TW201130839A - Pyrazole derivatives as JAK inhibitors - Google Patents

Abstract

New pyrazole 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

201130839 VI. Description of the invention: [Technical field to which the invention belongs]

The present invention relates to novel pyrazole derivatives, as well as processes for their preparation, pharmaceutical compositions thereof, and their use as a deduction agent for Janus kinase (JAK) for therapy. P [Prior Art] Cytokines have a key function 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 enzymatic activity that is capable of mediating signal transduction' and therefore need to be associated with tyrosine kinase for this purpose. The JAK family of kinases includes four distinct members, namely JAJQ, jAK2, JAK3, and TYK2', which bind to type I and sputum 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 gpl30 Chains (IL-6 family) and common gamma chains (IL-2, IL-4, IL_7, IL-9, IL-15, and IL-21) (R!〇dig et al. (1998). Disruption of the JAK1 gene Definitions 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 201130839 kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin -6. J. 14: 1421; Briscoe et al. (1996). Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state. Five MBO J. 15:799); JAK2 in hematopoiesis Factors (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. Ce//, 93:385) ; JAK3 is in common See receptor (IL-2 family) in (Park et al., (1995) γ of the key. Developmental defects of lymphoid cells in JAK3 kinase-deficient mice.

3:771; Thomis et al., (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Price/(9)ce, 270:794; Russell et al., (1995). Mutation of JAK3 in a partient with SCID : Essential role of JAK3 in lymphoid development. «Sczewce, 270:797); and Tyk2 in the receptors of IL-12, IL-23, IL-13 and type I IFN (Karaghiosoff et al., (2000). Partial impairment Of cytokine responses in Tyk2-deficient mice. Immunityf 13:549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function. Immunity, 13:561 Minegishi et al. (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745 ) 0 5 201130839 Receptor stimulation sequentially leads to jAK caused by phosphorylation Activation, receptor phosphorus

Acidification, STAT protein recruitment, and STAT activation and dimerization. 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: STAH, 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-STATl), while other associations may

It has cell type dependence (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. Because this specialized association of 'JAK3 knockout mice and common gamma chain deficient mice have the same phenotype (Thomis et al, (1995) · Defects in Β lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. 270:794; DiSanto et al People, (1995).

Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. 92:377). Furthermore, this phenotype is largely shared with SCID patients who retain mutations/defects in common gamma chains or JAK3 genes (O'Shea et al., (2004). JAK3 and the pathogenesis of severe combined immunodeficiency. M9// m fine "o /, 4l · 727). JAK3-deficient mice survive, but exhibit abnormal lymphocyte formation' This leads to a decrease in thymus size (which is wild-type 201130839 1 〇〇-1/1〇) 〇 JAK3-deficient peripheral T cells are unresponsive and have activation/memory cells Phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice.«/. ZewA:· 5/〇/. 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 (v〇 n 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. ·/f) Φ Md, 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. www?/,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. (10) 94: 932: 939) have shown that T., loss of JAK3 in the cell compartment promotes the expansion of the myeloid lineage, resulting in dysregulated bone marrow form.

JAK2-deficient mice are lethal 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 201130839, 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. Ce//, 93:385). JAK1-deficient mice die during the perinatal period due to breastfeeding defects. jAKi specifically binds to the gp13〇 chain shared by the IL-6 cytokine family (ie, LIF, CNTF, OSM, CT-1) and binds to JAK3 as a common common γ chain by binding to non-consensus receptor subunits. The basic components of the body. In this regard, JAK1-deficient mice showed a hematopoietic defect similar to that of JAK3-deficient mice. In addition, it shows a defective response to neurotrophic factors and all interferons (sputum cytokine receptors) (Rodri et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the Jaks in cytokine- Cell, 93:373) ° Finally, Tyk2-deficient mice showed a weakened response to IL-12 and IL-23 and only a partial decrease in response to IFN-α (Karaghiosoff et al., (2000). Partial impairment Of cytokine responses in Tyk2_deficient mice. /wwwmXy,13:549 ; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function, /mm(10),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 201130839 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 (muitipie sclerosis) )), gingivitis, transplant rejection, and solid and liquid malignant diseases (such as myelopr〇liferative disorders, leukemia, and lymphoma). Inhibition of JAK kinases (especially jaki and jAK3) produces potent immunosuppression, which is therapeutically useful for preventing transplant rejection. In this regard, the JAK inhibitor CP-690,550 (tasocitinib) has been shown in several animal transplant models by extending the average survival time of the graft (the mouse's heretopic heart transplant, implanted mouse ears) Efficacy of heart allografts, rhesus kidney allografts, rat aorta, and tracheal transplantation (West K (2009). CP-690,550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumat&id Arthritis, transplant rejection, psoriasis arid other immune-mediated disorders. Curr. Op. Invest. Drugs 10: 491). An imbalance between the proinflammatory and anti-inflammatory cytokine activity 201130839 in rheumatoid joints induces autoimmune induction followed by induction of chronic inflammation and tissue destruction. In this regard, the pathogenic effect 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 gpl30 receptor chain (Heinrich et al., (2003). Principles of interleukin (IL)-6-type cytokine signaling and its regulation. «/. 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 the proliferation of Th1 and Th17 cells, respectively; IL-15 and GM_CSF (Mclnnes and Schett, (2007). Cytokines in the pathogenesis of rheumatoid arthritis Nature Rew /wmwm?/· 7:429·). Receptors of 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. Λα. 10:R14). Inflammatory bowel disease (IBD) includes two major forms of enteritis: ulcerative colitis and Crohn's disease. Increasing evidence has shown that 201130839 shows that a variety of cytokines (including interleukin and interferon) are involved in the pathogenesis of IBD (Strober et al., (2002). The immunology of mucosal models of inflammation. and ev /mmwwo/. 20: 495). It has been shown that activation of the IL-6/STAT3 cascade in TLA cells induces long-term survival of pathogenic sputum 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. M to /. 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 these cells (Lovato et al., (2003) Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. J Biol 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 white matter + plaque formation. 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 huma& brain disorders. «/C7z>2/«vesi. 118:3557 ), It is a cytokine that signals through the JAK-STAT pathway. The use of tyrphostin (JAK inhibitor) has been shown to inhibit IL-12-induced STAT3 phosphorylation and to reduce the incidence of active and passive 201130839 experimental autoimmune encephalitis (EAE). And severity (Bright et al, (1999) Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. JImmunol. 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 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 Thl7 and Thl responses in experimental autoimmune encephalomyelitis. J· /wmwwo/. 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 that there is a cytokine network that controls the interaction between immune and epithelial cells (Nick〇1〇ff Bj (2〇〇7)

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 psoriatic skin. Il_23 induces the formation of Th17 cells, which in turn produce IL-17 and iL_22, which is responsible for thickening of the epidermis. IL-23 and IL-22 induce phosphorylation of STAT-3, which is abundantly present in psoriasis skin towels. Therefore] AK_#1 can be therapeutic in this environment. Therefore, it has been found that in the spontaneous tau cell-dependent mouse model of psoriasis = JAK1/3 inhibitor R348 reduces psoriasis skin inflammation ang et al. (2009). JAK3 inhibition significantly 12 201130839 attenuates psoriasiform skin inflammation on CD 18 mutant PL/J mice, «//mwwwo/· 183:2183 ) 〇

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 receptors 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. Five 582: 154). In addition, JAK3-deficient mice exhibited weak eosinophil recruitment and mucus secretion into the trachea after OVA challenge compared with 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). corpse five 71 295:912.). In this regard, systemic administration of CP-690, 550 JAK inhibitors in mice has been shown to reduce eosinophil counts in BAL and reduce eosinophil chemotaxis in a mouse model of eosinophilic hypertrophy in the lungs. Factor and IL13 content (Kudlacz et al, (2008). The JAK3 inhibitor CP-690, 550 is a potent anti-inflammatory 13 201130839 agent in a murine model of pulmonary eosinophilia. European J. Pharm. 582:154) ° More and more There is much 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. A: G/Owi/z 18:135). In this regard, drugs or biological products that interfere with IL-2 signaling, such as cyclosporine or anti-lL-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 hyperemia , 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 Suppression 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. i75: 5489). Increasing evidence demonstrates that STAT3 activity is involved in tumor formation (eg, cell cycle disorders, promoting uncontrolled growth, induced accumulation) Key role in factors and inhibition of apoptosis (Siddiquee et al, 201130839 (2008). STAT3 as a target for inducing apoptosis in solid and haematological tumors. CW/ and team 18: 254). It has been shown by means of dominance - Negative mutant or antisense oligonucleotides antagonize STAT3 to promote cancer cells

Apoptosis, inhibition of angiogenesis, and up-regulation of host immunity. Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors provides 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 in which the JAK-STAT pathway is dysregulated can benefit from JAK inhibition. Recent research has suggested a range of myeloproliferative diseases (Ihle and

Gililand, 2007) (including polycythemia vera, myelofibrosis, and essential thrombocythemia) chromosomal translocations and mutations in the pseudo-kinase domain (such as JAK2V617F) Mutation) dysregulates 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: 15, 201130839 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. Omcer 5W, 99: 1% 5) and CYT387 (Pardanani et al., (2009). CYT387, a selective JAK1/JAK2 inhibitor: invitro assessment of k Inase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. 23:1441) for the treatment of 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. 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 leukeVnia 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 201130839) can be used as a development, anticipation, and path Or to regulate ΙΑΚ _ (especially ΤΑΚ丨, jak2 a human. kinase) in the treatment of treatment or prevention of disease symptoms = ^ biological diseases (such as leukemia, lymphoma, solid tumors); migration / rejection" (four) transplantation application (eg graft versus host disease), from, immune diseases (eg diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease); respiratory inflammatory diseases (eg asthma, chronic obstructive sputum + disease), inflammation Related eye diseases or allergic eye diseases (eg dry eye, glaucoma, uveitis, diabetic retinopathy (along the sacred sacred sputum), allergic conjunctivitis or age-related macular degeneration) and skin inflammation Sexual diseases (such as atopic dermatitis or psoriasis).

> Given that many conditions are expected to benefit from the immediate manifestation of 'alpha therapy' involving modulation of the Μκ pathway or JAK kinase, novel compounds that modulate the AK pathway and the use of such compounds should provide substantial therapeutic benefit to a variety of patients. Provided herein are novel heteroaryl imidazolidone derivatives for use in the treatment of a condition that is therapeutically useful for targeting the JAK pathway or inhibiting JAK kinase. The compounds described in the present invention are both effective JAK-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), leukemia, lymphoma and solid tumors; bone marrow and Organ transplant rejection; 17, 201130839 or immune-mediated diseases such as autoimmune and inflammatory diseases, including f-arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative, ''sigma enteritis or Crohn's disease), inflammation-related eye disease or allergic eye disease (such as dry eye, uveitis or allergic conjunctivitis), allergic rhinitis, asthma, molting (: D), and skin inflammatory diseases (such as "invention Therefore, the present invention relates to a substance 'or a pharmaceutically acceptable compound thereof or a derivative of a derivative of a derivative: 4 (4) or a N-oxide or a r4

18 201130839 wherein m is 0 or an integer from 1 to 3; Z represents an oxygen atom or a group NR5; W represents a nitrogen atom or a -CR3 group; x group X, Y and T independently represent a nitrogen atom or a CR9 group, When the γ or τ towel is a nitrogen atom, the face K, R2, R3, R4 and R9 each independently represent a hydrogen atom; a cyano group; a linear or branched chain CrC6 alkyl group; and a C2_c4 base group. ', alkynyl; CrQ halogen group; CrQ hydroxyalkyl; C3-C10 ring-burning. Γ 2 4 cycloalkenyl; monocyclic or polycyclic CVC14 aryl; ' :Κ:1() contains at least one 5 to a heteroaryl group of a hetero atom from 0, S and N; containing at least - (iv) a pyrene, S heterogeneous to a 14-membered group; containing a monocyclic C5_C9 filament or a _ group directly bonded to 5 to 9 members a bicyclic group of a cyclofilament or a heterocyclic group, the material comprising at least one hetero atom selected from the group consisting of ruthenium, S and N; an aza-weiss having one to a carbon atom or having a dicyclohexene having 12 a base, wherein the alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, bicyclo, azaindole & base: Aza-bicyclic dilute base unsubstituted or one Or a plurality of substituents selected from the group consisting of substituted substituents and substituted by the silk; Kb

Or &, 112, 113, κ4 and r9 independently represent the guanidine 3 group -s〇R 201130839 group, -s(o)2r13 group, -s(o)2nr13r14 group, -nr13s(o) 2r14 group, -NR13S(0)2NR14 group, -(CH2)n〇R13 group, -C(〇)〇R13 group, -0-C(0)R13 group, -C(0)- (CH2)n-R13 group, -NR13R14 group, -C(〇HCH2)n-NR13R14 group, -NR13C(0)-(CH2)n-R14 group or -NR13C(0)-(CH2) a group of n-NR14Ri5 wherein each η is 〇, 1 or 2; or in the presence of two adjacent -CR9 groups, two adjacent _cr9 groups and their bonded carbon atoms are optionally formed a C5_Cl2 aryl group or a 4 to 12 membered heteroaryl group, a cycloalkyl group or a heterocyclic group, the heteroaryl group and the heterocyclic group containing at least one hetero atom selected from the group consisting of ruthenium, S and N, the aryl group and the heteroaryl group a group, a cycloalkyl group, and a heterocyclic group unsubstituted or one or more selected from the group consisting of a linear or branched chain CrC6 alkyl group, a monocyclic or polycyclic c5-C14 aryl group, containing at least one selected from the group consisting of ruthenium a 5 to 14 membered heteroaryl group of a hetero atom of S, N, and a substituent of 5 to 14 membered heterofluorenyl groups containing at least one hetero atom selected from the group consisting of ruthenium, s, and N a substitution wherein the alkyl group, the aryl group, the heteroaryl group, and the heterocyclic group substituent are unsubstituted or one or more selected from a halogen atom, a hydroxyl group, a cyano group, a linear chain or a branched chain Substituted with a substituent of a Ci_C6 alkyl group or a Ci_C4 haloalkyl group;

Rs represents a hydrogen atom, a linear or branched chain CrC6 alkyl group, and the alkyl group is optionally selected from one or more selected from the group consisting of a hydroxyl group, a cyano group, a CrC4 tooth alkyl group, a crc4:light alkyl group, a CrC1G cycloalkyl group, a benzene group. Substituent substituent of the 6-membered saturated heterocyclic ring or 'R5 represents _S(0)2R(1) group, _s(9)2NR(7)Rn group, -C(9)〇R1〇 group, ((9)_(CH2)n_Ri〇 group or -CCOHCHJn -NRjoRn group; 201130839 尺6 and R·7 each independently represent a hydrogen atom or a straight octaalkyl group, the alkyl group optionally being selected from one or more selected from the group consisting of a hydroxy branched chain C-C6 dentate group, a crc4 a substituent such as a pyridyl group, a Cl_c4 alkoxy group, a cyanide group, a Ci-Q group or a 6-membered saturated N-containing heterocyclic ring; 7.3, an alkoxy group; a hydrogen atom; an atom; a cyano group; ; straight bond or silk; c2-c4 alkenyl; c2-c4 fast radical; CrC4 self-burning base knife 3 = base; 〇3-(: 10 ring alkyl; c3_Cl0 ring thin base; single ring or multiple Ze ^ 5 ί 1 to 1: a hetero atom selected from o, s, and N; to: a heteroaryl group; containing at least one hetero atom selected from 0, s, and N, a heterocyclic group; a monocyclic c5_c9 Green or _ direct knot = 9 member cyclofilament or heterocyclic group bicyclic group, Each having at least one hetero atom selected from the group consisting of ruthenium, S, and N; and having at most one carbon source only __ bis- sulphide has aza-bicycloalkenyl group of 12 Base, dentate, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, bicyclo, aza-bicyclo and aza-bicyclic are unsubstituted or Substituent substitution of one or more substituents selected from the group consisting of Ra, a thiol-CN group or a _(crC4 alkyl)-C(0)NR'R" group, wherein R' and R" are the same or different and are selected from a hydrogen atom and a linear or branched C.rC4 alkyl group; and the alkyl group is unsubstituted or substituted with one or more substituents selected from Rb; or the ruler 8 represents a -SR13 group, a -SOR13 group , _s(0)2R13 group, -S(0)2NR13R14 group, _NR13S(0)2R14 group, _NR13S(0)2NR14 group, -(CH2)n〇R13 group, _C(0)0r13 group Group, base 21 201130839 group, -CXOHCHU3 group, as 4 base-C(0)-(CH2)n-NR13R14 group, _NRi3C(〇)_(CH2) _r solid, -NR13C(〇HCH2)n-NRl4R15 a group in which each n is 2 [, ?, or or Rs together with the nitrogen atom to which Rs and Rs are bonded together, ^ 10 a saturated heterocyclic group containing - or two nitrogen atoms as a heterocyclic to a straight or branched chain CrC6 alkyl group, a monocyclic or polycyclic C5_Ci aryl 2 and having at least one selected from the group consisting of 0, S and N 5 to 144' of a hetero atom containing 5 to at least one hetero atom selected from ruthenium, S and N: luki '-s〇2r10 group '-C(〇HCH2)n_Ri〇 group impurity = -C( 〇HCH2)n-NR10Rn group substitution, wherein each n is 〇, ι or 2, one-wherein the alkyl, aryl, heteroaryl and heterocyclic groups are not taken-through or multi-pour from the self-made sub-record a cyano group, a linear or branched bond α-alkyl or a substituent substituted with a VC4 # silk, and the alkyl group of which is not substituted or substituted with - or a plurality selected from a dentate atom, a cyano group or Substituted by a substituent of CA alkane; the limitation is that when m is 〇, 仏 is not observed. a group, s〇r]3 group, _s(o)2r13 group, _s(〇)2nr13r14 group, _NRi3S(0)2Ri4 group, -NR13S(0)2NR14 group, _(CH2)n〇 Ri3 group, _〇_c(〇)Ri3 group, -NR^R]4 group gj, as (1) can be a group such as a group or a -NR13C(0)-(CH2)n-NR14R15 group. among them

Ra is a halogen atom; a cyano group; a hydroxy group; a linear or branched chain CrC6 alkyl group 'Crc4 - affinyl group; a crC4 alkoxy group; a crc4 hydroxyalkyl group; a C3-C7 cyclodendyl group or a CVC7 ring-dilute group, which is unsubstituted Or substituted by one or more substituents selected from Substituting 22 201130839 Re; monocyclic or polycyclic C5_Ci4 aryl, substituted by one or more substituents selected from substituent Re; ς to small - one choice 5 to 14 membered heteroaryl groups of the hetero atom of o, s and oxime, and substituted by or substituted with or a plurality of substituents selected from the substituent Re; 至少 at least one selected from the group consisting of 〇, s and Ν 5 to 14 members of a hetero atom are unsubstituted or via- or a plurality of substituents selected from the group consisting of a substituent Re _ ^ ♦; a ship 1 () group; Na) 2Rig group; a group, Nazhou claw base团; 〇 i〇s(〇) 2N]^ group 0 11 _(CH2)n〇Rl. Group; _C(〇)〇Ri. Group; = -c(〇HCH2)n_Rl0 group; ·NR]〇Rii yl 2'-C(〇HCH2)n_NR1QRll group; 视(1)卿戈-nr1〇C(〇MCH士NRllRl2 group, each of which 4., ^,

Rb is a group; a Crc4 halogen group; a CrC4 alkoxy group; a μ-alkyl group, a CrC7 cycloalkyl group or a CVC7 cycloalkenyl group, which is not selected from the group of Re-retrieved Re; Substituted or via- or a plurality of selected from the substituent Re, 4 of which contains at least one hetero atom selected from o, s and N, which is unsubstituted or trans- or more a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from the group consisting of 0, s and N, which is unsubstituted or substituted with or a plurality of substituents selected from the substituent k Substituted; -SR10 group; -SOR. group; ·_Λ〇 group; -8(ο)2Νκ1〇υ3ΐ; -nr10s(〇)2Rii group; 视 i〇s(〇)2nr"group;- (CH2)nOR1G group; ·〇:(0)〇Κι. a group; _〇_ group, -C(〇)-(CH2)n-R10 group; _NRi〇Rn group; 23 201130839 -C^OHCHJn-NRioRn group; -NR10C(〇)_(CH2) The n-Rn group is a group -NR1〇C(〇)_(CH2)n-NRiiRi2, wherein each η is 〇, ι or

Rio, Rn and R!2 each independently represent a hydrogen atom, a cyano group, a straight or branched chain CrC6 alkyl 'CrC4 ialkyl, a crc4 hydroxyalkyl group, an alkoxycarbonyl group, a Cr〇7 cycloalkyl 'phenyl group' a 5- to 6-membered monocyclic heteroaryl group containing 2 or 3 hetero atoms selected from the group consisting of ^, Ο, and S, containing 5, 6 or 6 membered heterocyclic groups of a nitrogen atom, containing a single ring c^ a -c:6 aryl or heteroaryl group directly bonded to a bicyclic group of a 5- to 6-membered cycloalkyl or heterocyclic group, the heteroaryl or heterocyclic group having 1, 2 or 3 nitrogen atoms, Haloalkyl, light alkyl, alkoxycarbonyl, cycloalkyl, phenyl, heteroaryl, heterocyclyl, and bicyclic are unsubstituted or substituted with one or more substituents selected from substituent Rc, and The alkyl group is unsubstituted or substituted with one or more substituents selected from the substituent Rd;

Rc is a halogen atom 'trans group, cyano group, straight bond or branch bond c!-C6 alkyl group C1-C4 halogen group, C1-C4 alkoxy group 'C1-C4 light base' 匸3_〇7 ring A base group having 5, 6 or 3 membered monocyclic heteroaryl groups containing 1, 2 or 3 nitrogen atoms, having 5 to 6 membered heterocyclic groups of 1, 2 or 3 nitrogen atoms, or containing 1, 2 or a c3-C7 heterocycloalkyl ketone group of three nitrogen atoms, said phenyl group being unsubstituted or substituted by one or more halogen atoms, and said heteroaryl group, heterocyclic group and heterocycloalkyl ketone group are not Substituted or substituted with one or more straight or branched chain CrC3 alkyl groups;

Rd is a cyano group, a CrC4 haloalkyl group, a CrC4 alkoxy group 'CrG via a phenolic group' CrC7 cycloalkyl group, a phenyl group, a 5 to 6 membered monocyclic heteroaryl group having 1, 2 or 3 nitrogen atoms, and contains 1, 5 to 6 membered heterocyclic rings of 2 or 3 nitrogen atoms 24 201130839, or a C3-C7 heterocycloalkyl ketone group having 1, 2 or 3 nitrogen atoms which are unsubstituted or have one or more a dentate atom substituted, and the heteroaryl, heterocyclyl, and heterocycloalkyl ketone groups are unsubstituted or substituted with one or more straight or branched chain crc3 alkyl groups;

Re is a halogen atom, a hydroxyl group, a cyano group, a straight or branched chain group or a CrC4 haloalkyl group;

Rl3, RM and R1S each independently represent a hydrogen atom, a cyano group, a linear or branched chain CrC6 alkyl group, a CrC4 haloalkyl group, a crc4 hydroxyalkyl group, a CrC4 alkoxycarbonyl group, a CVC7 cycloalkyl group, a monocyclic or polycyclic c5_Ci4 group. An aryl group having 5 to 14 membered heteroaryl groups containing at least one hetero atom selected from the group consisting of ruthenium, S and N, or a 5 to 14 membered heterocyclic group containing at least one hetero atom selected from the group consisting of ruthenium, S and N, ^ The #丝, ship base, spider, hetero, aryl, and heterocyclic groups are unsubstituted or substituted by one or more selected from substituents, and the ring base is optionally selected from - or more -JAK) (JanUS; Bi Xue = formula (1) of the sitting derivative, or its doctor

And RdR9 is as above. 9 soil lying and m, Z, W, X, Y mei group "in the compound of formula (1)" represents a -CR9 group and m, Z, W, x and as defined above. 25 201130839 In another embodiment, the formula 9 represents a group of the core 9 and wherein Y represents a Ν, meaning, when Rs represents and R1 to R9 are as defined above. The heterocyclic group is substituted with at least a heterocyclic group of 5 to 7 members of the atom or a ^^ atom, and the substituent on the nitrogen is not a third butoxy group. The synthesis method described in the 'G binary' and the intermediate pathology or disease (MK) to improve the disease and solid tumor; bone cancer, leukemia, lymphoid malignant disease transplant rejection; immunity Diseases, lymphoid malignancies, and proliferative disorders, white* reactions; and immune-mediated myeloid and organ transplant rejection of wet arthritis, multiple sclerosis, inflammatory (10)), atopic skin m-cirrhosis. Sexual, extensive, and dilute, and the compound of formula (1) can be used to treat spinal cord hyperplasia: two treatments for malignant diseases and solid tumors. In this case = inhibition of the individual's Janus Township. Strip = eight compounds can be used to treat bone marrow and organ transplant rejection reactions from m-guided diseases and inflammatory diseases, such as bone marrow to 26 201130839 and organ transplant rejection; And immune-mediated and organ transplant rejection. Or a substance, such as a bone marrow, according to the invention, or a pharmaceutically acceptable salt or a solvent thereof, wherein the pyrazole derivative of the compound is substituted by ======= or wherein the treatment By inhibiting Jie Er: learning the disease ^ invention also provides a method for treating the pathological condition or disease by inhibiting the Janus kinase, which is selected from the vertebral proliferative Symptoms, ",: raw = solid tumors, bone marrow and organ transplant rejection = disease" such as spinal proliferative disorders, white blood stasis entities _; bone marrow and organ transplant rejection, and immune-mediated diseases, more specifically The pathological condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, hair, '6 eyes, grapevine inflammation, allergic conjunctivitis, allergic rhinitis, and chronic obstructive pulmonary disease (C0PD) A method of atopic skin dermatitis comprising administering to a subject in need of such treatment a therapeutically effective amount = a compound as defined herein or a compound as defined herein and a therapeutically acceptable diluent or carrier Pharmaceutical composition of the agent. The treatment is achieved by the Genus kinase of the individual. The present invention also provides a Genus kinase 27 that inhibits an individual in need thereof. The therapeutic individual is administered as a compound or a pharmaceutical combination comprising a substance as defined herein and a pharmaceutically acceptable diluent or carrier. The invention also provides a combination product comprising: (1) As one or more other active substances herein, which are known to have proliferative disorders (such as true plethora, primary bloody disease or myelofibrosis), leukemia, lymphoid m disease, and tli (4) and 11-graft rejection; immunization Mediated diseases as well as inflammatory diseases 'such as spinal proliferative disorders, leukemias, lymphoid malignancies, and solid bone marrow and organ transplant rejection; to mediated, mediated diseases' more specifically, the neoplasms Or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), dry eye, uveitis, allergy Conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (c〇pD), atopic dermatitis, and psoriasis. As used herein, the term CrQ alkyl includes the optionally substituted linear or branched chain group. It has from 1 to 6 carbon atoms, preferably from 4 to carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, n-. Pentyl, hydrazine-methylbutyl, 2-mercaptobutyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethyl, n-hexyl, 1 -ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, ι,3-didecylbutyl, 2,2-didecyl Butyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, and isohexyl. 28 201130839 As used herein, the term 'CrC4 alkenyl encompasses a linear or substituted A branched mono- or polyunsaturated group having from 2 to 4 carbon atoms. Examples include vinyl, allyl, 1-propenyl, isopropyl, butanyl, 2,butenyl and 3-butenyl. The term CVC4 block, as used herein, encompasses optionally substituted straight or branched chain mono- or polyunsaturated groups having from 2 to 4 carbon atoms. Examples include 1-propanyl, 2-propynyl, l-butanyl, 2-butyryl and 3-butynyl. When the alkyl, alkenyl or alkynyl group is optionally substituted, it is intended to include a straight or branched alkyl, alkenyl or block group as defined above, which may be unsubstituted or in any position Substituted by one or more substituents (e.g., 3 or 3 substituents). When two or more substituents are present, each substituent may be the same or different. The optionally substituted thiol group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituent on the alkenyl group is usually unsubstituted by itself. Preferred substituents on the alkenyl group are a dentate atom and a hydroxyl group, and more preferably a _ atom. The optionally substituted alkynyl group is typically unsubstituted or substituted with hydrazine, 2 or 3 substituents which may be the same or different. Substituents on alkynyl groups are usually unsubstituted themselves. Preferred substituents on the alkynyl group are a dentate atom and a hydroxyl group and more preferably a halogen atom. Tv, , as used herein, the term Cl-C4 dentate alkyl is a alkyl group bonded to one or more, preferably 2 or 3 dentate atoms, such as a ^ or Ci2 alkyl group. The haloalkyl group is preferably selected from the group consisting of _ccl3 & _CF3. 29 201130839 As used herein, the term Ci-C4 alkylate encompasses a straight or branched alkyl group having from 1 to 4 carbon atoms, wherein one or more, preferably one or two, More preferably one hydroxy substitution. Examples of such groups include mercapto, ethyl, propyl and hydroxybutyl groups. The term Q-C4 methoxyl, as used herein, includes optionally substituted straight or branched chain oxygen-containing groups each having an alkyl moiety of from 4 to 4 carbon atoms. The alkoxy group is usually unsubstituted or substituted with hydrazine, 2 or 3 substituents which may be the same or different. Substituents on alkoxy groups are generally not themselves substituted. Preferred alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, first butoxy, tert-butoxy, trifluoromethoxy, difluoromethyl Oxyl, hydroxymethoxy, 2-hydroxyethoxy and 2-hydroxypropoxy. The term CrC4 alkoxycarbonyl as used herein encompasses a group of the formula -C(〇)〇(CrC4 alkyl), wherein the Crc4 alkyl group is a straight or branched chain hydrocarbon group having from J to 4 carbon atoms. Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, a second butoxycarbonyl, and a third butoxycarbonyl group. The term C3_Ci〇cycloalkyl as used herein encompasses saturated monocyclic or polycyclic carbocyclyl groups having from 3 to 1 carbon atoms, preferably from 3 to 7 carbon atoms. The C3_C1()cycloalkyl group is usually unsubstituted or substituted with 2 or 3 substituents which may be the same or different. When the Q-Qo cycloalkyl group has 2 or more substitutions, the substituents may be the same or different. The substitution on the C3_Ci 〇cycloalkyl group is often unsubstituted. The polycyclic cycloalkyl group contains two or more fused 5-cycloalkyl groups, preferably two cycloalkyl groups. The polycyclic cycloalkyl group is typically selected from the group consisting of decalin 201130839, 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 C3-C10 cycloalkenyl, as used herein, encompasses a partially unsaturated carbocyclic group having from 3 to 1 carbon atoms = preferably from 3 to 7 carbon atoms. The Q-Cw cycloalkenyl group is usually unsubstituted or substituted with a substituent of 2 or 3. When from. When the cycloalkenyl group has 2 groups, the substituents may be the same or different. Substituents on the ring-like base are usually unsubstituted by themselves. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, cyclodecyl and cyclo-indenyl. As used herein, the term q-c 4 aryl typically encompasses c5_Ci4, preferably C6-C14, more preferably C6-C1G monocyclic or polycyclic aryl such as phenyl, naphthyl, anthryl and phenanthryl. Phenyl is preferred. The optionally substituted Cs-Q4 aryl group is usually unsubstituted or substituted with hydrazine, 2 or 3 substituents which may be the same or different. When the C5_Cm aryl group has 2 or more substituents, the substituents may be the same or different. Substituents on the C5_^4 aryl group are generally unsubstituted by themselves unless otherwise specified. 5 14 Fresh and? Used, -~ii+ only (four) (four) $coverage> to the employee% system, preferably 5 to 10 member ring system, better 5 to 6 member ring system. It comprises at least one heteroaromatic ring and contains at least one selected from the group consisting of hydrazine, = and heteroatoms. 5 to 14, the aryl group may be a single ring or two or more ring members, at least one of which contains a hetero atom. The optionally substituted 5 to 14 membered heteroaryl group is typically unsubstituted 31 201130839 or substituted with 1, 2 or 3 substituents which may be the same or different. When the 5 to 14 membered heteroaryl group has 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, substituents on the 5 to 14 membered heteroaryl are generally unsubstituted by themselves. Examples include beta thiol, oxime, gnashing, oxime, oxime, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazole Benzomidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridyl, benzothiazolyl, indolyl, oxazolyl, indolyl, quinolyl, isoquinolyl, anthracene Azinyl, 00 pyridine, quinoxalinyl, quinazolinyl, fluorenyl, 01 linyl, trisal, fluorenyl, fluorhydryl, isoindolyl, isodecyl, Imidazolidinyl, acridinyl, thionyl, pyrazolyl, 2Η-pyrazolo[3,4-d]-pyridinyl, 1Η-tonoxaz[3,4-d]acridinyl, thieno[ 2,3-d] Mouth bite and various hydrazines. Each bite base. - As used herein, the term 5 to 14 membered heterocyclic group generally encompasses a non-aromatic saturated or unsaturated CVQ4 carbocyclic ring system, preferably a C5_Ci〇 carbocyclic ring system, a more preferred CVC6 carbocyclic ring system, wherein one or more (eg 1, 2, 3 or 4 carbon atoms), preferably i or 2 carbon atoms, are selected from the group consisting of N, 〇 and s Atomic substitution. Heterocyclic groups can be monocyclic or two or two a fused ring in which at least one ring 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 5- to 14-membered heterocyclic group is usually unsubstituted or substituted by 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 ring group include a britylene group, a bite base, and an n-portion 32 201130839. Linke, a base, a county, a thio-like, a scaly, a (four) alen, a Pi_lidinyl, a finance base. , 嗤 嗤 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基, 3_aza-tetrahydrofuranyl and tetranuenyl, such as (four), 対 吻 各 各 、 、 、 、 、 、 、 、 、 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 吗 、 、 Bite base, 06 bite base, triterpene group, sulfhydryl group, tetrasyl group "Miwa bite base, imidyl group, oxygen G8 group, 4,5 · fluorenyl group, 2 · stupid material _1 (3 Η) —ketone, 1,3-dioxol-2-one and 3-aza-tetrahydrofuranyl. Where the 5 to 14 membered heterocyclic group bears 2 or more substituents, the substituents may be the same or different. As used herein, the term 6 member saturated hydrazine-containing heterocyclic group is a 匸6 saturated carbocyclic ring system. Wherein one of the carbon atoms is replaced by hydrazine and, as the case may be, 2, 3 or preferably 2 or more other carbon atoms are replaced by a hetero atom selected from n and hydrazine. 'The 6-membered saturated N-containing heterocyclic group Usually unsubstituted or substituted with hydrazine, 2 or 3 substituents which may be the same or different. Unless otherwise specified, the substituents on the 6-membered saturated N-containing heterocyclic group are usually unsubstituted by themselves. Examples of cyclic groups include piperidinyl and piperazinyl. As used herein, the term CVC7 heterocycloalkyl fluorenyl typically encompasses a non-aromatic saturated or unsaturated (: 3 〇 7 carbocyclic ring system in which one carbon atom Substitution with a C=0 group and 1, 2 or 3, preferably 1 or 2, more preferably j, other carbon atoms are preferably replaced by N. Examples include acridone groups. As used herein, the term aza having at most 2 carbon atoms. 33 201130839 Bicycloalkyl refers to a group of n-heterocyclic groups which are fused by a condensed m-like group as herein. The term having up to a bicycloalkenyl group encompasses an aza-bicycloalkyl group having at least hetero-bond as defined herein. Unsaturated rabbit-carbon

