TW201309671A - Pyridin-2(1H)-one derivatives as JAK inhibitors - Google Patents

Abstract

New pyridin-2(1H)-one derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

Description

Pyridine-2(1H)-one derivative as a JAK inhibitor

The present invention relates to a pyridine-2(1H)-one derivative as a JAK inhibitor and a process for the preparation thereof, comprising the pharmaceutical composition thereof and the use thereof as an inhibitor of Janus Kinase (JAK) for therapy Use in.

Cytokines have key 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 the intrinsic enzymatic activity that mediates signal transduction and therefore require association with tyrosine kinase for this purpose. The JAK family of kinases includes four distinct members, namely JAK1, JAK2, JAK3, and TYK2, which bind to type I and type II cytokine receptors to control signal transduction (Murray PJ, (2007). The JAK-STAT signalling Pathway: input and output integration. J Immunol , 178: 2623). JAK kinases are each selective for receptors of certain cytokines. In this regard, JAK-deficient cell lines and mice have confirmed the basic role of each JAK protein in receptor signaling: JAK1 is a type II cytokine receptor (IFN and IL-10 family), and their receptors share gp130 Chains (IL-6 family) and common gamma chains (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 factor (Epo) , Tpo, GM-CSF, IL-3, IL-5) and type II IFN (Parganas et al, (1998). JAK2 is essential for signalling through a variety of cytokine receptors. Cell , 93: 385); JAK3 Common receptors for the gamma chain (IL-2 family) (Park et al., (199) 5).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 IL-12, IL-23, IL-13 and type I IFN Receptors (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity , 13: 549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, after it is required For IL-12-mediated T cell function. Immunity, 13:561; Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745) .

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

The phenotype of defective mice has provided insight into the function of each JAK and its cytokine receptor signaling. JAK3 is specifically associated with the common gamma chain of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptors. Due to this specialized association, JAK3 knockout mice and common gamma chain deficient mice have the same phenotype (Thomis et al, (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Science , 270:794; DiSanto et al. (1995). Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. PNAS , 92: 377). Furthermore, this phenotype is largely shared with SCID patients who retain mutations/defects in the common gamma chain or JAK3 gene (O'Shea et al., (2004). JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol , 41:727). JAK3-deficient mice survive but exhibit abnormal lymphocyte formation, which results in a decrease in thymus size (1/100-1/10 of the wild type). JAK3 deficient peripheral T cells are unresponsive and have an activation/memory cell phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice. J. Leuk. Biol. 63: 669). The thymic defects in these mice are very similar to those seen in IL-7 and IL-7 receptor knockout mice, suggesting that the absence of IL-7 signaling may indicate that JAK3-/- mice have this defect (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). Similar to SCID humans, these mice have no NK cells, which may be due to the absence of IL-15 signaling (the survival factor of these cells). Unlike SCID patients, JAK3 knockout mice show defective B cell lymphocyte formation, whereas in human patients, B cells are present in the circulation but do not respond, resulting in hypoglobulinemia (O'Shea et al., ( 2004). JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol , 41: 727). The explanation for this is the species-specific difference in the function of IL-7 in mouse and human B and T cell development. On the other hand, Grossman et al. (1999. Dysregulated myelopoiesis in mice lacking JAK3. Blood , 94: 932: 939) have shown that loss of JAK3 in the T cell compartment promotes expansion of the myeloid lineage, resulting in dysregulated bone marrow formation.

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

JAK1-deficient mice die during the perinatal period due to breastfeeding defects. JAK1 specifically binds to the gp130 chain shared by the IL-6 cytokine family (ie, LIF, CNTF, OSM, CT-1) and binds to JAK3 as a common gamma chain receptor by binding to non-consensus receptor subunits. The basic components. In this regard, JAK1-deficient mice showed a hematopoietic defect similar to that of JAK3-deficient mice. In addition, it shows a defect response to neurotrophic factors and all interferons (type II cytokine receptors) (Rodri et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine- Induced biological response. Cell , 93: 373).

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

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

Inhibition of JAK kinases (especially JAK1 and JAK3) produces potent immunosuppression, which is therapeutically useful for preventing transplant rejection. In this regard, the JAK inhibitor CP-690,550 (tofacitinib, formerly known as tasocitinib) has been shown in several animal transplant models by extending the average survival time of the graft (small) Efficacy of the mouse's heretopic heart transplantation, implantation of cardiac allografts in mouse ears, renal allografts in macaques, rat aorta, and tracheal transplantation (West K (2009). CP-690, 550, a JAK3) Inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr . Op . Invest . Drugs 10:491).

In rheumatoid joints, an imbalance between pro-inflammatory and anti-inflammatory cytokine activity promotes induction of autoimmune, followed by induction of chronic inflammation and tissue destruction. In this regard, the pathogenic role of IL-6 in rheumatoid arthritis (RA) has been clinically confirmed by the use of the anti-IL-6R antibody tocilizumab. IL-6 activates the transcription factor STAT3 via 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 abnormal growth and survival properties of RA synovial cells (Ivashkiv and Hu (2003). The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arth & Rheum. 48:2092). Other cytokines involved in the pathogenesis of arthritis include IL-12 and IL-23, which are involved in Th1 and Th17 cell proliferation, respectively; IL-15 and GM-CSF (McInnes and Schett, (2007). Cytokines in the pathogenesis of Rheumatoid arthritis. Nature Rew Immunol. 7: 429.). The receptors for these cytokines also use JAK proteins for signal transduction, making JAK inhibitors a potential pleiotropic drug in this pathology. Thus, several JAK inhibitors have been shown to reduce inflammation and tissue destruction in animal models of murine collagen-induced arthritis and rat adjuvant-induced arthritis (Milici et al., (2008). Cartilage conservation by Inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arth. Res. 10: R14).

Inflammatory bowel disease (IBD) includes two major forms of enteritis: ulcerative colitis and Crohn's disease. Increasing evidence has shown that a variety of 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 long-term survival of pathogenic T cells (Atreya et al., (2000). Blockade of interleukin 6 trans signaling suppresses T-cell Resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn's disease and experimental colitis in vivo. Nature Med. 6: 583). In particular, STAT3 has been shown to be constitutively active in intestinal T cells of patients with Crohn's disease and it has been shown that JAK inhibitors block the constitutive activation of STAT3 in such 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 JAK inhibitors are therapeutic in this environment.

Multiple sclerosis is an autoimmune demyelinating disease characterized by the formation of plaques in the white matter. The role of cytokines in the development of multiple sclerosis has long been known. Potential therapies include blocking IFN-g, IL-12, and IL-23 (Steinman L. (2008). Nuanced roles of cytokines in three major human brain disorders. J Clin Invest. 118: 3557), which is via JAK-STAT A cytokine that signals signaling. The use of tyrosine phosphorylation inhibitor (tyrphostin) (JAK inhibitor) has been shown to inhibit IL-12-induced STAT3 phosphorylation and to reduce the incidence of active and passive experimental autoimmune encephalitis (EAE). Severity (Bright et al., (1999) Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol. 162:6255). Another multi-kinase inhibitor, CEP701, has been shown to reduce the secretion of TNF-α, IL-6, and IL-23, as well as to reduce the levels of phosphorylated STAT1, STAT3, and STAT5 in peripheral DCs of mice with EAE, thereby 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 involving the process of permeation and activation of immune cells at the end of epithelial remodeling. The current theory behind the etiology of psoriasis states the existence of a cytokine network that controls the interaction between immune and epithelial cells (Nickoloff BJ. (2007). Cracking the cytokine code in psoriasis, Nat Med , 13:2420). In this regard, IL-23 produced by dendritic cells was found to increase with IL-12 in psoriasis skin. IL-23 induces the formation of Th17 cells, which in turn produce IL-17 and IL-22, which are responsible for thickening of the epidermis. IL-23 and IL-22 induce phosphorylation of STAT-3, which is abundantly present in psoriasis skin. Therefore, JAK inhibitors can be therapeutic in this environment. Therefore, it has been found that in the spontaneous T cell-dependent mouse model of psoriasis, the JAK1/3 inhibitor, R348, reduces psoriasis-like skin inflammation (Chang et al., (2009). JAK3 inhibition significant attenuates psoriasiform skin inflammation on CD18 mutant PL /J mice. J Immunol. 183:2183).

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

There is growing evidence that cytokines play a causative role in ocular inflammatory diseases such as uveitis or dry eye syndrome. Some cytokines (such as IL-2, IL-6, IL-12, and IFNg) associated with experimental autoimmune uveitis will be affected by 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 biological products that interfere with IL-2 signaling, such as cyclosporine or anti-IL-2 receptor antibodies (daclizumab), have been shown in keratoconjunctivitis sicca and Efficacy in the treatment of refractory uveitis (Lim et al, (2006). Biologic therapies for inflammatory eye disease. Clin Exp Opht 34: 365). Similarly, allergic conjunctivitis (a common allergic eye disease characterized by conjunctival congestion) , mast cell activation, and eosinophil infiltration can benefit from JAK inhibition. STAT6-deficient mice that show a TH2-mediated immune response (which is usually triggered by IL-4) do not produce typical early and late responses, indicating that via JAK Inhibition of the elimination of the IL-4 pathway can be therapeutic in this environment (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 increasing evidence that STAT3 activity plays a key role in the processes involved in tumor formation, such as cell cycle disorders, promoting uncontrolled growth, inducing survival factors, and inhibiting apoptosis (Siddiquee et al., (2008). STAT3 as a target for inducing apoptosis in solid and haematological tumors. Cell Res. 18:254). Antagonism of STAT3 by means of a dominant-negative mutant or an antisense oligonucleotide has been shown to promote cancer cell apoptosis, angiogenesis inhibition, and up-regulation of host immunity. Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors may provide a therapeutic option for the treatment of this disease. In this regard, the use of the JAK inhibitor tyrosine phosphorylation inhibitor has been shown to induce malignant cell apoptosis 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 JAK-STAT path disorders can benefit from JAK inhibition. Recent research has suggested that in the myelodysplastic disease range (IhIe and Gililand, 2007) (including polycythemia vera, myelofibrosis, and essential thrombocythemia) Chromosomal translocations in the kinase domain and mutations (such as the JAK2V617F mutation) dysregulate JAK2 kinase activity. In this regard, several JAK inhibitors have been proposed to effectively treat 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. Cancer Cell , 13: 311), CEP701 (Hexner et al., (2008). Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood , 111: 5663), CP-690, 550 (Manshouri et al. , (2008). The JAK kinase inhibitor CP-690, 550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Sci , 99: 1265) and CYT387 (Pardanani et al, (2009). CYT387, a selective JAK1/JAK2 Inhibitor:invitro assessment of kinase selectivity and preclinical studies Leukemia , 23: 1441) is used to treat myeloproliferative diseases based on its antiproliferative activity against cells bearing the JAK2V617F mutation. Similarly, T cell leukemia caused by the transformation of human T cell leukemia virus (HTLV-1) is associated with constitutive activation of JAK3 and STAT5 (Migone et al., (1995). Constitutively activated JAK-STAT pathway in T cells transformed with HTLV- I. Science, 269:79) and JAK inhibitors are therapeutic in this environment (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 caused by T cells (Flex et al, (2008). Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205: 751-8) This indicates that this kinase can be used as a target for the development of novel anti-leukemia drugs.

The conditions that are expected to target the JAK pathway or modulate JAK kinase (especially JAK1, JAK2, and JAK3 kinase) therapeutically suitable for treating or preventing a disease include: neoplastic diseases (eg, leukemia, lymphoma, solid tumor); transplant rejection, Bone marrow transplantation applications (eg, graft versus host disease); autoimmune diseases (eg, diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease); respiratory inflammatory diseases (eg, asthma, chronic obstructive pulmonary disease) , inflammation-related eye diseases or allergic eye diseases (such as dry eye, glaucoma, uveitis, diabetic retinopathy, allergic conjunctivitis or age-related macular degeneration) and skin inflammatory diseases ( For example, atopic dermatitis or psoriasis.

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

Provided herein are novel pyridine-2(1H)-one derivatives useful for the treatment of conditions that target the JAK pathway or inhibit the therapeutically useful form of JAK kinase.

The compounds described in the present invention are both potent JAK1, JAK2 and JAK3 inhibitors, i.e., pan-JAK inhibitors. This property makes it suitable for the treatment or prevention of pathological conditions or diseases, such as spinal proliferative disorders (such as true plethremia, essential thrombocythemia or myelofibrosis), white blood Disease, lymphoma, and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crowe Enr's disease), inflammation-related eye disease or allergic eye disease (such as dry eye, uveitis or allergic conjunctivitis), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), and skin inflammatory diseases (such as atopic skin) Inflammation or psoriasis).

Certain pyridine-2(1H)-one derivatives have been found to be novel and potent JAK inhibitors and are therefore useful in the treatment or prevention of such diseases.

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

Wherein m is 0, 1, 2 or 3; and A and B each independently represent a nitrogen atom or a -CR ₇ group, wherein at least one of A and B represents a -CR ₇ group; D represents a nitrogen atom or - a CR ₅ group, wherein when one of A and B represents a nitrogen atom, D represents a -CR ₅ group; W represents a group selected from the group consisting of -NR ₈ -, -(CR ₉ R ₁₀ )-, O- or -S- group of connections; R ₁ represents a hydrogen atom; a straight-chain or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₁ -C ₄ alkoxy; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; containing at least one hetero atom selected from O, S and N a 5- to 14-membered heteroaryl; or a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from O, S, and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, The heterocyclic group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, and C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkylsulfonyl group, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl group; R ₂ and R ₇ each Site represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₁₀ cycloalkyl C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; containing at least one selected from O a 5 to 14 membered heterocyclic group of a hetero atom of S, and N, or a monocyclic C ₆ -C ₉ aryl group or a 5 to 9 membered heteroaryl group fused to a 5 to 9 membered cycloalkyl or heterocyclic group a bicyclic group, the heteroaryl or heterocyclic group containing at least one hetero atom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups, and A bicyclic group described as a monocyclic C ₆ -C ₉ aryl or a 5 to 9 membered heteroaryl group fused to a 5 to 9 membered cycloalkyl or heterocyclic group is unsubstituted or substituted with one or more selected from the group consisting of Substituent: halogen atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; a cyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; containing at least one 5 to 14 membered heterocyclic groups selected from hetero atoms of O, S and N; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group ;-NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH _{2 1-3} -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group a group of -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ ;-(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2 The monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further substituted with one or more carboxyl groups; R ₃ and R ₄ each independently represent a hydrogen atom, a C ₁ -C ₄ haloalkyl group, C ₁ a C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more substituents selected from C ₁ -C ₄ alkoxy groups, Cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₅ and R ₆ each independently represent a hydrogen atom; a halogen atom; a cyano group; a straight or branched chain C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; a 5 to 14 membered heteroaryl group selected from hetero atoms of O, S and N; a 5 to 14 membered heterocyclic group containing at least one hetero atom selected from O, S and N; -(CH ₂ ) _n OR ₁₁ a group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group ;-C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ a _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; wherein the cycloalkyl, cycloalkenyl, aryl group And the heteroaryl group and the heterocyclic group are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, and a C ₁ -C ₄ halogen group; Alkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ a group; where n is 0, 1 2; R _8, R ₉ and R ₁₀ each independently represent a hydrogen atom, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group, a The alkyl group is unsubstituted or substituted with one or more substituents selected from C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidin a pyridine group; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; containing 1, 2 or 3 selected from O, S and N a 5- to 9-membered heterocyclic group of a hetero atom, which is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkane a C ₁ -C ₄ haloalkyl or C ₁ -C ₄ hydroxyalkyl group; or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or one or more selected from the group consisting of Substituted substituents: C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; wherein the compound of formula (I) is not: a) 3-[[5-Chloro-2-[[2,5-dimethyl-4-(piperidin-4-yl)phenyl]amino]pyrimidin-4-yl]amino]pyridine-2 (1H)-ketone; and b)2-[7 -[[5-chloro-4-[(2-o-oxy-1,2-dihydropyridin-3-yl)amino]pyrimidin-2-yl]amino]-8-methoxy-1, 2,4,5-Tetrahydrobenzo[d]azepin-3-yl]-N,N-dimethylacetamide.

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

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

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

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

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

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibition of Janus kinase (JAK), wherein the pathological condition or disease is selected from the group consisting of a spinal proliferative disorder, leukemia, lymph Malignant diseases as well as solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, in more detail, pathological conditions or diseases are selected from rheumatoid arthritis, multiple sclerosis, inflammatory Enteropathy, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis; the method comprising administering to a subject in need of such treatment An effective amount of a compound of the invention or a pharmaceutical composition of the invention.

The invention also provides a combination product comprising (i) a compound of the invention as described herein; and (ii) one or more additional active substances known to be useful in the treatment of a proliferative disorder of the spinal cord (such as true plethora, primary) Thrombocytopenia or myelofibrosis), leukemia, lymphoid malignancies, and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, pathological conditions or diseases are selected from Rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), dry eye, uveitis, allergic conjunctivitis, over Sensitive rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

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

The term C ₁ -C ₄ haloalkyl, as used herein, is an alkyl group bonded to one or more, preferably 1, 2 or 3, halogen atoms, for example C ₁ -C ₄ or C ₁ -C ₂ alkyl. The haloalkyl group is preferably selected from the group consisting of -CCl ₃ , -CHF ₂ and -CF ₃ .

The term C ₁ -C ₄ hydroxyalkyl, as used herein, encompasses a straight or branched alkyl group having from 1 to 4 carbon atoms, either of which may be one or more, preferably one or two, More preferably one hydroxy substitution. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.

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

The term C ₁ -C ₄ alkylsulfonyl, as used herein, encompasses a radical having the following substitutions: an optionally substituted straight chain having from 1 to 4 carbon atoms and attached to a divalent —SO ₂ — group Or branched alkyl.

The term C ₃ -C ₁₀ cycloalkyl, as used herein, encompasses a saturated monocyclic or polycyclic carbocyclyl having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. The optionally substituted C ₃ -C ₁₀ cycloalkyl group is usually unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When the C ₃ -C ₁₀ cycloalkyl group has 2 or more substituents, the substituents may be the same or different. Typically, the substituent on the C ₃ -C ₁₀ cycloalkyl group is itself unsubstituted. The polycyclic cycloalkyl group contains two or more fused cycloalkyl groups, preferably two cycloalkyl groups. Typically, the polycyclic cycloalkyl group is selected from the group consisting of decahydronaphthyl (decalyl), bicyclo [2.2.2] octyl, adamantyl, camphoryl or borneol.

Examples of the monocyclic cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and a cyclodecyl group.

The term C ₃ -C ₁₀ cycloalkenyl, as used herein, encompasses partially unsaturated carbocyclic groups having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. The C ₃ -C ₁₀ cycloalkenyl group is usually unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When the C ₃ -C ₁₀ cycloalkenyl group has 2 or more substituents, the substituents may be the same or different. Typically, the substituent on the cycloalkenyl group is itself unsubstituted.

Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl, and cyclodecenyl.

As used herein, the term C ₆ -C ₁₄ aryl typically encompasses C ₆ -C ₁₄ , preferably C ₆ -C ₁₀ monocyclic or bicyclic aryl, such as phenyl, naphthyl, anthryl and phenanthryl. Phenyl is preferred. The optionally substituted C ₆ -C ₁₄ aryl group is generally unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. When the C ₆ -C ₁₄ aryl group has 2 or more substituents, the substituents may be the same or different. Unless otherwise stated, a substituent on a C ₆ -C ₁₄ aryl group is generally unsubstituted by itself.

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

The optionally substituted 5 to 14 membered heteroaryl is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. When a 5 to 14 membered heteroaryl group has 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, a substituent on a 5 to 14 membered heteroaryl group is generally unsubstituted by itself.

Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazole Base, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, carbazolyl, fluorenyl, quinolyl, isoquinolyl, pyridazinyl, pyridine, quinoxaline Lolinyl, quinazolinyl, quinazolyl, phenyl, triazolyl, pyridazinyl, porphyrinyl, isoindolyl, isodecyl, imidazolidinyl, acridinyl, thiol , pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl and various pyrrolo Pyridyl.

The term 5- to 14-membered heterocyclic group, as used herein, generally encompasses a non-aromatic saturated or unsaturated C ₅ -C ₁₄ carbon ring system, preferably a C ₅ -C ₁₀ carbon ring system, more preferably a C ₅ -C ₆ A carbocyclic system wherein one or more (e.g., 1, 2, 3 or 4 carbon atoms), preferably 1 or 2 carbon atoms, are replaced by a heteroatom selected from the group consisting of N, O and S. The heterocyclic group may be a single ring or two or more fused rings, at least one of which contains a hetero atom. When a 5- to 14-membered heterocyclic group has 2 or more substituents, the substituents may be the same or different.

The optionally substituted 5 to 14 membered heterocyclic group is usually unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituent on the 5- to 14-membered heterocyclic group is usually unsubstituted by itself.

Examples of the 5- to 14-membered heterocyclic group include piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl. , pyridine, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxy, thio, aziridine, oxetane, sulfanyl, azetidin Alkyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1(3H)-one, 1,3-dioxol-2-one, tetrahydrofuranyl, 3-aza- Tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropentanyl, tetrahydrothiopyranyl, 1,4-azathioalkyl, oxepanyl, thiephanyl , azepanyl, 1,4-dioxanyl, 1,4-oxathiepanyl, 1,4-oxa nitrogen Heterocyclic heptyl, 1,4-dithiaheptanyl, 1,4-thiezepanyl, 1,4-diazepanyl, Tropanyl, (1S,5R)-3-aza-bicyclo[3.1.0]hexyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyran Base, 2H-piperidyl, 2,3-hydrobenzofuran , 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, isoindoline-yl and indolinyl.

When a 5- to 14-membered heterocyclic group has 2 or more substituents, the substituents may be the same or different.

As used herein, a bicyclo group wherein the term monocyclic C ₆ -C ₉ aryl or 5 to 9 membered heteroaryl is fused to a 5 to 9 membered cycloalkyl or heterocyclic group generally refers to a monocyclic C _{6 group.} comprising part of a total bond between the -C ₉ aryl group or 5-9 heteroaryl with 5-9 cycloalkyl or heterocyclyl, wherein said heteroaryl or heterocyclyl contains at least one selected from O, S and N heteroatoms. Typically, the bicyclic group is a phenyl or a 5 or 6 membered heteroaryl group fused to a 5 or 6 membered cycloalkyl or heterocyclic group, preferably a 6 membered cycloalkyl or heterocyclic group. Typically, the heteroaryl or heterocyclic group contains 1, 2 or 3, preferably 1 or 2, for example 1 hetero atom selected from O, S and N, preferably N. Examples include alkyl or 1,2,3,4-tetrahydronaphthyl. The 1,2,3,4-tetrahydronaphthyl group is preferred.

As used herein, some of the atoms, groups, moieties, chains, and rings present in the general structure of the invention are "optionally substituted". This means that the atoms, groups, moieties, chains and rings may be unsubstituted or substituted at any position via one or more (eg 1, 2, 3 or 4) substituents, thereby bonding The substituted atoms, groups, moieties, chains, and hydrogen atoms of the ring are replaced by chemically acceptable atoms, groups, moieties, chains, and rings. When two or more substituents are present, each substituent may be the same or different. The substituents are generally unsubstituted by themselves.

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

Compounds containing one or more pairs of palm centers may be enantiomerically or non- It is used in the form of an enantiomerically pure form, a racemic mixture, and a mixture of one or more stereoisomers. The scope of the invention as set forth and claimed encompasses racemic forms of the compounds as well as individual enantiomers, diastereomers, and mixtures of stereoisomers.

Conventional techniques for the preparation/isolation of individual enantiomers involve the resolution of the racemate from a suitable optically pure precursor for palm synthesis or using, for example, palmitic high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be combined with a suitable optically active compound (eg, an alcohol, or an acid or base, such as tartaric acid or 1-phenylethyl, if the compound contains an acidic or basic moiety) Amine) reaction. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or two diastereomers can be converted to the corresponding pure enantiomers by methods well known to those skilled in the art. isomer. The antagonistic compounds of the present invention (and their antagonistic precursors) can be obtained in an enantiomeric enriched form using asymmetric resin chromatography (usually HPLC) having from 0% to A mobile phase consisting of 50% (typically 2% to 20%) isopropanol and 0% to 5% alkylamine (typically 0.1% diethylamine) of a hydrocarbon (usually heptane or hexane). The concentrated solution is concentrated to give a concentrated mixture. Stereoisomer agglomerates can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds", Ernest L. Elie I (Wiley, New York, 1994).

The term pharmaceutically acceptable salt, as used herein, refers to a salt prepared from a base or acid that is acceptable for administration to a patient, such as a mammal. The salt may be derived from a pharmaceutically acceptable inorganic or organic base and a pharmaceutically acceptable inorganic or organic acid.

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

Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc salts and the like. Ammonium, calcium, magnesium, potassium and sodium salts are especially preferred.

Salts derived from pharmaceutically acceptable organic bases include the following salts: primary amines, secondary amines, and tertiary amines, including alkylamines, aralkylamines, heterocyclic amines, cyclic amines, naturally occurring amines, and Analogs such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine , ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucose Amine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, cocoa butter, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Other preferred salts of the invention are quaternary ammonium compounds wherein one equivalent of anion (X ^- ) is associated with a positive charge of the N atom. X ^- may be an anion of various inorganic acids, such as chloride, bromide, iodide, sulfate, nitrate, phosphate; or an anion of an organic acid, such as acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, mesylate and p-toluenesulfonate. X ^{- is} preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. X ^{- more} preferably chloride, bromide, trifluoroacetate or mesylate.

As used herein, an N-oxide is formed from a tertiary amine or imine present in a molecule using conventional oxidizing agents.

The compounds of the invention may exist in unsolvated as well as 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 used when the solvent is water. Examples of solvate forms include, but are not limited to, associated with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl hydrazine (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof A compound of the invention. It is especially contemplated in the present invention that a solvent molecule can be associated with a molecule of the compound of the invention, such as a hydrate.

Furthermore, it is specifically contemplated in the present invention that more than one solvent molecule can be associated with a molecule of the compound of the invention, such as a dihydrate. Additionally, it is specifically contemplated in the present invention that less than one solvent molecule can be associated with a molecule of the compound of the invention, such as a hemihydrate. Furthermore, the invention of the solvate of the present invention encompasses the bioavailability of the unsolvated form of the retention compound a solvate of the compound.

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

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

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

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

In general, the deuterated derivative of the compound of the present invention has an isotope enrichment factor (the ratio between the isotope abundance and the natural abundance of the isotope) in the presence of a site known as the potential site for deuteration on the compound. That is, 氘 is incorporated into a specific position of the molecule to replace the percentage of hydrogen, which is at least 3500 (52.5% 氘 incorporation).

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

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

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

Prodrugs of the present invention may be substituted, for example, by some of the parts known to those skilled in the art as "pro-moiety" (e.g., as described in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). The appropriate functional groups present in the compounds of the invention are prepared.

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

Typically, in the compound of formula (I), m, X, Y, W, A, B, D and R ₁ to R ₁₃ are as defined above; and wherein when D represents a nitrogen atom, A and B represent -CR ₇ The group, m is 0, and R _{2 is} not a substituted 2,3,4,5-tetrahydro-1H-benzo[ d ]azepine or a phenyl group substituted with a piperidinyl group.

In a particular embodiment, the compound of formula (I) is of formula (I')

Wherein m is 0 or an integer from 1 to 3; X and Y each independently represent a nitrogen atom or a -CR ₆ group, wherein at least one of X and Y represents a -CR ₆ group; A and B are each independently Represents a nitrogen atom or a -CR ₇ group, wherein at least one of A and B represents a -CR ₇ group; W represents a group selected from the group consisting of -NR ₈ -, -(CR ₉ R ₁₀ )-, -O - or -S- linking group; R ₁ represents a hydrogen atom; linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₁ - C ₄ alkoxy; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; containing at least one hetero atom selected from O, S and N a 5- to 14-membered heteroaryl; or a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from O, S, and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and hetero The cyclic group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ - C ₄ hydroxyalkyl, C ₁ -C ₄ alkylsulfonyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ and R ₇ Each independently represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; a C ₃ -C ₁₀ ring Alkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; containing at least one selected 5 to 14 membered heterocyclic groups of hetero atoms from O, S and N, or monocyclic C ₆ -C ₉ aryl or 5 to 9 membered heteroaryl groups and 5 to 9 membered cycloalkyl or heterocyclic groups a bicyclic group containing at least one hetero atom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups, And the bicyclic group which is a monocyclic C ₆ -C ₉ aryl group or a 5 to 9 membered heteroaryl group fused to a 5 to 9 membered cycloalkyl group or a heterocyclic group is unsubstituted or selected from one or more selected from the group consisting of Substituent substitution: halogen atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl ; monocyclic or bicyclic C ₆ -C ₁₄ aryl group; at least one selected from the group comprising 5-14 heteroaryl group O, S and N atoms, the heteroatoms; comprising At least one selected from O, 5 to 14-membered heterocyclic group of ;-( S and N heteroatoms CH _{2) 1-3} CN groups ;-( CH _{2) n} OR ₁₁ groups; -NR ₁₁ R ₁₂ group -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O a ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or one or more Further substituted by a carboxyl group; R ₃ and R ₄ each independently represent a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group, said alkane Substituent substituted or substituted with one or more substituents selected from C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidine R ₅ and R ₆ each independently represent a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 members containing at least one hetero atom selected from O, S and N Aryl; 5 to 14 membered heterocyclic group containing at least one hetero atom selected from O, S and N; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O )-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group a group of -C(O)-(CH ₂ ) _n -R ₁₁ ;-C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ groups; wherein each n is 0, 1 or 2; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or one or more Substituted with a substituent selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C _{7 group} a cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0, 1 or 2; R ₈ , R ₉ And R ₁₀ are independent Is a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or selected by one or more Substituted from the following substituents: C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; each of R ₁₁ , R ₁₂ and R ₁₃ Independently representing a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or one or more Substituted by a substituent selected from C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl.

Typically, in the compound of formula (I) or formula (I'), X and Y each independently represent a nitrogen atom or a -CR ₆ group, wherein at least one of X and Y represents a -CR ₆ group.

