bs, 1 H), 9.38 (bs, 1 H). c) ( ?)-3-(3-((6-Chloro-5-fluoro-2-(5-methylpyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4- yl)amino)piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a solid (83%) from (R)-6-chloro-5-fluoro-2-(5-methylpyrazolo[1 ,5-a]pyridin- 3-yl)-/V-(piperidin-3-yl)pyrimidin-4-amine (Preparation 9b) and 3-[(2,5-dioxopyrrolidin-1 - yl)oxy]-3-oxopropanenitrile following the experimental procedure as described in Preparation 8c followed by purification of the crude product by flash chromatography (hexanes/ethyl acetate).
LRMS (m/z): 428 (M+1 )+.
1H-NMR δ (400 MHz, DMSO-d6): 1.44 - 1 .75 (m, 2H), 1 .78 - 1 .88 (m, 1 H), 2.02 - 2.15 (m, 1 H), 2.41 (s, 3H), 2.62 (t, 1 H), 2.76 (t, 1 H), 2.96 - 3.13 (d, 1 H), 3.16 - 3.18 (d, 1 H), 3.62 - 3.78 (dd, 1 H), 3.87 - 4.30 (m, 4H), 4.60 - 4.68 (dd, 1 H), 6.90
- 6.92 (d, 1 H), 7.83 - 7.93 (dd, 1 H), 8.07 - 8.1 1 (d, 1 H), 8.52 - 8.57 (d, 1 H), 8.66 - 8.70 (dd, 1 H).
PREPARATION 10
( ?)-Λ/1 -(5-Fluoro-6-morpholino-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)- W2,/V2-dimethyl-/V1 -(piperidin-3-yl)ethane-1 ,2-diamine
a) Terf-butyl (3 ?)-3-[(5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate
A mixture of ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin- 4-yl)amino]piperidine-1 -carboxylate (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 vessel and was subjected to microwave irradiation for 2 hours at 130 °C. After cooling to room temperature the mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (170mg, 96%) as a brownish solid.
LRMS (m/z): 498 (M+1 )+. 1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.76 (bs, 1 H), 6.82 (td, 1 H), 7.24 - 7.32 (m, 1 H), 8.40 - 8.50 (dd, 2H), 8.55 (s, 1 H). b) Terf-butyl (3 ?)-3-[[2-(dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate
Sodium hydride (60% dispersion in mineral oil, 0.041 g, 1 .03 mmol) was added portionwise to a suspension of fe/f-butyl (3R)-3-[(5-fluoro-6-morpholin-4-yl-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylate (Preparation 10a, 0.17 g, 0.34 mmol) and (2-chloroethyl)dimethylamine hydrochloride (0.074 g, 0.51 mmol) in Λ/,Λ/'-dimethylformamide (2 mL) and the resulting mixture was stirred overnight at 55 °C. Additional (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 for further 72 hours at 65 °C. A third addition of 2-chloroethyl)dimethylamine hydrochloride (0.074 g, 0.51 mmol) and sodium hydride (0.041 g, 1.03 mmol) was made and the reaction mixture was stirred for 24 hours at 65 °C. Water (6 mL) was added and the precipitate formed was filtered, washed with water and dried under vacuum to yield the title compound (0.18 g, 77%) as a solid.
LRMS (m/z): 570 (M+2)+. c) ( ?)-Λ/1 -(5-Fluoro-6-morpholino-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)- W2,/V2-dimethyl-/V1 -(piperidin-3-yl)ethane-1 ,2-diamine
4.0M Solution of hydrogen chloride in 1 ,4-dioxane (1 .6 mL) was added to a solution of ie f-butyl (3R)-3-[[2-(dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate (Preparation 10b, 0.18 g, 0.32 mmol) in methanol (4 mL) and the resulting mixture was stirred overnight at room temperature. The solvents were evaporated and the resulting crude was treated with diethyl ether and filtered to give the title compound as a tetrahydrochloride salt (0.18 g, 82%).
LRMS (m/z): 469 (M+1 )+.
PREPARATION 1 1
1 -[(1 -Methyl -1 H-imidazol-2-yl)methyl]piperazine
a) Terf-butyl 4-[(1 -methyl-1 H-imidazol-2-yl)methyl]piperazine-1 -carboxylate
A solution of ie f-butyl 1 -piperazinecarboxylate (0.5 g, 2.68 mmol), 2-(chloromethyl)-1 - methyl-1 /-/-imidazole hydrochloride (0.45 g, 2.68 mmol), and triethylamine (0.79 mL, 5.67 mmol) in acetonitrile (20 mL) was stirred for 24 h at 65 °C. The solvent was evaporated and the crude partitioned with ethyl acetate and water. The organic phase was separated, washed with water, dried over magnesium sulfate and the solvent was evaporated to give the title compound (0.59 g, 74%).
LRMS (m/z): 281 (M+1 )+. b) 1 -[(1 -Methyl -1 H-imidazol-2-yl)methyl]piperazine
A mixture of ie f-butyl 4-[(1 -methyl-1 H-imidazol-2-yl)methyl]piperazine-1 -carboxylate (Preparation 1 1 a, 0.59 g, 2.10 mmol) and 1 .25 M hydrogen chloride solution in ethanol (30 mL) was stirred at room temperature for 8 hours. The solvent was evaporated and the residue was treated with diethyl ether, filtered, washed with acetonitrile and dried to yield the hydrochloride salt of the title compound (0.46 g, 67%) as a white solid.
LRMS (m/z): 181 (M+1 )+.
PREPARATION 12
5-Fluoro-6-{4-[(1 -methyl-1 H-imidazol-2-yl)m
3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
a) Terf-butyl (3 ?)-3-[(5-fluoro-6-{4-[(1 -methyl-1 H-imidazol-2-yl)methyl]piperazin-1 - yl}-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate
A suspension of ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl pyrimidin-4-yl)amino]piperidine-1 -carboxylate, (Preparation 6a, 0.1 g, 0,22 mmol), 1 - [(1 -methyl-1 H-imidazol-2-yl)methyl]piperazine (Preparation 1 1 b, 0.098 g, 0,34 mmol) and sodium hydrogencarbonate (0.17 g, 2,02 mmol) in Λ/,Λ/'-dimethylacetamide (0.6 mL) was stirred for 16 h at 130 °C. Excess of water was added and the precipitate formed was filtered, washed with water and dried. Purification of the solid by flash chromatography gave the title compound (0.087 g, 67%).
LRMS (m/z): 592 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .30 - 1.54 (m, 6H), 1 .67 - 1.88 (m, 3H), 1.93 - 2.13 (m, 1 H), 2.50 - 2.70 (m, 3H), 3.16 - 3.45 (m, 2H), 3.45 - 3.61 (m, 1 H), 3.62 - 3.81 (m, 6H), 4.15 - 4.30 (m, 1 H), 4.68 - 4.81 (m, 1 H), 6.77 - 6.86 (m, 1 H), 6.86 - 6.92 (d, 1 H), 6.92 - 7.00 (d, 1 H), 7.26 - 7.32 (m, 1 H), 8.36 - 8.64 (m, 1 H). b) 5-Fluoro-6-{4-[(1 -methyl-1 H-imidazol-2-yl)methyl]piperazin-1 -yl}-/V-[(3/?)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
A 4.0 M solution of hydrogen chloride in 1 ,4-dioxane (2 mL) was added to a solution of ie/f-butyl(3R)-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 -carboxylate (Preparation 12a, 0.087 g, 0.15 mmol) in methanol (4 mL) and the resulting mixture was stirred for 7 hours at room temperature. The solvents were evaporated and the residue was treated with diethyl ether, filtered and washed with acetonitrile to yield the hydrochloride salt of the title compound (0.082 g, 75%) as a solid.
LRMS (m/z): 492 (M+2)+.
PREPARATION 13
2-(Piperazin-1 -ylmethyl)-1 H-benzimidazole
a) Terf-butyl 4-(1 H-benzimidazol-2-ylmethyl)piperazine-1 -carboxylate
A mixture of fe/f-butyl 1 -piperazinecarboxylate (1 .0 g, 5.37 mmol), 2-(chloromethyl)-1 /-/- benzimidazole (0.89 g, 5.34 mmol), and potassium carbonate (0.82 gr, 5.93 mmol) in acetonitrile (20 mL) was stirred overnight at room temperature The solvent was evaporated and the resulting crude was suspended in water and filtered . The solid was crystalized in ethyl acetate/diisopropyl ether to yield the title compound (0.8 g, 45%) as a beige solid (45%).
LRMS (m/z): 317 (M+1 )+. b) 2-(Piperazin-1 -ylmethyl)-1 H-benzimidazole
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (5ml_) was added to a solution of ie f-butyl 4-(1 H-benzimidazol-2-ylmethyl)piperazine-1 -carboxylate (Preparation 13a, 0.8 g, 2.53 mmol) in methanol (6 mL) and the resulting mixture was stirred for 4 hours at room temperature. The solvents were evaporated and the residue was treated with ethyl acetate, filtered and washed with acetonitrile. Purification of the solid by flash chromatography in basic conditions gave the title compound as a white solid (0.15 g, 24%).
LRMS (m/z): 217 (M+1 )+.
PREPARATION 14
6-[4-(1 H-Benzimidazol-2-ylmethyl)piperazin-1 -yl]-5-fluoro-yV-[(3 ?)-piperidin-3-yl]- 2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
a) Terf-butyl (3 ?)-3-({6-[4-(1 H-benzimidazol-2-ylmethyl)piperazin-1 -yl]-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1 -carboxylate
A mixture of ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin- 4-yl)amino]piperidine-1 -carboxylate (Preparation 6a, 0.1 g, 0.22 mmol), 2-(piperazin-1 - ylmethyl)-1 H-benzimidazole (Preparation 13b, 0.063 g, 0.29 mmol) and sodium hydrogencarbonate (0.056 g, 0.67 mmol) in Λ/,Λ/'-dimethylacetamide (1 mL) was stirred for 12 h at 130 °C. Additional 2-(piperazin-1 -ylmethyl)-1 H-benzimidazole (20 mg) was added and the mixture was stirred for further 4 hours at 130 °C. After cooling to room temperature, water (6 mL) was added and the precipitate formed was filtered to give the title compound (0.128 g, 77%) as a brown solid.
LRMS (m/z): 628 (M+2)+. b) 6-[4-(1 H-Benzimidazol-2-ylmethyl)piperazin-1 -yl]-5-fluoro-/V-[(3/?)-piperidin-3- yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
4.0 M solution of hydrogen chloride in 1 ,4-dioxane (1 mL) was added to a solution of fe/f-butyl (3R)-3-({6-[4-(1 H-benzimidazol-2-ylmethyl)piperazin-1 -yl]-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1-carboxylate (Preparation 14a, 0.128 g, 0.2 mmol) in methanol (3 mL) and the resulting solution was stirred for 3 hours at room temperature. The solvents were evaporated and the residue was treated with diethyl ether and filtered to yield the pentahydrochloride salt of the title compound (0.162 gr, 93%).
LRMS (m/z): 528 (M+2)+.
PREPARATION 15
yV,yV-Dimethyl-2-(piperazin-1 -ylmethyl)pyridin-4-amine
a) Terf-butyl 4-[(4-bromopyridin-2-yl)methyl]piperazine-1 -carboxylate
Sodium triacetoxyborohydride (0.85 g, 4.01 mmol) was added to a solution of 4- bromopicolinaldehyde (0.25 g, 1 .34 mmol), ie f-butyl piperazine-1 -carboxylate (0.28 g, 1 .48 mmol) and acetic acid (0.02 mL, 0.4 mmol) in dichloromethane (5 mL) and the resulting mixture was stirred overnight at room temperature. The solvent was then evaporated and the residue was triturated with diethyl ether, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield the title compound (363 mg, 68%) as a solid.
LRMS (m/z): 356/358 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .46 (s, 9H), 2.46 (t, 4H), 3.46 (t, 4H), 3.64 (s, 2H), 7.62 (d, 1 H), 8.37 (d, 1 H). b) yV,yV-Dimethyl-2-(piperazin-1 -ylmethyl)pyridin-4-amine
A mixture of ie f-butyl 4-[(4-bromopyridin-2-yl)methyl]piperazine-1 -carboxylate (Preparation 15a, 0.1 g, 0.28 mmol) and 40% aqueous dimethylamine solution (0.18 mL, 1.42 mmol) 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 diethyl ether, filtered and dried in vacuo to yield the title compound (77 mg, 91 %) as a solid.
LRMS (m/z): 221 (M+1 )+. 1H-NMR δ (300 MHz, CD3OD): 2.77 (s, 4H), 3.17 - 3.33 (m, 10H), 3.77 (s, 2H), 6.83 - 6.98 (m, 2H), 8.05 (d, 1 H).
PREPARATION 16
1 -[(4-pyrrolidin-1 -ylpyridin-2-yl)methyl]piperazine
a) Terf-butyl 4-[(4-pyrrolidin-1 -ylpyridin-2-yl)methyl]piperazine-1 -carboxylate
A solution of fe/f-butyl 4-[(4-bromopyridin-2-yl)methyl]piperazine-1 -carboxylate (Preparation 15a, 0.10 g, 0.28 mmol) and pyrrolidine (0.12 mL, 1.40 mmol) in ethanol (1 mL) was stirred overnight at 80 °C. Additional pyrrolidine (0.12 mL, 1 .40 mmol) was added and the mixture was stirred overnight at 80 °C. The solvent and pyrrolidine in excess were evaporated to dryness and the residue was partitioned between water and dichloromethane. The organic layer was separated by a Phase Separator and the solvent evaporated to yield the title compound (86 mg, 88%) as a brown solid.
LRMS (m/z): 347 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.48 (d, 1 H), 8.15 (d, 1 H). b) 1 -[(4-Pyrrolidin-1 -ylpyridin-2-yl)methyl]piperazine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (0.65 mL, 2.60 mmol) was added to a stirred solution of ie f-butyl 4-[(4-pyrrolidin-1 -ylpyridin-2-yl)methyl]piperazine-1 - carboxylate (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 additional 4.0 M solution of hydrogen chloride in 1 ,4-dioxane (0.65 mL, 2.60 mmol) was added. After stirring overnight, the precipitate formed was filtered and dried in vacuo to yield the hydrochloride salt of the title compound (98 mg, 100%) as a yellow solid.
LRMS (m/z): 247 (M+1 )+.
PREPARATION 17
4-[(4^5-Fluoro-6-[(3 ?)^iperidin-3-ylamino]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin -4-yl}piperazin-1 -yl)methyl]phenol
a) Terf-butyl (3 ?)-3-({5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1 -yl]-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1 -carboxylate
A mixture of ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin- 4-yl)amino]piperidine-1 -carboxylate (Preparation 6a, 2.20 g, 4.92 mmol), 1 -(4-methoxy benzyl)piperazine (1 .5 g, 7.27 mmol) and sodium hydrogencarbonate (3.80 g, 45.23 mmol) in Λ/,/V-dimethylacetamide (10 mL) was stirred overnight at 130 °C. After cooling to room temperature, water was added and the solid formed was filtered and dried in vacuo to yield the title compound (2.86 g, 91 %).
LRMS (m/z): 618 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.72 (m, 1 H),
6.77 - 6.92 (m, 3H), 7.26 (m, 3H), 8.46 (m, 2H), 8.55 (s, 1 H). b) 5-Fluoro-6-[4-(4-methoxybenzyl)piperazin-1 -yl]-yV-[(3 ?)-piperidin-3-yl]-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
Trifluoroacetic acid (1 .80 mL, 23.37 mmol) was added dropwise to a solution of tert- butyl (3R)-3-({5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1 -yl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidine-1 -carboxylate (Preparation 17a, 2.86 g, 4.64 mmol) in dichloromethane (80 mL) and the resulting mixture was stirred overnight at room temperature. Additional trifluoroacetic acid (1.80 mL, 23.37 mmol) was added and after stirring for further 4 hours, water was added and the mixture was basified with 4% aqueous solution of sodium hydrogencarbonate. The organic layer was separated by a Phase Separator and the solvent was evaporated to dryness to yield the title compound (1 .98 g, 76%) as a brown foam.
LRMS (m/z): 518 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.50 (s, 2H), 3.68 - 3.78 (m, 4H), 3.81 (s, 3H), 4.23 (m, 1 H), 4.97 (m, 1 H), 6.81 (td, 1 H), 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 ?)-piperidin-3-ylamino]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}piperazin-1 -yl)methyl]phenol
1 .0 M Solution of boron tribromide in dichloromethane (2.5 mL, 2.5 mmol) was added dropwise to a solution of 5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1 -yl]-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 17b, 0.32 g, 0.62 mmol) in dichloromethane (30 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. Methanol (10 mL) was added dropwise and the reaction mixture was stirred for 10 minutes before the solvent was evaporated. Water and solid sodium hydrogencarbonate were added and the precipitate formed was filtered, washed with water and diisopropyl ether and dried in vacuo to yield the title compound (310 mg, 100%) as a yellow solid.
LRMS (m/z): 503 (M+1 )+. PREPARATION 18
yV,yV-Dimethyl-2-(4-(piperazin-1 -ylmethyl)phenoxy)ethanamine
a) 4-[2-(Dimethylamino)ethoxy]benzaldehyde
A mixture of 4-hydroxybenzaldehyde (6.0 g, 49.1 mmol), 2-chloro-/V,/V-dimethyl ethanamine hydrochloride (10.61 g, 73.70 mmol) and potassium carbonate (20.37 g, 147.4 mmol) in /V,/V-dimethylformamide (60 mL) was stirred overnight at 90 °C. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate and the solvent evaporated to yield the title compound (7.25 g, 72%) as a brown oil.
LRMS (m/z): 194 (M+1 )+. b) W,/V-Dimethyl-2-(4-(piperazin-1 -ylmethyl)phenoxy)ethanamine
A mixture of 4-[2-(dimethylamino)ethoxy]benzaldehyde (Preparation 18a, 7.25 g, 37.5 mmol), ie f-butyl piperazine-1 -carboxylate (6.98 g, 37.5 mmol) and sodium triacetoxyborohydride (9.54 g, 45.0 mmol) in dichloromethane (30 mL) was stirred at room temperature for 48 hours. The reaction mixture was washed with a 2N aqueous solution of sodium hydroxide and with a 0.1 N aqueous solution of hydrogen chloride. The solvent was evaporated to dryness, 4.0 M solution of hydrogen chloride in 1 ,4- dioxane (94 mL) was added to the residue and the resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was co- evaporated with 1 ,4-dioxane and toluene to dryness to yield the title compound (1 1.05 g, 71 %) as a hydrochloride salt.
LRMS (m/z): 264 (M+1 )+.
1H-NMR δ (300 MHz, CD3OD): 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-W-[(3 ?)-piperidin -3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
a) Terf-butyl (3 ?)-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5- fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidine-1 -carboxylate
Obtained as a solid (60%) from ie/f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate (Preparation 6a) and N,N- dimethyl-2-[4-(piperazin-1 -ylmethyl)phenoxy]ethanamine (Preparation 18b) following the experimental procedure as described in Preparation 17a followed by purification of the crude product by flash chromatography. LRMS (m/z): 674 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.71 (d, 1 H), 6.80 (m, 1 H), 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-yV-[(3 ?)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
4.0 M solution of hydrogen chloride in 1 ,4-dioxane (3.70 ml_, 14.80 mmol) was added to a stirred solution of ie/f-butyl (3/?)-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 - carboxylate (Preparation 19a, 0.99 g, 1 .46 mmol) in 1 ,4-dioxane (10 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction crude was filtered and the solid obtained was suspended in 1 ,4-dioxane and basified with 2.0 M solution of ammonia in ethanol. The suspension formed was filtered and the filtrate was evaporated in vacuo. The residue was purified by reverse phase chromatography (using water and methanol as eluents) to yield the title compound (503 mg, 60%)
LRMS (m/z): 575 (M+2)+. PREPARATION 20
yV,yV-Dimethyl-2-[3-(piperazin-1 -ylmethyl)phenoxy]ethanamine
a) 3-[2-(Dimethylamino)ethoxy]benzaldehyde
A mixture of 3-hydroxybenzaldehyde (0.20 g, 1 .64 mmol), 2-chloro-/V,/V-dimethyl ethanamine hydrochloride (0.36 g, 2.64 mmol) and potassium carbonate (0.9 g, 6.51 mmol) in acetonitrile (6 mL) was stirred overnight at 70 °C. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate and the solvent evaporated. The resulting crude was purified by flash chromatography (dichloromethane to dichloromethane/ethanol 95:5) to yield the title compound (1 17 mg, 35%).
LRMS (m/z): 194 (M+1 )+. b) W,/V-Dimethyl-2-[3-(piperazin-1 -ylmethyl)phenoxy]ethanamine
A mixture of 3-[2-(dimethylamino)ethoxy]benzaldehyde (Preparation 20a, 0.12 g, 0.61 mmol), ie f-butyl piperazine-1 -carboxylate (0.1 1 g, 0.61 mmol) and sodium triacetoxyborohydride (0.15 g, 0.7 mmol) in dichloromethane (5 mL) was stirred overnight at room temperature. The reaction mixture was washed with 2N aqueous solution of sodium hydroxide and 0.1 N aqueous solution of hydrogen chloride. The organic layer was separated, dried over magnesium sulfate and the solvent was evaporated. 5N Aqueous solution of hydrogen chloride (5 mL) was added to the residue and the resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue partitioned between dichloromethane and 2N aqueous solution of sodium hydroxide. The organic layer was separated by a Phase Separator and the solvent evaporated to dryness to yield the title compound (92 mg, 52%) as a colourless oil.
LRMS (m/z): 264 (M+1 )+.
PREPARATION 21
yV,yV-Dimethyl-3-(4-(piperazin-1 -ylmethyl)phenoxy)propan-1 -amine
a) 4-(3-(Dimethylamino)propoxy)benzaldehyde
3-Chloro-/V,/V-dimethylpropan-1 -amine dihydrochloride (3.10 g, 19.60 mmol) was added to a suspension of 4-hydroxybenzaldehyde (2.00 g, 16.40 mmol), cesium carbonate (13.30 g, 41.00 mmol) and potassium iodide (0.10 g, 0.61 mmol) in N,N- dimethylformamide (40 mL) and the resulting mixture was stirred at 80 °C for 2 hours.
After cooling to room temperature, the solid was filtered and washed with ethyl acetate.
The combined filtrate and washings were washed with water, 1 N aqueous solution of sodium hydroxide and brine, dried over magnesium sulfate and the solvent evaporated to yield the title compound as a solid (3.10 g, 91 %).
LRMS (m/z): 208 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3): 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, 1 H). b) Terf-butyl 4-(4-(3-(dimethylamino)propoxy)benzyl)piperazine-1 -carboxylate
A mixture of 4-(3-(dimethylamino)propoxy)benzaldehyde (Preparation 21 a, 2.00 g, 9.65 mmol) and ie f-butyl piperazine-1 -carboxylate (3.59 g, 19.3 mmol) in methanol (76 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.73 g, 1 1.6 mmol) and catalytic acetic acid were added and the mixture was stirred at room temperature for further 90 minutes. The solvent was evaporated and the residue was partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and washed with additional saturated aqueous hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent evaporated. The residue was purified by flash chromatography (using a gradient of methanol in dichloromethane) to yield the title compound (1 .23 g, 34%). LRMS (m/z): 378 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3): 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) /V,/V-Dimethyl-3-(4-(piperazin-1 -ylmethyl)phenoxy)propan-1 -amine
4.0M Solution of hydrogen chloride in 1 ,4-dioxane (17 mL, 68.2 mmol) was added to a stirred solution of fe/f-butyl 4-(4-(3-(dimethylamino)propoxy)benzyl)piperazine-1 - carboxylate (Preparation 21 b, 1 .29 g, 3.41 mmol) in 1 ,4-dioxane (22 mL) and water (0.10 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was treated with diethyl ether, filtered and dried in vacuo to yield the title compound (1.15g, 87%) as an hydrochloride salt.
LRMS (m/z): 278 (M+1 )+.
1H-NMR δ (400 MHz, D20): 2.26 (m, 2H), 2.96 (s, 6H), 3.94 (t, 2H), 3.61 (bs, 8H), 4.22 (m, 2H), 4.44 (s, 2H), 7.1 1 -7.13 (d, 2H), 7.49 -7.51 (d, 2H).
PREPARATION 22
1 -[4-(2-Piperidin-1 -ylethoxy)benzyl]piperazine
a) Terf-butyl 4-(4-hydroxybenzyl)piperazine-1 -carboxylate
Sodium triacetoxyborohydride (0.63 g, 2.95 mmol) was added to a solution of 4- hydroxybenzaldehyde (0.30 g, 2.47 mmol), ie f-butyl piperazine-1 -carboxylate (0.50 g, 2.70 mmol) and acetic acid (0.042 mL, 0.74 mmol) in dichloromethane (10 mL) and the resulting suspension was stirred for 72 hours at room temperature. The reaction mixture was partitioned between diethyl ether and water. The organic phase was separated, dried over sodium sulfate and the solvent was evaporated to give the title compound (0.55 g, 65%).
LRMS (m/z): 293 (M+1 )+. b) Terf-butyl 4-[4-(2-piperidin-1 -ylethoxy)benzyl]piperazine-1 -carboxylate
A suspension of ie f-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 mmol) and potassium carbonate (0.786 g, 5.69 mmol) in Λ/,Λ/'-dimethylformamide (4 mL) was stirred overnight at 50 °C. The reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting oil was partitioned between diethyl ether and 1 N aqueous solution of sodium hydroxide. The organic layer was separated, washed with water, dried over magnesium sulfate and the solvent was evaporated to give the title compound (0.484 g, 57%) LRMS (m/z): 404 (M+1 )+. c) 1 -[4-(2-Piperidin-1 -ylethoxy)benzyl]piperazine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (6 mL) was added to a solution of ie f-butyl 4-[4-(2-piperidin-1 -ylethoxy)benzyl]piperazine-1 -carboxylate (Preparation 22b, 0.488 g, 1 .19 mmol) in methanol (6 mL) and the resulting mixture was stirred for 3 hours at room temperature. The solvents were evaporated and the solid was treated with diethyl ether, filtered and washed with acetonitrile to yield the trihydrochloride salt of the title compound (0.27 g, 43%).
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
Cesium 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 a solution of 4-hydroxybenzaldehyde (1.50 g, 12.3 mmol) in Λ/,Λ/'-dimethylformamide (30 mL) and the resulting suspension was stirred for 2 hours at 60 °C and 1 hour at 80 °C. The reaction mixture was filtered and the solid was washed with excess of ethyl acetate. The combined organic layers were washed with water (100 mL). The aqueous phase was extracted with ethyl acetate (x3) and the organic fractions were combined and washed with 2.0 N aqueous sodium hydroxide solution, water and brine. The organic phase was separated, dried over magnesium sulfate and the solvent was evaporated to give the title compound (1 .93 g, 72%).
LRMS (m/z): 220 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3): 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, 1 H). b) Terf-butyl 4-(4-(2-(pyrrolidin-1 -yl)ethoxy)benzyl)piperazine-1 -carboxylate
Terf-Butyl piperazine-1 -carboxylate (3.16 g, 16.96 mmol) was added to a solution of 4- (2-(pyrrolidin-1 -yl)ethoxy)benzaldehyde (Preparation 23a, 1 .86 g, 8.48 mmol) in methanol (74 mL) and the resulting mixture was stirred for 10 minutes at room temperature. Sodium cyanoborohydride (0.64 g, 10.2 mmol) was then added and pH of the solution was adjusted to 5 by addition of acetic acid. After 1 .5 hours of stirring at room temperature, the solvent was evaporated under vacuum and the crude was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and the solvent evaporated. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ) to yield the title compound (1.74 g, 83%).
LRMS (m/z): 390 (M+1 )+.
1H-NMR δ (400 MHz, CDCI3):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
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (13.2 mL, 52.8 mmol) was added to a solution of ie f-butyl 4-(4-(2-(pyrrolidin-1 -yl)ethoxy)benzyl)piperazine-1 -carboxylate (Preparation 23b, 1.03 g, 2.65 mmol) in 1 ,4-dioxane (20 mL) and the resulting mixture was stirred 2.5 hours at room temperature. Excess of diethyl ether was added and the suspension was filtered and washed with diethyl ether to give the trihydrochloride salt of the title compound (0.99 g, 97%) as a solid.
LRMS (m/z): 290 (M+1 )+.
1H-NMR δ (400 MHz, D20): 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, 1 H), 4.42 - 4.44 (m, 4H), 7.14 - 7.16 (d, 2H), 7.51 - 7.53 (d, 2H).
PREPARATION 24
[2-(4-{[(2 ?,6S)-2,6-dimethylpiperazin-1 -yl]methyl}phenoxy)ethyl]dimethylamine Sodium triacetoxyborohydride (0.32 g, 1 .51 mmol) was added to a solution of ie f-butyl (3R,5S)-3,5-dimethylpiperazine-1 -carboxylate (0.28 g, 1 .30 mmol) and 4-[2-(dimethyl amino)ethoxy]benzaldehyde (Preparation 18a, 0.25 g, 1 .29 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was washed with 2M aqueous solution of sodium hydroxide and the organic layer was separated, dried over magnesium sulfate and the solvent evaporated to dryness. 4M Solution of hydrochloric acid in 1 ,4-dioxane was added to the residue and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness to yield the hydrochloride salt of the title compound (299 mg, 45%) as a solid.
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 acetone (40 mL) was stirred at 50 °C for 1 hour. The reaction was cooled to room temperature and potassium iodide (0.06 g, 0.33 mmol) and 2-chloro-/V,/V-dimethylethanamine (1 .08 g, 7.46 mmol) were added and the mixture was stirred overnight at 50 °C. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated to dryness. The residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with 2N aqueous solution of sodium hydroxide, dried over magnesium sulfate and the solvent evaporated to yield the title compound (980 mg, 67%) as a white solid.
LRMS (m/z): 222 (M+1 )+. b) Terf-butyl 4-{4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazine-1 - carboxylate
A mixture of 4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzaldehyde (Preparation 25a, 0.98 g, 4.43 mmol) and ie f-butyl piperazine-1 -carboxylate (0.99 g, 5.31 mmol) in methanol (40 mL) was stirred for 1 hour at room temperature. Acetic acid (0.51 mL, 8.86 mmol) and sodium cyanoborohydride (0.33 mg, 5.31 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with 2N aqueous solution of sodium hydroxide, dried over magnesium sulfate and the solvent evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane /methanol 9:1 ) to yield the title compound (628 mg, 36%).
LRMS (m/z): 392 (M+1 )+. c) {2-[2,6-Dimethyl-4-(piperazin-1 -ylmethyl)phenoxy]ethyl}dimethylamine
A mixture of ie f-butyl 4-{4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazine-1 - carboxylate (Preparation 25b, 0.63 g, 1.60 mmol) and 4.0 M solution of hydrogen chloride in 1 ,4-dioxane (8 mL, 32 mmol) was stirred at room temperature for 1 hour. The reaction mixture was filtered and the solid washed with diethyl ether and dried in vacuo to yield the hydrochloride salt of the title compound (61 1 mg, 96%) as a solid.
LRMS (m/z): 292 (M+1 )+.
1H-NMR δ (400 MHz, D20): 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
Obtained as a solid (50%) from 4-hydroxy-2,6-dimethylbenzaldehyde and 2-chloro- Λ/,/V-dimethylethanamine following the experimental procedure as described in Preparation 25a.
LRMS (m/z): 222 (M+1 )+. b) Terf-butyl 4-{4-[2-(dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazine-1 - carboxylate
Obtained as a solid (48%) from 4-[2-(dimethylamino)ethoxy]-2,6-dimethylbenzaldehyde (Preparation 26a) and ie f-butyl piperazine-1 -carboxylate following the experimental procedure as described in Preparation 25b followed by purification of the crude product 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}dimethylamine
Obtained as a solid hydrochloride salt (100%) from ie f-butyl 4-{4-[2-(dimethylamino) ethoxy]-2,6-dimethylbenzyl} piperazine-1 -carboxylate (Preparation 26b) following the experimental procedure as described in Preparation 25c.
LRMS (m/z): 292 (M+1 )+.
1H-NMR δ (400 MHz, D20): 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) yV,yV-Dimethyl-2-[4-(2-piperazin-1 -ylethyl)phenoxy]ethanamine
a) Terf-butyl 4-[2-(4-hydroxyphenyl)ethyl]piperazine-1 -carboxylate
A mixture of 4-(2-bromoethyl)phenol (0.9 g, 4.48 mmol), ie/f-butyl 1 -piperazine carboxylate (1 .0 g, 5.37 mmol) and /V-ethyl-/V-isopropyl-2-propanamine (1.56 mL, 8.95 mmol) in acetonitrile (18 mL) was stirred at 90 °C for 48 hours. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with 2N aqueous sodium hydroxide solution and brine, dried over sodium sulfate and the solvent evaporated to yield the title compound (1 .13 g, 82%) as a brown oil.
LRMS (m/z): 307 (M+1 )+. b) Terf-butyl 4-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)piperazine-1 - carboxylate
A mixture of ie f-butyl 4-[2-(4-hydroxyphenyl)ethyl]piperazine-1 -carboxylate (Preparation 27a, 1 .13 g, 3.70 mmol), 2-chloro-/V,/V-dimethylethanamine hydrochloride (0.64 g, 4.40 mmol), potassium iodide (0.06 g, 0.37 mmol) and potassium carbonate (1 .53 g, 1 1.0 mmol) in acetone (20 mL) was heated 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 and evaporated to dryness. The residue was purified by flash chromatography to yield the title compound (0.60 g, 43%).
LRMS (m/z): 378 (M+1 )+. c) yV,yV-Dimethyl-2-[4-(2-piperazin-1 -ylethyl)phenoxy]ethanamine
Obtained as a solid hydrochloride salt (99%) from ie f-butyl 4-(2-{4-[2-(dimethylamino) ethoxy]phenyl}ethyl)piperazine-1 -carboxylate (Preparation 27b) following the experimental procedure as described in Preparation 25c.
LRMS (m/z): 278 (M+1 )+.
1H-NMR δ (300 MHz, DMSO-d6): 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 ?)-3-[(5-Fluoro-6^iperazin-1 -yl-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl) amino]piperidin-1 -yl}-3-oxopropanenitrile
a) Terf-butyl 4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazine-1 -carboxylate
A suspension of 3-{(3R)-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), tert- butyl 1 -piperazinecarboxylate (0.108 g, 0.58 mmol) and sodium hydrogencarbonate (0.131 g, 1.56 mmol) in Λ/,Λ/'-dimethylacetamide (0.8 mL) was stirred for 56 hours at 100 °C. After cooling to room temperature, excess of water was added and the precipitate was filtered, washed with water and dried in vacuo to yield the title compound (0.246 g, 80%) as a solid.
LRMS (m/z): 565 (M+2)+. b) 3-{(3 ?)-3-[(5-Fluoro-6-piperazin-1 -yl-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl) amino]piperidin-1 -yl}-3-oxopropanenitrile
A 4M solution of hydrogen chloride in 1 ,4-dioxane (2.13 mL) was added to a solution of ie f-butyl 4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)piperazine-1 -carboxylate (Preparation 28a, 0.24 g, 0.43 mmol) in ethanol (4 mL) and the resulting solution was stirred overnight at room temperature. The solvents were evaporated and the residue was treated with acetronitrile and filtered. Purification of the solid by flash chromatography (dichloromethane/methanol/ammonia 40:4:0.2) gave the title compound (0.078 g, 38%).
LRMS (m/z): 464 (M+1 )+. PREPARATION 29
2-(Dimethylamino)ethyl 4-formylbenzoate
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, 1 12 mmol) was stirred overnight at 100 °C. The reaction mixture was partitioned between diethyl ether and water. The organic layer was separated, washed with water, dried over magnesium sulfate and the solvent evaporated to yield the title compound (0.29 g, 17%) as an oil.
LRMS (m/z): 224 (M+1 )+. b) 2-(Dimethylamino)ethyl 4-formylbenzoate
Manganese dioxide (0.674 g, 7.75 mmol) was added to a solution of 2- (dimethylamino)ethyl 4-(hydroxymethyl)benzoate (Preparation 29a, 0.172 g, 0.77 mmol) in chloroform (1 .7 mL) and the resulting suspension was stirred 48 hours at 45 °C. The suspension was diluted with dichloromethane and filtered through diatomaceous earth (Celite®). The filtrate was evaporated to dryness and purification by flash chromatography (ethyl acetate) of the resulting residue gave the title compound as a yellow oil (0.106 g, 60%)
LRMS (m/z): 222 (M+1 )+.
PREPARATION 30
Terf-butyl 4-(piperazin-1 -ylmethyl)piperidine-1 -carboxylate
a) Benzyl 4-{[1 -(ieri-butoxycarbonyl)piperidin-4-yl]methyl}piperazine-1 - carboxylate A mixture of ie f-butyl 4-formylpiperidine-1 -carboxylate (0.98 g, 4.60 mmol), benzyl piperazine-1 -carboxylate (1 .02 g, 4.61 mmol) and sodium triacetoxyborohydride (1 .01 g, 4.76 mmol) in dichloromethane (30 mL) was stirred overnight at room temperature. The crude was washed with 2N aqueous solution of sodium hydroxide and 2N aqueous solution of hydrogen chloride, dried over magnesium sulfate and the solvent was evaporated to yield the title compound (1 .68 g, 87%) as a white solid.
LRMS (m/z): 418 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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) Terf-butyl 4-(piperazin-1 -ylmethyl)piperidine-1 -carboxylate
10% Palladium on carbon (0.10 g, 0.97 mmol) was added to a suspension of benzyl 4- {[1 -(ie f-butoxycarbonyl)piperidin-4-yl]methyl}piperazine-1 -carboxylate (Preparation 30a, 0.80 g, 2.31 mmol) in ethanol (15 mL) and the resulting mixture was stirred under an hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was evaporated. The residue was filtered through a SCX column, washed with methanol and eluted with a 2N solution of ammonia in methanol. The solvent was evaporated to dryness to yield the title compound (539 mg, 99%) as a white solid.