As used herein, a bicyclic group containing a monocyclic C bond to a 5- to 9-membered naphthenic group, which is directly rr to a decyl group or a benzyl group, usually refers to a monocyclic C5-C9 group. Or a heterocyclic group bonded to the group by a single bond. Examples include a stupid base or a brew base. "Silk or miscellaneous J base, as used herein, the knot, the group, the part, the hammer of the present invention are replaced by the '', and the two are more than two." This means that this is replaced by The iso-group H chain and the ring may be unsubstituted or substituted at any position via one or more (eg 1, 2, 3 or 4) substituents, thereby bonding to the unsubstituted atom, group, Part, _ atom, group, moiety, chain and ring 』= When two or more substituents, each substituent may be the same or different. The substituent is usually unsubstituted by itself. When the group is bridged by a stretched or extended dioxy group, the bridged alkyl group is bonded to the ring at a non-adjacent atom. As used herein, the term dentate atom encompasses gas, gas, moisture, and filled atoms. The material is usually a domain, gas or _, preferably chlorine or fluorine. The term halo has the same meaning when used as a prefix. - As used herein, the term pharmaceutically acceptable salt is included and pharmaceutically Accepted acid or salt formed. Pharmaceutically acceptable acid package 34 201130839 Containing inorganic acids, For example, hydrochloric acid, sulfuric acid, gamma, di-tank acid, hydrogen-acid acid, acid-reading acid, and jujube; and organic L-hydrogen, anti-t-butene/succinic acid, acid, mandelic acid, ascorbic acid, oxalic acid, diced Second, ^ acid, benzene m, acetic acid, Jia Yun, B, benzene Gu ^ ^ ' This % acid. Pharmaceutically acceptable bases include metal (such as sodium or potassium) and soil test metals (such as oxidized And organic tests such as alkylamines, aralkylamines, and heterocyclic amines. Other preferred salts of the invention are quaternary ammonium compounds in which one equivalent of cerium ion (X·) is associated with a positive charge of the N atom. χ can be a variety of adipic acids: anions, such as gas ions, bromide ions, iodide ions, sulfates, nitrates, phosphates; or organic acid anions, such as acetate, maleate, anti-butene Acid, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, sulfonate and p-toluenesulfonate. X- is preferably an anion selected from the group consisting of: , bromide, iodide, sulfate, nitrate, acetate, cis Butyleneate, oxalate, succinate or trifluoroacetate. X-more preferably is a gas ion, a bromide ion, a trifluoroacetate or a sulfonate. As used herein, 'N-oxide is used A conventional oxidizing agent is formed from a tertiary amine or imine present in a molecule. As used herein, the term solvate means additionally comprising a stoichiometric or non-stoichiometric amount combined by non-covalent intermolecular forces. a compound of a solvent such as water, acetone, ethanol, decyl alcohol, dioxane, 2-propanol or the like. When the solvent is water, the term hydrate is used instead of the solvate. 35 201130839 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. Deuterium (D or 2h) is a stable isotope of hydrogen, which is 0.015 mol. presence. Hydroquinone exchange (incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a helium 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, the enthalpy 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 5 〇〇〇 (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 sites of the deuteration site are independent of other deuteration sites. The isotope enrichment factor can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR). Usually, the compound of formula (I) is not a cyano-3(6-(4-hydroxycyclohexylamino) benzo-2-yl] oxazolo[l,5-a]pyridine, a cyano group- 3-[6-(4-hydroxycyclohexylguanidino)pyridin-2-yl·|Bizozolo[l,5-a]pyridine, cyano-3-[6-(N-ethyl-N -(4-hydroxycyclohexyl)amino)pyridine 36 201130839 -2-yl]° than spit [l,5-a]%b bite, 5-ranyl-3-[6-(Brigade π--4 -Amino)atbbit-2-yl]ntbσ sits and [1,5-a] ° 唆, 5-cyano-3-[6-(methyl(piperidin-4-yl)amino) Acridine-2-yl p-pyrazolo[l,5,a] mouth bite, 5-ranyl-3-[6·(1-(2-) aryl-aryl)-3-chen-3-yl Amino)0 is more than bite-2_yl]1^salt[l,5-a]° than bite, (0-5-cyano-3-[6-(l-(2-cyanoethyl)) Piperidin-3-ylamino). More than biti-2-yl]π than salivation [l,5-a]n ratio bite and (and)-5-disorder -3-[6-(_/V ~曱基-1 -(2-乱基乙基基)派咬-3-ylamino)ππσ-2-yl]π 嗤[1,5-a]e ratio bite, and above a salt of the compound; and 3-[6-(1_methyl-methylpentylamino)π-pyridin-2-yl ptb11 sits and [l,5-a]0-pyridyl, 3-[6-(4 - 曱 旅 旅 -1- -1 base) ° ratio bite-2-base] 11 ratio And [l,5-a]n is more than pyridine, 3-[6-(3-carbamic hexylamino) 1* is 0-but-2-yl] 11 to 0 and [1,5-&] '1 than bite, trans-3-[6-(4- 基 ί 己 - - _ / V 曱 曱 )) bite-2-yl] ntb 〇 sitting and 3-[6-(1 - ethoxy派 咬-4-ylamino) π than bit-2-yl]π ratio σ sits and [1,5-3.] °fcb' tii Γ*· trans-3-[6-(4-amino group Cyclohexylamino)acridin-2-yl; hboxazolo[l,5-a]acridine, trans-3-[6_(4·trans- succinylamino) σ ratio bit-2_yl]^ Sitting σ and [1,5-a]0 to 37 201130839 pyridine, 3-[6-(tetrahydro-4//-piperidin-4-ylamino)pyridine-2-yl]pyrazole ji[ l,5-a] 0 than bite, H6-(N-methylcyclohexylamino) 吼 bit_2_ carbazole and [uyti pyridine, 3-[6·(3-hydroxymethylpiperidine· Io_yl)pyridine·2_yl]pyrazolo[ua]pyridine, 3_[6_(1-methylpiperidylamino)πpyridin-2-yl]pyrazolo[l,5-a] 〇, 3-[6-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo[l,5-a]° pyridine, 3-[6_(2-Phenylpropylamino)pyridin-2-yl]pyrazolo[ya]pyridine, 〇S>3-[6-(l-phenylethylamino)npyridin-2-yl]pyridinium Zoxa[ya]pyridine, 3·[6_(ι-benzylamino)pyridin-2-yl]pyrazolopyridine , (7)-ΗΗ1·cyclohexylethylamine))pyridyl]pyrazolo[l,5-a]pyridine, 〇S)-3-[6-(l-methoxypropan-2-ylamino) Pyridin-2-yl]pyrazolo[l,5-a]n is more than Ding, 3_[6-(methylamino)acridin-2-yl]pyrazolo[ιχpyridine, 3_[6_(aniline) Acridine-2_yl]pyrazolo[l,5_a]pyridine, H6 decapyridyl-3-ylamino) acridine-2-yl]pyrazolo[丨,5々]pyridine, 3- [6-(Bite _4_ylamino) D is more than 唆·2, ki]D is oxazolo[Ua] pyridine, anti-3_[6-(4-aminocyclohexylamino)acridine_ 2-yl]_5·cyanopyrazolo[l,5-a]nbipyridine, 5-cyano-(5>3-[6_(1·phenylethylamino) 吼24·η] And [i,5_a] 38 201130839 〇 咬,5-乱基-3-[6-(4-pyridinyl)ntb bit-2-yl]ntb 0 并[l,5-a] 0 Specific bite, 5-acyl-3-[6-(N-fluorenyl-(3-light-ylpropyl)amino)° 咬-2-yl] 匕π匕[1,5-a 1^Bite, 3-[6-(3-Aminocyclohexylamino)acridin-2-yl]-5-cyanocarbazolo[l,5-a] 0 ratio bite, 5-cyano group -3-[6-(N-fluorenyl-N-(2-methylamino)ethylamino) acridine-2-yl] oxime [1,5-3]° ratio bite, 5-disorganized -3-[6-((1-ethoxylated) brigade-3-ylamino)π ratio -2-yl] 0 is sitting at 0 and [1,5·^]σϋσ, 3-[6-(2-aminoethylamino) acridine-2-yl]-5-cyanocarbazole [ 1,5-a] mouth bite, (6)-5 - chaotic base-3-[6-(2· 曱 π π 唆 唆 唆 - -1 - base) 0 ratio bite-2-yl] π ratio 0 Sit and [l,5-a]%b bite, (and)-5-disorganized-3-[6-(2-carboxy pi-pyridyl-1-yl) σ-bit-2-yl] ° sits at 0 and [l,5-a]n is more than bite, 5-disorganized-3-[6-(7V-ethyl-N-(4-ylbutyl)amino) π ratio bite-2 -Based on ° ° ° and [l,5-a]n than bite, 5_ disorder base _3-[6-(3-pyridylamino) ° bite-2-yl]ntbπ sit and [l ,5-a] Πbite, (S)-5-disorder-3-[6-(1-(ethoxy group) 〇 σ -3- -3-ylamino) π ratio bite-2_ anti- 3-[6-(4-Ethylaminocyclohexylamino)pyridin-2-yl]pyrazolo[1,5-a] 39 201130839 Debbie, anti-3-[6-(4-A Continuation of the amine group J hexylamino group) ° ratio π -2- group] ° ratio σ sit and [1,5-a] 0 than the mouth, 3-[6-(3-(2- side oxygen (pyridin-1-yl)anilinyl) "pyridin-2-yl; hoxazolo[l,5-a] mouth bite, 3-[6-(Ν-ί^_hexylamino)比 ° -2- 基 基 基 基 ° ° ° [ [ [ [ [ [ [ [ [ [ [ 1 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 -based p-pyrazole [l 5-a] 0 is more than bite, 3-[6-(4-ethylaminophenylanilino)α is more than 1,4-yl]ntb β sits and [1,5-a]σ ratio bite, 3-[ 6-(3-Ethylaminoanilino)ntb sigma-2-yl]° ratio σ sits and [1,5-3·]0 ratio bite, 3-[6-((3-mercaptocarbonyl) Anilino) acridin-2-yl]oxazolo[1,5-a] 0 is a bite, 3-[6-(3-hydroxyphenyl-N-nonylamino)pyridin-2-yl]" Bisazo[1,5-ap is pyridine, 3-[6-(Ν-ί^_propyl-ylamino)0 is more than σ-but-2-yl]0 than σ sits[1,5-a 0-pyridine, (S)-3-[6-(l-phenylethylamino)-piperidin-2-yl]-5-hydroxydecylcarbazolo[l,5-a]D ratio bite, 3 -[6-(Big -4-amino-amino) π is more than -2-yl]. Sit and [1,5-a] σ than bite, 3-[6-(tour 唆-4-ylamino) ° bite-2-yl]-5-rebel π ratio α sit and [ 1,5-a] 0 is more than bite, 3-[6_(1_乙乙基基π定-4-ylamino)0 is 0-but-2-yl]σ ratio σ sits and [l,5-a ] 201130839 〇 咬, 5-N-mercapto-3-[6-((1·乙乙基)派味-3-ylamino)° 咬-2-基]η比唑和[l,5- a] pyridine, (S)-5-amino-3-[6-(bunk-3-ylamino)π-bit-2-yl]pyrene[l'5-a]nit^. The compounds of formula (I) may also contain no salts or solvates of such compounds. The above compounds are disclosed in WO 2010/072823. In general, the compounds of the formula do not comprise the compounds disclosed in WO 2010/072823, including the salts, solvates and stereoisomers disclosed therein. For example, a compound as defined herein may not comprise a compound of formula (I) below, wherein

Ri, R2 and R_4 each represent a hydrogen atom; W represents a -CR3 group; Z represents a group -NR5; X, Y and T each represent a group -CR9, wherein R9 represents a hydrogen atom; R3 represents hydrogen, halogen, C! · 4 alkyl, halogen Q-4 alkyl, via Q_4 alkyl, R27-C1.4 alkyl halogen, cyano, -C(0)-NR24R24, -C(0)R25, -C(0 ) 0R25, -OR24, -S(0)2R25, -S(0)2NR24R24, -NR24R24, -NHCOR24, N(Ci_4 alkyl)COR24, _NHCONR24R24, alkyl)CONR24R24, -NHC(0)0R35,- NKm alkyl)c(〇)〇R35, -NHS(0)2R25, Ν((^_4烧-基)S(0)2R25 or Cy!, wherein Cyi is optionally substituted by one or more selected from R28 Substituent; R5 represents a non-wind I atom, a C1 _4 alkyl group, a halo C 4 alkyl group, a trans group C1-4 alkyl group or a Cm alkyl group which is substituted with a group selected from a cyano group, a trans group or a Cyi group ' 201130839 wherein the condition is substituted by one or more R28, for example, Rs may represent a hydrogen atom, a Cm alkyl group, a halogen Cm alkyl group, a hydroxy C 4 alkyl group or a R 27-CW alkyl group or Cy2, wherein Cy2 is optionally Or a plurality of R28 substitutions; the group -(CR6R7)m-R8 represents CM alkyl, Q.4 haloalkyl, hydroxy Cm alkyl, R2U-CM alkyl, -C〇NR2〇9R2〇9, -CO R210, -C(O)OR210, -S(O)2R210, -S〇2NR209R2〇9 or Cy3 ' wherein Cy3 is optionally substituted by one or more R212; or R5 together with R8 and the nitrogen atom to which it is bonded Forming a Cy4 group, wherein Cy4 is optionally substituted by one or more R212; each R24 independently represents hydrogen or R25; each R_25 independently represents Ci-4 alkyl, halo Ci-4 alkyl, C!-4 burning oxygen a Ci-4-alkyl group, a thio-Ci-4 group, a nitrogen-based Cl-4 group, a Cy!-Ci_4 alkyl group, or a cyi, wherein Cy! is optionally substituted by one or more R28; each R35 is independently Represents Ci-4 alkyl group, functional group Ci-4 alkyl group, C]-4 alkoxy Cm alkyl group, via group Ci-4 alkyl group, chaotic group C-4 alkyl group or CypCi_4 alkyl group, of which Cy! The case is substituted by one or more R28; for example, each R35 independently represents CM alkyl, halo CM alkyl, CM alkoxy CM alkyl, hydroxy CM alkyl, cyano Cw alkyl, CyrCM alkane Or Cyyi, wherein Cyi is optionally substituted by one or more R28; each Κ·28 independently represents Ci.4 alkyl, halo-Cl-4 alkyl, Ci-4 entertainment*oxy C--4 alkyl , base group Cw alkyl, cyano Gl-4 leuco, dentate or thiol; R27 represents cyano, -C(0)-NR24R24 , -C(0)R25, -C(0)0R25, -OR24, -S(0)2R25, -S(0)2NR24R24, -NR24R24, -NHCOR24, 42 201130839 -NCCm alkyl)COR24, -NHCONR24R24, -nCCm alkyl) CONR24R24, -NHC(0)OR25, -ΝβΜ 基)c(〇)〇R25, -NHS(0)2R25, alkyl)S(0)2R25 or Cy, where Cy! Substituted by one or more substituents selected from R28; each R2G9 independently represents hydrogen or R21〇; each R^O independently represents alkyl, halo Cm alkyl, hydroxy Cm alkyl, Rsu-C! Alkyl or Cys 'wherein Cy5 is optionally substituted with one or more substituents selected from R213; R211 represents halogen, cyano, -CONR214R214, -COR215, -c(o)or215, -〇R214, -so2R215, - S〇2NR2I4R214, -NR214R214, -NHCOR214, _N(Cm alkyl)COR214, -NHCONRu^wNCCm alkyl)CONR2hR214, _NHC(0)0R215, -N(Q-4 alkyl)C(0)0R215, -NHS (0) 2R215, ΝπΜ alkyl) S(0)2R215 or

Cys' wherein Cys is optionally substituted with one or more substituents selected from r213; for example, 'can mean halogen, cyano, _CONR214R214, -CORm, -C(0)0R215, -〇r214, -s〇2R2i5 , -0C0NR214R214, -S02NR214R214, _NR214R214, _NHCOR214, -NCCm alkyl)COR214, -NHCONR214R214, -NCCm alkyl)CONR214R214, -NHC(0)0R215, -N(CM alkyl)C(〇)〇R215,- NHS(0)2R215, NCCi-4 alkyl)S(0)2R215 or Cy5, wherein Cy5 is optionally substituted with one or more substituents selected from R2n; each R212 independently represents CM alkyl, halo Cm alkane Base, hydroxyl

Cl·4, RwCi-4 alkyl or r212 represents any of the meanings described for r211; 43 201130839 Each R2]3 independently represents Cm alkyl, Cm south courtyard, Ci·4 gas base (^- 4-alkyl, hydroxy-CN4 alkyl, cyano-Ci-4 alkyl, halogen, cyano, -CONR216R2I6, -COR217, -C(0)0R217, -OR216, -OCONR216R2I6, ·8(0)2Κ·217, _S〇2NR2i6R216, -NR216R216, -NHCOR216, -NCCm alkyl)COR2i6, -NHCONR216R216, -N(CU4 alkyl) conr216r216, -nhc(o)or217, -N(C!.4^ base)C(0) 0R217, -NHS(0)2R217, alkyl)S(0)2R217; each R214 independently represents hydrogen or R215; each Rm independently represents a CM alkyl group, a halogen group c-4 alkyl group, a CM OH group Q_4 An alkyl group, a hydroxyCl.4 alkyl group, a cyanoCi 4 alkyl group, a Cy5_Ch alkyl group or a Cl, wherein Cys is optionally substituted by one or more r213; '4 each Rm independently represents hydrogen or R217; Independently representing C1-4 alkyl, haloCu4 alkyl, c, ridge

201130839 Unsaturated or: a two-membered single-ring or 8- to 12-membered bicyclic ring is saturated, partially self-looped, and optionally contains from 1 to 4 heteroatoms bonded to eight*, wherein the ring Through any available c original full, = the rest of the knife, and one or more of the c*s ring atoms are oxidized as appropriate to form a co, s〇 or s〇2 group; 'S clothing atom

Cy4 is not saturated or partially unsaturated. 3 to 7 members 罝戸Mi® ', medium Cy4 contains a total of 1 to 4 heteroatoms independently selected from the sub-products, brothers; and Cy4 Multiple c or s atoms are oxidized to form CO, so or s〇2 groups; and no 3 to 7 membered monocyclic or 8 to 12 shelled bicyclic rings are saturated, partially or aromatic carbocycles, and depending on the situation Contains 〖 to 4 I county, where the ring is via any two. Shielded in the remainder of the molecule, and one or more of the C or S ring atoms are optionally oxidized to form a C〇, SO or S〇2 group, as well as salts and solvates of such compounds, especially for such compounds Salts, solvates and stereoisomers. Usually, the compound of formula (I) is not H4-[4-[(5-gas-4" is more than 嗤[!,5♦ than bite_3_yl_m2)amino]-3-methoxy Keto-phenyl] brigade small base] ethyl ketone; 5-gas-N-(2-decyloxy-4 tetradecazinyl) phenyl) _4_ (such as sitting and [to] π ratio bite -3- Base) shouting π定_2_amine; ' 1-[4-[4-[(5_气-4-吼w and bite ·3· base, bite · 2 · group) amine group]-3-A Oxy-phenyl]piperazine small group]_2_hydroxy-ethanone; 45 201130839 (2R)-H4: [4_[(5_qi, such as sputum and (1) (10) (four) winter base, squeaky 2-base) amine group] -3-methoxy-stupyl&gt;Chenzin-1-yl]_2_hydroxy·propyl_丨_嗣; (2S)-l-[4_[4mt sitting and D'5 external peak 3_based ♦ -2_ yl)amino]_1 2 3 methoxy-phenyl]pyridin-1-yl]-2-hydroxym 1- [4-[4-[(5- -4-pyrene) 5♦ 比 基 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 5- Qi 4-吼 并 [1,5 ♦ _ _ _ _ _ _ _ _ _ _ _ _ 胺 胺 ) ) ) ) ; ; ; ; ; ; ; ; ; ; ; ; (2S) small (3·(4_(5·gas-4-(t sitting and [1,5 outer (tetra) _3·yl))) 2·ylamino)-3-decyloxyphenyl)azacyclo Butane_1_yl)_2_hydroxypropanthene-ketone; (2R)-l_(3-(4-(5-gas-4) Sit more than α and [small bite _3 base spicy bite 2_ ylamino)-3-methoxybenyl) azetidinium _ι_yl)_2_pyridylpyridinium 5-chloro-v·[ 2·methoxy-oxyl phenyl]=pyridin-3-yl-pyrimidin-2-amine; 46 1 [4-[4-[(5·chloro-4·« is more than saliva[l,5- a] «Bist -3-yl-Bistyl-2-yl)amino]-3-decyloxyphenyl]-l-α-bottomyl]-2-yl-acetazin; (2R)- 1-[4-[4-[5-Ga-4-pyrazolo[l,5-a]pyridin-3-yl H2.yl)amino]-3-methoxy-styl]·1- η 咬 ] 】 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _辰咬基]·2·经基-丙小酉同; &quot;5-气-Ν-(2-methoxy-5-0chens-I-yl-phenyl)-4-ni4..e Sit and [i,5_a] 0 than bite 3-base-penetration-2-amine; 2 [4-[(5-gas-4-.biazole[1,5-a]pilot]3 -yl-pyrimidine-2-yl)amine 3 yl]_3.methoxy-phenyl]propane-1,3-diol; 201130839 5-气_Ν·[2-曱oxy-4-(9 -oxa-3,7-diazabis 3 _7-yl)phenyl]pyrazolo[Ha]pyridine_3· pyridine amide Iamine; HH3-[(5-gas such as azole and ♦比 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Η4-[3·[(5-Ga-4-pyrazolo[ua]pyridine_3_yl-pyridin-2-yl)amino H-methoxy-phenyl]piperazine·1_yl]_2 Indole-based ethyl ketone; Ν-[3-[(5-Ga-4-pyridino[ua]pyridine-3-yl-acridin-2-yl)amino M-decyloxy-phenyl] 2-mercaptoamine)acetamide; ΗΗ(5-piperidazole[丨^pyridine_3_yl-pyrimidin-2-yl)amino]_5_decyloxy, porphyrin-1-yl]B Ketone; N-(5-chloro-4-pyrazolox,5_a]pyridine_3_yl-pyrimidine_2-yl-π哚哚琳-6-amine; 1 [6 [(5~;iL- 4-Di: bn sitting and [ΐχ π 咬 咬 - 喷 喷 喷 喷 喷 喷 胺 胺 胺 胺 胺 胺 胺 胺 胺 ] 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 5· gas-d sit and [1,5_a] bite _3_ base_spray bite 2 base) amine]_5-methoxy·tidelin·1 _ group] 2 aryl methylamino) ethyl ketone; 1-[4-[3-曱-oxy-4-[(5-fluorenyl_4_π is 嗤[i,5_a]D than bite_3_yl_ spur-2-yl)amino]phenyl ] dispatched small base] ethyl ketone; N-(2-methoxy-4-ylpiperazine 4_yl-phenyl)·5-methyl·4_pyrazolo-U,5-a]pyridine-3- Base-pyrimidine-2-amine; 1·[4-[3-methoxy-4-[5-methyl_4_r-free][i,5-a]n ratio bite_3_base_bite- 2·amino)amino] stupid] π 嗓 嗓 small base] _2 · (methylamino) Ketone; 2-[4-[3·decyloxy_4-[(5-fluorenyl_4-n ratio spit [l,5-a&gt; than bitten-3-yl-sneeze-2-yl) Amino]phenyl]pyrene]_yl]ethanol; 201130839 N-[2-decyloxy-4-(4.piperidinyl)phenyl]-5-indenyl-4-pyridyl ,5-a]wi:b^-3-yl-mouth β定·2_amine; 2-mercapto-1-[4-[3-曱oxy_4-[(5-methyl-4-) ° 嗤 and [i,5_a]nJ^ -3--3---bisting bit>2-yl)amino]phenyl]]-indenyl]ethanone; (2R)-2-hydroxy-1_[ 4·[3-曱-oxy_4-[(5-fluorenyl-4-pyrazolo[LSa] phenanthrenyl-purine 2·yl)amino]phenyl]丙小_ ; '(2S)-2-hydroxy-l_[4-[3-methoxy_4-[(5-fluorenyl·4·pyrazolo(1)孓... 口 各 各 - 痛 痛 痛 痛 痛 痛 痛2·ylamino]phenyl] succinctyl] propyl ketone; 'N-(2-decyloxy-5-piperazine·1_yl-phenyl)_5_indolyl [l,5-a]pyridin-3-yl, pyridine·2·amine; 1_[4-[4-methoxy_3-[(5-fluorenyl-4-). Bisazo[i,5-a]pyroo_3yl-pyrimidin-2-yl)amino]phenyl] 嗓_1_yl]_2-(methylamino)ethanone; Η5-methoxy- 6-[(5-fluorenylpyrazolo[l,5-a]pyridine_3_yl_cough-2-yl)amino]0 bowbendene·ι_基]ethyl ketone; 2- (Dimethylamino)-1-[5_decyloxy_6_[(5-methyl such as carbazolo[D a] 0 is more than -3-yl-carcinogen-2)-amino).哚哚琳_ι_基] Ethyl ketone; 1_[4-[4-[(5-fluoro-4-t sitting and [ΐ,5-φ ratio bite_3_基_唆唆_2•)) amine 5-yloxy-phenyl]oxazinyl-i]ethyl ketone; 5-fluoro-indole-(2-methoxy-4-ylpiperazine-fluorenyl-phenyl)_4·吼 并 0 比 比 基 基 基 基 基 基 基 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Oxy-propenyl] π-tinazine small group]·2_(decylamino)ethanone; 5-fluoro-indole-[2-methoxy winter (4_Benbityl)phenyl]-4" than saliva And 0 is more than 3-amino-ring--2-amine; 48 201130839 5-fluoro-indole-(2.methoxy-5-anthracene small-phenyl) such as azole and like-a] ° Than -3-yl-penetration-2-amine; '2_(dimethylamino)-1-[6-[5-fluoro Ipyrazoloindole, 5_φ pyridine _3· base mouth bite_2_ Amino] _5_methoxy- Π 哚 _1 _1 _ _ ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke Heterobicyclo[3 3"]壬_7·yl)phenyl]_4_pyrazolo[l,5_a]pyridine_3_yl-pyridin-2-amine; chloro_4_pyridox[l,5 -a]pyridine-3·yl-pyridinyl)aminol·3·methoxy-phenyl]methyl]propane-1,3-diol; 2-[4-[4-[(5 - gas-4-oxazolo[l,5-a]pyridine-3-yl, pyridyl)aminomethoxy- Phenyl]pyrazine-1-yl]_2-methyl-propanol; 2-[4-[3-methoxy-4-[(5-methyl-4-hydrazino[i,5- a]n ratio bite_3_yl-pyrimidin-2-yl)amino]phenyl]piperazine small group]_2-methylpropanol; 1_[4-[3-methoxy-4-[(5 _Methyl-4-hydrazone [l,5-a]° than -3-yl- _ 喷 _2 _ _2 _2 ) 胺 胺 胺 ; ; 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- [4-[(5-Cyclopropyl-4-pyrazolo[l,5-a]pyridine-3-yl-pyridin-2-yl)3⁄4yl]_3_methoxy-phenyl]0辰η秦·1_基]乙嗣; 2-(dimethylamino)-1-[4_[4-methoxy-3-[(5-methyl-4-pyrazolo[1,5- Smaller than -3-yl. Mouth-2-yl)amino]phenyl]α underpinyl] ethyl ketone; 1-[4-[3-methoxy-4-[(5-methyl) 4-pyrazolo[1,5-a]pyridin-3-yl-pyridine-2-yl)amino]phenyl]_1_0 henyl]] 2_(decylamino)ethanone; 1- [4 -[4-[(5-fluoro-4-n-biazolyl-1,54pyridine-3-yl-pyrimidin-2-yl)amino]-methoxy-phenyl]-1-piperidine 2-[4-(1-Ethyl-4-piperidyl)_2-nonyloxy-anilino]-4-pyrazolo-U,5-a] Bite-3-yl-penetration·5-carbonitrile; 49 201130839 2-[4-[l-(2-Pyridinyl)-piperidinyl]_2_decyloxy-anilino]-4 -&quo t; 嗤[1,5-a]pyridine_3_yl- </RTI> </RTI> _5_phthalonitrile; and pharmaceutically acceptable salts thereof. Such compounds are generally not included in the scope of the invention for the following uses: for the production of antiproliferative effects in humans or animals; for example for the treatment of insulin-like growth factor alone or in part IGF-1R) a tyrosine kinase-mediated disease or medical condition; for example, for preventing or treating a tumor that is sensitive to inhibition of insulin-like growth factor-丨 receptor (IGF_1R) tyrosine kinase, which is involved in causing a tumor A cell transduction step for cell proliferation and/or survival; for example for the treatment of cancer. When used in combination with methotrexate, such compounds are generally not included in the scope of the present invention. The above compounds are disclosed in WO 2010/049731. In general, the compound of formula (q does not comprise the compound disclosed in WO 2010/049731, including the salt disclosed therein. Typically, the compound as defined herein is not a compound of formula (1) and a pharmaceutically acceptable salt thereof: 〃 -m is 〇; • Z is NH; -W is CRlb'; -X is, CR2 'wherein R2 represents a halogen atom, a cyano group, a trifluoromethyl group, a cyclopropyl group or an unsubstituted CrC3 alkyl group; -Y is CH; _ T is a nitrogen atom; 50 201130839 -Ri and Κ·2 are both Η, -R4 is Rla; -R8 represents the following part:

(R4,)q' wherein R3' represents a trans, cyano, halo, (Ci-C6) alkyl, (C1-C4) methoxy, (CrC4) haloalkyl or (CrC4) hydroxyalkyl • Each R4′ may be the same or different and is selected from the group consisting of a thiol group, a cyano group, a halogen group, a decyl group, a carboxyl group, a (C“C6) alkyl group, a (CrC4) alkoxy group, and a (C2-C6) alkano group. (CVQ) alkoxycarbonyl, (c3-c7)cycloalkyl, (C3-C7)cycloalkylcarbonyl, amine, (Q-C6)alkylamino, bis[(CrC6)alkyl]amino Aminyl, (CrQ)alkylamine, mercapto, bis[(CrC6)alkyl]amine sulfhydryl, sulfonyl, (q-C6)alkylamine sulfonyl, bis[(crc6) Alkyl sulfonyl, -S(0)mtR' (wherein R' is selected from hydrogen and ((^q)alkyl and m represents 〇, i or 2), -N(R,')C (〇)R, (wherein R' is as defined above and R&quot; is selected from hydrogen and (CVQ)alkyl) and -XQ (wherein χ is a direct bond and q means at least one selected from the group consisting of nitrogen, oxygen and sulfur a saturated heterocyclic ring of 5, 6, 7, 9 or 10 members of a heterocyclic ring), 8 R4 groups together with a nitrogen, oxygen and sulfur ring heterocyclic ring to which they are attached, each group in r4 or Two on adjacent carbon atoms The anti-atomic atoms together form at least one saturated or unsaturated monocyclic ring selected from atoms 5 or 6 members. The ring may be optionally substituted with one or more substituents independently selected from the group consisting of: a base group, a dentate group, Gas radical, mercapto, carboxyl, (Crc6) alkyl, (c3_C7) ring, (CrC7) cycloalkylcarbonyl, (CrC6) alkoxy, amine, (Ci_c6) alkylamine, two [ (Crc6)alkyl]amino, (c2-c6)alkylhydrazine, (CrC6) azoxy, amidyl, (CrC6)alkylamine, bis[(Cl_c6)alkyl]amine Alkyl, sulfonyl, (rcc6)alkylamine sulfonyl, bis[(crC6)alkyl]amine sulfonyl, -S(0)m, R' (wherein R, and m, each as above As defined herein, -N(R'')C(〇)R' (wherein R, and R" are each as defined above) and -XQ (where X and q are each as defined above), any of The substituent may optionally be selected from one or more selected from the group consisting of (Crc4)alkyl, (Ci_c4)alkoxy, hydroxy, yl, cyano, thiol (Crc:4) alkyl and -XQ, (wherein X As defined above and Q' denotes saturation of at least one ring nitrogen atom 5 or other substituents of the heterocyclic ring); and • each RU' and Rlb· may be the same or different and are selected from the group consisting of hydrogen, halo, cyano, (CrQ)alkyl, amine, (cvq)alkyl The amine group and the bis[(Ci Q)alkyl]amino group, each of Rla and Rlb may optionally be selected from one or more selected from the group consisting of a trans group, a halo group, a cyano group, a (Crc6) alkyl group, Crc4) alkoxy, aminyl, (crc6)alkylamino, bis[(CrC6)alkyl]amino, (wherein R' and R" are as defined above) and saturated monocyclic 5, 6, 7 or The 8-membered ring (which optionally includes - or a plurality of substituents independently selected from nitrogen, oxygen, and sulfur) is substituted. 'These compounds are generally not included in the invention for the following uses: they produce antiproliferative effects in human or animal tissues; for example, for treatment alone or in part by the Tengda-like growth factor receptor (IGF_1R) 52 201130839 疾病 敝 敝 对 对 对 对 对 对 对 对 对 对 对 对 对 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制 抑制: Tumor cell proliferation and/or survival: for example, for the treatment of cancer. When the compound of the invention (4) is coated with a compound such as a succination, this is usually 'in the compound of the formula (1), R1 represents a hydrogen atom, a hydroxyl group, a cyano group, a linear or branched bond CrQ, and a sulphate. CVQ is calcined, C3_Cl〇 cycloalkyl 4_NR, R,, a group; ^ self-burning group, == and each represents a nitrogen atom, a linear or branched chain, and a group, crc4 4 alkyl or Ci&lt;;4 Hydroxyalkyl; 1 c6 alkane R2 R3 and R4 are the same or different and each represents a hydrogen atom, a thiol group, a cyano group, a linear or branched chain CrC6 alkyl 4-hydroxygen CVC4 hydroxyalkyl group or a c3_Ci() cycloalkyl group; alkyl,

Rs represents a hydrogen atom, a straight or branched chain Crc6 alkyl group, a phase or a substituent selected from the group consisting of a cyano group, a cyano group, a C1_C4 fluorenyl group, a C1 C3-C1G ring wire; or &amp;&amp; 4/fluorenyl or a nitrogen atom-yarn into a 5 to 9 贞 saturated transyl group containing a nitrogen atom as a hetero atom and the heterocyclyl ring is taken or two -C(〇HCH2) n_R group or _c(〇MCH2)n_NR, R,, group or hydroxy η is 0, 1 or 2 'R represents a hydrogen atom or a straight or branched chain A wherein Ci~4 is a halogen group, C1-C4 A thiol or a cyano group and r* and pj, each of which represents a hydrogen atom, a straight chain or a branched Wrc6 alkyl group or a CrC4 hydroxyalkyl group; the radicals R6 and R7 are the same or different and each represents a hydrogen atom ,直链戈八53 201130839 chain cvc6 alkyl, CrC4 _ alkyl or Ci_C4 hydroxyalkyl; R9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain CVCg Hyun, base, crc4 _ 炫, C"C4 is a calcinyl group, a 5 to 1 member heterocyclic group or a 5 to 10 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group are unsubstituted or one or more selected from a halogen atom, a linear chain Or branching key CrC6)^ base, cyano group Substituted with a substituent of a hydroxy or CrC4 alkoxy group; or R9 represents a -C(0)-〇-R. group or a -C(〇HCH2)n-NR'R" group where η is 〇, i or 2, and R· and Rn are the same or different and each represents a hydrogen atom, a linear or branched chain CrC6 alkyl group, a CrC4 dentate group or a CrC* hydroxyalkyl group; or in the presence of two adjacent -CR9 groups The two adjacent -CR9 groups and the carbon atoms to which they are bonded optionally form a C6_C1() aryl group which is unsubstituted or which is pyrolyzed by one or more selected from a halogen atom, a linear or branched chain crc6. Substituted by a substituent of a radical, a thiol or a crc4 alkoxy group; R8 represents a hydrogen atom, a straight or branched chain CrC6 alkyl group, a CrC4 haloalkyl group, a CrC4 hydroxyalkyl group, a C3-C1() cycloalkyl group, a C6-C1 group () aryl, 5 to 10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, fluorene and S, containing 1, 2 or 3 heteroatoms selected from n, fluorene and S To 10 member heterocyclic group '-L-Het-R,", _l_A, -AS〇2-R,, -A-SO-R'&quot;,-A-A', -ALC(0)NR'R&quot ; , -AL-CN » -AC(0)-Het'-L-CN &gt;-AC(0)-NRfR&quot;&gt; -AC(0)z-AM &gt;-AC(〇)-R&quot;* » -A-C02-R' » -A- C(0)zLA"',, A_C(9)z_L_R&quot;,, (9)z_L_CN or -AC(0)zL-Het_R' groups, wherein z is 1 or 2, R, and R, are the same or different and each represents a hydrogen atom or a straight Chain or branched chain CrC6 alkyl, CrC4 dentate or CVQ hydroxyalkyl, and R," represents a straight or branched chain Ci_c^ 54 201130839, CrC4 dentate or cc optionally combined with phenyl, and 4 Heterocyclyl as well as heteroaryl and heteroaryl unsubstituted or sub-base, heterocyclic, aryl-based, straight-chain or sub-nuclear atom, spectroscopy, aryl, and wherein rc or alkoxy The substituent is taken as a linear or branched chain CrC6 extension group.