In one embodiment, in the compound of Formula (I) or Formula (I'), X represents a nitrogen atom and Y represents a -CR ₆ group.

In another embodiment, in the compound of Formula (I) or Formula (I'), Y represents a nitrogen atom and X represents a -CR ₆ group.

In another embodiment, in the compound of Formula (I) or Formula (I'), both X and Y represent a -CR ₆ group.

For the avoidance of doubt, when two -CR ₆ groups are present, they may be the same or different.

In the compound of formula (I) or formula (I'), both X and Y preferably represent a -CR ₆ group.

In one embodiment, in the compound of Formula (I) or Formula (I'), A represents a nitrogen atom and B represents a -CR ₇ group.

In another embodiment, in the compound of Formula (I) or Formula (I'), B represents a nitrogen atom and A represents a -CR ₇ group.

In another embodiment, in the compound of Formula (I) or Formula (I'), A and B independently represent a -CR ₇ group.

For the avoidance of doubt, when two -CR ₇ groups are present, they may be the same or different.

Preferably, in the compound of formula (I) or formula (I'), A represents a nitrogen atom and B represents a -CR ₇ group.

Typically, in the compound of formula (I), D represents a nitrogen atom or a -CR ₅ group, wherein when one of A and B represents a nitrogen atom, D represents a -CR ₅ group.

In one embodiment, in the compound of formula (I), when A and B independently represent a -CR ₇ group, D represents a nitrogen atom.

In another embodiment, in the compound of formula (I), when A represents a nitrogen atom and B represents a -CR ₇ group, D represents a -CR ₅ group.

In another embodiment, in the compound of formula (I), when A represents a -CR ₇ group and B represents a nitrogen atom, D represents a -CR ₅ group.

Usually, in the compound of the formula (I) or the formula (I'), R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxy group. Alkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl.

In the compound of formula (I) or formula (I'), R ₁ preferably represents a hydrogen atom, a straight or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxy group. Alkyl, C ₃ -C ₇ cycloalkyl, phenyl or pyridyl.

In the compound of the formula (I) or the formula (I'), R _{1 more} preferably represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group or a C ₁ -C ₃ hydroxy group. alkyl. R ₁ preferably represents a hydrogen atom.

Typically, in the compound of formula (I), R ₂ represents a straight or branched C ₁ -C ₆ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; a C ₃ -C ₇ ring Alkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, S and N; containing 1, 2 or 3 selected from 5 to 7 membered heterocyclic groups of hetero atoms of O, S and N,

Wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: a halogen atom; a cyano group; a straight or branched chain C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; containing at least one selected 5 to 14 membered heteroaryl groups of hetero atoms from O, S and N; 5 to 14 membered heterocyclic groups containing at least one hetero atom selected from O, S and N; -(CH ₂ ) _1-3 CN group a group of -(CH ₂ ) _n OR ₁₁ ;-NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n- NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH _{2 ) n '-C (O) -} (CH 2) n -NR 11 R 12 group _{;-( CH 2) n' -S (} O) 2 (CH 2) n R 11 group ;-( CH _{2) n '-S (O) 2 (} CH 2) n NR 11 R 12 _{groups; -NR 11 S (O) 2} (CH 2) n R 12 group or _{-NR 11 S (O) 2 (} CH 2) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ are as defined above and said monocyclic or bicyclic C ₆ -C ₁₄ aryl is not Substituted or A plurality of carboxyl groups further substituted.

In the compound of formula (I), R ₂ preferably represents a straight or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ ring An alkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group or a piperidinyl group;

Wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen Atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; phenyl; Substituted phenyl; pyridyl; triazolyl; thiazolyl; pyrimidinyl; piperidinyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ a group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-( CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group a group of -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ or a group -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ wherein each n' and n is 0, 1 Or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ are as defined above.

In the compound of the formula (I), R _{2 more} preferably represents a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group or a piperidinyl group, wherein the cycloalkyl group, the phenyl group, the pyridyl group or the pyrimidinyl group are unsubstituted. Or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen atoms, straight or branched C ₁ -C ₃ alkyl groups, C ₁ -C ₃ haloalkyl groups, triazolyl groups, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -NR ₁₁ a R ₁₂ group or -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ ; wherein each n' and n is 0, 1 or 2; and wherein R ₁₁ and R ₁₂ are each independently represented A hydrogen atom, a methyl group or a piperidinyl group substituted with a hydroxyl group.

In the compound of the formula (I), the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups which R ₂ may represent are particularly preferably unsubstituted or 1, 2 or 3, preferably 1 or Substituted by two substituents selected from the group consisting of: a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; a triazolyl group; a -(CH ₂ ) _1-3 CN group; -C(O) -(CH ₂ ) _1-3 -CN group; or -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ ; wherein n' is 0, 1 or 2 and R ₁₁ represents a hydroxyl group Substituted piperidinyl.

More preferably, R ₂ represents a cyclohexyl group, a pyridyl group or a piperidinyl group, wherein the cyclohexyl group, pyridyl group and piperidinyl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen atoms, three Azolyl, -(CH ₂ ) _1-3 CN group, -C(O)-(CH ₂ ) _1-3 -CN group or -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ ; wherein n' is 0, 1 or 2 and R ₁₁ represents a piperidinyl group substituted by a hydroxy group.

Preferably, in the compound of the formula (I), when R ₂ is a C ₃ -C ₇ cycloalkyl group, it is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group. The group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched chain C ₁ -C ₃ alkyl group, C ₁ -C ₃ Haloalkyl, -(CH ₂ ) _1-3 CN group, hydroxy or -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ ; wherein n' is 0, 1 or 2 and R ₁₁ represents a piperidinyl group substituted with a hydroxyl group. More preferably, when R ₂ is a C ₃ -C ₇ cycloalkyl group, it is preferably a cyclohexyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a straight chain or a branched chain C ₁ -C ₃ alkyl (preferably methyl), -(CH ₂ ) _1-3 CN group, hydroxy or -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ ; 'is 0, 1 or 2 and R ₁₁ represents a piperidinyl group substituted by a hydroxy group.

Preferably, in the compound of formula (I), when R ₂ is a C ₃ -C ₇ cycloalkyl group, m is 0. In other words, when R ₂ is a C ₃ -C ₇ cycloalkyl group, it is directly bonded to the nitrogen atom of the -NR ₁ group.

Preferably, in the compound of formula (I), when R ₂ is pyridyl, the group is attached to the remainder of the molecule via a ring carbon atom, in other words, it is attached to the -NR ₁ group via a ring carbon atom. The nitrogen atom-bonded group -(R ₃ -CR ₄ ) _m -. The pyridyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom (preferably a fluorine atom or a chlorine atom); a cyano group; a linear or branched C ₁ -C ₃ alkyl group; _1- C ₄ haloalkyl (preferably -CHF ₂ group or -CF ₃ group); C ₃ -C ₇ cycloalkyl; phenyl; pyridyl; pyrimidinyl; piperidinyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C( O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group ;-(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) _{a 2} (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a straight or branched chain C ₁ -C ₃ alkyl. The pyridyl group is more preferably substituted with 1 or 2 halogen atoms.

Preferably, in the compound of formula (I), when R ₂ is piperidinyl, it is attached to the remainder of the molecule via a ring carbon atom. In this case, m is 0. In other words, when R ₂ is piperidinyl, it is directly bonded to the nitrogen atom of the -NR ₁ group.

Preferably, in the compound of formula (I), when R ₂ is piperidinyl, it is unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom (preferably a fluorine atom or chlorine). Atom); cyano; straight or branched C ₁ -C ₃ alkyl; C ₁ -C ₄ haloalkyl (preferably -CHF ₂ group or -CF ₃ group); C ₃ -C ₇ naphthenic Phenyl; pyridyl; pyrimidinyl; piperidinyl; triazolyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group ;-(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group;- NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2; And wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. Preferably, when R ₂ is piperidinyl, it is substituted with 1 or 2 substituents selected from a halogen atom, a -C(O)-(CH ₂ ) _1-3 -CN group or a triazole base.

Typically, in the compound of formula (I'), R ₂ represents a straight or branched C ₁ -C ₆ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; C ₃ -C ₇ Cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, S and N; containing 1, 2 or 3 a 5- to 7-membered heterocyclic group derived from a hetero atom of O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or selected from one or more Substituted by the following substituent: halogen atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ naphthenic Monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; containing at least one hetero atom selected from O, S and N 5 to 14 membered heterocyclic group; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH _{2 n-} R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C( O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ a group of (CH ₂ ) _n NR ₁₂ R ₁₃ ; wherein each n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ are as defined above and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group Unsubstituted or further substituted with one or more carboxyl groups.

In the compound of the formula (I'), R ₂ preferably represents a straight or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ group. Cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl; wherein said cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl , pyrrolidinyl or piperidinyl unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of: a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; C ₁ -C _4- haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; phenyl; phenyl substituted by carboxy; pyridyl; triazolyl; thiazolyl; pyrimidinyl; piperidinyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH _{2 group n} NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; Each n is 0, 1 or 2 and wherein R ₁₁ , R ₁₂ and R ₁₃ are as defined above.

In the compound of the formula (I'), R _{2 more} preferably represents a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group or a piperidinyl group, wherein the cycloalkyl group, the phenyl group, the pyridyl group or the pyrimidinyl group are not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen atoms, straight or branched C ₁ -C ₃ alkyl groups, C ₁ -C ₃ haloalkyl groups, triazolyl groups, -(CH _{2 ) 1-3} CN group, -(CH ₂ ) _n OR ₁₁ group, -C(O)-(CH ₂ ) _1-3 -CN group or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein each n is 0, 1 or 2; and wherein R ₁₁ and R ₁₂ each independently represent a hydrogen atom or a methyl group.

In the compound of the formula (I'), the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups which R ₂ may represent are particularly preferably unsubstituted or 1, 2 or 3, preferably 1 Or 2 substituents selected from the group consisting of: a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; a triazolyl group; a -(CH ₂ ) _1-3 CN group; and a -C ( O)-(CH ₂ ) _1-3 -CN group.

More preferably, R ₂ represents a cyclohexyl group, a pyridyl group or a piperidinyl group, wherein the cyclohexyl group, pyridyl group and piperidinyl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen atoms, three An azolyl group, a -(CH ₂ ) _1-3 CN group or a -C(O)-(CH ₂ ) _1-3 -CN group.

Preferably, when R ₂ is a C ₃ -C ₇ cycloalkyl group, it is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, and the group is unsubstituted or passed through 1, 2 or 3 substituents selected from the group consisting of a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, -(CH ₂ ) _1-3 CN group or hydroxyl group. More preferably, when R ₂ is a C ₃ -C ₇ cycloalkyl group, it is preferably a cyclohexyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a straight chain or a branched chain C ₁ -C ₃ alkyl (preferably methyl), -(CH ₂ ) _1-3 CN group or hydroxy group.

Preferably, in the compound of the formula (I'), when R ₂ is a C ₃ -C ₇ cycloalkyl group, m is 0. In other words, when R ₂ is a C ₃ -C ₇ cycloalkyl group, it is directly bonded to the nitrogen atom of the -NR ₁ group.

Preferably, in the compound of the formula (I'), when R ₂ is a pyridyl group, the group is bonded to the remainder of the molecule via a ring carbon atom, in other words, it is bonded to the -NR ₁ group via a ring carbon atom. The nitrogen-bonded group of the group -(R ₃ -CR ₄ ) _m -. The pyridyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom (preferably a fluorine atom or a chlorine atom); a cyano group; a linear or branched C ₁ -C ₃ alkyl group; _1- C ₄ haloalkyl (preferably -CHF ₂ group or -CF ₃ group); C ₃ -C ₇ cycloalkyl; phenyl; pyridyl; pyrimidinyl; piperidinyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C( O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group ;-C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R _{a 12} group; a NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or And wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. The pyridyl group is more preferably substituted with 1 or 2 halogen atoms.

Preferably, in the compound of formula (I'), when R ₂ is piperidinyl, it is attached to the remainder of the molecule via a ring carbon atom. In this case, m is 0. In other words, when R ₂ is piperidinyl, it is directly bonded to the nitrogen atom of the -NR ₁ group.

Preferably, in the compound of the formula (I'), when R ₂ is piperidinyl, it is unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom (preferably a fluorine atom or a chlorine atom; a cyano group; a linear or branched C ₁ -C ₃ alkyl group; a C ₁ -C ₄ haloalkyl group (preferably a -CHF ₂ group or a -CF ₃ group); a C ₃ -C ₇ ring Alkyl; phenyl; pyridyl; pyrimidinyl; piperidinyl; triazolyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group ;-NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ a _1-3 -CN group; a -C(O)-(CH ₂ ) _n -R ₁₁ group; a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ a group of S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ ; wherein each n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a straight or branched chain C _1- C ₃ alkyl. Preferably, when R ₂ is piperidinyl, it is substituted with 1 or 2 substituents selected from a halogen atom, a -C(O)-(CH ₂ ) _1-3 -CN group or a triazole base.

In general, in the compound of the formula (I) or the formula (I'), R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ alkoxy substitution. Preferably, R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

More preferably, R ₃ and R ₄ each independently represent a hydrogen atom or a methyl group.

Usually, in the compound of the formula (I) or the formula (I'), R ₅ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O) -(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S( O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ a group; wherein each n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

In the compound of the formula (I) or the formula (I'), R ₅ preferably represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group or a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0, 1 or 2; and wherein R ₁₁ And R ₁₂ each independently represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

In the compound of the formula (I) or the formula (I'), R _{5 more} preferably represents a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched C ₁ -C ₃ alkyl group, C ₁ - a C ₃ haloalkyl group or a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0 or 1; and wherein R ₁₁ and R ₁₂ each independently represent a hydrogen atom or a methyl group.

R _{5 more} preferably represents a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched C ₁ -C ₃ alkyl group or a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group. And wherein n is 0 or 1; and wherein R ₁₁ and R ₁₂ independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

Typically, in the compound of formula (I) or formula (I'), R ₆ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 1, 2 or 3 heteroatoms selected from O, S and N a 7-membered heteroaryl; or a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclic groups Unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ - a C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0, 1 or 2; and wherein R ₁₁ and R ₁₂ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

In the compound of the formula (I) or the formula (I'), R ₆ preferably represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl; wherein the cycloalkane a group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydropyranyl group or a morpholinyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen atoms, Cyano, linear or branched C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl.

In the compound of the formula (I) or the formula (I'), R _{6 more} preferably represents a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), a cyano group, a linear or branched C ₁ -C ₃ alkyl group, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or morpholinyl.

More preferably, R ₆ represents a hydrogen atom or a halogen atom (preferably a fluorine atom or a chlorine atom).

Preferably, when R ₆ is pyridyl, it is attached to the remainder of the molecule via a ring carbon atom. In other words, when R ₆ is a pyridyl group, it is bonded to the pyridine-2(1H)-one ring via a ring carbon atom of a pyridyl group.

Preferably, when R ₆ is pyrimidinyl or morpholinyl, it is attached to the remainder of the molecule via a ring nitrogen atom. In other words, when R ₆ is a pyrimidinyl group or a morpholinyl group, it is bonded to the pyridine-2(1H)-one ring via a ring nitrogen atom of a pyrimidinyl group or a morpholinyl group.

Usually, in the compound of the formula (I) or the formula (I'), R ₇ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 1, 2 or 3 heteroatoms selected from O, S and N a 7-membered heteroaryl; or a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclic groups Unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ - C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH _{2 n} -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O ) ₂ (CH ₂ ) an _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ are each independently The ground represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

In the compound of the formula (I) or the formula (I'), R ₇ preferably represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholine base;

Wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl is unsubstituted or 1, 2 or 3 Substituted by a substituent selected from the group consisting of a halogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ naphthenic group Phenyl, phenyl, carboxy substituted phenyl, pyridyl, triazolyl, thiazolyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _{1- 3-} CN group, -C(O)-(CH ₂ ) _n -R ₁₂ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₂ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O a ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0 or 1; and wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a methyl group.

The cycloalkyl, aryl, heteroaryl and heterocyclic groups which R ₇ may represent are particularly preferably unsubstituted or substituted by 1, 2 or 3, preferably 1 or 2, substituents selected from halogen atoms. a straight or branched C ₁ -C ₆ alkyl group, a phenyl group, a carboxy substituted phenyl group, and a —(CH ₂ ) _n OR ₁₁ group, wherein n is 0, 1 or 2 and wherein R ₁₁ represents hydrogen Aromatic or linear or branched C ₁ -C ₃ alkyl.

R ₇ preferably represents a hydrogen atom, a piperidinyl group, a thiazolyl group or a morpholinyl group; wherein the piperidinyl group, the thiazolyl group and the morpholinyl group are unsubstituted or have one or two substituents selected from a hydroxyl group or a benzoic acid group. Replace.

Preferably, when R ₇ is pyridinyl, pyrimidinyl, triazolyl or thiazolyl, it is attached to the remainder of the molecule via a ring carbon atom. In other words, when R ₇ is pyridinyl, pyrimidinyl, triazolyl or thiazolyl, it is bonded to the formula (I) or formula (I' via a ring carbon atom of a pyridyl, pyrimidinyl, triazolyl or thiazolyl group. The central ring of the compound.

Preferably, when R ₇ is pyrimidinyl or morpholinyl, it is attached to the remainder of the molecule via a ring nitrogen atom. In other words, when R ₇ is pyrimidinyl or morpholinyl, it is bonded to the central ring of the compound of formula (I) via a ring nitrogen atom of a pyrimidinyl or morpholinyl group.

Typically, in the compound of formula (I) or formula (I'), m is 0, 1 or 2; preferably 0 or 1.

Typically, in the compound of formula (I) or formula (I'), n represents 0, 1 or 2.

Typically, in the compounds of formula (I), n' represents 0, 1 or 2.

Typically, in the compound of formula (I) or formula (I'), R ₈ represents a hydrogen atom or a straight or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ alkane Oxygen substitution. R ₈ preferably represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. More preferably, R ₈ represents a hydrogen atom.

In general, in the compound of the formula (I) or the formula (I'), R ₉ and R ₁₀ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group. Preferably, R ₉ and R ₁₀ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. More preferably, R ₉ and R ₁₀ each represent a hydrogen atom.

In general, in the compound of the formula (I), R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom; a linear or branched C ₁ -C ₃ alkyl group; or 1, 2 or 3 selected from O, a 5- to 7-membered heterocyclic group of a hetero atom of S and N, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from a halogen atom, a hydroxyl group, a straight chain or a branched chain C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ hydroxyalkyl. Preferably, in the compound of the formula (I), R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

In general, in the compound of the formula (I'), R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

Typically, in the compound of formula (I) or formula (I'), W represents a linking group selected from the group consisting of a -NR ₈ - group, a -(CR ₉ R ₁₀ )- group, -O- or -S-, Wherein R ₈ , R ₉ and R ₁₀ are as defined above. In the compound of formula (I) or formula (I'), W preferably represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group, wherein R ₈ , R ₉ and R ₁₀ as defined above. More preferably, W represents a -NR ₈ - group, wherein R _{8 is} as defined above. W even more preferably represents a -NR ₈ - group, wherein R ₈ is a hydrogen atom or a C ₁ -C ₃ alkyl group. W preferably represents a -NR ₈ - group, wherein R ₈ is a hydrogen atom or a methyl group. W even better represents the -NH- group.

When R ₂ , R ₅ , R ₆ and R ₇ may represent a cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic group via one or more -NR ₁₁ C(O)-(CH ₂ ) _{When n-} R ₁₂ group or one or more -C(O)-(CH ₂ ) _n -R ₁₁ groups are substituted, and n is 0, then R ₁₁ or R ₁₂ preferably does not represent a hydrogen atom.

In a particularly preferred embodiment, m is 0, 1 or 2 in the compound of formula (I); X is a nitrogen atom and Y is a -CR ₆ group; or Y is a nitrogen atom and X is a -CR ₆ group Or both X and Y are -CR ₆ groups; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group; W represents a group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group a linking group; preferably a -NR ₈ - group; R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group , C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ represents straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 members containing 1, 2 or 3 heteroatoms selected from O, S and N a heteroaryl group; a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic ring The base is unsubstituted or substituted with one or more substituents selected from the group consisting of: Su atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl group; a monocyclic or bicyclic a C ₆ -C ₁₄ aryl group; a 5 to 14 membered heteroaryl group containing at least one hetero atom selected from O, S and N; a 5 to 14 membered heterocyclic ring containing at least one hetero atom selected from O, S and N a group of -(CH ₂ ) _1-3 CN; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH _{2 n-} R ₁₁ group; -(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH _{2 n} R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or a group of -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ ; wherein each n' and n are 0, 1 or 2 and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or Further substituted with one or more carboxy groups, R ₃ and R ₄ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₆ alkyl group, wherein the alkyl group is unsubstituted or C ₁ -C ₂ alkoxy substituent; R ₅ represents a hydrogen atom A halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, - (CH _{2 n} OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) _{a 2} (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom; a halogen atom; Cyano; straight or branched C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ - a C ₁₀ aryl group; a 5 to 7 membered heteroaryl group containing 1, 2 or 3 hetero atoms selected from O, S and N; and 5, 1 or 3 hetero atoms selected from O, S and N a 7-membered heterocyclic group wherein the cycloalkyl group, the aryl group, the heteroaryl group, and the heterocyclic group are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, and a straight Chain or branched C ₁ -C ₆ alkane , C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0, 1 or 2

R ₇ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; a C ₃ -C ₇ naphthenic group; Monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, S and N; containing 1, 2 or 3 selected from O a 5- to 7-membered heterocyclic group of a hetero atom of S, and N, wherein the cycloalkyl group, the aryl group, the heteroaryl group, and the heterocyclic group are unsubstituted or have 1, 2 or 3 substituents selected from the group consisting of Substitution: halogen atom, cyano group, linear or branched C ₁ -C ₆ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, phenyl group a phenyl group substituted with a carboxyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group, a -(CH ₂ ) _1-3 CN group, a -(CH ₂ ) _n OR ₁₁ group, a -NR ₁₁ R ₁₂ group, NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _{1 -3} -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ ( CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S ( O) ₂ (CH ₂ ) _n NR _{a 12} R ₁₃ group; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ alkane Oxy substituted; R ₉ and R ₁₀ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom; straight or branched chain C ₁ -C ₃ alkyl; or a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, which are unsubstituted or 1, 2 or 3 Substituted with a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a C ₁ -C ₄ hydroxyalkyl group.

In another particularly preferred embodiment, in the compound of formula (I): m is 0, 1 or 2; both X and Y represent a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group and D is a -CR ₅ group; or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or -CR ₅ a group; W represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; preferably a -NR ₈ - group; R ₁ represents a hydrogen atom, a straight chain or a branched chain C _1- C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ represents Linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl a 5 to 7 membered heteroaryl group containing 1, 2 or 3 hetero atoms selected from O, S and N; 5 to 7 members containing 1, 2 or 3 hetero atoms selected from O, S and N a heterocyclic group wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or substituted by one or more substituents selected from the group consisting of halogen atoms; cyano; straight chain Or branched chain C ₁ -C ₆ alkyl; C ₁ - C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; containing at least one hetero atom selected from O, S and N 5 to 14 membered heteroaryl; 5 to 14 membered heterocyclic group containing at least one hetero atom selected from O, S and N; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ a group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group ;-C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH ₂ ) _n' -C(O)-( CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; n' and n are 0, 1 or 2 and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further substituted by one or more carboxyl groups, and R ₃ and R ₄ each independently represent a hydrogen atom or a straight a chain or branched C ₁ -C ₆ alkyl group which is unsubstituted or substituted with a C ₁ -C ₂ alkoxy group; R ₅ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched chain C ₁ -C ₄ alkyl, C _1- C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C ( O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN a group, a -C(O)-(CH ₂ ) _n -R ₁₁ group, a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ ( CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; C ₁ -C _4- haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; containing 1, 2 or 3 selected from O, S and N a 5 to 7 membered heteroaryl group of a hetero atom; a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl group, the aryl group, the heteroaryl group And the heterocyclic group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, and a C ₁ -C ₄ haloalkyl group. , C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl , Phenyl, pyridyl, pyrimidinyl, piperidinyl or _{-C (O) - (CH 2} ) n -NR 11 R 12 group; wherein n is 0, 1 or 2R ₇ represents a hydrogen atom; a halogen atom; cyano Linear or branched C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 hetero atoms selected from O, S and N; 5 to 1, 2 or 3 heteroatoms selected from O, S and N a 7-membered heterocyclic group wherein the cycloalkyl group, the aryl group, the heteroaryl group and the heterocyclic group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, and a linear chain Or branched chain C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl , pyrimidinyl, piperidinyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH _{2 n-} R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C() _{O) - (CH 2) n} -R 11 group, -C (O) - (CH 2) n -NR 11 R 12 _{groups, -S (O) 2 (CH} 2) n R 11 group _{, -S (O) 2 (CH} 2) n NR 11 R 12 _{groups, -NR 11 S (O) 2} (CH 2) n R 12 group or _{-NR 11 S (O) 2 (} CH 2) n a group of NR ₁₂ R ₁₃ ; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ Alkoxy substituted; R ₉ and R ₁₀ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom; straight or branched chain a C ₁ -C ₃ alkyl group; or a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, which are unsubstituted or 1, 2 or 3 Substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a C ₁ -C ₄ hydroxyalkyl group.

In another particularly preferred embodiment, in the compound of formula (I): m is 0 or 1; both X and Y represent a -CR ₆ group; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group ;W represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; preferably a -NR ₈ - group; R ₁ represents a hydrogen atom, a straight or branched chain C ₁ - C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₁ -C ₃ hydroxyalkyl; R ₂ represents straight or branched C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl; wherein said cycloalkyl, phenyl, Pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen atom; cyano; straight or branched chain C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; phenyl; carboxy substituted phenyl; pyridyl; triazole Thiazole ; Pyrimidinyl; piperidinyl ;-( CH _{2) n} OR ₁₁ groups; -NR ₁₁ R _{12 groups; -NR 11 C (O) -} (CH 2) n -R 12 groups; -NR ₁₁ C (O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group group _{;-( CH2) n '-C (O} ) - (CH 2) n -NR 11 R 12 group _{;-( CH 2) n' -S (} O) 2 (CH 2) n R 11 group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2; R ₃ and R ₄ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group ; R ₅ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ ring Alkyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ a group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n- R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ a S(O) ₂ (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom , halogen atom, cyano group, linear or branched C ₁ -C ₃ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, phenyl group, Pyridyl, pyrimidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl; R ₇ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched chain C ₁ -C ₃ Alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, Piperidinyl, tetrahydropyranyl or morpholinyl; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl Or the morpholinyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, triazolyl, thiazolyl, pyrimidinyl, piperidinyl, -( CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n - NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₂ group, -C(O)-(CH ₂ ) _n- NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₂ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S ( O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a straight a chain or a branched chain C ₁ -C ₃ alkyl; R ₉ and R ₁₀ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; and R ₁₁ , R ₁₂ and R ₁₃ each independently represent hydrogen. An atomic or linear or branched C ₁ -C ₃ alkyl group; or a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, said heterocyclic group being unsubstituted Or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a C ₁ -C ₄ hydroxyalkane base.

In another particularly preferred embodiment, in the compound of formula (I): m is 0 or 1; both X and Y represent a -CR ₆ group; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group ;W represents a -NH- group or a -CH ₂ - group; preferably an -NH- group; R ₁ represents a hydrogen atom, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ hydroxyalkyl group or a linear chain; Or a branched C ₁ -C ₃ alkyl group; R ₂ represents a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a morpholinyl group, wherein the cycloalkyl group, the phenyl group, Pyridyl, pyrimidinyl, piperidinyl or morpholinyl unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen atoms, straight or branched C ₁ -C ₃ alkyl groups, C ₁ -C ₃ haloalkyl, triazolyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _0-2 OR ₁₁ group or -C(O)-(CH ₂ ) _1-3 - a CN group; R ₃ and R ₄ each independently represent a hydrogen atom or a methyl group; R ₅ represents a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, C ₃ -C ₇ cycloalkyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0 or 1; R ₆ represents a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₃ -C ₇ naphthenic group Or a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a morpholinyl group, wherein the cycloalkyl group, phenyl group, pyridyl group, pyrimidinyl group, piperidinyl group or morpholinyl group is unsubstituted or 1, 2 Or 3 substituents selected from the group consisting of: a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a triazolyl group, a -(CH ₂ ) _1-3 CN group a group or a -(CH ₂ ) _0-2 OR ₁₁ group; R ₇ represents a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₃ -C group ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group unsubstituted or 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a phenyl group, a phenyl group substituted with a carboxyl group , triazolyl, - (CH _{2) 1-3} CN group or - (CH _{2) 0-2} oR ₁₁ group; R _8, R ₉ and R ₁₀ each independently represent A hydrogen atom or a methyl group; R ₁₁ and R ₁₂ each independently represent a hydrogen atom or a methyl group.

In another particularly preferred embodiment, in the compound of formula (I): m is 0 or 1; both X and Y represent a -CR ₆ group; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group ;W represents a -NH- group or a -CH ₂ - group; preferably an -NH- group; R ₁ represents a hydrogen atom; R ₂ represents a cyclohexyl group, a pyridyl group or a piperidinyl group, wherein the cyclohexyl group, pyridine The group and the group such as piperidinyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a triazolyl group, a -(CH ₂ ) _1-3 CN group, and -C(O). a -(CH ₂ ) _1-3 -CN group or a -(CH ₂ )-S(O) ₂ -pyrimidinyl group which is unsubstituted or substituted with 1, 2 or 3 hydroxy groups; R ₃ and R ₄ each independently represents a hydrogen atom or a methyl group; R ₅ represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₃ alkyl group, a -OCH ₃ group or -C(O)-(CH) ₂ ) an _n- NR ₁₁ R ₁₂ group; wherein n is 0 or 1; and wherein R ₁₁ and R ₁₂ independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; R ₆ represents a hydrogen atom, Halogen Or pyrazolyl; R ₇ represents a hydrogen atom, piperidinyl, thiazolyl or morpholinyl; wherein the piperidinyl, thiazolyl and morpholinyl are unsubstituted or 1 or 2 are selected from hydroxy or benzene Substituted by a formic acid substituent.