LRMS (m/z): 284 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H). PREPARATION 31
1 -(2 , 6-Di methyl pyri d i n -4-y I )pi perazi ne
a) Terf-butyl 4-(2,6-dimethylpyridin-4-yl)piperazine-1 -carboxylate
A Schlenk tube was charged with ie f-butyl piperazine-1 -carboxylate (0.12 g, 0.62 mmol), 4-bromo-2,6-dimethylpyridine (0.15 g, 0.81 mmol), sodium ie/f-butoxide (0.09 g, 0.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 g, 0.02 mmol) and toluene (4 mL). The Schlenk tube was subjected to three cycles of evacuation- backfilling with argon and then tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °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 ethyl acetate (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title compound (198 mg, 100%) as an oil.
LRMS (m/z): 292 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .70 mL, 6.80 mmol) was added to a stirred solution of ie f-butyl 4-(2,6-dimethylpyridin-4-yl)piperazine-1 -carboxylate (Preparation 31 a, 0.20 g, 0.68 mmol) in 1 ,4-dioxane (3 mL) and the resulting mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and basified by addition of 4% aqueous solution of sodium hydrogencarbonate. Water was evaporated to dryness and dichloromethane was added. After stirring vigorously for 30 minutes, the solid was filtered and the filtrate was evaporated to dryness to yield the title compound (190 mg, 100%).
LRMS (m/z): 192 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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) Terf-butyl 4-(2-chloropyridin-4-yl)piperazine-1 -carboxylate
A Schlenk tube was charged with ie f-butyl piperazine-1 -carboxylate (1 .74 g, 9.34 mmol), 4-bromo-2-chloropyridine (1 .35 g, 7.02 mmol), sodium ie/f-butoxide (1 .35 g, 14.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.32 g, 0.55 mmol) and toluene (45 mL). The Schlenk tube was subjected to three cycles of evacuation- backfilling with argon and then tris(dibenzylideneacetone)dipalladium (0.17 g, 0.19 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred at 90 °C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth (Celite®) and washed with ethyl acetate. The filtrate and washings were combined and the solvents were evaporated to dryness. The residue was purified by flash chromatography (hexanes to 3:7 hexanes/ethyl acetate) to yield the title compound (1 .34 g, 64%) as a yellow solid.
LRMS (m/z): 298 (M+1 )+. 1H-NMR δ (300 MHz, CDCI3): 1 .49 (s, 9H), 3.30 - 3.37 (m, 4H), 3.53 - 3.60 (m, 4H), 6.57 (dd, 1 H), 6.65 (d, 1 H), 8.04 (d, 1 H). b) Terf-butyl 4-(2-pyrrolidin-1 -ylpyridin-4-yl)piperazine-1 -carboxylate
A Schlenk tube was charged with fe/f-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 fe/f-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 cycles of evacuation-backfilling with argon and then palladium acetate (0.01 g, 0.05 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 80 °C. After cooling to room emperature, the reaction mixture was filtered through diatomaceous earth (Celite®) and washed with ethyl acetate. The filtrate and washings were combined and the solvents were evaporated to dryness. The residue was purified by reverse phase chromatography (water/acetonitrile/methanol as eluents) to yield the title compound (320 mg, 96%) as an oil.
LRMS (m/z): 192 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 2.00 - 2.1 1 (m, 4H), 3.40 - 3.48 (m, 4H), 3.53 (m, 4H), 3.57 - 3.63 (m, 4H), 6.22 (dd, 1 H), 7.95 (d, 1 H), 8.52 (s, 1 H). c) 1 -(2-Pyrrolidin-1 -ylpyridin-4-yl)piperazine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1.12 mL, 4.48 mmol) was added to a stirred solution of ie f-butyl 4-(2-pyrrolidin-1 -ylpyridin-4-yl)piperazine-1 -carboxylate (Preparation 32b, 0.15 g, 0.45 mmol) in 1 ,4-dioxane (2 mL) and the resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered and the solid washed with 1 ,4-dioxane and dried in vacuo to yield the hydrochloride salt of the title compound (92 mg, 84%) as a white solid.
LRMS (m/z): 233 (M+1 )+.
1H-NMR δ (300 MHz, CD3OD): 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, 1 H), 6.65 (d, 1 H), 7.62 (d, 1 H).
PREPARATION 33
yV,yV-dimethyl-4-piperazin-1 -ylpyridin-2 -amine
a) Terf-butyl 4-[2-(dimethylamino)pyridin-4-yl]piperazine-1 -carboxylate
Obtained as a colourless oil (39%) from ie f-butyl 4-(2-chloropyridin-4-yl)piperazine-1 - carboxylate (Preparation 32a) and dimethylamine hydrochloride following the experimental procedure as described in Preparation 32b followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/diethyl ether 1 :1 ).
LRMS (m/z): 307 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .48 (s, 9H), 3.06 (s, 6H), 3.24 - 3.31 (m, 4H), 3.51 - 3.60 (m, 4H), 5.79 (d, 1 H), 6.12 (dd, 1 H), 7.94 (d, 1 H). b) W,/V-Dimethyl-4-piperazin-1 -ylpyridin-2-amine
Obtained as a solid hydrochloride salt (66%) from ie f-butyl 4-[2-(dimethylamino) pyridin-4-yl]piperazine-1 -carboxylate (Preparation 33a) following the experimental procedure as described in Preparation 32c.
LRMS (m/z): 207 (M+1 )+.
PREPARATION 34
yV,yV-Dimethyl-2-piperazin-1 -ylpyridin-4-amine
a) 2-Chloro-W,W-dimethylpyridin-4-amine
Obtained as a colourless oil (70%) from 4-bromo-2-chloropyridine and dimethylamine hydrochloride following the experimental procedure as described in Preparation 32a followed by purification of the crude product by flash chromatography.
LRMS (m/z): 157/159 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 3.01 (s, 6H), 6.42 (dd, 1 H), 6.49 (d, 1 H), 7.98 (d,
1 H). b) Terf-butyl 4-[4-(dimethylamino)pyridin-2-yl]piperazine-1 -carboxylate
Obtained as a colourless oil (54%) from 2-chloro-/V,/V-dimethylpyridin-4-amine (Preparation 34a) and ie/f-butyl piperazine-1 -carboxylate following the experimental procedure as described in Preparation 32b followed by purification of the crude product by flash chromatography (hexane to diethyl ether).
LRMS (m/z): 307 (M+1 )+. c) yV,yV-Dimethyl-2-piperazin-1 -ylpyridin-4-amine
Obtained as a solid hydrochloride salt (91 %) from fe/f-butyl 4-[4-(dimethylamino) pyridin-2-yl]piperazine-1 -carboxylate (Preparation 34b) following the experimental procedure as described in Preparation 32c.
LRMS (m/z): 207 (M+1 )+.
PREPARATION 35 Terf-butyl 4-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]piperidine-1 -carboxylate
Obtained as a solid (51 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and fe/f-butyl 4-piperazin-1 -ylpiperidine-1 -carboxylate following the experimental procedure as described in Preparation 12a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ).
LRMS (m/z): 647 (M+1 )+. PREPARATION 36
2-(Piperidin-4-ylmethyl)isoindoline
a) Terf-butyl 4-(1 ,3-dihydro-2H-isoindol-2-ylmethyl)piperidine-1 -carboxylate
Sodium triacetoxyborohydride (0.47 g, 2.22 mmol) was added to a solution of isoindoline (0.22 g, 1.85 mmol), ie f-butyl 4-formyl-1 -piperidinecarboxylate (0.40 g, 1.88 mmol) and acetic acid (0.033 mL, 0.58 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between excess of diethyl ether and water. The organic phase was separated, washed with diluted aqueous sodium hydroxide solution, dried over sodium sulfate and the solvent was evaporated to give the title compound (0.61 g, 83%)
LRMS (m/z): 317 (M+1 )+. b) 2-(Piperidin-4-ylmethyl)isoindoline
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (13 mL) was added to a solution of ie f-butyl 4-(1 ,3-dihydro-2H-isoindol-2-ylmethyl)piperidine-1 -carboxylate (Preparation 36a, 0.610 g, 1 .93 mmol) in methanol (10 mL) and the resulting mixture was stirred for 4 hours at room temperature. Diethyl ether was added until complete precipitation of a blue solid. The solid was filtered and washed with diethyl ether to yield the dihydrochloride salt of the title compound (0.37 g, 63%) as a blue solid.
LRMS (m/z): 217 (M+1 )+.
PREPARATION 37
W,W-Dimethyl-2-(4-(piperidin-4-ylmethyl)phenoxy)ethanamine
a) Terf-butyl 4-(4-hydroxybenzyl)piperidine-1 -carboxylate
A mixture of 4-(4-hydroxybenzyl)piperidine hydrochloride (0.38 g, 1 .67 mmol), di-ie/f- butyl dicarbonate (0.37 g, 1 .69 mmol) and sodium hydrogencarbonate (1 .4 g, 16.70 mmol) in a 1 :1 mixture of 1 ,4-dioxane and water (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with additional water and brine, dried over sodium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (n-hexane to n-hexane/ethyl acetate 6:4) to yield the title compound (205 mg, 42%) as a white solid.
LRMS (m/z): 292 (M+1 )+. b) Terf-butyl 4-{4-[2-(dimethylamino)ethoxy]benzyl}piperidine-1 -carboxylate
A mixture of fe/f-butyl 4-(4-hydroxybenzyl)piperidine-1 -carboxylate (Preparation 37a, 0.20 g, 0.70 mmol), 2-chloro-/V,/V-dimethylethanamine hydrochloride (0.12 g, 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, washed with additional water and brine, dried over sodium sulfate and evaporated to dryness to yield the title compound (198 mg, 77%) as a yellow oil.
LRMS (m/z): 363 (M+1 )+. c) yV,yV-Dimethyl-2-(4-(piperidin-4-ylmethyl)phenoxy)ethanamine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .50 mL, 5.46 mmol) was added to a stirred solution of ie f-butyl 4-{4-[2-(dimethylamino)ethoxy]benzyl}piperidine-1 - carboxylate (Preparation 37b, 0.20 g, 0.55 mmol) in 1 ,4-dioxane (3 mL) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was co-evaporated with 1 ,4-dioxane and toluene to yield the hydrochloride salt of the title compound (182 mg, 97%) as a solid.
LRMS (m/z): 263 (M+1 )+.
1H-NMR δ (300 MHz, DMSO-d6): 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-W-piperidin-4-ylpyridin-4-amine
a) Terf-butyl 4-[(2,6-dimethylpyridin-4-yl)amino]piperidine-1 -carboxylate
A Schlenk tube was charged with ie f-butyl 4-aminopiperidine-1 -carboxylate (0.249 g, 1 .24 mmol), 4-bromo-2,6-dimethylpyridine (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 cycles of evacuation-backfilling with argon and then tris(dibenzylideneacetone) dipalladium (76 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (10 mg, 0.02 mmol) were added. After three further cycles of evacuation- backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth Celite® and the filtrate was concentrated to dryness. The crude residue was purified by reverse phase chromatography (gradient from water to methanol) to yield the title compound (188 mg, 60%).
LRMS (m/z): 306 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.92 (d, 1 H), 4.06 (d, 2H), 6.15 (s, 2H). b) 2,6-Dimethyl-W-piperidin-4-ylpyridin-4-amine
Obtained as a solid hydrochloride salt (100%) from ie f-butyl 4-[(2,6-dimethylpyridin-4- yl)amino]piperidine-1 -carboxylate (Preparation 38a) following the experimental procedure as described in Preparation 37c.
LRMS (m/z): 206 (M+1 )+.
PREPARATION 39
Benzyl 4-(piperidin-4-ylmethyl)piperazine-1 -carboxylate
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (15 ml_, 60 mmol) was added to a solution of benzyl 4-{[1 -(ie f-butoxycarbonyl)piperidin-4-yl]methyl}piperazine-1 - carboxylate (Preparation 30a, 0.86 g, 2.06 mmol) in methanol (15 mL) at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was filtered through a SCX column (using methanol to wash and a 2N solution of ammonia in methanol to elute the product). The solvent was evaporated to dryness to yield the title compound ( 649 mg, 99%) as a white solid.
LRMS (m/z): 318 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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
W,W,2-Trimethyl-6-[1 -(piperidin-4-ylmethyl)piperidin-4-yl]pyridin-4-amine a) Terf-butyl 4-({4-[4-(dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -yl}methyl) piperidine-1 -carboxylate
Sodium triacetoxyborohydride (0.24 g, 1 .13 mmol) was added to a solution of N,N,2- trimethyl-6-piperidin-4-ylpyridin-4-amine dihydrochloride (0.28 g, 0.96 mmol), ie f-butyl 4-formyl-1 -piperidinecarboxylate (0.20 g, 0.94 mmol) and triethylamine (0.25 mL, 1 .79 mmol) in dichloromethane (4 mL) and the resulting mixture was stirred overnight at room temperature. The crude was partitioned in excess of diethyl ether and water. The organic phase was separated, washed with diluted aqueous sodium hydroxide solution, dried over sodium sulfate and the solvent evaporated to give the title compound (0.31 g, 72%)
LRMS (m/z): 417 (M+1 )+. b) W,W,2-Trimethyl-6-[1 -(piperidin-4-ylmethyl)piperidin-4-yl]pyridin-4-amine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (4 mL) was added to a solution of ie f-butyl 4-({4-[4-(dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -yl}methyl)piperidine- 1 -carboxylate (Preparation 40a, 0.308 g, 0.74 mmol) in ethanol (10 mL) and the resulting mixture was stirred overnight at room temperature. The solvents were evaporated and the residue was treated with diethyl ether and filtered to yield the trihydrochloride salt of the title compound (0.37 gr, 98%) as a solid.
LRMS (m/z): 317 (M+1 )+.
PREPARATION 41
(/?)-7erf-butyl 4-(4-(((6-((1 -(2-cyanoacetyl)piperidin-3-yl)amino)-5-fluoro-2-
(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)methyl)phenyl)piperazine-1 - carboxylate
A microwave reactor was charged with 3-{(3R)-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 ie f-butyl 4-[4-(aminomethyl)phenyl]piperazine-1 -carboxylate (0.42 g, 1.45 mmol) in /V-methylpyrrolidone (1 .5 mL). The reaction mixture was subjected to microwave irradiation for 2 hours at 140 °C then poured into water. The precipitate was filtered, washed with water, dried and purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (77 mg, 32%).
LRMS (m/z): 669 (M+1 )+. PREPARATION 42
( ?)-5-Fluoro-6-(4-(4-methylpiperazin-1 -yl)phenyl)-N-(piperidin-3-yl)-2-(pyrazolo
[1 ,5-a]pyridin-3-yl)pyrimidin-4-amine
a) (/?)-7erf-butyl 3-((5-fluoro-6-(4-(4-methylpiperazin-1 -yl)phenyl)-2-(pyrazolo[1 ,5- a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidine-1 -carboxylate
A Schlenk tube was charged with ie/f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate (Preparation 6a, 0.30 g, 0.67mmol), 1 -methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl] piperazine (0.253 g, 0.84 mmol), 2M cesium carbonate aqueous solution ( 1 .0 mL, 2.0 mmol) and 1 ,4-dioxane (1 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride dichloromethane complex (0.075 g, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 90 °C overnight. The residue was diluted with water and extracted with a mixture of diethyl ether/pentane 1 :1 . The organic layer was washed with water, dried over magnesium sulfate and the solvents were evaporated to yield the title compound (0.4 g, 87%) as a gum.
LRMS (m/z): 588 (M+2)+. b) 5-Fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-yV-[(3 ?)-piperidin-3-yl]-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .9 mL) was added to a solution of ie f-butyl (3R)-3-({5-fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin- 3-ylpyrimidin-4-yl}amino)piperidine-1 -carboxylate (Preparation 42a, 0.222 g, 0.38 mmol) in methanol (2.5 mL) and the resulting mixture was stirred for 4 hours at room temperature. The solvent was evaporated and the residue was treated with dietyl ether. The yellow solid formed was filtered and washed with acetonitrile to yield the trihydrochloride salt of the title compound (0.15 g, 62%).
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)phenyl] piperazin-1 -ium bromide
(Bromomethyl)benzene (0.786 mL, 0.66 mmol) was added to a stirred solution of 1 - methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (0.2 g, 0.66 mmol) in tetrahydrofuran (1 mL) and the resulting mixture was stirred overnight at room temperature. Diethyl ether (2 mL) was added and the prepicitate was filtered and washed with diethyl ether to yield the title compound (0.185 g, 57%) as a white solid.
LRMS (m/z): 393 (M)+. PREPARATION 44
1 -(4-7erf-butylbenzyl)-1 -methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenyl]piperazin-1 -ium bromide 1 -(Bromomethyl)-4-ie f-butylbenzene (0.150 g, 0.66 mmol) was added to a stirred solution of 1 -methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (0.2 g, 0.66 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred overnight at room temperature. Additional 1 -(bromomethyl)-4-ie f-butylbenzene (0.02 g) was added and the reaction mixture was stirred for further 24 hours at room temperature. The solvent was evaporated and the residue was treated with hexane and filtered. The white solid was washed with diethyl ether to yield the title compound (0.32 g, 86%).
LRMS (m/z): 449 (M)+. PREPARATION 45
3-((3 ?)-3-{[5-Fluoro-6-(4-piperazin-1 -ylphenyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
a) Terf-butyl 4-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]piperazine-1 -carboxylate
A Schlenk tube was charged with 3-{(3R)-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), ie/f-butyl 4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl] piperazine-1 -carboxylate (0.24 g, 0.61 mmol), 2M aqueous cesium carbonate solution (0.73 mL, 1 .45 mmol) and 1 ,4-dioxane (5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino) ferrocene]palladium(ll) dichloride dichloromethane complex (0.04 g, 0.05 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was removed and the residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 93:7) to yield the title compound (145 mg, 46%) as a solid.
LRMS (m/z): 640 (M+1 )+. b) 3-((3 ?)-3-{[5-Fluoro-6-(4-piperazin-1 -ylphenyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (0.57 mL, 2.27 mmol) was added to a stirred solution of ie f-butyl 4-[4-(6-{[(3R)-1-(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]piperazine-1 -carboxylate (Preparation 45a, 0.15 g, 0.23 mmol) in 1 ,4-dioxane (8 mL) and the resulting mixture was stirred at room temperature for 16 hours. Additional 4.0 M solution of hydrogen chloride in 1 ,4-dioxane (0.50 mL, 1 .98 mmol) was then added and the reaction mixture was stirred overnight at room temperature. The precipitate was filtered and washed with 1 ,4-dioxane to yield the dihydrochloride salt of the title compound (120 mg, 86%) as a solid.
LRMS (m/z): 540 (M+1 )+. PREPARATION 46
(/^-^-(S-Fluoro-G-^-^-methylpiperazin-l -y
yl)pyrimidin-4-yl)-W A^-dimethyl-W^piperi^^
a) (/?)-7erf-butyl 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 - carboxylate
Sodium hydride (60% dispersion in mineral oil, 0.081 g, 2.03 mmol) was added portionwise to a suspension of ie f-butyl (3R)-3-({5-fluoro-6-[4-(4-methylpiperazin-1 -yl) phenyl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1 -carboxylate (Preparation 42a, 0.4 g, 0.68 mmol) and (2-chloroethyl)dimethylamine hydrochloride (0.15 g, 1 .04 mmol) in Λ/,Λ/'-dimethylformamide (2 mL) and the resulting mixture was stirred overnight at 55 °C. Additional (2-chloroethyl)dimethylamine hydrochloride (0.15 g, 1 .04 mmol) and sodium hydride (60% dispersion in mineral oil, 0.081 g, 2.03 mmol) were added every 24 hours and the reaction mixture was stirred for 3 days at 55 °C. After cooling to room temperature, water was added and the precipitate formed was filtered, washed with water and dried under vacuum. The brown solid was washed with hexane to obtain the title compound (0.272 g, 45%).
LRMS (m/z): 659 (M+2)+. b) (/?)-W^5-Fluoro-6-(4-(4-methylpiperazin-1 -yl)phenyl)-2-(pyrazolo[1 ,5-a]pyridin- S-ylJpyrimidin^-ylJ-W^W^dimethyl-W^ipiperidin-S-ylJethane-l ^-diamine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .5 mL) was added to a solution of ie/f-butyl (3R)-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 -carboxylate (Preparation 46a, 0.272 g, 0.30 mmol) in methanol (15 mL) and the resulting mixture was stirred overnight at room temperature. The solvents were evaporated and the solid was treated with acetonitrile and filtered to give the pentahydrochloride salt of the title compound (0.3 g, 82%). Purification of this solid by flash chromatography under basic conditions gave the title compound (0.07 g, 31 %) as a brown gum.
LRMS (m/z): 559 (M+2)+.
PREPARATION 47
1 -Methyl -4-(4-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)phenyl)piperidine A Schlenk tube was charged with 4-(4-bromophenyl)-1 -methylpiperidine (0.50 g, 1.97 mmol), 4!4!4'!4'!5!5!5'!5'-octamethyl-2!2'-bi-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 was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis (diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (0.08 g, 0.1 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The reaction mixture cooled to room temperature and partitioned between dichloromethane and water. The organic phase was separated, diluted with pentane, washed with diluted aqueous sodium hydroxide solution, dried over magnesium sulfate and the solvents were evaporated to dryness. The residue was treated with pentane and filtered. The filtrate was evaporated under vacuum to give the title compound (0.45 g, 67%) as a brown solid.
LRMS (m/z): 302 (M+1 )+.
PREPARATION 48
3-((3 ?)-3-{[5-Fluoro-6-(4-formylphenyl)-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
a) 3-[(3 ?)-3-({5-Fluoro-6-[4-(hydroxymethyl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
A Schlenk tube was charged with 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c, 1 .00 g, 2.42 mmol), 4-hydroxymethylphenylboronic acid (0.55 g, 3.62 mmol), 2.0 M aqueous sodium carbonate solution (1 .21 ml_, 2.42 mmol) and 1 ,2-dimethoxyethane (15 ml_). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (279 mg, 0.24 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The solvent was removed and the residue was purified by flash chromatography (hexanes to hexanes/ethyl acetate 1 :9) to yield the title compound (915 mg, 77%) as a white solid.
LRMS (m/z): 486 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .7 - 1 .9 (m, 2H), 2.1 -2.3 (m, 2H), 3.2 - 3.5 (m, 4H), 3.6 - 3.7 (m, 1 H), 3.9 (dd, 1 H), 4.3 (bs, 2H), 4.6 (dd, 1 H), 4.8 (t, 2H), 5.1 (bs, 1 H), 6.9 (dt, 1 H), 7.3 - 7.4 (m, 1 H), 7.5 - 7.6 (m, 2H), 8.1 (d, 2H), 8.5 - 8.6 (m, 2H), 8.7 (s, 1 H). b) 3-((3 ?)-3-{r5-Fluoro-6-(4-formvlphenvl)-2-pvrazolori ,5-a1pvridin-3-vlpyrimidin- 4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a white solid (33%) from 3-[(3R)-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) following the experimental procedure as described in Preparation 29b followed by purification of the crude product by flash chromatography (gradient from hexanes to ethyl acetate).
LRMS (m/z): 484 (M+1 )+. PREPARATION 49
[4-(Pyrrolidin-1 -ylmethyl)phenyl]boronic acid
Sodium triacetoxyborohydride (8.49 g, 40.05 mmol) was added to a solution of pyrrolidine (1 .1 g, 15.5 mmol), 4-formylphenylboronic acid (2.0 g, 13.34 mmol) and acetic acid (0.23 ml_, 4 mmol) in dichloromethane (40 mL) and the resulting mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by reverse phase chromatography to give the title compound (2.0 g, 73%) as a white solid.
LRMS (m/z): 206 (M+1 )+. PREPARATION 50
3- ((3 ?)-3-{[6-(4-Formylphenyl)-5-methyl-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
a) 3-[(3 ?)-3-({6-[4-(Hydroxymethyl)phenyl]-5-methyl-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
A Schlenk tube was charged with 3-{(3R)-3-[(6-chloro-5-methyl-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 8c, 0.35 g, 0.85 mmol), 4-hydroxymethylphenylboronic acid (0.19 g, 1 .28 mmol), 2.0 M aqueous sodium carbonate solution (0.64 mL, 1 .28 mmol) and 1 ,2-dimethoxyethane (4 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The solvent was removed and the residue was purified by flash chromatography (hexane/ethyl acetate from 50% to 100%) to yield the title compound (0.27 g, 64%) as a white solid.
LRMS (m/z): 482 (M+1 )+.
1H-NMR δ (300 MHz, CD3OD): 1 .57 - 1 .92 (m, 4H), 1 .97 (s, 3H), 2.75 (m, 1 H), 2.88 (m, 1 H), 3.15 (d, 1 H), 3.69 (d, 1 H), 3.84 (d, 1 H), 4.12 - 4.41 (m, 2H), 4.50 (s, 2H), 4.61 (s, 2H), 6.79 - 6.98 (m, 1 H), 7.23 - 7.51 (m, 5H), 8.39 - 8.62 (m, 3H). b) 3-((3 ?)-3-{[6-(4-Formylphenyl)-5-methyl-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin- 4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a solid (85%) from 3-[(3R)-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 following the experimental procedure as described in Preparation 29b.
LRMS (m/z): 480 (M+1 )+.
PREPARATION 51
[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -yl}methyl)phenyl] boronic acid
Sodium triacetoxyborohydride (1 .0 g, 4.72 mmol) was added to a solution of N,N,2- trimethyl-6-piperidin-4-ylpyridin-4-amine dihydrochloride (0.49 g, 1 .69 mmol), (4- formylphenyl)boronic acid (0.25 g, 1 .67 mmol) and triethylamine (0.47 mL, 3.34 mmol) in dichloromethane (8 mL) and the resulting mixture was stirred 88 hours at room temperature. The reaction mixture was partitioned between diethyl ether and aqueous diluted potassium carbonate solution. The gum remaining in the interphase was separated, dissolved in ethanol, filtered and the solvent was evaporated to give the title compound (0.32 g, 48%) as a white solid.
LRMS (m/z): 354 (M+1 )+. PREPARATION 52
3-((3 ?)-3-{[5-Fluoro-6-(2-fluoro-4-formylphenyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
a) 3-[(3 ?)-3-({5-Fluoro-6-[2-fluoro-4-(hydroxymethyl)phenyl]-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a white solid (54%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and (2-fluoro-4-(hydroxymethyl)phenyl)boronic acid following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 504 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .73 - 2.08 (m, 4H), 2.12 - 2.36 (m, 1 H), 3.31 - 3.44 (m, 2H), 3.49 (dd, 2H), 3.58 - 3.79 (m, 1 H), 3.88 - 4.09 (m, 1 H), 4.24 - 4.42 (m, 1 H), 4.77 - 4.93 (m, 2H), 5.10 (d, 1 H), 6.82 - 6.96 (m, 1 H), 7.20 - 7.30 (m, 1 H), 7.30 - 7.40 (m, 2H), 7.79 (t, 1 H), 8.44 - 8.56 (m, 2H), 8.65 (d, 1 H). b) 3-((3 ?)-3-{[5-Fluoro-6-(2-fluoro-4-formylphenyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a white solid (68%) from 3-[(3R)-3-({5-fluoro-6-[2-fluoro-4-(hydroxymethyl) phenyl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropane nitrile (Preparation 52a) and manganese (IV) oxide following the experimental procedure as described in Preparation 29b.
LRMS (m/z): 502 (M+1 )+.
PREPARATION 53
3-((3 ?)-3-{[5-Fluoro-6-(3-formylphenyl)-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
a) 3-[(3 ?)-3-({5-Fluoro-6-[3-(hydroxymethyl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a white solid (76%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 3-hydroxymethylphenylboronic acid following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (hexanes to ethyl acetate).
LRMS (m/z): 486 (M+1 )+. b) 3-((3 ?)-3-{[5-Fluoro-6-(3-formylphenyl)-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin- 4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a white solid (44%) from 3-[(3R)-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 following the experimental procedure as described in Preparation 29b followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 484 (M+1 )+.
PREPARATION 54
3- {(3 ?)-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) Terf-butyl (3 ?)-3-[(2,6-dichloro-5-fluoropyrimidin-4-yl)amino]piperidine-1 - carboxylate A solution of 2,4,6-trichloro-5-fluoropyrimidine (0.05 g, 2.48 mmol) in ethanol (10 mL) was added dropwise to a stirred solution of fe/f-butyl (3R)-3-aminopiperidine-1 - carboxylate (0.55 g, 2.73 mmol) in ethanol (10 mL) at -20 °C. The resulting mixture was stirred at -20 °C for 1 h before being partitioned between water and chloroform. The organic phase was separated, dried over sodium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes to hexanes/ethyl acetate 8:2) to yield the title compound (0.78 g, 86%) as a colourless oil.
LRMS (m/z): 365/367 (M+1 )+. b) Terf-butyl (3 ?)-3-({2-chloro-5-fluoro-6-[4-(hydroxymethyl)phenyl]pyrimidin-4- yl}amino)piperidine-1 -carboxylate
Obtained as a white solid (23%) from ie f-butyl (3R)-3-[(2,6-dichloro-5-fluoropyrimidin- 4-yl)amino]piperidine-1 -carboxylate (Preparation 54a) and 4-(hydroxymethyl)phenyl boronic acid following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (hexanes to hexanes/ethyl acetate 6:4).
LRMS (m/z): 437 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .43 (s, 9H), 1 .50 - 1 .80 (m, 5H), 3.30 - 3.60 (m, 4H), 4.18 (bs, 1 H), 4.75 (s, 2H), 5.40 (s, 1 H), 7.45 (d, 2H), 7.96 (dd, 2H). c) Terf-butyl (3 ?)-3-{[2-chloro-5-fluoro-6-(4-formylphenyl)pyrimidin-4-yl]amino} piperidine-1 -carboxylate
Obtained as a colourless oil (61 %) from ie/f-butyl (3R)-3-({2-chloro-5-fluoro-6-[4- (hydroxymethyl)phenyl]pyrimidin-4-yl}amino) piperidine-1 -carboxylate (Preparation 54b) and manganese (IV) oxide following the experimental procedure as described in Preparation 29b followed by purification of the crude product by flash chromatography (gradient from hexanes to hexanes/ethyl acetate 6:4).
LRMS (m/z): 435 (M+1 )+. d) Terf-butyl (3 ?)-3-[(2-chloro-5-fluoro-6-{4-[(4-methyl-1 ,4-diazepan-1 -yl)methyl] phenyl}pyrimidin-4-yl)amino]piperidine-1 -carboxylate
Sodium triacetoxyborohydride (262 mg, 1 .24 mmol) was added to a solution of ie/f- butyl (3R)-3-{[2-chloro-5-fluoro-6-(4-formylphenyl)pyrimidin-4-yl]amino}piperidine-1 - carboxylate (Preparation 54c, 336 mg, 0.77 mmol), 1 -methyl-1 ,4-diazepane (132 mg, 1 .15 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was washed with water, the organic phase was dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (292 mg, 69%) as a brown solid.
LRMS (m/z): 534 (M+1 )+. e) 2-Chloro-5-fluoro-6-{4-[(4-methyl-1 ,4-diazepan-1 -yl)methyl]phenyl}-/V-[(3/?)- piperidin-3-yl]pyrimidin-4-amine
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (0.42 ml_, 1 .7 mmol) was added to a stirred solution of ie/f-butyl (3R)-3-[(2-chloro-5-fluoro-6-{4-[(4-methyl-1 ,4-diazepan-1 - yl)methyl]phenyl}pyrimidin-4-yl)amino]piperidine-1-carboxylate (Preparation 54d, 90 mg, 0.17 mmol) in 1 ,4-dioxane (2 mL) and the resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was co- evaporated with 1 ,4-dioxane and toluene to yield the title compound (97 mg, 99%) as a hydrochloride salt.
LRMS (m/z): 434 (M+1 )+. f) 3-{(3 ?)-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
3-[(2,5-Dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile (42 mg, 0.25 mmol) was added to a solution of 2-chloro-5-fluoro-6-{4-[(4-methyl-1 ,4-diazepan-1 -yl)methyl]phenyl}-/V- [(3R)-piperidin-3-yl]pyrimidin-4-amine (Preparation 54e, 90 mg, 0.21 mmol) and triethylamine (0.1 1 mL, 0.77 mmol) in dichloromethane (1 mL) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried over sodium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (chloroform to chloroform/methanol /ammonia 40:2:0.2) to yield the title compound (42 mg, 40%) as a yellow solid.
LRMS (m/z): 501 (M+1 )+.
PREPARATION 55
yV,yV-Dimethyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy) ethanamine
A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (0.22 g, 1 .00 mmol), 2-chloro-/V,/V-dimethylethanamine hydrochloride (0.17 g, 1 .15 mmol) and cesium carbonate (1 .3 g, 4.00 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, washed with additional water and brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (254 mg, 86%) as a brownish oil.
LRMS (m/z): 291 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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
W-(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)-W',W'-dimethyl-N-[(3 ?)^iperidin-3-yl]ethane-1 ,2-diamin
a) Terf-butyl (3 ?)-3-[(6-{4-[2-(dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate
A Schlenk tube was charged with ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate (Preparation 6a, 0.40 g, 0.9 mmol), /V,/V-dimethyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy) ethanamine (Preparation 55, 0.39 g, 1 .3 mmol), 2.0 M aqueous cesium carbonate solution (0.89 g, 2.7 mmol) and 1 ,2-dimethoxyethane (3 ml_). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (73 mg, 0.09 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was evaporated and the residue was purified by flash chromatography (hexanes to ethyl acetate) to yield the title compound (0.34 g, 64%) as a white solid.
LRMS (m/z): 577 (M+1 )+. b) Terf-butyl (3 ?)-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 - carboxylate
Sodium hydride (60% dispersion in mineral oil, 50 mg, 1 .96 mmol) was added portionwise to a suspension of ie f-butyl (3R)-3-[(6-{4-[2-(dimethylamino)ethoxy] phenyl}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 - carboxylate (Preparation 56a, 0.34 g, 0.6 mmol) and 2-chloro-/V,/V-dimethylethanamine hydrochloride (0.13 g, 1.17 mmol) in /V,/V-dimethylformamide (10 mL) and the resulting mixture was heated at 55 °C for 18 h. Water was added and the precipitate formed was filtered, washed with water and dried to yield the title compound (0.4 g, 83%) as a brown solid.
LRMS (m/z): 648 (M+1 )+. c) W-(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)-W',W'-dimethyl-W-[(3/?)^
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .5 ml_, 5.86 mmol) was added to a stirred solution of ie f-butyl (3/?)-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 - carboxylate (Preparation 56b, 0.35 g, 0.54 mmol) in 1 ,4-dioxane (5 mL) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was co-evaporated with 1 ,4-dioxane and toluene to yield the title compound (0.4 g, 99%) as a hydrochloride salt.
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
Obtained as a brown oil (84%) from 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenol and 1 -(2-chloroethyl)pyrrolidine following the experimental procedure as described in Preparation 55 followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 98:2).
LRMS (m/z): 318 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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
W,W-Dimethyl-1 -{2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]ethyl} piperidin-4-amine
Obtained as a brown oil (50%) from 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenol and 1 -(2-chloroethyl)-/V,/V-dimethylpiperidin-4-amine following the experimental procedure as described in Preparation 55 followed by purification of the crude product by flash chromatography (chloroform to chloroform/methanol/ammonia 96:4:0.4).
LRMS (m/z): 375 (M+1 )+.
PREPARATION 59
(/?)-7erf-butyl 4-(4-(6-((1 -(2-cyanoacetyl)piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo
[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)phenoxy)piperidine-1 -carboxylate
Obtained as a solid (87%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie f-butyl 4-(4-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)phenoxy)piperidine-1 -carboxylate following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (hexanes to ethyl acetate).
LRMS (m/z): 656 (M+2)+.
1H-NMR δ (400 MHz, CDCI3): 1 .60 - 1 .66 m, 1 H), 1.75 - 1.85 (m, 3H), 1.92 - 2.05 (m, 3H), 2.18 - 2.60 (m, 1 H), 3.32 - 3.48 (m, 6H), 3.59 (s, 1 H), 3.69 - 3.77
(m, 2H), 3.84 - 3.98 (m, 1 H), 4.26 - 4.35 (m, 1 H), 4.58 - 4.61 (m, 1 H), 5.05 (bs, 1 H), 6.82 - 6.92 (m, 1 H), 7.10 - 7.40 (m, 2H), 7.33 - 7.38 (m, 1 H), 8.1 1 (d, 2H), 8.49 - 8.60 (m, 2H), 8.61 - 8.73 (d, 1 H). PREPARATION 60
Terf-butyl 4-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperazine-1 -carboxylate
Obtained as a solid (46%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie f-butyl 4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1 -carboxylate following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 93:7).
LRMS (m/z): 642 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.74 - 6.84 (m, 1 H), 6.92 (m, 1 H), 7.35 (m, 2H), 8.14 - 8.78 (m,
4H).
PREPARATION 61
(2-(4-Methyl-1 ,4-diazepan-1 -yl)pyridin-4-yl)boronic acid
a) 1 -(4-Bromopyridin-2-yl)-4-methyl-1 ,4-diazepane
A mixture of 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 dimethylsulphoxide (30 mL) was heated at 100°C overnight. The reaction mixture was poured into water and extracted with diethyl ether (x3). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was concentrated to dryness to yield the title compound (6.1 g, 89%).