Het denotes 〇 or NRIV, and this means _, :: direct key or branch 〜 base, Ci 依基或c, _c= A, A', A'' and A"' are the same or different and each table base, 5 to Η) member heterocyclic group, C6_Cl. aryl or 5 to; 〇 = courtyard, cyclofilament 'transalkyl, aryl and heteroaryl are not selected from the atom, the base, the cyano group, Substituted by a linear one, or a substituent of a base or a CVC oxy group. The knives are ^ ^ ΐί ^l〇XZkc: a gas or an R" group; wherein R' and R" are the same d

Table (4) Atomic, linear or branched chain CrC channel J

CrC4 hydroxyalkyl, and R丨, r2, &amp;, ~, R, 丨4 4 alkyl or

Het, A, A', AM, and A'" are as defined above. 6 7, R8, L,

Preferably, in the compound of formula (I), Z is NR I represents a hydrogen atom, a straight chain or a branched chain crc6: ^x /,

Cycloalkyl, phenyl or 6-membered saturated with N 55 201130839 R5 represents -S(O)2R10 group, _s(〇)2NRi〇R]i group, _c〇R川 group, -C(〇HCH2) An n-RI0 group or a _c (0&gt;(CH2)dRn group, wherein 1 〇, 1 or 2 and Ri 〇 and Ri are as defined above. Generally, in the compound of the formula (1), Y represents a -CR9 group. Typically, in the compound of formula (1), τ represents a code group. Preferably, the ecchymosin represents a _CR9 group. Typically, in the compound of formula (I), at least one of χ, γ and τ ( Preferably, at least _ of X and γ represents Ν. and ?L(I-)= γ in the compound may represent Ν ' In the above case, χ and Τ each represent a -CR9 group. U.S. R8 represents a 5- to 7-membered heterocyclyl-substituted substituent having a nitrogen atom as defined herein. When the field is not N and Rs represents 5 to 7^ of a nitrogen atom, the impurity a ring group is a brigade substituted with one or more substituents selected from the group consisting of a ring substituted at least on a ring nitrogen of a dentate group, said substituent: a straight or branched chain Crc3 alkyl group; a halogen atom; The money base is unsubstituted or has one or more nitrogen groups Generation, -1,2,4-triazolyl; and ... C (〇MCHW' group, wherein η is 0 or i and R, is cyano, 56 201130839 alkyl, (tetra) or (iv) cycloalkyl. In the compound of Cyanide A. (1), R1 represents a hydrogen atom, a halogen-branched chain of CrC6, a group derived from Wei-ki or a bond, and a bond of "two and R" is the same or different and each represents a hydrogenogen*, a linear chain Or: i-C6 alkyl, CrC4 haloalkyl is preferably a 2 group; R1 纽 represents a hydrogen atom. 虱 atom or sub, =m(i) compound, 'heart indicates nitrogen atom, dentinogen or straight seam or Branching bond; R = , often 'in the compound of formula (1), R3 represents a hydrogen atom: preferably: a group: a straight chain or a branched chain (10) group or (8) a: a germanium atom, a minus or a straight chain or a branched chain c "c It is not a wind atom or a cyano group. y, in the compound of formula (1), K represents a nitrogen atom, a south primordyl 2 chain or a branched chain crQ alkyl group or a (iv) cycloalkyl group, · R4 t ί residue or lang Or a branched chain crCj group; &amp; more preferably represents a wind atom. +, in the compound of formula (1), Z4NR5 and R5 represent a hydrogenogen, a chain or a branched chain crc4 silk 'as the case may be - or a plurality selected from the i-generation ClRQ= The radical of the f^?r(:4· or C3_C7 hetero group It is not a hydrogen atom or a linear or branched bond C, a -C3 alkyl group; r5 preferably represents a hydrogen atom. 5 Generally, in the compound of the formula (1), & and R? independently represent hydrogen 57 201130839 Atom or linear or Branched chain CrC6 alkyl group and preferably independently non-hydrogen atom or linear or branched chain Crc3 alkyl. Table Generally, in the compound of formula (1), R8 represents a straight bond or a split ' ', (d)-based 'CrC4 ship base, CrCl. Wei Ji, kc: Heteroaryl 1η3 is selected from n,. The 5° to the heteroatom group '3 of the hetero atom has 2 or 3 5 to 10 membered heterocyclic groups selected from N, fluorene and an atom, -L-Het-R",, -LA, -a A, —,' _A_L_CN :; -AC(〇)Tear R&quot;,-A_C(0)z_a",_A_(10)_R„,,_a cqCNr| 广(0)必&quot;,-a_c(o)心 or _A_C( 0) a zL-Het-R' group, wherein z is j or 2, R, or different and each represents a hydrogen atom or a straight or branched chain CrQ filament, cc° or Cl_c4m group 'and R''' indicates straight a chain or branched chain η(tetra) or CrC4, said heterocyclyl and heteroaryl, as appropriate, and phenyl, and wherein said cyclo, heterocyclyl, aryl and heteroaryl are unsubstituted or Or, or a plurality of selected from the group consisting of: ^ 轩 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Branched chain CrC5 stretched; L is more preferably a linear or branched alkyl group. I 3 hangs, Het represents 〇 or NRIV and Het' represents NRIV, where riv is a hydrogen atom or a straight or branched chain CrC4 alkyl group, It is preferably a hydrogen atom or a linear or branched CrC2 alkyl group. Het preferably represents hydrazine. 58 201130839 Usually, A A', A'', and A," are the same or different and each represent a C3_C6 cycloalkyl group, a 5- to 6-membered heterocyclic group, a stupid group, a 5- to 6-membered heteroaryl group, the cycloalkyl group, a heterocyclic group, The phenyl and heteroaryl groups are unsubstituted or substituted with hydrazine, 2 or 3 dentate atoms or hydroxyl groups, cyano groups, straight or branched chain CrC2 alkyl groups or Ci_c alkoxy groups. 2 hanging, A is a 5- to 6-membered heterocyclic group, a phenyl group or a C3-C6 cycloalkyl group, the heterocyclic group, a phenyl group and a cycloalkyl group are unsubstituted or 2 or 3, preferably 1 Or 2 halogen atoms or a hydroxyl group or a Ci_C2 alkyl group. Preferably, A is piperidinyl, phenyl or cyclohexyl, and the piperidinyl, phenyl and cyclohexyl groups are unsubstituted or substituted by a halogen atom or a hydroxyl group or a Ci_c2 alkyl group. ^通十, A' is a stupid or 5- or 6-membered heteroaryl group, and the phenyl group and the heteropoly group are unsubstituted or substituted by 2 or 3 halogen atoms or a cyano group, a via group or an if2 alkyl group. Preferably, A, is a phenyl group, is a 5- or 6-membered heterocyclic group which is unsubstituted or has 1 or 2 halogen atoms or a cyanate oxime. , cyclofilament or 5 or 6 j, the heterocyclic group, the ring-based group and the heteroaryl group of the earthy earth are unsubstituted or substituted by 3 or i atom or cyano group, via a group or a burnt group. More Yin A is a pyrrolidinyl group, a cyclopropyl group or a pyridyl group, and the pyrrolidinyl group, the fluorenyl group, and the unsubstituted unsubstituted neon or 2-ary atom or gas group are 5 to 6 members of the heterogeneous green The aryl group is unsubstituted or substituted by ke================================================================================================= C4 haloalkyl 'Crc4 alkyl, cycloalkyl, CVc10 aryl, 5 to 10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, oxime and ^, containing 1, 2 or 3 5 to 10 membered heterocyclic groups selected from heteroatoms of N, fluorene and S, _L-Het-R, &quot;, _l_a, -AA' » -AL-CN » -AC(0)-R,m , -AC(0)zL-R'&quot; -AC(0)zL-CN, or -AC(0)zL-Het-R' group, where 2 is 丄 or 2 and R... represents a straight or branched chain QC: 3 alkyl, Cr (: 3 haloalkyl or ^- hydroxyalkyl, and wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are substituted or one or more selected from the group consisting of Substituted by a substituent of an atom, a cyano group, a cyano group, a straight bond or a branched chain of a CrC6 alkyl group or a CrC4 alkoxy group, and wherein it is a linear or branched chain CrC3 alkyl group, eight

Het represents 〇 or NRiv 'where Riv is a hydrogen atom, a straight bond or a bond C1-C4 alkyl group, a C1-C4 haloalkyl group or a crC4 galvanic, A and A, the same or different each represents a CrCiG ring-burning base heterocycle a group, a Q-Cl0 aryl group or a 5-fluorene heteroaryl group, a heterocyclic group, an aromatic silk, and a heterocyclic green unsubstituted or via an azinc atom, a thiol group, a cyano group, a straight bond or a branch bond Ci·^ Substituted from a substituent of the (d) group. Soil or C丨·Q alkoxy is preferably 'in the compound of formula (I),

CrC6 alkyl, CrC4 dentate alkyl, G c ', linear or branched 2 or 3 substituents selected from N, 0 and S heteroatoms '3 have 1, base, containing 1, 2 or 3 From N, 〇 and s to 6 members of the monocyclic heteroaryl heterocyclic group, or - (CHAOR group, the hetero atom of 1 is 5 to 7, (4) 〇 or 1 and the ruler indicates 201130839 linear or branched chain ca burning a group or a Cl_C4 halogen group; the (tetra) group, a cyclofilament, a phenyl group, a heteroaryl group, and a heterocyclic group or substituted with a plurality of substituents selected from Ra; and the burned soil is not substituted with 4 or Substituted at one or more substituents selected from the group consisting of; a substituent; a cyano group; a thiol group; a straight chain or a branched chain; a bromo group; a Crc oxy group; a C3 hydroxy group; 5, a plurality of substituents selected from the substituent Re; a phenyl group, which is substituted or substituted by "or more" from the substituent Re; ^ ϋ ϋ \3 Γ is selected from Ν, 〇 and s a 5- to 6-membered monocyclic ring of an atom, which is unsubstituted or substituted with one or more substituents selected from the substituent Re, which are unsubstituted or substituted with one or more substituents; ^(0)011, a group or 2) an nR group 'where η is 〇 or 1, a, eK: 4 _ group; (10) alkoxy; ring-burning II. i, glycerol or by - or a plurality of substituents selected from the substituent Re is taken as a technique. One or more members selected from the group consisting of substituents Re, 21, 2 or 3 A Re selected from heteroatoms of N, fluorene and S, which are unsubstituted or selected by one or more Self-substitution 5 or by-take 7 fresh Ν _ 基 ring, which has no taken group or, from, ,, a group, where ... or 1; c (.) (10) group or R is a ruthenium atom 'straight chain or Branched chain CrC6 alkyl, CrC4 haloalkyl, 61 201130839 C3-C7 cycloalkyl, stupid, 5- to 6-membered monocyclic heteroaryl containing = atom \5 to 6 from diterpene and S ring And a member of the saturated N-containing R" is a cyano group, a linear or branched alkyl group = a ring-based "phenyl" containing or a heterocyclic atom selected from the group consisting of 5 to 6 membered monocyclic heteroaryls. 〇 and S ring-based ring; wherein the ruthenium, stupid group, member has an N-hetero-substituted or a- or a plurality of substituents selected from the group consisting of unsubstituted groups or self-filaments (10) D-nucleus crC6 2 s 4 from silk, CK: 7 ring-burning, stupid, with right] times:: 5::f two selected from heteroatoms of N, 〇 and s Π or 3 = # heterocyclic groups selected from N, 0 and S heteroatoms, or 2) n0R groups, wherein ❻ or chain or branched chain CrC6 filament or Ci_c4 _ alkyl group: one group, a heterozygous 5 to 7 hexyl group selected from N, fluorene and s, or a -(CH2)nOR group, wherein n is 0 or i and the sizing represents a straight bond or a branched chain CrC6 An alkyl group or a CrC4 dentate group; wherein the octagonal group, cyclohexyl group, phenyl group, heteroaryl group and heterocyclic group are unsubstituted or substituted with one or more substituents selected from Ra; The alkyl group is unsubstituted or substituted with one or more substituents selected from Rb;

Ra is a halogen atom; a cyano group; a hydroxyl group; a linear or branched chain (^-(6 alkyl 'C丨-C4 halogen group; containing ι, 2 or 3 selected from n, 0, and s 62 201130839 a 5- to 6-membered monocyclic heteroaryl group of an atom which is unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain CrC6 alkyl group or a CrC4-alkyl group; _c(〇)〇R, a group or a -C(0)-(CH2)nR" group, wherein η is 〇 or i,

Rb is cyano; CrC4_alkyl; Ci_C4 alkoxy; C3_c7 cycloalkyl, unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group or a cyano group; Substituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a cyano group or a linear or branched Ci_c6 alkyl group, a _C(〇)OR' group or a -c(〇)-(CH2)nR, a group wherein n is a hydrazine or a hydrazine, a hydrogen atom, a linear or branched chain CrC6 alkyl group, a CrC4 haloalkyl group or a C3_C7 cycloalkyl group;

The ruler is a cyano group, a linear or branched chain CrC6 alkyl group, a CrC4 haloalkyl group or a C3_C7 cycloalkyl group. X Γ p In the κ embodiment, &amp; represents a linear or branched chain CrC6 alkyl group, an alkyl group, a C3_C7 cycloalkyl group, and contains 1, 2 or 3 members selected from N, C l 〇 or a hetero atom. a heterocyclic group, or a _(CH2)n〇R group, wherein 11 or 3 are selected from N, 0 and a group; and R represents a straight or branched chain CrQ alkyl group or a CVC4 halogen burnt earth. R8 may represent a 6-membered heterocyclic group containing 1, 2 heteroatoms; or a plurality of selected from 1 group, a minus group, and a heterogeneous or a one or more S from: a substituted silk; The radical group is unsubstituted or substituted at a substituent selected from the group, and wherein, as in h 63 201130839, more preferably, when h is an alkyl group or a haloalkyl group, it is an unsubstituted alkyl group or When the '' is a cycloalkyl group or a phenyl group', it is unsubstituted or more than j selected from a S atom, a cyano group, a hydroxyl group, a linear or branched bond, a Ci_C6 pit, a _c (_t group or _c(〇HcH2)n R" group-substituting 'where n is 0 or 1 'R, which is a hydrogen atom, a linear or branched i-C3 alkyl group or a CrC3 halogen group and a ruler&quot; a straight bond or a branch of a H or a (tetra) group; and # & is a heteroaryl or heterocyclyl, eight unsubstituted or substituted with one or more substituents selected from Ra, wherein Ra is as defined above ', preferably' § r8 is a heteroaryl group which contains - or two nitrogen atoms - = 5 to 6 membered heteroaryl groups. The money group is preferred. Preferably '#R8 is a heterozygous earth day $, which is unsubstituted or taken by one or more fangs atoms When r8 is a heterocyclic group, it preferably contains one or two or five members of a hetero atom selected from N (more preferably - or two nitrogen atoms), such as 6 members. A heterocyclic group. Preferred examples are a ketone group and a tetrazukibium oxime group. Preferably, the heterocyclic group is bonded to the remainder of the molecule via a ring carbon atom, in other words, via a ring carbon atom. The substituent bonded to the group (CR6 Dm-. piperidinyl group may be present at any ring atom 'but preferably a Wei atom. Difficultly, at least one substitution is on the ring nitrogen atom. Most preferably, R8 represents a linear or branched chain CrC6 alkyl group; CrC4 tooth = soil, crc: 7 ring-yard group, the cycloalkyl group is unsubstituted or substituted by one or more dentate atoms and a substituent of a hydroxyl group; stupid base, Said phenyl unsubstituted or substituted by - or a plurality of halogen atoms; _ (CH2) n-〇 R group, wherein 64 201130839 n is 0 or 1 and R represents a linear or branched chain crc3 alkyl; pyridyl, The &quot; is unsubstituted or substituted with one or more substituents selected from the group consisting of a ii atom and a hydroxyl group; tetrahydropyranyl, the tetrahydropyranyl group Substituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; or the piperidinyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: _ straight or branched chain a Crc3 alkyl group; a halogen atom; a pyridyl group which is unsubstituted or substituted with one or more cyano groups; _triazolyl; and • &lt;(0)·((:Η2)ηΑ&quot; a group, wherein n is hydrazine or 1 and R, is a cyano group, a straight or branched chain CpC: 6 alkyl, a crC4 haloalkyl or a c3-c7 cycloalkyl. For example, R8 may represent a straight chain or a branch. a chain Ci_C6 alkyl; a CrC4 haloalkyl; a CVC7 cycloalkyl group which is unsubstituted or substituted with one or more via groups; a phenyl group which is unsubstituted or trans- or polyhedral Atomic substitution; (CHA-OR group, where n is 〇 or! And R represents a straight bond or a branched chain CrC3 alkyl group; a neofilament, which is unsubstituted or substituted with one or more substituents selected from the group consisting of: (4) based on the uncorrected or untwisted Substituted by an aryl group; to be a &lt;-C(〇&gt;(CH2)nR" group, wherein η is 〇 or 丨 and 厌, is a cyano group, a straight chain or a branched chain c "c6 silk, crc4岐Or R8 may represent a straight or branched bond Ci_Q wire; Ci_Q halide 65 201130839 alkyl; C3-C7 cycloalkyl group. The cycloalkyl group is unsubstituted or one or more selected from halogen atoms. And a substituent substituted with a radical; -(CH2)n-〇R group, wherein η is 〇 or 1 and R represents a linear or branched chain CrC3 alkyl; tetrahydropyranyl, said tetrahydropyran The group is unsubstituted or substituted with one or more substituents selected from a halogen atom and a light group; or a π group, which is unsubstituted or substituted with one or more substituents selected from the group consisting of: a straight or branched chain Crc3 alkyl; - a halogen atom; - α is more than a thiol group which is unsubstituted or substituted with one or more cyano groups; -1,2,4-trisal, and --C(〇HCH2)nR a '' group, wherein η is 0 or 1 and R" is a cyano group, a straight or branched chain CrC6 alkyl group, a CrQ haloalkyl group or a C3_C7 cycloalkyl group. Particularly preferred substituents on the Rs piperidinyl group are selected Substituents from: -pyridyl, unsubstituted or substituted by one or more cyano groups; -1,2,4-triazolyl, and -C(0)-(CH2VRn groups) Wherein η is 0 or 1 and R, is a cyano group or a linear or branched chain CrC3 alkyl group. For example, a preferred substituent on the R8 group is a substituent selected from the group consisting of: - pyridyl group, The pyridyl group is unsubstituted or substituted with one or more cyano groups; and a group wherein n is 0 or 1 and R, is a cyano group 66 201130839 or a straight or branched chain crc3 alkyl group. The core represents a 6-membered heterocyclyl group such as tetraargonpyranyl A = radical '.(tetra)yl. Preferred substituents on such radicals are defined in the formula - when the 118 indicates the presence of a ring, the heterocycle Substituting - or a plurality of substitutions / substitutions at least on the ring nitrogen atom of the heterocyclic group, and ^ = a third butoxycarbonyl group. Preferably, the heterocyclic group is one or more deuterated groups. Substituting (four) Wherein the substitution is at least on a (tetra) group selected from: - a straight or branched bond Ci_C3 alkyl; - a halogen atom; - a pyridyl group which is unsubstituted or has one or more cyanides a group substituted with a -1,2,4-triazolyl group; and a -C(0)-(CH2)n-R'' group, wherein η is 〇 or 1 and R, is a cyano group, a straight chain or Branched chain Ci-C6 leucoyl, Ci-C4 halogen group or c3-C7 cycloalkyl group. Preferred substituents are selected from the group consisting of: -pyridyl, which is unsubstituted or substituted by one or more cyano groups ; -1,2,4-triazolyl' and ° -C(0)-(CH2VR'' group' wherein n is 〇 or 1 and R, is a cyano group or a linear or branched chain CrC3 炫. Usually, in the compound of the formula (I), 'R9 represents a hydrogen atom, i-primogen 67 201130839, a hydroxyl group, a cyano group or a linear or branched Crc6 alkyl group; and 119 preferably represents a hydrogen atom, a halogen atom or a straight chain or a branch. Chain crc3 alkyl. Usually, in the compound of the formula (I), m is 0, 1 or 2, preferably 0 or 1. In a particularly preferred embodiment, the compound of the invention has the formula (I-C)

Wherein m is 0 or an integer from 1 to 3; Z represents an oxygen atom or an NR5 group; W represents a nitrogen atom or a -CR3 group; and X and Y independently represent a nitrogen atom or a -CR9 group, wherein X And at least one of Y represents a nitrogen atom, and the other represents a -CR9 group; R! represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched bond C]-C6 alkyl group, C1-C4 a halogen group, a C1-C4 alkyl group, a C3-C10 cycloalkyl group or a -NKR' group; wherein R' and R'' are the same or different and each represents a hydrogen atom, a straight or branched chain CrC6 alkyl group, CrC4 haloalkyl or CrC4 hydroxyalkane 68 201130839; R2, I and R4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear branched chain CrC6 alkyl group, a CrC4_alkyl group, a CrC4 hydroxy group Alkyl or C3-C1()cyclohexyl}yl" represents a deuterium atom, a linear or branched chain CrQ alkyl group which is unsubstituted or one or more selected from the group consisting of hydroxyl, cyano, crC: 4 alkane Substituent, Cr (:4), substituted by a C--Ciq cycloalkyl group, a base L bite group or a 6-membered saturated N-containing heterocyclic ring; R6 and R·/ are unfortunate and each table No gas atom, direct bond or minute Branch C--C6 alkyl, C--C4 dentate or Ci-C4 alkyl; R9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain Ci-C; CVC4 dentate, CrC4 hydroxyalkyl or _NR, R,, a group; wherein R' and R&quot; are the same or different and each represents a hydrogen atom, a straight or a CrQ alkyl group, a CrC4 alkyl 4CrC4.alkyl group ; _ R8 represents a linear or branched chain CrC6 alkyl group, crc4 haloalkyl group, crc7 cycloalkyl group 'phenyl group' containing 2 or 3 heterocyclic rings of 5 to 6 members selected from hetero atoms of N, 0 and S An aryl group containing 2 or 3 groups of 5 to 7 membered heterocyclic groups or _(CH 2 ) n 〇 R groups selected from the group consisting of N and fluorene, wherein bis =, fluorene or 1 and R represents a linear chain Or a branched chain Ci_C6 alkylhaloalkyl; oxime, substituted from an alkyl group, a cycloalkylphenyl group, a heteroaryl group, and a heterocyclic group f, or substituted with a substituent derived from Ra; and said Soil not &amp; substituted or via - or a plurality of substituents selected from Rb;

Ra is a dentate atom; a cyano group; a thiol group; a straight chain or a branched chain (^(: 6 alkyl 69 201130839 base 'C丨-C4 dentate base; C丨-C4 alkoxy; c3{production_ generation or One or more selected from the group consisting of a substituent, Re, which is unsubstituted or substituted with - or a plurality of substituents selected from the group consisting of a substituent R, a phenyl group having 2 or 3 selected from N Substituted by a substituent of hydrazine, hydrazine and s; a heteroaryl-containing group which is unsubstituted or substituted with a plurality of 5- to 6-membered monocyclic groups selected from the group; 6-membered saturated fluorenyl ring, =, Substituting a substituent (5) for a substituent selected from the substituent Re; unsubstituted or via one or more C(0HCH2)nR" groups, wherein n is 〇 or ι ', (0) 0R' group or

Rb is cyano; C] _C4 _ alkyl; % alkoxy; group, unsubstituted or one or more selected from 3 7 'merion; phenyl, unsubstituted or one or more =================================================================================================== Saturated N-containing heterocyclyl ring, substituted or via- or a plurality of substituents selected from substituent Re/(10) group or -C(〇HCH2)nR" group, wherein n is 〇 or ^, -()

Re is a halogen atom, a hydroxyl group, a cyano group

Or a Q-Q(tetra) group; a cyanohydrin or a branched chain Q-CW R' is a hydrogen atom, a straight or branched chain Ci_Q alkyl C3-C7 cycloalkyl, a phenyl group, containing a fluorene, a dentate group

The 5- to 6-membered monocyclic heteroaryl of the whip atom has an N'Qa&amp;S ring-based ring; and the heterocyclic group or 5 to 6 members are saturated with _R" as a cyano group, a linear or branched chain CrC6 alkane C3 Prepared base, phenyl 'containing 2 or 3 selected from; 201130839 or 5 to 6 members saturated with N heteroheteroaryl and heterocyclic groups; 5 to 6 members of linear or branched chain CrC6 heteroatoms a monocyclic heteroaryl group, or a cyclic ring; wherein the cycloalkyl group, phenyl group, hetero-substituted or substituted by one or more substituents selected from the group consisting of a benzyl group, a cyano group, an alkyl group or a CrC4 dentate group. In the formula (IC) (4), when a 5- to 7-membered hetero-(n) group containing a nitrogen atom is represented, the heterocyclic group is usually substituted with a substituent, wherein the substituent is at least at the heterocyclic group. The ring nitrogen is 1 and the substituent on the ring nitrogen of the heterocyclic group is generally not a third butoxy group. Preferred substituents of the compound of formula (Ic) are as defined above for formula (1) and further below In general, in the compound of the formula (Ic), X and γ independently represent a gas atom or a -CR9 group, wherein at least one of X and γ represents a nitrogen atom and the other Shows a -CR9 group. Generally, when X represents a nitrogen atom, Y represents a -CR9 group. Typically, when X represents a _CR9 group, γ represents a nitrogen atom. Usually 'in the compound of the formula (Ic) of the present invention And Z is an NR5 group, wherein R5 represents a hydrogen atom or a linear or branched chain CrC6 alkyl group which is unsubstituted or one or more selected from the group consisting of a hydroxyl group, a cyano group, a CrC4 alkyl group, and a C]_C4. Substituting a C3-C1G cycloalkyl group, a phenyl group, a pyridyl group or a 6-membered saturated N-containing heterocyclic ring. In general, in the compound of the formula (Ic) of the present invention, Ri represents a hydrogen atom and a ? Atom, cyano, straight or branched chain CrC6 alkyl, C3-C7 cycloalkyl or -NRR group 'wherein and R" are the same or different and each represents a hydrogen atom, a straight or branched chain CrC6 alkyl or CrC4 tooth Alkyl; Ri is preferably shown in Table 71 201130839 as a hydrogen atom, a straight or branched chain CrC3 alkyl group or a -NH2 group; and Ri more preferably represents a hydrogen atom. Usually, in the compound of the formula (Ic) of the present invention, R2 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched crc6 alkyl group or a c3-c7 cycloalkyl group; and R2 preferably represents a hydrogen atom or a straight chain or Branched chain crc3 alkyl; the ruler 2 preferably represents a hydrogen atom. In general, in the compound of the formula (Ι-C) of the present invention, R3 represents a halogen atom, a halogen atom, a cyano group, a linear or branched chain CrC6 alkyl group or a C3-C7 cycloalkyl group; and r3 preferably represents a hydrogen atom and a cyanogen group; Or a straight or branched chain crc3 alkyl; R3 preferably represents a hydrogen atom or a cyano group. Usually, in the compound of the formula (Ic) of the present invention, R4 represents an argon atom, a halogen atom, a cyano group, a linear or branched Crc6 alkyl group or a C3-C7 cycloalkyl group; and R4 preferably represents a hydrogen atom or a straight chain or Branched chain CVQ alkyl; R4 more preferably represents a hydrogen atom. In general, in the compound of the formula (Ic) of the present invention, R5 represents a hydrogen atom or a linear or branched chain CrC4 alkyl group which is unsubstituted or one or more selected from the group consisting of a hydroxyl group, a crc4 haloalkyl group, a crc4 hydroxyalkyl group. Or a substituent of a c3-c7 cycloalkyl group; r5 preferably represents a hydrogen atom or a straight or branched chain crc3 alkyl group; and R5 more preferably represents a hydrogen atom. In general, in the compound of the formula (Ι-C) of the present invention, R6 and the flank 7 independently represent a τρ nitrogen atom or a direct bond or a branched bond Ci-Cg alkyl; Κ·6 and R7 preferably independently represent a hydrogen atom or a straight Chain or branched chain crc3 alkyl. In general, in the compound of the formula (Ic) of the present invention, R8 represents a straight or branched chain crc6 alkyl group, crc4 haloalkyl group, c3-c7 cycloalkyl group, phenyl group, 72 201130839 contains 1, 2 or 3 selected from a 5-ring heteroaryl group of a hetero atom of N, hydrazine and s, containing 1, 2 or 3 groups selected from N, fluorene and 8 = 5 to 7 membered heterocyclic groups, or _(CH2)n〇R groups, Wherein n is 〇 or : represents a linear or branched QQ alkyl group or a Cl_c4 _ alkyl group; wherein the haloalkyl group, the cycloalkyl group, the phenyl group, the heteroaryl group are unsubstituted, and the ring is selected from Ra Substituting the silky; = the group is unsubstituted or substituted by one or more substituents selected from Rb., the lanthanum is a dentate atom; the cyano group; the thiol group; the linear or soil branching bond ^· group, the crc4 halogen burning a group; a C3_c7 alkoxy group; a c3_c7 cycloalkyl group which is not substituted or substituted with or a plurality of substituents selected from the substituent Re; a stupid =, ·, tt substituted or a plurality or selected from a substituent The substituent of Re is taken from two or two or five heteroatoms of a hetero atom of N, fluorene and s, which are unsubstituted or fluorene-selected from a substituent r: Substituted; 6(tetra) and N-containing heterocyclyl rings, none of which are selected from substituents The substituents; -C (0) 0 = C (0) - (CH2) n-R 'group, wherein η is a square or 15 β

Rb is cyano; crc4 haloalkyl; CrC is unsubstituted or via- or a plurality selected from the group consisting of 3-7 cycloalkane; phenyl, which is unsubstituted or substituted by a substituent. Substituent substitution; containing up to 6 members of the early aryl group; its uncounted generation _ or polybasic Re substituted filaments; 6 贞 fresh j substituted or by - or a plurality selected from the substituent Re; '· It has not taken a group or a -C(〇MCH2)n_R&quot; group, where n is: or &quot;' _C_R' 73 201130839

Re is a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain group or a CpQ haloalkyl group; R' is a hydrogen atom, a straight or branched chain CrC6 alkyl group, a CrC4 haloalkyl group, a C3-C7i alkylene group, a benzene group a '5 to 6 membered monocyclic heteroaryl group containing 1, 2 or 3 hetero atoms selected from the group consisting of ruthenium, osmium and s, or a 5 to 6 membered saturated ruthenium containing heterocyclic ring; and R" is a cyano group' A straight or branched chain, a cardioalkyl group, a CrC4 i alkyl group, a 3 C? cycloalkyl group 'phenyl group' containing 5, 6 or 3 membered monocyclic heterocycles selected from 1, 2 or 3 heteroatoms selected from N, 〇 and § An aryl group, or a 5 to 6 membered saturated N-containing heterocyclic ring; wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or one or more selected from the group consisting of hydroxyl, cyano, and straight a chain or branched chain substituted with a CrC6 alkyl group or a CrC4 alkyl group. When a 5- to 7-membered heterocyclic group containing a nitrogen atom is used, the heterocyclic group is usually substituted with one or more substituents, wherein The substitution is at least on the ring nitrogen of the heterocyclic group, and the substituent on the ring nitrogen of the heterocyclic group is usually not the third butoxycarbonyl group. Preferably, the compound of the present invention (1-0 compound) Medium, 118 means straight key = branch CVQ alkyl, Cl_c: 4-haloalkyl, CVC7 cycloalkyl, phenyl, 1, 2 or 3 5 to 6 monocyclic heteroaryl selected from heteroatoms of N, 0 and S, containing 2 or 2 3 5 to 7 membered heterocyclic groups selected from the group consisting of ruthenium, osmium and S, or -(CHAOR group, wherein η is 〇° and Han represents a straight or branched chain Ci-C6 yard or crc4 a dentate group; the above-mentioned alkyl-, cycloalkyl, phenyl, heteroaryl, and heterocyclic hydrazine substituted or substituted with one or more substituents selected from Ra; and the alkane 201130839