In a particularly preferred embodiment, m is 0, 1 or 2 in the compound of formula (I'); X is a nitrogen atom and Y is a -CR ₆ group; or Y is a nitrogen atom and X is a -CR ₆ group Or X and Y are all -CR ₆ groups; A is a nitrogen atom and B is a -CR ₇ group; or B is a nitrogen atom and A is a -CR ₇ group; or both A and B are -CR ₇ a group; W represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; R ₁ represents a hydrogen atom, a straight or branched chain C ₁ -C ₆ alkyl group, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ represents straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; containing 1, 2 or 3 a 5 to 7 membered heteroaryl group selected from hetero atoms of O, S and N; a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkane a group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group are unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkane group; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl Group; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl group; at least one selected from the group comprising 5-14 heteroaryl group O, S and N atoms, the heteroatom; containing at least one selected from 5 to 14 membered heterocyclic groups of hetero atoms of O, S and N; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _{1- 3-} CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O a ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further substituted by one or more carboxyl groups And R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or substituted with a C ₁ -C ₂ alkoxy group; R ₅ represents a hydrogen atom , halogen atom, cyano group, linear or branched C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ a group, a -C(O)-(CH ₂ ) _1-3 -CN group, a -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n - NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ ( CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom; a halogen atom; a cyano group Linear or branched C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ An aryl group; a 5 to 7 membered heteroaryl group containing 1, 2 or 3 hetero atoms selected from O, S and N; 5 to 7 containing 1, 2 or 3 hetero atoms selected from O, S and N Heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms, cyano groups, straight chains or Branched chain C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O)-(CH ₂ ) _n -N R ₁₁ R ₁₂ group; wherein n is 0, 1 or 2

R ₇ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; a C ₃ -C ₇ naphthenic group; Monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, S and N; containing 1, 2 or 3 selected from O a 5- to 7-membered heterocyclic group of a hetero atom of S, and N, wherein the cycloalkyl group, the aryl group, the heteroaryl group, and the heterocyclic group are unsubstituted or have 1, 2 or 3 substituents selected from the group consisting of Substitution: halogen atom, cyano group, linear or branched C ₁ -C ₆ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, phenyl group a phenyl group substituted with a carboxyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group, a -(CH ₂ ) _1-3 CN group, a -(CH ₂ ) _n OR ₁₁ group, a -NR ₁₁ R ₁₂ group, NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _{1 -3} -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ ( CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S ( O) ₂ (CH ₂ ) _n N a group of R ₁₂ R ₁₃ wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a straight or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ Alkoxy substituted; R ₉ and R ₁₀ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; and R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a straight or branched chain C ₁ -C ₃ alkyl.

In another particularly preferred embodiment, in the compound of formula (I'): m is 0 or 1; X and Y are each independently a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group Or B is a nitrogen atom and A is a -CR ₇ group; or both A and B are -CR ₇ groups; W represents a linkage selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group a group; R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group or a C ₁ -C ₃ hydroxyalkyl group; and R ₂ represents a straight or branched chain C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrole a pyridyl or piperidinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl group is unsubstituted or 1, 2 or 3 is selected from Substituted by the following substituent: halogen atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ naphthenic Phenyl; phenyl substituted by carboxy; pyridyl; triazolyl; thiazolyl; pyrimidinyl; piperidinyl; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; ₁₁ C ( O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN a group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ ( CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; R ₅ represents hydrogen Atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, -( CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0 , 1 or 2; R ₆ represents a hydrogen atom, a halogen Atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl , pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl; R ₇ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, C ₁ - C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydrogen a piperidyl or morpholinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl groups are not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group , C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, triazolyl, thiazolyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O )-(CH ₂ ) _{1 -3} -CN group, -C(O)-(CH ₂ ) _n -R ₁₂ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ ( CH ₂ ) _n R ₁₂ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S ( O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; each of R ₉ and R ₁₀ The hydrogen atom or the linear or branched C ₁ -C ₃ alkyl group is independently represented; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group.

In another particularly preferred embodiment, in the compound of formula (I'): m is 0 or 1; both X and Y represent a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group; B is a nitrogen atom and A is a -CR ₇ group; or both A and B are a -CR ₇ group; W represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group ; R ₁ represents a hydrogen atom, a C ₁ -C ₃ haloalkyl group, a C ₁ -C ₃ hydroxyalkyl group or a linear or branched C ₁ -C ₃ alkyl group; R ₂ represents a C ₃ -C ₇ cycloalkyl group, a phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group is unsubstituted or 1, 2 or 3 Substituted by a substituent selected from the group consisting of a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a triazolyl group, a -(CH ₂ ) _1-3 CN group, a -(CH ₂ ) _0-2 OR ₁₁ group or a -C(O)-(CH ₂ ) _1-3 -CN group; R ₃ and R ₄ each independently represent a hydrogen atom or a methyl group; R ₅ represents hydrogen Atom, a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₃ -C ₇ cycloalkyl group or a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0 or 1; R ₆ represents a hydrogen atom, a halogen Atom, straight or branched C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl Wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms, straight chains or branches a chain C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, triazolyl, -(CH ₂ ) _1-3 CN group or -(CH ₂ ) _0-2 OR ₁₁ group; R ₇ represents a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₃ haloalkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or Morpholinyl, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group , straight or branched C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, phenyl, carboxy substituted phenyl, triazolyl, -(CH ₂ ) _1-3 CN group or - (CH ₂ ) _0-2 OR ₁₁ group; R ₈ , R ₉ and R ₁₀ each independently represent a hydrogen atom or a methyl group; R ₁₁ and R ₁₂ each independently represent Show a hydrogen atom or a methyl group.

In another particularly preferred embodiment, in the compound of formula (I'): m is 0 or 1; both X and Y represent a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group; B is a nitrogen atom and A is a -CR ₇ group; or both A and B are a -CR ₇ group; W represents a -NH- group or a -CH ₂ - group; R ₁ represents a hydrogen atom; R ₂ represents a ring Hexyl, pyridyl or piperidinyl, wherein the cyclohexyl, pyridyl and piperidinyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen atoms, triazolyl, -(CH) ₂ ) _1-3 CN group or -C(O)-(CH ₂ ) _1-3 -CN group; R ₃ and R ₄ each independently represent a hydrogen atom or a methyl group; R ₅ represents a hydrogen atom, a halogen atom a straight or branched C ₁ -C ₃ alkyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0 or 1; and wherein R ₁₁ and R _{12 are} independently represented a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; R ₆ represents a hydrogen atom or a halogen atom; R ₇ represents a hydrogen atom, a piperidinyl group, a thiazolyl group or a morpholinyl group; wherein the piperidinyl group, the thiazole group The base and morpholinyl are unsubstituted or substituted with 1 or 2 substituents selected from hydroxy or benzoic acid.

Specific individual compounds of the invention comprise: (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine-2(1H)-one; (S -3-(5-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one; (S)-3 -(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methoxypyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-3- (4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-hydroxypyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-4-(1- (5-fluoropyridin-2-yl)ethylamino)-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidine-5-carboxamide; (S)- 5-chloro-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine-2(1H)-one; (S )-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)-5-(1H-pyrazol-4-yl) Pyridine-2(1H)-one; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(4-hydroxypiperidin-1-yl)pyrimidine -2-ylamino)pyridine-2(1H)-one; (S)-3-(5-fluoro-4-(1-(5-fluoropyridin-2-yl)ethylamino)-6-( N-morpholinylpyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-3-(6-(1-(5-fluoro) 2-yl) ethylamino) pyrazin-2-ylamino) pyridine Acridine-2(1H)-one; (S)-3-(6-(1-(5-fluoropyridin-2-yl)ethylamino)pyridin-2-ylamino)pyridine-2(1H)- Ketone; 2-((1r,4r)-4-(5-methyl-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino) Cyclohexyl)acetonitrile; 3-(4-((1r,4r)-4-((3-hydroxypiperidin-1-ylsulfonyl)methyl)cyclohexylamino)pyrimidin-2-ylamino) Pyridine-2(1H)-one; (R)-3-oxo-3-(3-(2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidine- 4-(aminoamino)piperidin-1-yl)propanenitrile; (R)-3-(3-(5-methyl-2-(2- oxo-1,2-dihydropyridine-3- (amino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxopropanenitrile; (R)-3-(3-(5-fluoro-2-(2-)oxy -1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxomethoxypropionitrile; (R)-3-(4-(1 -(4H-1,2,4-triazol-3-yl)piperidin-3-ylamino)-5-fluoropyrimidin-2-ylamino)pyridine-2(1H)-one; (R) 3-(3-(2-(5-chloro-2-oxo-l,2-dihydropyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)piperidine- 1-yl)-3-oxomethoxypropionitrile; (R)-3-(3-(5-fluoro-6-(N-morpholinyl)-2-(2- oxo-1,2- Dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxomethoxypropionitrile; (R)-3-(3- (5-Methyl-6-(N-morpholinyl)-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidine- 1-yl)-3-oxooxypropionitrile; (R)-3-(3-(5-methyl-4-(N-morpholinyl)-6-(2- oxo-1,2) -dihydropyridin-3-ylamino)pyrimidin-2-ylamino)piperidin-1-yl)-3-oxomethoxypropionitrile; (R)-3-(3-(4-(5- Chloro-2-oxo-1,2-dihydropyridin-3-ylamine 5-(methyl)-6-(N-morpholinyl)pyrimidin-2-ylamino)piperidin-1-yl)-3-oxopropanenitrile; (R)-3-(3- (5-Chloro-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxo-propyl Nitrile; 3-[(4-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}pyrimidin-2-yl)methyl]pyridine-2(1H)-one; (S)-3-(5-(6-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-o-oxy-1,2-dihydropyridin-3-yl) Amino)pyrimidin-4-yl)thiazol-2-yl)benzoic acid; or a pharmaceutically acceptable salt or solvate thereof or N-oxide or a stereoisomer or a deuterated derivative. In one embodiment, a particular individual compound of the invention comprises: (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-ylamino)pyridine-2 (1H)-keto; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine-2 (1H )-ketone; (S)-5-chloro-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine-2 (1H)-keto; (S)-4-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-o-oxy-1,2-dihydropyridin-3-yl Amino)pyrimidine-5-carboxamide; (R)-3-oxo-3-(3-(2-(2-oxo-oxy-1,2-dihydropyridin-3-ylamino)) Pyrimidin-4-ylamino)piperidin-1-yl)propanenitrile; (R)-3-(3-(5-methyl-2-(2- oxo-1,2-dihydropyridine)- 3-aminoaminopyrimidin-4-ylamino)piperidin-1-yl)-3-oxopropanenitrile; (R)-3-(3-(5-fluoro-2-(2-side) Oxy-1,2-dihydropyridin-3-ylamino)pyrimidine (啶)-4-(amino)piperidin-1-yl)-3-oxopropanonitrile; (R)-3-(4-(1-(4H-1,2,4-triazole-3-) (piperidin-3-ylamino)-5-fluoropyrimidin-2-ylamino)pyridine-2(1H)-one; (R)-3-(3-(2-(5-chloro-2) -Sideoxy-1,2-dihydropyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)piperidin-1-yl)-3-oxomethoxypropionitrile; (S -3-(6-(1-(5-fluoropyridin-2-yl)ethylamino)pyrazin-2-ylamino)pyridine-2(1H)-one; 2-((1r,4r) 4-(5-methyl-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetonitrile; (S)-3 -(4-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(4-hydroxypiperidin-1-yl)pyrimidin-2-ylamino)pyridine-2(1H)- Ketone; 3-[(5-chloro-4-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}pyrimidin-2-yl)amino]pyridine-2 (1H )-ketone; (S)-3-((4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-yl)methyl)pyridine-2(1H)-one; S)-3-((5-fluoro-4-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(N-morpholinyl)pyrimidin-2-yl)methyl)pyridine -2(1H)-one; 3-[(6-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}pyridin-2-yl)amino]pyridine-2 (1H)-keto; (S)-3-(5-(6-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2- oxo-1,2-di Hydropyridine-3 -aminoaminopyrimidin-4-yl)thiazol-2-yl)benzoic acid; or a pharmaceutically acceptable salt or solvate thereof or N-oxide or a stereoisomer or a deuterated derivative.

According to one embodiment of the invention, the compound of formula (I) can be as a process Prepared from the compound of formula (II) as described in 1.

When a defined R group is susceptible to or incompatible with the process under the conditions described above, conventional protecting groups can be used according to standard practice, see, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons (1999). Removal of the protecting group may form the last step in the synthesis of the compound of formula (I).

The term amine protecting group refers to a protecting group suitable for preventing undesired reactions of the amine nitrogen. Representative amine protecting groups include, but are not limited to, indenyl; ethyl hydrazino, such as alkanoyl, such as ethenyl; alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, Such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), tribenzyl (Tr) and 1,1-di-(4'-A Oxyphenyl)methyl; decyl group, such as trimethyl decyl (TMS), tert-butyl dimethyl decyl (TBS); trimethyl decyloxy ethoxymethyl (SEM) and Similar group.

The term hydroxy protecting group means that it is suitable to prevent undesired reactions of the hydroxy group. The protection base. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; fluorenyl groups such as alkanoyl groups such as ethenyl; arylmethyl groups such as benzyl (Bn) , p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (dibenzyl, DPM); tetrahydropyranyl ether (THP ether), such as methoxy-THP Or ethoxy-THP; a decyl group such as trimethyl decyl (TMS), tert-butyl dimethyl decyl (TBS); trimethyl decyloxy ethoxymethyl (SEM) and the like Group.

In a solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, a suitable reagent such as a mixture of trimethylsulfonyl chloride and sodium iodide, or an aqueous solution of hydrogen bromide at 100 ° C (II) a compound to give a compound of formula (I).

In the specific case of the formula (II) of W = NH, the compound of the formula (II-a) can be produced by a synthesis method as shown in Scheme 2:

In the presence of a base such as N,N -diisopropylethylamine or triethylamine, such as tetrahydrofuran, acetonitrile, ethanol, n-butanol, 1-methylpyrrolidin-2-one or N,N'-di The compound of the formula (III) is reacted with an amine of the formula (IV) in a solvent of methylformamide at a temperature ranging from ambient temperature to 180 ° C to obtain a compound of the formula (V).

Suitable catalysts (such as catalytic materials produced from (dibenzylideneacetone) dipalladium (0) and 9,9-dimethyl-4,5-bis(diphenylphosphino)) and bases (such as carbonic acid) The compound of formula (V) is treated with an amine of formula (VI) in the presence of hydrazine in a solvent such as 1,4-dioxane at a temperature in the range of from 80 to 120 ° C to obtain formula (II-a). Compound.

In the specific case of a compound of formula (V) wherein A = N and B represents a -CR ₇ group (R _{7 is} as defined in the scope of the patent application) and D represents a -CR ₅ group, the compound of formula (Va) may Prepared by the synthetic method shown in Scheme 3:

The pyrimidine of the formula (VII) and the amine of the formula (IV) can be obtained in the presence of a base such as N,N -diisopropylethylamine in a solvent such as ethanol at a temperature ranging from ambient temperature to reflux. The reaction is carried out to obtain a compound of the formula (VIII).

When a nucleophile of the appropriate formula (IX) is present in a solvent such as N,N' -dimethylformamide in a solvent such as N,N' -dimethylformamide at a temperature ranging from ambient temperature to 130 °C ( When a compound of formula (VIII) is treated, such as 4-(t-butyl-dimethylnonyloxy)piperidine, a compound of formula (Va) is obtained.

In another synthetic route, in a solvent such as ethanol, at -78 ° C to The pyrimidine of formula (VII) is reacted with a nucleophile of appropriate formula (IX), such as morpholine, at a temperature within the ambient temperature range to provide a compound of formula (X).

The formula (IV) can be used in the presence of a base such as N,N' -diisopropylethylamine in a solvent such as ethanol or n-butanol at a temperature ranging from ambient temperature to 130 ° C. Amine treatment to convert a compound of formula (X) to a compound of formula (Va).

Residue -(R ₃ -CR ₄ ) _m -R ₂ , R ₅ or R ₇ (in the specific case of B = CR ₇ and D = CR ₅ ) contains a "protected" hetero atom such as nitrogen or oxygen The compound of formula (I), (II) or (V) can be "removed by a protecting group" by removing a protecting group to obtain a residue -(R ₃ -CR ₄ ) _m -R ₂ , R ₅ or R ₇ A compound of formula (I), (II) or (V) which "removes a protecting group" of a hetero atom. Typical examples of protecting groups for heteroatoms such as nitrogen and oxygen and their removal (removal of protecting groups) can be found in several textbooks, for example: Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540. In addition, the "deprotecting group" heteroatom can be further functionalized by, for example, alkylation, amide amination, sulfonylation or arylation under standard reaction conditions.

Residue -(R ₃ -CR ₄ ) _m -R ₂ , R ₅ or R ₇ (in the particular case of B = CR ₇ and D = CR ₅ ) contains a carboxylic acid functionalized with a suitable protecting group such as ethyl ester Part of the compound of formula (I), (II) or (V) can be removed under standard conditions at the carboxylic acid moiety ( Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). The corresponding carboxylic acid can then be further functionalized under standard conditions to give the corresponding guanamine.

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

Instance

The synthesis of the compounds of the present invention and the synthesis of the intermediates used therein are illustrated by the following Examples (1-26) (including Preparation Examples (Preparations 1-28)), and the synthesis is given to provide sufficient clarity to those skilled in the art. The present invention is to be construed as being limited in its scope, and is not to be construed as limiting.

preparation

Preparation 1

( S )- N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl) -N ² -(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine

a) ( S )-2-Chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)pyrimidine-4-amine

Add ( S )-1-(5-fluoropyridin-2-yl) to a stirred solution of 2,4-dichloropyrimidine (250 mg, 1.68 mmol) in tetrahydrofuran (2 mL) at ambient temperature A solution of ethylamine (prepared as described in WO2006/123113, 235 mg, 1.68 mmol) in tetrahydrofuran (2 mL). A solution of triethylamine (0.23 mL, 1.68 mmol) in tetrahydrofuran (2 mL) was then added dropwise and the mixture was warmed overnight at <RTIgt; After cooling to ambient temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate. The residue was purified by reverse phase chromatography (C-18 cerium oxide from Waters©, water/acetonitrile/methanol as a dissolving agent [buffered with 0.1% v/v formic acid), 0% to 100%). The title compound (43 mg, 10%).

LRMS (m/z): 253 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.54 (d, 3H), 5.16 (br s, 1H), 6.16-6.35 (m, 2H), 7.29 (dd, 1H), 7.39 (t, 1H), 7.97 ( d, 1H), 8.40 (d, 1H).

b)( S )- N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl) -N ² -(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine

( S )-2-Chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine was charged into a dry resealable Schlenk tube. Preparation 1a, 43 mg, 0.17 mmol, 2-methoxypyridin-3-amine (23 mg, 0.19 mmol), cesium carbonate (111 mg, 0.34 mmol) and 1,4-dioxin Alkane (3 ml). The Schlenk tube was subjected to three evacuation cycles with argon backfill followed by ginseng (dibenzylideneacetone) dipalladium (0) (16 mg, 0.02 mmol) and 9,9-dimethyl Base-4,5-bis(diphenylphosphino) (10 mg, 0.02 mmol). After three additional evacuations - after argon backfilling, the Schlenk tube was capped, then stirred and heated to 100 °C. After 24 hours, the mixture was cooled to ambient temperature and the solvent was evaporated under reduced pressure. Ethyl acetate was added and the organic solution was washed well with water (× 3), brine, dried (MgSO _4), and the solvent was evaporated under reduced pressure. Purification of the residue by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the dissolving agent [buffered with 0.1% v/v formic acid), 0% to 100%) The title compound (11 mg, 19%).

LRMS (m/z): 341 (M+1) ⁺ .

Preparation 2

( S )- N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl) -N ² -(2-methoxypyridin-3-yl)-5-methylpyrimidine-2,4-diamine

a) ( S )-2-Chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)-5-methylpyrimidin-4-amine

Stir ( S )-1-(5-fluoropyridin-2-yl)ethylamine dihydrochloride (prepared as described in WO2006/123113, 560 mg, 2.63 mmol), 2,4-dichloro-5 -Methylpyrimidine (620 mg, 2.63 mmol) and a mixture of diisopropylethylamine (1.4 mL, 7.9 mmol) in n-butanol (1 mL) at 110 ° C in a microwave oven Heat for 45 minutes. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was washed with water and brine, dried (MgSO ₄ The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 267 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.56 (d, 3H), 1.65 (s, 3H), 5.43 (t, 1H), 6.37 (br s, 1H), 7.28-7.37 (m, 1H), 7.38- 7.50 (m, 1H), 7.83 (s, 1H), 8.43 (d, 1H).

b)( S )- N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl) -N ² -(2-methoxypyridin-3-yl)-5-methylpyrimidine-2,4-diamine

Purification from ( S )-2-chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)-5-methylpyrimidin-4-amine according to the experimental procedure as described in Preparation 1b 2a) and 2-methoxypyridin-3-amine gave a yellow oil (69%).

LRMS (m/z): 355 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.60 (d, 3H), 1.65 (s, 3H), 4.02 (s, 3H), 5.40 (q, 1H), 5.77 (d, 1H), 6.86 (dd, 1H) ), 7.35 (ddd, 2H), 7.70 (dd, 1H), 7.77 (s, 1H), 8.45 (d, 1H), 8.59 (dd, 1H).

Preparation 3

(S)-5-Chloro- N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxypyridin-3-yl)pyrimidine-2,4-di amine

a) ( S )-2,5-Dichloro- N- (1-(5-fluoropyridin-2-yl)ethyl)pyrimidine-4-amine

Purify the crude product by flash chromatography (0-100% ethyl acetate in hexanes) from 2,4,5-trichloropyrimidine and ( S ) according to the procedure as described in Preparation 2a. 1-(5-Fluoropyridin-2-yl)ethylamine dihydrochloride (prepared as described in WO2006/123113) gave a colorless oil (57%).

LRMS (m/z): 287 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.55 (d, 3H), 5.33-5.42 (m, 1H), 7.06 (br s, 1H), 7.31 (dd, 1H), 7.40-7.46 (m, 1H), 8.03 (s, 1H), 8.44 (d, 1H).

b)( S )-5-Chloro- N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxypyridin-3-yl)pyrimidine-2,4 -diamine

Purify the crude product by flash chromatography (0-100% ethyl acetate in hexanes) from ( S )-2,5-dichloro- N. -(1-(5-Fluoropyridin-2-yl)ethyl)pyrimidine-4-amine (Preparation 3a) and 2-methoxypyridin-3-amine gave a colourless oil (50%).

LRMS (m/z): 375 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.61 (d, 3H), 4.02 (s, 3H), 5.30-5.39 (m, 1H), 6.42 (br s, 1H), 6.86 (dd, 1H), 7.28- 7.42 (m, 3H), 7.74 (dd, 1H), 7.95 (s, 1H), 8.41 - 8.56 (m, 1H).

Preparation 4

( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl)-5-methoxy- N 2-(2-methoxypyridin-3-yl)pyrimidine-2,4 -diamine

a) (S)-2-Chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)-5-methoxypyrimidine-4-amine

Following the experimental procedure as described in Preparation 2a, followed by flash chromatography (0-100% ethyl acetate in hexanes) to purify the crude product from 2,4-dichloro-5-methoxy Pyrimidine and ( S )-1-(5-fluoropyridin-2-yl)ethylamine dihydrochloride (prepared as described in WO2006/123113) gave a white solid (91%).

LRMS (m/z): 283 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.57 (d, 3H), 3.84 (s, 3H), 5.31-5.43 (m, 1H), 6.84 (d, 1H), 7.32-7.47 (m, 2H), 7.52 (s, 1H), 8.43 (d, 1H).

b)( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl)-5-methoxy- N 2-(2-methoxypyridin-3-yl)pyrimidine-2 4-diamine

Following the experimental procedure as described in Preparation 1b, followed by flash chromatography (0-100% ethyl acetate in hexane) to purify the crude product from (S)-2-chloro- N- (1) -(5-Fluoropyridin-2-yl)ethyl)-5-methoxypyrimidine-4-amine (Preparation 4a) and 2-methoxypyridin-3-amine afforded a yellow solid (79%).

LRMS (m/z): 371 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.59 (d, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 5.25-5.42 (m, 1H), 6.20 (d, 1H), 6.83 (dd , 1H), 7.20 (s, 1H), 7.26-7.34 (m, 1H), 7.54 (s, 1H), 7.67 (dd, 1H), 8.45 (d, 1H), 8.53 (dd, 1H).

Preparation 5

( S )-4-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-methoxypyridin-3-ylamino)pyrimidine-5-carboxamide

a) ( S )-2-Chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylic acid ethyl ester

Stir 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester (prepared as described in WO 2009/131687, 0.29 g, 1.31 mmol), ( S )-1-(5-fluoropyridine-2) at ambient temperature Ethylamine hydrochloride (prepared as described in WO2006/123113, 0.28 g, 1.59 mmol) and diisopropylethylamine (0.69 ml, 3.96 mmol) in acetonitrile (3 mL) The solution was overnight. Water was then added and the reaction mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried (MgSO _4), filtered, and the solvent was evaporated under reduced pressure to give the title compound as an oil (0.49 g, 85%).

LRMS (m/z): 325 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.41 (t, 3H), 1.58 (d, 3H), 4.39 (q, 2H), 5.42-5.55 (m, 1H), 7.31 (dd, 1H), 7. , 1H), 8.49 (d, 1H), 8.69 (s, 1H), 9.37 (d, 1H).

b) ( S )-2-Chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylic acid

To the ethyl ( S )-2-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylate (preparation 5a, 490 mg, 1.51 mmol) in methanol ( A solution of lithium hydroxide monohydrate (633 mg, 15.09 mmol) in water (6 ml) was added to a solution of a mixture of 6 ml) and tetrahydrofuran (2 ml), and the mixture was stirred at ambient temperature for 3 hours. . The solvent was evaporated under reduced pressure and water was added to the residue. The pH was then adjusted to about 6 using 2M aqueous hydrochloric acid and the aqueous suspension was extracted with diethyl ether (×3). The organic phase was washed with water and brine, dried (MgSO _4), filtered, and the solvent was evaporated under reduced pressure to give a semi-solid of the title compound (0.21 g, 41%).

LRMS (m/z): 297 (M + 1) ⁺ .

c) ( S )-2-( 1H -benzo[ d ][1,2,3]triazol-1-yloxy)-4-(1-(5-fluoropyridin-2-yl)ethylamine Pyrimidine-5-carboxamide

To ( S )-2-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylic acid (preparation 5b, 210 mg, 0.62 mmol) in N, N' - dimethylformamide (5 mL) was added the solution of N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide hydrochloride (177 mg, 0.92 mmol) And 1-hydroxybenzotriazole (125 mg, 0.93 mmol), and the mixture was stirred at ambient temperature for 30 min. Then 1,4-dioxane (3 ml) containing 0.5 M aqueous ammonia solution was added and the reaction mixture was stirred at ambient temperature overnight. The solvent was evaporated and the residue obtained was dissolved in diethyl ether. The organic solution was washed with water and brine, dried (Na ₂ SO _4), filtered and the solvent was evaporated under reduced pressure. Purification of the residue by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the dissolving agent [buffered with 0.1% v/v formic acid), 0% to 100%) The title compound (30 mg, 12%).

LRMS (m/z): 395 (M + 1) ⁺ .

d) ( S )-4-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-methoxypyridin-3-ylamino)pyrimidine-5-carboxamide

Heating ( S )-2-( 1H -benzo[ d ][1,2,3]triazol-1-yloxy)-4-(1-(5-fluoropyridin-2-yl) at 120 °C Ethyl)pyrimidine-5-carboxamide (preparation 5c, 30 mg, 0.08 mmol), 2-methoxypyridin-3-amine (14 mg, 0.11 mmol) and hydrated p-toluenesulfonic acid (15 mg, 0.08 mmol) in 1,4-dioxane (3 mL) for 4 h. The solvent was evaporated under reduced pressure and purified by reversed phase chromatography (C-18 EtOAc from Waters, water/acetonitrile/methanol as solvant [buffered with 0.1% vol/vol. s.), 0% to 100%) The obtained residue was purified to crystal crystal crystal crystal crystal crystal

LRMS (m/z): 384 (M + 1) ⁺ .

Preparation 6

5-chloro-2-methoxypyridin-3-amine

a) 5-Chloro-2-methoxy-3-nitropyridine

To a solution of 2,5-dichloro-3-nitropyridine (1.00 g, 5.2 mmol) in methanol (10 mL), sodium methoxide (0.84 g, 16.6 mmol) in methanol (4) The solution in ML) was stirred and heated to reflux. After 7 hours, the mixture was cooled with EtOAc EtOAc m.

¹ H NMR δ (CDCl ₃ ): 4.11 (s, 3H), 8.23 (s, 1H), 8.32 (s, 1H).

b) 5-Chloro-2-methoxypyridin-3-amine

Zinc bromide (0.27 g, 1.2 m) was added to a solution of 5-chloro-2-methoxy-3-nitropyridine (Preparation 6a, 1.13 g, 5.99 mmol) in ethyl acetate (20 mL) Mohr) and 10% platinum/carbon (0.58 grams, 2.97 millimolar), and the resulting mixture was hydrogenated at 10 psi in a Parr apparatus for 2 hours. The mixture was then diatomaceous earth (Celite ^®) was filtered, and the filter cake was washed with ethyl acetate. The combined filtrate and EtOAc (EtOAc m.

LRMS (m/z): 159 (M + 1) ⁺ .

¹ H NMR δ (CDCl ₃ ): 3.97 (s, 3H), 6.98 (s, 1H), 7.50 (s, 1H).