LRMS (m/z): 270, 272 (M, M+2)+. 1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.66 - 6.70 (m, 1 H), 7.95 (d, 1 H). b) (2-(4-Methyl-1 ,4-diazepan-1 -yl)pyridin-4-yl)boronic acid
A Shlenk tube was charged with 1 -(4-bromopyridin-2-yl)-4-methyl-1 ,4-diazepane (Preparation 61 a, 0.67 g, 2.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxa borolane (0.76 g, 2.98 mmol), potassium acetate (0.73 g, 7.44 mmol) and 1 ,4-dioxane (8 ml_). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride complex with dichloromethane (0.10 g, 0.12 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C for 4 hours. The mixture was cooled, filtered thorugh diatomaceous earth (Celite®) and the solvent was concentrated to dryness. The residue was treated with petroleum ether, filtered and the solvent was evaporated to dryness to yield the title compound (0.5 g, 86%) as a yellow oil.
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-diazepan-1 - yl)ethanol
a) 2-(4-(4-Bromopyridin-2-yl)-1 ,4-diazepan-1 -yl)ethanol
Obtained as an oil (55%) from 4-bromo-2-fluoropyridine and 2-(1 ,4-diazepan-1 - yl)ethanol following the experimental procedure as described in Preparation 61 a.
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-diazepan- 1 -yl)ethanol
Obtained as a yellow solid (97%) 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'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 266 (M+1 )+.
PREPARATION 63
(2-(4-(Dimethylamino)piperidin-1 -yl)pyridin-4-yl)boronic acid
a) 1 -(4-bromopyridin-2-yl)-yV,yV-dimethylpiperidin-4-amine Obtained as a yellow solid (90%) from 4-bromo-2-fluoropyridine and N,N- dimethylpiperidin-4-amine following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 284, 286 (M, M+2)+. b) (2-(4-(Dimethylamino)piperidin-1 -yl)pyridin-4-yl)boronic acid
Obtained as an orange oil (100%) from 1 -(4-bromopyridin-2-yl)-/V,/V-dimethylpiperidin- 4-amine (Preparation 63a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 250 (M+1 )+.
PREPARATION 64
( ?)-1 -(3-((6-Chloro-5-fluoro-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino) piperidin-1 -yl)-2-hydroxyethanone
A mixture of 6-chloro-5-fluoro-/V-[(3R)-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), 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3- oxide hexafluorophosphate (0.54 g, 1.42 mmol) and triethylamine (0.53 mL, 3.82 mmol) in /V,/V-dimethylformamide (2 mL) was stirred at room temperature for 18 hours. Water was added and the reaction mixture was stirred for 30 min. The precipitate was filtered, washed with water and diisopropyl ether and dried to yield the title compound (0.37 g, 80%) as a white solid.
LRMS (m/z): 405 (M+1 )+. PREPARATION 65
(6-{[4-(Dimethylamino)piperidin-1 -yl]methyl}pyridin-3-yl)boronic acid
a) 1 -((5-Bromopyridin-2-yl)methyl)-yV,yV-dimethylpiperidin-4-amine
A mixture of 5-bromopyridine-2-carbaldehyde (0.30 g, 1 .61 mmol) and Λ/,/V-dimethyl piperidin-4-amine (0.121 mg, 1.61 mmol) in dichloromethane (15 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.41 g, 1 .93 mmol) and catalytic acetic acid were added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with saturated aqueous hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol /ammonia 100:8:1 ) to yield the title compound (0.22 g, 45%). LRMS (m/z): 298, 300 (M, M+2)+. b) (6-{[4-(Dimethylamino)piperidin-1 -yl]methyl}pyridin-3-yl)boronic acid
Obtained as an orange oil (82%) from 1 -[(5-bromopyridin-2-yl)methyl]-/V,/V- dimethylpiperidin-4-amine (Preparation 65a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 264 (M+1 )+. PREPARATION 66
[6-(4-Methyl-1 ,4-diazepan-1 -yl)pyridin-3-yl]boronic acid
a) 1 -(5-Bromopyridin-2-yl)-4-methyl-1 ,4-diazepane
Obtained as an oil (90%) from 5-bromo-2-fluoropyridine and 1 -methyl-1 ,4-diazepane following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 270, 272 (M, M+2)+. b) [6-(4-Methyl-1 ,4-diazepan-1 -yl)pyridin-3-yl]boronic acid
Obtained as a brown oil (93%) 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'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 236 (M+1 )+.
PREPARATION 67
(6-(4-(Dimethylamino)piperidin-1 -yl)pyridin-3-yl)boronic acid
a) 1 -(5-Bromopyridin-2-yl)-yV,yV-dimethylpiperidin-4-amine
Obtained as an oil (88%) from 5-bromo-2-fluoropyridine and /V,/V-dimethylpiperidin-4- amine following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 284, 286 (M, M+2)+. b) (6-(4-(Dimethylamino)piperidin-1 -yl)pyridin-3-yl)boronic acid
Obtained as an orange oil (100%) from 1 -(5-bromopyridin-2-yl)-/V,/V-dimethylpiperidin- 4-amine (Preparation 67a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 250 (M+1 )+.
PREPARATION 68
reri-butyl(2-(4-(piperazin-1ylmethyl)phenoxy)ethyl)carbamate a) 2-(7erf-butoxycarbonylamino)ethyl methanesulfonate
A solution of methanesulfonyl chloride (1 .44 mL, 18.60 mmol) in dichloromethane (15 mL) was added dropwise to a stirred solution of ie f-butyl (2-hydroxyethyl)carbamate (2.0 g, 12.41 mmol) and triethylamine (3.46 mL, 24.82 mmol) in dichloromethane (15 mL) at 0 °C. After stirring for 1 .5 hours at 0 °C, the reaction mixture was partitioned between water and pentane. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated to dryness to give the title compound (3.0 g, 94%) as an oil.
LRMS (m/z): 240 (M+1 )+. b) Terf-butyl (2-(4-formylphenoxy)ethyl)carbamate
A mixture of 2-(ie f-butoxycarbonylamino)ethyl methanesulfonate (Preparation 68a, 3.0 g, 12.54 mmol), 4-hydroxybenzaldehyde (1 .53 g, 12.54 mmol) and potassium carbonate (5.21 g, 37.70 mmol) in Λ/,Λ/'-dimethylformamide (20 mL) was stirred overnight at 60 °C. The crude was partitioned between diethyl ether and water. The organic phase was separated, washed with water and diluted aqueous sodium hydroxide solution, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title compound (2.63 g, 87%) as an oil.
LRMS (m/z): 266 (M+1 )+. c) Benzyl 4-(4-(2-((ieri-butoxycarbonyl)amino)ethoxy)benzyl)piperazine-1 - carboxylate
Obtained as an oil (71 %) from ie f-butyl (2-(4-formylphenoxy)ethyl)carbamate (Preparation 68b) and benzyl piperazine-1 -carboxylate following the experimental procedure as described in Preparation 54d.
LRMS (m/z): 470 (M+1 )+. d) reri-butyl(2-(4-(piperazin-1ylmethyl)phenoxy)ethyl)carbamate
Obtained as an oil (75%) from benzyl 4-(4-(2-((ie f-butoxycarbonyl)amino)ethoxy) benzyl)piperazine-1 -carboxylate (Preparation 68c) following the experimental procedure as described in Preparation 30b.
LRMS (m/z): 336 (M+1 )+.
PREPARATION 69
( ?)-7erf-butyl (2-(4-((4-(6-((1 -(2-cyanoacetyl)piperidin-3-yl)amino)-5-fluoro-2-
(pyrazolo [1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1 -yl)methyl)phenoxy)ethyl) carbamate Obtained as white solid (51 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and fe/f-butyl(2-(4-(piperazin-1 ylmethyl)phenoxy)ethyl)carbamate (Preparation 68d) following the experimental procedure as described in Preparation 17a.
LRMS (m/z): 713 (M+1 )+.
PREPARATION 70
3-{[4-(6-{[2-(Dimethylamino)ethyl][(3 ?)^iperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol
a) Terf-butyl (3 ?)-3-{(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)
[2-(dimethylamino)ethyl]amino}piperidine-1 -carboxylate
Sodium hydride (60% dispersion in mineral oil, 0.125 g, 3.13 mmol) was added portionwise to a solution of ie f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidine-1 -carboxylate (Preparation 6a, 0.40 g, 0.90 mmol) in /V,/V-dimethylformamide (4 mL) 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 resulting mixture was stirred at 55 °C for 4 hours and overnight at room temperature. Water was added and the resulting precipitate was filtered, washed with water and dried. Purification of the precipitate by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ) gave the title compound (0.18 g, 37%) as a solid.
LRMS (m/z): 519 (M+2)+. b) Terf-butyl (3 ?)-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 - carboxylate
Obtained as a white solid (14%) from ie f-butyl (3R)-3-{(6-chloro-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl]amino}piperidine-1 -carboxylate (Preparation 70a) and 3-(piperazin-1 -ylmethyl)phenol following the experimental procedure as described in Preparation 17a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane /methanol 95:5).
LRMS (m/z): 675 (M+2)+. c) 3-{[4-(6-{[2-(Dimethylamino)ethyl][(3 ?)-piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol Obtained as a solid hydrochloride salt (99%) from ie f-butyl (3R)-3-([2-(dimethylamino) ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl]-2-pyrazolo[1 ,5-a]pyridin-3-yl pyrimidin-4-yl}amino)piperidine-1 -carboxylate (Preparation 70b) following the experimental procedure as described in Preparation 6b.
LRMS (m/z): 575 (M+2)+.
PREPARATION 71
Terf-butyl methyl{2-[4-(piperazin-1 -ylmethyl)phenoxy]ethyl}carbamate
a) Benzyl 4-(4-{2-[(ieri-butoxycarbonyl)(methyl)amino]ethoxy}benzyl)piperazine- 1 -carboxylate
Sodium hydride (60% dispersion in mineral oil, 0.1 15 g, 4.79 mmol) was added portionwise to a solution of benzyl 4-(4-{2-[(ie f-butoxycarbonyl)amino]ethoxy}benzyl) piperazine-1 -carboxylate (Preparation 68c, 0.749 g, 1.60 mmol) in Ν,Ν'- dimethylformamide (4.5 mL) at 0 °C and the resulting mixture was stirred at room temperature for 1 hour. Methyl iodide (0.149 mL, 2.39 mmol) was then added at 0 °C and the reaction mixture was stirred at room temperature for 3 hours before being partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over sodium sulfate and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 85:15:0.2) gave the title compound (0.022 g, 54%).
LRMS (m/z): 485 (M+2)+. b) Terf-butyl methyl{2-[4-(piperazin-1 -ylmethyl)phenoxy]ethyl}carbamate
10% Palladium on carbon (0.050 g, 0.47 mmol) was added to a solution of benzyl 4-(4- {2-[(ie f-butoxycarbonyl)(methyl)amino]ethoxy}benzyl)piperazine-1 -carboxylate
(Preparation 71 a, 0.55 g, 1 .14 mmol) in methanol (25 mL) and the resulting mixture was stirred under an hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was evaporated to dryness. The residue was purified by cation exchange chromatography (elution with 2N ammonia solution in methanol) to yield the title compound (0.378 g, 90%).
LRMS (m/z): 351 (M+1 )+. PREPARATION 72 Terf-butyl [2-(4-{[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenoxy)ethyl] methyl carbamate
Obtained as a solid (63%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie f-butyl methyl{2-[4-(piperazin-1 -ylmethyl)phenoxy]ethyl}carbamate (Preparation 71 b) following the experimental procedure as described in Preparation 28a followed by purification by flash chromatography (dichloromethane to dichloromethane/methanol /ammonia 85:15:0.2).
LRMS (m/z): 728 (M+1 )+.
PREPARATION 73
(/?)-7erf-butyl (3-(3-((5-fluoro-6-(4-(4-methylpiperazin-1 -yl)phenyl)-2-(pyrazolo
[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropyl)carbamate (R)-5-Fluoro-6-(4-(4-methylpiperazin-1 -yl)phenyl)-/V-(piperidin-3-yl)-2-(pyrazolo[1 ,5-a] pyridin-3-yl)pyrimidin-4-amine (Preparation 42b, 68 mg, 0.14 mmol) was added to a solution of 3-((ie f-butoxycarbonyl)amino)propanoic acid (32 mg, 0.17 mmol), 1 -[bis (dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide
hexafluorophosphate (64 mg, 0.17 mmol) and diisopropylethylamine (0.039 ml_, 0.22 mmol) in Λ/,Λ/'-dimethylformamide (1 .5 mL) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between excess of diethyl ether and water. The organic phase was separated, washed with water, dried over sodium sulfate and the solvent was evaporated to give the title compound (53 mg, 48%)
LRMS (m/z): 658 (M+1 )+.
PREPARATION 74
3-(6-{[2-(Dimethylamino)ethyl][(3 ?)-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(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 20 mL, 20 mmol) was added to a suspension of 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-tetraza-1 -phospha bicyclo{3.3.3}undecane (0.04 g, 0.17 mmol) in toluene (32 mL) and the reaction mixture 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 subjected again to three cycles of evacuation-backfilling with argon. The reaction mixture was heated at 80 °C overnight, then cooled to room temperature, filtered through diatomaceous earth (Celite®) and the solvent was evaporated to dryness. The residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol /ammonia 40:8:1 ) to yield the title compound (0.99 g, 45%).
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
A microwave reactor was charged 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'-bi-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 cycles of evacuation- backfilling with argon and then tricyclohexylphosphine (0.15 g, 0.53 mmol) and bis(dibenzylideneacetone)palladium(0) (0.08 g, 0.14 mmol) were added. After three further cycles of evacuation-backfilling with argon, the reaction mixture was subjected to microwave irradiation for 2 hours at 150 °C, filtered through diatomaceous earth (Celite®) and the solvent was evaporated to dryness. The residue was treated with diethyl ether and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 90:10) to yield the title compound (0.83, 58%) as a solid.
LRMS (m/z): 319 (M+1 )+. c) Terf-butyl (3 ?)-3-([2-(dimethylamino)ethyl]{5-fluoro-6-[3-hydroxy-5-(4-methyl piperazin-1 -yl)phenyl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino) piperidine-1 -carboxylate
Obtained as a solid (77%) from ie/f-butyl (3R)-3-{(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)[2-(dimethylamino)ethyl]amino}piperidine-1 -carboxylate (Preparation 70a) and 3-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxa borolan-2-yl)phenol (Preparation 74b) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol /ammonia 100:8:1 ).
LRMS (m/z): 675 (M+2)+. d) 3-(6-{[2-(Dimethylamino)ethyl][(3 ?)-piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1 -yl)phenol
Obtained as a solid hydrochloride salt (100%) from ie/f-butyl (3R)-3-([2-(dimethyl amino)ethyl]{5-fluoro-6-[3-hydroxy-5-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl}amino)piperidine-1 -carboxylate (Preparation 74c) following the experimental procedure as described in Preparation 6b.
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
Borane-dimethylsulphide complex (1 .1 mL, 1 1.58 mmol) was added dropwise to a solution of 4-bromo-2-hydroxybenzoic acid (1 .0 g, 4.64 mmol) in tetrahydrofuran (15 mL) at 0 °C and the resulting mixture was stirred overnight at room temperature. After cooling to 0 °C, 0.5N hydrochloric acid (5 mL) was added dropwise followed by water (2 mL). The reaction mixture was stirred at room temperature for 30 minutes before the solvents were evaporated to dryness. The residue was partitioned between diluted aqueous sodium hydroxide solution and a 1 :1 mixture of diethyl ether/hexane. The aqueous phase was separated, acidified by addition of concentrated hydrochloric acid solution and extracted with a 1 :1 mixture of diethyl ether/hexane. The organic layer was separated, dried over magnesium sulfate and the solvent was partially evaporated. The precipitate formed was filtered and dried to yield the title compound (0.75 g, 77%) as a white solid.
LRMS (m/z): 204 (M+1 )+. b) 2-(Hydroxymethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol
A Schlenk tube was charged with 5-bromo-2-(hydroxymethyl)phenol (Preparation 75a, 0.75 g, 3.69 mmol), 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, 1 1.1 1 mmol) and 1 ,4-dioxane (7.5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (0.15 g, 0.18 mmol) was added. After three further cycles of evacuation- backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The organic phase was separated, diluted with pentane, washed with diluted aqueous sodium hydroxide solution, dried over magnesium sulfate and the solvents were evaporated to dryness. The residue was treated with hexane and filtered to yield the title compound (0.35 g, 36%).
LRMS (m/z): 251 (M+1 )+.
PREPARATION 76 ( ?)-3-(3-((5-Fluoro-6-(4-formyl-3-hydroxyphenyl)-2-(pyrazolo[1 ,5-a]pyridin-3-yl) pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropanenitrile
a) ( ?)-3-(3-((5-Fluoro-6-(3-hydroxy-4-(hydroxymethyl)phenyl)-2-(pyrazolo[1 ,5-a] pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a white solid (46%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-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) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (hexanes to ethyl acetate).
LRMS (m/z): 502 (M+1 )+. b) ( ?)-3-(3-((5-Fluoro-6-(4-formyl-3-hydroxyphenyl)-2-(pyrazolo[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 a solution of (R)-3-(3-((5-fluoro- 6-(3-hydroxy-4-(hydroxymethyl)phenyl)-2-(pyrazolo[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 (3 mL) and the resulting suspension was stirred 5 hours at 45 °C. Additional manganese dioxide (0.126 g, 1.45 mmol) was added and the suspension was stirred overnight at 45 °C and a weekend at room temperature. A third addition of manganese dioxide (0.126 g, 1 .45 mmol) was made and the suspension was stirred overnight at 45 °C before being diluted with tetrahydrofuran and filtered through diatomaceous earth (Celite®). The filtrate was evaporated to dryness, treated with diethyl ether and filtered to give the title compound as a yellow solid (0.148 g, 75%).
LRMS (m/z): 500 (M+1 )+.
PREPARATION 77
3- {[(1 -methylpiperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-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 -methyl piperidin-4-amine (0.434 mL, 3.46 mmol) in dichloromethane (20 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (1 .46 g, 6.91 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:1 ) to yield 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- dioxaborolan-2-yl)phenol
A microwave reactor was charged with 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'- bi-1 ,3,2-dioxaborolane (0.934 g, 3.68 mmol), potassium acetate (0.492 g, 5.01 mmol) and 1 ,2-dimethoxyethane (5 mL). The reactor was subjected to three cycles of evacuation-backfilling with argon and then tricyclohexylphosphine (0.1 13 g, 0.12 mmol) and bis(dibenzylideneacetone)palladium(0) (0.058 g, 0.30 mmol) were added. After three further cycles of evacuation-backfilling with argon, the reaction mixture was subjected to microwave irradiation for 2 hours at 150 °C, filtered through diatomaceous earth (Celite®) and the solvent was evaporated to dryness. The residue was treated with diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried to yield the title compound (0.592 g, 43%) as a white solid.
LRMS (m/z): 347 (M+1 )+. PREPARATION 78
3-{[[(1 -Methylpiperidin-4-yl)methyl](piperidin-4-yl)amino]methyl}phenol a) Terf-butyl 4-[(3-hydroxybenzyl)amino]piperidine-1 -carboxylate
Sodium borohydride (0.50 g, 13.22 mmol) was added portionwise to a solution of 3- hydroxybenzaldehyde (1 .50 g, 12.28 mmol) and ie f-butyl 4-aminopiperidine-1 - carboxylate (2.50 g, 12.48 mmol) in ethanol (15 mL) and the mixture was stirred at room temperature for 2 hours. After cooling to 0 °C, a saturated aqueous ammonium chloride solution (50 mL) was added and the reaction mixture was extracted with ethyl acetate (X2). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (gradient from dichloromethane to dichloromethane /methanol/ammonia 40:8:1 ) gave the title compound (1.80 g, 43%) as a solid.
LRMS (m/z): 307 (M+1 )+. b) Terf-butyl 4-{(3-hydroxybenzyl)[(1 -methylpiperidin-4-yl)methyl]amino} piperidine-1 -carboxylate Obtained as a solid (61 %) from ie f-butyl 4-[(3-hydroxybenzyl)amino]piperidine-1 - carboxylate (Preparation 78a) and 1 -methylpiperidine-4-carbaldehyde following the experimental procedure as described in Preparation 54d followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol /ammonia 100:8:1 ).
LRMS (m/z): 419 (M+2)+. c) 3-{[[(1 -Methylpiperidin-4-yl)methyl](piperidin-4-yl)amino]methyl}phenol
Obtained as a solid trihydrochloride salt (100%) from ie f-butyl 4-{(3-hydroxybenzyl)[(1 - methylpiperidin-4-yl)methyl]amino}piperidine-1 -carboxylate (Preparation 78b) following the experimental procedure as described in Preparation 6b.
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) ferf-Butyl [1 -(3-piperidin-1 -ylpropyl)piperidin-4-yl]carbamate
A solution of ie/f-butyl piperidin-4-ylcarbamate (1 .19 g, 5.94 mmol), 1 -(3-chloropropyl) piperidine (1 .295 g, 6.54 mmol) and Λ/,/V-diisopropylethylamine (2.28 ml_, 13.09 mmol) in chloroform (50 mL) was stirred at 62 °C for 18 hours. Additional 1 -(3-chloropropyl) piperidine (0.350 g, 1 .60 mmol) and Λ/,/V-diisopropylethylamine (0.57 mL, 3.267 mmol) were added and the reaction mixture was stirred at 62 °C for further 3 hours. The solvent was evaporated and the residue was washed with diethyl ether and dried to yield the title compound (1.38 g, 71 %) that was used in the next synthetic step without any further purification. b) 1 -(3-Piperidin-1 -ylpropyl)piperidin-4-amine
Obtained (99%) from fe/f-butyl [1 -(3-piperidin-1 -ylpropyl)piperidin-4-yl]carbamate (Preparation 79a) following the experimental procedure as described in Preparation 6b followed by cation exchange chromatography (elution with 2N ammonia solution in methanol). c) 3-Chloro-5-({[1 -(3-piperidin-1 -ylpropyl)piperidin-4-yl]amino}methyl)phenol
Obtained (80%) from 1 -(3-piperidin-1 -ylpropyl)piperidin-4-amine (Preparation 79b) and 3-chloro-5-hydroxybenzaldehyde following the experimental procedure as described in Preparation 77a.
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
Obtained as an oil (69%) from 3-chloro-5-({[1-(3-piperidin-1 -ylpropyl)piperidin-4-yl] amino}methyl)phenol (Preparation 79c) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 376 (M+1 )+.
PREPARATION 80
(6-{4-[(re^butoxycarbonyl)(methyl)amino]piperidin-1 -yl}pyridin-3-yl)boronic acid
a) Terf-butyl [1 -(5-bromopyridin-2-yl)piperidin-4-yl]methylcarbamate
Obtained as an oil (92%) from 5-bromo-2-fluoropyridine and ie f-butyl methyl(piperidin- 4-yl)carbamate following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 370, 372 (M, M+2)+. b) (6-{4-[(re^butoxycarbonyl)(methyl)amino]piperidin-1 -yl}pyridin-3-yl)boronic acid
Obtained as a solid (40%) from ie f-butyl [1 -(5-bromopyridin-2-yl)piperidin-4-yl]methyl carbamate (Preparation 80a) and 4!4!4'!4'!5!5!5'!5'-octamethyl-2,2'-bi-1 ,3,2-dioxa borolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 336 (M+1 )+.
PREPARATION 81
Terf-Butyl {1 -[5-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}methylcarbamate
Obtained as a solid (31 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and (6-{4- [(ie/f-butoxycarbonyl)(methyl)amino]piperidin-1 -yl}pyridin-3-yl)boronic acid (Preparation 80b) following the experimental procedure as described in Preparation 50a.
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- dioxaborolan-2-yl)phenol
a) 3-Chloro-5-[(4-pyrrolidin-1 -ylpiperidin-1 -yl)methyl]phenol A mixture 3-chloro-5-hydroxybenzaldehyde (1 .50 g, 9.58 mmol) and 4-pyrrolidin-1 -yl piperidine (1 .63 g, 10.54 mmol) in dichloromethane (30 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.05 g, 14.37 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane /methanol/ammonia 100:8:1 ) to yield the title compound (2.25 g, 80%).
LRMS (m/z): 296 (M+1 )+. b) 3-[(4-Pyrrolidin-1 -ylpiperidin-1 -yl)methyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenol
A microwave reactor was charged 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'- bi-1 ,3,2-dioxaborolane (2.13 g, 8.39 mmol), potassium acetate (1 .12 g, 1 1.45 mmol) and 1 ,2-dimethoxyethane (10ml_). The reactor was subjected to three cycles of evacuation-backfilling with argon and then tricyclohexylphosphine (0.26 g, 0.92 mmol) and bis(dibenzylideneacetone)palladium(0) (0.13 g, 0.23 mmol) were added. After three further cycles of evacuation-backfilling with argon, the reaction mixture was subjected to microwave irradiation for 2 hours at 150 °C, filtered through diatomaceous earth (Celite®) and the solvent was evaporated to dryness. The residue was treated with diethyl ether and the white solid formed was filtered, washed with diethyl ether and dried to yield the title compound (2.92 g, 89%).
LRMS (m/z): 387 (M+1 )+.
PREPARATION 83
3-(1 -Methylpiperidin-4-yl)-5-(piperazin-1 -ylmethyl)phenol
a) Terf-butyl 4-(3-bromo-5-hydroxybenzyl)piperazine-1 -carboxylate
Obtained as a white solid (90%) from 3-bromo-5-hydroxybenzaldehyde and ie f-butyl piperazine-1 -carboxylate following the experimental procedure as described in Preparation 82a.
LRMS (m/z): 371 , 373 (M, M+2)+. b) Terf-butyl 4-[3-hydroxy-5-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)benzyl] piperazine-1 -carboxylate Obtained as a solid (74%) from ie f-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 following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 388 (M+1 )+. c) Terf-butyl 4-[3-hydroxy-5-(1 -methylpiperidin-4-yl)benzyl]piperazine-1 - carboxylate
A solution of ie f-butyl 4-[3-hydroxy-5-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)benzyl] piperazine-1 -carboxylate (Preparation 83b, 0.50 g, 1.29 mmol) in ethanol (24 mL) was hydrogenated in an H-Cube® continuous-flow hydrogenation reactor at 50 °C and atmospheric pressure using a 10% Pd/C MicroCatCart®. The resulting solution was concentrated to yield the title compound (0.39 g, 78%) as an oil.
LRMS (m/z): 390 (M+1 )+. d) 3-(1 -Methylpiperidin-4-yl)-5-(piperazin-1 -ylmethyl)phenol
Obtained as a solid trihydrochloride salt (100%) from ie/f-butyl 4-[3-hydroxy-5-(1 - methyl-1 ,2,3,6-tetrahydropyridin-4-yl)benzyl]piperazine-1 -carboxylate (Preparation 83c) following the experimental procedure as described in Preparation 6b.
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- dioxaborolan-2-yl)phenol
a) 1 -(Benzyloxy)-3,5-dichlorobenzene
(Bromomethyl)benzene (3.03 g, 17.73 mmol) was added to a suspension of 3,5- dichlorophenol (2.89 g, 17.73 mmol) and cesium carbonate (8.66 g, 26.60 mmol) in Λ/,/V-dimethylformamide (50 mL) and the resulting mixture 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, filtered and the solvent was concentrated in vacuo. The resulting crude was purified by flash chromatography (gradient from hexanes to ethyl acetate) to yield the title compound (4.12 g, 90%) as a colourless oil.
LRMS (m/z): 253, 255 (M, M+2)+. b) Terf-butyl 4-[3-(benzyloxy)-5-chlorophenyl]piperazine-1 -carboxylate A mixture of 1 -(benzyloxy)-3,5-dichlorobenzene (Preparation 84a, 2.00 g, 7.90 mmol), ie f-butyl piperazine-1 -carboxylate (2.21 g, 1 1.85 mmol) and sodium ie f-butoxide (1.14 g, 1 1.85 mmol) in toluene (20 mL) was subjected to three cycles of evacuation- backfilling with argon. Bis(dibenzylideneacetone)palladium(0) (0.72 g, 0.79 mmol) and 2-(di-ie f-butylphosphino)biphenyl (0.47 g, 1 .58 mmol) were added. After three further cycles of evacuation-backfilling 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 resulting crude was purified by flash chromatography (gradient from hexanes to ethyl acetate) to yield the title compound (1 .49 g, 46%) as a white solid.
LRMS (m/z): 403, 405 (M, M+2)+. c) 1 -[3-(Benzyloxy)-5-chlorophenyl]piperazine
Obtained as a white solid hydrochloride salt (99%) from ie f-butyl 4-[3-(benzyloxy)-5- chlorophenyl]piperazine-1 -carboxylate (Preparation 84b) following the experimental procedure as described in Preparation 6b.
LRMS (m/z): 303, 305 (M, M+2)+. d) 1 -[3-(Benzyloxy)-5-chlorophenyl]-4-(3-piperidin-1 -ylpropyl)piperazine
Obtained as yellow oil (85%) from 1 -[3-(benzyloxy)-5-chlorophenyl]piperazine (Preparation 84c) and 1 -(3-chloropropyl)piperidine following the experimental procedure as described in Preparation 79a.
LRMS (m/z): 428, 430 (M, M+2)+. e) 3-Chloro-5-[4-(3-piperidin-1 -ylpropyl)piperazin-1 -yl]phenol
Obtained (84%) from 1 -[3-(benzyloxy)-5-chlorophenyl]-4-(3-piperidin-1 -ylpropyl) piperazine (Preparation 84d) following the experimental procedure as described in Preparation 30b followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 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- dioxaborolan-2-yl)phenol
Obtained as a brown solid (44%) from 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'-bi-1 ,3,2-dioxa borolane following the experimental procedure as described in Preparation 82b. LRMS (m/z): 430 (M+1 )+.
PREPARATION 85
3- {[Piperidin-4-yl(3-piperidin-1 -ylpropyl)amino]methyl}phenol
a) Terf-butyl 4-[(3-piperidin-1 -ylpropyl)amino]piperidine-1 -carboxylate
Sodium triacetoxyborohydride (1 .27 g, 5.99 mmol) was added to a solution of fe/f-butyl
4- oxopiperidine-1 -carboxylate (1 .00 g, 5.02 mmol), (3-piperidin-1 -ylpropyl)amine (1 .27 g, 8.93 mmol) and acetic acid (0.1 mL) in dichloroethane (5 mL) and the resulting mixture was stirred at 50 °C for 5 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane and 1 N aqueous solution of sodium hydroxide. The organic layer was separated, washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The resulting crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5) to give the title compound (1.04 g, 58%) as an oil.
LRMS (m/z): 326 (M+1 )+. b) Terf-butyl 4-[(3-hydroxybenzyl)(3-piperidin-1 -ylpropyl)amino]piperidine-1 - carboxylate
Obtained as a solid (34%) from ie f-butyl 4-[(3-piperidin-1 -ylpropyl)amino]piperidine-1 - carboxylate (Preparation 85a) and 3-hydroxybenzaldehyde following the experimental procedure as described in Preparation 82a.
LRMS (m/z): 432 (M+1 )+. c) 3-{[Piperidin-4-yl(3-piperidin-1 -ylpropyl)amino]methyl}phenol
Obtained as a solid trihydrochloride salt (100%) from ie f-butyl 4-[(3-hydroxybenzyl)(3- piperidin-1 -ylpropyl)amino]piperidine-1 -carboxylate (Preparation 85b) following the experimental procedure as described in Preparation 6b.
LRMS (m/z): 332 (M+1 )+. PREPARATION 86
3-{[4-(Cyclopentylamino)piperidin-1 -yl]methyl}-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenol
a) Terf-butyl [1 -(3-chloro-5-hydroxybenzyl)piperidin-4-yl]carbamate
Obtained as a solid (63%) from 3-chloro-5-hydrozybenzaldehyde and ie/f-butyl piperidin-4-ylcarbamate following the experimental procedure as described in Preparation 82a.
LRMS (m/z): 341 (M+1 )+. b) 3-[(4-Aminopiperidin-1 -yl)methyl]-5-chlorophenol
Obtained as a solid dihydrochloride salt (100%) from ie f-butyl [1 -(3-chloro-5-hydroxy benzyl)piperidin-4-yl]carbamate (Preparation 86a) following the experimental procedure as described in Preparation 6b.
LRMS (m/z): 241 (M+1 )+. c) 3-Chloro-5-{[4-(cyclopentylamino)piperidin-1 -yl]methyl}phenol
Obtained as an oil (47%) from 3-[(4-aminopiperidin-1 -yl)methyl]-5-chlorophenol (Preparation 86b) and cyclopentanone following the 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- dioxaborolan-2-yl)phenol
Obtained as a solid (57%) from 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 following the experimental procedure as described in Preparation 82b.
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-dioxaborolan-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 following 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
Obtained as an oil (60%) from 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'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 347 (M+1 )+.
PREPARATION 88
{2-[4-(7erf-butoxycarbonyl)-1 ,4-diazepan-1 -yl]pyridin-4-yl}boronic acid a) Terf-butyl 4-(4-bromopyridin-2-yl)-1 ,4-diazepane-1 -carboxylate
Obtained as a white solid (70%) from 4-bromo-2-fluoropyridine and ie f-butyl 1 ,4- diazepane-1 -carboxylate following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 356, 358 (M, M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .73 - 2.07 (m, 6H), 2.1 1 - 2.32 (m, 1 H), 2.79 - 3.01 (m, 2H), 3.05 - 3.18 (m, 2H), 3.20 - 3.34 (m, 1 H), 3.36 - 3.54 (m, 3H), 3.56 - 3.73 (m, 1 H), 3.79 - 3.90 (m, 4H), 3.91 - 4.61 (m, 1 H), 4.26 - 4.44 (m, 1 H), 4.97 - 5.20 (m, 1 H), 6.84 - 7.00 (m, 1 H), 7.09 - 7.22 (m, 1 H), 7.30 - 7.43 (m, 2H), 8.24 - 8.39 (m, 1 H), 8.46 - 8.76 (m, 3H). b) {2-[4-(7erf-butoxycarbonyl)-1 ,4-diazepan-1 -yl]pyridin-4-yl}boronic acid
Obtained as a brown oil (100%) from ie f-butyl 4-(4-bromopyridin-2-yl)-1 ,4-diazepane- 1 -carboxylate (Preparation 88a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 322 (M+1 )+.
PREPARATION 89
Terf-butyl 4-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]-1 ,4-diazepane-1 -carboxylate
Obtained as a solid (60%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and {2-[4- (ie/f-butoxycarbonyl)-1 ,4-diazepan-1 -yl]pyridin-4-yl}boronic acid (Preparation 88b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 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- dioxaborolan-2-yl)phenol
a) 3-chloro-5-{[methyl(1 -methylpiperidin-4-yl)amino]methyl}phenol
Obtained (62%) from 3-chloro-5-hydroxybenzaldehyde and /V,1 -dimethylpiperidin-4- amine following the experimental procedure as 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- dioxaborolan-2-yl)phenol
Obtained as an oil (70%) from 3-chloro-5-{[methyl(1 -methylpiperidin-4-yl)amino] methyl}phenol (Preparation 90a) and 4A4\4\5!5!5\5'-octamethyl-2!2'-bi-1 !3,2- dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 361 (M+1 )+.
PREPARATION 91
3-{(3 ?)-3-[(6-Chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)(methyl) amino]piperidin-1 -yl}-3-oxopropanenitrile
a) Terf-butyl (3 ?)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl) (methyl)amino]piperidine-1 -carboxylate
Obtained as a solid (59%) from ie/f-butyl (3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl) amino]piperidine-1 -carboxylate (Preparation 6a) and methyl iodide following the experimental procedure as described in Preparation 71 a.
LRMS (m/z): 461 (M+1 )+. b) 6-Chloro-5-fluoro-W-methyl-W-[(3 ?)-piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-amine
Obtained as a solid hydrochloride salt (100%) from ie/f-butyl (3R)-3-[(6-chloro-5-fluoro-
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)(methyl)amino]piperidine-1 -carboxylate (Preparation 91 a) following the experimental procedure as described in Preparation 6b.
LRMS (m/z): 361 (M+1 )+. c) 3-{(3 ?)-3-[(6-Chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl)(methyl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Obtained (83%) as a solid from 6-chloro-5-fluoro-/V-methyl-/V-[(3R)-piperidin-3-yl]-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 91 b) and 3-[(2,5-dioxo pyrrolidin-1 -yl)oxy]-3-oxopropanenitrile following the experimental procedure as described in Preparation 6c.
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 Obtained as a solid (50%) from 3-chloro-5-hydrozybenzaldehyde and cyclopentylamine following the experimental 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
Obtained as an oil (70%) from 3-chloro-5-[(cyclopentylamino)methyl]phenol (Preparation 92a) and 4!4!4'!4'!5!5!5'!5'-octamethyl-2!2'-bi(1 !3,2-dioxaborolane) following the experimental procedure as described in Preparation 82b.
LRMS (m/z): 318 (M+1 )+.
PREPARATION 93
Terf-butyl 4-[3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]-1 ,4- diazepane-1 -carboxylate
a) Terf-butyl 4-(3-chloro-5-hydroxybenzyl)-1 ,4-diazepane-1 -carboxylate
Obtained (84%) from 3-chloro-5-hydroxybenzaldehyde and ie f-butyl 1 ,4-diazepane-1 - carboxylate following the experimental procedure as described in Preparation 77a.
LRMS (m/z): 341 (M+1 )+. b) Terf-butyl 4-[3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]- 1 ,4-diazepane-1 -carboxylate
Obtained as an oil (67%) from ie f-butyl 4-(3-chloro-5-hydroxybenzyl)-1 ,4-diazepane-1 - carboxylate (Preparation 93a) and 4,4,4',4',5!5!5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxa borolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 433 (M+1 )+.