Substituent unsubstituted or via - or a plurality selected from R to be a dentate atom; cyano; hydroxy; a substituted group; a base; (d) a dentate group; containing a 2 or 3 ^^ white or a two-branched (tetra) hetero atom 5 to 6 stomach monocyclic heteroaryl 'J from N,. And the S is selected from the group consisting of dentate broad, thiol, cyano, or substituted by one or more substituents of a CrC4 dentate alkyl group, wherein n is a sulphide or a sulphide nR" group, wherein n is 〇 or, 卿基圆或;:代;;代: 笨基, its unsubstituted or '=多== : 子二= or straight or branch key... base ==, 'er group or _c (〇)_(CH2)n_R, a group wherein η is 〇 or R' is an argon atom, a straight or branched chain c or a C3-C7 Wei group; and a pit group, a Crc4(tetra) group cvc^, a straight chain or a branched chain core group, a W group or a branch of 2 or 3 selected; a bis = κ_ group, wherein Cl-C6^^CrC4, or 3 6-membered heterocyclic groups selected from hetero atoms of N, 0 and S; Wherein the dentate group, the cycloalkyl group and the heterocyclic group are unsubstituted or substituted by a substituent of 75 201130839 or = selected from Ra; and the alkyl group is not substituted by a substituent of ίί Rb, wherein Ra and Rb is more preferably, in the compound of the formula (j-c) of the present invention, a group or a hexa group, which is unsubstituted or has one or more ; = f-gly-c_R' group or -c(())_(CH2)n_R'' group substituents ηΛϋ or 1 'R' Is a hydrogen atom, a linear or branched bond "alkyl or CVC3 dentate alkyl and R" is cyano, straight or branched c group or CrC3 haloalkyl; and as heteroaryl or heterocyclic i 3 Substituted or by- or a plurality selected from the substituents defined by =. 'TRa as in the compound of the formula (Ic) above, when Rs is a heteroaryl group, it contains - or two nitrogen atoms of 5 to 6 members Aryl. 吼 silk is = ΐ ΐ 代 when it is heteroaryl, its unsubstituted or via - or a plurality of dentates in the compound of formula (Ic), when r8 is heterozygous - or two selected from N And a hetero atom (more '5' or 6 membered heterocyclic group containing 'f' is preferably a nitrogen atom), for example, 6 members: two groups and Pylon are preferred. M is better. Compared with two:::: two The base is bonded to the rest of the molecule via a ring carbon atom, and the ring is bonded to the group ζ·(αι6 from the _._ group is often present at least on the nitrogen atom and may exist as appropriate In any other ring of the formula 76 201130839. Preferably, in the compound of the formula (Ic) of the present invention, r8 represents a linear or branched chain CrC6 alkyl group; a crC4 functional group; a c3-c7 cycloalkyl group, Ring burning Unsubstituted or substituted with - or a plurality of substituents selected from the group consisting of a money atom and a radical; the styl group is unsubstituted or substituted with - or a plurality of functional atoms; -(CH2)n-〇R a group, wherein 40 or represents a linear or branched chain CrC3 filament; π is more than a bite group, said 0 is unsubstituted or via - or a plurality of filaments selected from the group consisting of halogen and green: The tetrahydro bromo group is unsubstituted or substituted by one or more substituents selected from the group consisting of a sulfonic acid atom and a thiol group; or the chelating group is unsubstituted or one or more Substituted by a substituent selected from: - a straight or branched chain crc3 alkyl; - a S atom; a pyridyl group, which is unsubstituted or substituted with one or more cyano groups; i - l2 〆 - three Azolyl; and -&lt;(〇Η(:Η2)ηΑ'' group' wherein η is 0 or i and R" is a straight or branched chain (VQ alkyl, CrC4 dentate or C3_C7 ring In one embodiment, the compound of the formula (Ic) of the present invention has a branch of a filament, and the Q-based group has a 1, 2 or 3 heterogeneous horses selected from the group consisting of N, oxime and S. Up to 6 members of monocyclic heteroaryl containing Bu 2 or 3 a 5- to 7-membered heterocyclic group selected from a μ c 2 hetero atom, or a 2 hemp group, *,, '〇 or 1 and R represents a straight or branched chain CrC6 alkyl group or Crc 4 , a halogen ^ 77 201130839 group; Wherein the dentate alkyl group, the cycloalkyl group, the phenyl group and the heterocyclic group are unsubstituted or substituted with one or more substituents selected from Ra; and the alkyl group is unsubstituted or selected from a plurality of Substituents for Rb are substituted for 'wherein Ra and the ruler are as defined above. Alternatively, Rs may represent a straight or branched chain CrC6 alkyl group; a CrC4 dentate alkyl group; a C3-C7 cycloalkyl group wherein the cycloalkyl group is unsubstituted or substituted with one or more selected from a dentate atom and a thiol group. Substituted, _(CH2)n-OR group, wherein η is 〇 or 1 and R represents a linear or branched bond C1-C3 alkyl group; tetrahydro α bottom π south group, the tetrahydro 0 bottom group is not Substituted or substituted with one or more substituents selected from a dentate atom and a hydroxyl group; or a benzyl group, the substituent is unsubstituted or substituted with one or more substituents selected from the group consisting of: a chain or branched chain Ci-C3 alkyl; - a halogen atom; - a pyridyl group which is unsubstituted or substituted with one or more cyano groups; -1,2,4-triazolyl; and -C (0)-(CH2)nR, 'group, wherein n is 0 or 1 and R' is a cyano group, a linear or branched chain CrC6 leukox group, and a CrG dentate group. Particularly preferred substituents on the ring nitrogen of the ^^ slightly bitten group in the compound of the formula (I-c) of the present invention are substituents from the following: -σ is a bite group which is unsubstituted or substituted by a bite group. One or more cyano substituted; _ 1,2,4-trimethyl, and 78 201130839 $ an ancient group 'where n is 0 or 1 and R' is a gas-based or straight-chain or branched-chain crc3 alkyl group. In one embodiment, T? 生汉8 represents a 6-membered heterocyclic group, such as tetrahydropyranyl or a group, such as a yl group. Preferred substituents on the scale steel are as defined above. μ Π巧:' When the center of the formula (lc) represents a nitrogen atom = 7 to 7 Å, the heterocyclic group is substituted with - or a plurality of substituents, wherein the substitution is at least on the ring nitrogen atom of the heterocyclic group, And wherein the base is not the second butoxide county. Preferably, the heterocyclic group is a thiol group substituted with one or more substituents, wherein the substitution is at least on the ring nitrogen of the (iv) group. The substituent is selected from: • a linear or branched chain CrC3 alkyl group; a halogen atom; a pyridyl group which is unsubstituted or substituted with one or more cyano groups; ι -1, 2, 4- Three squats And -C(〇HCH2)n-R'' group, wherein η is 〇 or 1 and R, is a cyano group, a straight bond or a branched bond Q-C6 leukoxene, a C1-C4 _ burnt group or ^3_(^7cycloalkyl. Preferred substituents are selected from the group consisting of: _pyridyl, which is unsubstituted or substituted by one or more cyano groups; , , -1,2,4-triazole And - (: (0) - (〇12) 〆 'group' wherein n is 0 or 1 and R, is a cyano group or a linear or branched chain CrC3 swell. 79 201130839 Generally, in the present invention In the compound of the formula (I-c), R9 represents a halogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain CrC6 alkyl group or a -NR'R" group, wherein R' and R" are the same or different and each represents a hydrogen atom \ a direct bond or a bond Ci-C0 alkyl or a crC 4 dentate; &amp; preferably represents a hydrogen atom, a halogen atom, a linear or branched bond (^-(^alkyl or _nh2 group. Usually In the compound of the formula (Ι-c), m is 0, 1 or 2, preferably 0 or 1. In another particularly preferred embodiment, in the compound of the formula (Ic): m is 0, 1 Or 2; W represents a nitrogen atom or a -CR3 group, preferably a _CR3 group; X and Y independently represent a nitrogen atom Or a -CR9 group, wherein at least one of x and Y represents a nitrogen atom, and the other represents a _CR9 group; Ri represents a hydrogen atom or a ΝΗ2 group; and R2 represents an argon atom or a linear or branched chain CrC3 Alkyl; R3 represents a hydrogen atom, a cyano group or a linear or branched chain; R4 represents a hydrogen atom or a straight or branched chain CrC3 group; R5 represents a hydrogen atom or a straight or branched chain CrC3 alkyl group;

Re and &amp; independently represent a hydrogen atom or a straight or branched chain CrC3 alkyl group, R8 represents a linear or branched CVC6 alkyl group; crc4i alkyl group; C3-C7 cycloalkyl group said cycloalkyl group is unsubstituted Or substituted by one or more substituents selected from a dentate atom and a hydroxyl group; a phenyl group which is unsubstituted or substituted with one or more halogen atoms; -(CH2)n-〇R group, wherein n is 0 or 1 and R represents a linear or branched chain CrC3 alkyl group; pyridyl group, the pyridyl group 201130839 is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; a tetrahydropyranyl group which is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; and a tether base which is unsubstituted or one or more selected from the group consisting of Substituted substituents: • a straight or branched bond C1-C3 alkyl, a halogen atom; a pyridyl group which is unsubstituted or substituted with one or more cyano groups; and --C(〇HCH2 a nR" group, wherein η is 〇 or 1 and a ft, 'is a cyano group, a straight or branched chain crc6 alkyl group, a qQ ii alkyl group or (:3_(:7 naphthenic) And R9 represents a hydrogen atom, a halogen atom, a linear or branched chain crc3 蝝 或 or ΝΗ 2 group. In another preferred embodiment, in the compound of the formula (Ι-C): m is 0, 1 or 2 W represents a nitrogen atom or a _Cr3 group, preferably a hepta group; Z represents an nr5 group; X and Y independently represent a nitrogen atom or a _CR9 group, wherein at least one of X Θ and Y represents a nitrogen atom, and the other represents a _Cr9 group Ri, Ri represents a hydrogen atom or a _nh2 group; R2 represents a hydrogen atom or a straight or branched chain crc3 alkyl group; and R3 represents a hydrogen atom, a cyano group or a straight chain or Branched chain crc3 alkyl; R4 represents a hydrogen atom or a straight or branched chain crc3 alkyl;

Rs represents a hydrogen atom or a straight or branched chain Crc3 alkyl; 201130839 R6 and R7 independently represent a hydrogen atom or a straight or branched chain Ci_C3 炫* ^ R8 represents a straight or branched chain crC6 alkyl; CrC4 haloalkyl a Crc7 alkyl group which is unsubstituted or substituted with one or more substituents selected from a dentate atom and a hydroxyl group; a phenyl group which is unsubstituted or one or more a substituted atom; a _(CH2)n_0R group, wherein η is 〇 or i and R represents a straight or branched chain CrC3 alkyl group; a pyridyl group which is unsubstituted or one or more selected from teeth Substituted with a substituent of a aryl group and a hydroxy group, tetrahydropyranyl group, which is unsubstituted or substituted with one or more substituents selected from a #-atom atom and a hydroxyl group; and a piperidinyl group, The mother bite is unsubstituted or substituted with one or more substituents selected from the group consisting of: - a straight or branched chain CrC3 alkyl group; a halogen atom; a pyridyl group, which is unsubstituted or one or more a cyano group; -1,2,4-triazolyl; and a -C(0)-(CH2)n-R'' group wherein η is 〇 or 1 and R, is cyanide Straight-chain or branched CrC6 alkyl, haloalkyl or CRC4 crC7 cycloalkyl; and I represents an argon atom, a halogen atom, a straight-chain or branched alkyl or -NH2 group crc3. ~ Typically, when R8 is piperidinyl, it is substituted by one or more substituents wherein the substituent is at least on the ring nitrogen of the piperidinyl group, which is selected from 201130839 - a straight or branched bond C1 a -C3 alkyl group, a halogen atom; a pyridyl group which is unsubstituted or substituted with one or more cyano groups; -1,2,4-triazolyl; and -C(0)-( CH2)n-R'' group, wherein η is 0 or 1 and R'' is cyano, straight or branched bond, C1-C4 dentate or C3-C7 ring. More typically, the substituent is selected from: - a straight or branched chain crc3 alkyl; - a halogen atom; - a pyridyl group which is unsubstituted or substituted with one or more cyano groups; and -C (0)-(CH2)n-R&quot; group, wherein η is 0 or 1 and R&quot; is a cyano group, a straight or branched chain CrC6 alkyl group, a CrC4 haloalkyl group or a C3-C7 cycloalkyl group. In a particularly preferred embodiment, m is 0, 1 or 2 in the compound of formula (I); W represents a nitrogen atom or a -CR3 group, preferably a -CR3 group; Z represents an NR5 group; X and Y independently represents a nitrogen atom or a -CR9 group, wherein when one of X and Y represents a gas atom, the other represents a -CR9 group; T represents a -CR9 group;

Ri represents a hydrogen atom or a -NH 2 group; R 2 represents a hydrogen atom or a linear or branched chain CrC 3 alkyl group; R 3 represents a halogen atom, a cyano group or a linear or branched chain CrC 3 alkyl group;

83 201130839 R4 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group; R5 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group; R0 and R7 independently represent a hydrogen atom or a straight or branched chain CrC3 alkyl group, indicating straight a chain or branched chain CrQ building group; a crC4 haloalkyl group; a crc7 cycloalkyl group, the cycloalkyl group being unsubstituted or substituted with one or more via groups; a stupid group, the phenyl group being unsubstituted or via one or a plurality of dentate atoms are substituted. -(CH2)n-OR group ' wherein η is 0 or 1 and the squad represents a linear or branched bond CrC3 alkyl group; and a piperidinyl group which is unsubstituted or Substituting a plurality of substituents selected from the group consisting of: - pyridyl 'the pyridyl group is unsubstituted or substituted with one or more gas groups; and the earth - C(0)-(CH2)n-Rn group 'where η is 〇 or 1 and r' is nitrogen or a straight or branched chain CrC6 alkyl group, CrC: 4 quotient alkyl group or C3_c7 ring-based group. Moreover, R9 represents a hydrogen atom, a halogen atom or a linear or branched chain. In another particularly preferred embodiment, the compound has the formula (I a) 201130839 R4

Wherein m is 0, 1 or 2; W represents a nitrogen atom or a -CR3 group, preferably a -CR3 group; X represents a nitrogen atom or a -cr9 group;

Ri represents a hydrogen atom or a -NH2 group; R2 represents a hydrogen atom or a straight or branched chain CrC3 alkyl group; represents a hydrogen atom, a cyano group or a linear or branched chain CrC3 alkyl group; R4 represents an argon atom or a straight chain or a branched chain CrC3 alkyl; R5 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group; R6 and R7 independently represent a hydrogen atom or a straight or branched chain crc3 alkyl group, R8 represents a straight bond or a branched bond Ci_C6 alkyl group, C1- a C4 halogenated group, a C3-C7 cycloalkyl group, said cycloalkyl group being unsubstituted or substituted by one or more hydroxyl groups; a phenyl group which is unsubstituted or substituted by one or more halogen atoms; CH2) an n-OR group, wherein η is 0 or 1 and R represents a linear or branched chain CrC3 alkyl group; and a piperidinyl group which is unsubstituted or deuterated one or more 85 201130839 selected from the following a substituent substituted: - «pyridyl, the pyridyl group is unsubstituted or substituted with one or more cyano groups; and -C(0)-(CH2)n-R'' group 'where η is 〇 or 1 and Rii is a cyano group, a linear or branched chain CrG alkyl group, a crC4 halogen compound group or a c3_c7 cycloalkyl group; and R9 represents a halogen atom, a halogen atom or a straight bond or a branched bond CrC3 alkyl group. In another particularly preferred embodiment, in the compound of formula (Ia): m is 0 or 1; W represents a nitrogen atom or a -Cl group, preferably a -cr3 group; X represents a nitrogen atom or a -CR9 group R; represents a hydrogen atom; R2 represents a hydrogen atom; R3 represents a hydrogen atom or a cyano group; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a linear or branched bond CrC3 alkyl group; R6 and R7 independently represent a ruthenium atom or a straight Chain or branching key Crc alkyl;

Rs represents a linear or branched chain CrC6 alkyl group; a crC4 halogen group; a c3-c7 cycloalkyl group, which is unsubstituted or substituted with one or more via groups; a phenyl group, the phenyl group is not Substituted or substituted with one or more dentate atoms; (CH2)n-OR group 'where η is 0 or 1 and R represents a straight bond or a branched suspected CrC3 alkyl group; and a piperidinyl group, the piperidinyl group Substituted or substituted with one or more substituents selected from: 86 201130839 - pyridyl, unsubstituted or substituted by one or more cyano groups; and -C(〇HCH2)n-Rn a group wherein n is 0 or 1 and R" is a cyano group, a straight or branched chain CrC3 alkyl group or a CrC4 haloalkyl group; and R9 represents a halogen atom, a halogen atom or a linear or branched chain CrC3 alkyl group. In a particularly preferred embodiment, the compound has the formula (Ib):

Wherein m is 0, 1 or 2; X represents a nitrogen atom or a -CR9 group; represents a deuterium atom or a -NH2 group; R2 represents a deuterium atom or a straight or branched chain CrC3 alkyl group; R4 represents an argon Aromatic or linear or branched chain CrC3 alkyl; R5 represents a halogen atom or a linear or branched chain CrC3 alkyl; R6 and R7 independently represent a hydrogen atom or a straight or branched chain CrC3 87 201130839 alkyl, R8 represents a straight chain or Branched chain (VQ alkyl; CrC4 south alkyl; CrC7 cycloalkyl, said cycloalkyl being unsubstituted or substituted with one or more via groups; phenyl, said phenyl being unsubstituted or one or more a dentate atom substituted; (CHA-OR group, wherein n is 〇 or ! and 尺 represents a linear or branched chain CrC3 alkyl group; and a piperidinyl group which is unsubstituted or one or more Substituted with a substituent selected from the group consisting of: '-pyridyl, unsubstituted or substituted with one or more cyano groups; and -C(0)-(CH2)nR" group where n is 〇 Or 1 and R, is a cyano, straight or branched chain crC6 alkyl, C1-C4-alkyl or CrC7 cycloalkyl; and R9 represents a hydrogen atom, a halogen atom or a straight or branched chain Ci_C3 . In another particular preferred embodiment yl embodiment, in the compound of formula (I_b) are: m is 0 or 1; X Table no gas atoms;

Ri represents a hydrogen atom; R2 represents a hydrogen atom; R4 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group;

Rs represents a hydrogen atom or a linear or branched CrC3 alkyl group; R·6 and independently represents a hydrogen atom or a linear or branched alkyl group, and represents a straight or branched chain CrQ alkyl group; CrC7 cycloalkyl group, a cycloalkyl group which is unsubstituted or substituted with one or more hydroxy groups; a phenyl group, the phenyl 88 201130839 group is unsubstituted or substituted with one or more halogen atoms; the piperidinyl group is unsubstituted or one or more One is selected from the group consisting of _ π than a bite group, the σ being unsubstituted or substituted by a +, ^ '.; and or a cyano group taking -C(0HCH2)nR" a group 'wherein η is 〇 or 1 and R is a straight or branched chain CrC3 alkyl group or a CrC3 haloalkyl group; and ', ', earth, R9 represents a hydrogen atom, a halogen atom or a linear or branched chain Ci_c is produced by the present invention. Specific individual compounds include: 1 3, Yuantu ° 3-(4-{[(is)-i-phenylethyl]amine group {mouth bite-to-base^ than salidi^--5-carbonitrile; ' , -ajDt 3-{4-[(cyclohexylmethyl)amino]pyrimidin-2-yl}pyrazolo[^]pyridine·5-carbonitrile; 3-[4-(phenylhydrazino)pyrimidine _2-yl]pyrazole is called pyridine bite _5_甲猜; 3]4_[(2,2_-propylpropyl)amino group] shouting _2_based}0 Squatting parallel mouth, 5 々 pyridine-5-carbonitrile; ' 3-(4-{[(15&gt;2-methoxy-1-methylethyl)amino)pyrimidinyl) And [1,5-0]pyridine-5-carbonitrile; Η4-[(cyclopropylmethyl)amino]phthyridin-2-yl}pyrazolopyridine-5-carbonitrile; 3-{4-[ (2,2,2-difluoroethylene storm) Amino group] 〇 〇 _2 _2 _2 并 并 并 并 并 并 并 并 并 并 并 并 并 [ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Base 2-pyrazolo[ΐ,5-β]pyridin-3-ylpyrimidin-4-amine; 3-{6-[(cyclohexylmethyl)amino]acridin-2-yl}pyrazolo[丨,5 pyridine•5-carbonitrile; 89 201130839 3-{6-[(2,2-Dimethylpropyl)amino]pyridine_2-yl}pyrazolo[ij a]pyridin-5-A Guess; 3-{6-[(3-fluorobenzyl)amino]pyridin-2-yl}pyrazole is more than pyridine-5-, gambling, 3_[6·(methionyl) Π is 0 _2_基]0 is wow and [J,5·^^ is more than _5_甲猜. 3-(6-{[(10) phenethyl)amino}pyridyl) π-pyridyl D, ^Bipyridine-5-carbonitrile; 3_(4-{[(3 and)-1_(cyanoethyl)piperidinyl-3-yl]aminopyrimidin-2-yl)pyrazolo[1,5 -α]pyridine-5-carbonitrile; soil 3-(4-{[(3Λ)-1-ethylhydrazinopiperidinyl-3-yl]aminopyrimidin-2-yl)pyrazoloindole, 5- ΖΖ]π than bite-5-carbonitrile; 3-(4-{[ (3i?)-l-(5-Cyanoacridin-2-yl)-derived _3_yl]amino}ylidene-2-yl)pyrazolo[1,5·α]pyridine_5_ Nitrile; 3-(4-{[(3i?)-l-(3,3,3-trifluoropropyl)piperidinyl-3-yl]amino)pyrimidin-2-yl)pyrazolo[ 1,5-β]pyridine_5·carbonitrile; 3-{4-[[(3/?)-1-(cyanocarbonyl)piperidine-3-yl](methyl)amino]pyrimidine-2 -yl}pyrazolo[ι,5-α]pyridine-5-phthalonitrile; 3-(4-((trans)-4-hydroxycyclohexylamino)pyridin-2-yl)n-pyrazolo(1) ^ 比 pyridine-5-carbonitrile; ( (cyclohexylmethyl)-2-n ratio π sit and [ι,5_α]η azine _3_ base shouting 0 _4·amine; Phenylethyl)-2-(oxazolo[w-pyrazine-3_yl)-cyclohexane·4_amine; benzyl-2-pyrazole[ι,5·α]pyrazine_3·yl Pyrimidine _4_amine; hydrazine; 2,2-dimethylpropyl)_2-pyrazolo(1)^;-"pyrazine-3-ylpyrimidine_4_ 201130839 amine; 3-sideoxy-3-{(3 And)-3-[(2-pyrazolo[1,5-α]pyridazin-3-ylpyrimidin-4-yl)amino][alpha] bottom bite-l-yl}hys; 6-{(3i Indole-3-[(2-pyrazolo[1,5-β]pyridazin-3-ylpyrimidin-4-yl)amino] 旅π定_1_基} 验 ,, 2-pyrazole [1,5-α]pyrazin-3-yl-indole 4(3π)-1-(3,3,3-trifluoropropenyl) dent-3-yl] mouth 11 4-amine, 3-{(3i〇-3-[mercapto(2-hydroxypyrazolo[1,5-α] «pyrazin-3-ylpyrimidin-4-yl)amino][alpha] -1-yl}'-3-oxo-propanoid, 3-{(37--3-[(5-chloro-2-oxazolo[1,5-β]pyridazin-3-ylpyrimidine- 4-yl)amino] succinyl-1-yl}-3-oxo-propion, 3-{(37〇-3-[(5-fluoro-2-pyrazolo[1,5-α]pyrr Azin-3-ylpyrimidin-4-yl)amino]0-n-l-l-yl}-3-oxo-propion, 5-fluoro-2-pyrazolo[1,5-4 pyridazine- 3-yl-A4(3i?)-l-(3,3,3-trifluoropropenyl)piperidin-3-yl]pyrimidin-4-amine; 3-{(3i?)-3-[( 5-mercapto-2-pyrazolo[1,5-β]pyrazin-3-ylpyrimidin-4-yl)amino] brigade bite __ base}·_3-side oxypropyl guess, (S )-N-(l-(5-fluoroindole-2-yl)ethyl)-2-(«biazolo[l,5-a]pyridazin-3-yl)-biting-4-amine N-((5-fluoroacridin-2-yl)indolyl)-2 decapyrazolo[l,5-a]«pyrazin-3-yl)pyrimidine-4-amine; 5-lact-N ~((5-gas 0 is more than -2-yl) fluorenyl)-2-(α is more than 0 and [l,5-a]0 is 0-0-3-yl) 03⁄4 bite-4-amine, N4 -(4,4-difluorocyclohexyl)-2-(oxazolo[l,5-a]pyridazin-3-yl)pyrimidine

91 201130839 -4,5-diamine; (S)-5-gas|(1-(5-7-pyridyl-2-yl)ethyl)·2-7-pyrazole and ti, ° ratio. Qin-3-yl) squeezing 4-amine; 2- 〇boxazolo[1,5_a]pyrazine_3_yl)_N4_(tetrahydroanthracene-pyranyl) mouth bite-4,5- Diamine; (8)-3-tertiaryoxy·3_(3·(6«saphtho[丨,^] scale_3_yl)*Qin·2_ylamino)α-bottom-1-yl)propanenitrile; (R)-3-Sideoxy_3-(3-(6-(η vs. saliva[i,5_a]n is more than 唆_3_yl)0 than azine_2_ylamino) 底 bottom bite·1 · base) propionitrile; '(R)-3-tertiaryoxy-3-(3-(2-(°-azolo[1,5 but pyridyl))yl)-4-aminoamino) -1-yl)propanenitrile; 3-(3-(5-fluoro-2-(pyrazolo[i,5-a]pyridine-3-yl)pyrimidin-4-ylamino) 0 -yl)-3-oxo-propanonitrile; 3-(3-(5_ gas-2-(吼α坐和[ι,5_φ ratio^_3·基) mouth biting _4-amino group) 1-yl)-3-oxopropanenitrile; 3-(4-fluoro-3-(6-pyrazol[1,5啕pyridinyl)pyrazine-2-ylamino) B-pyridin-1 · )) 3-oxopropiononitrile; 3-(4_methyl-3_(6 ten than β 并 and [仏小比 bit·3•基泄嘻_2_ylamino) pie bite-1 -yl)-3-oxopropanenitrile; pyridin-3-yl)pyrazin-2-amine; , N-(l-(4H-l,2,4d3-yl)-derived _3_yl)_2_( π is more than sputum and 0 is -3-amino) shouting 4-amine; vV [(3 and) _1-(aminoethyl) 唆 唆 3 base _6 • pyrazolo [ι, 5_α bite 92201130839] pyrazol-3-yl-amine ° call ratio, and their pharmaceutically acceptable salts, solvates, N- oxides or derivatives atmosphere. An example of a preferred compound is: 3-(4-{[(lS)-l-phenethyl]amino}pyrimidin-2-ylpyrazole [l,5-ap ratio bite-5-曱 guess, 3-{4-[(cyclohexylmethyl)amino]pyrimidin-2-yl}oxazolo[1,5-α]acridin-5-indolecarbonitrile; 3-[4-(benzoguanamine) Pyrimidin-2-yl]«biazo[1,5-β]acridin-5-indolecarbonitrile; 3-{4-[(2,2-dipropylpropyl)amino]pyrimidin-2-yl} Pyrazolo[1,5-α]pyridin-5-曱 guess, 3-(4-^(15^-2-methoxy-1-indenyl)amino}pyrimidin-2-yl; Oxazo[1,5-α]pyridine-5-phthalonitrile; 3-{4-[(cyclopropylmethyl)amino]pyrimidin-2-yl}oxazolo[1,5-β]吼Pyridin-5-phthalonitrile; 3-{4-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}carbazolo[1,5 called ° bite-5 -曱 guess , phenethyl)-2-pyrazolo[1,5-α]pyridin-3-ylpyrimidin-4-amine; 3-{6-[(cyclohexyl)amino]«pyridin-2-吼 吼 oxazolo[1,5-α]acridine-5-- gamma; 3-{6-[(2,2-dimercaptopropyl)amino; pyridine-2-yl}pyrazolo[1 ,5-α] mouth bite -5-曱 guess, 3-{6-[(3-disindolyl)amino]〇 is more than 唆-2-yl}° than sitting and [1,5-&lt ; 2] bite-5-A guess; 93 201130839 H6-(benzylamino)pyridin-2-yl]pyrazolo[I,5 is called pyridyl ·5A guess. 3-(6-{[(1»5*)-1_phenethyl]amine group than bite_2_yl) is more than saliva [1 5 ^ pyridine-5-carbonitrile; ' -(5)吼3-(4_{[(3 and)-ΗCyanoethinyl) "Chenyl"] Amino} 喷 _2 · Pyrazolo[1,5-α]pyridine-5-A Nitrile; soil 3-(4-{[(3i〇-1 -ethylhydrazinopiperidine-3-yl)amino}pyrimidinyl[1,5-«]pyridine-5·phthalonitrile; J sit 3- (4-{[(3;?)-1-(5-cyanopyridine-2-yl)piperidinyl]amine-based guanidine-2-yl)n is more than saliva [ΐ,5·α] π ratio biting _5_carbonitrile; 3-(4-{[(3 outer 1 -(3,3,3-trifluoropropyl)piperidinyl]amino}}}} ) &quot; than sitting and biting _5_carbonitrile; H4-[_)-H cyanomethyl) sent bite] (methyl)amino]cyclo-2-amino}pyrazole [ ΐ,5-α]pyridine-5-carbonitrile; 3_(4-((trans)-4-ylcyclohexylamino)) bite_2_yl) 〇 唾 唾 啦 啦 -5 -5 - - - - - - #-(环己曱基比比) sit and [I,5 kumbitazine _3_ base pain bite _4·amine; (8) good (1-phenylethyl)-2-(吼 仏 仏 仏 仏 比 比_3基)射·4·amine; benzylidene-2-indolo[1,5-α]pyridin_3_ylpyrimidine_4_amine; ΑΚ2,2-dimethylpropyl than saliva And Π, 5 比 嗪 · · 3 3 3 ; ; ; ; ; ; ;; Magic -3-[(2" than saliva and 冲 比 嗪 · 3 3 3 3 3 3 胺 派 派 派 派 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 - 吼 并 and [1,5 kun than 嗓 _3_ base for the winter base) amine] 94 201130839 Bite bit -1- base} in the test of nitrile; 2- 0 than 嗤 [1,5_♦ than the azine-3 -yl-A4 (3 external 1-(3,3,3-trifluoropropanyl) 0-bottom-3_yl]pyrimidine_4_amine; 3" (3 external 3_[mercapto (2-pyrazole) And [1,5-α]pyridazin-3-ylindol-4-yl)amino]pyridin-1-yl}-3-sided oxypropionitrile; 3- {(3/?)-3 -[(5-Gatro-2-oxazolo[ΐ,5_α]pyrazine-3-ylpyrimidinyl-4-yl)amino]α-chenyl-1-yl}_3_ pendant oxypropionitrile; 3-{ (3 and)-3-[(5-fluoro-2-oxazolopyrazine-3-ylpyrimidin-4-yl)amino]piperidin-1-yl}_3_ pendant oxypropionitrile; 5- Gas-2-&quot; than saliva and oxime azine _3_基#[(3 幻·1(3,3,3 trifluoropropyl fluorenyl) sent bit-3-yl] guanamine; 3 {( 3 and) -3-[(5-methyl_2·吼 并 [ [ [ 嗓 3 3 3 3 3 3 3 _ _ _ _ _ -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- ; ; ; ; ; ; ; ; ; ; And pharmaceutically acceptable salts, solvates, oxynitrides or deuterated derivatives thereof. Of great interest: 3-(4-{[(lS) small stupid ethyl]amino}対_2 phenyl is more than spit and acridine-5-indeneonitrile; 3 {4 [(2,2 one A 2-amino)amino] continue to bite-2 keb compared to saliva [^-piperidine-5-carbonitrile; 3-(4-{[(1) 2-methoxysuccinylethyl)amine } 嘧啶 _2 _ _ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Alkylpyrimidine _4.amine; 3_(4_{[(3 and)-indolyl cyanoethyl)pyridinyl-3-yl]aminopyridin-2-yl) 95 201130839 0 to 0 sitting and [1,5 -α]0 than bite·5-carbonitrile; Η4_{[(3 and)-1-(3,3,3-trifluoropropenyl)0 agidine _3_yl]amine-yl-2-yl )&lt;» than the saliva and [1,5-α]° ratio biting 5--carbonitrile; 3-{4-[[(3 external 1-(cyanocarbonyl) brigade _3•yl] Amino]]]-2-yl}»» is more than π and [ι,5-α]η is more than _5_carbonitrile; 3_(4_((trans)_4_ylcyclohexylamino)pyrimidine唆_2_基)„Bizozole[^ 比 啶 -5-5-曱carbonitrile; '(8) 善(1-Phenylethyl)-2 七比唾和...♦比嘻_3-基)射_4_amine ; #·苯苯-2-pyrazolo[1,5 bicazine _3_ phenylpyrazine; (2,2-dipropyl propyl) 嗤 π, 5 ♦ 嗓 _3_ Base shot _4_ amine; 3-#J ft A-3-{(3i?)-3-[(2-t b^jl -4-yl)amino]piperidinyl}propionitrile; 6-steel-3-K2-♦ sitting and D,5♦pyrazine_3•gibricyl)amino]piperidine- 1-yl}nicotinonitrile; amino]piperidin-1-yl}-3-oxopropiononitrile; 3-breast·3-[(5·气_2_t sit and Π, 5 kiss slightly 3_ base _4 base) Amino]piperidin-1-yl}-3-sided oxypropionitrile; 3-xykanazine·3 carbyl-4-yl)amino]piperidin-1-yl}-3-side Oxypropionitrile; 5-fluoro-2-indole[1,5-♦pyrazine_3_yl3_tripropenyl)pyridinyl]pyrimidine-4-amine; j I ' '-96 963030 3-{(3/〇-3-[(5-mercapto-2-pyrazolo[1,5-α]pyrazin-3-ylpyrimidin-4-yl)amino] brigade bite __ base ]^-3-Sideoxycyan, (S)-N-(1-(5-fluoroacridin-2-yl)ethyl)-2-7-pyrazolo[1,5-a]pyridazine- 3-yl) biting-4-amine, N-((5-fluoroacridin-2-yl)indolyl)-2-(carbazolo[1,5-a]«pyrazin-3-yl) Pyrimidine-4-amine; 5-chloro-N-((5-fluoroacridin-2-yl)methyl)-2-(orhrobazolo[1,5-a]pyridazin-3-yl)淀-4-amine; N4-(4,4-difluorocyclohexyl)-2-(oxazolo[l,5-a]pyridazin-3-yl)pyrimidine-4,5-diamine, (S -5-Gas-N-(l-(5-fluoroacridin-2-yl)ethyl)-2-(carbazolo[l,5-a] oxime 0-methyl-3-yl) mouth bite -4- , 2-(carbazolo[1,5-a] η-pyridin-3-yl)-N4-(tetraar-2H-pyran-4-yl)pyrimidine-4,5-diamine; (R) -3-Sideoxy-3-(3-(6-(atti0)[1,5-a]n is more than indol-3-yl)ntb 嗓-2_ylamino) brigade bite __ base) Guess, (R)-3-sideoxy_3-(3-(6_(π is more than [1,5-a]4bσ-3-yl) °pyrazin-2-ylamino) bite _1_基), C., (1^)-3-oxo-3-(3-(2-(11°°[[,5-&amp;]11 ratio]-3-) pain唆-4-ylamino) brigade bit _1_base) C., &gt; 3-(3-(5-gas-2-(ntb sitting and [1,5-a]π ratio 11 -3- i base) ringing-4-ylamino) brigade-1-yl)-3-oxo-propanoid, 3-(3-(5-gas-2-(carbazo[1,5-a] ] «Bipyridin-3-yl)pyrimidin-4-ylamino) π-bottom-1-yl)-3-oxo-propion, 97 201130839 3-(4-Fluoro-3-(6-(^) Sit and [preferentially) π-pyridazine_2-ylamino) ketone-1-yl)-3-oxo-propanonitrile, 3-(4-methyl-n-salt-[[基 秦 胺 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基_6_(pyridyl to pyridin-3-yl)pyrazin-2-amine; Ν-(1_(4Η·1,2,4·three-salt-3-yl) _3_yl)pyridin-3-yl) Pyrimidine-4-amine; Λ4( 3 and) -1-(aminoethyl aryl) cleavage _3 base _6 pyridine-3-ylpyrazin-2-amine; solvate, cerium-oxide or pharmaceutically acceptable Salt deuterated derivatives. Preferred individual compounds of the invention comprise: 3 (4-{[(lS)-l-phenethyl]amino}-penetrating _2-yl) hydrazine _&amp;]pyridinium-5-indolecarbonitrile ; ' 3-{4-[(2,2-Methylpropyl)amino]carcinoma "Deacetyl-2-yl} oxime is squat and [ι,5-β]indolepyridin-5-indoleonitrile; ' 3_(4-{[(l»S)-2-decyloxy-1-hydrazinoethyl]amine}}}}}pyrido[1,5-α]pyridine-5 - phthalonitrile; N-(l-phenethyl)_2_π than 嗤[1,5-α]° ratio 定-3-yl aceamine; 3-(M[(MH-(cyanoethyl) ) piperidinyl]amino} 唆 ))) 0 嗤[1,5-α] η than bite _5_曱 nitrile; 3_(4-{[(3Λ)-1-(3,3, 3-trifluoropropanyl) 0 chen ate · 3 · yl] aminyl-2-yl) pyrazolo [ι, 5_α] pyridyl-5-carbonitrile; 98 201130839 3-{4-[[( 3i?)-l-(Cyanocarbonyl)piperidin-3-yl](methyl)amino]pyrimidin-2-yl^ ratio 11 Sit and a guess, 3-(4-((trans))-4- Hydroxycyclohexylamino)pyrimidin-2-yl)pyrazolo[l,5-a]pyridin-5-曱 guess, 〇7V-(1-phenylethyl)-2-( °-pyrazolo[ 1,5-a]pyridazin-3-ylpyrimidin-4-amine; benzyl-2-0 is more than 11 sits and [1,5-α]0 is more than 嗓-3 -yl 0^bit-4- Amine, TV-(2,2-dipropyl)-2-pyrazolo[1,5-β]pyrazine- 3-ylpyrimidin-4-amine; 3-sided oxy-3-{(3^-3-[(2-oxazolo[1,5-β]pyridazin-3-ylpyrimidin-4-yl) Aminopropyl, 6-{(37?)-3-[(2-π ratio 11 sits and [l,5-&lt;3]atbn Qin.-3-yl-neptin-4-yl)amino] α底唆-1 -基}• 猜 ,, 3-{(37?)-3-[methyl(2-«-pyrazolo[1,5-α]pyridazin-3-ylpyrimidine-4- Amino] 旅 -1- -1- yl] '-3- oxy aceta guess; 3 - {(3i?) -3-[(5 - chloro-2_ntb σ sit and [1,5-ί3] σ嗓-3-yl butyl-4-yl) Amino]α 唆 唆-1-yl}-3-sided oxypropyl guess, 3-{(3 magic-3-[(5-fluoro-2- Oxazo[1,5-α]pyridazin-3-ylpyrimidin-4-yl) Amino]°辰辰-1_基}·_3-lateral oxypropyl guess, 5-disorder-2-πιΐισ And [1,5-0]13⁄411 Qin-3-yl-_/V-[(3i?)-l-(3,3,3-dipropionyl)piperidin-3-yl]pyrimidine-4 -amine; 3-{(3 and)-3-[(5-methyl-2-pyrazolo[1,5-α]pyrazin-3-ylpyrimidin-4-yl)amino] brigade bite (1-)-N-(l-(5-fluoroacridin-2-yl)ethyl)-2-(carbazolo[1,5- a]pyridazine 99 201130839 -3-yl) mouth bite-4-amine; N-(pyridylpyridin-2-yl)indolyl)·2 decapyrazolo[1,5_a]n ratio 4-amine; "soil" 5·gas-Ν-((5·fluoropyridine) 2_yl) fluorenyl)_2·(pyrazolo[1,5pyridin-3-yl)pyrimidine-4-amine; '°Qin N4#,4·^cyclohexyl)·2·(対[u_aKazine j base) -4,5-diamine;