Preparation 7

( S )- N ² -(5-chloro-2-methoxypyridin-3-yl) -N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl)-5-methylpyrimidine-2,4-diamine

Following the experimental procedure as described in Preparation 1b, followed by flash chromatography (2:1 hexanes/ethyl acetate) to purify the crude product from ( S )-2-chloro- N- (1-( 5-Fluoropyridin-2-yl)ethyl)-5-methylpyrimidin-4-amine (Preparation 2a) and 5-chloro-2-methoxypyridin-3-amine (Preparation 6b) afforded a yellow solid. %).

LRMS (m/z): 389 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.62 (d, 3H), 2.06 (br s, 3H), 4.01 (s, 3H), 5.44 (t, 2H), 6.03 (d, 2H), 7.30-7.47 ( m, 2H), 7.65 (d, 1H), 7.78 (s, 1H), 8.44 (d, 1H), 8.88 (d, 1H).

Preparation 8

5-(1-benzyl-1 H -pyrazol-4-yl)-2-methoxypyridin-3-amine

a) 5-(1-Benzyl-1 H -pyrazol-4-yl)-2-methoxy-3-nitropyridine

The dried resealable Schlank tube was charged with 5-bromo-2-methoxy-3-nitropyridine (3.58 g, 15.36 mmol), 1-benzyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-1H-pyrazole (5.23 g, 18.43 Millol), potassium carbonate (4.24 g, 30.72 mmol), 1,4-dioxane (50 ml) and water (5 ml). The Schlank tube was subjected to three evacuation cycles with argon backfill and ruthenium (triphenylphosphine) palladium (0) (1.77 grams, 1.53 millimoles) was added. After three additional evacuations - after argon backfilling, the Schlank tube was sealed and the mixture was stirred and heated to 100 ° C in an oil bath. After 3 days, the mixture was cooled, filtered over EtOAc (EtOAc)EtOAc. The combined filtrate and EtOAc (EtOAc m.

¹ H-NMR δ (CDCl ₃ ): 4.11 (s, 3H), 5.36 (s, 2H), 7.33 (m, 5H), 7.64 (d, 1H), 7.81 (d, 1H), 8.30 (d, 1H) ), 8.49 (d, 1H).

b) 5-(1-Benzyl-1 H -pyrazol-4-yl)-2-methoxypyridin-3-amine

Add 5-(1-benzyl-1 H -pyrazol-4-yl)-2-methoxy to a cooled (10 ° C) suspension of zinc (3.67 g, 56.25 g) in acetic acid (50 mL) A suspension of the base 3-nitropyridine (Preparation 8a, 3.5 g, 11.28 mmol) in acetic acid (50 mL), and the mixture was stirred at ambient temperature for 1.5 h. The mixture was filtered and the solid was washed with dichloromethane (50 mL). The combined filtrate and EtOAc were evaporated eluting EtOAcqqqqqq 1:1 mixture treatment. The resulting solid was filtered, EtOAcjjjjjjj

¹ H-NMR δ (CDCl ₃ ): 3.79 (br s, 2H), 3.98 (s, 3H), 5.32 (s, 2H), 6.95 (d, 1H), 7.22-7.40 (m, 5H), 7.52 ( d, 1H), 7.68 (d, 1H), 7.72 (d, 1H).

Preparation 9

( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxy-5-(1 H -pyrazol-4-yl)pyridine-3 -yl)-5-methylpyrimidine-2,4-diamine

a)( S ) -N 2-(5-(1-benzyl-1 H -pyrazol-4-yl)-2-methoxypyridin-3-yl) -N 4-(1-(5- Fluoridin-2-yl)ethyl)-5-methylpyrimidine-2,4-diamine

Following the experimental procedure described in Preparation 1b, from ( S )-2-chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)-5-methylpyrimidin-4-amine (Preparation 2a) And 5-(1-benzyl-1 H -pyrazol-4-yl)-2-methoxypyridin-3-amine (Preparation 8b) gave a white foam (69%).

LRMS (m/z): 511 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.54 (d, 3H), 2.05 (s, 3H), 4.03 (s, 3H), 5.37 (s, 2H), 5.39-5.52 (m, 1H), 5.97 (d) , 1H), 7.18 (dd, 1H), 7.24 (d, 1H), 7.28-7.37 (m, 5H), 7.69 (s, 1H), 7.77 (d, 1H), 7.82 (d, 1H), 7.85 ( d, 1H), 8.38 (d, 1H), 8.91 (d, 1H).

b)( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxy-5-(1 H -pyrazol-4-yl)pyridine -3-yl)-5-methylpyrimidine-2,4-diamine

To ( S ) -N 2-(5-(1-benzyl-1 H -pyrazol-4-yl)-2-methoxypyridin-3-yl) -N 4-(1-(5-fluoro) a solution of pyridin-2-yl)ethyl)-5-methylpyrimidine-2,4-diamine (preparation 9a, 0.214 g, 0.42 mmol) in 1:1 mixture (4 mL) of methanol / THF A 5N aqueous hydrochloric acid solution (0.126 ml, 0.63 mmol) and 20% of palladium hydroxide/carbon (0.07 g, 0.50 mmol) were added, and the reaction mixture was stirred at 50 ° C overnight under a hydrogen atmosphere. Then, 5N aqueous hydrochloric acid (0.126 ml, 0.63 mmol) and a palladium catalyst (0.07 g) were added, and the mixture was stirred overnight under a hydrogen atmosphere. The mixture was then filtered through Celite® and the filter cake was washed with methanol. The combined filtrate and washings were evaporated, and a 1:1 mixture (4 ml) of methanol/tetrahydrofuran was added to the residue. Next, 5N aqueous hydrochloric acid (0.126 ml, 0.63 mmol) and 20% palladium hydroxide/carbon (0.07 g, 0.50 mmol) were added to the obtained solution, and the reaction mixture was stirred at 50 ° C overnight under a hydrogen atmosphere. The mixture was then filtered through Celite® and the filter cake was washed with methanol. The combined filtrate and EtOAc (EtOAc m.

LRMS (m/z): 421 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.49 (d, 3H), 2.15 (s, 3H), 4.02 (s, 3H), 5.25-5.28 (m, 1H), 7.07 (dd, 1H), 7.32-7.34 (m, 1H), 7.59 (d, 1H), 7.82 (s, 2H), 8.08 (d, 1H), 8.36 (d, 1H), 8.41 (d, 1H).

Preparation 10

3-[(4-(4-{[ T -butyl(dimethyl)decyl)oxy}piperidin-1-yl)-6-{[(1 S )-1-(5-fluoropyridine) -2-yl)ethyl]amino}pyrimidin-2-yl)amino]pyridine-2(1 H )-one

a) 2,6-Dichloro- N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]pyrimidine-4-amine

Add ( S )-1-(5-fluoropyridin-2-yl)ethylamine hydrochloride to a solution of 2,4,6-trichloropyrimidine (0.75 g, 4.09 mmol) in ethanol (15 ml) Salt (1.05 g, 4.91 mmol) as described in WO2006/123113 and N,N' -diisopropylethylamine (2.80 ml, 16.36 mmol), and the resulting mixture was stirred and sealed in a test tube After heating to 80 ° C for 1 hour. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water and brine, dried (MgSO _4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj

¹ H-NMR δ (DMSO- d ₆ ): 1.45 (d, 3H), 5.18-5.27 (m, 1H), 6.63 (s, 1H), 7.46 (dd, 1H), 7.70 (td, 1H), 8.53 (d, 1H), 8.70 (d, 1H).

b) 6-(4-{[Tertibutyl(dimethyl)decyl]oxy}piperidin-1-yl)-2-chloro- N -[( 1S )-1-(5-fluoro Pyridin-2-yl)ethyl]pyrimidine-4-amine

Stir 2,6-dichloro- N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine (preparation 10a, 0.66 g, 2.31 mmol), 4 - (Third butyl-dimethyl decyloxy) piperidine (prepared as described in WO 2004/006926, 0.60 g, 2.77 mmol) and cesium carbonate (1.13 g, 3.46 mmol) at N, N A mixture of ' -dimethylformamide (15 ml) was heated to 130 ° C in a sealed tube for 2 hours. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate (×3). The combined the organic extracts were washed with water and brine, dried (MgSO _4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR δ (DMSO- d ₆ ): 0.04 (s, 6H), 0.85 (s, 9H), 1.02-1.36 (m, 2H), 1.40 (d, 3H), 1.48-1.65 (m, 2H) , 3.11-3.29 (m, 2H), 3.74-3.94 (m, 3H), 5.03 (m, 1H), 5.84 (s, 1H), 7.37 (dd, 1H), 7.64 (td, 1H), 7.79 (d , 1H), 8.47 (d, 1H).

c) 6-(4-{[T-butyl(dimethyl)decyl]oxy}piperidin-1-yl) -N ⁴ -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl] -N ² -(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine

Following the experimental procedure as described in Preparation 1b, followed by purification of the crude product by flash chromatography (10-40% ethyl acetate /hexane) from 6-(4-{[ Methyl)decyl]oxy}piperidin-1-yl)-2-chloro- N -[( 1S )-1-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine ( Preparation 10b) and 2-methoxypyridin-3-amine gave a white solid (59%).

¹ H-NMR δ (CDCl ₃ ): 0.09 (s, 6H), 0.91 (s, 9H), 1.52 (d, 3H), 1.67-1.84 (m, 2H), 3.45 (m, 2H), 3.92 (m) , 1H), 3.98 (s, 3H), 3.96-4.14 (m, 2H), 4.90 (m, 1H), 5.01 (s, 1H), 5.16 (d, 1H), 6.60 (s, 1H), 6.82 ( Dd, 1H), 7.34 (dd, 2H), 7.70 (dd, 1H), 8.27 (dd, 1H), 8.40 (s, 1H).

d) 3-[(4-(4-{[T-butyl(dimethyl)decyl)oxy}piperidin-1-yl)-6-{[(1 S )-1-(5- Fluoridin-2-yl)ethyl]amino}pyrimidin-2-yl)amino]pyridine-2(1 H )-one

To 6-(4-{[ T -butyl(dimethyl)decyl]oxy}piperidin-1-yl) -N ⁴ -[(1 S )-1-(5-fluoropyridine-2- Ethyl] -N ² -(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine (preparation 10c, 415 mg, 0.75 mmol) in acetonitrile (5 mL) Trimethyldecyl chloride (0.285 mL, 2.25 mmol) and sodium iodide (337 mg, 2.25 mmol) were added to the stirred solution, and the reaction mixture was heated to 80 ° C for 4.5 hours. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate (×3). The pH was then adjusted to about 6 using a 2M aqueous sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate (×3). The combined the organic extracts were washed with water and brine, dried (MgSO _4), filtered and the solvent was evaporated under reduced pressure to obtain a brown oil of the title compound (0.52 g, 100%), which was used without further purification In the next synthesis step.

LRMS (m/z): 539 (M+1) ⁺ .

Preparation 11

( S )-5-fluoro- N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxypyridin-3-yl)-6-(N-? Polinyl pyrimidine-2,4-diamine

a) 4-(2,6-Dichloro-5-fluoropyrimidin-4-yl)morpholine

Add morpholine (1.5 ml, 17.05 mmol) to a cooled (-20 ° C) solution of 2,4,6-trichloro-5-fluoropyrimidine (3.00 g, 14.93 mmol) in ethanol (150 mL) The ear was solution in ethanol (25 mL) and the mixture was stirred at -20 ° C for 30 min and stirred at ambient temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was separated, dried and evaporated. The resulting white solid was triturated with EtOAc (EtOAc)EtOAc.

LRMS (m/z): 252/254 (M+1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 3.77-3.80 (m, 4H), 3.82-3.85 (m, 4H).

b) ( S )-2-Chloro-5-fluoro- N- (1-(5-fluoropyridin-2-yl)ethyl)-6-(N-morpholine Pyrimidine-4-amine

Heating 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (preparation 11a, 1.18 g, 4.68 mmol), ( S )-1-(5-fluoropyridine) at 130 °C 2-yl)ethylamine hydrochloride (prepared as described in WO2006/123113, 1.00 g, 4.69 mmol) and N,N' -diisopropylethylamine (3.27 ml, 18.77 mmol) A mixture of n-butanol (20 mL) for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc EtOAc The title compound in the form of the isomer (0.700 g, 42%). The chemical structures of the two regioisomers were confirmed by NMR experiments (gHSQCAD and gHMBCAD).

LRMS (m/z): 356/358 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.54 (3H, dd), 3.60-3.75 (8H, m), 5.17-5.37 (1H, m), 6.07 (1H, br d), 7.24-7.32 (1H, m ), 7.36-7.42 (1H, m), 8.42 (1H, t).

c) ( S )-5-fluoro- N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxypyridin-3-yl)-6-(N -morpholinylpyrimidine-2,4-diamine

Following the experimental procedure as described in Preparation 1b, followed by purification of the crude product by flash chromatography (0-20% methanol in dichloromethane) from ( S )-2-chloro-5-fluoro- N -(1-(5-fluoropyridin-2-yl)ethyl)-6-(N-morpholinyl)pyrimidine-4-amine (Preparation 11b) and 2-methoxypyridin-3-amine were obtained (69 %).

LRMS (m/z): 444 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.58 (3H, s), 3.63 (4H, m) 3.77 (4H, m), 4.02 (3H, s), 5.30 (1H, m), 5.65 (1H, br d 6.83 (1H, dd), 7.10 (1H, s), 7.33 (2H, m), 7.68 (1H, dd), 8.42 (1H, dd).

Preparation 12

N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]- N '-(2-methoxypyridin-3-yl)pyrazine-2,6-diamine

a) 6-Chloro- N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]pyrazin-2-amine

Prepared to 2,6-dichloropyrazine (525 mg, 3.52 mmol) and ( S )-1-(5-fluoropyridin-2-yl)ethylamine hydrochloride (as described in WO2006/123113, N,N' -diisopropylethylamine (2.50 ml, 14.35 mmol) was added dropwise to a solution of 1- chloropyrrolidin-2-one (4 ml). The resulting mixture was stirred and heated in a microwave oven at 180 ° C for 6 hours. After chilling to EtOAc (EtOAc m.)

LRMS (m/z): 253 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.54 (d, 3H), 5.14 (m, 1H), 5.97 (d, 1H), 7.29-7.42 (m, 2H), 7.78 (d, 2H), 8.42 (d) , 1H).

b) N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]- N '-(2-methoxypyridin-3-yl)pyrazine-2,6-diamine

Following the experimental procedure as described in Preparation 1b, followed by purification of the crude product by flash chromatography (95:5 chloroform/methanol) from 6-chloro- N -[( 1S )-1-(5- Fluoropyridin-2-yl)ethyl]pyrazin-2-amine (Preparation 12a) and 2-methoxypyridin-3-amine gave a yellow solid (64%).

LRMS (m/z): 341 (M+1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.59 (d, 3H), 4.03 (s, 3H), 5.05 (m, 1H), 5.35 (d, 1H), 6.85 (m, 1H) 7.34 (m, 3H) , 7.39 (s, 1H), 7.48 (s, 1H), 7.73 (m, 2H).

Preparation 13

( S ) -N 2-(1-(5-fluoropyridin-2-yl)ethyl) -N 6-(2-methoxypyridin-3-yl)pyridine-2,6-diamine

a) (S)-6-Chloro- N- (1-(5-fluoropyridin-2-yl)ethyl)pyridin-2-amine

Add ( S )-1-(2) to a solution of 2,6-dichloropyridine (0.203 g, 1.38 mmol) in N,N' -diisopropylethylamine (1.2 mL, 6.89 mmol) 5-Fluoropyridin-2-yl)ethylamine hydrochloride (prepared as described in WO2006/123113, 0.291 g, 1.37 mmol), and the resulting mixture was stirred and heated to reflux for 2 days. The solvent was evaporated under reduced EtOAc.

LRMS (m/z): 252 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.53 (d, 3H), 4.87-5.04 (m, 1H), 5.55 (d, 1H), 6.18 (d, 1H), 6.56 (d, 1H), 7.27 (dd , 1H), 7.32-7.45 (m, 2H), 8.34-8.43 (m, 1H).

b)( S ) -N 2-(1-(5-fluoropyridin-2-yl)ethyl) -N 6-(2-methoxypyridin-3-yl)pyridine-2,6-diamine

Purify the crude product by flash chromatography (0-100% ethyl acetate in hexanes) from (S)-6-chloro- N- (1). -(5-Fluoropyridin-2-yl)ethyl)pyridin-2-amine (Preparation 13a) and 2-methoxypyridin-3-amine gave an orange oil (90%).

LRMS (m/z): 340 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.57 (d, 3H), 4.01 (s, 3H), 4.93-5.06 (m, 1H), 5.06 (d, 1H), 5.84 (d, 1H), 6.01-6.13 (m, 1H), 6.74 (s, 1H), 6.83 (dd, 1H), 7.19-7.27 (m, 1H), 7.28-7.43 (m, 2H), 7.68 (dd, 1H), 8.38 (dd, 1H) ), 8.40-8.44 (m, 1H).

Preparation 14

2-((1r,4r)-4-aminocyclohexyl)acetonitrile

a) (1 r , 4 r )-4-(hydroxymethyl)cyclohexylamino acid tert-butyl ester

To a stirred solution of (( 1r , 4r )-4-aminocyclohexyl)methanol (1.50 g, 11.6 mmol) in tetrahydrofuran (20 mL) was added dibutyl dicarbonate (3.04 g) , 13.9 millimoles). After stirring overnight at ambient temperature, the mixture was evaporated and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO ₄₎ and evaporated. The residue was taken from EtOAc EtOAcjjjjjjj

LRMS (m/z): 228 (MH) ⁺ .

¹ H NMR δ (DMSO- d ₆ ): 0.84-0.95 (m, 2H), 1.05-1.18 (m, 2H), 1.20-1.29 (m, 2H), 1.40 (s, 9H), 1.71-1.80 (m) , 3H), 3.14 (m, 1H), 3.21 (t, 2H), 4.41 (t, 1H), 6.73 (d, 1H).

b) 4-methylbenzenesulfonic acid ((1 r , 4 r )-4-( t -butoxycarbonylamino)cyclohexyl)methyl ester

To the (1 r , 4 r )-4-(hydroxymethyl)cyclohexylcarbamic acid tert-butyl ester (preparation 14a, 2.11 g, 9.2 mmol) and triethylamine (1.59 ml, 11.4 mmol) A solution of 4-methylbenzene-1-sulfonium chloride (2.28 g, 11.96 mmol) in dichloromethane was added to a solution in dichloromethane (50 mL) and the mixture was stirred at ambient temperature overnight. . The mixture was washed with 1M aqueous sodium hydroxide solution, and dried (MgSO ₄₎ the organic layer, solvent was evaporated and purified by flash chromatography (ether / hexane) to give the residue, the title compound was obtained as a white solid of (2.91 g, 83 %).

LRMS (m/z): 382 (MH) ⁺ .

¹ H NMR δ (CDCl ₃ ): 0.90-1.12 (m, 4H), 1.43 (s, 3H), 1.78 (dd, 2H), 1.99 (d, 2H), 3.34 (m, 1H), 3.46 (t, 1H), 3.81 (d, 2H), 4.37 (m, 1H), 7.34 (d, 2H), 7.77 (d, 2H).

c) (1 r , 4 r )-4-(cyanomethyl)cyclohexylcarbamic acid tert-butyl ester

To 4-methylbenzenesulfonic acid ((1r,4r)-4-(t-butoxycarbonylamino)cyclohexyl)methyl ester (preparation 14b, 1.00 g, 2.6 mmol) in dimethyl hydrazine ( Sodium cyanide (0.38 g, 7.8 mmol) was added to the solution in 10 ml), and the mixture was stirred and heated to 55 °C. After stirring for 20 hours, the mixture was diluted with ethyl acetate and saturated aqueous potassium carbonate solution, washed with water and brine, dried (MgSO ₄₎ and evaporated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut

LRMS (m/z): 239 (M+H) ⁺ .

¹ H NMR δ (CDCl ₃ ): 1.06-1.25 (m, 4H), 1.44 (s, 9H), 1.65 (m, 1H), 1.90 (d, 2H), 2.06 (d, 2H), 2.25 (d, 2H), 3.39 (m, 1H), 4.38 (m, 1H).

d) 2-((1 r , 4 r )-4-aminocyclohexyl)acetonitrile hydrochloride

Stir (1 r , 4 r )-4-(cyanomethyl)cyclohexylcarbamic acid tert-butyl ester (preparation 14c, 0.348 g, 1.46 mmol) and 4 M hydrogen chloride 1,4- at ambient temperature A mixture of dioxane solution (3.65 mL) was taken overnight. The solvent was evaporated in vacuo and the residue was purified elut The resulting suspension was filtered to give crystalljjjjjjjj

LRMS (m/z): 139 (M+H) ⁺ .

¹ H NMR δ (DMSO- d ₆ ): 1.14 (ddd, 2H), 1.37 (ddd, 2H), 1.60 (m, 1H), 1.83 (d, 2H), 1.99 (d, 2H), 2.50 (d, 2H), 2.94 (m, 1H), 8.08 (br s, 2H).

Preparation 15

2-((1 r ,4 r )-4-(2-(2-methoxypyridin-3-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexyl)acetonitrile

a) 2-((1 r ,4 r )-4-(2-chloro-5-methylpyrimidin-4-yl)amino)cyclohexyl)acetonitrile

To 2,4-dichloro-5-methylpyrimidine (187 mg, 1.15 mmol) and 2-((1 r , 4 r )-4-aminocyclohexyl)acetonitrile hydrochloride (preparation 14d, 200 M, N , N' -diisopropylethylamine (0.72 ml, 4.13 mmol) was added dropwise to a stirred solution of N,N' -dimethylformamide (1.5 mL). Ear), and the resulting mixture was stirred and heated at 90 ° C for 3 hours. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO _4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 265 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.15 - 1.40 (m, 4H), 1.72 (m, 1H), 1.97 (m, 5H), 2.19 (m, 2H), 2.31 (d, 2H), 4.05 (m) , 1H), 4.46 (bd, 1H), 7.81 (s, 1H).

b) 2-((1 r ,4 r )-4-(2-(2-methoxypyridin-3-yl)amino)-5-methylpyrimidin-4-yl)amino)cyclohexyl) Acetonitrile

Following the experimental procedure described in Preparation 1b, followed by purification of the crude product by flash chromatography (hexane/diethyl ether) from 2-(( 1r , 4r )-4-(2-chloro-5- Methylpyrimidin-4-yl)amino)cyclohexyl)acetonitrile (Preparation 15a) and 2-methoxypyridin-3-amine gave a white solid (48%).

LRMS (m/z): 353 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.20-1.45 (m, 4H), 1.76 (m, 1H), 1.99 (m, 5H), 2.27 (d, 2H), 2.35 (d, 2H), 4.03 (m) , 4H), 4.34 (bd, 1H), 6.87 (dd, 1H), 7.71 (dd, 1H), 7.74 (d, 1H), 8.70 (dd, 1H).

Preparation 16

((1r,4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methanesulfonyl chloride

a) (1r, 4r)-4-aminocyclohexanecarboxylic acid ethyl ester hydrochloride

To a suspension of (1r,4r)-4-aminocyclohexanecarboxylic acid (6.32 g, 35.2 mmol) in ethanol (100 ml), EtOAc. Up to 60 ° C. After 20 hours, the mixture was evaporated EtOAcjjjjjjjjjjjjj

¹ H NMR δ (DMSO- d ₆ ): 1.17 (t, 3H), 1.26-1.46 (m, 4H), 1.87-1.98 (m, 4H), 2.23 (m, 1H), 2.95 (m, 1H), 4.04 (q, 2H), 8.06 (br s, 3H).

b) ((1r, 4r)-4-aminocyclohexyl)methanol

(1r, 4r)-4-Aminocyclohexanecarboxylic acid ethyl ester hydrochloride was added portionwise to a stirred solution (69 mL, 69.0 mmol) from EtOAc (EtOAc). (Preparation 16a, 7.20 g, 34.7 mmol) in tetrahydrofuran (200 mL). After 1 hour, the ice bath was removed and the mixture was stirred at ambient temperature for 1 hour then allowed to stand overnight. The stirred mixture was cooled in an ice bath, and water (6.9 mL), 15% aqueous sodium hydroxide (21 mL) and water (21 mL) After stirring for an additional 30 minutes at ambient temperature, the mixture was filtered through a pad of Celite® and washed with THF. The combined filtrates were washed with EtOAcqqqqqqqq

¹ H NMR δ (DMSO- d ₆ ): 0.78-1.01 (m, 4H), 1.23 (m, 1H), 1.65-1.75 (m, 4H), 2.41 (m, 1H), 3.18 (d, 2H), 4.36 (br s, 1H).

c) 2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)isoindoline-1,3-dione

To ((1r,4r)-4-aminocyclohexyl)methanol (preparation 16b, 1.00 g, 7.74 mmol) and isobenzofuran-1,3-dione (1.15 g, 7.76 mmol) Triethylamine (4.46 mL, 32.0 mmol) was added to a suspension in toluene (50 mL) and the mixture was stirred and warmed to 50. After 20 hours, the mixture was evaporated, and the residue was dissolved in ethyl acetate, and with 2M aqueous sodium hydroxide, water, brine, dried (MgSO ₄₎ and evaporated to give a white solid of the title compound (1.68 g , 84%).

LRMS (m/z): 260 (M + 1) ⁺ .

¹ H NMR δ (CDCl ₃ ): 1.15 (dq, 1H), 1.31 (t, 1H), 1.64 (m, 1H), 1.81 (m, 2H), 1.96 (m, 2H), 2.30 (dq, 1H) , 3.52 (t, 2H), 4.13 (tt, 1H), 7.70 (m, 2H), 7.82 (m, 2H).

d) methanesulfonic acid ((1r, 4r)-4-(1,3-dihydroxyisoindoline-2-yl)cyclohexyl)methyl ester

To 2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)isoindoline-1,3-dione (preparation 16c, 1.00 g, 3.86 mmol) and triethylamine (0.59 ml) Methane sulfonium chloride (0.31 ml, 4.01 mmol) was added dropwise to a stirred (ice) solution in dichloromethane (20 mL). After 20 hours, the mixture was concentrated in vacuo and residue was partitioned betweenEtOAc and water. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO ₄₎ and evaporated to give a white solid of the title compound (1.25 g, 96%).

LRMS (m/z): 338 (M + 1) ⁺ .

¹ H NMR δ (CDCl ₃ ): 1.24 (m, 2H), 1.80-2.02 (m, 5H), 2.32 (dq, 2H), 3.04 (s, 3H), 4.08 - 4.18 (m, 3H), 7.71 ( m, 2H), 7.83 (m, 2H).

e) S -((1r,4r)-4-(1,3-di- oxyisoindoline-2-yl)cyclohexyl)methyl thioacetate

Stir methanesulfonic acid ((1r, 4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methyl ester (preparation 16d, 1.25g, 3.70mmol) and sulfur A mixture of potassium acetate (1.27 g, 11.1 mmol) in N , N' -dimethylformamide (15 mL) was heated to 50 °C. After 4 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO ₄₎ and evaporated to give a white solid of the title compound (1.13 g, 96%).

LRMS (m/z): 318 (M + 1) ⁺ .

¹ H NMR δ (CDCl ₃ ): 1.15 (dq, 2H), 1.64 (m, 1H), 1.76 (m, 2H), 1.96 (m, 2H), 2.27 (dq, 2H), 2.36 (s, 3H) , 2.85 (d, 2H), 4.11 (tt, 1H), 7.70 (m, 2H), 7.81 (m, 2H).

f) ((1r, 4r)-4-(1,3-di- oxyisoindoline-2-yl)cyclohexyl)methanesulfonic acid

S -((1r,4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methyl thioacetate (preparation 16e, 0.50 g, 1.6 m) over 7 min A 30% aqueous hydrogen peroxide solution (0.88 ml, 8.6 mmol) was added dropwise to a stirred suspension of formic acid (4 mL). The highly exothermic reaction ensures the formation of a solution which then rapidly deposits a solid. After 1 h, the mixture was evaporated EtOAcjjjjjjjjjjj

LRMS (m/z): 322 (M-1) ⁺ .

¹ H NMR δ (DMSO- d ₆ ): 1.03 (m, 2H), 1.68 (m, 3H), 2.08 (m, 4H), 2.38 (d, 2H), 3.94 (m, 1H), 7.80-7.86 ( m, 4H).

g) ((1r, 4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methanesulfonyl chloride

To ((1r,4r)-4-(1,3-dioxaoxyisoindol-2-yl)cyclohexyl)methanesulfonic acid (preparation 16f, 0.333 g, 1.03 mmol) in dichloromethane Add ruthenium dichloride (0.27 ml, 3.63 mmol) to a mixture of (5 ml) and N , N' -dimethylformamide (0.1 ml), stir the mixture, and in the Schlenk tube Heat to 40 ° C. After 4 hours, the mixture was cooled and evaporated and the residue was crystallised from ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO ₄₎ and evaporated to give a white solid of the title compound (0.294 g, 84%).

¹ H NMR δ (DMSO- d ₆ ): 1.04 (m, 2H), 1.68 (m, 3H), 2.08 (m, 4H), 2.41 (d, 2H), 3.94 (m, 1H), 7.79-7.86 ( m, 4H).

h) ((1r, 4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methanesulfonium chloride (alternative preparation)

To S -((1r,4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methyl thioacetate (preparation 16e, 2.05 g, 6.5 mmol) A 2M aqueous hydrochloric acid solution (3.3 ml) was added to a stirred (ice-br.). N -chlorobutanediimide (3.45 g, 25.8 mmol) was added portionwise to the above mixture, after which the ice bath was removed. An exothermic reaction then occurred and the temperature was maintained at < 20 °C by periodic cooling in an ice-water bath. A homogeneous solution was formed which was followed by precipitation of a white solid. After 20 minutes, the thick mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO ₄₎ and evaporated to give a white solid of the title compound (2.53 grams, by ¹ H NMR was about 85%), pure enough to be used as such In the subsequent reaction.