PREPARATION 94
Terf-butyl 4-[3-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-5-hydroxybenzyl]-1 ,4-diazepane-1 -carboxylate Obtained as a solid (73%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie/f-butyl 4-[3-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]-1 ,4-diazepane-1 - carboxylate (Preparation 93b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product 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 ,^ dioxaborolan-2-yl)phenol
a) 3-Chloro-5-{6-[4-(dimethylamino)piperidin-1 -yl]pyridin-3-yl}phenol
Obtained as a solid (50%) from (6-(4-(dimethylamino)piperidin-1 -yl)pyridin-3-yl)boronic acid (Preparation 67b) and 3-bromo-5-chlorophenol following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (gradient from 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
Obtained as a solid (96%) from 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'-bi(1 !3,2- dioxaborolane) following the experimental procedure as described in Preparation 82b.
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-dioxaborolan-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 following the experimental procedure as 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
Obtained as an oil (61 %) from 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'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 347 (M+1 )+.
PREPARATION 97
1 -Methylpiperidin-4-yl piperidine-4-carboxylate
a) 1 -7erf-butyl 4-(1 -methylpiperidin-4-yl) piperidine-1 ,4-dicarboxylate Λ/,Λ/'-Carbonyldiimidazole (0.18 g, 1 .1 1 mmol) was added to a solution of \ -(tert- butoxycarbonyl)piperidine-4-carboxylic acid (0.17 g, 0.74 mmol) in tetrahydrofuran (6 mL) and the resulting solution was stirred for 4h at room temperature. Additional Ν,Ν'- carbonyldiimidazole (0.12 g, 0.7 mmol) was added and the solution was stirred for further 2h at room temperature. 1 -Methylpiperidin-4-ol (0.15 g, 1.30 mmol) was then added and the solution was stirred overnight at room temperature. The solvent was evaporated under vacuum and the crude was partitioned between dietyl ether and water. The organic phase was separated, washed with sodium hydrogencarbonate saturated solution, dried over sodium sulfate and the solvent was evaporated to dryness. The resulting crude was dissolved in diethyl ether and hexane was additioned until a precipitate was formed. The solid was filtered. Additional hexane was added to the filtrate until precipitation of an oil that was discarded. The combined organic layers were concentrated to give the title compound as a colorless oil (21 1 mg, 44%)
LRMS (m/z): 327 (M+1 )+. b) 1 -methylpiperidin-4-yl piperidine-4-carboxylate
4M Solution of hydrogen chloride in dioxane (1 .7 mL) was added to a solution of 1 -ferf- butyl 4-(1 -methylpiperidin-4-yl)piperidine-1 ,4-dicarboxylate (Preparation 97a, 0.2 g, 0.65 mmol) in propan-2-ol (4 mL) and the resulting mixture was stirred at room temperature for 5 hours. The solvents were evaporated and the residue was treated with diethyl ether, filtered and washed with diethyl ether to yield the hydrochloride salt of the title compound (0.15 g, 69%) as a white solid.
LRMS (m/z): 227 (M+1 )+. PREPARATION 98
(6-{4-[(reri-butoxycarbonyl)(cyclopentyl)amino]piperidin-1 -yl}pyridin-3-yl) boronic acid
a) 1 -Benzyl-W-cyclopentylpiperidin-4-amine
Obtained as an oil (68%) from 1 -benzylpiperidin-4-one and cyclopentylamine following the experimental procedure as described in Preparation 49.
LRMS (m/z): 259 (M+1 )+. b) Terf-butyl (1 -benzylpiperidin-4-yl)cyclopentylcarbamate
Potassium carbonate (1.20 g, 8.68 mmol) in water (15 mL) and di-ie f-butyl dicarbonate (1 .74 g, 7.97 mmol) in 1 ,4-dioxane (15 mL) were added to a solution of 1 -benzyl-/V- cyclopentylpiperidin-4-amine (Preparation 98a, 1 .87 g, 7.24 mmol) in 1 ,4-dioxane (32 mL) and the reaction mixture was stirred at 50 °C overnight. The solvents were 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 brine, dried over magnesium sulphate, filtered and concentrated to yield the title compound (1.53 g, 59%).
LRMS (m/z): 359 (M+1 )+. c) Terf-butyl cyclopentyl(piperidin-4-yl)carbamate
10% Palladium on carbon (0.45 g, 4.28 mmol) and ammonium formiate (1 .35 g, 21 .4 mmol) were added to a solution of ie f-butyl (1 -benzylpiperidin-4-yl)cyclopentyl carbamate (Preparation 98b, 1 .53 g, 4.27 mmol) in methanol (22 mL) and the reaction mixture was stirred at 60 °C for 3 hours and then cooled to room temperature. The catalyst was filtered, washed with methanol and the combined filtrates were concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated to yield the title compound (0.83 g, 72%) as a colourless oil.
LRMS (m/z): 269 (M+1 )+. d) Terf-butyl [1 -(5-bromopyridin-2-yl)piperidin-4-yl]cyclopentylcarbamate
Obtained as an orange oil (100%) from ie f-butyl cyclopentyl(piperidin-4-yl)carbamate (Preparation 98c) and 5-bromo-2-fluoropyridine following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 424, 426 (M, M+2)+. e) (6-{4-[(reri-butoxycarbonyl)(cyclopentyl)amino]piperidin-1 -yl}pyridin-3-yl) boronic acid
Obtained as a solid (92%) from ie/f-butyl [1 -(5-bromopyridin-2-yl)piperidin-4-yl] cyclo pentylcarbamate (Preparation 98d) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 390 (M+1 )+.
PREPARATION 99
Terf-butyl {1 -[5-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}cyclopentylcarbamate
A microwave reactor was charged with 3-{(3R)-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), ie/f-butyl {1 -[5-(6-{[(3R)-1-(cyanoacetyl)piperidin-3-yl]am fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4yl}cyclopen carbamate (Preparation 98e, 0.66 g, 1 .70 mmol), 2M aqueous cesium carbonate solution (0.73 ml_, 1 .75 mmol) and 1 ,4-dioxane (4 ml_). The reactor was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino) ferrocene]palladium(ll) dichloride complex with dichloromethane (0.024 g, 0.03 mmol) was added. After three further cycles of evacuation-backfilling with argon, the reactor was sealed and the reaction mixture was subjected to microwave irradiation for 2 hours at 140 °C, filtered through diatomaceous earth (Celite®) and evaporated to dryness. The residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/diethylamine 95:5:0.001 ) to yield the title compound (0.072 g, 21 %) as a solid.
LRMS (m/z): 724 (M+2)+. PREPARATION 100
2-{[4-(Dimethylamino)piperidin-1 -yl]methyl}-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenol
a) 4-Chloro-2-{[4-(dimethylamino)piperidin-1 -yl]methyl}phenol
Obtained as a solid (86%) from 5-chloro-2-hydroxybenzaldehyde and N,N- dimethylpiperidin-4-amine following the experimental procedure as described in Preparation 82a followed by purification of the crude product by flash chromatography (dichloromethane 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- dioxaborolan-2-yl)phenol
Obtained as a solid (99%) from 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-dioxa borolane) following the experimental procedure as described in Preparation 82b.
LRMS (m/z): 361 (M+1 )+.
PREPARATION 101
Terf-butyl 4-[2-hydroxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl] piperazine-1 -carboxylate
a) Terf-butyl 4-(4-chloro-2-hydroxybenzyl)piperazine-1 -carboxylate
Obtained as a yellow oil (86%) from 4-chloro-2-hydroxybenzaldehyde and ie f-butyl piperazine-1 -carboxylate following the experimental procedure as described in Preparation 82a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 327 (M+1 )+. b) Terf-butyl 4-[2-hydroxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl] piperazine-1 -carboxylate
Obtained as a white solid (35%) from ie f-butyl 4-(4-chloro-2-hydroxybenzyl)piperazine- 1 -carboxylate (Preparation 101 a) and 4,4,4',4',5!5!5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxa borolane) following the experimental procedure as described in Preparation 82b followed by purification by of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol 95:5).
LRMS (m/z): 419 (M+1 )+.
PREPARATION 102
Terf-butyl 4-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-2-hydroxybenzyl]piperazine-1 -carboxylate
Obtained as a solid (74%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie f-butyl 4-[2-hydroxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]piperazine-1 - carboxylate (Preparation 101 b) following the experimental procedure described in Preparation 99 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/metanol 95:5).
LRMS (m/z): 670 (M+1 )+. PREPARATION 103
(3-Hydroxy-4-{[(1 -methylpiperidin-4-yl)amino]methyl}phenyl)boronic acid a) 5-Chloro-2-{[(1 -methylpiperidin-4-yl)amino]methyl}phenol
Obtained (91 %) from 4-chloro-2-hydroxybenzaldehyde and 1 -methylpiperidin-4-amine following the experimental procedure as described in Preparation 77a.
LRMS (m/z): 255 (M+1 )+. b) (3-Hydroxy-4-{[(1 -methylpiperidin-4-yl)amino]methyl}phenyl)boronic acid
Obtained (47%) from 5-chloro-2-{[(1 -methylpiperidin-4-yl)amino]methyl}phenol (Preparation 103a) and 4,4,4',4',5!5!5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 77b followed by purification of the crude product by reverse phase 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
4M Solution of hydrogen chloride in 1 ,4-dioxane (3 mL) was added to a solution of 1 - ie f-butyl 4-ethyl 4-methylpiperidine-1 ,4-dicarboxylate (0.34 g, 1.25 mmol) in ethanol (4 mL) and the resulting mixture was stirred for 6 hours at room temperature. The solvents were evaporated and the residue was treated with diethyl ether, filtered and washed with diethyl ether to yield the hydrochloride salt of the title compound (0.3 g, 99%) as a white solid.
LRMS (m/z): 172 (M+1 )+. b) I '-Terf-butyl 4-ethyl 4-methyl-[1 ,4'-bipiperidine]-1 ',4-dicarboxylate
A mixture of ethyl 4-methylpiperidine-4-carboxylate hydrochloride (Preparation 104a, 0.30 g, 1 .44 mmol), ie f-butyl 4-oxopiperidine-1 -carboxylate (0.32 g, 1 .59 mmol), sodium triacetoxyborohydride (0.37 g, 1 .73 mmol) and triethylamine (0.20 mL, 1.45 mmol) in dichloromethane (5 mL) was stirred overnight at room temperature. Acetic acid (4 drops) was added and the reaction mixture was stirred for further 24 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried over magnesium sulphate and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (dichloromethane to dichoromethane/methanol/ammonia 40:4.0:0.2) gave the title compound (0.23 g, 42%) as yellow oil.
LRMS (m/z): 355 (M+1 )+. c) Ethyl 4-methyl-[1 ,4'-bipiperidine]-4-carboxylate
4M Solution of hydrogen chloride in 1 ,4-dioxane (3.2 mL) was added to a solution of 1 '- ie/f-butyl 4-ethyl 4-methyl-[1 ,4'-bipiperidine]-1 ',4-dicarboxylate (Preparation 104b, 0.23 g, 0.65 mmol) in ethanol (4 mL) and the resulting mixture was stirred for 5 hours at room temperature. The solvents were evaporated and the residue was treated with diethyl ether and filtered to yield the hydrochloride salt of the title compound (0.082 g, 92%) as a white solid.
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
Obtained as a colourless oil (62%) from 4-bromo-2-(methylthio)benzaldehyde and 1 - methyl-1 ,4-diazepane following the experimental procedure as described in Preparation 82a followed by purification of the crude product 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-yl) benzyl]-1 ,4-diazepane
Obtained as a yellow oil (79%) from 1 -[4-bromo-2-(methylthio)benzyl]-4-methyl-1 ,4- diazepane (Preparation 105a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxa borolane) following the experimental procedure as described in Preparation 61 b.
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
Obtained as a solid (96%) from 5-bromo-2-(methylthio)benzaldehyde and 1 -methyl-1 ,4- diazepane following the experimental procedure as described in Preparation 82a followed by purification of the crude product 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-yl) benzyl]-1 ,4-diazepane
Obtained as a solid (92%) 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'-bi(1 ,3,2-dioxa borolane) following the experimental procedure as described in Preparation 61 b.
LRMS (m/z): 377 (M+1 )+.
PREPARATION 107
[4-({2-[4-(Dimethylamino)piperidin-1 -yl]ethyl}thio)phenyl]boronic acid
a) 1 -(2-Chloroethyl)-yV,yV-dimethylpiperidin-4-amine
1 -Bromo-2-chloroethane (1 .95 mL, 23.43 mmol) was added to a solution of N,N- dimethylpiperidine-4-amine (2.0 g, 15.60 mmol) and potassium carbonate (4.31 g, 31.20 mmol) in acetone (10 mL) and the reaction mixture was stirred at room temperature for 18 hours. The solid was filtered and the filtrate was evaporated to yield the title compound (2.65 g, 89%) which was used in the next synthetic step without any further purification.
LRMS (m/z): 191 (M+1 )+. b) [4-({2-[4-(Dimethylamino)piperidin-1 -yl]ethyl}thio)phenyl]boronic acid
A mixture of 1 -(2-chloroethyl)-/V,/V-dimethylpiperidin-4-amine (Preparation 107a, 0.399 g, 2.09 mmol), (4-mercaptophenyl)boronic acid (0.129 g, 0.84 mmol) and cesium carbonate (1 .09 g, 3.35 mmol) in tetrahydrofuran (3 mL) was placed in a microwave vessel and was subjected to microwave irradiation for 6 hours at 130 °C. 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 and the solvent was evaporated. The resulting crude was purified by reverse phase chromatography (water to methanol) to yield the title compound (0.136 g, 53%) as a solid.
LRMS (m/z): 309 (M+1 )+.
PREPARATION 108
{6-[4-(Dimethylamino)piperidin-1 -yl]-5-hydroxypyridin-3-yl}boronic acid
a) 5-Bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridine
Diisopropylethylamine (0.41 mL, 2.34 mmol) and [2-(chloromethoxy)ethyl](trimethyl) silane (0.32 mL, 1.80 mmol) were added to a solution of 5-bromo-2-fluoropyridin-3-ol (0.30 g, 1.56 mmol) in dichloromethane (8 mL) at 0 °C and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The resulting crude was purified by flash chromatography (gradient from hexanes to diethyl ether) to yield the title compound (0.31 g, 62%). b) 1 -(5-Bromo-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-2-yl)-yV,yV-dimethyl piperidin-4-amine
Obtained as an oil (39%) from 5-bromo-2-fluoro-3-{[2-(trimethylsilyl)ethoxy]methoxy} pyridine (Preparation 108a) and /V,/V-dimethylpiperidin-4-amine following the experimental procedure as described in Preparation 61 a.
LRMS (m/z): 430, 432 (M, M+2)+. c) 5-Bromo-2-[4-(dimethylamino)piperidin-1 -yl]pyridin-3-ol
A solution of 1 -(5-bromo-3-{[2-(trimethylsilyl)ethox
piperidin-4-amine (Preparation 108b, 0.23 g, 0.53 mmol) in trifluoroacetic acid (2.20 mL) was stirred at room temperature for 30 minutes. Solvent was evaporated to dryness and the residue was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The aqueous layer was separated, basified with 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.13 g, 79%).
LRMS (m/z): 300, 302 (M, M+2)+. d) {6-[4-(Dimethylamino)piperidin-1 -yl]-5-hydroxypyridin-3-yl}boronic acid
Obtained as an oil (92%) 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) following the experimental procedure as described in Preparation 61 b.
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
Obtained as a white solid (100%) from 5-chloro-2-hydroxybenzaldehyde and cyclopentylamine following the 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
Obtained as a solid (33%) from 4-chloro-2-[(cyclopentylamino)methyl]phenol (Preparation 109a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure as described in Preparation 82b.
LRMS (m/z): 318 (M+1 )+.
PREPARATION 1 10
2-[(Cyclopentylamino)methyl]-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenol
a) 5-Chloro-2-[(cyclopentylamino)methyl]phenol Obtained as a white solid (100%) from 4-chloro-2-hydroxybenzaldehyde and cyclopentylamine following the experimental 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
Obtained as a solid (29%) from 5-chloro-2-[(cyclopentylamino)methyl]phenol (Preparation 1 10a) and 4!4!4'!4'!5!5!5'!5'-octamethyl-2!2'-bi(1 !3,2-dioxaborolane) following the experimental procedure as described in Preparation 82b.
LRMS (m/z): 318 (M+1 )+.
PREPARATION 1 1 1
Terf-butyl 4-((4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoyl)oxypiperidine -1 -carboxylate
a) Terf-butyl 4-((4-bromobenzoyl)oxy)piperidine-1 -carboxylate
Triethylamine (0.76 mL, 5.48 mmol) and ie f-butyl 4-hydroxypiperidine-1 -carboxylate (0.54 g, 2.68 mmol) were added to a solution of 4-bromobenzoyl chloride (0.6 g, 2.73 mmol) in tetrahydrofuran (3 mL) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between dietyl ether and water. The organic phase was separated, washed with saturated aqueous potassium carbonate solution, dried over magnesium sulfate and the solvents were evaporated to dryness. The crude was treated with hexane, filtered and the filtrate was evaporated to dryness to yield the title compound (0.93 g, 71 %) as a colorless oil.
LRMS (m/z): 385 (M+1 )+. b) Terf-butyl 4-((4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoyl)
oxypiperidine-1 -carboxylate
A Schlenk tube was charged with ie f-butyl 4-((4-bromobenzoyl)oxy)piperidine-1 - carboxylate (Preparation 1 1 1 a, 0.93 g, 2.42 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 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 was subjected to three cycles of evacuation- backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex (0.10 g, 0.12 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with excess of diethyl ether and filtered. The solvents were evaporated to dryness, treated with hexane and filtered. The filtrate was diluted with a 1 :1 solution of methanol/water and the organic layer was separated, washed with water, dried over magnesium sulphate and evaporated to dryness to give the title compound (0.98 g, 84%) as an oil.
LRMS (m/z): 432 (M+1 )+.
PREPARATION 1 12
(/?)-7erf-butyl 4-((4-(6-((1 -(2-cyanoacetyl)piperidin-3-yl)amino)-5-fluoro-2- (pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)benzoyl)oxy)piperidine-1 -carboxylate Obtained as a brown gum from (R)-3-(3-((6-chloro-5-fluoro-2-(pyrazolo[1 ,5-a]pyridin-3- yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropanenitrile (Preparation 6c) and tert- butyl 4-((4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoyl)oxypiperidine-1 - carboxylate (Preparation 1 1 1 b) following the experimental procedure as described in Preparation 56a. The crude reaction was partitioned between a 2:1 mixture of ethyl acetate/hexane and water. The organic phase was separated, washed with water, dried over magnesium sulfate and the solvents were evaporated to dryness to yield the title compound which was used in the next synthetic step without any further purification.
LRMS (m/z): 683 (M+1 )+.
PREPARATION 1 13
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 methanamine (40% in water, 4.6 ml_, 52.72 mmol) in methanol (30 mL) was stirred at room temperature for 30 minutes. Sodium borohydride (0.199 g, 5.26 mmol) was added portionwise at 0 °C and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed and the resulting crude was partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 80:20:2) to yield the title compound (0.322 g, 71 %).
LRMS (m/z): 172 (M+1 )+. b) 2-[(Methylamino)methyl]-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol Obtained as a solid (38%) from 5-chloro-2-[(methylamino)methyl]phenol (Preparation 1 13a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 264 (M+1 )+.
PREPARATION 1 14
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
A solution of 5-chloro-2-[(methylamino)methyl]phenol (Preparation 1 13a, 0.579 g, 3.37 mmol), 4-chloropyridine (0.506 g, 3.37 mmol) and 4-methylmorpholine (0.473 ml_, 3.71 mmol) in /V-methyl-2-pyrrolidone (4.5 mL) was stirred in a sealed tube at 120 °C for 18 hours. The solvent was evaporated to dryness and the residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 85:15:1 ) to yield the title compound (0.447 g, 53%).
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
Obtained as a solid (37%) from 5-chloro-2-{[methyl(pyridin-4-yl)amino]methyl}phenol (Preparation 1 14a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 341 (M+1 )+. PREPARATION 1 15
4-Fluoro-2-((piperidin-4-ylamino)methyl)phenol
a) Terf-butyl 4-((5-fluoro-2-hydroxybenzyl)amino)piperidine-1 -carboxylate
A solution of ie f-butyl 4-aminopiperidine-1 -carboxylate (0.2 g, 1 mmol) and 5-fluoro-2- hydroxybenzaldehyde (0.14 g, 1 mmol) in dichloromethane (1 mL) was stirred overnight at room temperature. Sodium cyanoborohydride (0.13 g, 2.07 mmol) was added portionwise and the reaction mixture was stirred for further 24 hours at room temperature before being partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated to dryness. The residue was treated with hexane and filtered to give the title compound (0.22 g, 59%) as a white solid.
LRMS (m/z): 325 (M+1 )+. b) 4-Fluoro-2-((piperidin-4-ylamino)methyl)phenol
A mixture of ie f-butyl 4-((5-fluoro-2-hydroxybenzyl)amino)piperidine-1 -carboxylate (Preparation 1 15a, 0.22 g, 0.68 mmol) and 1.25M hydrogen chloride solution in ethanol (4 mL) was stirred overnight at room temperature. The solvent was evaporated and the residue was treated with diethyl ether, filtered, washed with acetonitrile and dried to yield the hydrochloride salt of the title compound (0.14 g, 67%) as a white solid.
LRMS (m/z): 225 (M+1 )+.
PREPARATION 1 16
Terf-butyl [2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl] methyl carbamate
a) 4-Chloro-2-[(methylamino)methyl]phenol
Obtained (79%) from 5-chloro-2-hydroxybenzaldehyde and 40% methylamine solution in water following the experimental procedure as described in Preparation 1 13a.
LRMS (m/z): 172 (M+1 )+. b) Terf-butyl (5-chloro-2-hydroxybenzyl)methylcarbamate
A mixture of 4-chloro-2-[(methylamino)methyl]phenol (Preparation 1 16a, 0.30 g, 1.75 mmol) and di-fe/f-butyl dicarbonate (0.458 g, 2.10 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with additional water and brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (0.569 g, 99%) as a white solid.
LRMS (m/z): 272 (M+1 )+. c) Terf-butyl [2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl] methyl carbamate
Obtained as an oil (61 %) from ie f-butyl (5-chloro-2-hydroxybenzyl)methylcarbamate (Preparation 1 16b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane following the experimental procedure as described in Preparation 77b.
LRMS (m/z): 347 (M+1 )+.
PREPARATION 1 17
Terf-butyl [5-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-2-hydroxybenzyl]methylcarbamate
Obtained as a solid (45%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie/f-butyl [2-hydroxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl]methylcarbamate (Preparation 1 16c) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (hexane to ethyl acetate).
LRMS (m/z): 615 (M+1 )+.
EXAMPLES
EXAMPLE 1
3-{(3 ?)-3-[[2-(Dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
A solution of /V-(5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)- /V',/V-dimethyl-/V-[(3R)-piperidin-3-yl]ethane-1 ,2-diamine tetrahydrochloride salt (Preparation 10c, 0.18 g, 0.29 mmol), 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3-oxopropane nitrile (0.080 g, 0.44 mmol)) and triethylamine (0.224 mL, 1 .76 mmol) in Λ/,Λ/'-dimethyl formamide (2 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water (6 mL) and the precipitate formed was filtered. Purification of the precipitate by flash chromatography gave the title compound (0.057 g, 35%) as a yellow solid.
LRMS (m/z): 537 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .87 - 2.18 (m, 4H), 2.18 - 2.42 (s, 6H), 2.45 - 2.70 (m, 3H), 2.84 - 3.01 (dd, 1 H), 3.03 - 3.23 (dd, 1 H), 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, 1 H), 7.27 - 7.38 (m, 2H), 8.21 - 8.44 (m, 1 H), 8.44 - 8.61 (m, 1 H).
EXAMPLE 2
3-{(3 ?)-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
A solution of 5-fluoro-6-{4-[(1 -methyl-1 H-imidazol-2-yl)methyl]piperazin-1 -yl}-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 12b, 0.082 g, 0.12 mmol), 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile (0.033 g, 0.18 mmol) and triethylamine (0.12 mL, 0.85 mmol) in Λ/,Λ/'-dimethylformamide (1 mL) was stirred overnight at room temperature. The reaction mixture was diluted with excess of water and extracted with ethyl acetate. The organic phase was separated, washed with water, dried over sodium sulfate and the solvent was evaporated to dryness. Purification of the residue by flash chromatography gave the title compound (0.025 g, 36%) as a solid.
LRMS (m/z): 559 (M+2)+.
1H-NMR δ (400 MHz, CDCI3): 1 .17 - 1.45 (m, 6H), 1 .71 - 1.82 (m, 2H), 2.08 -
2.23 (m, 1 H), 2.53 - 2.69 (m, 2H), 3.06 - 3.16 (m, 1 H), 3.30 - 3.43 (m, 1 H), 3.43 - 3.62 (m, 2H), 3.62 - 3.69 (m, 1 H), 3.69 - 3.85 (m, 4H), 4.12 - 4.29 (m, 1 H), 4.48 - 4.70 (m, 1 H), 6.75 - 7.04 (m, 3H), 7.04 - 7.16 (m,1 H), 7.27 - 7.39 (m, 1 H), 8.28 - 8.61 (m, 3H).
EXAMPLE 3
3-[(3 ?)-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-oxopropanenitrile
Obtained as an yellow solid (45%) from 6-[4-(1 H-benzimidazol-2-ylmethyl)piperazin-1 - yl]-5-fluoro-/V-[(3R)-piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine pentahydrochloride salt (Preparation 14b) and 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3- oxopropanenitrile following the experimental procedure as described in Example 1 followed by purification of the crude product by flash chromatography.
LRMS (m/z): 595 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .04 - 1.39 (m, 1 H), 1 .72 - 1.99 (m, 2H), 2.07 -
2.28 (m, 1 H), 2.56 - 2.88 (m, 4H), 3.05 - 3.21 (m, 1 H), 3.24 - 3.68 (m, 3H), 3.68 . 4.04 (m, 4H), 4.07 - 4.34 (m, 1 H), 4.45 - 4.77 (m, 1 H), 6.73 - 6.99 (m, 1 H), 7.38 - 7.90 (m, 2H), 8.21 - 8.68 (m, 3H), 9.50 - 9.89 (m, 1 H). EXAMPLE 4
3-[(3 ?)-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-oxopropanenitrile
A mixture of 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl) amino]piperidin-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 hydrogencarbonate (0.09 g, 1.10 mmol) in Λ/,/V-dimethylacetamide (0.5 mL) was stirred overnight at 90 °C. Water was added and the precipitate formed was filtered. The precipitate was purified by flash chromatography (hexane to ethyl acetate) to yield the title compound (40 mg, 58%) as a pale yellow solid.
LRMS (m/z): 555 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .68 - 1 .78 (m, 4H), 2.63 (m, 4H), 3.40 (d, 2H), 3.45 - 3.48 (m, 2H), 3.56 (bs, 1 H), 3.72 (s, 2H), 3.75 - 3.85 (m, 6H), 4.20 (m, 1 H), 4.50 - 4.65 (m, 1 H), 6.83 (m, 1 H), 7.14 - 7.23 (m, 1 H), 7.24 - 7.33 (m, 1 H), 7.44 (d, 1 H), 7.68 (m, 1 H), 8.33 (d, 1 H), 8.40 - 8.52 (m, 2H), 8.54 - 8.62 (m, 1 H).
EXAMPLE 5
3-((3/?)-3-{[6-(4-{[4-(Dimethylamino)pyri^
pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as an brown solid (30%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V-dimethyl-2-(piperazin-1 -ylmethyl)pyridin-4-amine (Preparation 15b) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography.
LRMS (m/z): 599 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.61 (m,
1 H), 6.41 (dd, 1 H), 6.67 (d, 1 H), 6.84 (m, 1 H), 7.27 - 7.33 (dd, 1 H), 8.20 (d, 1 H), 8.30 - 8.58 (m, 3H).
EXAMPLE 6
3-{(3 ?)-3-[(5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-{4-[(4-pyrrolidin-1 -ylpyridin-2- yl)methyl]piperazin-1 -yl}pyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Obtained as a solid (40%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 1 -[(4- pyrrolidin-1 -ylpyridin-2-yl)methyl]piperazine (Preparation 16b) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (gradient of dichloromethane/methanol /ammonia).
LRMS (m/z): 624 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.60 (m, 1 H), 6.30 (d, 1 H), 6.54 (s, 1 H), 6.86 (m, 1 H), 7.30 (d, 1 H),
8.19 (d, 1 H), 8.30 - 8.58 (m, 3H).
EXAMPLE 7
3-[(3 ?)-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-oxopropanenitrile
3-[(2,5-Dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile (108 mg, 0.59 mmol) was added to a stirred solution of 4-[(4-{5-fluoro-6-[(3R)-piperidin-3-ylamino]-2-pyrazolo[1 ,5-a]pyridin- 3- ylpyrimidin-4-yl}piperazin-1 -yl)methyl]phenol (Preparation 17c, 0.20 g, 0.30 mmol) and triethylamine (0.22 ml_, 1 .18 mmol) in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the organic layer was separated, washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (91 mg, 40%) as an orange solid.
LRMS (m/z): 570 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .74 - 1 .95 (m, 4H), 2.51 - 2.66 (m, 4H), 3.39 (d, 1 H), 3.44 - 3.60 (m, 4H), 3.67 - 3.87 (m, 6H), 4.17 (m, 1 H), 4.47 - 4.67 (m, 1 H), 6.73 - 6.90 (m, 3H), 7.15 - 7.22 (m, 2H), 7.25 - 7.34 (m, 1 H), 8.34 (dd, 1 H), 8.40
- 8.60 (m, 2H).
EXAMPLE 8
4- {[4-(5-Fluoro-6-{[(3 ?)-1 -(3-hydroxy-3-methylbutanoyl)piperidin-3-yl]amino}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol
A mixture of 4-[(4-{5-fluoro-6-[(3R)-piperidin-3-ylamino]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}piperazin-1 -yl)methyl]phenol (Preparation 17c, 0.10 g, 0.20 mmol), 3- hydroxy-3-methylbutanoic acid (0.04 mL, 0.30 mmol), 1 -[bis(dimethylamino) methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (0.1 1 g, 0.30 mmol) and diisopropylethylamine (0.28 mL, 1 .62 mmol) in /V,/V-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, the organic layer was separated, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography and reverse phase chromatography (using water/methanol as eluents) to yield the title compound (25 mg, 19%) as a white solid.
LRMS (m/z): 604 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.60 - 4.75 (m, 1 H), 5.40 (bs, 1 H), 6.81 (m, 3H), 7.26 (m, 3H), 8.33 - 8.56 (m, 3H).
EXAMPLE 9
4-{[4-(5-Fluoro-6-{[(3 ?)-1 -glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin- 3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol
(Benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.079 g, 0.21 mmol) was added to a solution of 4-[(4-{5-fluoro-6-[(3R)-piperidin-3-ylamino]-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}piperazin-1 -yl)methyl]phenol (Preparation 17c, 0.080 g, 0.16 mmol), hydroxyacetic acid (0.015 g, 0.20 mmol) and triethylamine (0.031 ml_, 0.22 mmol) in Λ/,Λ/'-dimethylformamide (0.6 mL) and the resulting mixture was stirred at room temperature for 16 hours. Excess of water was added and the precipitate was filtered, washed with water and diisopropyl ether and dried to yield the title compound as a yellow solid (23 mg, 27%)
LRMS (m/z): 562 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .22 - 1.38 (m, 1 H), 1 .52 - 2.08 (m, 5H), 2.09 - 2.24 (m, 1 H), 2.51 - 2.69 (bs, 3H), 3.04 - 3.17 (m, 1 H), 3.17 - 3.28 (m, 1 H), 3.35 - 3.61 (m, 2H), 3.61 - 3.71 (m, 1 H), 3.71 - 3.84 (bs, 1 H), 3.84 - 3.94 (m, 1 H), 3.95 - 4.06 (d, 1 H), 4.1 1 - 4.30 (m, 2H), 4.55 - 4.70 (m, 1 H), 6.72 - 6.92 (m, 3H),
7.12 - 7.23 (d, 2H), 8.28 - 8.67 (m, 3H).
EXAMPLE 10
3-[(3 ?)-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-oxopropanenitrile
3-[(2,5-Dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile (0.03 g, 0.14 mmol) was added to a stirred solution of 5-fluoro-6-[4-(4-methoxybenzyl)piperazin-1 -yl]-/V-[(3R)-piperidin-3- yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 17b, 0.05 g, 0.09 mmol) and triethylamine (0.05 mL, 0.38 mmol) in dichloromethane (3 mL) and the mixture was stirred overnight at room temperature. Water was added and the organic layer was separated, washed with brine, dried over magnesium sulfate and the solvent evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ) to yield the title compound (40 mg, 73%) as an orange solid.
LRMS (m/z): 585 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.49 - 4.65 (m, 1 H), 6.77 - 6.93 (m, 3H), 7.19 - 7.31 (m, 1 H), 8.34 (m, 1 H), 8.40 - 8.59 (m, 2H). EXAMPLE 1 1
3-[(3 ?)-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-oxopropanenitrile
Obtained as a pale yellow solid (51 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 3-(piperazin-1 -ylmethyl)phenol following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (hexane to ethyl acetate). LRMS (m/z): 571 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .59 - 1 .94 (m, 4H), 2.58 (m, 4H), 3.44 (d, 2H), 3.45 - 3.53 (m, 4H), 3.57 (s, 1 H), 3.65 - 3.84 (m, 6H), 4.12 - 4.24 (m, 1 H), 4.65 - 4.75 (m, 1 H), 6.75 (dd, 1 H), 6.80 - 6.89 (m, 3H), 7.17 (td, 1 H), 7.23 - 7.34 (m, 1 H), 8.27 - 8.61 (m, 3H).
EXAMPLE 12
3-((3 ?)-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
Obtained as a white solid (64%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V-dimethyl-2-(4-(piperazin-1 -ylmethyl)phenoxy)ethanamine (Preparation 18b) following the experimental procedure as described in Example 4 followed by purification of the crude product by reverse phase chromatography (using water/methanol as eluents).
LRMS (m/z): 641 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .7 - 1 .9 (m, 4H), 2.1 - 2.2 (m, 1 H), 2.3 (s, 6H), 2.5 - 2.6 (m, 4H), 2.7 (t, 2H), 3.4 (d, 1 H), 3.4 - 3.6 (m, 4H), 3.7 - 3.9 (m, 5H), 4.1 (t, 2H), 4.2 (s, 1 H), 4.4 - 4.7 (m, 2H), 6.8 - 6.9 (m, 1 H), 6.9 (d, 2H), 7.2 (d, 2H),
7.2 - 7.3 (m, 1 H), 8.3 - 8.6 (m, 3H).
EXAMPLE 13
2-((3 ?)-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
A mixture of 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 19b, 0.1 1 g, 0.19 mmol), 2-hydroxyacetic acid (0.02 g, 0.24 mmol), 1 -[bis(dimethylamino) methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (0.1 1 g, 0.30 mmol) and triethylamine (0.04 mL, 0.24 mmol) in /V,/V-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The solvent was evaporated and the crude was purified by flash chromatography (dichloromethane to dichloromethane/ethanol 3:7) to yield the title compound (12 mg, 10%).
LRMS (m/z): 632 (M+1 )+.
EXAMPLE 14 6-(4-{4-[2-(Dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-yV-[(3 ?)-1 - (methoxyacetyl)piperidin-3-yl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
Triethylamine (0.034 mL, 0.24 mmol) was added to a mixture of (benzotriazol-1 -yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (0.069 g, 0.18 mmol) and methoxyacetic acid (0.016 g, 0.18 mmol) in chloroform (0.5 mL) and the resulting mixture was stirred at room temperature for 5 minutes. A solution of 6-(4-{4-[2- (dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)-piperidin-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) was then added and the resulting solution was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and diluted aqueous sodium hydroxide solution. The precipitated gum that was formed was separated and dissolved with methanol and excess of dietyl ether. The organic phase was dried over sodium sulfate and the solvent was evaporated under vacuum. Purification of the residue by flash chromatography (chloroform/methanol/ammonia 40:2.5:0.1 ) gave the title compound (0.033 g, 32%) as a gum.
LRMS (m/z): 647 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.45 - 3.52 (ds, 3H), 3.52 - 3.61 (m, 1 H), 3.63 - 3.81 (m, 5H), 3.81 - 3.85 (d, 2H), 3.97 - 4.02 (m,1 H), 4.03 - 4.10 (t, 2H), 4.10 - 4.34 (m, 3H), 4.66 -
4.77 (m, 1 H), 4.84 - 4.94 (d, 1 H), 6.74 - 6.86 (m, 1 H), 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-W-[(3 ?)-1 -(3,3,3-trifluoropropanoyl)piperidin-3-yl]pyrimidin-4-amin^
A mixture of 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 19b, 0.10 g, 0.18 mmol), 3,3,3-trifluoropropanoic acid (0.03 mL, 0.27 mmol), 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluoro phosphate (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 Phase Separator and the solvent was evaporated to dryness. The residue was purified by flash chromatography to yield the title compound (12 mg, 10%)
LRMS (m/z): 684 (M+1 )+. EXAMPLE 16
[3-((3 ?)-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
A mixture of 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 19b, 0.10 g, 0.17 mmol) and oxetan-3-ylideneacetonitrile (0.15 g, 1 .58 mmol) in acetonitrile (2 mL) was stirred at 85 °C. Additional oxetan-3-ylideneacetonitrile was added at 24 hours (0.15 g, 1 .58 mmol) and 48 hours (0.30 g, 3.16 mmol) and the reaction mixture was stirred for further 72 hours. The solvent was evaporated and the residue was purified by flash chromatography to yield the title compound (25 mg, 21 %).