(S)-5-chloro-N-(1-(5-fluoroindole-2-yl)ethyl)·2 decapyrazinopyrazin-3-yl)pyrimidine-4-amine; 'J 2 VII Bisinopyrene, 5♦ than 嗓_3_yl) (tetrahydro-welfare _ 喃 斗 咬 -4 -4,5-diamine; (R) _3_sideoxy-Η3-(6-(対和[丨, 5♦ specific noise · 3 amino-amino) piperidin-1-yl) propionitrile; rong (R) -3- side secret · 3 · (3_(6_(indenyl) scale_2·ylamino ) ketone-1-yl)propionitrile; octa(R)-3-o-oxy-3--(mouth-salt(p-decylamino)piperidin-1-yl)propanenitrile; &lt; (4) money _4·ylamino) (iv) Π, 5_Φ^3 gamma-based amine phantom 3-(4-fluoro-3·(6-(_^,5 external to '娘娘1·基)-3-lateral oxygen Alkylpropanenitrile; 豢2 ylamino group) is called methyl _3_(6 as a phthalocyanine-2-ylamine 100 201130839 yl) pyridin-1-yl)-3- oxopropiononitrile; N- (1-(4H-1,2,4-three-salt_3_yl) trace 唆_3_ base) clock than wow (1)

0 咬-3-yl)pyridazin-2-amine; 'J Ν-(1·(4Η-1,2,4-triazin-3-yl) tourism·3_base)_2•(吼And (1)

0 than biting-3-yl) squeezing 4-amine; 'J 尽 [(3 phanyl-1-(aminoethyl hydrazino) piperidinyl-3-yl]_6 pyrazolopyridin-3-ylpyrazine -2-amine; *·, "!* and its pharmaceutically acceptable salts, solvates, N-inhibited derivatives. % According to one embodiment of the present invention, a compound of the formula (I-d) is claimed A subformula of the compound of the formula (1) (wherein the central, heteroaryl moiety is a lancet ring, which can be prepared by the following synthetic route as illustrated in Scheme 1:: r4

(ld) 101 201130839 The compound of formula (Id) may be a gas-containing heteroaromatic compound of formula (III), by a temperature ranging from ambient temperature to 150 ° C, such as diisopropylethylamine or triethyl In the presence of an amine base, in a solvent such as dimethyl decylamine, dimethyl sulfoxide, tetrahydrofuran or ethanol, with or without microwave irradiation, with a nucleophile of the appropriate formula (IV) (such as an amine or Alcohol) reaction to obtain. The compound of the formula (III) can be produced by using a pyrimidine of the formula (II) at a temperature ranging from 25 ° C to reflux, for example, by a gasification agent v) or a chlorinated scale (v). In the specific case of Z = NR5, the formula (the compound can be directly from the compound of formula (11) by the scheme as described in the literature (J, 2007, 72 (10), 10194-10210), by 25 to 8 Gt: In the temperature range, in the presence of a suitable test such as hydrazine, 8 diazabicyclo[5.4.〇]undecene, in the presence of a suitable nucleophile such as a 'xyamidine' in the type (IV) nucleophile It is obtained by treatment with a suitable activator such as hexafluoroweibenzotrisyloxy-xylene (dimethylamino) scale. The compound of the formula (II-a), the subform of the intermediate of the formula (II) (the center thereof Obtained as a helium atom) as shown in Process 2: &quot; 102 201130839

The oxime of the formula (V) can be reacted with an unsaturated ester of the formula (VI) wherein LG is -OH, -OMe, -OEt or -NMe2 to give a pyrimidone of the formula (Π-a). The reaction can be carried out in a solvent such as ethanol in the presence of a suitable base such as triethylamine at a temperature ranging from ambient temperature to reflux. The intermediate of formula (V) can be prepared by the following synthetic route as illustrated in Scheme 3: r4

Process 3 in the temperature range of 0 ° C to ambient temperature, in the base of, for example, potassium carbonate

103 201130839 In the presence of a solvent such as dimethylformamide, the ethyl propiolate and the acryl rust of the formula (VIII) (in the specific case of W = CR3) or #amino ratio The azine rust salt (in the specific case of W = N) is reacted to give an ester of formula (IX). The 7V-amino acridine rust of the formula (VIII) and the guanamine ruthenium salt may be commercially available or may be used in the oxime. 〇 to the temperature range of the ambient temperature 'in a suitable solvent such as a gas-fired' to make the corresponding formula (VII) η bite (in the specific case of W = CR3) or pyrazine (in the specific case of W = N) The following is prepared by reacting an oxime-(2,4,6-triphenylsulfonyl) group with an amine. The carboxylic acid of the formula (X) can be produced by treating an ester of the formula (Ιχ) with a suitable base such as sodium hydroxide in a solvent such as ethanol at a temperature ranging from ambient temperature to reflux. The compound of formula (X) is treated with a suitable chlorinating agent such as sulfinium chloride at a temperature ranging from ambient temperature to reflux to provide an intermediate acid chloride which, when treated with an ammonia source such as an aqueous ammonium hydroxide solution, produces (XI) Amidoxime. The decylamine of the formula (XI) is reacted with a suitable dehydrating agent such as triterpene at a temperature ranging from ambient temperature to reflux to obtain a nitrile of the formula (XII). After treating the nitrile k of the formula (XI) with a catalytic solution of methanol in the ambient temperature at ambient temperature, the intermediate intermediate is treated with a chlorinated y alcohol solution at reflux temperature to obtain an intermediate of the formula (v). . In another: synthetic route, the compound (II_a) can be prepared by the following synthetic route as described in Scheme 4: 104 201130839 R4

In a temperature range from the pulse to the reflux, a suitable catalyst such as di-gasified bis(triphenylphosphine) ruthenium (9) and copper telluride (1), such as triethylamine, is used under palladium and copper catalyzed coupling conditions. In the presence of a test, a 2-pyrimidine of the formula (XIH) is reacted with an ethynyl trimethyl sulphate in a solution such as a tetrazene nitrite/solvent to obtain the formula (XVI). , smoke. At ambient temperature, in the case of a catalytic amount of B, in a suitable solvent such as tetrachloromethane, a suitable reagent such as tetrabutylammonium fluoride is used. (xvi) a compound which produces an alkyne of the desired final formula (χνπ). An alkyne of the formula (VIII) of the formula (χνπ) in a solvent such as AW·dimethylformamide in the presence of, for example, potassium carbonate at a temperature ranging from 〇c to room temperature σ is a compound of formula (XV) obtained by reacting with a bite 镔 (in the case of W = (^3), '105 201130839 or an amine-based azine salt (in the specific case of W = N). The (XV) compound can be directly bitten by the 2-gas c of the formula (XIII) by the reaction conditions in Suzuki-Miyaura (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457) is prepared by reacting with a boronic acid ester of the formula (XIV). The reaction can be carried out at a temperature range of 804201 in the presence of a ligand such as tricyclohexylphosphine, such as dimethyl decylamine. In a solvent, catalyzed by a suitable palladium catalyst such as ginseng (dibenzylideneacetone) dipalladium (0) with or without the use of microwave radiation in the presence of a base such as potassium phosphate. Under microwave heating at 130 ° c, In a suitable solvent such as acetonitrile, a mixture of ethanol and water containing potassium hydroxide is used under reflux, such as gasification of trimethyl decane / Treatment with a suitable reagent for sodium or treatment of the compound of the formula (χν) with hydrogenated hydrogen or an evolved aqueous hydrogen solution at 100 C gives the desired formula (ΙΙ-a) pyridone. Intermediate of the formula (XIV) borate Can be prepared as shown in Scheme 5:

The carboxylic acid of the formula (X) can be brominated by a ruthenium bromide, for example, in a solvent such as dimercaptoamine at ambient temperature in the presence of a base such as sodium carbonate. The agent is treated and converted into the formula (χνιπ) 106 201130839 Desert derivative. At a temperature range of 80-12 (TC, using a palladium catalyst such as Acetic Acid I}, in the presence of a ligand such as tricyclohexylphosphine, in a solvent such as diethylene glycol or a solution of water 'in In the presence of Wei _, in the absence of H, the boric acid ester of (XIV) is obtained by using a suitable thief (XVIII) of the double stalk. A compound of the formula (!·0), a subformula of the compound of the formula (1) wherein the central heteroaryl moiety is a (tetra) ring and R1 is a hydrogen atom, can be prepared by the following synthetic route as illustrated in Scheme 6: A r9 (XIX) )

Jr

Cl r9 r9 (XX)

Cl r9 r9 (XXI)

R4 r4

λ (IV) Process 6

The alkyne of formula (XX) can be prepared by using a suitable catalyst of (triphenylphosphine)-) and steel (1) under the conditions of coupling and copper catalysis, at 107 201130839 ϊίΤί The preparation is carried out by reacting a gas K of the formula (XIX) with a trimethylsilyl group in a solvent such as tetrahydrofuran with or without a microwave. At room temperature, in the presence of a catalytic amount of acetic acid, the material is suitable for spraying, and a material such as fluorinated ammonium amide is suitable [agent treatment. a compound of the formula (XX) which produces a desired final formula (χχι) at a temperature ranging from 0 C to ambient temperature, in the presence of, for example, a carbonic acid decantation, in a solvent such as '-dimethylformamide To make the arsenic of the formula (VIII) of the formula (ΧΧΙ) rust (in the specific case of W = cr3:) or the guanamine pyrazinium salt (in the specific case of w = N), a compound of formula (XXII). At ambient temperature to (10). The temperature of C is in the presence of a test such as 聊_diisopropylethylamine or triethylamine, such as Λ^·dimethylformamide or dimethyl sub-aprotic solvent. Iv) A nucleophile (such as an amine or an alcohol) is treated with a formula (χχΗ) gas: 'Production formula ((4) compound. In the specific case of Z = NR5 ^ Ie) compound can be used at 8〇-120. (in the temperature range, using a suitable catalyst such as acetic acid _), in the presence of a ligand such as U, H 2 , 2, _ bis (diphenylphosphine) and, for example, cesium carbonate, in the toluene Solubility is prepared by reacting a compound of formula (XXII) with a nitrogen nucleophile of formula (IV), with or without micro-audition. ((4) The compound of the formula (1) claimed in the compound '1) wherein the +heteroaryl moiety is a ratio of a azine ring and R1 is a hydrogen atom can be prepared by the following synthetic route as described in Scheme T: 108 201130839 «4 &gt;-w h-\ y~R2

(xxiii) (xxiv) (if) Process 7 The boronic acid ester of formula (XIV) can be obtained under the Suzuki-Miyazaki reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, P5, 2457) and Reaction of 2,6-dioxapyrazine of XXIII) to produce a compound of formula (XXIV). The reaction can be between 80 and 120. Under the temperature range of hydrazine, in the presence of a ligand such as tricyclohexylphosphine, in a solvent such as Λ/&quot;'-dimethyl arylamine, in the presence of a base such as potassium phosphate, in use or Catalyzed by a suitable palladium catalyst such as ginseng (dibenzylideneacetone) dipalladium (ruthenium) without the use of microwave radiation. The chloropyrene of formula (XXIV) is treated with a nucleophile of formula (IV) in an aprotic solvent such as dimethyl sulfoxide in the presence of a reagent such as cesium fluoride at a temperature ranging from ambient temperature to 140 C. Azine' produces a compound of formula (I-f). In the particular case of Z = NR5, the compound of formula (I-f) can be between 8 and 12 Torr. Under the temperature range of 〇, by using a suitable catalyst such as ginseng (dibenzylideneacetone), such as 9,9-dimethyl-4,5-bis(diphenylphosphino)anthracene The compound of formula (XXIV) is reacted with a ligand of 3〇5 and, for example, a saponin, in a solvent such as %#, dimethyl carbamide, with or without microwave light. The nitrogen nucleophile of formula (IV) is reacted to prepare. In another specific case, Z is a formula in which r5 is a hydrogen atom.

109 201130839 (II, ae) or af) compounds can be stepped into the step * 〇 °c to reflux > under the conditions of a solvent such as dimethyl dimethyl ketone, with an appropriate reaction such as hydrogen 'Warm additions such as the sputum recording agent, to 1r5 is now a compound of the formula (I_d), ae) or (10). In another case, T, the residue of R9 is a nitro group &lt; ((4), (5))

The compound of Hf) can be further reacted with a hydrogen such as ethanol or methanol in a solvent such as ethanol or methanol at ambient temperature to obtain R9 which is now an amine group (5). a compound of (Μ or (If). 隹 隹 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' (v) or (10); ^ = the amine moiety is removed under standard conditions (G careful plus ga G. _ _ _ _. The corresponding amine can be functionalized under fresh conditions to the corresponding guanamine, guanamine, urea, and the hydroxylated and (tetra)alkylamine. [Embodiment] The compound of the present invention and the intermediate used therein are given by the following Example (10)) (including Preparation Example (Preparation M1)): = ^ is given in order to provide sufficient clarity to those skilled in the art. It is a complete departure from the invention, but should not be construed as limiting the scope of the subject matter, as set forth in the foregoing part of the specification. Preparation 1 201130839 2-ethynyl-4-methoxypyrimidine

a) 4_Methoxy[(trimethylpropenyl)ethynyl]pyrimidine-to-dry resealable Schlenk tube t loaded with H4-methoxy (2.6 G, 17.99 mmol, ethynyl tris, xantane (3.05 ml, 2158 mmol), tetrahydrofuran (24 ml) = and diethylamine C12, 53 ml ' 89.9 〇 millimolar). The cycle of the Schlenk tube = secondary argon argon backfill, followed by the addition of iodide _ = gram '0.72 moles) and the second gasified bis(triphenylphosphine) (9) (m ^ gram ' 0.72 毫Moore). The cycle of argon gas backfilling was carried out three times, and the Schlenk official was stirred up and the mixture was stirred at 9 Torr. Heat in a simmering oil bath. After 16 hours, the mixture was passed and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water and the organic layer was separated, dried with 4% aqueous sodium carbonate, dried (MgSO.sub.4) and evaporated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut LRMS (m/z): 207 (M+l)+. !H-NMR δ (300 MHz, CDC13): 0.0 (s, 9H), 3.7 (s, 3H) 6.4 (d, lH), 8.1 (d, lH). ' b) 2-Ethyl-4-pyrene oxime 111 201130839 Add tetrabutyl fluoride (G 97 ml 丨M tetrahydrogen solution '0.97 mmol) to the disturbed mixture at room temperature a solution of 4_methoxy 2,7-tris-methyl: hexyl)ethynylpyrimidine (preparation la, 〇2〇g, 〇97 mmol) in tetrahydrofuran (1.4 ml) and acetic acid (56 μl) in. After ^ minutes, a 10% aqueous solution of potassium carbonate was added to the reaction mixture and the mixture was extracted with methane. The organic layer was separated, dried (Mgs04) and steamed. The residue was purified by flash chromatography eluting elut elut elut elut LRMS (m/z): 135 (M+l)+. 4.0 (s, 3H), 'H-NMR δ (300 MHz, CDC13): 3.1 (s, 1H), 6.7 (d, 1H), 8.4 (d, 1H). ' 2 ' Preparation of 2 2,4,6-trimethylbenzoic acid 1-Amino-4_yl group

Preparation of 〇-(2,4,6-triphenylsulfonyl)hydroxylamine at 0 ° C, prepared as described in 1977, 1; 2.17 g, 1 〇1 anhydrous dioxane The (21 ml) solution was added dropwise to stirred iso-nicotinic nitrile (1.05 g, 10.1 mmol) in dry di-methane (1 mL) and the mixture was stirred at s. The ethyl ether was then added to the mixture and the resulting precipitate 112 was collected by filtration. The title compound was washed with diethyl ether and dried in vacuo to give the title compound (3.03 g, 94%) as a white solid. LRMS (m/z): 120 (M+l)+, 199 (M-1)·. JH-NMR δ (300 MHz, CD3OD): 2.2 (s, 3H), 2.6 (s, 6H)s 6.9 ( Bs, 2H), 8.3 (d, 1H), 8.9 (d, 1H). 'Preparation 3 3-(4-Hydroxypyrimidinyl)pyrazolo[i,5_fl]pyridine_5-carbonitrile

a) 3-(4-Methoxypyrimidin-2-yl)pyrazolo[l,5-d]pyridine-5-carbonitrile 2,4,6-tridecyl group at 6 ° C under 6 ° C 1-Amino-4-amidopyridinium benzenesulfonate (preparation 2, 12.10 g, 37.88 mmol) was added portionwise to stirred 2-ethynyl-4-methoxypyrimidine (preparation lb, 2.54 g) , 18,94 millimoles) and potassium carbonate (3.93 grams '28 43 mM) in a suspension of anhydrous #'-dimethylformamide (47 ml) and the resulting mixture was stirred at ambient temperature 48 hours. The solvent was evaporated and dioxane &amp; added to the residue. The solid formed was filtered and the filtrate was evaporated to dryness. The crude product was purified by EtOAcjjjjjjjjj LRMS (m/z): 252 (M+l)+. ^-NMR δ (300 MHz, CDC13): 4.1 (s, 3H), 6.6 (d lH) 7.0 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H) , 9.1 (s, iH). 'b) 3-(4-Hydroxypyrimidin-2-yl)pyrazolo[l,5-e]pyridine_5_甲猜113 201130839 Gas tridecyl decane (0.61 ml, 4.83 mmol) and hydrazine Sodium (0.72 g, 4.83 mmol) was added to the stirred 3-(4-methoxyxyridin-2-yl)pyrazolo[w-fl]pyridine-5-indolecarbonitrile (Preparation 3a, 0.14) The mixture was heated in a sealed tube at 7 (rc) and allowed to stand overnight. The mixture was then cooled and the solvent was evaporated. Water (4 mL) and 10 An aqueous solution of sodium thiosulfate (5 ml) &amp; was added to the residue and the suspension was stirred for 20 min. The suspension was filtered and dried in vacuo to give the title compound in quantitative yield, without further step. Purification was used in the next synthesis step. LRMS (m/z): 238 (M+l) +. b-NMR δ (300 MHz, DMSO-i/6): 6.3 (d, 1H), 7.5 (d, 1H), 8.1 (d, 1H), 9.0 (s, 1H), 9.1 (s, 1H), 9.1 (d, 1H). Preparation 4 2-pyrazolo[l,5-fl]pyridine-3- Pyrimidine-4-ol

a) 3-(4-decyloxypyrimidin-2-yl)pyrazolo[l,5-ii]pyridine according to the experimental procedure as described in Preparation 3a, from 2-ethynyl-4-ylmethoxypyrimidine The bite (preparation lb) and the moth-l-amine octagonal rust gave a solid (49%) which was subsequently purified by flash chromatography (4:1 hexane/ethyl acetate). LRMS (m/z): 227 (M+l)+. 'H-NMR δ (300 MHz, CDC13): 4.1 (s, 3H), 6.5 (dd, 1H) 114 201130839 8.6 (dd, 1H), 8.6 (d, 6.9 (t, 1H), 7.4 (dd, 1H ), 8.5 (dd, 1H), 1H), 8·7 (s, 1H). 'b) 2·pyrazolo[1,5-exobiidine_3·ylpyrimidin-4-ol added 48% aqueous hydrogen bromide (19 5 ml) to 3♦ methoxy ke-2-yl K is sparged and heated to 1 Torr in a mixture with a bite (preparation, 〇% gram, 卫 莫). After 3 hours, the mixture was cooled, and the obtained residue was evaporated, mjjjjjjjj LRMS (m/z): 213 (M+l)+. Preparation of 5- 2-ethane-6-ethynylpyridine

SiMe3

a) 2-Ga-6-[(Trimethylmethane)-ethyl hydrazide] 〇 唆 according to the experimental procedure as described in Preparation la, from 2,6-dipyridine and ethynyl tridecyl decane The oil was obtained (38%) then purified by flash chromatography (hexane to 30:1 hexane / ethyl acetate). LRMS (m/z): 210 (M+l)+. b) 2-Ga-6-B fast-base ratio bite Obtained oil from 2-Ga-6-[(trimethyldecyl)ethynyl]pyridine (Preparation 5a) according to the experimental procedure as described in Preparation lb (29%), purified by flash chromatography (hexanes to 10:1 hexane / ethyl acetate) ^-NMR δ (300 MHz, CDC13): 3.2 (s, 1H), 7.3 (d, 1H), 7.4 (d, 1H), 7.6 (t, 1H). Preparation 6 3-(6-Gapyridin-2-yl)pyrazolo[l,5-a]pyridine_5-carbonitrile

According to the experimental procedure as described in Preparation 3a, biting from 2-chloro-6-ethynyl (preparation 5b) and 1-amino-4-cyanoguanidine 2,4,6-trimethylbenzenesulfonate A solid (30%) was obtained from the bite (Preparation 2), which was then purified by flash chromatography (99:1 miltoise/sterol). LRMS (m/z): 255 (M+l)+. H-NMR δ (300 MHz, CDC13): 6.9-7.1 (m, 1H), 7.2-7.3 (m, 1H), 7.5-7.8 (m, 2H), 8.4-8.7 (m, 2H), 9.0- 9.1 (m, 1H) ° Preparation 7 3-{4-[(3 and)-Acridine-3-ylamino]pyrimidine-2-ylpyrazole and bite-5-carbonitrile

116 201130839 Ο (31〇-3·{[2 cyano 吼 并 and U 5 a 対 基 基 基 胺 } } 旅 旅 旅 旅 -1- -1- -1- -1- -1- 嚷 嚷 嚷 嚷 -4- 将 将 将 将 将 将 10 10 10 10 - Amino-based red formic acid third butyl (149 mmol) added to the _ called 4 撼 money. Xie carbonitrile coffee b, 〇.7 〇 grams, 2.98 acid (benzotriazol-1-yloxy) table , ear, chaotic phosphorus, Mo,) ί and 8, diazabicyclo [5·4·. ] Ten-carbon-7, (〇.67 g, .48 house Moule) at dimethyl ketoamine (1) mil at room temperature _ the resulting mixture for 16 hours. Then under decompression $ remove the agent and will The residue was transferred to a mixture of EtOAc (EtOAc m.) The crude product was purified and the residue was obtained by reverse phase chromatography (Cl.sub.2 from Waters), water/acetonitrile/nonyl alcohol as the dissolving agent [passed by 01〇/〇v/v formic acid buffer) ] 〇% to 100%) re-purified to give the title compound (〇83 g, 66 〇/〇) and as a main reaction by-product of 3_(4·(ιη·benzo[d][l,2,3]3 Oxazole··················································· (Μ-1)-. ^-NMR δ (300 MHz, CDC13): 0.7-0.9 (m, 4H), 1. 5 (s, 9H), 1.6-1.7 (m, 2H), 1.7-1.9 (m , 2H), 2.0-2.1 (m, 1H), 5.0 (bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8. 6 (d, 1H), 8.8 (s, 1H), 9.1 (t, 1H). 1)) 3-{4_[(3Λ)-piperidin-3- Amino]pyrimidin-2-yl}pyrazolo[l,5-aj 117 201130839 Pyridine-5-carbonitrile Trifluoroacetic acid (0.61 ml, 7.97 mmol) was added to (8)·3·(2-( 5_Cyanopyrazolo[ι,5·β]pyridine_3_基r bite 4 Wu a see piperidine-1-decanoic acid tert-butyl ester (preparation 7a, 0.12 g, 〇27 base) In a solution of chlorodecane (4 ml) and stirring at room temperature, a 4% aqueous solution of sodium hydrogencarbonate and solid sodium hydrogencarbonate were added until the pH was basic and the mixture was further extracted with dioxane. The <RTI ID=0.0>(</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; M+l)+,318 (M-1)-.]H-NMR δ (300 MHz, CDC13): 0.8-0.9 (m, 4H), 1.5 (s, 9H), 1.8-2.3 (m, 5H) , 5.7 (bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.2 (d, 1H), 8.6 (d, 1H), 8.7 (s, 1H), 9.1 (bs, 1H). Preparation 8

(Ι〇·3·(4-(methyl(piperidin-3-yl)amino)pyrimidin-2-yl)oxazolo[1,5-λ]0 is more than a bite

a) (and)-3-((2-(5-cyano)pyrazole[1,5-&lt;1] "bipyridin-3-yl)pyrimidin-4-yl)(methyl)amine Piperidine-1-carboxylic acid tert-butyl ester sodium hydride (60% mineral oil dispersion, 102 mg, 2.55 mM 118 201130839 ear = added to the cooled ((rc) (10)-3 side $ atmosphere base 吼 7a , 0 83 ^ όί }Break bite * citrate third butyl to the solution (preparation of .3 a gram, 1.98 millimoles) of the solution ^ dimethyl dimethyl hydrazine) and the reaction mixture at the same temperature for 30 minutes Then add = generation (4) 35 ml ' 2.17 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The residue in the solvent zone of the vacuum towel was partitioned between water and ethyl acetate. The organic layer was separated, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LRMS (m/z): 434 (M+l)+. b) (and)-; 3-(4-(曱基(旅咬_3_基)基基) 鸣_2_基)0 than 啥[1,5-&lt;|] acridine-5 -carbonitrile according to the experimental procedure as described in Preparation 7b, from (π)·3-((2_(5-cyanopyrazolo[1,5-α]pyridin-3-yl)pyrimidin-4yl (Methyl)amino)benzidine tricarboxylic acid tert-butyl ester (Preparation 8a) gave a pale orange solid (77%). LRMS (m/z): 334 (M+l)+. ^-NMR δ (400 MHz, DMSO-c/6): 1.5-1.9 (m, 5H), 2.3-2.5 (m, 2H), 2.7 (t, 1H), 2.8-3.1 (m, 5H), 6.6 (bs, 1H), 7.3 (dd, 1H), 8.3 (d, 1H), 8.8 (s, 1H), 8.9-9.0 (m, 2H). Preparation of 9 2,4,6-trimethylbenzenesulfonic acid 1-aminopyridazine ‘4-镔 119 201130839

According to the experimental procedure as described in Preparation 2, a white solid (75) was obtained from pyrazine and (9-(2,4,6-dimethylphenyl fluorenyl) via an amine (such as my, 1). %) H-NMR δ (400 MHz, DMSO-i/6): 2.2 (s, 3H), 2.5 (s, 6H), 6.8 (s, 2H), 8.7 (d, 2H), 9.2 (d, 2H), 9.6 (s, 2H) ° Preparation 10, 20 to 20 and 嗓_3_ base) bite · 4_ ol Ν α0.

a) 3-(4-methoxyindole-2-yl) is compared to saliva [^540 嗓 according to the experimental procedure as described in Preparation 3a, from 2-ethynyl-4-methoxy pyrimidine ( Preparation of lb) and 2,4,6-trimercaptobenzenesulfonic acid 1-aminopyrazine·1·rust (Preparation 9) gave a solid (43%). LRMS (m/z): 228 (M+l)+. 'H-NMR δ (400 MHz, CDC13): 4.1 (s, 3H), 6.6 (d, 1H), 8.0 (d, 1H), 8.4 (dd, 1H), 8.5 (d, 1H), 8.8 (s , 1H), 10.0 (s, 1H). 120 201130839 b ) 2-(° than saliva [1,5·β] ° than 嗓_3_ base) Pain-4-ol according to the experimental procedure as described in Preparation 4b, from 3-(4-曱(oxypyrimidin-2-yl)oxazolo[1,5-α]pyridazine (Preparation 10a) afforded (83%). LRMS (m/z): 214 (M+l)+, 212 (M-1). ^-NMR δ (300 MHz, DMSO-J6): 6.4 (d, 1H), 8.2 (d, 1H), 8.2 (s, 1H), 9.0 (dd, 1H), 9.0 (s, 1H), 9.9 ( d, 1H). Preparation 11 (piperidin-3-yl)-2-(pyrazolo[l,5-fl]pyrazin-3-yl)pyrimidine-4-

a) (/^-3-(2 pyrazolo[1,5-α] "pyrazin-3-yl)pyrimidin-4-ylamino) piperidine-1-carboxylic acid tert-butyl ester as prepared The experimental procedure described in 7a consists of 2-(pyrazolo[1,5-fl]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and (3 and)-3-aminopiperidine The tert-butyl phthalate was obtained (50%) and then purified by flash chromatography (dichloromethane: to 97:3 dichloromethane / methanol). LRMS (m/z): 396 (M+l)+. b) (piperidin-3-yl)-2-(pyrazolo[1,5-indole]pyrazin-3-yl)pyrimidine-4-amine 121 201130839 according to the experimental procedure as described in Preparation 7b, (Λ)-3-(2-(pyrazolo[1,5-α]pyrazin-3-yl)patridine-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 11a) And trifluoroacetic acid was obtained (91%). LRMS (m/z): 296 (M+l)+. iH-NMR δ (400 MHz, CDC13): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 3H), 2.7-3.0 (m, 4H), 3.2-3.3 (m, 1H), 5.5 (bs , 1H), 6.2 (d, 1H), 8.0 (d, 1H), 8.2 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), l〇.〇(s, 1H). Preparation 12 TV-methyl-7V-[(3i?)-Blan-3-yl]-2-e is more than [嗤,[1,5·β]β is more than pyridyl-4-pyrimidine-4-amine

a) (3i?)-3-[methyl(2-π-butan-amino)piperidine-1-carboxylic acid tert-butyl ester according to the experimental procedure as described in Preparation 8a, from (i〇-3- (2-(pyrazolo[1,5·α]pyridinium,3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (preparation 1 la} and anthraquinone obtained ( 9%&gt;, followed by reverse phase chromatography (with alcohol as a containment agent [via Waters C-18 cerium oxide, water/acetonitrile/methyl 0.1% v/v formic acid buffer] 5 Purification from % to 50%) 122 201130839 LRMS (m/z): 410 (M+l)+ b) M-mercapto-[[3 and]piperidin-3-yl] is more than [1,5 -ii] pyrazin-3-yl-snack-4-amine according to the experimental procedure as described in Preparation 7b 'from (3 and)-3-[methyl(2-pyrazolo[1,5-α]] N-butyrazine-3-ylpyrimidin-4-yl)amino]piperidine-1-decanoic acid tert-butyl ester (preparation 12a) and trifluoroacetic acid afforded (94%). LRMS (m/z): 310 ( M+l)+. Preparation 13 5-Ga-2-ethynyl-4-oxirane bite