Preparation 17

1-(((1r,4r)-4-aminocyclohexyl)methylsulfonyl)piperidin-3-ol

a) 2-((1r,4r)-4-((3-hydroxypiperidin-1-ylsulfonyl)methyl)cyclohexyl)isoindoline-1,3-dione

To ((1r,4r)-4-(1,3-di- oxyisoindol-2-yl)cyclohexyl)methanesulfonium chloride (preparation 16g, 1.00g, 2.49mmol) in dichloro Piperidin-3-ol (0.89 g, 8.80 mmol) was added to the stirred solution in methane (20 mL). After 1 hour, the mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO ₄₎ and evaporated to give a white solid of the title compound (0.98 g, 97%).

LRMS (m/z): 407 (M + 1) ⁺ .

¹ H NMR δ (CDCl ₃ ): 1.24 (dq, 2H), 1.55-1.69 (m, 3H), 1.75-1-95 (m, 4H), 2.08-2.20 (m, 2H), 2.35 (dq, 2H) ), 2.83 (m, 2H), 3.07 (dd, 1H), 3.17 (m, 1H), 3.32 (m, 1H), 3.50 (dd, 1H), 3.89 (m, 1H), 4.12 (tt, 1H) , 7.71 (m, 2H), 7.83 (m, 2H).

b) 1-(((1r,4r)-4-aminocyclohexyl)methylsulfonyl)piperidin-3-ol hydrochloride

To 2-((1r,4r)-4-((3-hydroxypiperidin-1-ylsulfonyl)methyl)cyclohexyl)isoindoline-1,3-dione (Preparation 17a, 0.98 g) 2.4 (0.44 ml, 9.0 mmol) was added to a stirred suspension of ethanol (45 mL) and the mixture was heated to 60 °C. After 6 hours, the mixture was cooled and evaporated. The solid residue was taken up in aq. The title compound (0.74 g, 98%) was obtained as a white solid.

LRMS (m/z): 277 (M+1) ⁺ .

¹ H NMR δ (DMSO- d ₆ ): 1.06-1.45 (m, 6H), 1.65-2.00 (m, 6H), 2.57 (m, 1H), 2.76 (m, 1H), 2.90 (m, 2H), 3.30 (m, 1H), 3.47 (m, 2H), 8.02 (br s, 3H) (the remaining two protons are hidden under the residual solvent peak).

Preparation 18

1-(((1r,4r)-4-(2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)cyclohexyl)methylsulfonyl)piperidine-3 -alcohol

a) 1-(((1r,4r)-4-(2-chloropyrimidin-4-ylamino)cyclohexyl)methylsulfonyl)piperidin-3-ol

1-(((1r,4r)-4-Aminocyclohexyl)methylsulfonyl)piperidin-3-ol hydrochloride in the Kimball vial (Preparation 17b, 0.408 g, 1.48 N,N' -diisopropylethylamine (0.51 ml, 2.95 mmol) and 2,4 were added to a suspension of N,N' -dimethylformamide (5 ml). - Dichloropyrimidine (0.200 g, 1.34 mmol). The vial was sealed and the suspension was shaken and heated to 90 ° C overnight. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine, dried (MgSO _4), and the solvent was evaporated under reduced pressure. The title compound (0.118 g, 21%).

¹ H NMR δ (CDCl ₃ ): 1.30 (m, 4H) 1.61 (m, 2H) 1.80-2.20 (m, 8H), 2.81 (m, 2H), 3.02 (dd, 1H), 3.11 (m, 1H) , 3.30 (m, 1H), 3.50 (dd, 1H), 3.91 (m, 1H), 5.02 (s, 1H), 6.21 (d, 1H), 8.04 (m, 1H).

b) 1-(((1r,4r)-4-(2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)cyclohexyl)methylsulfonyl)piperidine 3-ol

Following the experimental procedure as described in Preparation 1b, followed by purification of the crude product by flash chromatography (0-5% methanol in dichloromethane) from 1-(((1r, 4r)-4- 2-Chloropyrimidin-4-ylamino)cyclohexyl)methylsulfonyl)piperidin-3-ol (Preparation 18a) and 2-methoxypyridin-3-amine gave a solid (56%).

¹ H NMR δ (CDCl ₃ ): 1.24-1.30 (m, 4H), 1.55-1.62 (m, 2H), 1.84-2.25 (m, 8H), 2.82 (m, 2H), 3.03 (dd, 1H), 3.11 (m, 1H), 3.30 (m, 1H), 3.51 (dd, 1H), 3.88 (m, 1H), 4.02 (s, 3H), 4.73 (s, 1H), 5.84 (d, 1H), 6.84 (dd, 1H), 7.37 (s, 1H), 7.73 (d, 1H), 7.92 (d, 1H), 8.70 (d, 1H).

Preparation 19

( R )-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

a) ( R )-3-(2-chloropyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Stir 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (2.7 g, 13.5 mmol) and N,N' A solution of diisopropylethylamine (2.3 mL, 13.4 mmol) in N,N' -dimethylformamide (15 mL). After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO _4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj

LRMS (m/z): 313 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.45 (s, 9H), 1.54-1.81 (m, 4H), 1.94 (br s, 1H), 3.05-3.59 (m, 3H), 3.72 (br s, 1H) , 5.13-5.31 (m, 1H), 6.28 (br s, 1H), 8.04 (br s, 1H).

b) ( R )-3-(2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Follow the experimental procedure as described in Preparation 1b, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator) buffered with 0.1% v/v formic acid [0% to 100%) purified crude product from ( R )-3-(2-chloropyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 19a) and 2-methoxy Pyridine-3-amine gave a white solid (43%).

LRMS (m/z): 401 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.44 (s, 9H), 1.54-1.81 (m, 2H), 1.86-2.03 (m, 1H), 2.95 (m, 2H), 3.16-3.39 (m, 2H) , 3.50 (m, 1H), 3.82 (d, 1H), 4.02 (s, 3H), 5.03 (m, 1H), 5.91 (d, 1H), 6.87 (dd, 1H), 7.77 (dd, 1H), 7.93 (d, 1H), 8.23 (s, 1H), 8.57 (d, 1H).

c) ( R )-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

Stirring ( R )-3-(2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 19b, 340 mg, 0.85 A suspension of 48% aqueous hydrogen bromide (2.9 mL, 25.46 mmol) was heated at 100 °C for 4 hours. After cooling to ambient temperature, the title compound was crystalljjjjjjjjjjj

LRMS (m/z): 287 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.58 (d, 1H), 1.75-1.97 (m, 2H), 2.07 (dd, 1H), 2.86-3.10 (m, 2H), 3.24 (d, 1H) , 3.31-3.50 (m, 1H), 4.33 (dd, 1H), 6.34 (d, 1H), 6.45 (t, 1H), 7.25 (br s, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.78-8.92 (m, 1H), 8.94-9.08 (m, 1H), 9.32 (d, 1H), 9.76 (s, 1H), 12.19 (br s, 1H).

Preparation 20

( R )-3-(5-Methyl-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

a) ( R )-3-(2-chloro-5-methylpyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

An oil (100%) was obtained from 2,4-dichloro-5-methylpyrimidine and ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester according to the experimental procedure as described in Preparation 19a. ).

LRMS (m/z): 327 (M + 1) ⁺ .

b) ( R )-3-(2-(2-methoxypyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Follow the experimental procedure as described in Preparation 1b, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator) buffered with 0.1% v/v formic acid [0% to 100%) purified crude product from ( R )-3-(2-chloro-5-methylpyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 20a) and 2-Methoxypyridin-3-amine gave a solid (36%).

LRMS (m/z): 415 (M + 1) ⁺ .

c) ( R )-3-(5-Methyl-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

Following ( R )-3-(2-(2-methoxypyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)piperidine according to the experimental procedure as described in Preparation 19c 1-butylic acid tert-butyl ester (Preparation 20b) gave the hydrobromide salt (63%).

LRMS (m/z): 381 (M+1) ⁺ .

Preparation 21

2,4-dichloro-5-fluoropyrimidine

Adding oxychlorochloride to a stirred mixture of 5-fluoropyrimidine-2,4(1 H ,3 H )-dione (3.0 g, 23 mmol) and phosphorus pentachloride (14.41 g, 69 mmol) Phosphorus (12.6 ml, 130 mmol). The reaction mixture was stirred and heated to reflux for 5 h then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and then stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. Dried (MgSO ₄₎ the organic layers were combined, filtered and evaporated to give the title compound as a yellow solid of (84%).

LRMS (m/z): 167 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 8.49 (s, 1H).

Preparation 22

( R )-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

a) ( R )-3-(2-chloro-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

An oil was obtained from 2,4-dichloro-5-fluoropyrimidine (Preparation 21) and ( R )-3-Aminopiperidine-1-carboxylic acid tert-butyl ester according to the experimental procedure as described in Preparation 19a. (100%).

LRMS (m/z): 331 (M + 1) ⁺ .

b) ( R )-3-(5-fluoro-2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Follow the experimental procedure as described in Preparation 1b, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator) buffered with 0.1% v/v formic acid [0% to 100%) purified crude product from ( R )-3-(2-chloro-5-fluoropyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 22a) and 2 -Methoxypyridin-3-amine gave a solid (32%).

LRMS (m/z): 419 (M+1) ⁺ .

c) ( R )-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

Following ( R )-3-(5-fluoro-2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)piperidine- as described in Preparation 19c 1-Dicarboxylic acid tert-butyl ester (Preparation 22b) gave the hydrobromide salt (94%).

LRMS (m/z): 385 (M + 1) ⁺ .

Preparation 23

( R )-5-Chloro-3-(5-methyl-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

a) ( R )-3-(2-(5-chloro-2-methoxypyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)piperidine-1-carboxylic acid third Butyl ester

Follow the experimental procedure as described in Preparation 1b, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator) buffered with 0.1% v/v formic acid [0% to 100%) purified crude product from ( R )-3-(2-chloro-5-methylpyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 20a) and 5-Chloro-2-methoxypyridin-3-amine (Preparation 6b) gave a solid (14%).

LRMS (m/z): 449 (M + 1) ⁺ .

b) ( R )-5-Chloro-3-(5-methyl-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

Following ( R )-3-(2-(5-chloro-2-methoxypyridin-3-ylamino)-5-methylpyrimidin-4-ylamine according to the experimental procedure as described in Preparation 19c Piperidine-1-carboxylic acid tert-butyl ester (Preparation 23a) gave the hydrobromide salt (73%).

LRMS (m/z): 335 (M + 1) ⁺ .

Preparation 24

( R )-3-(5-fluoro-4-(N-morpholinyl)-6-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one

a) ( R )-3-(2-chloro-5-fluoro-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Add ( R )-3 to a solution of 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Preparation 11a, 1.01 g, 4.00 mmol) in ethanol (48 mL) - Aminopiperidin-1-carboxylic acid tert-butyl ester (1.60 g, 7.99 mmol), and the resulting mixture was stirred and heated to reflux for 3 days. After cooling to ambient temperature, the solvent was evaporated <RTI ID=0.0> The organic layer was separated, washed with water, dried (MgSO ₄ The residue was purified by flash chromatography eluting elut elut elut elut elut elut

LRMS (m/z): 416 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.44 (s, 9H), 1.62-1.70 (m, 2H), 1.85-1.90 (m, 1H), 3.40-3.41 (m, 3H), 3.63-3.66 (m, 4H), 3.74-3.77 (m, 4H), 4.08-4.13 (m, 2H), 4.86 (br s, 1H).

b) ( R )-3-(5-fluoro-2-(2-methoxypyridin-3-ylamino)-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine- 1-butyl formate

The crude product was purified by flash chromatography (0-100% ethyl acetate in hexanes) from ( R )-3-(2-chloro-5). -Fluoro-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 24a) and 2-methoxypyridin-3-amine to obtain a white foam (87%).

LRMS (m/z): 504 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.43 (s, 9H), 1.63-1.79 (m, 3H), 1.93-2.01 (m, 1H), 3.22-3.34 (m, 3H), 3.49-3.55 (m, 1H), 3.61-3.64 (m, 4H), 3.77-3.81 (m, 4H), 4.70 (br s, 1H), 6.86 (dd, 1H), 7.15 (s, 1H), 7.69 (dd, 1H), 8.57 (dd, 1H).

c) ( R )-3-(5-fluoro-4-(N-morpholinyl)-6-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H ) -ketone

Stirring ( R )-3-(5-fluoro-2-(2-methoxypyridin-3-ylamino)-6-(N-morpholinyl)pyrimidin-4-ylamino) at ambient temperature A mixture of piperidine-l-carboxylic acid tert-butyl ester (preparation 24b, 0.099 g, 0.30 mmol) and a solution of hydrogen chloride in 4N EtOAc (EtOAc) The solvent was evaporated under reduced pressure and the residue was crystalljjjjjjjjj The organic layer was separated and the aqueous was washed with ethyl acetate (x 2). Dried (Na ₂ SO ₄₎ of the combined organic extracts and the solvent was evaporated under reduced pressure to give a yellow foam body form of the title compound (0.088 g, 93%), which was used without further purification in the next synthetic step in.

LRMS (m/z): 390 (M + 1) ⁺ .

Preparation 25

( R )-3-(2-chloro-5-methyl-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester and ( R )-3- (4-Chloro-5-methyl-6-(N-morpholinyl)pyrimidin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester

a) 4-(2,6-Dichloro-5-methylpyrimidin-4-yl)morpholine

Following the experimental procedure as described in Preparation 11a, followed by flash chromatography (0-100% ethyl acetate in hexanes) to purify the crude product from 2,4,6-trichloro-5- The major isomer (white solid, 47%) was obtained from the pyrimidine and morpholine.

LRMS (m/z): 249 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 2.22 (s, 3H), 3.43 - 3.52 (m, 4H), 3.73 - 3.83 (m, 4H).

b) ( R )-3-(2-chloro-5-methyl-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester and ( R )- 3-(4-chloro-5-methyl-6-(N-morpholinyl)pyrimidin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester

Follow the experimental procedure as described in Preparation 24a followed by flash chromatography (0-100% ethyl acetate in hexanes) from 4-(2,6-dichloro-5-methyl) Pyrimidin-4-yl)morpholine (Preparation 25a) and ( R )-3-Aminopiperidine-1-carboxylic acid tert-butyl ester were obtained. The chemical structure of the two regioisomers was specified based on NMR nOe studies: ( R )-3-(2-chloro-5-methyl-6-(N-morpholinyl)pyrimidine was obtained as a minor isomer. 3-butylamino)piperidine-1-carboxylic acid tert-butyl ester (25%, orange foam) and ( R )-3-(4-chloro-5-methyl-6 as the major isomer -(N-morpholinyl)pyrimidin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (59%, colorless oil).

( R )-3-(2-chloro-5-methyl-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (minor isomer) : LRMS (m/z): 413 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.43 (s, 9H), 1.59-1.71 (m, 4H), 1.89 (m, 3H), 3.21 (m, 4H), 3.30-3.64 (m, 4H), 3.78 (m, 4H), 4.16 (br s, 1H).

( R )-3-(4-Chloro-5-methyl-6-(N-morpholinyl)pyrimidin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (major isomer): LRMS (m/z): 413 (M+1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.41 (s, 9H), 1.55 (m, 2H), 1.73 (m, 1H), 1.90 (m, 1H), 2.10 (s, 2H), 2.16 (s, 3H) ), 3.33 (m, 4H), 3.86 (m, 4H), 4.89 (br s, 1H).

Preparation 26

( R )-3-(5-Methyl-4-(N-morpholinyl)-6-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )- ketone

a) ( R )-3-(2-(2-Methoxypyridin-3-ylamino)-5-methyl-6-(N-morpholinylpyrimidin-4-ylamino)piperidine 1-butylic acid tert-butyl ester

The crude product was purified by flash chromatography (0-100% ethyl acetate in hexanes) from ( R )-3-(2-chloro-5). -methyl-6-(N-morpholinyl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (preparation 25b) and 2-methoxypyridin-3-amine to obtain orange foam Body (79%).

LRMS (m/z): 500 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.23-1.28 (m, 1H), 1.58 (s, 3H), 1.73 (m, 3H), 1.90 (s, 3H), 3.20 (t, 4H), 3.43 (m) , 4H), 3.83 (t, 4H), 4.03 (s, 3H), 4.13 (br s, 1H), 6.87 (dd, 1H), 7.21 (br s, 1H), 7.68 (dd, 1H), 8.73 ( Dd, 1H).

b) ( R )-3-(5-Methyl-4-(N-morpholinyl)-6-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2 (1 H )-ketone

( R )-3-(2-(2-Methoxypyridin-3-ylamino)-5-methyl-6-(N-morpholinyl)pyrimidine in a sealed tube at ambient temperature Stirred mixture of 4-butylamino)piperidine-1-carboxylic acid tert-butyl ester (preparation 26a, 0.212 g, 0.42 mmol) and 4N solution of hydrogen chloride in 1,4-dioxane (4 mL) Methanol was added until a clear solution formed. After stirring for an additional 3 hours, a 4N solution (3 mL) of hydrogen chloride in 1,4-dioxane was then added and the mixture was stirred and warmed overnight at 40 °C. The solvent was evaporated under reduced pressure and the residue was crystalljjjjjjjjj The organic layer was separated and the aqueous was washed with ethyl acetate (x 2). Dried (Na ₂ SO ₄₎ of the combined organic extracts and the solvent was evaporated under reduced pressure to give an orange foam body shape of the title compound (0.082 g, 37%), which was used without further purification in the next synthetic step in.

LRMS (m/z): 386 (M + 1) ⁺ .

Preparation 27

( R )-3-(5-Methyl-6-(N-morpholinyl)-2-(piperidin-3-ylamino)pyrimidin-4-ylamino)pyridine-2(1 H )- ketone

a) ( R )-3-(4-(2-Methoxypyridin-3-ylamino)-5-methyl-6-(N-morpholinylpyrimidin-2-ylamino)piperidine 1-butylic acid tert-butyl ester

The crude product was purified by flash chromatography (0-100% ethyl acetate in hexanes) from ( R )-3-(2-chloro-5). -Methyl-6-(N-morpholinyl)pyrimidin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 25b) and 4-methoxypyridin-3-amine afforded a yellow oil (60%).

LRMS (m/z): 500 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.40 (9H, br s), 1.52-1.80 (4H, m), 2.05 (3H, s), 3.22 (6H, s), 3.60 (2H, m), 3.78- 3.95 (5H, m), 4.05 (3H, s), 4.70 (1H, brd), 6.88 (2H, m), 7.73 (1H, dd), 8.73 (1H, dd).

b) ( R )-3-(5-Methyl-6-(N-morpholinyl)-2-(piperidin-3-ylamino)pyrimidin-4-ylamino)pyridine-2 (1 H )-ketone

Stirring ( R )-3-(4-(2-methoxypyridin-3-ylamino)-5-methyl-6-(N-morpholinyl)pyrimidin-2-ylamino at ambient temperature A mixture of piperidine-l-carboxylic acid tert-butyl ester (preparation 27a, 0.523 g, 1.05 mmol) and a solution of hydrogen chloride in 4N solution (10 mL) in 1,4-dioxane for 3 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. Solid potassium carbonate was added to the aqueous phase until an alkaline pH was reached, and the aqueous solution was extracted with dichloromethane (×3). Dried (Na ₂ SO ₄₎ of the combined organic extracts and the solvent was evaporated under reduced pressure to obtain a yellow solid of the title compound (0.110 g, 23%), which was used without further purification in the next synthetic step.

LRMS (m/z): 386 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.50-1.83 (4H, m), 2.08 (3H, s), 2.57-2.75 (2H, m), 2.87-2.95 (2H, m), 3.17-3.30 (4H, m), 3.71 (1H, s), 3.75-3.84 (4H, m), 4.85 (1H, brd), 6.34 (1H, t), 6.91 (1H, dd), 8.64 (1H, dd).

Preparation 28

( R )-5-Chloro-3-(5-methyl-6-(N-morpholinyl)-2-(piperidin-3-ylamino)pyrimidin-4-ylamino)pyridine-2 ( 1 H )-ketone

a) ( R )-3-(4-(5-Chloro-2-methoxypyridin-3-ylamino)-5-methyl-6-(N-morpholinyl)pyrimidin-2-ylamine Tert-butyl piperidine-1-carboxylic acid

Purify the crude product by flash chromatography (0-100% ethyl acetate in hexanes) from ( R )-3-(4-chloro-5). -Methyl-6-(N-morpholinyl)pyrimidin-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 25b) and 5-chloro-2-methoxypyridin-3-amine (Preparation 6b) A yellow foam (83%) was obtained.

LRMS (m/z): 534/536 (M+1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.39 (9H, br s), 1.60-1.80 (4H, m), 2.05 (3H, s), 3.20 (4H, s), 3.20-3.35 (2H, m), 3.50-3.60 (2H, m), 3.80 (4H, m), 3.92 (1H, br s), 4.05 (3H, s), 6.85 (1H, s), 7.65 (1H, d), 8.88 (1H, br s).

b) ( R )-5-Chloro-3-(5-methyl-6-(N-morpholinyl)-2-(piperidin-3-ylamino)pyrimidin-4-ylamino)pyridine- 2(1 H )-ketone

To ( R )-3-(4-(5-chloro-2-methoxypyridin-3-ylamino)-5-methyl-6-(N-morpholinyl)pyrimidine at ambient temperature Addition of tert-butyl 2-aminoamino)piperidine-1-carboxylate (preparation 28a, 0.332 g, 0.62 mmol) to a mixture of hydrogen chloride in 4N solution (6 mL) in 1,4-dioxane Methanol until a clear solution formed. After 3 days, the solvent was evaporated and the residue was crystalljjjjjjjjj The organic layer was separated and the aqueous was washed with ethyl acetate (x 2). Dried (Na ₂ SO ₄₎ of the combined organic extracts and the solvent was evaporated under reduced pressure to obtain a yellow solid of the title compound (0.175 g, 63%), which was used without further purification in the next synthetic step.

LRMS (m/z): 420/422 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.57 (2H, m), 1.80 (2H, m), 2.07 (3H, s), 2.60-2.80 (2H, m), 2.90-3.00 (2H, m), 3.17 -3.33 (4H, m), 3.76-3.84 (4H, m), 3.90 (1H, m), 4.90 (1H, br d), 6.95 (1H, d), 7.68 (1H, s), 8.71 (1H, s).

Instance

Example 1

(S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-ylamino)pyridine-2(1H)-one

Stirring ( S ) -N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl) -N ² -(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine (preparation A suspension of 1b, 11 mg, 0.03 mmol, in 48% aqueous hydrogen bromide (2 mL) and heated to 100 ° C for 5 hr. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The pH of the aqueous phase was then adjusted to ca. 8 using 2M aqueous sodium hydroxide and extracted with dichloromethane (×3). The combined the organic extracts were washed with water and brine, dried (MgS04 _4), filtered, and the solvent was evaporated under reduced pressure to give the title compound as a solid (4 mg, 38%).

LRMS (m/z): 327 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.57 (d, 3H), 5.19 (br s, 1H), 5.79 (d, 1H), 5.91 (d, 1H), 6.32 (d, 1H), 6.93 (dd, 1H), 7.29-7.47 (m, 3H), 7.96 (d, 2H), 8.43 (d, 2H), 11.76 (br s, 1H).

Example 2

(S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine-2(1H)-one

To ( S ) -N ⁴ -(1-(5-fluoropyridin-2-yl)ethyl) -N ² -(2-methoxypyridin-3-yl)-5-methylpyrimidine-2,4 - Diamine (Preparation 2b, 185 mg, 0.52 mmol) in acetonitrile (5 mL), EtOAc (EtOAc (EtOAc) , 1.57 mmol, and the mixture was stirred and heated to 80 ° C for 45 minutes. After cooling to ambient temperature, the mixture was concentrated and treated with saturated aqueous sodium thiosulfate. After stirring for 10 minutes, the title compound was evaporated.

LRMS (m/z): 341 (M+1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.63 (d, 3H), 2.14 (s, 3H), 5.22-5.47 (m, 1H), 6.17-6.31 (m, 1H), 7.06 (br s, 1H) ), 7.55 (dd, 1H), 7.71 (br s, 1H), 7.87 (s, 2H), 7.96 (d, 2H), 8.60 (br s, 1H), 11.98 (br s, 1H).

Example 3

3-[(5-Chloro-4-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}pyrimidin-2-yl)amino]pyridine-2 (1 H )-ketone

( S )-5-Chloro- N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxypyridin-3-yl)pyrimidine-2,4- A mixture of diamine (preparation 3b, 0.184 g, 0.49 mmol) and 48% aqueous hydrogen bromide (1.6 mL) was heated to 100 ° C for 3 hours. The solvent was evaporated under reduced pressure and the~~~~~ Dried (Na. ₂ SO ₄₎ of the combined organic extracts and the solvent was evaporated to give the title compound as a white solid of (0.154 g, 91%).

LRMS (m/z): 361 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.60 (d, 3H), 5.33-5.37 (m, 1H), 6.28-6.33 (m, 1H), 6.43 (d, 1H), 6.92 (d, 1H), 7.31 - 7.45 (m, 2H), 7.98 (s, 1H), 8.02 (s, 1H), 8.35 (dd, 1H), 8.46 (d, 1H), 11.07 (br s, 1H).

Example 4

3-[(4-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}-5-methoxypyrimidin-2-yl)amino]pyridine-2 ( 1 H )-ketone

Following the experimental procedure as described in Example 3, from ( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl)-5-methoxy- N 2-(2-methoxy Pyridin-3-yl)-pyrimidine-2,4-diamine (Preparation 4b) gave a white solid (33%).

LRMS (m/z): 357 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.58 (d, 3H), 3.85 (s, 3H), 5.42-5.26 (m, 1H), 6.21 (d, 1H), 6.29 (dd, 1H), 6.90 (dd , 1H), 7.56 (s, 1H), 7.41-7.29 (m, 2H), 7.85 (br s, 1H), 8.38 (dd, 1H), 8.45 (d, 1H), 12.03 (s, 1H).

Example 5

3-[(4-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}-5-hydroxypyrimidin-2-yl)amino]pyridine-2 (1 H )-ketone

Stirring ( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl)-5-methoxy- N 2-(2-methoxypyridin-3-yl)pyrimidine-2, A mixture of 4-diamine (preparation 4b, 0.200 g, 0.54 mmol) and 48% aqueous hydrogen bromide (1.8 mL) and heated to 100 ° C overnight. The solvent was evaporated under reduced pressure and the~~~~~ A concentrated aqueous solution of hydrogen chloride was added to the aqueous solution until the acidic pH was obtained, and the white solid formed was filtered and dried to give the title compound (0.047 g, 25%).

LRMS (m/z): 343 (M + 1) ⁺ .

¹ H-NMR δ (CD ₃ OD): 1.68 (d, 3H), 5.37-5.44 (m, 1H), 6.34-6.49 (m, 1H), 7.15 (d, 1H), 7.35 (s, 1H), 7.43-7.67 (m, 2H), 8.05 (d, 1H), 8.48 (d, 1H).

Example 6

(S)-4-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidine-5 -Procarbamide

Following the experimental procedure as described in Example 2, from ( S )-4-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-methoxypyridin-3-ylamine Pyrimidine-5-carboxamide (Preparation 5d) gave a white solid (60%).

LRMS (m/z): 370 (M + 1) ⁺ .

Example 7

(S)-5-Chloro-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine-2(1H)- ketone

Following the experimental procedure as described in Example 2, from ( S ) -N ² -(5-chloro-2-methoxypyridin-3-yl)- N ⁴ -(1-(5-fluoropyridine-2- (Ethyl)-5-methylpyrimidine-2,4-diamine (Preparation 7) gave a brown solid (98%).

LRMS (m/z): 375 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.70 (d, 3H), 2.17 (s, 3H), 5.47 (t, 1H), 7.40 (d, 2H), 7.59 (dd, 2H), 7.78 (td) , 1H), 7.98 (s, 1H), 8.08 (d, 1H), 8.57 (d, 1H), 8.67-8.81 (m, 1H), 9.48 (br s, 1H).

Example 8

3-[(4-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}-5-methylpyrimidin-2-yl)amino]-5-(1 H -pyrazol-4-yl)pyridine-2(1 H )-one

Follow the experimental procedure as described in Example 3, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator [0.1% v/v formic acid buffer] 0% to 100%) purified crude product from ( S ) -N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxy-5-(1 H -pyrazol-4-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine (Preparation 9b) gave a white solid (yield: 7%).

LRMS (m/z): 407 (M + 1) ⁺ .

¹ H-NMR δ (CD ₃ OD): 1.63 (d, 3H), 2.10 (s, 3H), 4.63 (s, 1H), 5.47-5.67 (m, 1H), 7.18 (d, 1H), 7.40 ( Dd, 1H), 7.44 - 7.54 (m, 1H), 7.74 (s, 1H), 7.96 (s, 2H), 8.33 (s, 1H), 8.66 (d, 1H).

Example 9

3-{[4-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}-6-(4-hydroxyl Piperidin-1-yl)pyrimidin-2-yl]amino}pyridine-2(1 H )-one

To 3-[(4-(4-{[ T -butyl(dimethyl)decyl)oxy}piperidin-1-yl)-6-{[(1 S )-1-(5-fluoro) Pyridin-2-yl)ethyl]amino}pyrimidin-2-yl)amino]pyridine-2(1 H )-one (preparation 10d, 520 mg, 0.96 mmol) in tetrahydrofuran (5 mL) Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 4.82 ml, 4.82 mmol) was added to the suspension, and the mixture was stirred and heated to 70 ° C for 4 hours. After cooling to ambient temperature, the mixture was partitioned between water and ethyl acetate. With ethyl acetate (× 3) layer was washed with water, and the combined the organic extracts were washed with water, dried (Na ₂ SO ₄₎ and the solvent was evaporated under reduced pressure. The residue was treated with ether and the solid formed was filtered, washed with ether, and by reverse phase chromatography (Waters ^© from silicon dioxide of the C-18, water / acetonitrile / methanol as eluent [0.1% v / v The title compound (19 mg, 5%) was obtained.

LRMS (m/z): 426 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.15-1.36 (m, 2H), 1.46 (d, 3H), 1.66 (m, 2H), 3.63 (m, 1H), 4.07 (m, 2H), 4.99 (m,1H), 5.45(s,1H), 6.17(t,1H), 6.63(m,1H), 6.86(d,1H), 7.42(dd,1H),7.54-7.62(m,2H), 7.96 (dd, 1H), 8.44 (d, 1H).