LRMS (m/z): 670 (M+2)+. EXAMPLE 17
(2S)-1 -((3 ?)-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
A mixture of 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 19b, 0.1 1 g, 0.18 mmol), (S)-2-acetoxypropanoic acid (0.03 mL, 0.21 mmol), (benzotriazol-1 -yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (0.10 g, 0.21 mmol) and triethylamine (0.05 mL, 0.34 mmol) in dichloromethane (2 mL) was stirred at room temperature for 3 hours. Additional dichloromethane was added and the reaction mixture was washed with water, dried by Phase Separator and the solvent evaporated to give a residue that was purified by flash chromatography to yield (1 S)-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 acetate (108 mg, 67%).
LRMS (m/z): 689 (M+2)+.
A mixture of (1 S)-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 acetate (108 mg, 0.16 mmol) and 0.5N solution of sodium methoxide in methanol (0.94 mL, 0.47 mmol) in methanol (2 mL) was stirred at room temperature for 1 hour. The solvent was evaporated and the crude was triturated with methylene chloride. The solid formed was filtered through diatomaceous earth (Celite®) and the filtrate was evaporated to give a residue that was purified by flash chromatography (dichloromethane to dichloromethane/ethanol 8:2) to yield the title compound (45 mg, 36%).
LRMS (m/z): 647 (M+2)+. EXAMPLE 18
( ?)-1 -(( ?)-3-((6-(4-(4-(2-(Dimethylamino)ethoxy)benzyl)piperazin-1 -yl)-5-fluoro (pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-1 -oxobutan-2-ol and (S)-1 -(( ?)-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
A mixture of 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}piperazin-1 -yl)-5-fluoro-/V-[(3R)- piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 19b, 0.07 g, 0.12 mmol), sodium 2-hydroxybutanoate (0.02 g, 0.14 mmol), (benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.06 g, 0.14 mmol) and triethylamine (0.05 ml_, 0.36 mmol) in dichloromethane (1 mL) was stirred at room temperature for 3 hours and overnight at 40 °C. Additional dichloromethane was added and the reaction mixture was washed with water, separated by Phase Separator and the solvent evaporated to give a residue that was purified by reverse phase chromatography to yield the title compounds (26 mg, 32%) as a 1 :1 mixture of diastereoisomers.
LRMS (m/z): 661 (M+2)+.
EXAMPLE 19
3-((3 ?)-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- oxopropanenitrile
Obtained as a solid (38%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and N,N- dimethyl-2-[3-(piperazin-1 -ylmethyl)phenoxy]ethanamine (Preparation 20b)
following the experimental procedure as described in Example 4 followed by purification of the crude product by reverse phase chromatography (using water/methanol as eluents).
LRMS (m/z): 641 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 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 ?)-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
Obtained as a solid (33%) from (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 (Preparation 9c) and /V,/V-dimethyl-2-(4-(piperazin-1 -ylmethyl)phenoxy)ethanamine (Preparation 18b) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (using dichloromethane and methanol as eluents).
1H-NMR δ (400 MHz, DMSO-d6): 0.81 (m, 1 H), 1 .02 - 1 .49 (m, 1 H), 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, 1 H), 8.44 - 8.51 (d, 1 H), 8.57 - 8.66 (m, 1 H).
EXAMPLE 21
3-((3 ?)-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
Obtained as a solid (34%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and N,N- dimethyl-3-(4-(piperazin-1 -ylmethyl)phenoxy)propan-1 -amine (Preparation 21 c) following the experimental procedure as described in Example 4.
LRMS (m/z): 656 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.45 - 3.60 (m, 4H), 3.70 - 3.84 (m, 6H), 4.07 (t, 2H), 4.20 (bs, 1 H), 4.50 - 4.64 (m, 1 H), 6.80 - 6.90 (m, 3H), 7.21 - 7.32 (m, 3H), 8.31 - 8.58 (m, 3H).
EXAMPLE 22
3-{(3 ?)-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
Obtained as a solid (33%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 1 -[4-(2- piperidin-1 -ylethoxy)benzyl]piperazine trihydrochloride (Preparation 22c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (chloroform to 2% metanol in chloroform).
LRMS (m/z): 682 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .38 - 1 .51 (m, 1 H), 1 .54 - 1 .67 (m, 2H), 1 .67 -
2.01 (m, 3H), 2.05 - 2.24(m, 1 H), 2.44 - 2.64 (m, 4H), 2.72 - 2.83 (t, 2H), 3.03 - 3.17 (dd, 1 H), 3.24 - 3.66 (m, 4H), 3.67 - 3.87 (m, 3H), 4.06 - 4.15 (t, 2H), 4.15 - 4.29 (bs, 1 H), 4.47 - 4.67 (m, 1 H), 6.76 - 6.94 (m, 3H), 7.22 - 7.33 (m, 3H), 8.28 - 8.60 (m, 3H).
EXAMPLE 23
3-{(3 ?)-3-[(5-Fluoro-2^yrazolo[1 ,5-a]pyridin-3-yl-6-{4-[4-(2-pyrrolidin-1 -ylethoxy) benzyl]piperazin-1 -yl}pyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Obtained as a solid (17%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 1 -[4-(2- pyrrolidin-1 -ylethoxy)benzyl]piperazine trihydrochloride (Preparation 23c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (dichloromethane/methanol/ammonia 40:4:0.2).
LRMS (m/z): 668 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 0.71 - 0.95 (m, 1 H), 1 .49 - 1.65 (m, 2H), 1 .78 -
1 .91 (s, 3H), 2.09 - 2.22 (m, 1 H), 2.36 - 2.46 (m, 1 H), 2.47 - 2.74 (m, 4H), 2.84 - 2.98 (m, 2H), 3.29 - 3.42 (m, 1 H), 3.42 - 3.61 (m, 2H), 3.69 - 3.87 (m, 2H),
4.02 - 4.16 (m, 1 H), 4.16 - 4.38 (m, 1 H), 4.48 - 4.70 (m, 1 H), 6.74 - 6.95 (m, 3H), 7.05 - 7.17 (dd, 1 H), 7.30 - 7.41 (m, 1 H), 7.46 - 7.59 (m, 2H), 8.28 - 8.62 (m, 3H).
EXAMPLE 24
3-((3 ?)-3-{[6-((3 ?,5S)-4-{4-[2-(Dimethylamino)ethoxy]benzyl}-3,5-dimethyl piperazin-1 -yl)-5-fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino} piperidin-1 -yl)-3-oxopropanenitrile
Obtained as a pale yellow solid (8%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 2-(4-{[(2/?,6S)-2,6-dimethylpiperazin-1 -yl]methyl}phenoxy)ethyl]dimethylamine (Preparation 24) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 9:1 ).
LRMS (m/z): 670 (M+2)+. 1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.80 - 6.88 (m, 3H), 7.25 - 7.32 (m, 3H), 8.30 - 8.55 (m, 3H).
EXAMPLE 25
3-((3/?)-3-{[6-(4-{4-[2-(dimethylamino)ethoxy
5-fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (45%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and {2-[2,6- dimethyl-4-(piperazin-1 -ylmethyl)phenoxy]ethyl}dimethylamine (Preparation 25c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 9:1 ).
LRMS (m/z): 670 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.50 - 4.65 (m, 1 H), 6.78 - 6.86 (m, 1 H), 6.98 (s, 2H), 7.27 - 7.35 (m, 1 H), 8.33 - 8.58 (m, 3H).
EXAMPLE 26
3-((3 ?)-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazin-1 -yl)- 5-fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (48%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 2-[3,5- dimethyl-4-(piperazin-1 -ylmethyl)phenoxy]ethyl}dimethylamine (Preparation 26c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 9:1 ).
LRMS (m/z): 670 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.50 - 4.65 (m,
1 H), 6.61 (s, 2H), 6.78 - 6.86 (m, 1 H), 7.25 - 7.32 (m, 1 H), 8.33 - 8.58 (m, 3H). EXAMPLE 27
3-[(3 ?)-3-({6-[4-(2-{4-[2-(Dimethylamino)ethoxy]phenyl}ethyl)piperazin-1 -yl]-^ fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
Obtained as a brown solid (51 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V-dimethyl-2-[4-(2-piperazin-1 -ylethyl)phenoxy]ethanamine (Preparation 27c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 95:5).
LRMS (m/z): 656 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.8 - 6.9 (m, 3H), 7.1 (d, 2H), 7.3 - 7.4 (m, 1 H), 8.2 - 8.7 (m, 3H).
EXAMPLE 28
2-(Dimethylamino)ethyl 4-{[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}benzoate Sodium triacetoxyborohydride (0.043 g, 0.20 mmol) was added to a solution of 3- {(3R)-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 2- (dimethylamino)ethyl 4-formylbenzoate (Preparation 29b, 0.037 g, 0.17 mmol) in dichloromethane (2 mL) and the resulting mixture was stirred overnight at room temperature. Additional 2-(dimethylamino)ethyl 4-formylbenzoate (0.055 g) and sodium triacetoxyborohydride (0.020 g) were added and the solution was stirred for further 24 hours. The reaction mixture was partitioned between tetrahydrofuran and brine. The organic phase was separated, dried over magnesium sulfate and the solvent evaporated to dryness. Purification of the residue by flash chromatography (chloroform /methanol) gave the title compound as a solid (0.020 g, 14%)
LRMS (m/z): 670 (M+2)+.
EXAMPLE 29
Terf-butyl 4-{[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}piperidine-1 -carboxylate
Obtained as a brown solid (88%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and ie f-butyl 4-(piperazin-1 -ylmethyl)piperidine-1 -carboxylate (Preparation 30b) following the experimental procedure as described in Example 4.
LRMS (m/z): 662 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .1 1 (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 , 1 H), 6.80 - 6.90 (m, 1 H), 7.27 - 7.34 (m, 1 H), 8.36 (d, 1 H), 8.41 - 8.60 (m, 2H).
EXAMPLE 30
3-[(3 ?)-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
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .30 mL, 5.20 mmol) was added to a stirred solution of ie f-butyl 4-{[4-(6-{[(3R)-1-(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}piperidine-1 - carboxylate (Example 29, 0.17 g, 0.26 mmol) in 1 ,4-dioxane (5 mL) and the resulting mixture was stirred at room temperature for 2 hours. Diethyl ether was then added and the precipitate formed was filtered and washed with ethyl acetate and acetonitrile to yield the hydrochloride salt of the title compound (150 mg, 92%) as a solid.
LRMS (m/z): 562 (M+2)+.
EXAMPLE 31
3-[(3 ?)-3-({5-Fluoro-2^yrazolo[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^ oxopropanenitrile
A mixture of 3-[(3R)-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, 0.07 g, 0.12 mmol), 1 -(bromomethyl)-4-(trifluoromethyl)benzene (0.03 g, 0.10 mmol) and sodium hydrogencarbonate (0.08 g, 0.94 mmol) in Λ/,/V-dimethylacetamide (0.5 mL) was stirred overnight at 90 °C. Water was added and the suspension was filtered. The precipitate was purified by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ) to yield the title compound (53 mg, 70%) as a white solid.
LRMS (m/z): 720 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .27 (m, 3H, 1 .54 (m, 1 H), 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, 1 H), 4.46 - 4.66 (m, 2H), 6.85 (m, 1 H), 7.28 (m, 1 H), 7.44 (d, 2H), 7.57 (d, 2H), 8.36 (d, 1 H), 8.40 - 8.59 (m, 2H).
EXAMPLE 32
3-[(3 ?)-3-({5-Fluoro-6-[4-({1 -[(1 -methyl-1 H-imidazol-2-yl)methyl]piperidin-4-yl} methyl)piperazin-1 -yl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino) piperidin-1 -yl]-3-oxopropanenitrile
A mixture of 3-[(3R)-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, 0.1 1 mmol), 2-(chloromethyl)-1 -methyl-1 H-imidazole (0.02 g, 0.09 mmol) and sodium hydrogencarbonate (0.07 g, 0.84 mmol) in Λ/,/V-dimethylacetamide (1 .5 mL) was stirred at 90 °C for 8 hours. The crude was purified by reverse phase chromatography (water to 1 :1 acetonitrile/methanol) to yield the title compound (17 mg, 27%) as a white solid.
LRMS (m/z): 655 (M+1 )+.
1H-NMR δ D(300 MHz, CDCI3): 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, 1 H), 4.55 - 4.65 (m, 1 H), 6.76 - 6.89 (m, 2H), 6.92 (d, 1 H), 7.30 (m, 1 H), 8.35 (d, 1 H), 8.42 - 8.60 (m, 2H).
EXAMPLE 33
3-((3 ?)-3-{[6-(4-{[1 -(2,2-Dimethylpropyl)piperidin-4-yl]methyl}piperazin-1 -yl)-5- fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
A mixture of 3-[(3R)-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) and sodium triacetoxyborohydride (0.02 g, 0.09 mmol) in dichloromethane (0.5 mL) was stirred overnight at room temperature. The reaction mixture was washed with 2N aqueous sodium hydroxide solution and with 2N aqueous hydrogen chloride solution. The organic layer was separated, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ) to yield the title compound (15 mg, 31 %) as a white solid.
LRMS (m/z): 632 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.48 - 4.69 (m, 1 H), 6.85 (m, 1 H), 7.31 (m, 1 H), 8.36 (d, 1 H), 8.42 - 8.58 (m, 2H).
EXAMPLE 34
3-((3 ?)-3-{[5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-(4-{[1 -(pyridin-2-ylmethyl) piperidin-4-yl]methyl}piperazin-1 -yl)pyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
A mixture of 3-[(3R)-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 (0.02 g, 0.08 mmol) and sodium hydrogencarbonate (0.06 g, 0.80 mmol) in Λ/,/V-dimethylacetamide (1 mL) was stirred overnight at 90 °C. Water was added and the suspension formed was filtered. The precipitate was purified by flash chromatography (dichloromethane to dichloromethane /methanol 9:1 ) to yield the title compound (17 mg, 33%) as a white solid.
LRMS (m/z): 653 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 0.85 (m, 1 H), 1 .16 - 1 .45 (m, 3H), 1 .70 - 1 .90 (m, 4H), 2.1 1 (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, 1 H), 4.47 - 4.68 (m, 1 H), 6.72 - 6.92 (m, 1 H), 7.17 (m, 1 H), 7.23 - 7.34 (m, 1 H), 7.43 (d, 1 H), 7.65 (m, 1 H), 8.35 (d, 1 H), 8.39 - 8.61 (m, 3H).
EXAMPLE 35
3-[(3 ?)-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-oxopropanenitrile
Obtained as a brown solid (26%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 1 -(2,6-dimethylpyridin-4-yl)piperazine (Preparation 31 b) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (gradient of ethanol in hexanes).
LRMS (m/z): 570 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.69 (td, 1 H), 6.42 (s, 2H), 6.80 - 6.92 (m, 1 H), 7.32 (m, 1 H), 8.35 (d, 1 H), 8.42 - 8.55 (m, 2H).
EXAMPLE 36 3-[(3 ?)-3-({5-Fluoro-2^yrazolo[1 ,5-a]pyridin-3-yl-6-[4-(2^yrrolidin-1 -ylpyridin-4- yl)piperazin-1 -yl]pyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a solid (23%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 1 -(2- pyrrolidin-1 -ylpyridin-4-yl)piperazine (Preparation 32c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography.
LRMS (m/z): 610 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.62 - 4.73 (m, 1 H), 5.69 (d, 1 H), 6.15 (dd, 1 H), 6.80 - 6.93 (m, 1 H), 7.33 (m, 1 H), 7.94 (d, 1 H), 8.30 - 8.60 (m, 3H).
EXAMPLE 37
3-{(3 ?)-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-oxopropanenitrile
Obtained as a solid (38%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and N,N- dimethyl-4-piperazin-1 -ylpyridin-2-amine (Preparation 33b) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography.
LRMS (m/z): 585 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.67 (m, 1 H), 5.85 (d, 1 H), 6.18 (dd, 1 H), 6.79 - 6.93 (m, 1 H), 7.33 (m, 1 H), 7.96 (d, 1 H), 8.30 - 8.63 (m, 3H).
EXAMPLE 38
3-{(3 ?)-3-[(6-{4-[4-(Dimethylamino)pyridin-2-yl]piperazin-1 -yl}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Obtained as a solid (36%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and N,N- dimethyl-2-piperazin-1 -ylpyridin-4-amine (Preparation 34c) following the experimental procedure as described in Example 4 followed by purification of the crude product by reverse phase chromatography (using water and ethanol as eluents).
LRMS (m/z): 584 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.63 - 4.70 (m, 1 H), 5.80 (d, 1 H), 6.1 1 (dd, 1 H), 6.86 (m, 1 H), 7.32 (m, 1 H), 7.94 (d, 1 H), 8.33 - 8.63 (m, 3H).
EXAMPLE 39
3-((3 ?)-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
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (1 .0 mL, 4.0 mmol) was added to a stirred solution of ie f-butyl 4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]piperidine-1 -carboxylate (Preparation 35, 0.206 g, 0.32 mmol) in 1 ,4-dioxane (5 mL) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness and the resulting residue was purified by cation exchange chromatography (elution with 2N ammonia solution in methanol) to yield the title compound (165 mg, 93%) as free base.
LRMS (m/z): 547 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .45 (d, 2H), 1 .69 - 1 .96 (m, 5H), 2.16 (m, 1 H), 2.41 (m, 1 H), 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, 1 H), 7.28 - 7.35 (m, 1 H), 8.31 - 8.63 (m, 3H).
EXAMPLE 40
3- [(3 ?)-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-oxopropanenitrile
Obtained as a solid (56%) from 3-((3R)-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
(Example 39) and benzaldehyde following the experimental procedure as described in Example 33 followed by purification of the crude product by reverse phase chromatography (gradient from water to methanol).
LRMS (m/z): 637 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .65 (m., 4H), 1 .82 (m, 3H), 1 .99 (t, 2H), 2.16 (d,
1 H), 2.32 (t, 1 H), 2.70 (br. s., 4H), 2.97 (d, 2H), 3.29 - 3.61 (m, 5H), 3.77 (bs,
5H), 4.20 (bs, 1 H), 4.47 - 4.68 (m, 2H), 6.77 - 6.92 (m, 1 H), 7.29 - 7.38 (m, 6H),
8.31 - 8.62 (m, 3H). EXAMPLE 41
5-Fluoro-/V-[(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 A mixture of 6-chloro-5-fluoro-/V-[(1 S)-1 -(5-fluoropyridin-2-yl)ethyl]-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-amine (Preparation 7, 0.16 g, 0.41 mmol), 1 -(1 -methylpiperidin- 4-yl)piperazine (0.1 1 g, 0.60 mmol) and sodium hydrogencarbonate (0.14 g, 1.67 mmol) in /V,'/V-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 over magnesium sulfate and the solvent was concentrated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol/ ammonia 40:8:1 ) to yield the title compound (0.10 g, 44%) as a light brown solid.
LRMS (m/z): 534 (M+1 )+.
1 H-NMR δ (300 MHz, CDCI3): 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, 1 H), 5.59 (dd, 1 H), 6.63 - 6.88 (m, 1 H), 7.1 1 - 7.28 (m, 1 H), 7.31 - 7.50 (m, 2H), 8.28 (d, 1 H), 8.40 - 8.58 (m, 3H).
EXAMPLE 42
3-{(3 ?)-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-oxopropanenitrile
Obtained as a light orange solid (70 mg, 26%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
(Preparation 6c) and /V,/V-dimethyl-3-piperazin-1 -ylpropan-1 -amine following the experimental procedure as described in Example 4.
LRMS (m/z): 549 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .68 - 1 .84 (m, 4H), 2.09 - 2.21 (m, 1 H), 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, 1 H), 6.79 - 6.95 (m, 1 H), 7.30 - 7.39 (m, 1 H), 8.27 - 8.60 (m, 3H).
EXAMPLE 43
3-[(3 ?)-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-oxopropanenitrile
Obtained as a solid (46%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 4-(1 - pyrrolidinylmethyl)piperidine dihydrochloride following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (chloroform to chloroform/metanol 9:1 ).
LRMS (m/z): 547 (M+2)+. 1H-NMR δ (300 MHz, CDCI3): 1 .21 - 1.45 (m, 3H), 1 .71 - 2.00 (m, 5H), 2.07 - 2.25 (m,1 H), 2.31 - 2.47 (m,1 H), 2.47 - 2.71 (bs, 2H), 2.89 - 3.18 (m,2H), 3.26 - 3.68 (m, 3H), 3.72 - 3.87 (m, 1 H), 4.10 - 4.29 (bs, 1 H), 4.37 - 4.71 (m, 2H), 6.75
- 6.93 (m, 1 H), 7.28 - 7.39 (m, 1 H), 8.30 - 8.65 (m, 3H).
EXAMPLE 44
3-[(3 ?)-3-({6-[4-(1 ,3-Dihydro-2H-isoindol-2-ylmethyl)piperidin-1 -yl]-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
A suspension of 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl)amino]piperidin-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 mmol) and sodium hydrogencarbonate (0.142 g, 1 .69 mmol) in Λ/,Λ/'-dimethylacetamide (0.5 mL) was stirred overnight at 90 °C. Excess of water was added and the precipitate was filtered and washed with water. Purification of the precipitate by reverse phase chromatography gave a solid that was dissolved in ethyl acetate, treated with a 4.0 M solution of hydrogen chloride in 1 ,4-dioxane and filtered to yield the hydrochloride salt of the title compound (0.024 g, 21 %).
LRMS (m/z): 595 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .08 - 1.25 (m, 1 H), 1 .25 - 1.48 (m, 1 H), 1.48 -
1 .87 (m, 2H), 1.87 - 2.10 (m, 2H), 2.10 - 2.28 (m, 1 H), 2.91 - 3.14 (m, 2H), 3.81
- 4.24 (m, 2H), 4.24 - 4.46 (m, 1 H), 4.46 - 4.72 (m, 1 H), 4.77 - 4.98 (m, 1 H), 6.64 - 6.90 (m, 1 H), 6.92 - 7.10 (m, 1 H), 7.20 - 7.54 (m, 3H), 8.26 - 8.48 (m, 1 H), 8.48 - 8.66 (m, 1 H), 8.66 - 8.86 (m, 1 H), 10.71 - 1 1.06 (m, 2H).
EXAMPLE 45
3-((3 ?)-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
Obtained as a brown solid (20%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V-dimethyl-2-(4-(piperidin-4-ylmethyl)phenoxy)ethanamine (Preparation 37c) following the experimental procedure as described in Example 4 followed by purification of the crude product by reverse phase chromatography (water to water /methanol 2:8).
LRMS (m/z): 641 (M+1 )+. 1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.4 - 4.7 (m, 4H), 6.9 (d, 3H), 7.1 (d, 2H), 7.2 - 7.3 (m, 1 H), 8.3 - 8.6 (m, 3H).
EXAMPLE 46
3-{(3 ?)-3-[(6-{4-[[2-(Dimethylamino)ethyl](methyl)amino]piperidin-1 -yl}-5-flu pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl} oxopropanenitrile
Obtained as a solid (14%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and Ν,Ν,Ν'- trimethyl-/V'-piperidin-4-ylethane-1 ,2-diamine following the experimental procedure as described in Example 4 followed by purification of the crude product by reverse phase chromatography (gradient from water to methanol).
LRMS (m/z): 563 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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 - 2.88 (m, 2H), 3.40 (d, 1 H), 3.43 - 3.53 (m, 1 H), 3.77 - 3.83 (m, 2 H) 4.14 - 4.25 (m, 2H), 4.50 - 4.64 (m, 3H), 6.86 (td, 1 H), 7.30 (m, 1 H), 8.32 - 8.62 (m, 3H). EXAMPLE 47
3-[(3 ?)-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 - yl]-3 -oxopropanenitrile
A suspension of 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4- yl)amino]piperidin-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 Ν,Ν'- dimethylacetamide (0.5 mL) was stirred for 48 hours at 90 °C. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over magnesium sulfate and the solvent was evaporated to dryness. The resulting oil was treated with hexane and diisopropyl ether and filtered to give the title compound (0.030 g, 26%) as a solid.
LRMS (m/z): 599 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .72 - 1.93 (m, 1 H), 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, 1 H), 4.43 - 4.61 (m, 2H), 4.61 - 4.75 (m, 1 H), 6.74 - 6.94 (m, 1 H), 7.26 - 7.37 (m, 1 H), 8.27 - 8.68 (m, 3H).
EXAMPLE 48
3-{(3 ?)-3-[(6-{4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -y^
pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a solid (24%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and N,N,2- trimethyl-6-(piperidin-4-yl)pyridin-4-amine dihydrochloride following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (chloroform to chloroform/metanol 100:5).
LRMS (m/z): 597 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.41 - 3.60 (m, 2H), 3.60 - 3.77 (m, 2H), 4.07 - 4.27 (bs, 1 H), 4.40 - 4.68 (m, 2H), 6.13 - 6.23 (m, 2H), 6.70 - 6.87 (m, 1 H), 7.20
- 7.30 (m, 1 H), 8.26 - 8.55 (m, 3H). EXAMPLE 49
3-{(3 ?)-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- oxopropanenitrile
Obtained as a solid (59%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 2,6- dimethyl-/V-piperidin-4-ylpyridin-4-amine (Preparation 38b) following the experimental procedure as described in Example 4 followed by purification of the crude product by reverse phase chromatography (gradient from water to methanol).
LRMS (m/z): 535 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.46 - 3.84 (m, 5H), 4.06 (bs, 1 H), 4.22
(bs, 1 H), 4.34 - 4.57 (m, 3H), 4.64 (m, 1 H), 6.19 (s, 2H), 6.87 (dd, 1 H), 7.30 (t,
1 H), 8.29 - 8.61 (m, 3H). EXAMPLE 50
Benzyl 4-{[1 -(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1 -carboxylate Obtained as a white solid (83%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and benzyl 4-(piperidin-4-ylmethyl)piperazine-1 -carboxylate (Preparation 39) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (hexanes to ethyl acetate).
LRMS (m/z): 696 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .22 - 1 .35 (m, 5H), 1 .70 - 1 .90 (m, 4H), 2.18 (s, 1 H), 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, 1 H), 4.22 (m, 1 H), 4.45 - 4.52 (m, 2H), 4.59 (m, 1 H), 5.14 (s, 2H), 6.87 (m, 1 H), 7.23 - 7.42 (m, 6H), 8.37 (d, 1 H), 8.45 - 8.60 (m, 2H).
EXAMPLE 51
3-[(3 ?)-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
10% palladium on carbon (0.02 g, 0.17 mmol) was added to a suspension of benzyl 4- {[1 -(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1 -carboxylate (Example 50, 0.24 g, 0.35 mmol) in ethanol (15 mL) and the resulting mixture was stirred under an hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane /methanol 9:1 ) to yield the title compound (145 mg, 75%) as a white solid.
LRMS (m/z): 562 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.19 (m, 1 H), 4.45 - 4.52 (m, 2H), 4.59 (bs, 1 H), 6.80 - 6.88 (m, 1 H), 7.27 - 7.33 (m, 1 H), 8.37 (d, 1 H), 8.45 - 8.60 (m, 2H).
EXAMPLE 52
(/?)-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-oxopropanenitrile
Obtained as a white solid (39%) from 3-[(3R)-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 following the experimental procedure as described in Example 33 followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 9:1 ).
LRMS (m/z): 652 (M+2)+. 1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.22 (m, 1 H), 4.40 - 4.52 (m, 2H), 4.55 - 4.62 (m, 1 H), 6.80 - 6.90 (m, 1 H), 7.22 - 7.35 (m, 5H), 8.37 (d, 1 H), 8.44 - 8.58 (m ,2H).
EXAMPLE 53
3-[(3 ?)-3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -^^ piperidin-1 -yl]-5-fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino) piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a yellow solid (37%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V,2-trimethyl-6-[1 -(piperidin-4-ylmethyl)piperidin-4-yl]pyridin-4-amine trihydrochloride (Preparation 40b) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography.
LRMS (m/z): 687 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .20 - 1 .45 (m, 2H), 1 .63 - 2.32 (m, 12H), 2.39 - 2.51 (s, 2H), 2.57 - 2.74 (m, 1 H), 2.90 - 3.08 (s, 6H), 3.25 - 3.68 (m, 3H), 3.73 - 3.86 (d, 1 H), 4.1 1 - 4.29 (bs, 1 H), 4.39 - 4.67 (m, 3H), 6.21 - 6.31 (d, 2H), 6.77 - 6.92 (m, 1 H), 7.27 - 7.37 (m, 1 H), 8.34 - 8.63 (m, 3H).
EXAMPLE 54
3-[(3 ?)-3-({5-Fluoro-6-[(4-piperazin-1 -ylbenzyl)amino]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (0.42 mL, 1 .68 mmol) was added to a solution of (R)-ieri-butyl 4-(4-(((6-((1 -(2-cyanoacetyl)piperidin-3-yl)amino)-5-fluoro-2- (pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)methyl)phenyl)piperazine-1 - carboxylate (Preparation 41 , 77 mg, 0.1 1 mmol) in 1 ,4-dioxane (2 mL) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness and the residue was purified through a SCX column (methanol to 7.0 M ammonia in methanol) to yield the title compound (4 mg, 1 1 %) as a solid.
LRMS (m/z): 569 (M+1 )+.
EXAMPLE 55
3-[(3 ?)-3-({5-Fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin- 3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a solid (37%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-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 following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 93:7).
LRMS (m/z): 554 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .75 - 1.90 (m, 3H), 2.20 (s, 1 H), 2.29 (s, 2H), 2.95 (s, 3H), 3.45 - 3.60 (m, 10H), 3.85 - 3.98 (t, 2H), 4.30 (m, 1 H), 5.00 (s, 1 H), 6.82 - 6.95 (m, 1 H), 7.04 (m, 2H), 7.35 (t, 1 H), 8.1 1 (d, 2H), 8.42 - 8.76 (m, 3H). EXAMPLE 56
2- [(3 ?)-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
(Benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.075 g, 0.20 mmol) was added to a solution of 5-fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-/V- [(3R)-piperidin-3-yl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine (Preparation 42b, 0.09 g, 0.15 mmol), hydroxyacetic acid (0.016 g, 0.22 mmol) and triethylamine (0.105 ml_, 0.76 mmol) in Λ/,Λ/'-dimethylformamide (0.7 mL) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the resulting residue was purified by flash chromatography (dichloromethane to dichloromethane /methanol 10:1 ) to yield the title compound (0.046 g, 55%).
LRMS (m/z): 546 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .71 - 1 .97 (m, H), 2.34 - 2.41 (s, 1 H), 2.55 - 2.65 (dd, 1 H), 3.09 - 3.29 (m, 2H), 3.30 - 3.50 (m, 4H), 3.50 - 3.58 (m, 1 H), 3.72 - 3.85 (dd, 1 H), 3.94 - 4.10 (m, 2H), 4.18 - 4.39 (m, 3H), 4.61 - 4.74 (dd, 1 H), 4.95 - 5.08 (m, 1 H), 6.78 - 6.94 (m, 1 H), 6.98 - 7.09 (d, 2H), 7.13 - 7.25 (m, 1 H),
7.28 - 7.37 (m, 1 H), 8.06 - 8.15 (d, 2H), 8.46 - 8.79 (m, 3H).
EXAMPLE 57
1 -Benzyl -4-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide
Obtained as a yellow solid (27%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-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]piperazin-1 - ium bromide (Preparation 43) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography.
LRMS (m/z): 645 (M+1 )+. 1H-NMR δ (300 MHz, CD3OD): 0.78 - 1 .01 (m, 1 H), 1 .21 - 1 .46 (m, 5H), 1 .51 - 2.04 (m, 2H), 2.12 - 2.27 (m, 1 H), 2.69 - 2.88 (m, 1 H), 2.88 - 3.04 (m, 1 H), 3.04 - 3.28 (m, 2H), 3.42 - 3.68 (m, 2H), 3.68 - 4.39 (m, 4H), 4.70 - 4.79 (m, 1 H), 6.89 - 7.04 (m, 1 H), 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-re^Butylbenzyl)-4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide
Obtained as a white solid (28%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 1 -(4-ie/f-butylbenzyl)-1 -methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl] piperazin-1 -ium bromide (Preparation 44) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography.
LRMS (m/z): 701 (M+2)+.
1H-NMR δ (300 MHz, DMSO-d6): 1.24 - 1 .37 (s, 9H), 1 .47 - 1 .88 (m, 4H), 2.01 - 2.15 (bs, 1 H), 2.17 - 2.31 (m, 1 H), 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, 1 H), 3.84 - 4.38 (m, 5H),
4.64 - 4.76 (s, 2H), 7.01 - 7.09 (m, 1 H), 7.15 - 7.25 (d, 2H), 7.42 - 7.62 (m, 5H), 8.00 - 8.1 1 (d, 2H), 8.47 - 8.56 (d, 1 H), 8.66 - 8.84 (m, 2H).
EXAMPLE 59
3- ((3 ?)-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
A mixture of 3-((3R)-3-{[5-fluoro-6-(4-piperazin-1-ylphenyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 45b, 0.12 g, 0.22 mmol), 3-chloro-/V,/V-dimethylpropan-1 -amine (0.04 g, 0.22 mmol) and sodium hydrogencarbonate (0.06 g, 0.67 mmol) in Λ/,/V-dimethylacetamide (2 mL) was stirred at 100 °C for 48 hours. The reaction mixture was purified by reverse phase chromatography (water/methanol as eluents) to yield the title compound (37 mg, 24%).
LRMS (m/z): 626 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.87 (m, 1 H), 7.01 (dd, 1 H), 7.34 (m, 1 H), 8.07 (d, 2H), 8.43 - 8.61 (m, 3H).
EXAMPLE 60
3-[(3 ?)-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[4-(4-methylpiperazin-1 -yl)phen 2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
A solution of /V-{5-fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin- 3-ylpyrimidin-4-yl}-/V',/V'-dimethyl-/V-[(3R)-piperidin-3-yl]ethane-1 ,2-dia
(Preparation 46b, 0.07 g , 0.13 mmol), 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3-oxopropane nitrile, (0.027 g, 0.15 mmol)) and triethylamine (0.21 ml_, 0.15 mmol) in dichloromethane (3 mL) was stirred for 1 hour at room temperature. Excess of ethyl acetate was added and the reaction mixture was washed with water. The organic phase was dried over sodium sulfate and the solvents were evaporated to dryness. Purification of the residue by flash chromatography gave the title compound (0.036 g, 42%) as a solid.
LRMS (m/z): 626 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .91 - 2.22 (m, 5H), 2.24 - 2.31 (m, 1 H), 2.31 - 2.36 (s, 6H), 2.36 - 2.40 (s, 3H), 2.50 - 2.71 (m, 8H), 2.92 - 3.05 (m, 1 H), 3.09 - 3.25 (m, 1 H), 3.26 - 3.51 (m, 7H), 3.51 - 3.59 (d, 1 H), 3.59 - 3.86 (m, 4H), 4.32 -
4.50 (m, 2H), 4.63 - 4.74 (m, 1 H), 4.77 - 4.87 (m, 1 H), 6.80 - 6.93 (m, 1 H), 6.98 - 7.08 (d, 2H), 7.27 - 7.37 (m, 1 H), 7.99 - 8.08 (d, 2H), 8.46 - 8.66 (m, 3H).
EXAMPLE 61
3-[(3 ?)-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-oxopropanenitrile
Obtained as a solid (30%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-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) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography.
LRMS (m/z): 554 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 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, 1 H), 4.99 - 5.1 1 (m, 1 H), 6.82 - 6.96 (m, 1 H), 7.30 - 7.46 (m, 3H), 8.03 - 8.1 1 (d, 2H), 8.47 - 8.76 (m, 3H).
EXAMPLE 62
3-[(3 ?)-3-({5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1 -ylmethyl) phenyl]pyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a solid (13%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 4-(1 - pyrrolidinylmethyl)phenylboronic acid (Preparation 49) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography.
LRMS (m/z): 540 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .74 - 2.03 (m, 5H), 2.15 - 2.30 (m, 1 H), 2.47 - 2.67 (bs, 3H), 3.15 - 3.28 (m,1 H), 3.34 - 3.54 (m, 2H), 3.55 - 3.71 (m, 2H), 3.71 - 3.77 (m, 1 H), 3.86 - 4.05 (m, 1 H), 4.24 - 4.40 (bs, 1 H), 4.52 - 4.64 (dd, 1 H),
5.01 - 5.14 (bs, 1 H), 6.82 - 6.96 (m, 1 H), 7.30 - 7.41 (m, 1 H), 7.46 - 7.57 (m, 2H), 8.05 - 8.13 (d, 2H), 8.48 - 8.76 (m, 3H).
EXAMPLE 63
3-[(3 ?)-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-oxopropanenitrile
Obtained as a solid (19%) from 3-((3R)-3-{[6-(4-formylphenyl)-5-methyl-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 50b) and pyrrolidine following the experimental procedure as described in Example 33 followed by purification of the crude product by reverse phase chromatography (gradient from water to methanol).
LRMS (m/z): 535 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .84 (bs, 5H), 2.14 (s, 3H), 2.60 (bs, 3H), 3.39 (d, 1 H), 3.50 (dd, 2H), 3.58 (d, 1 H), 3.72 (s, 2H), 3.91 (dd, 1 H), 4.25 - 4.49 (m, 2H), 4.58 (d, 1 H), 4.74 (d, 1 H), 6.85 (dt, 2H), 7.30 (m, 1 H), 7.41 - 7.53 (m, 2H), 7.55 -
7.63 (m, 2H), 8.43 - 8.77 (m, 3H).