Ο 5-Ga-4-oxooxy-2-[(trimethyldecyl)ethynyl]pyrimidine according to the experimental procedure as described in Preparation la, from 2,5-diox-4-methoxypyrimidine (prepared as described in reira/ie, Z^. 2006, 4 7, 4415) and ethynyltrimethylnonane (44%), followed by flash chromatography (di-methane to 4:6 dioxane) Alkane/hexane) was purified. LRMS (m/z): 241 (M+l)+. 'H-NMR δ (300 MHz, CDC13): 0.1 (bs, 9H), 3.8 (bSj 3H), 8.1 (s, 1H). 'b) 5_Gas·2-B-Ketyl·4_Methoxy-mouth bite according to the experimental procedure as described in Preparation lb, from 5-chloro-4_methyl-based 123 201130839 -2-((三曱The hydrazinoalkyl)ethynylpyrimidine (Preparation 13a) gave a gray solid stomach (78%) which was subsequently purified by flash chromatography (9:1 hexanes/acetic acid). LRMS (m/z): 169 (M+l)+. 'H-NMR δ (300 MHz, CDC13): 3.1 (s, 1H), 4.1 (s, 3H) 8.4 (s, 1H). , , Preparation 14 5-Gas·2·° ratio 嗤[l,5-fl]D is more than 嗓-3-based 嚷4_ol

a) 3-(5-Gas-4-methoxypyrimidin-2-yl)pyrazolo[L5W]pyrazine according to the experimental procedure as described in Preparation 3a, from 5-chloro-2-ethynyl Aminopyrimidine (Preparation 13b) and trimethyl sulphonyl sulfonylpyrazine + (Preparation 9) gave an orange solid (84%), followed by flash chromatography (~~~~~~~~~~~ Methane / sterol) purification. LRMS (m/z): 262 (M+l)+. H-NMR δ (300 MHz, CDCI3): 4.2 (s, 3H), 8.0 (d, 1« '(d,1H), 8.5 (s,1H),8.7 (s,1H), lO.o ( s, 1H) b) 5-gas K嗤[ww]pyrazine·3 pyrimidine _4 alcohol according to the experimental procedure as described in Preparation 4b, from 3_(5-chloro-4-methylpyridinium 対2_^π than salivary Μ 比 比 嗪 ( (preparation of green solid "y 62%" 〇 124 201130839 Preparation 15 5-chloro-AM (3 and)-piperidin-3-yl]-2-pyrazole [1, 5_α]°pyrazin-3-ylpyrimidine-4-amine

a) (37?)-3·[(5-gas·2·π is more than 1[1,5-έΐ]11 than 嗓-3-yl-bend-4-yl) Amino] Piperidine-1- Tert-butyl formate according to the experimental procedure as described in Preparation 7a, from 5-chloro-2-(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 14b) And (i?)-3-aminopiperidine 1-decanoic acid tert-butyl ester obtained as a yellow solid (40%), which was subsequently purified by flash chromatography (hexanes to 6:4 hexanes / hexanes) . LRMS (m/z): 430 (M+l)+. !H-NMR δ (300 MHz, CDC13): 1.4 (bs, 9H), 1.7 (bs, 3H), 1.9-2.1 (m, 2H), 3.4 (bs, 1H), 3.7 (bs, 2H), 4.3 (bs, 1H), 5.6 (bs, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 9.9 (s, 1H). b) 5-gas _7V-[(3i?)-piperidin-3-yl]-2-»biszolo[l,5-ii]pyridazin-3-ylpyrimidin-4-amine according to preparation 7b The experimental procedure described in the 3-(5-chloro-2-(pyrazolo[1,5-ίφpyrazin-3-yl)pyrimidin-4-ylamino)piperidine-1-decanoic acid Tributyl ester (Preparation 15a) and trifluoroacetic acid afforded a yellow solid (87%).

125 201130839 LRMS (m/z): 330 (M+l)+. h-NMR δ (300 MHz, CDC13): 1.3 (bs, 2H), 1.9 (bs, 3H), 2.9 (bs, 3H), 3.2-3.3 (m, 1H), 4.4 (bs, 1H), 5.9 ( Bs, 1H), 8.0 (d, 1H), 8.2 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 9.9 (s, 1H). Preparation of 16 2-ethynyl-5-fluoro-4-methoxypyrimidine

a) 2-A-5-fluoro-4-methoxypyrimidine Add 2,4-dichloro-5-fluoropyrimidine to a mixture of sodium (450 mg, 19 mmol) in methanol (20 mL) A solution of 3.25 grams, 19 millimoles of methanol (10 ml). The reaction mixture was stirred overnight at room temperature then partitioned between water and diethyl ether. The organic phase was separated, washed with EtOAc EtOAc m. ]H-NMR δ (400 MHz, CDC13): 4.1 (s, 3H), 8.2 (s, 1H) 〇b) 5-fluoro-Φ·methoxy 2_[(trimethyldecyl)ethynyl] The pyrimidine was purified from 2-gas-5-fluoro-4-indole according to the experimental procedure as described in the preparation of la. Obtaining oxypyrimidine (Preparation 16a) and ethynyltrimethylnonane (17%) followed by flash chromatography (2:8 hexanes / dioxane to 1% dioxane) 126 201130839 LRMS (m/z): 225 (M+l)+. !H-NMR δ (400 MHz, CDC13): 0.1 (s, 9H), 3.8 (s, 3H), 8.0 (d, 1H). c) 2-ethynyl-5-fluoro-4-methoxypyrimidine according to the experimental procedure as described in Preparation lb, from 5-fluoro-4-decyloxy-2-((tridecyldecyl)acetylene The pyrimidine (preparation 16b) was obtained (82%), which was subsequently purified by flash chromatography (99:1 dioxane / methanol). ^-NMR δ (400 MHz, CDC13): 3.1 (d, 1H), 4.1 (s, 3H), 8.3 (d, 1H). Preparation 17 5-Fluoro-2-«* than spit [l,5-flf]D is more than 嗓-3-yl-mouth -4- alcohol

a) 3-(5-fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5·α]pyrazine according to the experimental procedure as described in Preparation 3a, from 2-ethynyl-5 -Fluoro-4-methoxypyrimidine (Preparation 16c) and 2,4,6-trimercaptobenzenesulfonic acid 1-Amino oxazin-1-yl (Preparation 9) were obtained (72%), followed by a flash Chromatography (dichlorodecane to 97:3 dichloromethane / methanol) was purified. LRMS (m/z): 246 (M+l)+. ^-NMR δ (400 MHz, CDC13): 4.2 (s, 3H), 8.0 (d, 1H), 8.4 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 10.0 (d, 1H).

127 201130839 b) 5-Fluoro-2-β is a mixture of salino[1,5-&lt;|]*1 -3-yl-biting-4-ol in a microwave container (13 ml 6) A solution of strontium, 78 mM) was added to 3-(5-extra-4-methoxyindol-2-yl) π than salino[Μα] t-qin (preparation 17a, 0.38 g, 1 mmol) )in. The resulting mixture was subjected to microwave irradiation at 120 ° C for 1 hour. After cooling to room temperature, an aqueous 8 n sodium hydroxide solution was added until an alkaline pH was reached. The solid which was formed was filtered and dried to give the title compound <RTIgt; LRMS (m/z): 232 (M+l)+. ^-NMR δ (400 MHz, DMSO-^): 8.1-8.2 (m, 3H), 9. 〇 (bs, 1H), 9.8 (bs, 1H). ''' Preparation 18 biting amine

a) (from) -3_[(5-fluoro:pyrazolopyrazinylpyrimidinyl-4-yl)amino)triazol-1-carboxylic acid tert-butyl ester according to the experimental procedure as described in Preparation 7a, by 5 _Fluoro-2_(pyrazoloindole, 5-oxa-3-yl) as 4-alcohol (preparation 17b) and (iv) _3•amino-based = formic acid terpene vinegar to obtain a white solid (), followed by a flash Purification by chromatography (dichlorosilane to 95:5 di-methane/methanol). 128 201130839 LRMS (m/z): 414 (M+l)+. !H-NMR δ (400 MHz, CDC13): I.4-I.5 (m, 2H)

9H), 1.8 (m, 1H), 1.9-2.0 (m, 1H), 2.0-2.1, (m, '1H, 4, 1H), 3.6 (bs, 1H), 3.7 (bs, 1H), 4.3- 4.4 (m, 1H), 8 im 8.1 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 9.9 (d, 1H). U b) 5-Fluoropyrene (10))-Butyridin-3-yl]-2-oxazolo[i,5_a]npyrimidin-4-amine band _ _ according to the experimental procedure as described in Preparation 7b, (and) _3_(5_fluoro-2-01-pyrazolo[1,5-α]pyrazin-3-yl) distyryl 4-methylamino acetazinic acid tert-butyl ester (preparation 18a) and Trifluoroacetic acid was obtained as a solid (94%) then purified by flash chromatography (dichloromethane to <RTIgt; LRMS (m/z): 314 (M+1). !H-NMR δ (400 MHz, CDCI3): 1.6 (m, 1H), 1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.1 (bs, 1H), 2.8-2.9 (m, 2H) , 3.3 (bs, 1H), 4.3-4.4 (m, 1H), 5.7 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H), 8.4 (dd, 1H), 8.6 (s, 1H) ), 9.9 (d, 1H) ° Preparation of 19 2-B-Pet-4-methoxy-5-methyl mouth bite

SiMe〇

a) 2-Actyl-4-methoxy-5-methylpyrimidine 129 201130839 Obtained as a white solid (85%) from 2,4-dis-5-mercaptopyrimidine according to the experimental procedure as described in Preparation 16a It was then purified by flash chromatography (hexane to 95:5 hexanes / ethyl acetate). LRMS (m/z): 159 (M+l)+. !H-NMR δ (400 MHz, CDC13): 2.1 (d, 3H), 4.0 (s, 3H), 8.1 (d, 1 H). b) 4-methoxy-5-methyl-2-[(trimethyldecyl)ethynyl]pyrimidine according to the experimental procedure as described in Preparation la, from 2-chloro-4-decyloxy-5 - Mercaptopyrimidine (Preparation 19a) and ethynyltridecyldecane afforded a yellow solid (19%). LRMS (m/z): 221 (M+l)+. ^-NMR δ (400 MHz, CDC13): 0.1 (s, 9H), 1.9 (d, 3H), 3.7 (s, 3H), 7.9 (s, 1H). c) 2-ethynyl-4-methoxy-5-methylpyrimidine according to the experimental procedure as described in Preparation lb, 4-methoxy-5-mercapto-2-((tridecyl)alkyl Ethyl acetyl pyrimidine (Preparation 19b) gave a white solid (55%) which was subsequently purified by flash chromatography (dichlorohexane). LRMS (m/z): 149 (M+l)+. ^-NMR δ (400 MHz, CDC13): 2.2 (s, 3H), 3.0 (s, 1H), 4.0 (s, 3H), 8.2 (s, 1H). - Preparation of 20 3-(4-methoxy-5-methylpyrimidin-2-yl)pyrazolo[l,5-fl]pyrazine 130 201130839

Methoxy-5-methylpyrimidinazole, 1,5-halothazine, according to the experimental procedure described in Preparation 3a, Methyl Hydroxide $5-fluorenyl pour (Preparation of 19 〇 and 2, Recognition of 曱 曱 ^ Acid bromide (Preparation 9) gave a yellow solid (&quot;%), followed by cardiochromatography (one gas smoldering to 95:5 dioxin/decanolization. LRMS (m/z): 242 (M+l ) + (s, 3H), 4.2 (s, 3H), 8-7 (s, 1H), 10.0 (d, ^-NMR δ (400 MHz, CDC13): 3.〇8.0 (d, 1H), 8.3 (d, 1H), 8.4 (dd, 1H), 1H). , b) 3-(4-methoxy_5_methylate_2_based odorization and deuteration ratio 35% hydration Oblique water-soluble, liquid (5 ml) was added to 3_(4-methoxy-5-methyl-hydroxy-2-ylindole and tl, 5♦-pyrazine (preparation, (four) grams, 2.89 millimoles) of ethanol ( 1 mM) solution. The mixture was placed in a microwave vessel and subjected to microwave irradiation at 130 ° C for 1 hour. After cooling to room temperature, the organic solvent was removed under reduced pressure and the residue was acidified with 5 N aqueous hydrogen chloride. The resulting solid was washed with EtOAc (mjqqqqqq : 3.3 (bs, 3H), 8.0 (bs? 1H), 8.1 (bs, 1H), 9.0 (bs, 2H), 9.8 (bs, 1 H). 131 201130839 Preparation 21 5-methyl-ΛΓ-[(3 And)-piperidin-3-yl]-2-pyrazolo[1,5-α]pyrazin-3-ylpyrimidin-4-amine

a) (3Λ)-3-[(5-Methyl-2-pyrazolo[l,5-ii]&quot;pyrazin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid Third butyl ester according to the experimental procedure as described in Preparation 7a, from 5-methyl-2-(pyrazolo[1,5-pyrazine-3-yl)pyrimidin-4-ol (Preparation 20b) and (3i?)-3-Aminopiperidine-1-carboxylic acid tert-butyl ester obtained as a yellow oil (yield: 58%), then purified by flash chromatography (hexane to 30: 70 hexane / ethyl acetate) . LRMS (m/z): 410 (M+l)+. !H-NMR δ (400 MHz, DMSO-^ai^ (bs, 1H), 1.4 (bs, 1H), 1.7 (bs, 1H), 1.8 (bs, 1H), 2.1 (s, 6H), 2.0 ( s, 3H), 2.8-2.9 (m, 1H), 3.4 (s, 3H), 3.9 (bs, 2H), 4.0 (q, 1H), 4.1 (bs, 1H), 8.0 (d, 1H), 8.1 (s, 1H), 8.9 (bs, 2H), 9.8 (s, 1H) ° b) 5-indolyl-#-[(3 and)·piperidin-3-yl]-2-pyrazolo[1 , 5-oxime pyrazin-3-ylpyrimidin-4-amine according to the experimental procedure as described in Preparation 7b, from (7?)-3-(5-mercapto-2-(pyrazolo[1, 5-Binyl]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 21a) and trifluoroacetic acid afforded a yellow oil (85%). LRMS (m/z): 310 (M+l)+. 132 201130839 b-NMR δ (400 MHz, CDC13): 1.6 (bs, 2H), 1.8 (bs, 2H), 2.1 (s, 3H), 2.7-2.9 (m, 1H), 3.2-3.3 (m, 2H) ), 4.4 (bs, 2H), 7.9 (d, 1H), 8.0 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 10.0 (s, 1H). Preparation 22 3-Moine than 唆[1,5-fl] ° bite

a) Pyrazolo[1,5-ii]pyridine-3-carboxylic acid ethyl ester ethyl propionate (50.2 ml, 49.54 mmol) and 1-aminopyridinium iodide rust (10.0 g, 45 mmol) The mixture was added to a suspension of potassium carbonate (8.71 g, 63.02 mmol) in dimethyl decylamine (100 ml) and the mixture was stirred at room temperature for 2 hours, then poured into 100 ml of water. Ethyl acetate was then added and the aqueous layer was separated and washed with ethyl acetate (twice). The combined organic layers were dried with MgSO4, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjj LRMS (m/z): 191 (M+l)+. !H-NMR δ (250 MHz, CDC13): 1.4 (t, 3H), 4.3 (q, 2H), 6.9 (t, 1H), 7.4 (t, 1H), 8.1 (s, 1H), 8.4 (s , 1H), 8.5 (d, 1H). b) 0 than saliva [l,5-ii]n than biting-3-carboxylic acid 2.5 N aqueous sodium hydroxide solution (36 ml) was added to the ratio of salivation [1,5-indole|pyridine-3-carboxylic acid B Ester (Preparation 22a, 4.3 g, 22.6 mmol) 133 201130839 in ethanol (70 mL) and the resulting reaction mixture was heated to reflux for 1 hour. After evaporating the ethanol, the reaction mixture was acidified with a 15% aqueous hydrochloric acid solution. The solid formed was filtered, washed with EtOAc EtOAcjjjjjjj LRMS (m/z): 163 (M+l)+. ^-NMR δ (250 MHz, DMSO-c/6): 7.1 (t, 1H), 7.6 (t, 1H), 8.1 (dd, 1H), 8.4 (s, 1H), 8.9 (d, 1H), 12.5 (s, 1H). 'c) 3-bromopyrazolo[l,5_a]pyridine Adds iV-bromobutaneimide (3.06 g, 17.22 mmol) and sodium bicarbonate (4.34 g, 51.66 mmol) to pyrazole And [丨5_β]pyridine-3-carboxylic acid (preparation 22b ' 2.81 g, 17.22 mol) in a solution of dimethylformamide (4 g ml), freshly obtained at room temperature for 4 hours, then stepped 100 liters of water. The resulting suspension was extracted twice with ethyl acetate and dried over magnesium sulfate and filtered and evaporated. The crude product was purified by EtOAc EtOAcqqqqq LRMS (m/z): 197 (M+l)+. ,7·2 (t,1H),

'H-NMR δ (250 MHz, CDC13): 6.8 (t, 13⁄4) (d, 1H), 7.9 (s, 1H), 8.4 (d, 1H). ' Preparation 23 3- Desert and [1嗓

134 201130839 a) Pyrazolo[1,5-α]pyrazine-3_decanoate ethyl ester according to the experimental procedure as described in Preparation 22a, from 1,4,6-trimercaptobenzenesulfonic acid 1-amine The pyrazine-1- rust (Preparation 9) and ethyl propionate gave an orange solid (28%) which was subsequently purified by flash chromatography (hexane to 4: 6 hexane / ethyl acetate). LRMS (m/z): 192 (M+l)+. b) ° 啥 and [1,5-α] ° than 嗓-3-decanoic acid according to the experimental procedure as described in Preparation 22b, from pyrazolo[1,5-α]pyrazine-3-carboxylic acid The ester (Preparation 23a) gave a white solid (99%). LRMS (m/z): 164 (M+l)+. c) 3-bromo-ratio 嗤[l,5-fl]° ratio 0 Qin according to the experimental procedure as described in Preparation 22c, sitting on 吼0 and [l,5-fl]pyridazine-3·decanoic acid (Preparation 23b) Obtained as a pale yellow solid (yield: 69%), then purified by flash chromatography (2:8 to 6:4 ethyl acetate /hexane). LRMS (m/z): 198 (M+l)+. Preparation 24 3-(4-Ga-5-mercaptopurine-2-yl)β 唆[[,5-ii]D 嗓

135 201130839 a) &quot;Bizozolo[1,5-α]pyrazine-3-methyl ugly amine: Will be sputum and [1,5-exo-indole-3-carboxylic acid (preparation 23b, 6 7 gram, The 41.1 millimolar sulfite (50 liter) suspension was heated to reflux for 7 hours. After cooling, the reaction mixture was concentrated in vacuo and residue was combined with EtOAc (2×30 mL). The obtained solid was suspended in an aqueous solution of ammonium oxalate (8 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated to dryness to give a crude coloured compound (10.0 g. &gt; 100%) which was used in the next synthetic step without further purification. LRMS (m/z): 163 (M+l)+. 8.7 (s, 1h NMR δ (300 MHz, DMS0-4): 8.1 (d, 1H) 1H), 8.9 (d, 1H), 9.6 (s, 1H). 'b)pyrazolo[1,5-α]pyrazine-3-carbonitrile: crude pyrazolo[1,5-α]pyrazine-3-carboxamide (preparation 24a, 6 66 g) The phosphonium trichloride (80 ml) suspension was heated to reflux for 2 $ hours. The reaction mixture was then poured onto a saturated aqueous solution of sodium bicarbonate (2 (9) mL) and then adjusted to pH 7-8 by the addition of 10% aqueous sodium hydroxide. The mixture was extracted with EtOAc (EtOAc m. 3.1 〇 gram, 52%) 〇LRMS (m/z): 145 (M+l)+. 4 NMR δ (300 MHz, DMSO-)·· 8·3 (d, 1H), 8.8 (s, 136 201130839 1H), 9.1 (d, 1H), 9.5 (s, 1H). O » than saliva [1,5_啦备3_Carbium imine amide 遵 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 新鲜 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 6: Mo 2) Add the house Moer) anhydrous methanol (35G mA =, stir the mixture under 42.3. η I «Main A $ tens of dry and at ambient temperature: = 20 hours after the mouth, add sodium methoxide ( 〇. Ear) and then stir the reaction mixture 4M, time 9 and t-shirt, 'concentrate the mixture to dry, get _ body, suspend it: B @ 乙ethyl and stir overnight. Filter the precipitate and in vacuum i The title compound (8 50 g, &lt;^%) was obtained as a white solid, which was used for the next step without further purification. 〇LRMS (m/z): 162 (M+l)+ 4 NMR δ (300 匪2, DMSO-can 8.2 (d, 1H), 8.8 (s 1H), 9.0 (d, 1H), 9·5 (s, 1H). ' ' d) 5_Nitro_ 2 decathiazole [ι,5_β]pyridazine_3_yl)pyrimidine·4·Alcohol stirs the crude carbazole and [1,5-α]pyridazine_3-carboximine imide salt in a sealed tube Acid salt (preparation 24c, 4.88 g), (Ζ)-3-(dimethylamino)_2-nitroenedienoic acid ethyl ester (8.04 g, 4 A mixture of 2.7 mmoles and triethylamine (6.25 mL &apos; 44.8 mmol) in ethanol (165 mL) and warmed to 90 &lt;0&gt;C. After 22 hours, the title compound was obtained (jjjjjjjjjjjjjjjj LRMS (m/z): 257 (M-l)+. 137 201130839 NMR δ (300 MHz, DMSO-i/6): 8.1 (d, 1H), 8.7 (s 1H), 8.8 (s, m), 8.9 (d, 1H), 9.9 (s, 1H). 'e) 3-(4-Ga-5-颂-base mouth-2-yl)" 唆 【 [1,5-ίϊ] n-pyrazine in a sealed tube with 5-nitro-2 decapyridazole [1,5-α]pyridazine_3·yl) shouted _4_alcohol (prepared 24d, 1.50 g '5.8 mM) of a phosphonium trioxide (12 ml) suspension and heated to 90 °C. After 2 hours, the mixture was concentrated in vacuo and the residue was azeotroped with toluene. The solid was treated with aq. EtOAc EtOAc (EtOAc) , LRMS (m/z): 277 (M+l)+. NMR δ (300 MHz, DMSO-禹): 8.3 (d, 1H), 9 〇 1H), 9.1 (d, 1H), 9.6 (s, 1H), 9.9 (s, 1H). 'S, Preparation 25 5-Mercapto-2-(ntt 并[1,5·έΐ]α 比嗜·_3-yl)-N-(tetrahydropyran-4-yl)pyrimidine-4-amine

Diisopropylethylamine (2.30 ml, 13.20 mmol) and acid tetrahydro-2H-pentan-4-amine (526 mg, 3.28 mmol) were added to = agitated: 3-(4- Gas _5_nitrode_2_yl)α ratio σ sits and [1,5-α]η ratio D Qin (manufactured 138 201130839 24e, 0.91 g, 3.29 mmol) of tetrahydrofuran (l5 float The mixture was stirred at room temperature for 3 hr. EtOAc (m.). l) +. Preparation 26 Ν-(4,4·Difluorocyclohexyl)_5_determinyl_2_(ο比佐[1,5-α]0 ··3-yl)pyrimidine-4-amine

According to the experimental procedure as described in Preparation 25, from 3-(4-chloro-5-nitropyrimidin-2-yl)pyrazolo[1,5-α]pyrazine (Preparation 24e) and 4,4- Difluorocyclohexylamine gave a yellow solid (86%). LRMS (m/z): 376 (M+l)+. 4 NMR δ (300 MHz, DMSO-4): 1.9-2.2 (m, 8H), 4.6 (m, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.9 (s, 1H), 9.0 (d, 1H), 9.2 (s, 1H), 9.9 (s, 1H). Preparation 27 3-(6-Chloroindol-2-yl)0 嗤[[,5-ii] bite 139 201130839

a) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin 4 _2-yl) "Bizozolo[1,5-α|pyridine will be 4,4,4 ,,4,5,5,5,5,-octamethyl-2,2,-bis(1,3,2-dioxaboron 4) (1.27 g '5.0 mmol), acetic acid (II) (0 〇5〇g, 〇228 mM), tricyclohexylphosphine (0.127 g, 0.46 mmol), potassium carbonate (0.945 g, 6.84 mmol) and water (〇.〇5 ml) Add to 3-&gt;Smelly 1» sit in a solution of 0 and [丨, Bu Chong than bite (prepared Dc, 〇g, 4% mmol) in diethylene glycol dimethyl ether (10 ml) and 1〇〇. The resulting mixture was heated under the arm for 2 hours. After cooling, the reaction mixture was filtered through Celite® and dissolved with methanol. The filtrate was evaporated and the crude product was used in the next step without further purification. LRMS (m/z): 245 (M+l)+. b) 3-(6-Chlorine ratio "Qin-2-yl) alpha is more than saliva [1,5·α|&quot; than biting 2,6-dichloropyrazine (0.316 g, 2.12 mmol) , ginseng (dibenzylideneacetone) dipalladium (0) (0.097 g, 0.106 mmol), tricyclohexylphosphine (0.06 g '0.212 mmol) and potassium phosphate (1.35 g, 6.36 mmol) To 3-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-4-yl) "Bisto[1,5-α]pyridine (Preparation 27a, 0.518 g, 2.12 millimoles of W-didecylguanamine (1 ml) suspension. The mixture was subjected to microwave irradiation for 40 minutes at 10 ° C. The reaction mixture was filtered through cdite® and dissolved with 140 201130839 sterol 'While the filtrate was evaporated. EtOAc EtOAcqqqqqq LRMS (m/z): 231 (M+l)+. ^-NMR 6 (250 MHz, CDC13): 7.0 (t, 1H), 7.4 (t, 1H), 8.3 (s, 1H), 8.5 ( s, 1H), 8.5 (m, 2H), 8.8 (s, 1H) 〇 Preparation 28 (Λ)-Λ "·(piperidin-3-yl)-6-(pyrazolo[l,5-tf] Pyridin-3-yl)pyrazine-2.amine

a) (and) -3- (6-(° than 嗤 and [l,5-a] etb bite each base) ° specific noise-2-ylamino) piperidine-1-carboxylic acid tert-butyl ester ( 3^-3-Aminopiperidine-1-decanoic acid tert-butyl ester (0.51 g, 2 54 mM) and cesium fluoride (0.83 g, 5.46 mmol) were added to the scrambled 3-( 6-Gas-2-yl; Kt嗤[l,5-a]D is a solution of the bite (preparation 27b, 0.42 g '1.82 mmol) in dimethyl sulfoxide (20 mL) at 100 ° The resulting mixture was stirred for 22 hours, then poured over EtOAc (EtOAc) (EtOAc). ': 7 to 7.3 ethyl acetate / hexanes. EtOAc EtOAc (EtOAc: EtOAc) 〇b)(8)-TV·(M.3_yl-2-amine -3-yl)e than hydrazine trifluoroacetic acid (4) 5 ml, 4. (Magic -3-(6-(pyrazolopyrene, 5) -α]pyridin-3-yl)pyrazine, ear) added to a solution of tert-butyl formate (preparation 28a, 0.3 gram gram of fluorenyl-amino) piperidine-1-chloromethane (10 ml) And in the second night of 'warm production 7 2: Moer', then at 50 ° C for another 24 hours. ^ $ The solution of the solution is redissolved in di-methane and washed: the residual phase, Filtration and evaporation of the solvent. <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; LRMS (m/z): 295 (M+l)+. Preparation 29 3-(6-Gapyrazin-2-yl)pyrrolidin[15-pyrazine

〇-· v=n

Cl

[!, 二Γ,4,5,5-tetramethyl-cut-dioxanyl (four) and reverse; ^ΐί prepared in the experimental procedure, after l (Krc under irradiation should be mouthwash hour, by 3 -Bromo-ratio to salivation [1,5-La oxime (Preparation 23c) 142 201130839. The crude product was used in the next synthesis step without further purification. LRMS (m/z): 246 (M:1)+. b) 3-(6-gas β -2--2-yl) ° 嗤 and [ι,5-α]β 比 according to the experimental procedure as described in Preparation 27b, from 3-(4,4,5 ,5-tetramethyl-1,3,2-dioxaboron-4-yl-2-yl)pyrene is more than saliva[ΐχ〇比嘻(Preparation 29a) gives a yellow solid (28% yield 'two steps'' Purified by flash chromatography (2:8 ethyl acetate /hexane). LRMS (m/z): 232 (M+l)+. Preparation 30 (J?)-#·(旅咬_3_基)_6·(°比峻和[1,5_fl]比嗓_3_基)吼嗓·2_amine

a) (and)-3-(6-(° than saliva[1,5-έΐ]®pyrazin-3-yl)°bazine-2-ylamino) piperidine-1-carboxylic acid tertidine The ester was (37^)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (0.41 g, 2,05 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (0.034 g, 0.037 mM), 9,9-dimercapto-4,5-bis(diphenylphosphino)indole 3〇5 (0.043 g, 0.074 mmol) and cesium carbonate (0.843 g, 2.6 mmol) Add to 3-(6-chloropyran-2-yl) ° 嗤[1,5-α]η azine (preparation 29b, 0.43 g, 1.86 mmol) of decyl decylamine The resulting mixture was purged (10 ml) with argon and then heated to 1 Torr. 〇后维 143 201130839 for 7 hours. After cooling to ambient temperature, the reaction mixture was filtered through Cdite® eluting with methanol. The filtrate was evaporated and purified EtOAc EtOAcjjjjjjjj LRMS (m/z): 396 (M+l)+. b-NMR $(250 IVIHz, CDC13): 1.4 (s, 9H), 1.8 (m, 2H), 2.0 (m, 2H), 3.5 (m, 3H), 3.7 (m, 1H), 4.1 (m, 1H), 4.8 (m, 1H), 7.8 (s, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (dd, 1H), 8.5 (s, 1H), 9.8 (d, 1H) ). b) (and (Brigade-3-yl)-6-(«比嗤[i,5_fl]吼_3_yl) indole-2-amine according to the experimental procedure as described in Preparation 28b, (and) _3-(6-(pyrazolo[1,5-α]pyrazin-3-yl)pyrazin-2-ylamino)piperidine-i-carboxylic acid tert-butyl ester (Preparation 30a) and A yellow foam (99%) was obtained from trifluoroacetic acid. The crude product was used in the next step without further purification. LRMS (m/z): 296 (M+l) +. 2-yl)pyrazolo[1,5-α]pyrazine

Heating at 110 ° C 2-(° than saliva [1,5·(3]η-pyrazin-3-yl), nicotine-4-ol 144 201130839 (preparation U)b, 15 〇 mg, 〇, 7 A millimolar oxychlorinated dish (ι 42 ml ' 15.51 mmol) solution overnight. After cooling to ambient temperature, the reaction mixture was carefully sideed on water and basified by the addition of 2 N aqueous sodium hydroxide solution. Ethyl acetate was then added and the organic phase was separated, washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH In the next synthesis step. LRMS (m/z): 232 (M+l) + 7.1 (d, 1H), lH NMR δ (300 MHz, CDC13): 7.0 (t, iH) 7.4 (d, 1H), 8.6 (dd, 2H) , 8.8 (s, 1H). ''' Preparation of 32 3_(4,5-di-pyrimidine-; 2-yl)pyrazole

&amp; 5_Gas-2-(pyrazole and oxygenated phosphorus were obtained according to the experimental procedure as described in Preparation 31, [1,5_α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 14b) Solid (57%). LRMS (m/z): 267 (M+l)+ Preparation 33 3·(4_Apyrimidin-2-yl)pyrazolo[1,5_β]pyridinium 145 201130839

OH Obtained as a pale yellow solid (99%) from 2-[([sup. ). LRMS (m/z): 231 (M+l)+]H NMR δ (300 MHz, CDC13): 7.0 (t, 1H), 7.1 (d, 1H), 7.4 (d, 1H), 8.6 (dd, 3H), 8.8 (s, 1H) ° Preparation 34 (Λ)-Λ "-(旅咬-3-基)-2-(»比嗤[1,5-&lt;1]&quot; than bite-3 -基)How to bite -4-

a) (and)-3-(2-(carbazolo[i,5_a]nbipyridin-3-yl)pyrimidin-4-ylamino) butylidene-1-carboxylic acid tert-butyl ester at 100〇C Heating 3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-α]pyf (preparation 33 '130 mg '0.56 mmol) and (8)-3-aminopiperidin-1- A solution of tert-butyl formate (326 mg, 丨.63 mmol) in ethanol (5 mL) was taken overnight. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of water and water. Separate the water layer and use the gas to simulate 146 201130839 201130839