Example 10

3-[(5-fluoro-4-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}-6-morpholin-4-ylpyrimidin-2-yl) Amino]pyridine-2(1 H )-one

To ( S )-5-fluoro- N 4-(1-(5-fluoropyridin-2-yl)ethyl) -N 2-(2-methoxypyridin-3-yl)-6-(N- Add methoxymethyl chloride (0.147 ml, 1.16 mmol) to a stirred solution of morpholinylpyrimidine-2,4-diamine (Preparation 11c, 172 mg, 0.39 mmol) in EtOAc (3 mL) The ear) and sodium iodide (174 mg, 1.16 mmol), and the mixture was stirred and heated at 80 ° C for 1 hour. After cooling to ambient temperature, the mixture was concentrated and treated with water. After stirring for 10 minutes, the precipitate was filtered, washed with water and dried to give &lt A concentrated aqueous sodium hydroxide solution was added to the aqueous phase until an alkaline pH was reached, followed by extraction of an aqueous alkaline solution with dichloromethane (×3). Dried (MgSO ₄₎ of the combined organic extracts and the solvent was evaporated under reduced pressure, to obtain additional amounts of solid material (0.096 g). The combined solids were dissolved in dichloromethane and washed with a saturated aqueous solution of potassium carbonate. The organic layer was separated, dried (MgSO ₄₎ and solvent evaporated under reduced pressure to give a brown solid of the title compound (0.134 g, 77%).

LRMS (m/z): 430 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.57 (3H, d), 3.64 (4H, m), 3.78 (4H, m), 5.29 (1H, m), 5.63 (1H, br d), 6.89 (1H, Dd), 7.32-7.37 (2H, m), 7.76 (1H, s), 8.18 (1H, dd), 8.44 (1H, d), 11.39 (1H, br s).

Example 11

3-[(6-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}pyrazin-2-yl)amino]pyridine-2(1 H )-one

Stirring N -[(1 S )-1-(5-fluoropyridin-2-yl)ethyl] -N '-(2-methoxypyridin-3-yl)pyrazine-2,6-diamine ( A suspension of 12b, 100 mg, 0.29 mmoles in 48% aqueous hydrogen bromide (1 mL) was obtained and was warmed at 100 &lt;0&gt;C for 3 h. After cooling to ambient temperature, the solvent was evaporated under reduced pressure. The residue was taken from EtOAc (EtOAc)EtOAc.

LRMS (m/z): 327 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.52 (d, 3H), 5.04 (m, 1H), 6.13 (m, 1H), 7.01 (d, 1H), 7.40 (s, 1H), 7.49 (m) , 1H), 7.70 (m, 1H), 7.78 (s, 1H), 7.93 (d, 1H), 8.57 (d, 1H), 9.18 (s, 1H), 11.92 (br s, 1H).

Example 12

3-[(6-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}pyridin-2-yl)amino]pyridine-2(1 H )-one

Following the experimental procedure as described in Example 3, from ( S ) -N 2-(1-(5-fluoropyridin-2-yl)ethyl) -N 6-(2-methoxypyridin-3-yl) Pyridine-2,6-diamine (Preparation 13b) gave a brown foam (96%).

LRMS (m/z): 326 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.58 (d, 3H), 4.93-5.04 (m, 1H), 5.08 (d, 1H), 5.85 (d, 1H), 6.09 (d, 1H), 6.23-6. (m, 1H), 6.85 (dd, 1H), 7.27-7.42 (m, 2H), 7.53 (s, 1H), 8.30 (dd, 1H), 8.44 (d, 1H), 11.17 (br s, 1H) .

Example 13

2-((1 r ,4 r )-4-(5-methyl-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino) Cyclohexyl)acetonitrile

To 2-((1 r ,4 r )-4-(2-(2-methoxypyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)cyclohexyl)acetonitrile 15b, 90 mg, 0.26 mmoles of trimethylsulfonyl chloride (97 μL, 0.77 mmol) and sodium iodide (115 mg, 0.77 mmol) in acetonitrile (15 mL) The mixture was stirred and heated at 80 ° C for 1 hour. After cooling to ambient temperature, water was added and the resulting suspension was stirred at ambient temperature for 20 minutes. The solid formed was filtered, washed with EtOAc (EtOAc)

LRMS (m/z): 339 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.21 (dd, 4H), 1.50 (dd, 4H), 1.67 (m, 1H), 1.80-2.20 (m, 5H), 3.93 (m, 1H), 6.30 (m, 1H), 7.82 (s, 1H), 8.21 (m, 1H), 9.45 (s, 1H), 12.15 (bd, 1H).

Example 14

3-({4-[( trans- 4-{[(3-hydroxypiperidin-1-yl)sulfonyl]methyl}cyclohexyl)amino]pyrimidin-2-yl}amino)pyridine-2 (1 H )-ketone

Follow the experimental procedure as described in Example 2, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator [0.1% v/v formic acid buffer] 0% to 100%) purified crude product from 1-(((1r,4r)-4-(2-(2-methoxypyridin-3-ylamino)pyrimidin-4-ylamino)cyclohexyl) Methylsulfonyl)piperidin-3-ol (Preparation 18b) gave a solid (47%).

¹ H-NMR δ (DMSO- d ₆ ): 1.21-1.50 (m, 6H), 1.70-2.10 (m, 8H), 2.45-3.50 (m, 6H), 3.73 (m, 1H), 5.01 (d, 1H), 5.97 (d, 1H), 6.23 (m, 1H), 6.94 (d, 1H), 7.29 (s, 1H), 7.69 (s, 1H), 7.79 (m, 1H), 8.36 (d, 1H) ).

Example 15

( R )-3-Sideoxy-3-(3-(2-(2-Sideoxy-1,2-dihydropyridin-3-ylamine) Pyrimidin-4-ylamino)piperidin-1-yl)propanenitrile

To ( R )-3-(4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one (Preparation 19c, 67 mg, 0.23 mmol) Add triethylamine (33 μL, 0.24 mmol) and 3-[(2,5-di-oxypyrrolidin-1-yl)oxy]-3- to a solution in dichloromethane (3 mL) The pendant oxypropionitrile (prepared as described in BE 875054 (A1), 51 mg, 0.28 mmol). The reaction mixture was stirred at ambient temperature for 24 hours and the solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO _4), and evaporated under reduced pressure by reverse phase chromatography (Waters ^© from silicon dioxide of the C-18, water / acetonitrile / methanol as eluent [0.1% v / v formic acid buffered] 0% The residue was purified with EtOAc EtOAcjjjjjj

LRMS (m/z): 354 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.55 (d, 1H), 1.74 (m, 1H), 1.95 (m, 1H), 2.13 - 2.34 (m, 1H), 3.08 (m, 2H), 3.48 -3.80 (m, 1H), 3.86 (m, 1H), 4.05 (d, 1H), 4.27 (m, 1H), 6.03 (d, 1H), 6.07-6.17 (m, 1H), 6.17-6.30 (m) , 1H), 6.93 (br s, 1H), 7.22-7.47 (m, 1H), 7.73 (s, 1H), 7.83-7.95 (m, 1H), 8.32 (br s, 1H), 11.84 (br s, 1H).

Example 16

( R )-3-(3-(5-methyl-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidine-1 -yl)-3-oxopropiononitrile

Following ( R )-3-(5-methyl-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2 (1 H ) according to the procedure described in Example 5. )-ketone (Preparation 20c) gave a solid (15%).

LRMS (m/z): 368 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.14-1.40 (m, 1H), 1.57-1.78 (m, 2H), 1.99 (br s, 3H), 2.59 (m, 2H), 3.10-3.33 (m, 1H) ), 3.42-3.69 (m, 2H), 3.76-4.35 (m, 2H), 4.55-5.01 (m, 1H), 6.11-6.41 (m, 1H), 6.75-7.01 (m, 1H), 7.70-7.92 (m, 1H), 8.08 (m, 2H), 8.30-8.53 (m, 1H), 11.18 (br s, 1H).

Example 17

( R )-3-(3-(5-fluoro-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1- 3-oxopropiononitrile

Following ( R )-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H ) according to the experimental procedure as described in Example 15. - Ketone (Preparation 22c) gave a solid (45%).

LRMS (m/z): 372 (M+1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.59-1.98 (m, 2H), 3.17-3.33 (m, 1H), 3.33-3.42 (m, 1H), 3.46-3.63 (m, 2H), 3.90 (d, 1H), 4.04(d,1H),4.13-4.22(m,1H), 4.27(d,1H), 4.91(m,1H),6.31-6.47(m,1H),6.98(dd,1H),7.86 (d, 1H), 7.91 (d, 1H), 8.00 (s, 1H), 8.11 (s, 1H), 8.50 (d, 1H).

Example 18

(R)-3-(4-(1-(4 H -1,2,4-triazol-3-yl)piperidin-3-ylamino)-5-fluoropyrimidin-2-ylamino) Pyridine-2(1H)-one

Stir ( R )-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one (Preparation 22c, 50 mg, 0.16 m a mixture of 3-bromo- 4H -1,2,4-triazole (prepared as described in J. Med. Chem. 2004, 47 (19), 4645, 12.2 mg, 0.08 mmol) And heated at 150 ° C overnight. The reaction mixture was cooled to ambient temperature and diluted with methanol. Diethyl ether was then added and the precipitate formed was filtered. The filtrate was concentrated under reduced br~~~~~~~~

LRMS (m/z): 372 (M+1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.61 (m, 2H), 1.73-1.86 (m, 1H), 1.88-2.06 (m, 2H), 2.83 (m, 4H), 3.09 (m, 1H) , 3.23 (m, 1H), 3.80 (m, 2H), 4.07 (br s, 3H), 4.30 (br s, 1H), 6.07 (t, 2H), 6.27 (t, 1H), 6.85-7.05 (m , 2H), 7.36-7.68 (m, 3H), 7.73-7.89 (m, 2H), 8.03 (d, 1H), 8.10-8.35 (m, 3H), 8.78 (br s, 1H), 11.87 (br s , 2H), 12.57 (br s, 1H), 13.05 (br s, 1H).

Example 19

( R )-3-(3-(2-(5-Chloro-2-oxo-l,2-dihydropyridin-3-ylamino)-5-methylpyrimidin-4-ylamino) Piperidin-1-yl)-3-oxopropiononitrile

Following the experimental procedure as described in Example 15, from ( R )-5-chloro-3-(5-methyl-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine- 2(1 H )-one (Preparation 23b) gave a solid (8%).

LRMS (m/z): 402 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.67 (t, 2H), 1.78-1.90 (m, 1H), 2.02 (s, 3H), 2.63-2.78 (m, 1H), 3.04 (dd, 1H) , 3.68-3.85 (m, 1H), 3.95-4.20 (m, 2H), 4.32 (d, 1H), 4.50 (d, 1H), 6.71 (dd, 1H), 7.19 (d, 1H), 7.77 (s) , 1H), 7.87 (d, 1H), 8.23 (s, 1H), 8.38 (d, 1H), 12.21 (br s, 1H).

Example 20

3-[(3 R )-3-({5-fluoro-6-morpholin-4-yl-2-[(2-o-oxy-1,2-dihydropyridin-3-yl)amino] Pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

Following the experimental procedure as described in Example 15, followed by flash chromatography (0-100% ethyl acetate in hexanes followed by 0-20% methanol in ethyl acetate) ( R )-3-(5-fluoro-4-(N-morpholinyl)-6-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridine-2(1 H )-one (Preparation 24c) gave a brown solid (34%).

LRMS (m/z): 457 (M + 1) ⁺ .

¹ H-NMR δ (CD ₃ OD): 1.25-1.29 (m, 1H), 1.64-1.71 (m, 2H), 1, 87 (m, 1H), 2.09-2.16 (m, 2H), 2.75-2.82 (m, 1H); 2.91-2.99 (m, 1H), 3.05-3.20 (m, 1H), 3.59-3.61 (m, 4H), 3.77 (m, 4H), 3.84-3.92 (m, 1H), 4.21. (d, 1H), 4.62 (s, 2H), 6.37-6.46 (m, 1H), 6.92-6.98 (m, 1H), 8.37-8.43 (m, 1H).

Example 21

3-[(3 R )-3-({5-methyl-6-morpholin-4-yl-2-[(2-o-oxy-1,2-dihydropyridin-3-yl)) Pyrimidin-4-yl}amino)piperidin-1-yl]-3-oxoxypropionitrilecarboxylate

Following the experimental procedure as described in Example 15, followed by reverse phase chromatography (C-18 cerium oxide from Waters ^© , water/acetonitrile/methanol as the eliminator [0.1% v/v formic acid buffer] 0% to 100%) purified crude product from ( R )-3-(5-methyl-4-(N-morpholinyl)-6-(piperidin-3-ylamino)pyrimidin-2-yl Amino)-pyridine-2( 1H )-one (Preparation 26b) gave a yellow solid (17%).

LRMS (m/z): 453 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.60-1.68 (m, 1H), 1.74-1.81 (m, 1H), 1.86 (s, 3H), 1.97-2.06 (m, 1H), 3.13 (m, 1H) 3.18(t,4H), 3.42(s,1H), 3.48(s,1H), 3.78(t,4H),3.97(m,1H),4.03(m,1H),4.18(d,1H),6.25 - 6.31 (m, 1H), 6.92 (dd, 1H), 7.78 (s, 1H), 8.39 (dd, 1H).

Example 22

3-[(3 R )-3-({5-methyl-4-morpholin-4-yl-6-[(2-o-oxy-1,2-dihydropyridin-3-yl)) Pyrimidin-2-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

Following the experimental procedure as described in Example 15, followed by purification of the crude product by flash chromatography (0-20% methanol in dichloromethane) from ( R )-3-(5-methyl-6) -(N-morpholinyl)-2-(piperidin-3-ylamino)pyrimidin-4-ylamino)pyridin-2( 1H )-one (Preparation 27b) afforded a green solid (70%).

LRMS (m/z): 453 (M + 1) ⁺ .

¹ H-NMR δ (CDCl ₃ ): 1.55-1.85 (4H, m), 2.11 (3H, s), 3.15-3.25 (4H, m), 3.35 (2H, d), 3.55 (2H, m), 3.80 -3.95 (6H, m), 4.67 (1H, br d), 6.38 (1H, dt), 6.95 (1H, m), 7.73 (1H, s), 8.53 (1H, br dd), 10.88 (1H, br s).

Example 23

3-[(3 R )-3-({4-[(5-chloro-2-indolyl-1,2-dihydropyridin-3-yl)amino]-5-methyl-6-? Phenyl-4-ylpyrimidin-2-yl}amino)piperidin-1-yl]-3-oxoxypropanenitrile

Following the experimental procedure as described in Example 15, from ( R )-5-chloro-3-(5-methyl-6-(N-morpholinyl)-2-(piperidin-3-ylamino) Pyrimidin-4-ylamino)pyridine-2( 1H )-one (Preparation 28b) gave a white solid (54%).

LRMS (m/z): 487 / 489 (M + 1) ⁺ .

¹ H-NMR δ (DMSO- d ₆ ): 1.53 (2H, m), 1.77 (2H, m), 1.97 (3H, s), 2.42-2.54 (4H, m), 3.05-3.17 (4H, m) , 3.60-3.77 (6H, m), 4.04 (1H, m), 6.75 (1H, br dd), 7.15 (1H, br dd), 7.75 (1H, s), 8.53 (1H, br s), 12.25 ( 1H, br s).

Following the procedure similar to that described above, the following compounds were obtained:

Example 24

3-[(3 R )-3-({5-chloro-2-[(2-o-oxy-1,2-dihydropyridin-3-yl)amino]pyrimidin-4-yl}amino) Piperidin-1-yl]-3-oxopropiononitrile

Example 25

3-[(4-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}pyrimidin-2-yl)methyl]pyridine-2(1H)-one

Example 26

3-(5-{6-{[(1 S )-1-(5-fluoropyridin-2-yl)ethyl]amino}-2-[(2-o-oxy-1,2-dihydro) Pyridin-3-yl)amino]pyrimidin-4-yl}-1,3-thiazol-2-yl)benzoic acid

Pharmacological activity

In vitro JAK kinase assay

Compounds were screened for their ability to inhibit JAK1, JAK2, and JAK3 using assays as indicated below.

Using the baculovirus expression system, human JAK1 (aa 850-1154), JAK2 (aa 826-1132), JAK3 (aa 795-1124), and Tyk2 (aa) The catalytic domain of 871-1187) appears as an N-terminal GST-fusion protein and is purchased from Carna Biosciences.

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

For an enzyme-containing, of ATP and peptide at 8 mM MOPS (pH 7.0), IC test compound the amount of 10 mM of each kinase mg Cl _2, 0.05% β- mercaptoethanol, 0.45 mg / ml BSA in ₅₀ of the reaction mixture. The ATP concentration in the reaction was 3 μM for JAK1, 0.2 μM for JAK2, 0.6 μM for JAK3, and 1.8 μM for Tyk2. The enzyme reaction was carried out for 30 minutes at room temperature. Next, 20 μl of quenching detection buffer (50 mM containing 0.115 μg/ml of phosphotylin phosphorylation (PT66)-cryptate (CisBio) and variable concentration of SA-XL665 (CisBio) was used. HEPES, 0.5 M KF, EDTA 0.25 M, 0.1% (w/v) BSA, pH 7.5) The reaction was stopped to keep the SA-B ratio constant. Incubate for 3 hours and read on a Victor 2V spectrofluorometer (PerkinElmer) set to read fluorescence resonance energy transfer.

Some of the abbreviations used above have the following meanings: AA: Amino acids

GST: glutathione-S-transferase

MOPS: 3-(N-morpholinyl)propanesulfonic acid

BSA: Bovine Serum Albumin

ATP: adenosine triphosphate

EDTA: ethylenediaminetetraacetic acid

HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

SA-XL665: Streptavidin (biotin-binding tetrameric protein isolated from Streptomyces avidinii ) XL665

The present invention is described in the table of IC ₅₀ values of some exemplary compounds 1. In Table 1, "A" indicates that the IC ₅₀ value is less than 0.1 μM (100 nM), and "B" indicates that the IC ₅₀ value is in the range of 0.1 μM (100 nM) to 1 μM (1000 nM), and C represents IC _{50 .} Value is above 1 μM (1000 nM).

As can be seen from Table 1, the compound of formula (I) is a potent inhibitor of JAK1, JAK2 and JAK3 kinase. The present invention preferably pyridin-2 (1H) - one derivatives inhibiting JAK1, JAK2 and JAK3 kinases of the IC ₅₀ values (measured as hereinbefore defined) of less than 1 μM (1000 nM), preferably less than for each of the Janus kinase 0.5 μM (500 nM), more preferably less than 0.2 μM (200 nM).

The invention also relates to a compound of the invention as described herein, which is suitable for use in the treatment of a human or animal body by therapy. The compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or as mixtures thereof. It can be obtained, for example, in the form of a solid plug, a powder or a film by a method such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

combination

The pyridine-2(1H)-one derivatives as defined herein may also be combined with other active compounds which are susceptible to pathological conditions or diseases which are ameliorated by inhibition of the Janus kinase.

Combinations of the invention may optionally include one or more other active agents known to be useful in the treatment of a spinal proliferative disorder (such as true plethremia, essential thrombocythemia or myelofibrosis), leukemia, lymphoid malignancies And solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, wherein the pathological condition or disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammation Sexual enteropathy, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis, such as: (a) dihydrofolate Reductase inhibitors, such as methotrexate or CH-1504; (b) dihydroorotate dehydrogenase (DHODH) inhibitors, such as leflunomide, teriflunomide Or a compound described in International Patent Application No. WO 2008/077639 and WO 2009/021696; (c) an immunomodulator such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; (d) DNA synthesis and repair inhibitors, such as Mitoxantrone or Cladribine; (e) immunosuppressants, such as Imuran (azathioprine) or purinethol (6-mercaptopurine or 6-MP); (f) anti-α4 integrin antibody, such as natalizumab (Natalizumab) (Tysabri) (g) an α4 integrin antagonist such as R-1295, TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; (h) corticoid and Glucocorticoids, such as prednisone or methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide or Beta-metasone; (i) fumarate, such as BG-12; (j) anti-tumor necrosis factor-α (anti-TNF-α), such as infliximab, Adalimumab or Certolizumab pegol; (k) soluble tumor necrosis factor-α (TNF-α) receptor, such as etanercept; (l) Anti-CD20 (lymphocyte protein) monoclonal antibodies, such as Rituximab, Ocreizumab, Ofatumumab or TRU-015; (m) Anti-CD52 (lymphocyte protein) a monoclonal antibody, such as alemtuzumab; (n) anti-CD25 (lymphocyte protein), such as daclizumab; (o) anti-CD88 (lymphocyte protein), such as Aikuzhu Monoclonal antibody (eculizumab) or pexilizumab; (p) anti-interleukin 6 receptor (IL-6R), such as tocilizumab; (q) anti-interleukin 12 receptor (IL-12R)/interleukin 23 receptor (IL-23R), such as ustekinumab; (r) calcineurin inhibitor, such as cyclosporine A ( Cyclosporine A) or tacrolimus; (s) inosine monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin, mizoribine (mizoribine) or mycophenolic acid; (t) cannabinoid receptor agonist, such as sateux (Sativex); (u) chemokine CCR1 antagonist, such as MLN-3897 or PS- 031291; (v) Chemokine CCR2 An anti-agent such as INCB-8696; (w) an inhibitor of necrosis factor-κB (NF-κB or NFKB) activation, such as Sulfasalazine, Iguratimod or MLN-0415; (x) Adenosine A _2A agonist, such as ATL-313, ATL-146e, CGS-21680, Regadenoson or UK-432,097; (y) sphingosine-1 (S1P) phosphate receptor Agents, such as fingolimod, BAF-312 or ACT128800; (z) sphingosine-1 (S1P) dissociating enzyme (liase) inhibitors, such as LX2931; (aa) spleen tyrosine kinase ( Syk) inhibitors, such as R-112; (bb) protein kinase inhibitor (PKC) inhibitors, such as NVP-AEB071; (cc) anticholinergic agents, such as tiotropium or adiponium ( (dd) β-adrenergic agonist, such as formoterol, indacaterol or abediterol (LAS100977); (ee) with double a compound of a muscarinic antagonist-β2 agonist activity (MABA); (ff) a histamine 1 (H1) receptor antagonist, such as azelastine or ebastine; (gg) chemoattractant receptors expressed on TH ₂ cells Homologous molecule (CRTH2) inhibitors, such as OC-459, AZD-1981, ACT-129968, QAV-680; (hh) vitamin D derivatives, such as 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, apericoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, ru Lumiracoxib, parecoxib sodium, rofecoxib, serenocoxib-1 or valdecoxib; (jj) anti-allergy (kk) antiviral agent; (ll) phosphodiesterase (PDE) III inhibitor; (mm) phosphodiesterase (PDE) IV inhibitor, such as roflumilast or GRC-4039; (nn) a dual phosphodiesterase (PDE) III/IV inhibitor; (oo) a xanthine derivative such as theophylline or theobromine; (pp) p38 cleavage-activating protein kinase ( P38 MAPK) inhibitors, ARRY-797; (qq) cleavage substance activates extracellular signal-regulated kinase kinase (MEK) inhibitors, such as ARRY-142886 or ARRY-438162; (rr) phosphoinositide 3-kinase (PI3K) inhibitor; (ss) Interferons, including interferon beta 1a, such as Avonex from Biogen Idec, CinnoVex from CinnaGen, and Rebif from EMD Serono, and interferon beta 1b, such as from Schering's Betaferon and Betaseron from Berlex; and (tt) interferon alpha, such as Sumiferon MP.

Specific examples of suitable corticosteroids and glucocorticoids which may be combined with the JAK inhibitors of the invention are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, Deflazacort, halopedone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, flucinaine Fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tiraptanide Tipredane), hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, alfalfa Mometasone furoate, rimexolone, prednisolone farnesyla Te), ciclesonide, butixocort propionate, RPR-106541, deprodone propionate, fluticasone propionate Propionate), fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide ), prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate (betamethasone) Betamethasone dipropionate), hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate, and hydrocortisone probutate.

Specific examples of suitable Syk kinase inhibitors that can be combined with the JAK inhibitors of the invention are fosfamatinib (from Rigel), R-348 (from Rigel), R-343 (from Rigel), R-112. (from Rigel), piceatannol, 2-(2-aminoethylamino)-4-[3-(trifluoromethyl)anilino]pyrimidine-5-carboxamide, R-091 (from Rigel), 6-[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-dihydro -2H-pyrido[3,2-b][1,4]oxazin-3-one benzenesulfonate (R-406 from Rigel), 1-(2,4,6-trihydroxyphenyl) -2-(4-methoxyphenyl)ethan-1-one, N-[4-[6-(cyclobutylamino)-9H-indol-2-ylamino]phenyl]-N-A Ethylamine (QAB-205 from Novartis), 2-[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-ylamino]pyridine-3 -carbamamine dihydrochloride (BAY-61-3606 from Bayer) and AVE-0950 (coming From Sanofi-Aventis).

Specific examples of suitable M3 antagonists (anticholinergic agents) which may be combined with the JAK inhibitors of the invention are tiotropium salts, oxitropium salts, flutropium salts, isopropyl esters. Ipratropium salt, glycopyrronium salt, trastium salt, zamifenacin, revatropate, espatropate, daro bromide Ammonium (darotropium bromide), CI-923, NPC-14695, BEA-2108, 3-[2-hydroxy-2,2-bis(2-thienyl)ethyloxy]-1-(3-phenoxy) Propyl)-1-azinium bicyclo[2.2.2]octane salt (especially aclidinium salt, more preferably aclidinium bromide), 1-(2-phenylethyl) 3-(9H--9-ylcarbonyloxy)-1-indolylbicyclo[2.2.2]octane salt, 2-sided oxy-1,2,3,4-tetrahydroquinazoline-3 -carboxylic acid internal-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (DAU-5884), 3-(4-benzylpiperazin-1-yl)-1-cyclo Butyl-1-hydroxy-1-phenylpropan-2-one (NPC-14695), N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]-2 (R)-[3,3-difluoro-1(R)-cyclopentyl]-2-hydroxy-2-phenylacetamide (J-104135), 2(R)-cyclopentyl-2- hydroxy-N-[1-[4(S) -Methylhexyl]piperidin-4-yl]-2-phenylacetamide (J-106366), 2(R)-cyclopentyl-2-hydroxy-N-[1-(4-methyl- 3-pentenyl)-4-piperidinyl]-2-phenylacetamide (J-104129), 1-[4-(2-aminoethyl)piperidin-1-yl]-2 ( R)-[3,3-Difluorocyclopenta-1(R)-yl]-2-hydroxy-2-phenylethan-1-one (Banyu-280634), N-[N-[2-[N -[1-(cyclohexylmethyl)piperidine-3(R)-ylmethyl]amine-carbamoyl]ethyl]amine-methylmethyl]-3,3,3-triphenylpropanamide (Banyu CPTP), 2(R)-cyclopentyl-2-hydroxy-2-phenylacetic acid 4-(3-Azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), iodide 3(R)-[4,4-bis(4-fluorophenyl) -2-Sideoxyimidazolidin-1-yl]-1-methyl-1-[2-o-oxy-2-(3-thienyl)ethyl]pyrrolidinium, trifluoroacetic acid N-[1 -(3-hydroxybenzyl)-1-methylpiperidinium-3(S)-yl]-N-[N-[4-(isopropoxycarbonyl)phenyl]aminecarbamyl]-L - tyramine, UCB-101333, Merck's OrM3, 7-endo-(2-hydroxy-2,2-diphenylethenyloxy)-9,9-dimethyl-3-oxo Hetero-9-azinium tricyclo[3.3.1.0(2,4)]decane salt, iodide 3(R)-[4,4-bis(4-fluorophenyl)-2-oxoxyimidazolidinium -1-yl]-1-methyl-1-(2-phenylethyl)pyrrolidinium, bromide trans-4-[2-[hydroxy-2,2-(dithiophen-2-yl) from Novartis Ethyloxy]-1-methyl-1-(2-phenoxyethyl)piperidinium (412682), 7-(2,2-diphenylpropanyloxy)-7,9 ,9-trimethyl-3-oxa-9-azinium tricyclo[3.3.1.0*2,4*]decane salt, 7-hydroxy-7,9,9-trimethyl-3-oxa -9-azepine tricyclo[3.3.1.0*2,4*]decane 9-methyl-9H-indole-9-carboxylate, all of which are racemic and their counterparts as appropriate Isomers, their diastereomers, and mixtures thereof, and Depending on the case, it is in the form of its pharmacologically compatible acid addition salt. Among the salts, chloride, bromide, iodide and methanesulfonate are preferred.

Specific examples of suitable β-adrenergic agonist (β2-agonist) which can be combined with the JAK inhibitor of the present invention are terbutaline sulphate, effluent fumarate Eformoterol fumarate, formoterol fumarate, bambuterol, ibuterol, isoprenaline hydrochloride, docetaxel (dopexamine), metaproterenol, tulobuterol, procaterol hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride, Albuterol sulphate, salbutamol sulphate, salmefamol, salmeterol xinafoate, carmoterol hydrochloride, hydrochloric acid (R)-salbutamol ( (R)-albuterol hydrochloride, Levalbuterol hydrochloride/Levosalbutamol hydrochloride, (-)-salbutamol hydrochloride, formoterol, tartaric acid (R,R)-formoterol ((R,R)-Formoterol tartrate), Arformoterol tartrate, sulfonterol, Bedordrine sulphate, indacaterol, Tentinterol Hydrochloride), milveterol hydrochloride, Olodaterol, fenoterol hydrobromide, Rimetrol hydrobromide, riproterol hydrochloride, Vilanterol, broxaterol, pirbuterol hydrochloride, methanesulfonic acid Bitolterol mesylate, clenbuterol hydrochloride, AZD-3199, GSK-159802, GSK-597901, GSK-678007, GSK-961081, 4-[2-[3-(1H- Benzimidazol-1-yl)-1,1-dimethylpropylamino]-1-hydroxyethyl]-2-(4-methoxybenzylamino)phenol, 1-[2H-5-hydroxyl -3- Sideoxy-4H-1,4-benzoxazine-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino] Ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-dimethoxyphenyl) )-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]-2-[3- (4-n-Butoxyphenyl)-2-methyl-2-propylamino]ethanol, KUL-1248, HOKU-81, SM-110444, RP-58802B, abediterol (LAS 100977) And the compounds described in PCT Patent Application Nos. WO 2007/124898, WO 2006/122788 A1, WO 2008/046598, WO 2008095720, WO 2009/068177, and WO 2010/072354.