EXAMPLE 64
3-[(3 ?)-3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-^
phenyl]-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]- 3-oxopropanenitrile Obtained as a yellow solid (14%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and [4-({4-[4-(dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -yl}methyl)phenyl]boronic acid (Preparation 51 ) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane /methanol/ammonia 40:4:0.2).
LRMS (m/z): 695 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 2.95 - 3.02 (s, 6H), 3.02 - 3.1 1 (m, 1 H), 3.16 - 3.27 (dd, 1 H), 3.33 - 3.55 (m, 2H), 3.55 - 3.70 (m,
2H), 3.86 - 4.03 (m, 1 H), 4.25 - 4.40 (bs, 1 H), 4.54 - 4.64 (dd, 1 H), 5.04 - 5.15 (m, 1 H), 6.21 - 6.31 (m, 2H), 6.82 - 6.95 (m, 1 H), 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 ?)-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- oxopropanenitrile
Obtained as a solid (26%) from 3-((3R)-3-{[5-fluoro-6-(4-formylphenyl)-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 48b) and /V,/V-dimethylpiperidin-4-amine following the experimental procedure as described in Example 33. Purification of the crude product by reverse phase chromatography (gradient from water with 0.1 % hydrochloric acid solution 40% to methanol) followed by elution through an exchange cartridge (using 2N ammonia solution in methanol as eluent) gave the title compound as free base.
LRMS (m/z): 597 (M+1 )+.
1H-NMR δ (300 MHz, CD3OD): 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, 1 H), 7.4 - 7.5 (m, 1 H), 7.7 (m, 2H), 8.2 (d, 2H), 8.6 - 8.7 (m,3H).
EXAMPLE 66
3-((3 ?)-3-{[6-(4-{[4-(Dimethylamino)piperidin-1 -yl]methyl}-2-fluorophenyl)-5- fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (20%) from 3-((3R)-3-{[5-fluoro-6-(2-fluoro-4-formylphenyl)-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 52b) and /V,/V-dimethylpiperidin-4-amine following the experimental procedure as described in Example 33. Purification of the crude product by reverse phase chromatography (gradient from water with 0.1 % hydrochloric acid 40% to methanol) followed by SCX column (eluting with methanol/ammonia) gave the title compound as free base.
LRMS (m/z): 614 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .74 - 1.87 (m, 3H), 1 .87 - 2.01 (m, 3H), 2.00 - 2.13 (m, 3H), 2.18 - 2.31 (m, 1 H), 2.44 (s, 6H), 3.02 (d, 2H), 3.29 - 3.53 (m, 4H), 3.58 (d, 3H), 3.66 - 3.78 (m, 1 H), 3.89 - 4.13 (m, 1 H), 4.27 - 4.45 (m, 1 H), 5.10 (d, 1 H), 6.71 - 7.05 (m, 1 H), 7.15 - 7.45 (m, 3H), 7.74 (t, 1 H), 8.35 - 8.79 (m, 3H).
EXAMPLE 67
3-((3 ?)-3-{[6-(3-{[4-(Dimethylamino)piperidin-1 -yl]methyl}phenyl)-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (14%) from 3-((3R)-3-{[5-fluoro-6-(3-formylphenyl)-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 53b) and /V,/V-dimethylpiperidin-4-amine following the experimental procedure as described in Example 33 followed by purification of the crude product by reverse phase chromatography (gradient from water with 0.1 % hydrochloric acid 37% to methanol).
LRMS (m/z): 596 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.25 - 4.44 (m, 1 H), 4.99 - 5.19 (m, 1 H), 6.85 - 6.97 (m, 1 H), 7.37 (t, 1 H), 7.42 - 7.59 (m, 2H), 7.91 - 8.15 (m, 2H), 8.46 - 8.61 (m, 2H), 8.62 - 8.79
(m, 1 H).
EXAMPLE 68
3-{(3 ?)-3-[(5-Fluoro-6-{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
Obtained as a solid (24%) from 3-((3R)-3-{[5-fluoro-6-(4-formylphenyl)-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 48b) and 1 -methyl-1 ,4-diazepane following the experimental procedure as described in Example 33 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 582 (M+1 )+. 1H-NMR δ (300 MHz, CDCI3): 1 .74 - 2.05 (m, 6H), 2.15 - 2.30 (m, 1 H), 2.39 (s, 3H), 2.57 - 2.93 (m, 8H), 3.28 - 3.54 (m, 3H), 3.59 (s, 1 H), 3.74 (s, 2H), 3.84 -
4.04 (m, 1 H), 4.20 - 4.44 (m, 1 H), 4.93 - 5.17 (m, 1 H), 6.81 - 7.04 (m, 1 H), 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 ?)-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
A mixture of 3-{(3R)-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 WO201 1 157397, 52 mg, 0.13 mmol) and tetrakis(triphenylphosphane)palladium(0) (10 mg, 0.01 mmol) in 1 ,4-dioxane (1 ml_) was heated at 100 °C for 18 hours. The reaction crude was purified by flash chromatography (chloroform to chloroform/methanol /ammonia 40:2:0.2) to yield the title compound (21 mg, 41 %) as a white solid.
LRMS (m/z): 584 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.3 - 3.5 (m, 4H), 4.47 (d, 1 H), 5.19 (s, 2H), 7.4 - 7.5 (m, 2H), 7.9 (dd, 1 H), 8.08 (d, 2H), 8.4 - 8.5 (m, 1 H), 8.7 - 8.8 (m, 1 H), 10.0 (d, 1 H).
EXAMPLE 70
3-[(3 ?)-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- oxopropanenitrile
Obtained as a brown solid (16%) from 3-((3R)-3-{[5-fluoro-6-(4-formylphenyl)-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile (Preparation 48b) and /V,/V-dimethyl-2-(piperidin-4-yloxy)ethanamine (prepared as described in PCT2009093032) following the experimental procedure as described in Example 33 followed by purification of the crude product by reverse phase chromatography (gradient from water to water/methanol (4:6)).
LRMS (m/z): 640 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .6 - 2.2 (m, 15H), 2.26 (s, 5H), 2.8 (d, 2H), 3.2 -
3.5 (m, 5H), 3.9 (d, 1 H), 4.3 (s, 2H), 5.0 - 5.2 (m, 2H), 6.9 (dd, 1 H), 7.3 - 7.4 (m, 1 H), 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 ?)-3-[(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3 -oxopropanenitrile
Obtained as a yellow solid (66%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V-dimethyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)ethanamine (Preparation 55) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (chloroform to chloroform/methanol/ammonia 40:2:0.2).
LRMS (m/z): 543 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .6 - 2.0 (m, 4H), 2.2 (d, 1 H), 2.4 (s, 6H), 2.8 (dd,
2H), 3.3 -3 .5 (m, 2H), 3.6 - 3.7 (m, 1 H), 3.8 - 4.0 (m, 1 H), 4.2 (dd, 2H), 4.3 (bs,
1 H), 4.6 (dd, 1 H), 5.0 (bs, 1 H), 6.8 - 7.0 (m, 1 H), 7.1 (dd, 2H), 7.3 - 7.5 (m, 2H),
8.1 (dd, 2H), 8.5 - 8.7 (m, 2H). EXAMPLE 72
3-((3 ?)-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 -yl)-3- oxopropanenitrile
Obtained as a yellow solid (54%) from /V-(6-{4-[2-(dimethylamino)ethoxy]phenyl}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-/^
ethane-1 ,2-diamine (Preparation 56c) and 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3- oxopropanenitrile following the experimental procedure as described in Example 10 followed by purification of the crude product by flash chromatography (chloroform to chloroform/methanol/ammonia 40:2:0.2).
LRMS (m/z): 615 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.79 (d, 1 H), 6.8 - 6.9 (m, 1 H), 7.0 - 7.1 (m, 2H), 7.3 - 7.4 (m, 1 H), 8.0 (dd, 2H), 8.5 - 8.6 (m, 3H).
EXAMPLE 73
[(3 ?)-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 -oxopropanenitrile
Obtained as a yellow solid (42%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-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) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (chloroform to chloroform/methanol/ammonia 40:2:0.2).
LRMS (m/z): 569 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .6 - 1 .9 (m, 9H), 2.7 (s, 4H), 3.0 (t, 2H), 3.4 - 3.5 (m, 2H), 3.6 (s, 1 H), 3.9 - 4.0 (m, 1 H), 4.2 (t, 2H), 4.3 (bs, 1 H), 4.6 (dd, 1 H), 5.0
(bs, 1 H), 6.8 - 7.0 (m, 1 H), 7.1 (dd, 2H), 7.3 - 7.4 (m, 1 H), 8.1 (d, 2H), 8.5 - 8.7 (m, 2H), 8.7 (s, 1 H).
EXAMPLE 74
3-((3 ?)-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- oxopropanenitrile
Obtained as a yellow solid (60%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and /V,/V-dimethyl-1 -{2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]ethyl} piperidin-4-amine (Preparation 58) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (chloroform to chloroform/methanol/ammonia 40:2:0.2).
LRMS (m/z): 627 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.90 (d, 1 H), 4.19 (t, 2H), 4.30 (bs, 1 H), 5.05 (bs, 1 H), 6.80 - 6.90 (m, 1 H), 7.04 (dd, 2H), 7.3 - 7.4 (m, 1 H), 8.1 1 (d, 2H), 8.50 - 8.70 (m, 3H). EXAMPLE 75
( ?)-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-oxopropanenitrile
4.0 N Solution of hydrogen chloride in 1 ,4-dioxane (3.30 mL, 1 .4 mmol) was added dropwise to a solution of (R)-ieri-butyl 4-(4-(6-((1-(2-cyanoacetyl)piperidin-3-yl)amino)- 5-fluoro-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)phenoxy)piperidine-1 -carboxylate (Preparation 59, 0.44 g, 0.67 mmol) in 1 ,4-dioxane (7 mL) and the resulting solution was stirred at room temperature for 5 hours. Diethyl ether was added and the precipitate was filtered, washed with additional diethyl ether and dried in vacuo to yield the hydrochloride salt of the title compound (404 mg, 96%) as a white solid.
LRMS (m/z): 555 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.87 - 3.98 (m, 1 H), 4.31 (bs, 1 H), 4.47 - 4.53 (m, 1 H), 5.02 (bs, 1 H), 6.84 - 6.92 (m, 1 H), 7.02 - 7.08 (m, 2H), 7.32 - 7.38 (m, 1 H), 8.1 1 (d, 2H), 8.49 - 8.59 (m, 2H), 8.62 - 8.72 (d, 1 H). EXAMPLE 76
( ?)-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
Obtained as a solid (76%) from (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-oxopropanenitrile (Example 75) and acetaldehyde following the experimental procedure as described in Preparation 21 b followed by purification of the crude product by reverse phase chromatography (using water and acetonitrile as solvents).
LRMS (m/z): 583 (M+1 )+.
1H-NMR δ (400 MHz, DMSO-d6): 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 - 3.84 (m, 2H), 4.05 -
4.60 (m, 2H), 4.17 - 4.23 (m, 2H), 4.26 - 4.34 (bs, 1 H), 4.45 - 4.54 (m, 2H), 4.70
- 4.76 (m, 1 H), 7.04 (t, 1 H), 7.16 - 7.19 (m, 1 H), 7.43 - 7.51 (m, 2H), 8.04 (d, 2H), 8.51 (d, 1 H), 8.69 - 8.74 (d, 1 H), 8.78 - 8.82 (m, 1 H).
EXAMPLE 77
( ?)-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
A mixture of (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-oxopropanenitrile (Example 75, 0.07 g, 0.1 1 mmol), 1 -(3-chloropropyl)piperidine (0.03 g, 0.13 mmol) and sodium hydrogen carbonate (0.08 g, 0.99 mmol) in Λ/,/V-dimethylacetamide (1 .5mL) was stirred overnight at 90 °C. Water was added and the precipitate formed was filtered, washed with additional water and dried. The solid was purified by reverse phase chromatography (using water and acetonitrile as solvents) to yield the title compound (24 mg, 32%).
LRMS (m/z): 681 (M+2)+.
1H-NMR δ (400 MHz, DMSO-d6): 1 .31 -1 .40 (m, 1 H), 1 .45 - 1 .51 (m, 2H), 1.52 - 1 .58 (m, 1 H), 1.64 - 1 .71 (m, 2H), 1.78 - 1 .84 (m, 1 H), 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, 1 H), 3.96 - 4.06 (m, 6H), 4.09 - 4.16 (m, 2H), 4.18 - 4.23 (m, 2H), 4.30 (bs, 1 H), 4.45 - 4.53 (m, 2H), 4.69 - 4.76 (m, 1 H), 7.04 (t, 1 H), 7.16 - 7.18 (m, 1 H), 7.48 - 7.56 (m, 2H), 8.03 (d, 2H), 8.51 (d, 1 H), 8.69 - 8.74 (d, 1 H), 8.78 - 8.82 (m, 1 H). EXAMPLE 78
3-[(3 ?)-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-oxopropanenitrile
Obtained as a solid (81 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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 following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 9:1 ).
LRMS (m/z): 555 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.32 (m, 1 H), 4.54 (dd, 1 H), 6.83 - 6.95 (m, 1 H), 7.27 (m, 1 H), 7.35 (dd, 1 H), 7.41 (s, 1 H), 8.35 (t, 1 H), 8.53 (dd, 2H), 8.66 (d, 1 H).
EXAMPLE 79
3-((3 ?)-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-oxopropanenitrile
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (0.57 mL, 2.26 mmol) was added to a stirred solution of ie f-butyl 4-[4-(6-{[(3R)-1-(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperazine-1 -carboxylate (Preparation 60, 0.17 g, 0.23 mmol) in 1 ,4-dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 hour. Additional 4.0 M solution of hydrogen chloride in 1 ,4-dioxane (0.57 mL, 2.26 mmol) was added and the reaction mixture was stirred at room temperature for further 2 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and water. 4% Aqueous sodium hydrogen carbonate solution was added until the pH was basic and then the organic layer was separated by Phase Separator and the solvent was evaporated to dryness. The residue was purified by flash chromatography to yield the title compound (56 mg, 43%) as a colourless solid.
LRMS (m/z): 541 (M+1 )+. 1H-NMR δ (300 MHz, DMSO-d6): 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, 1 H), 4.69 (d, 1 H), 7.07 (td, 1 H), 7.31 (d, 1 H), 7.49 (m, 1 H), 7.77 (t, 1 H), 8.36 (dd, 1 H), 8.49 (d, 1 H), 8.78 - 8.95 (m, 2H).
EXAMPLE 80
3-((3 ?)-3-{[6-(2-{4-[3-(Dimethylamino)propyl]piperazin-1 -yl}pyridin-4-yl)-5-fluoro-
2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
A mixture of 3-((3/?)-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-oxopropanenitrile (Example 79, 0.13 g, 0.23 mmol), 3-chloro-/V,/V-dimethylpropan-1 -amine hydrochloride (0.04 g, 0.33 mmol) and sodium hydrogencarbonate (0.06 g, 0.71 mmol) in Λ/,/V-dimethylacetamide (2 mL) was stirred at 90 °C for 25 hours. The crude was purified by reverse phase chromatography (water/methanol as eluents) to give a residue that was repurified by flash chromatography (dichloromethane to dichloromethane/ethanol 6:4) to yield the title compound (24 mg, 16%).
LRMS (m/z): 626 (M+1 )+.
1H-NMR δ (300 MHz, CD3OD): 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, 1 H), 4.60 (m, 2H), 7.02 (m, 1 H), 7.32 (d, 1 H), 7.48 (m, 2H), 8.27 (s, 1 H), 8.55 - 8.70 (m, 3H).
EXAMPLE 81
3-[(3 ?)-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-oxopropanenitrile
Obtained as a solid (25%) from 3-{(3R)-3-[(6-Chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and (2-(4- methyl-1 ,4-diazepan-1 -yl)pyridin-4-yl)boronic acid (Preparation 61 b) following the experimental procedure as described in Preparation 50a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane /methanol/ammonia 40:8:1 ).
LRMS (m/z): 569 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .72 - 1.99 (m, 3H), 2.02 - 2.19 (m, 3H), 2.19 - 2.29 (m, 1 H), 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, 1 H), 3.76 (t, 2H), 3.86 - 4.01 (m, 3H), 4.18 - 4.43 (m, 1 H), 4.94 - 5.30 (m, 1 H), 6.80 - 7.03 (m, 1 H), 7.23 - 7.26 (m, 2H), 7.36 (dd, 1 H), 8.31 (t, 1 H), 8.48 - 8.77 (m, 3H).
EXAMPLE 82
3-{(3 ?)-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]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a light brown solid (20%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by reverse phase chromatography (water to methanol).
LRMS (m/z): 599 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .75 - 1.97 (m, 3H), 1 .98 - 2.13 (m, 3H), 2.18 -
2.32 (m, 1 H), 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, 1 H), 4.96 - 5.30 (m, 1 H), 6.82 - 7.00 (m, 1 H), 7.19 (d, 1 H), 7.24 - 7.31 (m, 1 H), 7.31 - 7.44 (m, 1 H), 8.32 (t, 1 H), 8.47 - 8.78 (m, 3H).
EXAMPLE 83
3-{(3 ?)-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}-3- oxopropanenitrile
Obtained as an orange solid (35%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and (2-(4-(dimethylamino)piperidin-1 -yl)pyridin-4-yl)boronic acid (Preparation 63b) following the experimental procedure described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 95:5 and dichloromethane/metanol/ammonia 100:8:1 ).
LRMS (m/z): 583 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .47 - 1.72 (m, 3H), 1 .76 - 2.08 (m, 6H), 2.16 - 2.29 (m, 1 H), 2.34 (s, 6H), 2.39 - 2.54 (m, 1 H), 2.95 (t, 2 H), 3.34 - 3.54 (m, 2H), 3.56 - 3.76 (m, 1 H), 3.85 - 4.03 (m, 1 H), 4.25 - 4.41 (m, 1 H), 4.40 - 4.62 (m,
2H), 4.95 - 5.21 (m, 1 H), 6.78 - 7.02 (m, 1 H), 7.16 - 7.30 (m, 1 H), 7.31 - 7.42 (m, 1 H), 7.44 (s, 1 H), 8.35 (t, 1 H), 8.48 - 8.78 (m, 3H). EXAMPLE 84
2- {(3 ?)-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
Obtained as a solid (30%) from 2-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-2-oxoethanol (Preparation 64) and {2-[4- (dimethylamino)piperidin-1 -yl]pyridin-4-yl}boronic acid (Preparation 63b) following the procedure described for Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol 95:5 and dichloromethane/metanol/ammonia 100:8:1 ).
LRMS (m/z): 574 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 2.94 (t, 2H), 3.14 - 3.34 (m, 2H), 3.36 - 3.55 (m, 1 H), 3.94 - 4.12 (m, 1 H), 4.19 - 4.38 (m, 3H), 4.46 (d, 2H), 5.14 (t, 1 H), 6.74 - 6.98 (m, 1 H), 7.17 - 7.27 (m, 1 H), 7.29 - 7.39 (m, 1 H), 7.43 (s,
1 H), 8.34 (dd, 1 H), 8.49 - 8.85 (m, 3H).
EXAMPLE 85
3- ((3 ?)-3-{[6-(6-{[4-(Dimethylamino)piperidin-1 -yl]methyl}pyridin-3-yl)-5-fluoro-^ pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (8%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and (6-{[4- (dimethylamino)piperidin-1 -yl]methyl}pyridin-3-yl)boronic acid (Preparation 65b) following the procedure described for Preparation 50a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane /methanol/ammonia 100:8:1 ).
LRMS (m/z): 597 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.21 - 4.44 (m, 1 H), 5.13 (s, 1 H), 6.79 - 7.04 (m, 1 H), 7.35 - 7.45 (m, 1 H), 7.55 - 7.66 (m, 1 H), 8.41 (d, 1 H), 8.48 - 8.79 (m, 3H), 9.34 (d, 1 H). EXAMPLE 86
3-[(3 ?)-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-oxopropanenitrile Obtained as a solid (34%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and [6-(4- methyl-1 ,4-diazepan-1 -yl)pyridin-3-yl]boronic acid (Preparation 66b) following the procedure described for Preparation 50a followed by purification of the crude product by reverse phase chromatography (water to methanol).
LRMS (m/z): 569 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .50 - 1.73 (m, 1 H), 1 .74 - 1.92 (m, 2H), 1.98 - 2.15 (m, 2H), 2.17 - 2.31 (m, 1 H), 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, 1 H), 4.87 - 5.12 (m, 1 H), 6.56 - 6.71 (m, 1 H), 6.79 - 6.99 (m, 1 H), 7.33
- 7.45 (m, 1 H), 8.29 (dd, 1 H), 8.45 - 8.80 (m, 3H), 8.90 - 9.1 1 (m, 1 H).
EXAMPLE 87
3-{(3 ?)-3-[(6-{6-[4-(Dimethylamino)piperidin-1 -yl]pyridin-3-yl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a brownish solid (28%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and {6-[4-(dimethylamino)piperidin-1 -yl]pyridin-3-yl}boronic acid (Preparation 67b) following the procedure described for Preparation 50a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol 95:5 then dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 583 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 2.89 - 3.06 (m, 2H), 3.34 - 3.52 (m, 3H),
3.59 (s, 1 H), 3.74 - 4.06 (m, 1 H), 4.18 - 4.42 (m, 2H), 4.44 - 4.57 (m, 2H), 5.03 (s, 1 H), 6.76 (dd, 1 H), 6.84 - 6.97 (m, 1 H), 7.32 - 7.41 (m, 1 H), 8.29 (d, 1 H), 8.47 - 8.58 (m, 2H), 8.60 (s, 1 H), 9.04 (s, 1 H). EXAMPLE 88
3-{(3 ?)-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-oxopropanenitrile
Obtained as a solid (64%) from (R)-ie/f-butyl (2-(4-((4-(6-((1 -(2-cyanoacetyl)piperidin-3- yl)amino)-5-fluoro-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1 -yl)methyl) phenoxy)ethyl)carbamate (Preparation 69) following the procedure as described in Preparation 39.
LRMS (m/z): 613 (M+1 )+. 1H-NMR δ (300 MHz, DMSO-d6): 1 .41 - 1 .69 (m, 2H), 1.69 - 1 .84 (bs, 1 H), 1.87 - 2.08 (bs, 1 H), 2.35 - 2.63 (m, 6H), 2.64 - 2.79 (m, 1 H), 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, 1 H), 6.74 - 6.83 (m, 1 H), 6.83 - 6.93 (d, 2H), 6.93 - 7.02 (m, 1 H), 7.15 - 7.26 (d, 2H), 7.32 - 7.48 (m, 1 H), 8.29 - 8.42 (m, 1 H), 8.52
- 8.64 (m, 1 H), 8.68 - 8.80 (m, 1 H).
EXAMPLE 89
3-{(3 ?)-3-[(5-Fluoro-6-{4-[1 -(3-hydroxybenzyl)piperidin-4-yl]piperazin-1 -yl}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a solid (40%) from 3-((3R)-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 (Example 39) and 3-hydroxybenzaldehyde following the experimental procedure as described in Example 33 followed by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:1 ).
LRMS (m/z): 654 (M+1 )+.
1H NMR δ (300 MHz, 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, 1 H), 4.01 (br. s, 2H), 4.05 - 4.20 (m, 5H), 4.63 (d, 1 H), 6.55 - 6.88 (m, 3H), 6.95 - 7.12 (m, 2H), 7.33 - 7.48
(m, 1 H), 8.37 (d, 1 H), 8.52 - 8.61 (m, 1 H), 8.74 (t, 1 H).
EXAMPLE 90
3-[(3 ?)-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl] -2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
Obtained as a light brown solid (38%) from 3-{[4-(6-{[2-(dimethylamino)ethyl][(3R)- piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl] methyl}phenol (Preparation 70c) and 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3-oxopropane nitrile following the experimental procedure as described in Preparation 8c.
LRMS (m/z): 642 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 1 .90 - 2.13 (m, 5H), 2.27 - 2.45 (m, 5H), 2.51 - 2.74 (m, 7H), 2.89 (s, 1 H), 2.96 (s, 1 H), 3.27 - 3.50 (m, 1 H), 3.54 (s, 3H), 3.60 - 3.88 (m, 8H), 4.39 - 5.06 (m, 1 H), 6.71 - 6.80 (m, 1 H), 6.81 - 6.96 (m, 3H), 7.16 - 7.36 (m, 2H), 8.32 - 8.54 (m, 3H).
EXAMPLE 91 3-((3 ?)-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
Obtained as a solid (77%) from ie/f-butyl [2-(4-{[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3- yl]amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl} phenoxy)ethyl]methylcarbamate (Preparation 72) following the experimental procedure as described in Preparation 6b followed by flash chromatography (dichloromethane to dichloromethane/methanol/ ammonia 80:20:1 ).
LRMS (m/z): 628 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 2.57 (bs, 6H), 3.06 (t, 1 H), 3.39 (d, 1 H), 3.43 -
3.54 (m, 3H), 3.56 (s, 1 H), 3.69 - 3.83 (m, 5H), 4.14 (t, 1 H), 4.19 (br. s., 1 H),
4.48 - 4.66 (m, 2H), 6.78 - 6.93 (m, 3H), 7.27 - 7.33 (m, 2H), 8.34 (d, 1 H), 8.39 -
8.58 (m, 3H).
EXAMPLE 92
W-[(3 ?)-1 -(3-Aminopropanoyl)piperidin-3-yl]-5-fluoro-6-[4-(4-methylpiperazin-1 -yl) phenyl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
4M Solution of hydrogen chloride in 1 ,4-dioxane (0.4 mL) was added to a solution of (R)-ie/f-butyl (3-(3-((5-fluoro-6-(4-(4-methylpiperazin-1 -yl)phenyl)-2-(pyrazolo[1 ,5-a] pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropyl)carbamate (Preparation 73, 53 mg, 0.08 mmol) in methanol (4 mL) and the resulting mixture was stirred for 3 hours at room temperature. The solvents were evaporated and the residue was purified by flash chromatography (dichoromethane/methanol/ammonia 40:4.0:0.2) to give the title compound (15 mg, 32%) as a yellow solid.
LRMS (m/z): 558 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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 ?)-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- oxopropanenitrile Obtained as a solid (33%) from 3-(6-{[2-(dimethylamino)ethyl][(3R)-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-dioxopyrrolidin-1 -yl)oxy]-3-oxopropanenitrile following the experimental procedure as described in Preparation 8c followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 641 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.78 - 6.98 (m, 2H), 7.20 (s, 1 H), 8.39 - 8.67 (m, 2H).
EXAMPLE 94
3-(6-{[2-(Dimethylamino)ethyl][(3 ?)-1 -glycoloylpiperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1 -yl)phenol
Obtained as a solid (30%) from 3-(6-{[2-(dimethylamino)ethyl][(3R)-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 following the experimental procedure as described in Preparation 64 followed by purification by flash chromatography (gradient from dichloromethane to dichloromethane/methanol /ammonia 100:8:1 ).
LRMS (m/z): 633 (M+2)+.
1H-NMR δ (300 MHz, DMSO-d6): 1 .01 - 1 .43 (m, 1 H), 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, 1 H), 6.96 - 7.1 1 (m, 2H), 7.44 (dd, 1 H), 8.48 (t, 1 H), 8.55 - 8.66 (m, 1 H), 8.80 (d, 1 H), 9.48 (s, 1 H).
EXAMPLE 95
3-((3 ?)-3-{[6-(4-{[4-(Dimethylamino)piperidin-1 -yl]methyl}-3-hydroxyphenyl)-5- fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a yellow solid (14%) from (R)-3-(3-((5-fluoro-6-(4-formyl-3-hydroxyphenyl)- 2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropanenitrile (Preparation 76b) and /V,/V-dimethylpiperidin-4-amine following the experimental procedure as described in Example 33 followed by purification of the crude product by flash chromatography (dichoromethane/methanol/ammonia 40:4.0:0.2). LRMS (m/z): 612 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.61 - 3.71 (m, 1 H), 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, 1 H), 5.04 - 5.17 (d, 1 H), 6.82
- 6.95 (m, 1 H), 7.07 - 7.15 (m, 1 H), 7.32 - 7.41 (m, 1 H), 7.51 - 7.61 (m, 2H), 8.45 - 8.67 (m, 3H), 8.67 - 8.77 (s, 1 H).
EXAMPLE 96
3-((3 ?)-3-{[5-Fluoro-6-(3-hydroxy-5-{[(1 -methylpiperidin-4-yl)amino]methyl} phenyl)-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (87%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ ammonia 85:15:0.5).
LRMS (m/z): 599 (M+1 )+.
1H NMR δ (300 MHz, DMSO): 1 .20-1.39 (m, 3H), 1.50 - 1.95 (m, 5H), 2.05 (d,
1 H), 2.1 1 (s, 3H), 2.22 - 2.46 (m, 2H), 2.53 - 2.79 (m, 3H), 3.04 (dd, 1 H), 3.69 - 3.81 (m, 3H), 3.93 - 4.23 (m, 3H), 4.73 (dd, 1 H), 6.67 - 6.77 (m, 1 H), 6.90 (s, 1 H), 7.0 - 7.10 (m, 1 H), 7.34 (s, 1 H), 7.40 - 7.63 (m, 2H), 8.52 (d, 1 H), 8.65 - 8.87 (m, 2H), 9.61 (d, 1 H).
EXAMPLE 97
3-((3 ?)-3-{[5-Fluoro-6-(4-{(3-hydroxybenzyl)[(1 -methylpiperidin-4-yl)methyl] amino}piperidin-1 -yl)-2^yrazolo[1 ,5-a]pyridin-3-ylpy
1 -yl)-3-oxopropanenitrile
Obtained as a solid (5%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 3-{[[(1 - methylpiperidin-4-yl)methyl](piperidin-4-yl)amino]methyl}phenol (Preparation 78c) following the experimental procedure as described in Example 4 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ) and reverse phase chromatography (gradient from water to methanol).
LRMS (m/z): 696 (M+2)+. 1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 6.49 (d, 1 H), 6.60 - 6.66 (m, 1 H), 6.74 (d, 1 H), 6.79 - 6.94 (m, 1 H), 7.06 - 7.23 (m, 1 H), 7.28 - 7.43 (m, 1 H), 8.33 - 8.69 (m, 3H).
EXAMPLE 98
3-[(3 ?)-3-({5-Fluoro-6-[3-hydroxy-5-({[1 -(3^iperidin-1 -ylpropyl)piperidin-4-yl] amino}methyl)phenyl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino) piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a solid (8%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5).
LRMS (m/z): 710 (M+1 )+.
1H NMR δ (300 MHz, DMSO): 1 .21 - 1 .36 (m, 6-7H), 1.36 - 1 .50 (m, 4H), 1 .65 - 2.10 (m, 1 1 H), 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, 1 H), 6.72 - 6.93 (m, 3H), 7.45 - 7.56 (m, 2H), 7.34
(s, 1 H), 7.40 - 7.63 (m, 2H), 8.52 - 8.72 (m, 3H).
EXAMPLE 99
3-{(3 ?)-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
4.0 M Solution of hydrogen chloride in 1 ,4-dioxane (0.36 mL, 1 .44 mmol) was added to a solution of ie f-butyl {1 -[5-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl}methylcarbamate (Preparation 81 , 80 mg, 0.12 mmol) in 1 ,4-dioxane (3 mL) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness and the residue was partitioned between dichloromethane and 4% aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and the solvent was evaporated to dryness to yield the title compound (0.062 g, 87%) as a solid.
LRMS (m/z): 570 (M+2)+. 1H-NMR δ (300 MHz, CDCI3): 1 .33 - 1.51 (m, 2H), 1 .73 - 1.96 (m, 2H), 1.98 - 2.10 (m, 2H), 2.16 - 2.30 (m, 1 H), 2.51 (s, 3H), 2.62 - 2.78 (m, 1 H), 2.98 - 3.26 (m, 2H), 3.33 - 3.52 (m, 2H), 3.62 - 3.68 (m, 1 H), 3.71 (s, 4H), 3.85 - 4.04 (m, 1 H), 4.26 - 4.67 (m, 3H), 4.95 - 5.07 (m, 1 H), 6.80 (dd, 1 H), 6.84 - 6.96 (m, 1 H), 7.30 - 7.44 (m, 1 H), 8.29 (d, 1 H), 8.49 - 8.58 (m, 2H), 8.66 (d, 1 H), 9.04 (br. s.,
1 H).
EXAMPLE 100
3-{(3 ?)-3-[(5-Fluoro-6-{3-hydroxy-5-[(4^yrrolidin-1 -ylpiperidin-1 -yl)methyl] phenyl}-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a solid (39%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/metanol/ammonia 100:8:1 ).
LRMS (m/z): 638 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.50
(s, 1 H), 3.54 (m, 1 H), 3.60 (m, 1 H), 3.71 - 4.05 (m, 1 H), 4.13 - 4.37 (m, 1 H), 4.99 - 5.23 (m, 1 H), 6.74 - 7.01 (m, 2H), 7.29 - 7.38 (m, 1 H), 7.41 - 7.58 (m, 2H), 8.38 - 8.56 (m, 2H), 8.64 (d, 1 H). EXAMPLE 101
3-(5-Fluoro-6-{[(3 ?)-1 -glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)-5-{[(1 -methylpiperidin-4-yl)amino]methyl}phenol
Obtained as a solid (89%) from 2-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-2-oxoethanol (Preparation 64) and 3-{[(1 -methyl piperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol
(Preparation 77b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5).
LRMS (m/z): 589 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1 .47 - 1 .64 (m, 2H), 1 .67 - 2.21 (m, 9H), 2.30 (s,
3H), 2.55 - 2.63 (m, 1 H), 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, 1 H), 6.79 - 6.89 (m, 1 H), 6.93 (d, 1 H), 7.41 - 7.56 (m, 2H), 8.45 - 8.56 (m, 2H), 8.59 - 8.74 (m, 1 H).
EXAMPLE 102
3-{(3 ?)-3-[(5-Fluoro-6-{4-[3-hydroxy-5-(1 -methylpiperidin-4-yl)benzyl]piperazin-1 - yl}-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
A microwave reactor was charged with 3-{(3R)-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-(piperazin-1 -ylmethyl)phenol (Preparation 83d, 0.216 g, 0.54 mmol) and /V-methylpyrrolidone (1.5 mL). Diisopropylethylamine (0.315 mL, 1 .81 mmol) was added and the reaction mixture was subjected to microwave irradiation for 7 hours at 130 °C, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated to dryness. The resulting crude was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ) to yield the title compound (0.019 g, 15%) as a solid.
LRMS (m/z): 667 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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), 4.1 1 - 4.33 (m, 1 H), 4.46 - 4.73 (m, 1 H), 6.62 (s, 1 H), 6.74 (d, 2H), 6.80 - 6.98 (m, 1 H), 7.21 - 7.40 (m, 1 H), 8.25 - 8.62 (m, 3H). EXAMPLE 103
3-{(3 ?)-3-[(5-Fluoro-6-{3-hydroxy-5-[4-(3-piperidin-1 -ylpropyl)piperazin-1 -yl] phenyl}-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a solid (10%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a.
LRMS (m/z): 682 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.86 - 4.1 1 (m, 1 H), 4.18 - 4.40 (m, 1 H), 4.44 - 4.66 (m, 1 H), 4.99 - 5.21 (m, 1 H), 6.52 (br. s., 1 H), 6.80 - 6.96 (m, 1 H), 7.07 (br. s., 1 H), 7.20 - 7.36 (m, 2H), 8.39 - 8.74 (m, 3H).
EXAMPLE 104
3-{(3 ?)-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- oxopropanenitrile
Obtained as a solid (10%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 3- {[piperidin-4-yl(3-piperidin-1 -ylpropyl)amino]methyl}phenol (Preparation 85c) following the experimental procedure as described in Example 102 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 710 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.41 - 4.75 (m, 3H), 6.64 (d, 1 H), 6.78 (dd, 1 H), 6.83 - 6.93 (m, 1 H), 7.12 (t, 1 H), 7.19 - 7.25 (m, 1 H), 7.29 - 7.37 (m, 1 H), 8.25 - 8.64 (m, 3H).
EXAMPLE 105
3-((3 ?)-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
Obtained as a solid (15%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ) and reverse phase chromatography.
LRMS (m/z): 652 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .16 - 1 .74 (m, 10H), 1.97 - 2.16 (m, 10H), 2.58 (t, 1 H), 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, 1 H), 4.18 - 4.42 (m, 1 H), 5.09 (d, 1 H), 6.81 - 7.05 (m, 2H), 7.30 - 7.39 (m, 1 H), 7.44 (d, 2H), 8.36 - 8.91 (m, 3H). EXAMPLE 106
3-((3 ?)-3-{[5-Fluoro-6-(3-hydroxy-4-{[methyl(1 -methylpiperidin-4-yl)amino]methyl^ phenyl)-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a yellow solid (14%) from (R)-3-(3-((5-fluoro-6-(4-formyl-3-hydroxyphenyl)-
2- (pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropanenitrile (Preparation 76b) and /V,1 -dimethylpiperidin-4-amine following the experimental procedure as described in Example 33 followed by purification of the crude product by flash chromatography (dichoromethane/methanol/ammonia 40:4.0:0.2).
LRMS (m/z): 612 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .69 - 1.91 (m, 7H), 1 .96 - 2.1 1 (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), 3.1 1 - 3.25 (d, 1 H), 3.28 - 3.49 (m, 3H), 3.51 - 3.61 (m, 1 H), 3.61 - 3.76 (m, 2H), 3.84 - 3.93 (s, 2H), 3.93 - 4.05 (m, 1 H), 4.24 -
4.39 (bs, 1 H), 4.54 - 4.67 (dd, 1 H), 5.01 - 5.1 1 (m, 1 H), 6.81 - 6.95 (m, 1 H), 7.05 - 7.16 (m, 1 H), 7.29 - 7.41 (t, 1 H), 7.49 - 7.59 (m, 2H), 8.43 - 8.77 (m, 3H).