The title compound (150 mg, '68%) 〇 (2 times) was washed. Evaporation. The crude product is purified by the title compound (忾Λ + + LRMS (m/z): 395 (M+l) + 咕 NMR δ (300 MHz, CDCl3): 15 (s, 9H), 2 ] (m, 2h), 3.0 - 4.2 (m, 7H), 5.0 - 5.1 (m, 1H), 6.2 (d, 1H), 6.9 (t, 1H), 7.3 (d, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.7 (s, 1 H). b) (;?)_7V-(Brigade bite_3_base)·2_(吼唾和[^七The external ratio _3_yl) is described by the experimental procedure as described in Preparation 7b, from (/?)-3-(2·(pyrazolo[1,5-α]pyridine-3 T-butyl 3-pyrimidin-4-ylamino)piperidine-1-carboxylate (Preparation 34a) and trifluoroacetic acid afforded a pale yellow oil (yield: 89%). LRMS (m/z): 295 (M+l)+, 293 (M-1)-. 4 NMR δ (300 MHz, CDC13)].5 - 1.9 (m, 4H), 2.0 (td, 2H), 2.3 (bs, 1H), 2.6 - 3.0 (m, 2H), 3.2 (dd, 1H), 5.4 (bs, 1H), 6.2 (d, 1H), 6.9 (t, 1H), 7.3 (d, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8·6 (d, 1H) , 8.7 (s, 1 H). Preparation 35 5-Gas-2-(° 嗤[[,5-β]β is more than -3-yl)

147 201130839 a) 3-(5-Gas-4-methoxybite_2·yl) "» 嗤 嗤 咬 according to the experimental procedure as described in Preparation 3a, from 5-chloro-2-ethynyl = methoxy pyrimidine (Preparation 13b) and iodinated ι-aminopyridine rust gave a light, vapor solid (69%). After the usual work-up, the crude material was triturated with diethyl ether and the title compound was obtained, which was used in the next synthesis step without further purification. LRMS (m/z): 262 (M+l)+. b) 5-Ga-2-nboxazol [1,5-decapyridyl-3-ylpyrimidin-4-ol] according to the experimental procedure as described in Preparation 4b, from 3_(5-chloro-4-I-methoxy Pyrimidin-2-yl)pyrazolo[1,5-heart]pyridine (Preparation 35a) gave dark solid (61%) 〇LRMS (m/z): 247 (M+l)+. Preparation 36 3-(4,5-two-nozzle-2-yl)β than saliva and [ι,5_β]β ratio bite

According to the experimental procedure as described in Preparation 31, chloro-]-. More than salivary, 5-β^pyridin-3-ylpyrimidin-4-ol (Preparation 35b) and phosphorus hydride gave a pale yellow solid (84%). LRMS (m/z): 266 (M+l)+ 148 201130839 !H NMR δ (300 MHz, CDC13): 6.9 - 7.0 (m, m), 7.4 - 7.5 (m,1H), 8.6 (ddt, 2H ), 8.6 (d, 1H), 8.7 (s, 1H). Preparation 37 (i?)-5·Gas-N-(Bistidin-3-yl)-2-(»Bizozolo[l,5-abupyridin-3-yl)pyrimidine-4-amine

a) (and) _3_ (5 · gas · 2 · (&quot; 嗤 嗤 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _) The experimental procedure consists of 3_(4,5·dichloropyrimidin-2-yl)π-pyrazole[1,5·ί2]pyridine (preparation 36) and (8)_3_aminopiperidine-1-carboxylic acid tert-butyl ester Obtained an oil (100 〇 / 〇). LRMS (m/z): 429 (M+l) + NMR δ (300 MHz, CDC13): 1.8 (s, 9H), 2.1 (s, 2H), 3.0 (s, 4H), 4.0 (s, 2H) , 4.3 (s, 1H), 5.4 (bs, 1H), 6.9 (t, 1H), 7.3 - 7.4 (m, 1H), 8.2 (s, 1H), 8.5 (t, 2H), 8.7 (s, H ). b) CR)-5-gas·Ν-(piperidin-3-yl)-2-(pyrazolo[l,5-fl]pyridin-3-yl)pyrimidin-4-amine as prepared in Preparation 7b The experimental procedure described is based on (/^)-3-(5-gas-2-(pyrazolo[1,5-α]pyridin-3-yl)pyrimidin-4-ylamino)piperidin-1- The third ester of citric acid (preparation 37a) and trifluoroacetic acid gave an oil (1%). LRMS (m/z): 329 (M+l)+ 201130839 Preparation 38 Oxygen is sufficient [(6·Μ and U, S is called final 3 such as 嗔_2_yl)amino]] pyridine pyridine} ethyl Amino acid terephthalate

/OH' ΤΧ ΤΧ H H H H H H H H H H H H H H H H ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( [ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 0 (10) mg,. .37 millimolar) and diiso-4ethylamine = methyl = ear) added to (mono-3-yl^-3-yl)pyridazine-2-amine (Preparation 28b, 1 gram, 〇 The mixture was passed overnight in a solution of % J匕 dimethylformamide (2 ml) at ambient temperature. The reaction mixture was then partitioned between ethyl acetate and water and the organic layer was separated, washed with brine and dried. (MgS04) and evaporated by reverse phase chromatography (from Waters C-18 cerium oxide, water / 1:1 acetonitrile • methanol as a dissolving agent [via 〇1〇/〇v/v citrate buffer) The residue was purified to give the title compound (m,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ): 1.5 (s, 9 Η), 1.6 - 2.2 (m, 5 H), 3.2 - 4.2 (m, 7 Η), 4.8 (m, 1 H), 5.6 (s, 1 Η), 6.9 (t, 1 H), 7·3 (m, 1 H), 7.7 (s, 1 H), 8.2 (m, 1 H), 8.4 (m, 1 H), 8.4 (m, 1 H). MA19 5-Fluorine -2-pyrazolopyridine-3-ylpyrimidin-4-ol 150 201130839

〇3-(5-Gas-4-methoxypyrimidin-2-yl)||Bizozoloindole-dipyridylpyridinium according to the experimental procedure as described in Preparation 27b, from 3_(4,4,5, 5-tetradecyl-1,3,2-oxo-deuteroline 4-2_yl) 吼嗤[1,5_冲比 bit (preparation 27a) and 2-gas-5-fluoro-4-antimony A pyrimidine bit (Preparation 16a) gave a solid (23%). LRMS (m/z): 245 (M+l)+. H NMR δ (400 MHz, CDC13): 4.2 (s, 3H), 6.9 - 7.0 (m, 1H), 7.3 - 7.4 (m, 1H), 8.3 (d, 1H), 8.5 - 8.6 (m, 2H) ), 8.7 (bs, 1H) 〇b) 5-fluoro-2-pyrazolo[l,5-fl]pyridylpyrimidine-4-ol was prepared according to the experimental procedure as described in Preparation 4b, from 3_(5_ Fluoro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-α]pyridine (Preparation 39a) and 48% aqueous hydrogen bromide gave a solid (74%). LRMS (m/z): 231 (M+l) + Preparation 40 5-fluoro-indole 4(3Λ)-l-pyridine-3-yl]-2-pyrazolopyridine·3·pyrimidin-4-amine

151 201130839 a) (3 and) -3_[(5 · fluoro · 2 · ^ 并 and [wye than bit yl pyrimidine 4 yl) Amino] piperidine-1-carboxylic acid tert-butyl ester as prepared in Preparation 7a The experimental procedure described is based on 5-fluoro-2-pyrazole[1,5-&lt;3]° ratio 2-3-based keto-4-ol (preparation of 3%) and (3/?)-3 - Aminopyridin-1-carboxylic acid tert-butyl ester gave an oil (88%). LRMS (m/z): 413 (M+l)+ b) 5-fluoro-;V_[(3J?)-piperidin-3-yl]-2-pyrazolo-[1,5-α]pyridine -3-yl-bitet-4-amine according to the experimental procedure as described in Preparation 7b, from (3i?)-3-[(5-fluoro-2-pyrazolo[1,5-α]pyridine-3 -Pyrylpyrimidin-4-yl)amino]piperidine-1-decanoic acid tert-butyl ester (Preparation 40a) and trifluoroacetic acid afforded an oil (98%). LRMS (m/z): 313 (M+l)+. Preparation 41 [[(3s,4#〇-4-Fluoropiperidin-3-yl]-6-pyrazolo[1,5-&lt;ι]pyridin-3-ylpyrazin-2-amine

a) (3s,4/*)-4-gas-3-[(6-ntb 嗤[l,5-fl]&quot;Bist-3-yl 11 嗓-2-yl)amino]piperider Phenyl-1-carboxylate benzyl ester according to the experimental procedure as described in Preparation 28a, from 3-(6-chloropyrazine-2- 152 201130839) pyrazolo[1,5-α]pyridine (Preparation 27b) And (3i,4r)-3-amino-4-fluoropiperidin-1-indole benzoate (prepared as described in w 〇 2 〇 1 〇 / 〇 16 〇〇 5) gave a solid (39%). LRMS (m/z): 447 (M+l)+. b) haloperidinyl]pyrazolo[Μ-φ-pyridyl_3_pyrazin-2-amine will (3 extracardiac 4_fluoro_3_[(6_°biazolo[I,5-pyridyl-pyridine- 3-methylpyrazine-2·yl)amino]β-pyridin-1-carboxylic acid benzyl ester (preparation 41a, 229 mg, 〇51 mmol) was added to a 3N aqueous solution of hydrochloric acid (45 mL). The resulting mixture was heated overnight in a hydrazine tube at 1 〇〇t&gt;c. Then a 37% aqueous hydrochloric acid solution (10 ml) was added and the reaction mixture was stirred at 10 (rc for 4 hours. Cold, after week® temperature) The organic solvent was evaporated under reduced pressure. The obtained aqueous phase was washed with dichloromethane, and then basified by the addition of aqueous solution of sodium hydroxide (sodium hydroxide) to a basic pH and washed with dichloromethane (3 times). use

The combined organics were washed with EtOAc EtOAc m. , X LRMS (m/z): 313 (M+l)+. !H NMR δ (400 MHz, CDC13): 2.0 - 2.3 (m, 2 Η), 2 9 - 3.8 (m, 5 Η), 4.3 - 5.2 (m, 1 Η), 4.9 - 5.2 (m, 2 H ), 6.9 (m 1 H), 7.4 (m, 1 H), 7.8 (s, 1 H), 8.3 (s, 1 H), 8.4 (s, 1 H), 8.5 (m, 1H) 〇.. 'Example 1 3-(4-{[(l*S)-l-phenethyl]amino}嚷 bit_2_yl)0 than saliva[i,5 npyridin-5-carbonitrile' 153 201130839

According to the experimental procedure as described in Preparation 7a, 3-(4-hydroxypyrimidin-2-yl is more than saliva f1,5♦ than biting _5-carbonitrile (preparation 3b) and (5&gt; 1-phenyl The amine obtained monomethyl (tetra) (15%) 'subsequently purified by flash riding (99:1 dichloromethane/methanol) to give the residue 'by reverse phase chromatography (from Waters C_18 dioxide, Water/acetonitrile/methanol as a dissolving agent, with *formic acid buffer]0% to 100%), re-purified. LRMS (m/z): 341 (M)+. 2H), 8.1 (d, 1H), 8.5 (bs ,1H), 8.6 (s,1H),8.7 (d,1H) Example 2, b-NMR δ (300 MHz' CD3〇D): 1.6 (d,3H) 5 3 Coffee 1H), 5.5 (bs, 1H ), 7.1 (d, 1H), 7.2 (t, 1H), 7.4 α 2H), 7.5 (d! 3-{4-[(cyclohexylmethyl)amino] Qian-2-yl} sigh and sigh [ 1" than bite-5-carbonitrile

154 201130839 According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5~]pyridine-5-indolecarbonitrile (Preparation 3b) and cyclohexyldecylamine Monocaprate (22%) was obtained, followed by reverse phase chromatography (from Waters C-18 cerium oxide, water/acetonitrile/sterol) as a dissolution chicken [passed by 0.1% v/v citrate buffer ] 5% to 50%) purified. LRMS (m/z): 333 (M)+. ^-NMR δ (300 MHz, CD3OD): 1.1-1.3 (m, 4H), 1.7-1.8 (m, 5H), 1.9-1.9 (m, 2H), 3.3-3.4 (m, 2H), 6.3 (d, 1H), 7.2 (d, 1H), 8.0 (bs, 1H), 8.5 (s, 2H), 8.7 (s, 1H), 8.8 (d, 1H), 9.1 (bs, 1H). Example 3 3-[4-(Benzylamino)pyrimidin-2-yl]pyrazolo[1,5-ίΐ]pyridine-5-indolecarbonitrile

Obtained from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-α]pyridine-5-indolecarbonitrile (Preparation 3b) and phenylmethylamine according to the experimental procedure as described in Preparation 7a Monoformate (8%), followed by reverse phase chromatography (from Waters C-18 cerium oxide, water/acetonitrile/methanol as eliminator [0.1% v/v citric acid buffer] 5%) Up to 50%) purified. LRMS (m/z): 327 (M+l)+, 325 (M-1)·. ^-NMR δ (300 MHz, CDC13): 4.7 (bs, 2H), 6.3 (d, 1H), 155 201130839 6.9 (d, m), 7.3_7.4 (m Qiu, 〇 (s, m), 9.0 (bs, . . . 1 2 (d, 4H), 8.3 (d, 1H), 8 6 (d, example 4 ~: base)

Obtained as a yellow solid (11%) eluted elute elute elute elute LRMS (m/z): 307 (M+l)+, 305 (M-1)·. lH-NMR δ (300 MHz, CDC13): 1.1 (s, 9H), 3.3 (s, 2H) 5.2 (bs, 1H), 6.3 (d, 1H), 7.0 (d, 1H), 8.3 (d, lH ), 8.6 (d, 1H), 8-8 (s, 1H), 9.2 (bs, 1H) ° 156 1 ·(2·{[(15)-2-methoxy-1-methylethyl] Amino group} shouting 唆-2_ base) 0 to 2 saliva[1,5-β]π than pyridine·5_carbonitrile 201130839

According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)oxazolo[1,5-«]acridin-5-indolecarbonitrile (Preparation 3b) and [(15&gt; 2-Methoxy-1-methylethyl]amine was obtained as a yellow solid (10%) then purified by flash chromatography (10:1 hexane/ethyl acetate to 100% ethyl acetate). /z): 309 (M+l)+, 307 (M-1). ^-NMR δ (300 MHz, CDC13): 1.4 (d, 3H), 3.4 (s, 3H), 3.5 (d, 2H ), ( ( ( ( ( ( ( ( ( ( ( , 9.1 (s, 1H). Example 6 3_{4-[(Cyclopropenyl)amino]pyrimidin-2-yl}pyrazolo[1,5_«]pyridine-5-carbonitrile

According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidine, '-2-yl)pyrazolo[1,5-α]pyridine-5-indolecarbonitrile (Preparation 3b) and (Cyclopropyl) The methylamine afforded a pale yellow solid (15%) elute elute 157 201130839 LRMS (m/z): 291 (M+l)+, 289 (M-l). 'H-NMR δ (300 MHz, CDC13): 0.4 (m, 2H), 0.7 (m, 2H), 1.2 (m, 1H), 3.3 (bs, 2H), 5.1 (bs, 1H), 6.2 (d , 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1 (s, 1H). Example 7 3-{4-[(2,2,2-Trifluoroethyl)amino]pyrimidin-2-yl}oxazolo[l,5_ii] 咐•咬-5-carbonitrile

According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 3b) and (2,2, 2-Trifluoroethyl)amine was obtained as a pale yellow solid (10%), then purified by flash chromatography (10:1 to 1:1 hexane/ethyl acetate). LRMS (m/z): 319 (M+l)+, 317 (M-l)·. ^-NMR δ (300 MHz, CDC13): 4.2 (m, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.0 (s, 1H). Example 8 7V~(1_Phenylethyl)-2-n is more than 嗤[l,5-ii]n than biting -3-keetin-4-amine 158 201130839

Solid (5%) from 2-pyrazolo[1,5·α]pyridin-3-ylpyrimidin-4-ol (Preparation 4b) and 1-phenylethylamine according to the procedure described in Preparation 7a ° LRMS (m/z): 316 (M+l)+. iH-NMR δ (300 MHz, CD3OD): 1.6 (d, 3H), 4.6 (bs, 1H), 6.4 (bs, 1H), 7.0 (t, 1H), 7.2-7.3 (m, 2H), 7.3 ( t, 2H), 7.4 (d, 2H), 8.0 (d, 2H), 8.5 (s, 1H), 8.5 (d, 1 H). Example 9 3-{6-[(cyclohexylmethyl)amino]pyridin-2-yl}pyrazoloindole-5-carbonitrile

Under M〇C, 3-(b-°°-biting -2_base) is spit and [1,5_biting--5- (preparation 6, 3〇奎古λιλ 古衫·ττ, mg0·12 Millol), cyclohexylmethylamine (46 '.mole) and triethylamine (50 microliters, 〇36 mil

The mixture in pen liters is heated for 2 hours. Pick up the bodhisattva, the water and the resulting sediment and dry it in a vacuum. The title compound (13 mg &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& LRMS (m/z): 332 (M+l)+. ^-NMR δ (300 MHz, CDC13): 1.1 (m, 1H), 1.2-1.4 (m, 3H), 1.5-1.8 (m, 5H), 1.9 (m, 2H), 3.2 (m, 2H), 4.7 (bs, 1H), 6.3 (d, 1H), 6.9-7.0 (m, 2H), 7.5 (t, 1H), 8.4 (s, ih), 8.5 (d, 1H), 9.1 (s, 1H) . Example 10 3-{6-[(2,2-Dimethylpropyl)amino] acridine-2-yl}&quot;Bizozolo[1,5·«]吼 -5-5-carbonitrile

The dried resealable Schlenk tube was charged with 3-(6-chloropyridin-2-yl)D than hydrazine and [1,5-α]η ratio bite_5_indene nitrile (Preparation 6, 30 mg, 0.12 mmol, (2,2-monopropyl)amine (14 μl, 0.12 mmol), carbonic acid (77 mg, 0.24 mmol), 1,1,_2 Naphthalene-2,2,-diylbis(diphenylphosphine) (3 mg) and toluene (丨. 5 ml). The Schlenk tube was subjected to three times: evacuation - a cycle of backfilling with argon and addition of palladium (II) acetate (5 mg). After the second evacuation - after argon backfilling, the Schlenk tube was capped and placed in a 120 ° C oil bath and stirred for 16 hours. The mixture was then cooled and ethyl acetate was added. The organic layer was washed with water, dried (MgSO4) and evaporated. The title compound (13 mg, 34%) eluted elute LRMS (m/z): 306 (M+l)+. ^-NMR δ (300 MHz, CDC13): 1.0 (s, 9H), 3.2 (d, 2H), 4.7 (bs, 1H), 6.3 (d, 1H), 6.9-7.0 (m, 2H), 7.5 ( t, 1H), 8.4 (bs, 1H), 8.5 (d, 1H), 9.1 (bs, 1H). Example 11 3-{6-[(3-Fluorobenzyl)amino] acridine-2-yl}oxazolo[1,5-α]acridine-5-A

According to the experimental procedure as described in Example 10, from 3-(6-apyridin-2-yl)carbazolo[1,5-ίφ to pyridin-5-indolecarbonitrile (Preparation 6) and (3-fluorobenzene) The amine was obtained as a yellow solid (57%) then purified by flash chromatography (dichloromethane to 250:1 dioxane / methanol). LRMS (m/z): 344 (M+l)+. H-NMR δ (300 MHz, CDC13): 4.7 (bs, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 6.9 (d, 1H), 7.0 (t, 2H), 7.0-7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H), 8.4 (s, 1H), 8.5 (d, 1H), 8.8 (bs, 1H) ° Example 12 161 201130839 3 -[6-(phenylmethylamino)pyridin-2-yl]pyrazolo[1,5-α]pyridine-5-carbonitrile

According to the experimental procedure as described in Example 10, from 3-(6-chloropyridin-2-yl)pyrazolo[1,5-«]acridin-5-indolecarbonitrile (Preparation 6) and benzoguanamine A yellow solid (33%) was obtained which was subsequently purified by flash chromatography (100% dichloromethane to 300:1 methane / methanol). LRMS (m/z): 326 (M+l)+. !H-NMR δ (300 MHz, CDC13): 4.6 (d, 2H), 5.0 (bs, 1H), 6.3 (d, 1H), 6.9 (dd, 1H), 7.0 (d, 1H), 7.2-7.3 (m, 1H), 7.3-7.5 (m, 5H), 8.4 (s, 1H), 8.5 (d, 1H), 8.9 (bs, 1H). Example 13 3-(6-{[(L9)_l-phenethyl]amino"pyridin-2-yl)oxazolo[l,5-ii]» ratio bite-5-a guess

According to the experimental procedure as described in Example 10, from 3-(6-chloropyridin-2-yl)oxazolo[1,5-α]acridin-5-indolecarbonitrile (Preparation 6) and 〇S&gt;l -Phenylethylamine 162 201130839 Obtained as a yellow solid (39%) then purified by flash chromatography (dichloromethane to 350:1 dioxane / methanol). LRMS (m/z): 340 (M+l)+. H-NMR δ (300 MHz, CDC13): 1.7 (d, 3H), 4.9-5.0 (m, 1H), 5.0 (bs, 1H), 6.2 (d, 1H), 6.9 (dd, 1H), 7.0 (d, 1H), 7.2-7.3 (m, 2H), 7.3-7.5 (m, 4H), 8.4 (s, 1H), 8.5 (d, 1H), 8.9 (s, 1H) 〇 Example 14 3-( 4-{[(3i?)-l-(cyanoethyl)piperidin-3-yl]amino}pyrimidin-2-yl) 0 is more than [1,5-α]° ratio bite-5 -carbonitrile

3-[(2,5-Di-Ethyloxy 11-Butyl-1-yl)oxy]-3-oxo-propanoid (as prepared in ΒΕ875054 (Α1), 40 mg, 0.20 mmol) Add to the stirred 3-{4-[(3Λ)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-α]pyridine-5-indolecarbonitrile (preparation) 7b, 60 mg, 0.16 mmol) in ethanol (1.2 mL) and the mixture was stirred at ambient temperature for 20 hr. The solvent was then removed under reduced pressure and the residue was dissolved in a mixture of dichloromethane and 4% aqueous sodium bicarbonate. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut elut +,386 (M-1)-. b-NMR δ (300 MHz, CDC13, 2:1 mixture of rotamers): 1.7-1.9 (m, 4H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H), 2.9- 3.0 (m, 1H), 3.3-3.4 (m, 1H), 3.5 (d, 1H), 3.5-3.6 (m, 1H), 4.1 (bs, 1H), 4.6 (d, 1H), 6.3 ( d,1H), 6.4 (d,1H, minor rotamer), 7.0 (d,1H), 7.1 (d,1H, minor rotamer), 8.2 (d,1H),8,3 (d, 1H, minor rotamer), 8.5 (4) 1H), 8.6 (d, 1H, minor rotamer), 8·7 (s, m, minor rotamer), 8.8 ( s, 1H), 9.0 (s, 1H). Example 15 3·(Μ[(3/?)-1-Ethylpiperidine-3-yl)amino group W pyridine·2· carbazol [1,5-&lt;ι]π ratio bite- 5-carbonitrile

Diethylamine (44 μl, 0.32 mmol), acetic anhydride (8.2 μl, 〇.09 mmol) and dimethyl thiopyramine (1.2 mg, 〇.〇1 mmol) Add to the stirred 3_{4_[(3 and)-piperidin-3-ylamino]pyrimidin-2-yl} than wow and [1,5_ bite_5_indene nitrile (preparation several, 4〇 mg The mixture was stirred in a solution of dioxane (15 ml) in hexanes (15 mL) at ambient temperature for 20 hours, then partitioned between dichloromethane and 4% aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine, dried (MgSO.sub.4) and evaporated. The crude product was purified by EtOAc EtOAc (EtOAc) 1) 4&quot;, 361 (M-1)·. ^-NMR δ (300 MHz, CDC13): 0.7-0.9 (m, 2H), 1.9 (d, 2H), 2.1 (d, 1H), 2.2 (s, 3H), 3.2 - 3.5 (m, 1H), 3.6 (bs, 1H), 3.8 (bs, 1H), 4.3 - 4.5 (m, 1H), 5.0 (bs, 1H), 6.2 - 6.3 (m, 1H), 7.0 (t, 1H), 8.3 (dd, 1H), 8.6 (t, 1H), 8.8 (d, 1H), 9.1 (d, 1H). Example 16 3_(4_{[()) (small (5-cyano) ratio) (B-amino) amine group} shouting -2- group) π than 嗤 and bite-5-carbonitrile

6-gas in the test nitrile (0.04 g, 〇29 mmol) and triethylamine (0.15 ml '1.08 house Moer) added to the stirred pyridin-3-ylamino group] biting-2-yl }° 嗤[1,5-〇]1» than 唆_5-carbonitrile (preparation 7b, 0.11 g, 0.24 mmol) in di-methane (33 ml) and 165 201130839 ^ 5〇 The resulting mixture was stirred at C for 20 hours. The reaction mixture was then allowed to cool to a degree of enthalpy and a two-gas ablation and a 4% aqueous solution of sodium cannium carbonate were added. ^From the organic layer 'Water and money, Lai (MgS04) and evaporate in the sky. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut elut elut (M+l)+, 420 (M-Ι)·. iH-NMR δ (300 MHz, CDC13): 1.3·1.4 (m,1H), 1.8 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3.2-3.5 (m , 2H), 4.0-4.1 (m, 1H), 4.5-4.6 (m, 1H), 5.0 (bs, 1H), 6.3 (bs, 1H), 6.7 (d, 1H), 7.0 (dd, 1H), 7.6 (dd, 1H), 8.3 (d, 1H), 8.4 (bs! 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.0 (s, 1H). ' 'Example 17 3-(4-{[(3))-1-(3,3,3-trifluoropropyl)-biting each base 1 amine group} bite-2-yl) 1,5-&lt;1]0 than bite-5-carbonitrile

3,3,3-trifluoropropionic acid (0.03 ml, 0.29 mmol), six gas dish acid #-[(diammonium) (3H-[1,2,3]triazolo[4, 5_b]n-pyridyl_3_yloxymethylene]-#-mercaptoammonium (0.12 g, 0.30 mmol) and diiso 166 201130839 propylethylamine (0.21 ml, 1.21 mmol) added To the disturbed 3-{4·[(3Λ)-派咬-3-ylamino] mouth bite-2-yl}1» than 嗤[ι,5_α]π ratio bite_5_ carbonitrile (preparation 7b, 0.11 g, 0.24 mmol, in a solution of muscle dimethylformamide (3 ml) and stirring the mixture for 2 hrs at room temperature. The reaction mixture was then partitioned between dioxane and 4% carbonic acid. The organic layer was separated, washed with 4% aqueous sodium bicarbonate, dried (M.sub.4) and evaporated in vacuo. EtOAc EtOAc EtOAc The crude product was purified to give crystals crystals crystals crystals crystals crystals LRMS (m/z): 430 (M+l)+, 428 (M-Ι)·〇!H-NMR δ (300 MHz, CDC13): 1.9-2.0 (m , 1H), 3.〇.3 2 (m,2H),3.3-3.5 (m,4H),3.6-3.8 (m,1H),3.9 (d,ijj) 4.1-4.3 (m, 1H),4.5 (d, 1H), 5.0 (bs, 1H), 6.3 (dd, ih) 6.9-7.0 (m, 1H), 8.2-8.3 (m, 1H), 8.6 (t, 1H), 8.7 (d, 1H) , 9^(bs,1H). , ,. Example 18 3·Η-[[(3 and)-1-(cyanocarbonyl)-n-l-yl](methyl)amine] -基}** than sniffing [ι,5-ίΐ] "«比咬-5-carbonitrile

167 201130839 According to the experimental procedure as described in Example 14, by ( magic-3-(4-(indolyl)-piperidin-3-yl)aminopyrimidin-2-yl)carbazolo[1,5- ]]«bipyridin-5-carbonitrile (preparation 8b) and 3-[(2,5-di- oxetyrridin-1-yl)oxy]-3-oxo-propanonitrile (eg BE875054 ( Prepared as described in A1) to obtain a yellow solid (52%) which was subsequently purified by flash chromatography (dichloromethane to 9:1 dichloromethane / decyl alcohol) LRMS (m/z): 401 (M +l) +. ^-NMR δ (300 MHz, CDC13, 2:1 mixture of rotamers): 1.7-1.9 (m, 4H), 2.1-2.2 (m, 1H), 2.3-2.5 (m, 1H), 2.9-3.0 (m, 1H), 3.1 (s, 3H, minor rotamer), 3.2 (s, 3H, major rotamer), 3.3-3.4 (m, 1H), 3.5 ( d,1H), 3.6-3.7 (m, 1H), 4.2 (bs,1H), 4.5 (d,1H), 6.2 (d,1H), 6.5 (d, 1H, minor rotamer), 7.1 (d,1H), 7.2 (d,1H, minor rotamer), 8.2 (d,1H), 8.3 (d,1H, minor rotamer), 8.5 (d,1Η),8.7 ( d, 1H, minor rotamer), 8.7 (s, lH, minor rotamer), 8.8 (s, 1H), 9.0 (s, 1H). Example 19 3-(4-(( ) -4-hydroxy-cyclohexylamino) pyrimidin-2-yl) pyrazolo [1,5- &lt; |] pyridine-5-carbonitrile

168 201130839 Put trans-4-aminocyclohexanol (85 mg, 〇74 mmol 3·(4 benzophenanthrene (tetra)tris-supperyloxy) batch 2 Π, 5_冲比唆-5- The solution of carbonitrile (produced as a by-product of 7a, 1 〇 5 gram of f-mole) in dimethylformamide (3 ml) was mixed overnight at night and then the residue was left over. It is partitioned between ^ and acetic acid. (4) The organic layer is washed with water and saponin, dried (MgSOd and evaporated solvent. The crude product is purified by flash chromatography (dichloromethane to hexane / methanol). The title compound was obtained as a yellow solid: (yield: 66 mg, 67%). LRMS (m/z): 335 (M+l) +. b-NMR δ _ dirty z, DMS0 〇: Q 4 G 6 (m , 3H) 1-0-U (m, 3H), 1.2-1.3 (m, 2H), 2.3 (d, 1H), 2.7 (bs, 1H); = (bs, 1H), 5.5 (bs, 1H) , 6.5 (d,1H),6,6 (d,m),7 2 (bs, 7.9 (s, 1H), 8.1 (bs,1H), 8.2 (d,1H). Example 20 ^(ring Hexylmethyl)-2-ton saliva [仏啦嗓] base shot _4 amine

169 ' 201130839 acid salt (16%), followed by reverse phase chromatography (from Waters C-18 cerium oxide, water / acetonitrile / methanol as a leaching agent [via 0.1% v / v citrate buffer] 5 % to 50%) purified. LRMS (m/z): 309 (M+l)+. H-NMR δ (300 MHz, CD3OD): 0.8-1.0 (m, 1H), 1.0-1.2 (m, 2H), 1.2-1.4 (m, 4H), 1.7-1.8 (m, 4H), 1.9 ( d, 2H), 6.4 (bs, 1H), 7.8-8.1 (m, 2H), 8.4-8.6 (m, 1H), 8.7 (bs, 2H), 10.0 (bs, 1H). Example 21 phenethyl)-2-(pyrazolo[1,5-&lt;ι]pyrazin-3-yl)pyrimidine-4-amine

According to the experimental procedure as described in Preparation 7a, from 2-(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and (5&gt; 1-Phenyl B The amine was obtained as a solid (38%) then purified by flash chromatography (dichloromethane to &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&& NMR δ (300 MHz, CD3OD): 1.1-1.2 (m, 1H), 1.6 (d, 3H), 5.3 (bs, 1H), 7.1-7.2 (m, 1H), 7.3-7.4 (m, 2H), 7.4 (d, 2H), 7.9 (bs, 1H), 8.1 (d, 1H), 8.6 (d, 2H), 9.6 (bs, 1H). 170 201130839 Example 22 TV-Benzyl-2-pyrazole [1,5-α]pyrazin-3-ylpyrimidine-4-amine

Monocarboxylic acid was obtained from 2-(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and phenylhydrazineamine according to the experimental procedure as described in Preparation 7a Salt (48%), followed by reverse phase chromatography (from Waters C-18 cerium oxide, water / acetonitrile / decyl alcohol as eliminator [0.1% v/v formic acid buffer] 5% to 50%) )purification. LRMS (m/z): 303 (M+l)+. ^-NMR δ (300 MHz, CD3OD): 4.7 (s, 2H), 6.4 (bs, 1H), 7.2-7.3 (m, 1H), 7.3-7.5 (m, 4H), 8.0 (bs, 1H), 8.1 (bs, 1H), 8.5 (bs, 1H), 8.6 (bs, 2H), 9.7 (bs, 1H). Example 23 7V-(2,2-Dimethylpropyl)-2-pyrazolo[1,5-α]pyrazine-3-ylpyrimidin-4-amine

According to the experimental procedure as described in Preparation 7a, from 2-(pyrazolo[1,5-«]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and 2,2-Dimercaptopropane -1-amine

171 201130839 (43%) was then purified by flash chromatography (98:2 to 95:5 dichloromethane/methanol). LRMS (m/z): 283 (M+l)+. b-NMR δ (300 MHz, CDC13): 1.0 (s, 9H), 3.2 (bs, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 8.0 (d, 1H), 8.3 (d, 1H), 8.4 (d, 1H), 8.7-8.8 (m, 1H), 10.0 (bs, 1H). Example 24 3·Sideoxy-3-{(3J?)-3-indole (2-indazole-[l,5-decapyridazin-3-ylpyrimidin-4-yl)amine group] Bite bite- L-yl}propionitrile

According to the experimental procedure as described in Example 14, from hydrazine (piperidinyl-3-yl)_2 decapyrazolo[ι,5_α]pyrazine-3-ylpyrimidinamide (preparation llb) and 3-[(2 , 5-tertiary oxypyrrolidinyl)oxy]_3_sideoxypropionitrile (prepared as described in BE 875054 (A1)) gave a solid (55%) followed by flash chromatography (dioxane) Dry 9:1 dichlorodecane/methanol). LRMS (m/z): 363 (M+l)+. lH_NMR δ (400 MHz, CDC13, ι:1 mixture of rotamers): 1.7-2.0 (m, 6H), 2.1·2.2 (m, 2H), 3.4 (s, 2H, rotamer 1), 3.6 (s, 2H, rotamer 2), 4.2-4.4 (m, 1H), 5.0 (bs, 172 201130839 1H), 6.3 (d, 1H, rotamer 1), 6.3 (d, 1H, Rotamer 2), 8.0 (d, 1H, rotamer 1), 8.0 (d, 1H, rotamer 2), 8.3 (d, 1H, rotamer 1), 8.3 (d, 1H, rotamer 2), 8.4 (dd, 1H, rotamer 1), 8.5 (dd, 1H, rotamer 2), 8.7 (s, 1H, rotamer 1), 8.7 ( s, 1H, rotamer 2), 10.0 (s, 1 H). Example 25 6-{(3jR)-3-[(2-oxazolopyridazin-3-ylpyrimidin-4-yl)amino]piperidine-1-yl}nicotinonitrile