Specific examples of suitable phosphodiesterase IV (PDE IV) inhibitors which can be combined with the JAK inhibitors of the invention are benafentrine dimaleate, etazolate, and tarpaulin Theophylline (de-nbufylline), rolipram, cipamfylline, zardaverine, arofylline, filaminast, tyros Tipelukast, tofimilast, piclamilast, tolafentrine, mesoplanm, drotaverine hydrochloride, liris Lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, non-Minist, (R) -(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5-dichloro- 4-pyridyl)-2-[1-(4-fluorobenzyl)-5-hydroxyl -1H-indol-3-yl]-2-oxoethoxyacetamide (GSK-842470), 9-(2-fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613), N-(3,5-Dichloro-4-pyridyl)-8-methoxyquinolin-5-carboxamide (D-4418), 3-[3-(cyclopentyl) Oxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-indole hydrochloride (V-11294A), 6-[3-(N,N-di Methylamine-mercapto)phenylsulfonyl]-4-(3-methoxyanilino)-8-methylquinolin-3-carboxamide hydrochloride (GSK-256066), 4-[ 6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridine-2(1H)-one (T-440), (-)-trans-2-[3'-[3-(N-cyclopropylaminemethanyl)-4-yloxy-1,4-dihydro-1,8-pyridin-1-yl] 3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid, MK-0873, CDC-801, UK-500001, BLX-914, 2-methoxycarbonyl-4-cyano-4-(3-cyclopropyl) Oxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl) ring Hex-1-ol, 5(S)-[3-(cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin-2-one ( IPL-455903), ONO-6126 (Eur Respir J 2003, 22 (Supp. 45): Abst 2557) and PCT Patent Application No. WO 03/0976 Compounds as claimed in No. 13, WO 2004/058729, WO 2005/049581, WO 2005/123693, WO 2005/123692, and WO 2010/069504.

An example of a suitable phosphoinositide 3-kinase (PI3K) inhibitor that can be combined with a JAK inhibitor of the invention is 2-methyl-2-[4-[3-methyl-2-oxo-8-( 3-quinolinyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl]propanenitrile (BEZ-235 from Novartis), CAL-101 ( From Calistoga Pharmaceuticals) and N-ethyl-N'-[3-(3,4,5-trimethoxyanilino) Pyrido[2,3-b]pyrazine-6-yl]thiourea (AEZS-126 from Aeterna Zentaris).

The compounds of formula (I) according to the invention and combinations thereof are useful for the treatment of spinal proliferative disorders, leukemias, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, wherein JAK inhibitors are expected to be used Has beneficial effects, such as 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.

The active compounds in the combination 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 different routes.

All active agents are expected to be administered in close proximity, either simultaneously or in time. Alternatively, one or two active agents can be administered in the morning while other active agents are administered later in the day. Or in another embodiment, one or two active agents can be administered twice daily and the other active agent administered once daily, either simultaneously with one of the two daily doses, or separately. Preferably at least two and more preferably all of the active agents will be administered simultaneously. Preferably at least two and more preferably all of the active agents will be administered as a mixture.

The invention also relates to a combination of a compound of the invention and one or more other therapeutic agents for the treatment of pathological conditions or diseases which are readily ameliorated by inhibition of Janus kinase (JAK), in particular, wherein The pathological condition or disease is selected from the group consisting of a spinal proliferative disorder, leukemia, lymphatic Sexual diseases as well as solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, 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 compound of the invention in combination with one or more other therapeutic agents for the manufacture of a formulation or medicament for the treatment of such diseases.

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibition of a Janus kinase (JAK), wherein the pathological condition or disease is selected from the group consisting of a spinal proliferative disorder, Leukemia, lymphoid malignant disease, and solid tumor; bone marrow and organ transplant rejection; immune-mediated disease and inflammatory disease, more specifically, wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple Sclerosing disease, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis; the method includes effective treatment A combination of a compound of the invention and one or more additional therapeutic agents.

Depending on the nature of the condition to be treated, the active compound in the combination of the invention may be administered by any suitable route, for example, orally (in syrup, lozenge, capsule, buccal, controlled release formulation, rapid dissolution) Formulations, etc.); topical (in the form of a cream, ointment, lotion, nasal spray or aerosol); by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by Inhalation (in the form of dry powder, solution, dispersion, etc.).

The active compound in the combination (i.e., the pyridine-2(1H)-one derivative of the present invention) and other optionally active compounds may be co-administered in the same pharmaceutical composition or intended to be used by the same or different The routes are administered separately, simultaneously, concomitantly or sequentially in different compositions.

An embodiment of the invention consists of a kit of dispensing parts comprising a pyridine-2(1H)-one derivative of the invention and instructions for simultaneous, simultaneous, separate or sequential use in combination with another active compound The active compound is suitable for the treatment of spinal proliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, for the treatment of rheumatoid Arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

Another embodiment of the invention consists of a package comprising a pyridine-2(1H)-one derivative of the invention and another active compound suitable for the treatment of spinal proliferative disorders, leukemias, lymphoid malignancies And solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uv Inflammation, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis.

Pharmaceutical composition

The pharmaceutical composition of the present invention comprises the compound of the present invention and a medicine A acceptable diluent or carrier.

The term pharmaceutical composition, as used herein, refers to a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt, solvate, N-oxide, stereoisomeric A construct, a deuterated derivative or a prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and an excipient. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

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

The invention further provides a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable diluent or carrier and one or more additional therapeutic agents for use in treatments which are susceptible to improvement by inhibition of Janus kinase (JAK) A pathological condition or disease, such as the previously described disease.

The invention also relates to a pharmaceutical composition of the invention for use in the treatment of a pathological condition or disease which is ameliorated by inhibition of Janus kinase (JAK), in particular wherein the pathological condition or disease is selected from Spinal cord proliferative disorders, leukemias, lymphoid malignancies, and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more specifically, 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 the pharmaceutical compositions of the invention for the manufacture of a medicament for the treatment of such diseases.

The present invention also provides a method of treating a pathological condition or disease which is easily ameliorated by inhibition of a Janus kinase (JAK), wherein the pathological condition or disease is selected from the group consisting of a spinal proliferative disorder, Leukemia, lymphoid malignant disease, and solid tumor; bone marrow and organ transplant rejection; immune-mediated disease and inflammatory disease, more specifically, wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple Sclerosing disease, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis, including active administration A pharmaceutical composition of the invention in an amount.

The invention also provides a pharmaceutical composition comprising at least a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise from 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition, depending on the nature of the formulation and whether it is further diluted prior to administration. The composition of the composition is preferably suitable for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention, as well as methods for their preparation, will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

The pharmaceutically acceptable excipients which are combined with the active compounds or salts of the compounds to form the compositions of the present invention are well known per se and the excipients actually employed will depend, inter alia, on the intended method of administration of the compositions. Excipient Examples include, without limitation, calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Other carriers suitable for formulating the compounds of the invention can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

i) Oral investment

The compounds of the invention may be administered orally (peroral administration; oral ( per os , Latin)). Oral administration includes swallowing to allow the compound to be absorbed from the intestine and transmitted to the liver via the portal vein (the first metabolism of the liver) and eventually into the gastrointestinal (GI) tract.

The composition for oral administration may be a tablet, a delayed tablet, a sublingual tablet, a capsule, an inhaled aerosol, an inhalation solution, a dry powder inhaler or a liquid preparation (such as a mixture, a solution, an elixir, The form of the syrup or suspension), all forms containing the compound of the invention; the formulation can be prepared by methods well known in the art. The active ingredient can also be presented in the form of a bolus, elixirs or paste.

When the composition is in the form of a lozenge, any pharmaceutical carrier which is conventionally used in the preparation of solid formulations may be employed. Examples of such carriers include magnesium stearate, talc, gelatin, acacia, stearic acid, starch, lactose, and sucrose.

Tablets can be prepared by compression or molding, as appropriate, with one or more accessory ingredients. A compressed tablet can be in a free-flowing form (such as a powder or granule) by compression in a suitable machine, optionally in admixture with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant. Ingredients to prepare.

Molded lozenges can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablet may optionally be coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein.

For lozenge forms, depending on the dosage, the drug may be made from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to drugs, tablets generally also contain a disintegrant. Examples of the disintegrant include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, Microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. The disintegrant will generally comprise from 1% to 25% by weight, preferably from 5% to 20% by weight of the dosage form.

Adhesives are generally used to impart a good adhesion to the formulation of the tablet. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural gums and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrate, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline fibers. , starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, as well as slip agents such as cerium oxide and talc. When present, the amount of surfactant is typically from 0.2% to 5% by weight of the tablet, and the slip agent is typically from 0.2% to 1% by weight of the tablet.

Tablets also typically contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant is generally present in an amount of from 0.25% to 10% by weight of the tablet, preferably from 0.5% to 3% by weight of the tablet. Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

An exemplary lozenge contains up to about 80% by weight of the drug, from about 10% to about 90% by weight of the binder, from about 0% to about 85% by weight of the diluent, from about 2% to about 10% by weight of the disintegrant, and From about 0.25 wt% to about 10 wt% lubricant. The tablet blend can be compressed by direct compression or by rolling to form a tablet. Portions of the tablet blend or blend may be wet granulated, dry granulated or melt granulated, melt condensed or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; or encapsulated.

Formulations of lozenges are discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", H. Lieberman and L. Lachman, Marcel Dekker, N. Y., 1980.

When the composition is in the form of a capsule, any conventional encapsulation is suitable, for example, in a hard gelatin capsule. When the composition is in the form of a soft gelatin capsule, any pharmaceutical carrier commonly used in the preparation of dispersions or suspensions, such as aqueous gums, celluloses, phthalates or oils, may be considered and incorporated. Soft gelatin capsules.

Solid formulations for oral administration can be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, Pulsating release, controlled release, targeted release, and planned release.

Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Further details of other suitable release techniques, such as high energy dispersion and penetration and coating of the coated particles, can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing ingots to achieve controlled release is described in WO 00/35298. The disclosures of these references are hereby incorporated by reference in their entirety.

Liquid formulations comprise suspensions, solutions, syrups and elixirs. The formulation may be used as a filler in soft or hard capsules and usually comprises a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspension. The solution can be an aqueous solution of a soluble salt or other derivative of the active compound associated with, for example, sucrose to form a syrup. Suspensions may include the insoluble active compound of the present invention or a pharmaceutically acceptable salt thereof associated with water, as well as a suspending or flavouring agent. Liquid formulations can also be prepared by, for example, reconstituting a solid from a sachet.

Ii) administration through the oral mucosa

The compounds of the invention may also be administered via the oral mucosa. In the oral mucosa cavity, drug delivery is divided into three categories: (a) sublingual delivery, which delivers the drug systemically via the mucosa lining the bottom of the mouth, (b) buccal delivery, which is lining the cheek The mucosa (buccal mucosa) is administered with the drug, and (c) is delivered locally, which delivers the drug to the oral cavity.

Drugs administered via the oral mucosa can be designed using mucoadhesive, fast dissolving lozenges, and solid mouth lozenge formulations formulated with one or more mucoadhesive properties (bioadhesive) Polymer (such as hydroxypropylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyisobutylene or polyisoprene) And oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulfate, and others).

Iii) Inhalation administration

The compounds of the invention may also be administered by inhalation, usually in the form of a dry powder from a dry powder inhaler (alone; in the form of a mixture, for example in the form of a dry blend with lactose; or in the form of mixed component particles, for example with a phospholipid a mixture of choline phosphatidylcholines, or a nebulizer from a pressurized container, pump, spray, atomizer (preferably using an electrohydrodynamic force to produce a fine mist) or a sprayer ( Nebulizer) (with or without the use of an aerosol spray suitable for propellants such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). For intranasal use, the powder may contain a bioadhesive such as polyglucosamine or cyclodextrin.

The dry powder composition for delivery to the lungs by inhalation surface can be provided, for example, in the form of capsules such as gelatin and cartridges or blister, such as laminated aluminum foil, for use in an inhaler or insufflator in. Formulations generally contain a powder mix for inhalation of a compound of the present invention and a suitable powder base (carrier material) such as lactose or starch. Lactose is preferably used. Each capsule or cartridge may generally contain between 0.001 and 50 mg, more preferably 0.01 to 5 mg of the active ingredient or an equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient can be provided without excipients.

The package of the formulation may be suitable for delivery in unit dose or multiple doses. In many In the case of dose delivery, the formulation may be pre-metered or metered at the time of use. Thus, dry powder inhalers are divided into three groups: (a) single dose, (b) multiple unit dose, and (c) multiple dose devices.

For the first type of inhaler, a single dose has been weighed by the manufacturer into a small container, which is primarily a hard gelatin capsule. The capsule must be taken from a separate box or container and inserted into the receiving area of the inhaler. Next, the capsule must be opened or perforated with a needle or a cutting blade to allow a portion of the inhaled air stream to pass through the capsule during inhalation to carry away the powder or to discharge the powder from the capsule via such openings by means of centrifugal force. After inhalation, the empty capsule must be removed from the inhaler again. Inserting and removing the capsule typically requires disassembling the inhaler, which can be difficult and cumbersome for some patients.

Other disadvantages associated with the use of hard gelatin capsules for inhalation of powders are (a) the ability to prevent absorption of moisture from the surrounding air, and (b) the prior exposure to extreme relative humidity in the capsule (which can cause breaks or indentures). Problems with posterior opening or perforation and (c) possible inhalation of capsule fragments. Furthermore, for a variety of capsule inhalers, incomplete drainage has been reported (e.g., Nielsen et al., 1997).

As described in WO 92/03175, some capsule inhalers have magazines from which individual capsules can be transferred to a receiving chamber where perforation and evacuation are performed. Other capsule inhalers have a rotating cartridge with a capsule chamber that can be lined with the air conduit to expel the dose (e.g., WO 91/02558 and GB 2242134). It includes a multi-unit dose inhaler and a type of foam inhaler that supplies a limited amount of unit dose on a disc or ribbon.

The foam inhaler provides better moisture protection for the medicament than the capsule inhaler. The powder is obtained by perforating the cover and the foamed foil or by peeling off the cover foil. When a foamed strip is used in place of the disc, the number of doses can be increased, but it is inconvenient for the patient to replace the empty strip. Thus, the device with the dosage system in question is typically disposable, which includes techniques for transporting the strip and opening the foam bag.

Multi-dose inhalers do not contain a pre-measured amount of powder formulation. It consists of a relatively large container and a dose measuring principle that must be operated by the patient. The container has a plurality of doses that are individually separated from the powder mass by volumetric displacement. There are a variety of dose measuring elements, including a rotatable membrane (eg EP0069715) or a disc (eg GB 2041763; EP 0424790; DE 4239402 and EP 0674533), a rotatable cylinder (eg EP 0166294; GB 2165159 and WO 92/09322) And a rotatable frustum (for example WO 92/00771), all having a cavity that must be filled with powder from the container. Other multi-dose devices have measuring sliders (for example US 5201308 and WO 97/00703) or measuring pistons with partial or circumferential grooves to move a volume of powder from the container into the transfer chamber or air duct (eg EP 0505321, WO 92/04068 and WO 92/04928); or measuring sliders, such as Genuair® (formerly known as Novolizer SD2FL), which are described in the following patent applications: WO 97/000703, WO 03/000325 No. and WO2006/008027.

Reproducible dose measurement is a major concern for multi-dose inhaler devices One of the items.

Powder formulations must exhibit good and stable flow properties because the filling of the dose measuring cup or cavity is primarily affected by gravity.

For reloaded single dose and multi-unit dose inhalers, dose measurement accuracy and reproducibility can be ensured by the manufacturer. Multi-dose inhalers, on the other hand, may contain a higher number of doses, however the number of treatments for the loading dose is generally reduced.

Because the inspiratory air flow in a multi-dose device typically passes straight through the dose measuring cavity, and because the bulk and rigid dose measuring system of the multi-dose inhaler cannot be agitated by the inhaled air flow, it is easy to take away from the cavity The powder pieces are obtained with little deagglomeration during discharge.

Therefore, an independent disintegration member is necessary. However, in practice, it is not always part of the inhaler design. Due to the high number of doses in the multi-dose device, it is necessary to minimize the powder adhesion on the inner wall of the air conduit and the deagglomerating structure and/or must periodically clean such components without affecting the residual dose in the device. Some multi-dose inhalers have disposable drug containers that can be replaced after a prescribed number of doses have been taken (e.g., WO 97/000703). For the semi-permanent multi-dose inhaler with a disposable drug container, the requirement to prevent drug accumulation is even more stringent.

In addition to being applied via a dry powder inhaler, the composition of the invention can be administered in the form of an aerosol, which is operated via a gas propellant or by means of a so-called nebulizer, whereby a solution of the pharmacologically active substance can be sprayed under high pressure to produce respirable particles. mist. The advantage of such nebulizers is that the use of a gas propellant can be completely eliminated. The nebulizer is Respimat®, which is for example described in PCT In the patent application Nos. WO 91/14468 and WO 97/12687, the contents of which are hereby incorporated by reference.

Spray compositions for topical delivery to the lung by inhalation may, for example, be formulated as an aqueous solution or suspension or as an aerosol delivered from a pressurized pack, such as a metered dose inhaler, by means of a suitable liquefied propellant. Aerosol compositions suitable for inhalation may be in the form of a suspension or solution and usually contain the active ingredient together a suitable propellant such as a fluorocarbon or a hydrogen-containing chlorofluorocarbon or a mixture thereof, especially a hydrofluorocarbon such as dichloro Difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 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 can also be used as a propellant.

The aerosol composition can be free of excipients or, optionally, other formulation excipients well known in the art, such as surfactants (e.g., oleic acid or lecithin) and cosolvents (e.g., ethanol). The pressurized formulation will typically be stored in a canister (e.g., an aluminum can) that is closed with a valve (e.g., a metering valve) and mated with an actuator having a mouthpiece.

The agent for administration by inhalation preferably has a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually from 1 to 10 microns, preferably from 2 to 5 microns. When the inhalation reaches the small air tube, particles larger than 20 microns are generally too large. To achieve such particle sizes, the particle size of the active ingredient produced can be reduced by conventional methods (e.g., by subtraction). The desired portion can be separated by air grading or sieving. The particles will preferably be in crystalline form.

It is difficult to achieve high dose reproducibility due to the poor fluidity of the micronized powder and the tendency to extreme coalescence. To improve the efficiency of the dry powder composition, the granules The child should be larger in the inhaler but smaller when it is discharged into the respiratory tract. Therefore, excipients such as lactose or glucose are generally used. In the present invention, the particle size of the excipient will generally be much larger than the inhaled medicament. When the excipient is lactose, it will usually be provided in the form of ground lactose, preferably crystalline alpha monohydrate lactose.

The pressurized aerosol composition will typically be filled into a canister equipped with a valve, particularly a metering valve. The can is optionally coated with a plastic material such as a fluorocarbon polymer as described in WO 96/32150. The can is mated with an actuator suitable for intra-cheek delivery.

Iv) transnasal mucosal administration

The compounds of the invention may also be administered via the nasal mucosa.

A typical composition for administration via nasal mucosa is usually administered by a metered, atomized spray pump and is inert with a combination of conventional excipients such as buffers, antimicrobials, tonicity modifiers, and viscosity modifiers as appropriate. In the form of a solution or suspension in a reagent such as water.

v) parenteral administration

The compounds of the invention may also be administered directly into the bloodstream, muscle or viscera. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needle-free injectors, and infusion techniques.

The parenteral formulation is typically an aqueous solution which may contain excipients such as salts, carbohydrates, and buffers (preferably to a pH of from 3 to 9), but for some applications it may be suitably formulated as Sterile non-aqueous solution or Formulated in dry form for use in combination with a suitable vehicle such as sterile pyrogen-free water.

Preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of the invention used in the preparation of parenteral solutions can be increased by the use of suitable formulation techniques, such as incorporation of solubility enhancers.

Formulations for parenteral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and planned release. Thus, the compounds of the invention may be formulated as solid, semi-solid or shaken liquids for administration in the form of an implanted reservoir to provide modified release of the active compound. Examples of such formulations include drug coated intravascular stents and PGLA microspheres.

Vi) surface casting

The compounds of the invention may also be administered topically to the skin or mucosa, i.e., via dermal or transdermal administration. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, dermal patches, wafers, implants, sponges, Fibers, straps and microemulsions. Liposomes can also be used. Typical carriers include alcohols, water, mineral oil, liquid petrolatum, white paraffin, glycerol, polyethylene glycol, and propylene glycol. There may be penetration enhancers; see, for example, J Pharm Sci, 88 (10), 955-958, Finnin, and Morgan (October 1999). Other methods of surface administration include delivery by electroporation, iontophoresis, sonic electrophoresis, ultrasonic introduction, and microneedle or needle-free injection.

Formulations for topical administration can be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and planned release.

Vii) transrectal/vaginal administration

The compounds of the invention may be administered rectally or transvaginally, for example, in the form of a suppository, pessary or enemas. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. Formulations for transrectal/vaginal administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and planned release.

Viii) by eye

The compounds of the invention may also be administered directly to the eye or ear, usually in the form of isotonic, pH adjusted, micronized suspensions or solution drops in sterile physiological saline. Other formulations suitable for transocular and otic administration include ointments, biodegradable (eg, absorbable gel sponge, collagen), and non-biodegradable (eg, polyoxynized) implants, wafers, Lenses as well as microparticles or vesicle systems, such as niosome or liposomes. It may be combined with a polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer (such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose), or an isomeric polysaccharide polymer (eg gellan gum), as well as preservatives (such as benzalkonium chloride). The formulation can also be delivered by iontophoresis.

Formulations for transocular/audio-injection can be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, Pulsating release, controlled release, targeted release, or planned release.

Ix) Other technologies

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability so that Used in any of the above modes of administration.

The amount of active compound administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the designated physician. However, the effective dose is usually in the range of 0.01 to 3000 mg, more preferably 0.5 to 1000, of the active ingredient per day or an equivalent amount of a pharmaceutically acceptable salt thereof. The daily dose can be administered in one or more treatments per day, preferably one to four treatments.

Preferably, the pharmaceutical composition of the present invention is formulated in a form suitable for oral, inhalation or topical administration (particularly preferred by oral or inhalation administration).

The pharmaceutical formulation is preferably presented in unit dosage form and can be prepared by any methods known in the art of pharmacy.

Preferably, the composition is in unit dosage form, such as a lozenge, capsule or metered aerosol dose, such that the patient can administer a single dose.

Of course, the amount of each active agent required to achieve a therapeutic effect will vary with the particular active agent, the route of administration, the individual being treated, and the particular condition or disease being treated.

The following formulation forms are cited as examples of formulations:

Formulation example

Formulation Example 1 (oral suspension)

Formulation Example 2 (hard gelatin capsule for oral administration)

Formulation Example 3 (gelatin cartridge for inhalation)

Formulation Example 4 (for formulations using dry powder inhaler (DPI) inhalation)

Formulation Example 5 (for MDI formulation)

Modifications that do not affect, alter, alter or modify the basic aspects of the compounds, combinations or pharmaceutical compositions are encompassed within the scope of the invention.

Claims (29)