EXAMPLE 107
3- {(3 ?)-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
Obtained as a solid (48%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5).
LRMS (m/z): 598 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 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, 1 H), 3.29 - 3.72 (m, 5H), 3.82 - 4.06 (m, 3H), 4.31 (t, 1 H), 5.05 (br. s., 1 H), 6.79 - 6.93 (m, 1 H), 7.1 1 (d, 1 H), 7.34 (d, 1 H), 7.52 - 7.59 (m, 2H), 8.44 - 8.74 (m, 3H).
EXAMPLE 108 3-[(3 ?)-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
Obtained as a solid (67%) from ie/f-butyl 4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl] amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]-1 ,4-diazepane- 1 -carboxylate (Preparation 89) following the experimental procedure as described in Example 99 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 555 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .74 - 2.07 (m, 6H), 2.14 - 2.33 (m, 1 H), 2.83 - 3.00 (m, 2H), 3.05 - 3.19 (m, 2H), 3.19 - 3.34 (m, 1 H), 3.36 - 3.54 (m, 3H), 3.56
- 3.73 (m, 1 H), 3.78 - 4.01 (m, 4H), 4.28 - 4.66 (m, 2H), 5.13 (br. s., 1 H), 6.82 - 6.99 (m, 1 H), 7.13 - 7.23 (m, 1 H), 7.27 (br. s., 1 H), 7.31 - 7.44 (m, 1 H), 8.31 (br. s., 1 H), 8.46 - 8.79 (m, 3H). EXAMPLE 109
3-((3 ?)-3-{[5-Fluoro-6-(3-hydroxy-5-{[methyl(1 -methylpiperidin-4-yl)amino]methyl} phenyl)-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (52%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5).
LRMS (m/z): 612 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1 .64 - 1 .91 (m, 6H), 1 .97 - 2.04 (m, 3H), 2.27 (s, 3H), 2.30 (s, 3H), 2.49 (t, 1 H), 2.97 (d, 2H), 3.19 (dd, 1 H), 3.32 - 3.53 (m, 4H), 3.55 - 3.67 (m, 3H), 3.83 - 4.00 (m, 2H), 4.26 (d, 1 H), 4.52 (dd, 1 H) 5.08 (t, 1 H), 6.79 - 6.98 (m, 2H), 7.29 - 7.37 (m, 2H), 7.46 (d, 1 H), 7.58 (d, 1 H), 8.44 - 8.72 (m, 4H).
EXAMPLE 1 10
3-{(3 ?)-3-[[5-Fluoro-6-(3-hydroxy-5-{[(1 -methylpiperidin-4-yl)amino]methyl} phenyl)-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl](methyl)amino]piperidin-1 -yl}- 3-oxopropanenitrile Obtained as a solid (59%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)(methyl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 91 c) and 3-{[(1 -methylpiperidin-4-yl)amino]methyl}-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenol (Preparation 77b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 80:20:0.2).
LRMS (m/z): 612 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1 .45 - 1.65 (m, 3H), 1.84 - 2.17 (m, 8H), 2.26 - 2.35 (m, 4H), 2.59 (d, 1 H), 2.89 (dd, 2H), 3.17 (dd, 3H), 3.28 (d, 1 H), 3.47 - 3.53 (m, 2H), 3.57 (d, 1 H), 3.75 (s, 1 H), 3.85 (s, 2H), 4.34 - 4.51 (m, 1 H), 6.78 - 6.92 (m, 2H), 6.95 (d, 1 H), 7.40 (d, 1 H), 7.47 (br. s., 1 H), 8.50 (dd, 2H), 8.63 (d, 1 H).
EXAMPLE 1 1 1
3-{(3 ?)-3-[(6-{3-[(Cyclopentylamino)methyl]-5-hydroxyphenyl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridine-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a solid (21 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 569 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.50
(s, 2H), 3.55 - 3.67 (m, 1 H), 3.82 (d, 2H), 3.88 - 4.56 (m, 1 H), 4.22 (s, 1 H), 5.13 (br. s., 1 H), 6.76 - 7.02 (m, 2H), 7.09 - 7.35 (m, 1 H), 7.42 (d, 1 H), 7.55 (d, 1 H), 8.40 - 8.70 (m, 3H). EXAMPLE 1 12
3-[(3 ?)-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-oxopropanenitrile
Obtained as a solid (77%) from ie/f-butyl 4-[3-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3- yl]amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-5-hydroxybenzyl]-1 ,4- diazepane-1 -carboxylate (Preparation 94) following the experimental procedure as described in Preparation 6b followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 80:20:1 ). LRMS (m/z): 584 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1 .77 - 1.86 (m, 6H), 2.12 - 2.26 (m, 1 H), 2.73 - 2.77 (m, 3H), 2.95 - 3.04 (m, 3H), 3.14 - 3.27 (m, 1 H), 3.31 - 3.44 (m, 2H), 3.46 (s, 2H), 3.63 (d, 1 H), 3.70 (d, 2H), 3.87 (dd, 1 H), 4.24 -4.33 (m, 1 H), 4.52 (dd, 1 H), 6.88 (dd, 1 H), 7.05 (d, 1 H), 7.32 (d, 1 H), 7.50 (d, 2H), 8.42 - 8.58 (m, 2H),
8.59 - 8.73 (m, 1 H).
EXAMPLE 1 13
3-((3/?)-3-{[6-(3-{6-[4-(Dimethylamino)piperidm^
-5-fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
A microwave reactor was charged with 3-{(3R)-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 mmol), 2M aqueous cesium carbonate solution (0.25 mL, 0.50 mmol) and 1 ,4-dioxane (3 mL). The reactor was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride complex with dichloromethane (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the reactor was sealed and the reaction mixture was subjected to microwave irradiation for 2 hours at 140 °C, filtered through diatomaceous earth (Celite®) and evaporated to dryness. The residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol /ammonia 400:25:1 ) to yield the title compound (0.025 g, 22%) as a solid.
LRMS (m/z): 675 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .48 - 1 .66 (m, 3H), 1 .70 - 1 .87 (m, 3H), 1 .96 (d, 4H), 2.15 - 2.27 (m, 1 H), 2.35 (s, 6H), 2.39 - 2.52 (m, 1 H), 3.1 1 - 3.43 (m, 2H), 3.47 (d, 1 H), 3.60 (s, 1 H), 3.82 - 4.09 (m, 1 H), 4.18 - 4.63 (m, 4H), 5.09 - 5.25 (m, 1 H), 6.72 (d, 1 H), 6.78 - 6.94 (m, 1 H), 7.10 (d, 1 H), 7.30 - 7.38 (m, 1 H), 7.52 (br. s., 1 H), 7.66 - 7.85 (m, 2H), 8.42 - 8.57 (m, 3H), 8.66 (d, 1 H).
EXAMPLE 1 14
3-{(3 ?)-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
A mixture of 3-[(3R)-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-oxopropanenitrile (Example 1 12, 0.03 g, 0.05 mmol), formaldehyde (0.008 ml_, 0.1 1 mmol) and acetic acid (0.05 mL) in tetrahydrofuran (0.20 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.033 g, 0.16 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours before being partitioned between dichloromethane and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5) to yield the title compound (0.027 g, 85%).
LRMS (m/z): 598 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1 .73 - 2.06 (m, 6H), 2.08 (s, 3H), 2.55 (s, 2H), 2.73 - 2.85 (m, 3H), 2.92 (d, 1 H), 2.98 (d, 1 H), 3.20 - 3.30 (m, 1 H), 3.32 - 3.47 (m, 2H), 3.49 (s, 2H), 3.59 (s, 1 H), 3.70 (d, 1 H), 3.92 (t, 1 H), 4.22 - 4.36 (m, 1 H), 4.44 - 4.56 (m, 1 H), 5.12 (d, 1 H), 6.86 (dd, 1 H), 7.08 - 7.18 (m, 2H), 7.30 - 7.39 (m, 1 H), 7.51 (s, 1 H), 8.48 - 8.57 (m, 2H), 8.59 - 8.72 (m, 1 H).
EXAMPLE 1 15
3-{(3 ?)-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
Obtained as a solid (40%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Preparation 45a followed by flash chromatography (dichloromethane to dichloromethane/methanol/ ammonia 40:8:0.5)
LRMS (m/z): 598 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 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, 1 H), 4.56 (dd, 1 H), 5.00 - 5.05 (m, 1 H), 6.69 - 7.00 (m, 3H), 7.37 (d, 1 H), 7.82 (s, 1 H), 8.01 (d, 1 H), 8.49 - 8.58 (m, 2H), 8.61 - 8.73 (m, 1 H).
EXAMPLE 1 16
1 -methylpiperidin-4-yl 1 -[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fl 2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]piperidine-4-carboxylate Obtained as a greenish solid (32%) from (R)-3-(3-((5-fluoro-6-(4-formyl-3-hydroxy phenyl)-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropane nitrile (Preparation 48b) and 1 -methylpiperidin-4-yl piperidine-4-carboxylate (Preparation 97b) following the experimental procedure as described in Preparation 40a followed by purification of the crude product by flash chromatography (dichoromethane/methanol /ammonia 40:4.0:0.2).
LRMS (m/z): 694 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.32 - 3.52 (m, 2H), 3.54 - 3.61 (s, 2H), 3.61 - 3.77 (m, 2H), 3.85
- 4.04 (m, 1 H), 4.24 - 4.40 (bs, 1 H), 4.51 - 4.63 (dd, 2H), 4.72 - 4.87 (m, 2H), 5.00 - 5.12 (bs, 2H), 6.80 - 6.97 (m, 1 H), 7.30 - 7.42 (t, 1 H), 7.42 - 7.55 (t, 2H), 8.02 - 8.13 (d, 2H), 8.46 - 8.78 (m, 3H).
EXAMPLE 1 17
3-{(3 ?)-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- oxopropanenitrile
Obtained as a solid (16%) from ie/f-butyl {1 -[5-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl] amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)pyridin-2-yl]piperidin-4-yl} cyclopentylcarbamate (Preparation 99) following the experimental procedure as described in Example 99 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/metanol/ammonia 100:8:1 ).
LRMS (m/z): 623 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 2.72 - 2.94 (m, 1 H), 2.95
- 3.12 (m, 2H), 3.13 - 3.35 (m, 2H), 3.38 - 3.74 (m, 5H), 3.84 - 4.05 (m, 1 H), 4.19 - 4.52 (m, 3H), 4.90 - 5.10 (m, 1 H), 6.75 - 6.83 (m, 1 H), 6.83 - 6.96 (m,
1 H), 7.30 - 7.43 (m, 1 H), 8.28 (d, 1 H), 8.46 - 8.58 (m, 2H), 8.66 (d, 1 H), 8.92 - 9.09 (m, 1 H).
EXAMPLE 1 18
3-((3 ?)-3-{[6-(3-{[4-(Dimethylamino)piperidin-1 -yl]methyl}-4-hydroxyphenyl)-5- fluoro-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile Obtained as a solid (26%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Example 1 13 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/metanol/ammonia 100:8:1 ).
LRMS (m/z): 612 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.58 (dd, 1 H), 5.03 (t, 1 H), 6.76 - 7.02 (m,
3H), 7.32 - 7.42 (m, 1 H), 7.85 (s, 1 H), 7.96 - 8.06 (m, 1 H), 8.47 - 8.62 (m, 2H), 8.68 (d, 1 H).
EXAMPLE 1 19
3-[(3 ?)-3-({5-Fluoro-6-[3-hydroxy-4-(piperazin-1 -ylmethyl)phenyl]-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
Obtained as a solid (43%) from ie/f-butyl 4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl] amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-2-hydroxybenzyl] piperazine-1 -carboxylate (Preparation 102) following the experimental procedure as described in Example 99 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/metanol/ammonia 100:8:1 ).
LRMS (m/z): 570 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .46 - 2.09 (m, 7H), 2.15 - 2.37 (m, 1 H), 2.51 -
2.77 (m, 3H), 2.99 (s, 3H), 3.32 - 3.50 (m, 4H), 3.57 - 3.74 (m, 1 H), 3.80 (d, 2H), 3.88 - 4.10 (m, 1 H), 4.21 - 4.44 (m, 1 H), 5.08 (d, 1 H), 6.82 - 6.96 (m, 1 H), 7.1 1 - 7.21 (m, 1 H), 7.32 - 7.44 (m, 1 H), 7.49 - 7.64 (m, 2H), 8.46 - 8.61 (m, 2H), 8.61 - 8.77 (m, 1 H).
EXAMPLE 120
3-((3 ?)-3-{[5-fluoro-6-(3-hydroxy-4-{[(1 -methylpiperidin-4-yl)amino]methyl}phenyl)
-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (75%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and (3- hydroxy-4-{[(1 -methylpiperidin-4-yl)amino]methyl}phenyl)boronic acid (Preparation 103b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 40:8:0.5).
LRMS (m/z): 598 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 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, 1 H), 2.86 (d, 2H), 3.17 (dd, 1 H), 3.31 - 3.51 (01, 31-1), 3.59 (s, 1 H) 3.62 - 3.71 (m, 1 H), 3.87 - 4.05 (m, 1 H), 4.12 (d, 2H), 4.29 (b.s., 1 H), 4.61 (dd, 1 H), 5.06 (d, 1 H), 6.89 (dd, 1 H), 7.14 (dd, 1 H), 7.31 - 7.40 (m, 1 H), 7.54 - 7.60 (m, 2H) 8.49 - 8.58 (m, 2H), 8.59 - 8.75 (m, 1 H).
EXAMPLE 121
Ethyl 1'-[4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl)benzyl]-4-methyl-1 ,4'-bipiperidine-4-carboxylate
Obtained as a greenish solid (31 %) from (R)-3-(3-((5-fluoro-6-(4-formyl-3-hydroxy phenyl)-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3-oxopropane nitrile (Preparation 48b) and ethyl 4-methyl-[1 ,4'-bipiperidine]-4-carboxylate dihydrochloride (Preparation 104c) following the experimental procedure as described in Preparation 40a followed by purification of the crude product by flash chromatography (dichoromethane/methanol/ammonia 40:4:0.2).
LRMS (m/z): 722 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 3.32 - 3.51 (m, 3H), 3.51 - 3.73 (m, 3H), 3.85 - 4.03 (m, 1 H), 4.07 - 4.23 (q, 2H), 4.23 - 4.41 (bs, 1 H), 4.51 - 4.64 (d, 1 H), 4.99
- 5.15 (m, 2H), 6.80 - 6.98 (m, 1 H), 7.31 - 7.42 (t, 1 H), 7.42 - 7.53 (t, 2H), 8.00 - 8.13 (d, 2H), 8.47 - 8.80 (m, 3H).
EXAMPLE 122
3-[(3 ?)-3-({5-Fluoro-6-[4-[(4-methyl-1 ,4-diazepan-1 -yl)methyl]-3-(methylthio) phenyl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
Obtained as a light brown solid (37%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-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) following the experimental procedure as described in Example 1 13 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 628 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .75 - 2.05 (m, 5H), 2.17 - 2.31 (m, 1 H), 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, 1 H), 4.21 - 4.44 (m, 1 H), 4.98 - 5.17 (m, 1 H), 6.83 - 6.97 (m, 1 H), 7.32 - 7.40 (m, 1 H), 7.51 (t, 1 H), 7.86 (d, 1 H), 8.06 (s, 1 H), 8.45 - 8.80 (m, 3H).
EXAMPLE 123
3-[(3 ?)-3-({5-Fluoro-6-[3-[(4-methyl-1 ,4-diazepan-1 -yl)methyl]-4-(methylthio) phenyl]-2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
Obtained as a solid (26%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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) following the experimental procedure as described in Example 1 13 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 40:8:1 ).
LRMS (m/z): 628 (M+1 )+.
EXAMPLE 124
3-[(3/?)-3-({6-[4-({2-[4-(Dimethylamin^
pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3- oxopropanenitrile
Obtained as a solid (17%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and [4-({2-[4- (dimethylamino)piperidin-1 -yl]ethyl}thio)phenyl]boronic acid (Preparation 107b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/metanol/ammonia 40:8:1 ) and reverse phase chromatography (water to metanol).
LRMS (m/z): 642 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 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, 1 H), 3.02 (d, 2H), 3.12 - 3.17 (m, 2H), 3.24 (dd, 1 H), 3.34 - 3.52 (m, 3H), 3.59 (s, 1 H), 3.61 - 3.70 (m, 1 H), 3.91 (d,
1 H), 4.32 (br. s., 1 H), 4.56 (dd, 1 H), 5.07 (td, 1 H), 6.82 - 6.95 (m, 1 H), 7.32 - 7.40 (m, 1 H) 7.45 (dd, 2H), 8.07 (d, 2H), 8.50 - 8.59 (m, 2H), 8.60 - 8.74 (m, 1 H).
EXAMPLE 125
3-{(3 ?)-3-[(6-{6-[4-(Dimethylamino)piperidin-1 -yl]-5-hydroxypyridin-3-yl}-5-flu 2^yrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
Obtained as a solid (1 1 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and {6-[4- (dimethylamino)piperidin-1 -yl]-5-hydroxypyridin-3-yl}boronic acid (Preparation 108d) following the experimental procedure as described in Example 1 13 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 599 (M+2)+.
1H-NMR δ (300 MHz, CDCI3): 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), 3.1 1 - 3.52 (m, 3H), 3.57 - 3.71 (m, 1 H),
3.71 - 4.04 (m, 3H), 4.23 - 4.43 (m, 1 H), 5.12 (d, 1 H), 6.82 - 6.96 (m, 1 H), 7.29 -
7.42 (m, 1 H), 7.88 (s, 1 H), 8.44 - 8.76 (m, 4H). EXAMPLE 126
3-[(3 ?)-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-oxopropanenitrile
A solution of 3-[(3R)-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 propan-2-one (0.012 mL, 0.16 mmol) in dichloromethane (0.70 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxiborohydride (0.045 g, 0.21 mmol) was added and the mixture was stirred at room temperature overnight. Additional propan-2-one (0.012 mL, 0.16 mmol) and sodium triacetoxyborohydride (0.045 g, 0.21 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo and the residue was purified by flash chromatography (gradient from dichloromethane to dichloromethane/methanol /ammonia 40:8:1 ) to yield the title compound (0.034 g, 42%) as a solid.
LRMS (m/z): 597 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .04 (d, 6H), 1 .76 - 2.1 1 (m, 5H), 2.16 - 2.31 (m, 1 H), 2.57 - 2.71 (m, 2H), 2.76 - 2.90 (m, 2H), 2.91 - 3.08 (m, 1 H), 3.19 - 3.54
(m, 3H), 3.56 - 3.71 (m, 2H), 3.73 - 4.02 (m, 5H), 4.27 - 4.62 (m, 1 H), 5.03 - 5.20 (m, 1 H), 6.84 - 6.98 (m, 1 H), 7.1 1 - 7.20 (m, 1 H), 7.27 (s, 1 H), 7.35 (t, 1 H), 8.31 (t, 1 H), 8.49 - 8.77 (m, 3H).
EXAMPLE 127
3-{(3 ?)-3-[(6-{4-[(Cyclopentylamino)methyl]-3-hydroxyphenyl}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Obtained as a solid (1 1 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 2-[(cyclo pentylamino)methyl]-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (Preparation 1 10b) following the experimental procedure as described in Example 1 13 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 569 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .37 - 2.05 (m, 13H), 2.12 - 2.32 (m, 1 H), 3.08 - 3.27 (m, 1 H), 3.32 - 3.64 (m, 5H), 3.87 - 4.04 (m, 1 H), 4.07 (d, 2H), 4.25 - 4.42
(m, 1 H), 5.05 (dd, 1 H), 6.81 - 6.97 (m, 1 H), 7.09 - 7.22 (m, 1 H), 7.32 - 7.42 (m, 1 H), 7.52 - 7.64 (m, 2H), 8.45 - 8.76 (m, 3H).
EXAMPLE 128
3-{(3 ?)-3-[(6-{3-[(Cyclopentylamino)methyl]-4-hydroxyphenyl}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Obtained as a solid (1 1 %) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile (Preparation 6c) and 2-[(cyclo pentylamino)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (Preparation 109b) following the experimental procedure as described in Example 1 13 followed by purification of the crude product by flash chromatography (gradient from dichloromethane to dichloromethane/methanol/ammonia 100:8:1 ).
LRMS (m/z): 569 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .41 - 1.66 (m, 4H), 1 .70 - 1.87 (m, 5H), 1.86 - 2.03 (m, 5H), 2.13 - 2.33 (m, 1 H), 3.13 - 3.28 (m, 1 H), 3.32 - 3.52 (m, 3H), 3.54
- 3.74 (m, 1 H), 3.85 - 4.00 (m, 1 H), 4.12 (s, 2H), 4.25 - 4.43 (m, 1 H), 4.93 - 5.1 1 (m, 1 H), 6.82 - 7.03 (m, 2H), 7.33 - 7.42 (m, 1 H), 7.86 (s, 1 H), 7.92 - 8.06 (m, 1 H), 8.49 - 8.61 (m, 2H), 8.68 (d, 1 H). EXAMPLE 129
Piperidin-4-yl 4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate 4M Solution of hydrogen chloride in 1 ,4-dioxane (3.37 mL) was added to a solution of (R)-ieri-butyl 4-((4-(6-((1 -(2-cyanoacetyl)piperidin-3-yl)amino)-5-fluoro-2-(pyrazolo[1 ,5- a]pyridin-3-yl)pyrimidin-4-yl)benzoyl)oxy)piperidine-1 -carboxylate (Preparation 1 12, 0.46 g, 0.67 mmol) in propan-2-ol (10 mL) and the resulting mixture was stirred for 3 hours at 40 °C. The solvents were evaporated and the residue was treated with diethyl ether, filtered and washed with ethyl acetate and acetonitrile. The solid was dissolved in water and the aqueous solution was basified by addition of solid sodium hydrogen carbonate. The precipitate formed was filtered and purified by flash chromatography (dichoromethane/methanol/ammonia 40:4.0:0.2) to yield the title compound (40 mg, 22%).
LRMS (m/z): 583 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .56 - 1.99 (m, 3H), 1 .99 - 2.15 (m, 2H), 2.15 - 2.31 (m, 1 H), 2.37 - 2.53 (bs, 1 H), 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, 1 H), 4.25 - 4.43 (bs, 2H), 4.50 - 4.65 (d, 1 H), 5.04 - 5.26 (m, 2H), 6.80 - 6.99 (m, 1 H), 7.32 - 7.45 (t,
1 H), 8.08 - 8.31 (s, 4H), 8.45 - 8.80 (m, 3H).
EXAMPLE 130
3-{(3 ?)-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
Obtained as a solid (9%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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 1 13b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 85:15:1 ) and reverse phase chromatography (water to metanol).
LRMS (m/z): 515 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1 .69 - 2.04 (m, 6H), 2.14 - 2.31 (m, 2H), 2.43 - 2.59 (m, 3H), 3.16 (d, 1 H), 3.30 - 3.74 (m, 5H), 4.06 (d, 2H), 4.30 (br. s., 1 H),
4.62 (d, 1 H), 4.98 - 5.10 (m, 1 H), 6.82 - 6.94 (m, 1 H), 7.08 - 7.21 (m, 1 H), 7.35 (d, 1 H), 7.52 - 7.61 (m, 2H), 8.47 - 8.74 (m, 3H).
EXAMPLE 131
1 '-Methyl-1 ,4'-bipiperidin-4-yl 4-(6-{[(3 ?)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate Obtained as a white solid (46%) from piperidin-4-yl 4-(6-{[(3R)-1 -(cyanoacetyl)piperidin- 3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate (Example 129) and 1 -methylpiperidin-4-one following the experimental procedure as described in Example 33 followed by purification of the crude product by flash chromatography (dichoromethane/methanol/ammonia 40:4.0:0.2).
LRMS (m/z): 480 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 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, 1 H), 4.24 - 4.43 (bs, 1 H), 4.51 - 4.64 (d, 1 H), 4.68 - 4.78 (s, 1 H), 4.98 - 5.23 (m, 2H), 6.82 - 7.00 (m, 1 H), 7.32 - 7.45 (t, 1 H),
8.03 - 8.34 (s, 4H), 8.40 - 8.78 (m, 3H)
EXAMPLE 132
3-((3 ?)-3-{[5-Fluoro-6-(3-hydroxy-4-{[methyl(pyridin-4-yl)amino]methyl}phenyl)-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
Obtained as a solid (7%) from 3-{(3R)-3-[(6-chloro-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-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 1 14b) following the experimental procedure as described in Preparation 45a followed by purification of the crude product by flash chromatography (dichloromethane to dichloromethane/methanol/ammonia 85:15:1 ) and reverse phase chromatography (water to metanol).
LRMS (m/z): 592 (M+1 )+.
1H NMR δ (300 MHz, CDCI3) 1 .66 - 2.03 (m, 4H), 2.08 - 2.26 (m, 1 H), 3.09 (s,
3H), 3.30 - 3.53 (m, 2H), 3.54 - 3.73 (m, 2H), 3.85 (dd, 1 H), 4.30 (br. s., 1 H), 4.50 (d, 1 H), 4.65 (br. s., 2H), 6.59 - 6.64 (m, 2H), 6.86 (dd, 1 H), 7.06 (dd, 1 H), 7.28 - 7.37 (m, 1 H), 7.44 - 7.68 (m, 2H), 8.16 (br. s., 2H), 8.41 - 8.69 (m, 3H). EXAMPLE 133
3-{(3 ?)-3-[(5-Fluoro-6-{4-[(5-fluoro-2-hydroxybenzyl)amino]piperidin-1 -yl}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3- oxopropanenitrile
A suspension of (R)-3-(3-((6-chloro-5-fluoro-2-(pyrazolo[1 ,5-a]pyridin-3-yl)pyrimidin-4- yl)amino)piperidin-1 -yl)-3-oxopropanenitrile (Preparation 6c, 0.1 g, 0.24 mmol), 4- fluoro-2-((piperidin-4-ylamino)methyl)phenol dihydrochloride (Preparation 1 15b, 0.14 g, 0.47 mmol) and sodium hydrogencarbonate (0.1 g, 1 .19 mmol) in Ν,Ν'- dimethylacetamide (1 mL) was stirred at 80 °C for 24 hours. Additional sodium hydrogencarbonate (0.1 g) was added and the suspension was stirred at 80 °C for further 24 hours. Excess of water was added and the resulting precipitate was filtered, washed with water and purified by flash chromatography (dichoromethane/methanol /ammonia 40:4:0.2) to yield the title compound (87 mg, 53%) as a solid.
LRMS (m/z): 602 (M+1 )+.
1H-NMR δ (300 MHz, CDCI3): 1 .36 - 1.69 (m, 3H), 1 .69 - 1.99 (m, 4H), 2.02 - 2.23 (m, 3H), 2.74 - 2.92 (m, 1 H), 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, 1 H), 4.34
- 4.53 (m, 2H), 4.57 - 4.73 (m, 1 H), 6.65 - 6.80 (m, 2H), 6.80 - 6.94 (m, 2H), 7.29 - 7.37 (m, 1 H), 8.29 - 8.62 (m, 3H).
EXAMPLE 134
3-{(3 ?)-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-oxopropanenitrile
Obtained as a solid (75%) from ie f-butyl [5-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl] amino}-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-2-hydroxybenzyl]methyl carbamate (Preparation 1 17) following the experimental procedure as described in Preparation 6b followed by flash chromatography (dichloromethane to dichloromethane /methanol/ammonia 80:20:1 ).
LRMS (m/z): 515 (M+1 )+.
1H NMR δ (300 MHz, CDCI3): 1.72 - 1.98 (m, 3H), 2.21 (t, 1 H), 2.54 (s, 3H), 3.15 - 3.26 (m, 1 H), 3.38 - 3.50 (m, 3H), 3.59 (s, 1 H), 3.65 (d, 1 H), 3.87 - -3.97 (m, 1 H), 4.1 1 (s, 1 H), 4.31 (br. s., 1 H), 4.51 - 4.62 (m, 1 H), 5.01 (d, 1 H), 6.84 -
6.89 (m, 2H), 7.33 - 7.39 (m, 1 H), 7.86 (s, 1 H), 7.95 - 8.04 (m, 1 H), 8.47 - 8.61 (m, 2H), 8.61 - 8.75 (m, 1 H).
EXAMPLE 135
3-{[4-(Cyclopentylamino)piperidin-1 -yl]methyl}-5-(5-fluoro-6-{[(3 ?)-1 -glycoloyl piperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenol
EXAMPLE 136
3-((3 ?)-3-{{5-Fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl]-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl}[2-(methylamino)ethyl]amino}piperidin-1 -yl)-3- oxopropanenitrile EXAMPLE 137
3-{[4-(5-Fluoro-6-{[(3 ?)-1 -glycoloylpiperidin-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 ?)-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-oxopropanenitrile
EXAMPLE 139
2-((3 ?)-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
PHARMACOLOGICAL ACTIVITY
In vitro JAK kinase Assays
Compounds were screened for their ability to inhibit JAK1 , JAK2 and JAK3 using the assays as indicated below.
The catalytic domains of human JAK1 (aa 850-1 154), JAK2 (aa 826-1 132), JAK3 (aa 795-1 124) and Tyk2 (aa 871 -1 187) were expressed as N-terminal GST-fusion proteins using a baculovirus expression system and were purchased from Carna Biosciences. The enzymatic activity was assayed using as substrate a biotinylated peptide, poly (GT)-Biotin (CisBio). The peptide concentration in the reactions was 60 nM for JAK1 , 20 nM for JAK2, 140 nM for JAK3 and 50 nM for Tyk2. The degree of phosphorylation was detected by TR-FRET (time-resolved fluorescence energy transfer).
IC50s of compounds were measured for each kinase in a reaction mixture containing the enzyme, ATP and the peptide in 8 mM MOPS (pH 7.0), 10 mM MgCI2, 0.05% β- mercaptoethanol, 0.45 mg/ml BSA. The ATP concentration in the reactions was 3 μΜ for JAK1 , 0.2 μΜ for JAK2, 0.6 μΜ for JAK3 and 1.8 μΜ for Tyk2. The enzymatic reactions took place for 30 minutes at room temperature. Then, the reactions were stopped with 20 μί of quench detection buffer (50 mM HEPES, 0.5 M KF, EDTA 0.25 M, 0.1 % (w/v) BSA, pH 7.5) containing 0.1 15 μg/mL of anti-phosphoTyr (PT66)- Cryptate (CisBio) and a variable concentration of SA-XL665 (CisBio) to keep the SA-B ratio constant. Incubate for 3 h and read on Victor 2V spectrofluorometer (PerkinElmer) set to read fluorescence resonance energy transfer. Some of the acronyms used above have the following meaning:
AA: aminoacids
GST: glutathione-S-transferase
MOPS: 3-(N-morpholino)propane sulfonic acid
BSA: bovine serum albumin
ATP: adenosine tri-phosphate
EDTA: ethylenediaminetetraacetic acid
HEPES: 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid
SA-XL665: Streptavidin (biotin-binding tetrameric protein isolated from Streptomyces avidinii) XL665
Table 1 depicts IC50 values for certain exemplary compounds described in the invention. In Table 1 , "A" represents an IC50 value of less than 0.1 μΜ (100 nM), "B" represents an IC50 value in the range of 0.1 μΜ (100 nM) to 1 μΜ (1000 nM), and C represents an IC50 value higher than 1 μΜ (1000 nM).
Table 1
Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(μΜ) (μΜ) (μΜ)
1 A A A
6 A A A
8 A A A
14 B A C
20 A A B
24 A A B
28 A A A
34 A A A
37 A A A
41 A A A
42 A A A
46 A A A
47 A A A
49 A A A
51 A A A
54 A A A
57 A A A Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1
(μΜ) (μΜ) (μΜ)
63 A A A
66 A A B
69 A A B
77 A A A
82 A A A
85 A A A
92 B A C
94 B A A
97 A A C
110 A A A
119 A A A
120 A A A
123 A A A
125 A A A
129 A A A
It can be seen from Table 1 that the compounds of formula (I) are potent inhibitors of JAK1 , JAK2 and JAK3 kinases. Preferred compounds of the invention possess an IC50 value for the inhibition of JAK1 , JAK2 and JAK3 kinases (determined as defined above) of less than 1 μΜ (1000 nM), preferably of less than 0.5 μΜ (500 nM), more preferably of less than 0.2 μΜ (200 nM) for each Janus Kinase.
The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
Combinations
The compounds of the present invention may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases. The combinations of the invention can 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 mielofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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, such as (a) Dyhydrofolate reductase inhibitors, such as
Methotrexate or CH-1504; (b) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide, or the compounds described in the International Patent Application Nos. WO2008/077639 and WO2009/021696; (c) Immunomodulators such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; (d) Inhibitors of DNA synthesis and repair, such as Mitoxantrone or Cladribine; (e) Immunosuppressants, such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP); (f) Anti-alpha 4 integrin antibodies, such as Natalizumab (Tysabri); (g) Alpha 4 integrin antagonists such as R-1295 , TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; (h) Corticoids and glucocorticoids such as prednisone or methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide or beta-metasone; (i) Fumaric acid esters, such as BG-12; (j) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha), such as Infliximab, Adalimumab, or Certolizumab pegol; (k) Soluble Tumor necrosis factor-alpha (TNF- alpha) receptors such as Etanercept; (I) Anti-CD20 (lymphocyte protein) monoclonal antibodies such as Rituximab, Ocrelizumab 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-lnterleukin 6 Receptor (IL-6R), such as tocilizumab; (q) Anti-lnterleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R), such as ustekinumab; (r) Calcineurin inhibitors such as cyclosporine A, pimecrolimus or tacrolimus; (s) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, 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-kappaB (NF-kappaB or NFKB) Activation Inhibitors such as
Sulfasalazine, Iguratimod or MLN-0415; (x) Adenosine A2A agonists, such as ATL-313, ATL-146e, CGS-21680, Regadenoson or UK-432,097; (y) Sphingosine-1 (S1 P) phosphate receptor agonists such as fingolimod, BAF-312, or ACT128800; (z) Sphingosine-1 (S1 P) liase inhibitors such as LX2931 ; (aa) Spleen tyrosine kinase (Syk) inhibitors, such as R-1 12; (bb) Protein Kinase Inhibitors (PKC) inhibitors, such as NVP- AEB071 ; (cc) Anti-cholinergic agents such as tiotropium or aclidinium; (dd) Beta adrenergic agonists such as formoterol, indacaterol or abediterol (LAS100977); (ee) Compounds having bifunctional Muscarinic Antagonist-Beta2 Agonist activity (MABAs); (ff) Histamine 1 (H 1 ) receptor antagonists, such as azelastine or ebastine; (gg) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981 , ACT-129968, QAV-680; (hh) Vitamin D derivatives like 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, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib- 1 or valdecoxib; (jj) Anti-allergic agents; (kk) Anti-viral agents; (II) Phosphodiestearase (PDE) III inhibitors; (mm) Phosphosdiesterase (PDE) IV inhibitors such as AN2728, E- 6005, DRM02 roflumilast or GRC-4039; (nn) Dual Phosphodiestearase (PDE) lll/IV inhibitors; (oo) Xanthine derivatives, such as theophylline or theobromine; (pp) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors such as ARRY-797; (qq) Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, such as ARRY-142886 or ARRY-438162; (rr) Phosphoinositide 3-Kinases (PI3Ks) inhibitors; (ss) Interferons comprising Interferon beta 1 a such as Avonex from Biogen Idee,
CinnoVex from CinnaGen and Rebif from EMD Serono, and Interferon beta 1 b such as Betaferon from Schering and Betaseron from Berlex; (tt) Interferon alpha such as Sumiferon MP, (uu) TrkA (NGF receptor) inhibitors 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 the combinations of the invention may be used in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, wherein the use of a JAK inhibitor is expected to have a beneficial effect, for example rheumatoid arthritis, multiple sclerosis, 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 product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
It is contemplated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered together at the same time. Preferably, at least two, and more preferably all actives would be administered as an admixture. The invention is also directed to a combination product of the compounds of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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 encompasses the use of a combination of the compounds of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases. The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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; comprising administering a therapeutically effective amount of a combination of the compounds of the invention together with one or more other therapeutic agents. The active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc), preferably by inhalation.
The active compounds in the combination, i.e. the pyrazolopyrimidin-2-yl derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
One execution of the present invention consists of a kit of parts comprising a pyrazolopyrimidin-2-yl derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular useful in the treatment 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.
Another execution of the present invention consists of a package comprising a pyrazolopyrimidin-2-yl derivative of the invention and another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular useful in the treatment 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.
Pharmaceutical Compositions Pharmaceutical compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier. As used herein, the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers, deuterated derivatives thereof or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate 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 an organism and does not abrogate the biological activity and properties of the administered compound.
The invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), such as the ones previously described.
The invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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 encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases.
The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein 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, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application. Preferably the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration.
Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 .
The pharmaceutically acceptable excipients which are admixed with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001. i) Oral Administration
The compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.
Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art. The active ingredient may also be presented as a bolus, electuary or paste.
Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium
carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste- masking agents.
Exemplary tablets 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 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated. The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980.
Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule. Where the composition is in the form of a soft gelatine capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1 -14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such
formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. ii) Oral mucosal administration
The compounds of the invention can also be administered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug
administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.
Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others) iii) Inhaled administration
The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using
electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable 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 agent, for example, chitosan or cyclodextrin.
Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred. Each capsule or cartridge may generally contain between 0.001 -50 mg, more preferably 0.01 -5 mg of active ingredient or the equivalent amount of a
pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients.
Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
For inhalers of the first type, single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatine capsules. A capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler. Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After inhalation, the emptied capsule has to be removed from the inhaler again. Mostly, disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients. Other drawbacks related to the use of hard gelatine capsules for inhalation powders are (a) poor protection against moisture uptake from the ambient air, (b) problems with opening or perforation after the capsules have been exposed previously to extreme relative humidity, which causes fragmentation or indenture, and (c) possible inhalation of capsule fragments. Moreover, for a number of capsule inhalers, incomplete expulsion has been reported (e. g. Nielsen et al, 1997). Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 2242134). They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip.
Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles exist, including rotatable membranes (Ex. EP0069715) or disks (Ex. GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (Ex. EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustums (Ex. WO
92/00771 ), all having cavities which have to be filled with powder from the container. Other multi dose devices have measuring slides (Ex. US 5201308 and WO 97/00703) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit (Ex. EP 0505321 , WO 92/04068 and WO 92/04928), or measuring slides such as the Genuair® (formerly known as Novolizer SD2FL), which is described the following patent applications Nos: WO97/000703, WO03/000325 and WO2006/008027.
Reproducible dose measuring is one of the major concerns for multi dose inhaler devices. The powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity.
For reloaded single dose and multiple unit dose inhalers, the dose measuring accuracy and reproducibility can be guaranteed by the manufacturer. Multi dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
Because the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers can not be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge.
Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multi- dose devices, powder adhesion onto the inner walls of the air conduits and the de- agglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers that can be replaced after the prescribed number of doses has been taken (Ex. WO 97/000703). For such semi-permanent multi dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even stricter.
Apart from applications through dry powder inhalers the compositions of the invention can be administered in aerosols which operate via propellant gases or by means of so- called atomisers, via which solutions of pharmacologically-active substances can be sprayed under high pressure so that a mist of inhalable particles results. The advantage of these atomisers is that the use of propellant gases can be completely dispensed with. Such atomiser is the Respimat® which is described, for example, in PCT Patent Applications Nos. W0 91/14468 and WO 97/12687, reference here is being made to the contents thereof.
Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient (s) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1 ,1 , 1 , 2-tetrafluoroethane, 1 ,1 , 1 ,2, 3,3, 3- heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants (eg. oleic acid or lecithin) and cosolvens (eg. ethanol). Pressurised formulations will generally be retained in a canister (eg. an aluminium canister) closed with a valve (eg. a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1 -10 μηη, preferably 2-5 μηη. Particles having a size above 20 μηη are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.
Achieving high dose reproducibility with micronised powders is difficult because of their poor flowability and extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient such as lactose or glucose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, preferably crystalline alpha lactose monohydrate.
Pressurized aerosol compositions will generally be filled into canisters fitted with a valve, especially a metering valve. Canisters may optionally be coated with a plastics material e. g. a fluorocarbon polymer as described in W096/32150. Canisters will be fitted into an actuator adapted for buccal delivery. iv) Nasal mucosal administration The compounds of the invention may also be administered via the nasal mucosal. Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents. v) Parenteral Administration
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial, intramuscular and
subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. vi) Topical Administration
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and
microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis,
phonophoresis, sonophoresis and microneedle or needle-free injection.
Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. vii) Rectal/lntravaginal Administration
Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. viii) Ocular Administration
Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,
hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. ix) Other Technologies
Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01 -3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day. Preferably, the the pharmaceutical compositions of the invention are made up in a form suitable for oral, inhalation or topical administration, being particularly preferred oral or inhalation administration.
The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
The following preparations forms are cited as formulation examples: Formulation Examples
Formulation Example 1 (Oral suspension)
Ingredient Amount
Active Compound 3 mg
Citric acid 0,5 g Sodium chloride 2,0 g
Methyl paraben 0,1 g
Granulated sugar 25 g
Sorbitol (70% solution) 1 1 g
Veegum K 1 ,0 g
Flavoring 0,02 g
Dye 0,5 mg
Distilled water q.s. to 100 mL
Formulation Example 2 (Hard gelatine capsule for oral administration)
Figure imgf000210_0001
Formulation Example 3 (Gelatin cartridge for inhalation)
Figure imgf000210_0002
Formulation Example 4 (Formulation for inhalation with a DPI)
Ingredient Amount
Active Compound (micronized) 15 mg
Lactose 3000 mg Formulation Example 5 (Formulation for a MDI)
Figure imgf000211_0001
Modifications, which do not affect, alter, change or modify the essential aspects of the compounds, combinations or pharmaceutical compositions described, are included within the scope of the present invention.

Claims

Claims
1 . A compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N- oxide, or stereoisomer or deuterated derivative thereof:
Figure imgf000212_0001
Formula (I)
wherein
X is selected from the group consisting of -N- and -CRC- group, Gi is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyi group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyi, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci-4 alkyl group, a Ci-4 thioalkyl group, a Ci-2 hydroxyalkyl group, a di (C1-2 alkyl)amino-Ci-4 alkyl group and -N R'-S02-R" group,
U is selected from the group consisting of a -(CH2)(o-i)-, -0-, -N Rx-(CH2)(o-i)- group, wherein Rx is selected from a the group consisting of a hydrogen atom and a Ci-2 alkyl group optionally substituted with -(CH2)(0-2)N R'R"- group,
L2 is selected from the group consisting of a -(CH2)P-, -(CH2)-N R-, -N R-(CH2)-, -O- (CH2)(o-2), -C(0)0-, -S- and -N R- group, wherein R represents a hydrogen atom or a Ci-4 alkyl group optionally substituted with a group selected from -N R'R" group and a phenyl group wherein said phenyl group is optionally substituted with a hydroxyl group, R1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci-4 alkyl group optionally substituted with a -NR'R" group, a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a mono- or bicyclic 5- to 14-membered heteroaryl group containing at least one heteroatom selected from O, S and N and a mono- or bicyclic 5- to 14-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups 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 Ci-6 alkyl group, a linear or branched Ci-6 hydroxyalkyl group, a linear or branched Ci-4 alkoxy group, a -(0)(o-i)(CH2)(o-3)-NR'R" group, a -CO-0-Rd group, a -CH2-Re group, a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5-to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N wherein said heterocyclyl and heteroaryl group independently are optionally substituted with one or more substituents selected from the group consisting of a Ci-2 alkyl group, -C(0)0-(Ci-2 alkyl) group and a -NR'R" group;
R2 is selected from the group consisting of a hydrogen atom, a halogen atom and a Ci-4 alkyl group,
R3 is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group and a— (CH2)(2-4)NR'R"- group, G2 is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci-4 alkoxy group, a Ci-2 hydroxyalkyl group, -NR'R" group and a group of formula (a):
Figure imgf000213_0001
wherein L3 represents a direct bond, -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, a -(CH2)(o-i)-CN group, a -CF3 group, a linear or branched Ci-4 alkyl group, a linear or branched Ci-4 alkoxy group, a linear or branched Ci-4 hydroxyalkyl group and a Ci-4 aminoalkyl group wherein the alkyl and the hydroxyalkyl groups are optionally substituted with one or more methyl groups,
Ra and Rb are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci-4 alkyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 3- to 5-membered heterocyclic group containing at least one heteroatom selected from N, O and S, R5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group,
Rc is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, a C5-8 aryl group, a 5- to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of a halogen atom and a Ci-4 alkyl group,
Rd represents a linear or branched Ci-4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a -NR'R", or Rd represents a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N optionally substituted with a Ci-2 alkyl group,
Re is selected from the group consisting of a monocyclic C5-8 aryl group and a monocyclic 5- to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic ring are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci-4 alkyl group and a -CF3 group, R' and R" independently represents a hydrogen atom, a Ci-4 alkyl group or a C3-6 cycloalkyl group, or R' and R" together with the nitrogen atom to which they are attached form a 4- to 6- membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 , p has a value of 0, 1 or 2.
2. A compound according to claim 1 wherein: X is selected from the group consisting of -N- and -CRC- group,
Gi is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci-4 alkyl group, a Ci-2 hydroxyalkyl group, a di (Ci-2 alkyl)amino- Ci-4 alkyl group and -NR'-S02-R" group,
U is selected from the group consisting of a -(CH2)(o-i)-, -0-, -NRx-(CH2)(0-i)- group, wherein Rx is selected from a the group consisting of a hydrogen atom and a Ci-2 alkyl group optionally substituted with -(CH2)(0-2)NR'R"- group, L2 is selected from the group consisting of a -(CH2)P-, -(CH2)-NR-, -O-(CH2)(0-2), -S- and -NR- group, wherein R represents a hydrogen atom or a Ci-4 alkyl group optionally substituted with a group selected from -NR'R" group and a phenyl group wherein said phenyl group is optionally substituted with a hydroxyl group, R1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci-4 alkyl group optionally substituted with a -NR'R" group, a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a mono- or bicyclic 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups 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 Ci-6 alkyl group, a linear or branched Ci-6 hydroxyalkyl group, a linear or branched Ci-4 alkoxy group, a -(0)(o-i)(CH2)(o-3)-NR'R" group, a -CO-0-Rd group, a -CH2-Re group, a monocyclic 5-to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N and a monocyclic 5-to 8-membered heteroaryl group containing at least one heteroatom selected from O, S and N wherein said heterocyclyl and heteroaryl group independently are optionally substituted with one or more substituents selected from the group consisting of a Ci-2 alkyl group and a -NR'R" group; R2 is selected from the group consisting of a hydrogen atom, a halogen atom and a Ci-4 alkyl group,
R3 is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group and a - (CH2)(2-4)NR'R"- group,
G2 is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic C3-8 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci-4 alkoxy group, a Ci-2 hydroxyalkyl group, -NR'R" group and a group of formula (a):
Figure imgf000216_0001
wherein
L3 represents a direct bond, -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, a -(CH2)(0-i)-CN group, a -CF3 group, a linear or branched Ci-4 alkyl group, a linear or branched Ci-4 alkoxy group, a linear or branched Ci-4 hydroxyalkyl group and a Ci-4 aminoalkyl groupwherein the alkyl and the hydroxyalkyl groups are optionally substituted with one or more methyl groups, Ra and Rb are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci-4 alkyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 3- to 5-membered heterocyclic group containing at least one heteroatom selected from N, O and S,
R5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group, Rc is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, a C5-8 aryl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci-4 alkyl group,
Rd represents a linear or branched Ci-4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a-NR'R",
Re is selected from the group consisting of a monocyclic C5-8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic ring are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci-4 alkyl group and a -CF3 group, R' and R" independently represents a hydrogen atom, a Ci-4 alkyl group or a C3-6 cycloalkyl group, or R' and R" together with the nitrogen atom to which they are attached form a 4- to 6- membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 , p has a value of 0, 1 or 2.
3. A compound according to claim 2, wherein X represents a -CRc-group, wherein Rc is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, a phenyl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -NR'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci-4 alkyl group, and R' and R" independently represents a hydrogen atom or a Ci-4 alkyl group, preferably, Rc is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group, a Ci-2 alkoxy group, a phenyl group and a -NR'R" group, wherein R' and R" independently represents a hydrogen atom or a Ci-2 alkyl group.
4. A compound according to claim 3, wherein Rc is selected from the group consisting of a hydrogen atom and a methyl group, preferably, a hydrogen atom.
5. A compound according to any one of the preceding claims, wherein d is selected from the group consisting of a monocyclic C5-8 aryl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, a hydroxyl group, a Ci-4 alkyl group, a Ci-2 hydroxyalkyl group and -NR'- S02-R" group.
6. A compound according to claim 5, wherein d is selected from the group consisting of a phenyl group, a pyridyl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, pyridyl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, and a Ci-2 alkyl group.
7. A compound according to claim 6, wherein Gi is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group.
8. A compound according to any one of the preceding claims, wherein L-i is selected from the group consisting of a -(CH2)(o-i)-, -NRX-(CH2)(1)- group, wherein Rx is selected from the group consisting of a hydrogen atom and a Ci-2 alkyl group optionally substituted with -(CH2)(0-2)NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L-i is selected from the group consisting of direct bond and -NRX-(CH2)(1)- group, wherein Rx is selected from a the group consisting of a hydrogen atom and a methyl group.
9. A compound according to claim 8, wherein L-i represents a direct bond.
10. A compound according to any one of the preceding claims, wherein L2 is selected from the group consisting of a -(CH2)P-, -0-(CH2)(o-2)- and -NR- group, wherein R represents a hydrogen atom or a Ci-2 alkyl group optionally substituted with a -NR'R"- group, wherein p has a value of 0 or 1 and wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L2 is selected from the group consisting of a -(CH2)P-, -0-(CH2)2-, wherein p has a value of 0 or 1 .
1 1 . A compound according to any one of the preceding claims, wherein R1 is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group optionally substituted with a -NR'R" group, a monocyclic C5-8 aryl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from N, wherein the aryl, heteroaryl and heterocyclyl groups 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 Ci-5 alkyl group, a linear Ci-2 alkoxy group, a -(0)(o-i)(CH2)(o-3)-NR'R" group, a -CO-0-Rd group, a -CH2-Re group, wherein Rd represents a linear or branched Ci-4 alkyl group optionally substituted with one or more substituents selected from a methyl group and a-NR'R",
Re is selected from the group consisting of a monocyclic C5-8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from N, which cyclic ring are optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF3 group, R' and R" independently represents a hydrogen atom or a methyl group or R' and R" together with the nitrogen atom to which they are attached form a 4 to 6 membered N- containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group.
12. A compound according to claim 1 1 , wherein R1 is selected from the group consisting of a hydrogen atom, a monocyclic C5-8 aryl group and a monocyclic 5- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the aryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a linear or branched Ci-5 alkyl group, a linear Ci-2 alkoxy group, a -(0)(CH2)2-NR'R" group and a -NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group.
13. A compound according to claim 12, wherein R1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and
heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH2)2-NR'R" group and a -NR'R"- group, wherein both R' and R" represent a methyl group.
14. A compound according to any one of the preceding claims, wherein R2 is selected from the group consisting of a hydrogen atom and a halogen atom, preferably a halogen atom, more preferably, a fluorine atom.
15. A compound according to any one of the preceding claims, wherein R3 is selected from the group consisting of a hydrogen atom, a Ci-4 alkyl group and a -(CH2)(2- 4)NR'R"- group, wherein R' and R" are as defined in claim 1 or 2, preferably, R3 is selected from a hydrogen atom and a -methyl group, more preferably R3 represents a hydrogen atom.
16. A compound according to any one of the preceding claims, wherein R5 is selected from the group consisting of a hydrogen atom and a methyl group, preferably a hydrogen atom.
17. A compound according to any one of the preceding claims, wherein G2 is selected from the group consisting of a monocyclic N-containing 6- to 8-membered heteroaryl group and a monocyclic 5- to 8-membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a methyl group, group and a group of formula (a):
Figure imgf000220_0001
wherein
L3 represents -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, a cyano group, a -CF3 group and a methyl group,
Ra and Rb are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a methyl group or Ra and Rb together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or an O-containing 4-membered heterocyclic group,
m has a value of 0 or 1.
18. A compound according to claim 17, wherein G2 is selected from the group consisting of a pyridyl group and a monocyclic N-containing 6-membered heterocyclyl group, wherein the pyridyl and heterocyclyl groups are substituted by one or more substituents selected from a halogen atom and a group of formula (a):
Figure imgf000221_0001
wherein
L3 represents -CO- group,
R4 is selected from the group consisting of a hydroxyl group and a cyano group, both Ra and Rb represent a hydrogen atom, and m has a value of 1
19. A compound according to claim 18, wherein G2 represents a monocyclic N- containing 6-membered heterocyclyl group which is substituted by a group of formula (a):
Figure imgf000221_0002
wherein
l_3 , R4, Ra, Rb and m are as defined in claim 17.
20. A compound according to any one of the preceding claims, wherein
X represents a -CRc-group, wherein Rc represents a hydrogen atom,
Gi is selected from the group consisting of a phenyl group, a pyridyl group and a piperazinyl group,
U represents a direct bond,
L2 is selected from the group consisting of a -(CH2)P-, -0-(CH2)2-, wherein p has a value of 0 or 1 ,
R1 is selected from the group consisting of a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH2)2-NR'R" group and a -NR'R"- group, wherein both R' and R" represents a methyl group.
R2 is a fluorine atom,
R3 represents a hydrogen atom,
R5 represents a hydrogen atom,
G2 represents a monocyclic N-containing 6-membered heterocyclyl group which is substituted by a group of formula
Figure imgf000222_0001
wherein
L3 represents -CO- group,
R4 is selected from the group consisting of a hydroxyl group and a cyano group, both Ra and Rb represent a hydrogen atom, and m has a value of 1 .
21. A compound according to claim 1 , wherein
X is selected from the group consisting of -N- and -CRC- group, wherein Rc is selected from the group consisting of a hydrogen atom and a methyl group,
Gi is selected from the group consisting of a phenyl group, a monocyclic N-containing 6-membered heteroaryl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a fluorine atom, a hydroxyl group, -SCH3 group, -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino-Ci-2 alkyl group and - NR'-S02-R" group,
L-i is selected from the group consisting of a direct bond and -NH-(CH2)- group, L2 is selected from the group consisting of a -(CH2)P-, -(CH2)-NR-, -O-(CH2)(0-2), -C(0)0- , and -NR- group, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group,
R1 is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group, which alkyl group is substituted with a -NR'R" group, a phenyl group, a mono- or bicylic 5- to 9-membered heteroaryl group containing at least one nitrogen atom as heteroatom and a mono- or bicyclic 5- to 9-membered heterocyclyl group containing at least one nitrogen atom as heteroatom, wherein the phenyl, heteroaryl and heterocyclyl groups are 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 C4-5 alkyl group, a Ci-3 hydroxyalkyl group, a methoxy group, a -(0)(o-i)(CH2)(2-3)-NR'R" group, - NR'R" group, a -C(0)-0-Rd group, a -CH2-Re group and a monocyclic 6-membered heteroaryl group containing one heteroatom selected from N, wherein said heteroaryl substituent on the R1 moiety is optionally further substituted with one or two further substituents selected from the group consisting of a methyl group and a -NR'R" group, R2 is selected from the group consisting of a fluorine atom and a methyl group,
R3 is selected from the group consisting of a hydrogen atom and a -(CH2)2NR'R" group,
G2 is selected from the group consisting of a pyridyl group substituted with a fluorine atom and a piperidinyl substituted with a group of formula (a):
Figure imgf000223_0001
wherein
L3 represents a direct bond, -CO- group, or a -C(0)0- group,
R4 is selected from the group consisting of a hydroxyl group, -(CH2)(o-i)-CN, a - CF3 group, a methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups, and a Ci-2 aminoalkyl group,
both Ra and Rb are a hydrogen atom or Ra and Rb together with the carbon atom to which they are attached form a 4-membered heterocyclic group containing oxygen atom as heteroatom,
R5 is selected from the group consisting of a hydrogen atom and a methyl group,
Rd represents a t-butyl group, a linear Ci-2 alkyl group optionally substituted with one substituent selected from a phenyl group and a -NR'R",
Re is selected from the group consisting of a phenyl group optionally substituted with a CF3 group or with a t-butyl group, and a monocyclic 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as heteroatom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF3 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 form a 5 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a dimethylamino group,
n, m and q independently have a value of 0 or 1 , and
p has a value of 0, 1 or 2.
22. A compound according to claim 1 or 2, wherein
X is selected from the group consisting of -N- and -CRC- group, wherein Rc is selected from the group consisting of a hydrogen atom and a methyl group,
Gi is selected from the group consisting of a phenyl group, a monocyclic N-containing 6-membered heteroaryl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a fluorine atom, a hydroxyl group, -CHO group, a methyl group, a hydroxymethyl group, a dimethylamino-Ci-2 alkyl group and -NR'-S02-R" group,
L-i is selected from the group consisting of a direct bond and -NH-(CH2)- group, L2 is selected from the group consisting of a -(CH2)P-, -O-(CH2)(0-2) and -NR- group, wherein R represents a hydrogen atom, a methyl group or a propyl group substituted with a piperidinyl group,
R1 is selected from the group consisting of a hydrogen atom, a Ci-2 alkyl group substituted with a -NR'R" group, a phenyl group, a mono- or bicylic 5- to 9-membered heteroaryl group containing at least one nitrogen atom as heteroatom and a mono- or bicyclic 5- to 9-membered heterocyclyl group containing at least one nitrogen atom as heteroatom, wherein the phenyl, heteroaryl and heterocyclyl groups are 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 C4-5 alkyl group, a Ci-3 hydroxyalkyl group, a methoxy group, a -(0)(o-i)(CH2)(2-3)-NR'R" group, -NR'R" group, a -C(0)-0-Rd group, a -CH2-Re group and a monocyclic 6-membered heteroaryl group containing one heteroatom selected from N wherein said heteroaryl group is optionally substituted with one or two substituents selected from the group consisting of a methyl group and a -NR'R" group;
R2 is selected from the group consisting of a fluorine atom and a methyl group,
R3 is selected from the group consisting of a hydrogen atom and a -(CH2)2NR'R" group, G2 is selected from the group consisting of a pyridyl group substituted with a fluorine atom and a piperidinyl substituted with a group of formula (a):
Figure imgf000224_0001
wherein
L3 represents a direct bond, -CO- group, or a -C(0)0- group, R4 is selected from the group consisting of a hydroxyl group, -(CH2)(o-i)-CN, a - CF3 group, a methyl group, an ethyl group, a methoxy group, a hydroxypropyl group, a hydroxymethyl group optionally substituted with one or two methyl groups,
both Ra and Rb are a hydrogen atom or Ra and Rb together with the carbon atom to which they are attached form a 4-membered heterocyclic group containing oxygen atom as heteroatom,
R5 is selected from the group consisting of a hydrogen atom and a methyl group, Rd represents a t-butyl group, a linear Ci-2 alkyl group optionally substituted with one substituent selected from a phenyl group and a -NR'R",
Re is selected from the group consisting of a phenyl group optionally substituted with a CF3 group or with a t-butyl group, and a monocyclic 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as heteroatom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from a linear or branched Ci-4 alkyl group and a -CF3 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 form a 5 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a dimethylamino group,
n and m independently have a value of 0 or 1 , and
p has a value of 0, 1 or 2.
23. A compound according to claim 1 or 2 which is one of:
3-{(3R)-3-[[2-(Dimethylamino)ethyl](5-fluoro-6-morpholin-4-yl-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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
3-[(3R)-3-({6-[4-(1 /-/-Benzimidazol-2-ylmethyl)piperazin-1 -yl]-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-((3/?)-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-oxopropanenitrile 3-{(3/?)-3-[(5-ΡΙυοΓθ-2-ργΓ3ζοΙο[1 ,5-3]ργπάίη-3-γΙ-6-{4-[(4-ργΓΓθΝάίη-1 -γΙργπάίη-2- yl)methyl]piperazin-1 -yl}pyrimidin-4-yl)amino]pip^
3-[(3R)-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-oxopropanenitrile 4-{[4-(5-Fluoro-6-{[(3R)-1 -(3-hydroxy-3-methylbutanoyl)piperidin-3-yl]amino}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol
4- {[4-(5-Fluoro-6-{[(3R)-1 -glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol
3-[(3R)-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-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-((3/?)-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 2-((3/?)-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-/V-[(3R)-1 - (methoxyacetyl)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-/V-[(3R)-1 -(3,3,3-trifluoropropanoyl)piperidin-3-yl]pyrimidin-4-ami
[3-((3/?)-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
(2S)-1 -((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 -oxopropan-2-ol
(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 3-((3/?)-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-oxopropanenitri
3-((3/?)-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
3-((3/?)-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
3-{(3R)-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-{(3R)-3-[(5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-{4-[4-(2-pyrrolidin-1 -ylethoxy) benzyl]piperazin-1 -yl}pyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-((3R)-3-{[6-((3R,5S)-4-{4-[2-(Dimethylamino)ethoxy]benzyl}-3,5-dimethyl piperazin-1 -yl)-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino} piperidin- 1 -yl)-3-oxopropanenitrile 3-((3/?)-3-{[6-(4-{4-[2-(dimethylamino)ethoxy]-3,5-dimethylbenzyl}piperazin-1 -yl)-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
3-((3/?)-3-{[6-(4-{4-[2-(Dimethylamino)ethoxy]-2,6-dimethylbenzyl}piperazin-1 -yl)-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3- oxopropanenitrile
3-[(3R)-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- oxopropanenitrile
2- (Dimethylamino)ethyl 4-{[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro- 2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}benzoate
Terf-butyl 4-{[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}piperidine-1 -carboxylate
3- [(3/?)-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 3-[(3R)-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]-^ oxopropanenitrile
3-[(3R)-3-({5-Fluoro-6-[4-({1 -[(1 -methyl-1 H-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-oxopropanenitrile
3-((3R)-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-((3R)-3-{[5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-(4-{[1 -(pyridin-2-ylmethyl) piperidin-4-yl]methyl}piperazin-1 -yl)pyrimidin-4-yl]amino}piperidin-1 -yl)-^
oxopropanenitrile
3-[(3R)-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-oxopropanenitrile 3-[(3R)-3-({5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-[4-(2-pyrrolidin-1 -ylpyridin-4- yl)piperazin-1 -yl]pyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitrile
3-{(3R)-3-[(6-{4-[4-(Dimethylamino)pyridin-2-yl]piperazin-1 -yl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-((3R)-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/?)-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-oxopropanenitrile 5-Fluoro-/V-[(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/?)-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-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile 3-[(3R)-3-({6-[4-(1 ,3-Dihydro-2H-isoindol-2-ylmethyl)piperidin-1 -yl]-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-((3/?)-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 3-{(3R)-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} oxopropanenitrile
3-[(3 ?)-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 -yl]-3- oxopropanenitrile 3-{(3R)-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
3-{(3R)-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-oxopropanenitrile
Benzyl 4-{[1 -(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5- a]pyridin-3-ylpyrimidin-4-yl)piperidin-4-yl]methyl}piperazine-1 -carboxylate
3-[(3/?)-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
(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-oxopropanenitrile 3-[(3/?)-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-ylpyrimidin-4-yl}amino) piperidin- 1 -yl]-3-oxopropanenitrile
3-[(3R)-3-({5-Fluoro-6-[(4-piperazin-1 -ylbenzyl)amino]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile 3-[(3R)-3-({5-Fluoro-6-[4-(4-methylpiperazin-1 -yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
2-[(3/?)-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 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide 1 - (4-7e/f-Butylbenzyl)-4-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenyl]-1 -methylpiperazin-1 -ium bromide
3-((3/?)-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-oxopropanenitri 3-[(3R)-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-oxopropanenitri
3-[(3R)-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-oxopropanenitrile
3-[(3R)-3-({5-Fluoro-2-pyrazolo[1 ,5-a]pyridin-3-yl-6-[4-(pyrrolidin-1 -ylmethyl) phenyl]pyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-[(3/?)-3-({6-[4-({4-[4-(Dimethylamino)-6-methylpyridin-2-yl]piperidin-1 -yl}meth phenyl]-5-fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]^ oxopropanenitrile
3-((3R)-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-oxopropanenitri
3-((3/?)-3-{[6-(4-{[4-(Dimethylamino)piperidin-1 -yl]methyl}-2-fluorophenyl)-5-fluo
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitn 3-((3R)-3-{[6-(3-{[4-(Dimethylamino)piperidin-1 -yl]methyl}phenyl)-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitri
3- {(3R)-3-[(5-Fluoro-6-{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-oxopropanenitri
3-{(3R)-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/?)-3-({6-[4-({4-[2-(Dimethylamino)^
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitri
3- {(3R)-3-[(6-{4-[2-(Dimethylamino)ethoxy]phenyl3-5-fluoro-2-pyrazolo[1 ,5-a]pyridin- 3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile 3-((3R)-3-{(6-{4-[2-(Dimethylamino)ethoxy]phenyl}-5-fluoro-2-pyrazolo[1 ,5-a] pyridin-3-ylpyrimidin-4-yl)[2-(dimethylam
oxopropanenitrile
[(3R)-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-oxopropanenitrile
3-((3R)-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-oxopropanenitrile
(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-oxopropanenitrile (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-oxopropanenitrile
3-[(3R)-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-oxopropanenitrile
3-((3/?)-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-oxopropanenitrile
3-((3/?)-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-[(3R)-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-oxopropanenitrile
3-{(3R)-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]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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}-3-oxopropanenitrile
2- {(3R)-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/?)-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 3-[(3R)-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-oxopropanenitrile
3-{(3R)-3-[(6-{6-[4-(Dimethylamino)piperidin-1 -yl]pyridin-3-yl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitrile
3-{(3R)-3-[(5-Fluoro-6-{4-[1 -(3-hydroxybenzyl)piperidin-4-yl]piperazin-1 -yl}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-[(3R)-3-([2-(Dimethylamino)ethyl]{5-fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl]-
2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3- ((3R)-3-{[5-Fluoro-6-(4-{4-[2-(methylam
pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitril^
/V-[(3R)-1 -(3-Aminopropanoyl)piperidin-3-yl]-5-fluoro-6-[4-(4-methylpiperazin-1 - yl)phenyl]-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-amine
3-[(3R)-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- oxopropanenitrile
3-(6-{[2-(Dimethylamino)ethyl][(3R)-1 -glycoloylpiperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)-5-(4-methylpiperazin-1 -yl)phenol
3-((3/?)-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
3-((3R)-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-oxopropanenitri
3- ((3/?)-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- oxopropanenitrile
3-[(3R)-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-oxopropanenitrile 3-{(3R)-3-[(5-Fluoro-6-{6-[4-(methylamino)piperidin-1 -yl]pyridin-3-yl}-2-pyrazolo[1 ,^ a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitril^ 3-(5-Fluoro-6-{[(3R)-1 -glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3- ylpyrimidin-4-yl)-5-{[(1 -methylpiperidin-4-yl)amino]methyl}phenol
3- {(3/?)-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- oxopropanenitrile 3-{(3R)-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
3-{(3R)-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- oxopropanenitrile
3-((3/?)-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
3-((3/?)-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
3-{(3R)-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
3-[(3R)-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
3-((3R)-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
3-{(3R)-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 3-{(3R)-3-[(6-{3-[(Cyclopentylamino)methyl]-5-hydroxyphenyl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridine-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-[(3/?)-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-oxopropanenitrile 3-((3R)-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
3-{(3R)-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-{(3R)-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
1 -methylpiperidin-4-yl 1 -[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzyl]piperidine-4-carboxylate
3-{(3R)-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-oxopropanenitrile
3-((3/?)-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
3-[(3/?)-3-({5-Fluoro-6-[3-hydroxy-4-(piperazin-1 -ylmethyl)phenyl]-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-((3/?)-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
Ethyl 1 '-[4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo[1 ,5- a]pyridin-3-ylpyrimidin-4-yl)benzyl]-4-methyl-1 ,4'-bipiperidine-4-carboxylate 3-[(3R)-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- oxopropanenitrile
3- [(3R)-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- oxopropanenitrile 3-[(3/?)-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
3-{(3R)-3-[(6-{6-[4-(Dimethylamino)piperidin-1 -yl]-5-hydroxypyridin-3-yl}-5-fluoro-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile 3-[(3R)-3-({5-Fluoro-6-[2-(4-isopropyl-1 ,4-diazepan-l -yl)pyridin-4-yl]-2-pyrazolo
[1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
3-{(3R)-3-[(6-{4-[(Cyclopentylamino)methyl]-3-hydroxyphenyl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-3-[(6-{3-[(Cyclopentylamino)methyl]-4-hydroxyphenyl}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
Piperidin-4-yl 4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5-fluoro-2-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate
3-{(3R)-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 1 '-Methyl-1 ,4'-bipiperidin-4-yl 4-(6-{[(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino}-5- fluoro-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)benzoate
3-((3R)-3-{[5-Fluoro-6-(3-hydroxy-4-{[methyl(pyridin-4-yl)amino]methyl}phenyl)-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl]amino}piperidin-1 -yl)-3-oxopropanenitrile
3-{(3R)-3-[(5-Fluoro-6-{4-[(5-fluoro-2-hydroxybenzyl)amino]piperidin-1 -yl}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)amino]piperidin-1 -yl}-3-oxopropanenitrile
3-{(3R)-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-oxopropanenitrile
3-{[4-(Cyclopentylamino)piperidin-1 -yl]methyl}-5-(5-fluoro-6-{[(3R)-1 - glycoloylpiperidin-3-yl]amino}-2-pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)phenol 3-((3/?)-3-{{5-Fluoro-6-[4-(3-hydroxybenzyl)piperazin-1 -yl]-2-pyrazolo[1 ,5-a] pyridin-
3-ylpyrimidin-4-yl}[2-(methylamino)ethyl]amino}piperidin-1 -yl)-3-oxopropanenitn
3-{[4-(5-Fluoro-6-{[(3R)-1 -glycoloylpiperidin-3-yl][2-(methylamino)ethyl]amino}-2- pyrazolo[1 ,5-a]pyridin-3-ylpyrimidin-4-yl)piperazin-1 -yl]methyl}phenol S-IiSRJ-S-tte-^-il ^'-Bipiperidin-r-ylmethylJ-S-hydroxyphenyll-S-fluoro^-pyrazolo [1 ,5-a]pyridin-3-ylpyrimidin-4-yl}amino)piperidin-1 -yl]-3-oxopropanenitrile
2-((3R)-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,
or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.
24. A compound as defined in any one of claims 1 to 23, for use in the treatment of the human or animal body by therapy.
25. A compound as defined in any one of claims 1 to 23, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases.
26. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 23 in association with a pharmaceutically acceptable diluent or carrier.
27. Use of a compound as defined in any one of claims 1 to 23, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claim 25.
28. A method for treating a subject afflicted with a pathological condition or disease as defined in claim 25, which comprises administering to said subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 23, or a pharmaceutical composition as defined in claim 26.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016198663A1 (en) * 2015-06-11 2016-12-15 Almirall, S.A. 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors
CN110305024A (en) * 2018-03-27 2019-10-08 鲁南制药集团股份有限公司 A kind of synthetic method of Beloranib intermediate
WO2020152690A1 (en) * 2019-01-27 2020-07-30 Sol-Gel Technologies Ltd. Treatment of skin disorders with topical tapinarof combination compositions
US10822341B2 (en) 2016-02-24 2020-11-03 Pfizer Inc. Pyrazolo[1,5-a]pyrazin-4-yl derivatives
WO2021096304A1 (en) * 2019-11-15 2021-05-20 Ildong Pharmaceutical Co., Ltd. Glp-1 receptor agonist and use thereof
US11254668B2 (en) 2017-08-14 2022-02-22 Pfizer Inc. Pyrazolo[1,5-A]pyrazin-4-yl and related derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107400087B (en) * 2017-09-15 2019-12-13 济南美高生物医药科技有限公司 preparation method of 1- (2- (4- (chloromethyl) phenoxy) ethyl) azepane hydrochloride

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101161A1 (en) * 2010-02-18 2011-08-25 Almirall, S.A. Pyrazole derivatives as jak inhibitors
WO2013025628A1 (en) * 2011-08-15 2013-02-21 Ligand Pharmaceuticals Incorporated Janus kinase inhibitor compounds and methods

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101161A1 (en) * 2010-02-18 2011-08-25 Almirall, S.A. Pyrazole derivatives as jak inhibitors
WO2013025628A1 (en) * 2011-08-15 2013-02-21 Ligand Pharmaceuticals Incorporated Janus kinase inhibitor compounds and methods

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10759793B2 (en) 2015-06-11 2020-09-01 Almirall, S.A. 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as JAK inhibitors
CN107667106A (en) * 2015-06-11 2018-02-06 阿尔米雷尔有限公司 2 (base of Pyrazolopyridine 3) pyrimidine derivatives as JAK inhibitor
WO2016198663A1 (en) * 2015-06-11 2016-12-15 Almirall, S.A. 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors
AU2016275716B2 (en) * 2015-06-11 2020-01-23 Almirall, S.A. 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as JAK inhibitors
EA035312B1 (en) * 2015-06-11 2020-05-27 Альмираль, С.А. 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as jak inhibitors
AU2016275716C1 (en) * 2015-06-11 2020-10-15 Almirall, S.A. 2-(pyrazolopyridin-3-yl)pyrimidine derivatives as JAK inhibitors
US10822341B2 (en) 2016-02-24 2020-11-03 Pfizer Inc. Pyrazolo[1,5-a]pyrazin-4-yl derivatives
US11472809B2 (en) 2016-02-24 2022-10-18 Pfizer Inc. Pyrazolo[1,5-a]pyrazin-4-yl derivatives
US11254668B2 (en) 2017-08-14 2022-02-22 Pfizer Inc. Pyrazolo[1,5-A]pyrazin-4-yl and related derivatives
CN110305024A (en) * 2018-03-27 2019-10-08 鲁南制药集团股份有限公司 A kind of synthetic method of Beloranib intermediate
WO2020152690A1 (en) * 2019-01-27 2020-07-30 Sol-Gel Technologies Ltd. Treatment of skin disorders with topical tapinarof combination compositions
CN113473969A (en) * 2019-01-27 2021-10-01 索尔-格尔科技有限公司 Treatment of skin conditions with topical talpinaloff combination compositions
WO2021096304A1 (en) * 2019-11-15 2021-05-20 Ildong Pharmaceutical Co., Ltd. Glp-1 receptor agonist and use thereof
CN114728939A (en) * 2019-11-15 2022-07-08 日东制药株式会社 GLP-1 receptor agonists and uses thereof
US11643403B2 (en) 2019-11-15 2023-05-09 Ildong Pharmaceutical Co., Ltd. GLP-1 receptor agonist and use thereof
CN114728939B (en) * 2019-11-15 2023-12-08 日东制药株式会社 GLP-1 receptor agonists and uses thereof
US11932618B2 (en) 2019-11-15 2024-03-19 Ildong Pharmaceutical Co., Ltd. GLP-1 receptor agonist and use thereof

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