a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof or N-oxide or a stereoisomer or deuterated derivative: Wherein m is 0, 1, 2 or 3; X and Y each independently represent a nitrogen atom or a -CR ₆ group, wherein at least one of X and Y represents a -CR ₆ group; A and B are each independently Represents a nitrogen atom or a -CR ₇ group, wherein at least one of A and B represents a -CR ₇ group; D represents a nitrogen atom or a -CR ₅ group, wherein when one of A and B represents a nitrogen atom , D represents a -CR ₅ group; W represents a linking group selected from a -NR ₈ - group, a -(CR ₉ R ₁₀ )- group, -O- or -S-; R ₁ represents a hydrogen atom; Chain or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₁ -C ₄ alkoxy; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; or at least one selected from O, S And a 5- to 14-membered heterocyclic group of a hetero atom of N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic group are unsubstituted or substituted with one or more substituents selected from the group consisting of Substitution: halogen atom, cyano group, linear or branched C ₁ -C ₆ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₁ -C ₄ alkylsulfonyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ and R ₇ each independently represent a hydrogen atom; a halogen atom; a cyano group; Chain or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic Or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; 5 to 14 members containing at least one hetero atom selected from O, S and N a heterocyclic group, or a bicyclic group in which a monocyclic C ₆ -C ₉ aryl group or a 5 to 9 membered heteroaryl group is fused to a 5- to 9-membered cycloalkyl group or a heterocyclic group, said heteroaryl group or heterocyclic group Containing at least one hetero atom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups, and said monocyclic C ₆ -C ₉ aryl group or a bicyclic group having a 5- to 9-membered heteroaryl group fused to a 5- to 9-membered cycloalkyl or heterocyclic group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom; a cyano group; a straight chain or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; or a monocyclic bis C ₆ -C ₁₄ aryl group; at least one heteroatom selected from O, 5-14 heteroaryl, the N and S heteroatoms; containing at least one selected from 5-14 heterocycle O, S and N heteroatom of a group of -(CH ₂ ) _1-3 CN; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH _{2 n-} R ₁₁ group; -(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH _{2 n} R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or a group of -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ ; wherein each n' and n is 0, 1 or 2; the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or Further substituted by one or more carboxyl groups; R ₃ and R ₄ each independently represent a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkane a group which is unsubstituted or substituted with one or more substituents selected from the group consisting of C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, Pyrimidinyl or piperidinyl R ₅ and R ₆ each independently represent a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl group; a monocyclic or bicyclic C ₆ -C ₁₄ aryl group; at least one selected from the group comprising 5-14 heteroaryl group O, S and N heteroatom of a 5 to 14 membered heterocyclic group containing at least one hetero atom selected from O, S and N; a -(CH ₂ ) _n OR ₁₁ group; a -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)- (CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group a group of -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ ;-NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or selected from one or more of the following substituents: a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl , Phenyl, pyridyl, pyrimidinyl, piperidinyl or _{-C (O) - (CH 2} ) n -NR 11 R 12 group; wherein n is 0, 1 or 2; R _8, R ₉ and R ₁₀ each independently represents a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or subjected to one or Substituted by a plurality of substituents selected from C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₁₁ , R ₁₂ and R ₁₃ each independently represents a hydrogen atom; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; 5 to 9 members having 1, 2 or 3 hetero atoms selected from O, S and N a cycloalkyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, and a C ₁ -C ₄ haloalkyl group. Or a C ₁ -C ₄ hydroxyalkyl group; or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or substituted with one or more substituents selected from C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; wherein said compound of formula (I) is not: a) 3 - [[ 5-chloro-2-[[2,5-dimethyl-4-(piperidin-4-yl)phenyl]amino]pyrimidin-4-yl]amino]pyridine-2(1H)-one; And b) 2-[7-[[5-chloro-4-[(2-o-oxy-1,2-dihydropyridin-3-yl)amino]pyrimidin-2-yl]amino]-8 -Methoxy-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl]-N,N-dimethylacetamide. The compound of claim 1, wherein m, X, Y, W, A, B, D and R ₁ to R _{13 are} as defined in claim 1; and wherein D represents a nitrogen atom Wherein A and B represent a -CR ₇ group, m is 0, and R _{2 is} not a substituted 2,3,4,5-tetrahydro-1H-benzo[ d ]azepine or piperidinyl group. Substituted phenyl. A compound according to claim 1 or 2, which has the formula (I'): Wherein m is 0 or an integer from 1 to 3; X and Y each independently represent a nitrogen atom or a -CR ₆ group, wherein at least one of X and Y represents a -CR ₆ group; and A and B are each independently Represents a nitrogen atom or a -CR ₇ group, wherein at least one of A and B represents a -CR ₇ group; W represents a group selected from the group consisting of -NR ₈ -, -(CR ₉ R ₁₀ )-, -O - or -S- linking group; R ₁ represents a hydrogen atom; linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₁ - C ₄ alkoxy; C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; containing at least one hetero atom selected from O, S and N a 5- to 14-membered heteroaryl; or a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from O, S, and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and hetero The cyclic group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ - C ₄ hydroxyalkyl, C ₁ -C ₄ alkylsulfonyl group, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl group; R ₂ and R ₇ Independently represent a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₁₀ cycloalkyl Alkyl; C ₃ -C ₁₀ cycloalkenyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; containing at least one selected 5 to 14 membered heterocyclic groups of hetero atoms from O, S and N, or monocyclic C ₆ -C ₉ aryl or 5 to 9 membered heteroaryl groups and 5 to 9 membered cycloalkyl or heterocyclic groups a bicyclic group containing at least one hetero atom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups, And the bicyclic group which is a monocyclic C ₆ -C ₉ aryl group or a 5 to 9 membered heteroaryl group fused to a 5 to 9 membered cycloalkyl group or a heterocyclic group is unsubstituted or selected from one or more selected from the group consisting of Substituent substitution: halogen atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl a monocyclic or bicyclic C ₆ -C ₁₄ aryl group; a 5 to 14 membered heteroaryl group containing at least one hetero atom selected from O, S and N; a 5 to 14 membered heterocyclic group selected from the group consisting of hetero atoms of O, S and N; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O a ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or one or more Further substituted by a carboxyl group; R ₃ and R ₄ each independently represent a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group, said alkane Substituent substituted or substituted with one or more substituents selected from C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidine group; R ₅ and R ₆ each independently represent a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl C ₃ -C ₁₀ cycloalkyl; C ₃ -C ₁₀ cycloalkenyl group; a monocyclic or bicyclic C ₆ -C ₁₄ aryl group; at least one selected from the group comprising 5-14 O, S and N heteroatom of the heteroaryl a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from O, S, and N; a -(CH ₂ ) _n OR ₁₁ group; a -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O) -(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group ;-C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ a group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; wherein said cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl group is unsubstituted or substituted with one or more selected from Substituted from the following substituents: halogen atom, cyano group, linear or branched C ₁ -C ₆ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ ring An alkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0, 1 or 2; R ₈ , R ₉ and R ₁₀ is independently Represents a hydrogen atom, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl which is unsubstituted or substituted with one or more substituents selected from Substituted for the following: C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₁₁ , R ₁₂ and R ₁₃ are each independently Is a hydrogen atom, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or selected by one or more Substituted from the following substituents: C ₁ -C ₄ alkoxy, cyano, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl. A compound according to any one of the preceding claims, wherein W represents a linking group selected from the group consisting of -NR ₈ - or -(CR ₉ R ₁₀ )-, wherein R ₈ , R ₉ and R ₁₀ As defined in claim 1 of the patent application; and wherein W preferably represents a -NR ₈ - group, wherein R _{8 is} as defined in item 1 of the scope of the patent application. A compound according to any one of the preceding claims, wherein R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkane a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidinyl group; and wherein R ₁ preferably represents a hydrogen atom, a straight or branched chain C ₁ -C ₄ alkyl group, C ₁ - C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl or pyridyl; and wherein R _{1 more} preferably represents a hydrogen atom, a straight or branched chain C ₁ -C ₃ An alkyl group, a C ₁ -C ₃ haloalkyl group or a C ₁ -C ₃ hydroxyalkyl group; and wherein R ₁ preferably represents a hydrogen atom. The compound of any one of the preceding claims, wherein the R ₂ represents a linear or branched C ₁ -C ₆ alkyl group; C ₁ -C ₄ Haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; containing 1, 2 or 3 heteroatoms selected from O, S and N a 5 to 7 membered heteroaryl group of an atom; a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl group, cycloalkenyl group, aryl group, The heteroaryl group and the heterocyclic group are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; and a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; a C ₃ -C ₇ cycloalkyl group; a monocyclic or bicyclic C ₆ -C ₁₄ aryl group; 5 to 14 members containing at least one hetero atom selected from O, S and N a heteroaryl group; a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from O, S and N; a -(CH ₂ ) _1-3 CN group; a -(CH ₂ ) _n OR ₁₁ group; NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C( O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH2) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ a S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R _{13 are} as defined in claim 1 and The monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further substituted with one or more carboxyl groups. The compound of claim 3, wherein R ₂ represents a linear or branched C ₁ -C ₆ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; C ₃ - C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, S and N; containing 1, 2 or 3 a 5- to 7-membered heterocyclic group selected from hetero atoms of O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or one or more Substituted by a substituent selected from the group consisting of: a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ hydroxyalkyl group; C ₃ -C ₇ a cycloalkyl group; a monocyclic or bicyclic C ₆ -C ₁₄ aryl group; a 5 to 14 membered heteroaryl group containing at least one hetero atom selected from O, S and N; containing at least one selected from the group consisting of O, S and N 5 to 14 membered heterocyclic groups of the atom; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-( CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R _{a 12} group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R _{13 are} as claimed in claim 1 The monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further substituted with one or more carboxyl groups. A compound according to any one of the preceding claims, wherein R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ alkoxy substituted; and wherein R ₃ and R ₄ each independently independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; and wherein R ₃ and R _{4 are more} preferably each independently Represents a hydrogen atom or a methyl group. A compound according to any one of the preceding claims, wherein R ₅ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group, C _1- C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n - R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)- (CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group a group; wherein each n is 0, 1 or 2; and wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. A compound according to any one of the preceding claims, wherein R ₆ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 containing 1, 2 or 3 heteroatoms selected from O, S and N a heteroaryl group; or a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclic groups are not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C _{a 4} -hydroxyalkyl group, a C ₃ -C ₇ cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0 And 1 or 2; and wherein R ₁₁ and R ₁₂ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. A compound according to any one of the preceding claims, wherein R ₇ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 containing 1, 2 or 3 heteroatoms selected from O, S and N a heteroaryl group; a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl group, the aryl group, the heteroaryl group and the heterocyclic group are not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C _{4 group} Hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group a -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; Wherein R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. A compound according to any one of the preceding claims, wherein R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ alkoxy Substituent; and wherein R ₈ preferably represents a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; and wherein R _{8 more} preferably represents a hydrogen atom. The compound of claim 1, wherein: m is 0, 1 or 2; X is a nitrogen atom and Y is a -CR ₆ group; or Y is a nitrogen atom and X is a -CR ₆ group; X and Y are both -CR ₆ groups; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; or B is a nitrogen atom, A is a -CR ₇ group and D is -CR ₅ groups; or both A and B are -CR ₇ groups and D is a nitrogen atom or a -CR ₅ group; W represents a linkage selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group a group; preferably a -NR ₈ - group; R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ represents straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ - C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 members containing 1, 2 or 3 hetero atoms selected from O, S and N An aryl group; a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups Unsubstituted or substituted with one or more substituents selected from Generation: halogen atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; single ring Or bicyclic C ₆ -C ₁₄ aryl; 5 to 14 membered heteroaryl containing at least one hetero atom selected from O, S and N; 5 to 14 members containing at least one hetero atom selected from O, S and N Heterocyclyl; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-( CH ₂ ) _n -R ₁₁ group; -(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ ( CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group a group of -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ ; wherein each n' and n are 0, 1 or 2 and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is not Substituted or further substituted by one or more carboxy groups, R ₃ and R ₄ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ Alkyne substituted; R ₅ represents hydrogen Atom, halogen atom, cyano group, straight or branched chain C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, -( CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n - NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n- NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S ( O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom; Atom; cyano; straight or branched C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C _6- C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 hetero atoms selected from O, S and N; containing 1, 2 or 3 heteroatoms selected from O, S and N a 5- to 7-membered heterocyclic group wherein the cycloalkyl group, the aryl group, the heteroaryl group, and the heterocyclic group are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom and a cyano group. , straight or branched C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or -C(O _{) - (CH 2) n -NR} 11 R 12 group; wherein n is 0, 1 or 2R ₇ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl; C ₁ - C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; containing 1, 2 or 3 selected from O, S and N a 5 to 7 membered heteroaryl group of a hetero atom; a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl group, the aryl group, the heteroaryl group And the heterocyclic group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, and a C ₁ -C ₄ haloalkyl group. , C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _1-3 CN a group, a -(CH ₂ ) _n OR ₁₁ group, a -NR ₁₁ R ₁₂ group, a -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH _{2) n} -NR ₁₂ R ₁₃ group, -C (O) - (CH 2) 1-3 -CN group, -C (O) - (CH 2) n -R 11 Group, -C (O) - (CH 2) n -NR 11 R 12 _{groups, -S (O) 2 (CH} 2) n R 11 _{groups, -S (O) 2 (CH} 2) n NR 11 a R ₁₂ group, a -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 Or 2; R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or substituted by a C ₁ -C ₂ alkoxy group; R ₉ and R ₁₀ are each independently represented a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom; a linear or branched C ₁ -C ₃ alkyl group; or a 1, 2 or 3 to 7 membered heterocyclic groups selected from hetero atoms of O, S and N, which are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, Linear or branched C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ hydroxyalkyl. The compound of claim 13, wherein: m is 0, 1 or 2; X and Y both represent a -CR ₆ group; A is a nitrogen atom, B is a -CR ₇ group and D is -CR _a group of ₅ ; or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group; a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; preferably a -NR ₈ - group; R ₁ represents a hydrogen atom, a straight or branched chain C ₁ -C ₆ Alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ represents straight or branched a chain C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; , 2 or 3 5- to 7-membered heteroaryl groups selected from hetero atoms of O, S and N; 5 to 7 membered heterocyclic groups containing 1, 2 or 3 hetero atoms selected from O, S and N, Wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents selected from the group consisting of: a halogen atom; a cyano group; a straight or branched chain C ₁ -C ₆ alkyl; C ₁ -C _4- haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl; 5 containing at least one hetero atom selected from O, S and N To a 14-membered heteroaryl; 5 to 14 membered heterocyclic group containing at least one hetero atom selected from O, S and N; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group a group of -NR ₁₁ R ₁₂ ;-NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -(CH2) _n' -C(O)-(CH _{2 n-} NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' And n is 0, 1 or 2 and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further substituted by one or more carboxyl groups, and R ₃ and R ₄ each independently represent a hydrogen atom or a straight chain or a branched C ₁ -C ₆ alkyl group which is unsubstituted or substituted by a C ₁ -C ₂ alkoxy group; R ₅ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched chain C ₁ -C ₄ alkyl, C ₁ - C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O) -(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group , -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ a group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH _{2 n} NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ halogen Alkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; containing 1, 2 or 3 heteroatoms selected from O, S and N 5 to 7 membered heteroaryl; 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and hetero The cyclic group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl Phenyl, pyridyl, pyrimidinyl, piperidinyl or _{-C (O) - (CH 2} ) n -NR 11 R 12 group; wherein n is 0, 1 or 2 R ₇ represents a hydrogen atom; a halogen atom; cyano Linear or branched C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 to 7 membered heteroaryl containing 1, 2 or 3 hetero atoms selected from O, S and N; 5 to 1, 2 or 3 heteroatoms selected from O, S and N a 7-membered heterocyclic group wherein the cycloalkyl group, the aryl group, the heteroaryl group and the heterocyclic group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, and a linear chain Or branched chain C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl , pyrimidinyl, piperidinyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH _{2 n-} R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C() O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group , -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n a group of NR ₁₂ R ₁₃ ; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group which is unsubstituted or C ₁ -C ₂ Alkoxy substituted; R ₉ and R ₁₀ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom; straight or branched chain a C ₁ -C ₃ alkyl group; or a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, which are unsubstituted or 1, 2 or 3 Substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a C ₁ -C ₄ hydroxyalkyl group. The compound of claim 14, wherein: m is 0 or 1; X and Y both represent a -CR ₆ group; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; Or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group; a linking group from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; preferably a -NR ₈ - group; R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₃ alkyl group , C ₁ -C ₃ haloalkyl or C ₁ -C ₃ hydroxyalkyl; R ₂ represents a straight or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxy group Alkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl; wherein said cycloalkyl, phenyl, pyridyl, pyrimidine a group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group or a piperidinyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom; a cyano group; a linear or branched chain C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl group; a phenyl group; a substituted phenyl group of the carboxy; pyridyl; triazolyl; thiazolyl Pyrimidinyl; piperidinyl ;-( CH _{2) n} OR ₁₁ groups; -NR ₁₁ R _{12 groups; -NR 11 C (O) -} (CH 2) n -R 12 groups; -NR ₁₁ C ( O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group ;-(CH ₂ ) _n' -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -(CH ₂ ) _n' -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n' and n is 0, 1 or 2; R ₃ and R ₄ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group ; R ₅ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, a C ₃ -C ₇ ring Alkyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ a group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n- R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ a S(O) ₂ (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom , halogen atom, cyano group, linear or branched C ₁ -C ₃ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, phenyl group, Pyridyl, pyrimidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl; R ₇ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched chain C ₁ -C ₃ Alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, Piperidinyl, tetrahydropyranyl or morpholinyl; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl Or the morpholinyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, triazolyl, thiazolyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₂ group, -C(O)- (CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₂ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ a S(O) ₂ (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom Or a straight or branched C ₁ -C ₃ alkyl group; R ₉ and R ₁₀ each independently represent a hydrogen atom or a straight or branched C ₁ -C ₃ alkyl group; R ₁₁ , R ₁₂ and R ₁₃ are each independently a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; or a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, the heterocyclic group not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₄ alkyl group, a C ₁ -C ₄ haloalkyl group or a C ₁ -C _{4 group} Hydroxyalkyl. The compound of claim 1, wherein: m is 0 or 1; X and Y both represent a -CR ₆ group; A is a nitrogen atom, B is a -CR ₇ group and D is a -CR ₅ group; Or B is a nitrogen atom, A is a -CR ₇ group and D is a -CR ₅ group; or both A and B are a -CR ₇ group and D is a nitrogen atom or a -CR ₅ group; W represents - An NH-group or a -CH ₂ - group; preferably an -NH- group; R ₁ represents a hydrogen atom; R ₂ represents a cyclohexyl group, a pyridyl group or a piperidinyl group, wherein the cyclohexyl group, pyridyl group and piperidine The group or the like is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a triazolyl group, a -(CH ₂ ) _1-3 CN group, -C(O)-(CH) ₂ ) a _1-3- CN group or a -(CH ₂ )-S(O) ₂ -pyrimidinyl group which is unsubstituted or substituted with 1, 2 or 3 hydroxy groups; R ₃ and R ₄ are each independently The ground represents a hydrogen atom or a methyl group; R ₅ represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched C ₁ -C ₃ alkyl group, an -OCH ₃ group or -C(O)-(CH ₂ ) _n - NR ₁₁ R ₁₂ group; wherein n is 0 or 1; and wherein R ₁₁ and R ₁₂ independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; R ₆ represents a hydrogen atom, a halogen atom Or pyrazolyl; R ₇ represents a hydrogen atom, piperidinyl, thiazolyl or morpholino group; wherein the piperidinyl, morpholinyl and thiazolyl group unsubstituted or substituted with 1 or 2 substituents selected from hydroxy or acid The substituent is substituted. The compound of claim 3, wherein: m is 0, 1 or 2; X is a nitrogen atom and Y is a -CR ₆ group; or Y is a nitrogen atom and X is a -CR ₆ group; X and Y are both a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group; or B is a nitrogen atom and A is a -CR ₇ group; or both A and B are -CR ₇ groups; W represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; R ₁ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl or piperidinyl; R ₂ represents a straight or branched C ₁ -C ₆ alkyl group C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; containing 1, 2 or 3 selected from O a 5 to 7 membered heteroaryl group of a hetero atom of S, and N; a 5 to 7 membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N; wherein the cycloalkyl group, the ring The alkenyl group, the aryl group, the heteroaryl group and the heterocyclic group are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom; a cyano group; a linear or branched C ₁ -C ₆ alkyl group; ₁ -C ₄ haloalkyl; C ₁ -C ₄ Alkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₄ aryl group; at least one selected from the group comprising 5-14 heteroaryl group O, S and N atoms, the heteroatom; at least one selected from the group comprising 5 to 14 membered heterocyclic groups of hetero atoms from O, S and N; -(CH ₂ ) _1-3 CN group; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _{1 -3} -CN group; -C(O)-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ ( CH ₂ ) _n R ₁₁ group; -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S ( O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; and the monocyclic or bicyclic C ₆ -C ₁₄ aryl group is unsubstituted or further via one or more carboxyl groups R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group in which the alkyl group is unsubstituted or substituted with a C ₁ -C ₂ alkoxy group; and R ₅ represents a hydrogen atom. , halogen atom, cyano group, linear or branched C ₁ -C ₄ alkyl group, C ₁ -C ₄ haloalkyl group, C ₁ -C ₄ hydroxyalkyl group, C ₃ -C ₇ cycloalkyl group, -(CH _{2 n} OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) _{a 2} (CH ₂ ) _n R ₁₂ group or a -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ represents a hydrogen atom; a halogen atom; Cyano; straight or branched C ₁ -C ₄ alkyl; C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ - a C ₁₀ aryl group; a 5 to 7 membered heteroaryl group containing 1, 2 or 3 hetero atoms selected from O, S and N; and 5, 1 or 3 hetero atoms selected from O, S and N a 7-membered heterocyclic group wherein the cycloalkyl group, the aryl group, the heteroaryl group, and the heterocyclic group are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, and a straight Chain or branched C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidine Base or -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0, 1 or 2; R ₇ represents a hydrogen atom; a halogen atom; a cyano group; a linear or branched C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group , C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; monocyclic or bicyclic C ₆ -C ₁₀ aryl; 5 containing 1, 2 or 3 heteroatoms selected from O, S and N a 7-membered heteroaryl group; a 5- to 7-membered heterocyclic group containing 1, 2 or 3 hetero atoms selected from O, S and N, wherein the cycloalkyl group, the aryl group, the heteroaryl group, and the heterocyclic group Unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a cyano group, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, C ₁ - C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _1-3 CN group, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C(O)-(CH _{2 n} -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O ) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a straight or branched chain C ₁ - a C ₆ alkyl group which is unsubstituted or substituted by a C ₁ -C ₂ alkoxy group; R ₉ and R ₁₀ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. The compound of claim 17, wherein: m is 0 or 1; X and Y both represent a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group; or B is a nitrogen atom and A is a -CR ₇ group; or both A and B are a -CR ₇ group; W represents a linking group selected from a -NR ₈ - group or a -(CR ₉ R ₁₀ )- group; R ₁ represents hydrogen Atom, straight or branched C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₁ -C ₃ hydroxyalkyl; R ₂ represents straight or branched C ₁ -C ₆ alkyl, C _1- C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl; Wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidinyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen Atom; cyano; straight or branched C ₁ -C ₆ alkyl; C ₁ -C ₄ haloalkyl; C ₁ -C ₄ hydroxyalkyl; C ₃ -C ₇ cycloalkyl; phenyl; Substituted phenyl; pyridyl; triazolyl; thiazolyl; pyrimidinyl; piperidinyl; -(CH ₂ ) _n OR ₁₁ group; -NR ₁₁ R ₁₂ group; -NR ₁₁ C(O)-( CH ₂ ) _n- R ₁₂ group; -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group; -C(O)-(CH ₂ ) _1-3 -CN group; -C(O )-(CH ₂ ) _n -R ₁₁ group; -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; -S(O) ₂ (CH ₂ ) _n R ₁₁ group; -S (O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group; -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R _a group of ₁₃ ; wherein each n is 0, 1 or 2; and R ₃ and R ₄ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; and R ₅ represents a hydrogen atom, a halogen atom, or a cyano group; , straight or branched C ₁ -C ₃ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, -(CH ₂ ) _1-3 CN a group, a -(CH ₂ ) _n OR ₁₁ group, a -NR ₁₁ R ₁₂ group, a -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-( CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)-(CH ₂ ) _1-3 -CN group, -C(O)-(CH ₂ ) _n -R ₁₁ group, -C( O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₁ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₆ Represents a hydrogen atom or a halogen atom A cyano group, a linear or branched C ₁ -C ₃ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl Or pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl; R ₇ represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C ₁ -C ₃ alkyl group, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₃ -C ₇ cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyran Or a morpholinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or morpholinyl is unsubstituted or Substituted by 1, 2 or 3 substituents selected from the group consisting of a halogen atom, a linear or branched C ₁ -C ₆ alkyl group, a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, C _3- C ₇ cycloalkyl, phenyl, carboxy substituted phenyl, pyridyl, triazolyl, thiazolyl, pyrimidinyl, piperidinyl, -(CH ₂ ) _n OR ₁₁ group, -NR ₁₁ R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -R ₁₂ group, -NR ₁₁ C(O)-(CH ₂ ) _n -NR ₁₂ R ₁₃ group, -C(O)- (CH ₂ ) _1-3 -CN base a group, a -C(O)-(CH ₂ ) _n -R ₁₂ group, a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group, -S(O) ₂ (CH ₂ ) _n R ₁₂ group, -S(O) ₂ (CH ₂ ) _n NR ₁₁ R ₁₂ group, -NR ₁₁ S(O) ₂ (CH ₂ ) _n R ₁₂ group or -NR ₁₁ S(O) ₂ (CH ₂ ) _n NR ₁₂ R ₁₃ group; wherein each n is 0, 1 or 2; R ₈ represents a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group; and R ₉ and R ₁₀ each independently represent a hydrogen atom Or a straight or branched C ₁ -C ₃ alkyl group; R ₁₁ , R ₁₂ and R ₁₃ each independently represent a hydrogen atom or a linear or branched C ₁ -C ₃ alkyl group. The compound of claim 3, wherein: m is 0 or 1; X and Y both represent a -CR ₆ group; A is a nitrogen atom and B is a -CR ₇ group; or B is a nitrogen atom and A is a -CR ₇ group; or both A and B are -CR ₇ groups; W represents a -NH- group or a -CH ₂ - group; R ₁ represents a hydrogen atom; R ₂ represents a cyclohexyl group, a pyridyl group or Piperidinyl wherein the cyclohexyl, pyridyl and piperidinyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen atoms, triazolyl, -(CH ₂ ) _1-3 a CN group or a -C(O)-(CH ₂ ) _1-3 -CN group; R ₃ and R ₄ each independently represent a hydrogen atom or a methyl group; R ₅ represents a hydrogen atom, a halogen atom, a straight chain or a branch a C ₁ -C ₃ alkyl group or a -C(O)-(CH ₂ ) _n -NR ₁₁ R ₁₂ group; wherein n is 0 or 1; and wherein R ₁₁ and R ₁₂ independently represent a hydrogen atom or a linear chain Or a branched chain C ₁ -C ₃ alkyl; R ₆ represents a hydrogen atom or a halogen atom; R ₇ represents a hydrogen atom, a piperidinyl group, a thiazolyl group or a morpholinyl group; wherein the piperidinyl group, the thiazolyl group and the morpholinyl group Unsubstituted or substituted with 1 or 2 substituents selected from hydroxy or benzoic acid. A compound according to claim 1, which is one of the following compounds: (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-yl Amino)pyridin Pyridin-2(1H)-one; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine 2(1H)-one; (S)-3-(5-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-ylamino)pyridine-2 (1H )-ketone; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methoxypyrimidin-2-ylamino)pyridine-2 (1H) a ketone; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-hydroxypyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-4-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidine-5 -carbamamine; (S)-5-chloro-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)pyridine- 2(1H)-one; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-5-methylpyrimidin-2-ylamino)-5-( 1H-pyrazol-4-yl)pyridine-2(1H)-one; (S)-3-(4-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(4- Hydroxypiperidin-1-yl)pyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-3-(5-fluoro-4-(1-(5-fluoropyridin-2-yl) Ethylamino)-6-(N-morpholinyl)pyrimidin-2-ylamino)pyridine-2(1H)-one; (S)-3-(6-(1-(5-fluoropyridine)- 2-yl)ethylamino)pyrazin-2-ylamino)pyridine-2(1H)-one; (S)-3-(6-(1-(5-fluoropyridin-2-yl)ethylamine base) Pyridin-2-ylamino)pyridine-2(1H)-one; 2-((1r,4r)-4-(5-methyl-2-(2- oxo-1,2-dihydropyridine) -3-ylamine 3-pyrimidin-4-ylamino)cyclohexyl)acetonitrile; 3-(4-((1r,4r)-4-((3-hydroxypiperidin-1-ylsulfonyl)methyl)cyclohexylamine ()pyrimidin-2-ylamino)pyridin-2(1H)-one; (R)-3-oxooxy-3-(3-(2-(2-o-oxy-1,2-dihydro) Pyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)propanenitrile; (R)-3-(3-(5-methyl-2-(2- oxo-) 1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxomethoxypropionitrile; (R)-3-(3-(5- Fluor-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxopropanenitrile; R)-3-(4-(1-(4H-1,2,4-triazol-3-yl)piperidin-3-ylamino)-5-fluoropyrimidin-2-ylamino)pyridine- 2(1H)-keto; (R)-3-(3-(2-(5-chloro-2-oxo-l,2-dihydropyridin-3-ylamino)-5-methylpyrimidine -4-ylamino)piperidin-1-yl)-3-oxopropanonitrile; (R)-3-(3-(5-fluoro-6-(N-morpholinyl)-2-( 2-sided oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxopropanenitrile; (R)-3- (3-(5-Methyl-6-(N-morpholinyl)-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino)pyrimidin-4-ylamino) Piperidin-1-yl)-3-oxopropanonitrile; (R)-3-(3-(5-methyl-4-(N-morpholinyl)- 6-(2-Sideoxy-1,2-dihydropyridin-3-ylamino)pyrimidin-2-ylamino)piperidin-1-yl)-3-oxomethoxypropionitrile; (R) -3-(3-(4-(5-chloro-2-p-oxy-1,2-dihydropyridin-3-ylamino)-5-methyl-6-(N-morpholinyl)pyrimidine -2-ylamino)piperidin-1-yl)-3-oxopropanonitrile; (R)-3-(3-(5-chloro-2-(2- oxo-1,2-) Dihydropyridin-3-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-3-oxopropanenitrile; 3-[(4-{[(1S)-1-(5-fluoropyridin-2-yl)ethyl]amino}pyrimidin-2-yl)methyl]pyridine-2(1H)-one; (S -3(5-(6-(1-(5-fluoropyridin-2-yl)ethylamino)-2-(2-o-oxy-1,2-dihydropyridin-3-ylamino) Pyrimidin-4-yl)thiazol-2-yl)benzoic acid; or a pharmaceutically acceptable salt or solvate thereof or N-oxide or a stereoisomer or a deuterated derivative. The compound of any one of claims 1 to 20 for use in the treatment of a human or animal body by therapy. A compound according to any one of claims 1 to 20 for use in the treatment of a pathological condition or disease which is easily ameliorated by inhibition of Janus Kinase. The compound for use according to claim 22, wherein the pathological condition or disease is selected from the group consisting of a spinal proliferative disorder, leukemia, a lymphoid malignant disease, and a solid tumor; bone marrow and organ transplant rejection; Leading diseases as well as inflammatory diseases. The compound for use according to claim 22 or claim 23, wherein the pathological condition or disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, Uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, and a pharmaceutically acceptable diluent or carrier. One of the items 1 to 20 of the patent application scope Use of the compound described for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in any one of claims 22 to 24. A method of treating an individual suffering from a pathological condition or disease as defined in any one of claims 22 to 24, comprising administering to the individual a therapeutically effective amount as claimed in claim 1 The compound according to any one of the items 20, or the pharmaceutical composition according to claim 25 of the patent application. A combination product comprising: (i) a compound according to any one of claims 1 to 20; and (ii) another compound selected from the group consisting of: a) dihydrofolate reductase inhibition Agents such as methotrexate or CH-1504; b) dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or international patents Compounds described in Application No. WO 2008/077639 and WO 2009/021696; c) Immunomodulators such as Glatiramer acetate (Copaxone), Laquinimod Or Imiquimod; d) DNA synthesis and repair inhibitors, such as Mitoxantrone or Cladribine; e) immunosuppressive agents, such as Imuran (azolidine) a (azathioprine) or uri (Purinethol) (6-mercaptopurine or 6-MP); f) anti-α4 integrin antibody, such as natalizumab (Tysabri); g) α4 integrin antagonism Agents 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) fumarate, such as BG-12; j) anti-TNF-α (anti-TNF-α), such as Infliximab, Ada Adalimumab or Certolizumab pegol; k) soluble tumor necrosis factor alpha (TNF alpha) receptor, such as etanercept; l) anti-CD20 (lymphocyte protein) single Antibody, such as Rituximab, Ocrelizumab, Ofatumumab or TRU-015; m) anti-CD52 (lymphocyte protein) monoclonal antibodies, such as Ala Group of monoclonal antibodies (alemtuzumab); n) anti-CD25 (lymphocyte protein), such as daclizumab (oclizumab); o) anti-CD88 (lymphocyte protein), such as eculizumab or peculiar Anti-pexilizumab; p) anti-interleukin 6 receptor (IL-6R), such as tocilizumab; q) anti-interleukin 12 receptor (IL-1) 2R)/interleukin 23 receptor (IL-23R), such as ustekinumab; r) calcineurin inhibitor, such as cyclosporine A or he Tacrolimus; s) creatinine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin, mizoribine or mycophenolate Acid (mycophenolic acid); t) cannabinoid receptor agonist, such as sateux (Sativex); u) chemokine CCR1 antagonist, such as MLN-3897 or PS-031291; v) chemokine CCR2 Antagonists, such as INCB-8696; w) inhibitor of necrosis factor-κB (NF-κB or NFKB) activation, such as Sulfasalazine, Iguratimod or MLN-0415; x) adenosine A _2A agonist, such as ATL-313, ATL-146e, CGS-21680, Regadenoson or UK-432,097; y) sphingosine-1 (S1P) phosphate receptor agonist, Such as fingolimod, BAF-312 or ACT128800; z) sphingosine-1 (S1P) dissociating enzyme (liase) inhibitors, such as LX2931; aa) spleen tyrosine kinase (Syk) inhibitors, Such as R-112; bb) a white kinase inhibitor (PKC) inhibitor, such as NVP-AEB071; cc) an anticholinergic agent, such as tiotropium or aclidinium; dd) beta adrenergic agonist , such as formoterol, indacaterol or abediterol (LAS100977); ee) a compound having a bifunctional muscarinic antagonist-β2 agonist activity (MABA) ;ff) histamine 1 (H1) receptor antagonists, such as azelastine or ebastine; gg) chemoattractant receptor homologs (CRTH2) expressed on TH2 cells Inhibitors, such as OC-459, AZD-1981, ACT-129968, QAV-680; hh) vitamin D derivatives, such as calcipotriol (Daivonex); ii) anti-inflammatory agents, such as non- Steroid anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors, such as aceclofenac, diclofenac, ibuprofen, naproxen , aripoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumixib (lumi) Racoxib), parecoxib sodium, rofecoxib, serenocoxib-1 or valdecoxib; jj) anti-allergic agent; kk) Viral agent; ll) phosphodiesterase (PDE) III inhibitor; mm) phosphodiesterase (PDE) IV inhibitor, such as roflumilast or GRC-4039; nn) double phosphodiesterase ( PDE) III/IV inhibitor; oo) xanthine derivative, such as theophylline or theobromine; pp) p38 cleavage-activating protein kinase (p38 MAPK) inhibitor, such as ARRY-797; Qq) a cleavage substance that activates an extracellular signal-regulated kinase (MEK) inhibitor, such as ARRY-142886 or ARRY-438162; rr) phosphoinositide 3-kinase (PI3K) inhibitor; ss) interferon, including interferon beta 1a Such as Avonex from Biogen Idec, CinnoVex from CinnaGen, and Rebif from Merck Serono, and interferon beta 1b, such as Betaferon from Schering (Betaferon) ) and Betaseron from Berlex; and tt) interferon alpha, such as Sumiferon MP. A combination as described in claim 28, which is for simultaneous, separate or sequential use in the treatment of a human or animal body.