According to the experimental procedure as described in Example 16, (i?)-AK piperidine_3_yl)-2-(σ ratio α sits and [l,5-fl]ntbB Qin-3-yl) mouth 唆- 4-Amine (preparation of lib) and 6-gas nicotinic nitrile afforded a solid (23%) which was subsequently purified by flash chromatography (di- hexane to &lt;RTIgt; LRMS (m/z): 398 (M+l)+. ^-NMR δ (200 MHz, CDC13): 1.8 (m, 4H), 3.3-3.6 (m, 2H), 3.-S-4.3 (m, 2H), 4.4 (m, 1H), 5.0 (bs, 1H), 6.3 (d, 1H), 6.7 (d, 1H), 7.6 (dd, 1H), 8.0 (d, 1H), 8.3 (d, 1H), 8.3-8.5 (m, 2H), 8.7 (s , 1H), i0.0(s, lH). Example 26 173 201130839 Bizolo[ι,5-β1 yl) read-3-fine bite_4^Qin Na Na, 3,3-trifluoropropanthene

The experimental procedure described in US 17 is carried out by (8)-bottom bite-3 base-2 and D,5♦biazine_3_yl)♦ _4_amine (preparation of fairy 3,3,3- The dipropionic acid was obtained as a solid (12%), and the gas was burned to 9:1 dioxane broth/sterol). Hunting by cardiac chromatography (1 LRMS (m/z): 406 (M+l) + η-nmr δ _ MHz, CDC13, 4:3 mixture of rotamers (m, m), mo (m , 2H), 2 2, (m, 2H), 2 6 (s, wind major rotamer), 2, 7 &amp; 211, minor rotamer), 3.1-3.2 (m, 1H), 3.3 -3.4 (m, 1H), 3.8-3.9 (m, 1H), 4.3 (bs, 1H), (9 (bs, 1H, minor rotamer), 5 〇 (bs, m main rotamer) ), 6.3 (d, 1H, minor rotamer), 6.3 (d 1H major rotamer), 8.0 (d, 1 H), major rotamer), 8 〇 (d' m minor) Rotamer), 8.3 (d, 1H, major rotamer) 83' (d '1H, minor rotamer), 8.4 (d, 1H, major rotamer), 8 4 (mountain 1Η|minorous rotamer), 8.7 (s, 1H, minor rotamer) 8 7 (s iH, major rotamer), l〇.〇(s,lH). ' · ' ' 174 201130839 Example 27 3-{(3i?)-3-[methyl(2_carbazino[1,5-ίφ-pyrazin-3-ylpyrimidin-4-yl)amino] brigade bite -1-yl}-3-sided oxycaline

According to the experimental procedure as described in Example 14, decyl-Aq(37〇-piperidin-3-yl)-2-pyrazolo[1,5-4pyrazin-3-yl)pyrimidine-4 - an amine (preparation 12b) and 3-[(2,5-di- oxy oxy)- oxo- oxo oxy) (prepared as described in BE 875054 (A1)) Obtained (76%). LRMS (m/z): 377 (M+l)+. &quot;H-NMR δ (400 MHz, CDC13, 2:1 mixture of rotamers): 1.2-1.4 (m, 2H) 1.7-2.2 (m, 4H), 3.1 (s, 2H, major isomerism (3.1) (3.1, 3.3 (m, 1H) 3.5 (s, 3H, minor rotamer), 3.6 (s, 3H, major rotamer) ), 3.7-3.9 (m, 2H), 6.4 (d, 1H), 6.4 (d, 1H), 8.0 (d, 1H), 8.0 (d, 1H), 8.3 (4, 1H), 8.3 (d, 1H), 8.4 (dd, 1H), 8.4 (dd, 1H,), 8.7 (s, 1H), 8.7 (s, 1H), 9.9 (s, 1H), 9.9 (s, 1H). Example 28 3-{(3 and)-3·[(5_gas-2-° ratio saliva[1,5-β]π ratio eQin-3_ylamine-4-yl) Amine] Brigade Bite_1-base}-3-side gas-based cyan 175 201130839

According to the experimental procedure as described in Example 14, from 5-gas-Λ4 piperidin-3-yl)-2·(pyrazolo[l,5-fl]pyrazin-3-yl)pyrimidin-4-amine (Preparation 15b) and 3-[(2,5-di- oxy- D-l-l-l-l-yl)oxy]-3-oxo-propanoid (prepared as described in BE 875054 (A1)) White solid (61%) was purified by flash chromatography (dichlorohexane to 9:1 dioxane / methanol). LRMS (m/z): 397 (M+l)+. H-NMR δ (300 MHz, CDC13): 1.7-2.0 (m, 2H), 2.2 (bs, 2H), 3.3-3.5 (m, 2H), 3.6 (s, 2H), 3.8 (bs, 1H) , 4.4 (bs, 2H), 5.4 (bs, 1H), 8.0 (bs, 1H), 8.3 (s, 1H), 8.4 (bs, 1H), 8.8 (s, 1H), 9.9 (s, 1H). Example 29 3-{(3i?)-3-[(5-fluoro-2-oxazolo[l,5_ii]e-pyrazin-3-ylpyrimidin-4yl)amino]piperidin-1-yl }-3-sided oxypropionitrile

According to the experimental procedure as described in Example 14, from (and) -5-fluoro-indolyl 176 201130839 pyridine-3-yl)·2_((iv) and [^ as a sulphide and 5: side oxy pair Prepared as described in cerebral leak (Α1)) Obtained a white solid by flash chromatography (2:1 to 8:2 difluoromethane/methanol) after purification 4 LRMS (m/z): 381 (M+l) +. W-NMR δ (400 MHz, CDC13, the equivalent of rotamers • upper / 3⁄4

()): 1.7-2.0 (m, 4H), 2.1-2.25 (m, 1H), 3.3-3.4 1T v us 1H) 3.4-3.6 (m, 1H), 3.6 (s, 2H), 3.8-3.9 (m) , 1H), 4.3-4.4 (m, 1 '5.1〇, 111), 8.0 ((1,1 isomer 2), 8.0 ((1,111, 旋)) 1), 8.1 ( d, lH, rotamer 2), 8.2 (d, lH, rotamer 8.4 (d, 1H, rotamer 2), 8.4 (d, lH, rotamer ι), 86), 1H, rotamer 2), 8.7 (s, 1H, rotamer 1), 9.9 1H S' Example 30, ° 5-fluoro-2-pyrazolo[1,5·α]pyrazine-3 -based = propionyl)piperidin-3-yl]pyrimidine-4-amine gas

According to the experimental procedure described in the _ _ _ Π , 由 由 由 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻 幻Mouth bite 4-amine (preparation 18b) and 3,3,3-trifluoropropanoic acid afforded a white solid (42%) elute elute . 177 201130839 LRMS (m/z): 424 (M+l)+. ^-NMR δ (400 MHz, CDC13, rotating lumps): 1.7-1.8 (m, 2H), 1.8-2.0 (m, 4) i 1:1 mixture 3.3-3.4 (m, lH, rotation) Construct 1), 3.4-3.5 (mi^2·2 (m, 1H), 2), 3.6 (d, 1H, rotamer 1), 3.9 (d, 1H, two rotamers 4.2 (d, 1H, rotamer 1), 4.4 (bs, ιΗ, 2 疋 isomer 2), (d, 1H, rotamer 1), 5.2 (d, 1H, rotating steroid 2), 5.1 1H , rotamer 1), 8·〇 (d, 1H, rotamer 2), 8.0 (d, rotamer l), 8.2 (d, 1H, rotamer '2) 8 2) ' 8a (d, 1H, isomer 1), 8.4 (d, 1H, rotamer 2), 8 6' · 4 (d, twist, rotator 1), 8.7 (s, 1H, rotation Isomer 2), 9 9 's '丨S^ Rotational Isomerization 9.9 (bs, 1H, rotamer 2), orisomer 1), Example 31 3·{(3Λ)-3- [(5-Mercapto-2_β than salino[ls small))amino]piperidin-1-yl}_3_ pendant oxypropionitrile-pyridyl-4-

派=====序,_基_)- and 3-[(2,5·di- oxy), 3_yl _4_amine (Preparation 21b) Reposted in BE875054(A1)· _ The oxy]-3-oxo-neoxy nitrile (e.g., 丨 表) was obtained as a white solid (45%), which was purified by recrystallization from ethanol. LRMS (m/z): 377 (M+l)+. b-NMR δ (400 MHz, DMS0-4, 1:1 mixture of rotamers): 1.6-1.7 (m, 2H), 1.8 (bs, 2H), 2.1 (s, 3H), 2.1-2.2 ( m, 1H, rotamer 2), 2.6-2.8 (m, 1H, rotamer 1), 3.0-3.2 (m, 1H), 3.4 (s, 2H), 3.7 (d, 1H, rotation) Construct 2), 3·8 (d, 1H, rotamer 1), 3.9-4.2 (m, 1H, rotamer 2), 4.3 (bs, 1H, rotamer 1), 6.6 ( d, 1H, rotamer 2), 6.7 (d, 1H, rotamer 1) 8.0 (bs, 1H, rotamer 2), 8.1 (bs, 1H, rotamer 1), 8.8 (s, 1H, rotamer 2), 8.8 (s, 1H, rotamer 1), 8.9 (bs, 1H), 9·8 (s, 1H, rotamer 2), 9.8 (s , 1H, rotamer 1). Example 32 (S)-7V-(l-(5-fluoropyridin-2-yl)ethyl)_2_(pyrazolo[l,5-fl]pyrazine-3 _ base)

In the microwave oven, 3-(4-chloropurine-2-yl) π is compared with saliva [丨^吼嗓 (preparation 31,170 mg, 0.61 mmol), (6)-1-(5-fluoropyridine-2 -yl)ethylamine (85 mg, 0.61 mmol, as described in WO2006/82392A1) and diisopropylethylamine (122 microliters, 0.70 millimolar) in the condition #'- 179 201130839 Minute in meglumine (5 ml). Then, after decompressing 合 '合σσ', 'to 150, it is maintained for 75 h, the solvent is removed and the residue is partitioned between 4. / Shishan 妒 solution and ethyl acetate. The organic phase is separated, using ^ 匕'乂(MgS04) and concentrated to give crude /, 5% to 5G%) purified to give the title compound (9 mg, 4%) by the reversed acid (31 mg, 0.027 mmol) A solution of the title compound (in the form of the free base, 9 mg, 0.027 mmol) in ethanol (2 ml), and then evaporated to give the corresponding fumarate. The resulting solid was dried under vacuum to give η mg of the desired anti-succinic acid salt. LRMS (m/z): 336 (M+l) + b NMR δ (400 MHz, CDC13, fumarate) :1.6 (d, 3H), 5.9 - 6.1 (m, 1H), 6.2 - 6.4 (m, 1H), 7.4 (dd, 2H), 8.0 (d, 1H), 8.2 (d, 1H), 8.4 (dd , 2H), 8.7 (s, 1H), 10.0 (s, 1H). Example 33 7V-((5-fluoro"pyridin-2-yl)methyl)-2-(carbazolo[1,5- &lt;ι】Biazine·3·yl) 唆-4-amine

180 201130839 According to the experimental procedure as described in Preparation 7a, from 2 to 7 spit and known as tqin-3-yl), the bite-4-ol (preparation 1〇b) and (5• gas octopamine Obtaining solid (5/〇) 'k after reverse phase chromatography (from Waters ◎ [Μ Μ dioxide 夕 ' water / acetonitrile / decyl alcohol as a leaching agent [via 〇 1% v / v? acid slow 〇% to loo%) Purification LRMS (m/z): 322 (M+l)+, 320 (M-Ι)·.H NMR δ (400 MHz, CDC13): 4.7 - 5.0 (m, 2H) , 6.3 -

6.4 (m, 1H), 7.4 (d, 2H), 8.0 (d, 1H), 8.3 (d, 1H), 8.4 (dd 2H) 8.7 (s, 1H), 10.00 (d, 1H). U Example 34 5_气#((S-气吼 bit_2_基)methyl)_2 than saliva-3-yl) 咬-4-amine J Sang

3-(4,5-Di-pyrimidin-2-yl)indazolo[ι,5_β]π 嘻(injury d 75 mg, 0.26 mmol), (5-fluoropyridine_2-yl) The mixture of methylamine (33, 〇·26, moor) and diisopropylethylamine (52 μl, 3q 亳, in tetrahydrofuran (3 ml)) was heated to reflux and maintained. Evaporate the solvent and purify the crude by reverse phase chromatography (C-18 dioxide from Wo Xiaoyu, water/acetonitrile/nonanol as the leaching agent [Tsangji formic acid buffer] 0% to 1 () 〇%) Product obtained the title compound (= 181 201130839 mg, 39%). LRMS (m/z): 356 (M+l) + NMR δ (300 MHz, CDC13): 4.8 - 5.0 (m, 2H), 6 7 (bs, 1H), 7.4 (d, 2H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (dd, lm 〇6 1H), 8.7 (s, 1H), 9.8 (s, 1H) ' · ' Example 35 2-(pyrazoloindole 1,5-&lt;|]pyrazin-3-yl-(tetrahydro-2-indole-5-yl)pyrimidine-4,5-diamine

Add 10%/carbon (0.392 grams, 0.37 millimolar) to 5·nitro-2-(1^saphtho[1,5-α]ρ than indol-3-yl)-fluorene tetrahydro-2 /f-P. sulphate. The mixture was prepared in a suspension of ethanol (5 liters) of the amine-4-amine (preparation 25, 0.785 g, 2.31 mmol) and under a hydrogen atmosphere at ambient temperature. After 4 hours, the mixture was filtered through Celite® and the filter cake was washed with ethanol. The combined sputum and EtOAc were evaporated to give the title compound (m. &quot; LRMS (m/z): 312 (M+l)+. !H NMR δ (300 MHz, DMSO-^): 1.6 (ddd, 2H), 2.1 (d, 2H), 3.5 (t, 2H), 4.0 (d, 2H), 4.2 - 4.3 (m, 1H), 5 〇'(s,2H): 182 201130839 6.4 (d,1H),7.7 (s,1H), 7.9 (d,1H),8.5 (s,1H), 8.8 (dd,1H), 9.8 (d, 1H). Example 36 #-(4,4-Difluorocyclohexyl)-2 decapyrazolo[l,5-fl]&quot;Biazin-3-yl)pyrimidine -4,5.Diamine

According to the experimental procedure as described in Example 35, #-(4,4-difluorocyclohexyl)-5-nitro-yl-2-indoleazo[1,5·β]pyridazine_3_yl Mouthidine-4-amine (Preparation 26) gave an off-white solid (87%). LRMS (m/z): 346 (M+l)+. TH NMR δ (300 MHz, DUSO-d6): 1.7 (m, 2H), 2.0-2.2 (m, 6H), 4.3 (m, 1H), 5.0 (s, 2H), 6.4 (d, 1H), 7.7 (s, 1H), 8.0 (d, 1H), 8.6 (s, 1H), 8.8 (d, 1H), 9.8 (s, 1H). Example 37 Chloro-7V-(l-(5-fluoropyridin-2-yl)ethyl)-2-(pyrazolo[ι,5_α]pyridin-3-yl)pyrimidine-4-amine 183 201130839

According to the experimental procedure as described in Example 34, 3_(4,5 dichlorocarcinoma bites _2 boat than 嗤[1,5♦biazine (preparation 32) and expect 1-(5-chaotic bite _2 ······································ (Mountain 3H), 5.4 5.6 (m, 1H), 6.6 - 6.8 (m, 1H), 7.3 - 7.5 (m, 2H), 7.9 - 8.1 (m, 1H), 8.3 (s, 1H), 8.3 - 8.5 (m, 1H), 8.5 - 8.6 (m&gt; m), 8.7 (s, 1H), 9.9 (s, 1 H). Example 38 Sideoxy-3-(3-(6-(carbazol[l] ,5_fl]e-biazine·3·yl)e-pyrazine-2-ylamino) brigade-1-yl)propionitrile

184 201130839 oxazin-3-yl)pyrazine-2-amine (preparation 30b, 0.23 g, 0.78 mmol), [(2,5-di- oxy σ 洛 -1--1-yl)oxy]- 3-Phenyloxycyanate (prepared as described in ΒΕ 875054 (Α1), 0.17 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmol) in dioxane (10 mL) The solution was stirred overnight. The title compound (0.158 g, 38%) was obtained. LRMS (m/z): 363 (M+l)+. H-NMR δ (400 MHz, DMSO-J6): 1.7 (m, 2H), 1.8 (m, 1H), 2.1 (m, 1H), 3.2 (m, 2H), 4.3-3.5 (m, 5H) , 6.9 (s, 1H), 7.9 (s, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.8 (m, 2H), 9.8 (s, 1H). Example 39 〇R)-3-Sideoxy-3-(3_(6-(&quot;Biazolo[1,5-α]Pyridine-3-yl)&quot;Biazin-2-ylamino) Pie bite-1-base) C.

Following (5-(pyridin; (Preparation 28b) and 3-[(2,5-di- oxy σ 鸣 唆 唆-1 -yl)oxy]-3-oxo-propanoid (prepared as described in 185 201130839 BE875054 (A1) Obtained as a light green solid (50%) then purified by flash chromatography (95:5 di-hexane/methanol). LRMS (m/z): 362 (M+l)+. ^-NMR δ (400 MHz, DMSO-J6): 1.6 (m, 2H), 1.8 (m, 1H), 2.1 (m, 1H), 3.2 (m, 1H), 4.4-3.6 (m, 5H), 4.5 (s, 1H), 6.9 (m, 1H), 7.0 (t, 1H), 7.4 (t, 1H), 7.8 (m, 1H), 8.3 (s, 1H), 8.4 (m, 1H), 8.6 (s, 1H), 8.7 (d, 1H). Example 40 (Λ)-3-Sideoxy-3-(3-(2-(oxazolo[1,5-&lt;i] acridine-3-yl)pyrimidin-4-ylamino) brigade bite -1-base) C.

According to the experimental procedure as described in Example 38, consisting of ((/?)-#_(piperidin-3-yl)-2 decapyrazolo[1,5-β]«pyridin-3-yl)pyrimidine 4-Amine (Preparation 34) and 3-[(2,5-di- oxofluorenyl)-yloxypropanenitrile (prepared as described in ΒΕ875054 (Α1)) A solid (41%) was obtained which was subsequently purified by recrystallization from acetonitrile. LRMS (m/z): 362 (M+l)+. ]H NMR δ (300 MHz, CDC13): 1.5-2.1 (m, 4H), 2.1 (d, 2H), 3.3 - 3.6 (m, 2H), 3.8 (d, 1H), 4.0 - 4.3 (m, 1H) ), 4.4 - 4.5 (m, 1H), 4.9 - 5.2 (m, 1H) 6.2 (t, 1H), 6.9 (d, 1H), 7.3 (t, 1H), 186 201130839 8.3 (d, 1H), 8 · 5 (d, 2H), 8.7 (d, 1H). Example 41 (Λ)-3-(3-(5·gas-2-(°-pyrazolo[l,5-flp-pyridin-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)- 3-sided oxypropionitrile

According to the experimental procedure as described in Example 38, from (Λ)-5-chloro-indole "-(piperidin-3-yl)-2-(α ratio α sits and [1,5-&lt;3]° Than 唆-3-yl) mouth bite-4-amine (preparation 37b) and 3-[(2,5-di- oxo oxindole-1-yl)oxy]-3- oxo-propion Prepared as described in BE 875054 (A1), obtaining a white solid (41%), followed by reverse phase chromatography (from Waters C-18 cerium oxide, water / acetonitrile / decyl alcohol as a dissolving agent) Purification of 0.1% v/v citric acid buffer] 0% to 100%. LRMS (m/z): 396 (M+l) + ]H NMR δ (300 MHz, DMSO-i/6): 1.5-1.9 ( m, 3H), 2.0 (s, 1H), 2.7 (dd, 1H), 2.9 - 3.2 (m, 1H), 3.7 (dd, 1H), 3.9 - 4.2 (m, 2H), 4.3 (d, 1H) , 4.7 (d, 1H), 7.0 - 7.2 (m, 2H), 7.5 (dd, 1H), 8.3 (d, 1H), 8.4 (d, 1H), 8.7 (d, 1H), 8.8 (t, 1H) Example 42 CR)-7V-(1-(4H-1,2,4-triazol-3-yl)piperidin-3-yl)-2-(pyrazolo[1,5-&lt;| 】** than bite-3·base) mouth bite 4-amine 187 201130839

In the case of l5〇°C, (8)-Λ^·(Brigade.3·基基)_27 than “Sit and [1,5-external bite-3-yl) mouth citrate (preparation 34 '298 mg) , 1.01 millimolar) with 3-bromo-1 tablet-1,2,4-triazole (75 mg, 〇51 mmol, such as 〇/· MWc-/C/zem/Wry 2004, 〇&quot; The mixture prepared as described in 4645_4648 was heated overnight. The crude mixture was purified by reverse phase chromatography (from cerium oxide, water/acetonitrile/methanol as the dissolving agent [0% to 100% by hydrazine) to obtain an island 0 V/v formic acid buffer] Mg, 52%). Heading of solids LRMS (m/z): 362 (M+l)+. !H NMR δ (300 MHz, DMSO-^6): j 5 ^ 1H), 1.8 (m, 1H), 2.0 (m, 1H), 2.8 (m, lm / 1H), h7 (mS, Λ jO lH 3 4 (m, 1H), 3.7 (m, 1H), 4.2 (m, 2H), 6.3 (bs, m 7.3 (m, 1H), 7.4 (m, 1H), 8.1 (m, 1H) 8 ; , , 7.0 (t,1H), 1H), 8.6 (s,1H), 8.8 (d,1H). ,, 2 (s, 1H), 8.5 (m, Example 43, keb 6·pyrazoloindole, 1,5·α]pyr 7V-[(3 and)_1_(aminoethenyl)piperidine·3- Bite·3·Ιβ比嗓-2_amine 188 201130839

Add a solution of dihydrogen chloride in dioxane (4 Torr, 10 mL) to (2-trioxy-2-{(3i〇-3-[(6-oxazolo[1,5-α]acridin-3) - hydrazin-2-yl)amino] piperidine-1-yl}ethyl)amino decanoic acid tert-butyl ester (preparation 38, 88 mg, 0.23 mmol) in methanol (3 ml) The mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated to EtOAc (EtOAc): 352 (M+l)+. Example 44 (Λ)·3-(3-(5· 气吐丨1,5-β] ° than bite-3·yl) Buty-4-ylamino) Brigade Bite_1-yl)-3-lateral oxycaline

According to the experimental sequence as described in Example 38, 5-fluoro-A4 (37〇- 口辰____) sits and is compared to 唆-3_ base. -4-amine (preparation 40) and 3-[(2,5-di-oxyl-pyridyl-1-yl)oxy]-3-oxo-propanoid (prepared as described in BE 875054 (A1)) gave a solid (68%), Purification by flash chromatography (dichloromethane to 9:1 dichloromethane/methanol). RMS (m/z): 380 (M+l)+.]H NMR δ (400 MHz, DMSO-i/6): 1.5-1.7 (m, 1H), 1.8 (bs, 1H), 2.1 (d, 1H), 2.6 - 2.7 (m, 1H), 2.7 - 2.9 (m, 1H), 3.1 ( Td, 1H), 3.6 (bs, 1H), 3.8 (bs, 1H), 3.9 - 4.0 (m, 1H), 4.1 (q, 2H), 4.7 (d, 1H), 7.0 (t, 1H), 7.4 - 7.5 (m, 1H), 7.5 - 7.6 (m, 1H), 8.2 (d, 1H), 8.4 (d, 1H), 8.8 (t, 1H). Example 45 3-((3s,4r)_4- Fluor-3-(6-(pyrazolo[1,5-&lt;1]pyridin-3-yl)pyrazin-2-ylamino)chine-1-yl)-3-isopropion

According to the experimental procedure as described in Example 38, from A4(3s,4r)-4-fluoropiperidin-3-yl]-6-pyrazolo[1,5-indolepyridin-3-ylpyrazine- 2-amine (Preparation 41) and 3-[(2,5-di-oxyl-1•Bilo-1-yl)oxy]-3-oxo-propanoid (as described in BE 875054 (A1)) Preparation) A green solid (47%) was obtained, which was subsequently purified by flash chromatography (dichloromethane to <RTIgt; LRMS (m/z): 381 (M+l)+. ' NMR δ (400 MHz, CDC13, 1:1 mixture of rotamers): 1·9 - 2.3 (m, 2H), 2.9 - 3.8 (m, 5H), 4.3 - 5.2 (m, 4H), 6.9 (m,1H), 7.4 (m,1H), 7.8 (s,1H, rotamer A), 7.9 (s, 190 201130839 1H, rotamer B), 8.2 (d, 1H, rotamer A), 8.3 (s, 1 H, rotamer A), 8.3 (s, 1H, rotamer B), 8.4 (d, lH, rotamer B), 8.4 (s, 1H) , 8.5 (d, 1H, rotamer A), 8.6 (d, 1H, rotamer B). Example 46 3-((3r,4r)-4-methyl-3-(6-(0 than bite [1,5·ίΐ]0 is more than -3-yl) 0-0 0-2-amine Base) brigade bite-1-yl)-3-side oxycaline

Example 47 (i?)-7V-(l-(4H-l,2,4-triazol-3-yl)piperidin-3-yl)-6-(pyrazolo[1,5-&lt;1 ]° than bite _3-base) ° ratio 11 Qin-2-amine

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, the catalytic domains of human JAK1 (aa 8 5 0-1154 ), 191 201130839 JAK2 (aa 826-1132), JAK3 (aa 795-1124), and Tyk2 (aa 871-1187) were expressed as n GST-fusion protein and purchased from

Carna Biosciences ° uses biotin § hex peptide poly(GT)-biotin (cisBio) as a substrate to characterize enzyme activity. The concentration of the peptide in the reaction is 6〇nM for JAK1, 20 nM for JAK2, 140 nM for JAK3 and 50 nM° for Tyk2 by time-regulated fluorescence energy transfer (TR-FRET) The degree of phosphorylation is detected. The IC5 of the compound was measured for each kinase in the reaction mixture containing the enzyme, ATP and peptide in 8 mM MOPS (pH 7.0), 10 mMMgCl2, 0.05% β-mercaptoethanol, 〇 45 mg/ml BSA. The ATP concentration in the reaction was 3 μΜ for JAK1, 0.2 μΜ for JAK2, 0.6 μΜ for JAK3, and 1.8 μΜ for Tyk2. The enzyme reaction was carried out for 30 minutes at room temperature. Next, use 2 μl of microliters of anti-tyrosine phosphorylation (phosphoyr) (ΡΤ66)-cryptate (CisBio) and variable concentration of SA-XL665 (CisBio) quenching detection buffer ( 50 mM HEPES, 0.5 M KF, EDTA 0.25 Μ, 0.1% (w/v) BSA, pH 7.5) Stop the reaction to keep the sa-B ratio constant. The incubation was carried out for 3 hours and read on a Vict〇r 2v spectrofluorometer (PerkinElmer) set to read fluorescence resonance energy transfer. Some of the abbreviations used above have the following meanings: AA: Amino acid GST: cercosatin §; _ transferase MOPS: 3-(N-morpholinyl)propanesulfonic acid 192 201130839 BSA: Bovine serum albumin ATP: Adenosine triphosphate EDTA: ethylenediaminetetraacetic acid HEPES: 4·(2·ethyl)_ι_σ辰乙乙酸酸 Table 1 describes the IC50 values of certain exemplary compounds described in the present invention. In Table 1, 'A' indicates that the IC50 value is less than 0.1 μΜ (100 nM), and B is IQ. The value is in the range of 〇.10]^(1〇〇11]^) to 141^, and C represents The IC5 〇 value is higher than 1 μΜ.

Example No. 5 IC50 JAK3 (μΜ) IC5〇JAK2 (μΜ) IC50JAKI (μΜ) __A AB 7 14 19 ~ 21 AC r AAB __ ABAA 25 ____A AB 27 ~~~30~ Λ C —~_____A_ —ΙΙΖλ^ _A ABB JJ ______ BAB j / AA &gt; It can be seen from Table 1 that the compound of formula (1) is a potent inhibitor of JAIU, JAK2 and JAK3 $ enzymes. The preferred heteroaryl imidazolidone derivatives of the invention inhibit the JA50 values of JAK1, JAK2 and JAK3 kinases (as determined above) of less than 1 μΜ 'for each JAK kinase preferably less than 〇5 μΜ. Combinations The pyrazole derivatives as defined herein may also be combined with other S compound groups that are susceptible to pathological conditions or diseases which are ameliorated by inhibition of Jay and tablet kinases 193 201130839.瘅 ί Γ 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视 可视Disease and entity meaning; f_ and (4) transplant rejection; guiding disease 'more specifically' wherein the pathological condition or disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory disease, Dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (CQPD), atopic dermatitis, and psoriasis, such as: (a) dihydrofolate reductase inhibitor , such as methylamine «Methotrexate or CH-1504; (b) DHODH inhibitors, such as leflunomide, teriflun〇mide or international patent application no. Compounds described in 8/〇77639 and WO20092696; (c) immunomodulators such as Glatiramer ace plus e (Copaxone), Laquinimod or Immortal (Im (i) DNA synthesis and repair inhibitors, such as Mitoxantrone or Cladribine; (e) Anti-α4 integrin antibodies such as Natalizumab (Tysabri) (f) α4 integrin antagonists such as R_i295, TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; (g), corticoids and glucocorticoids Hormone (glucocorticoid) such as prednisone or methylprednisolone, fluticasone, mometasone 194 201130839 (mometasone) or beta-metasone; (h) a diacate such as; (i) an anti-TNFα antibody, such as Infliximab, Adalimumab or Certolizumabpol; (j) Soluble TNFα receptor, Such as etanercept; (k) anti-CD20 monoclonal antibodies, such as rituximab (Rituximab), okrezumab (〇crelizurnab), arbo

Monotherapy (Ofatumumab) or TRU-015; (1) anti-CD52, such as alemtuzumab; (m) anti-CD25, such as daclizumab; (η) anti-CD88, such as Aiku Eculizumab or pexilizumab; ( 〇) anti-IL12R/IL23R ' such as ustekinumab; (p) | calcineurin inhibitor, such as Cyclosporin A

(cyclosporine A) or tacrolimus; (q) IMPDH inhibitors such as myCOphenolate mophetyl; (class 0 cannabinoid receptor agonists, such as satifi (Sativex) (s) a chemokine CCR1 antagonist, such as MLN-3897 or PS-031291; (t) a chemokine CCR2 antagonist, such as INCB_8696; (u) an activation inhibitor, such as MLN-0415; (v) SIP Receptor agonists, such as those described in fingolimod, BAF-312, ACT 128800 or International Patent Application No. PCT/EP2009/007348 and PCTVEP 2009/008968; (w) sip dissociating enzyme (liase) inhibitors such as LX2931; (X) Syk inhibitors, such as R-112; (y) PKC inhibitors, such as NVP-AEB071; (z) M3 antagonists, such as tiotropium or adi (aclidinium); (aa) long 195 201130839 effector beta-adrenergic agonist 'such as salmeter〇i (salmeter〇i), formoterol or indatater〇1; (bb) Vitamin D derivatives such as calcipatrix (Daivonex); (cc) phosphodiesterase iv inhibitors, such as Roflumilast or GRC-4039; (dd) P38 inhibitors such as ARRY-797; (ee) MEK inhibitors such as ARRY-142886 or

ARRY-438162; (ff) ΡΙ3Κδγ inhibitor; (gg) interferon, including interferon β la, such as Avonex from Biogen Idee, CinnoVex from CinnaGen, and from EMD

Serono's Rebif, and interferon|3lb, such as Betaferon from Schering and Betaseron from Berlex; and (hh) interferon alpha, such as Sumi Feilong ( Sumifer〇n) MP 〇 usually 'other active substance is not amidoxime. Preferably, the other active substance is selected from the group consisting of: (b) a DHODH inhibitor such as leflunomide, teriflunomide or international patent application No. WO2008/077639 and WO200900696. Said compound; (c) an immunomodulatory agent, such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; (e) Cx4 integrin antibodies, such as Natalizimiab (Tysabri); (f) a4 integrin antagonists, such as R-1295, TBC-4746, CDP-323, ELND-002, Firagrass Or TMC-2003; (g) cortic〇id and glucocorticoid, such as prednisone 196 201130839 or methylprednisolone, fluticasone, mometa Mometasone or beta-metasone; (h) fumarate, such as; (i) anti-TNFα antibodies, such as infliximab, adalimumab (Adalimumab) Or race: tortuzumab (Certolizumab pegol); (j) soluble TNFα receptors, such as etanercept; (k) anti-CD20 monoclonal antibodies, such as rituximab (Rituximab), okrezumab (Ocrelizumab), oxacabumab (Ofatumumab) or TRU-015; (η) anti-CD88, such as eculizumab or pexilizumab; (〇) anti-IL12R/IL23R, such as ustekinumab (p) Calcineurin inhibitors such as cyclosporine A or tacrolimus; (q) IMPDH inhibitors such as mycophenolate morpholine (mycophenolatemophetyl); (r) cannabinoid receptor agonists, such as sateux (Sativex); (s) chemokine CCR1 antagonists, such as MLN-3897 or PS-031291; (t) chemokines CCR2 antagonists, such as INCB-8696; (u) NF-κΒ activation inhibitors, such as MLN-0415; (v) S1P receptor agonists, such as fingolim (fing〇lim〇d), BAF-312 &lt; ACT 128800 or the compounds described in International Patent Application No. PCT/EP2009/007348 and PCT/EP2009/008968; (w) S1P dissociation enzyme (liase) inhibition An agent such as LX2931; (X) a Syk inhibitor such as R_U2; (y) a PKC inhibitor such as NVP-AEB071; (z) an M3 antagonist such as tiotropium (ti〇tr〇pium) or adiponium ( (a) long-acting beta-adrenergic stimulating effect 197 201130839 Agents such as salmeterol, formoterol or indacaterol; (bb) vitamin D derivatization For example, calcipotriol (DaV0nex); (cc) phosphodiesterase IV inhibitors such as roflumiiast or grc-4039; (dd) p38 inhibitors, such as ARRY-797; (ee) ARRY-438162; (ff) ΡΙ3Κδγ inhibitor; (gg) interferon β la, such as Avonex from Bi〇gen Idee, CinnoVex from CinnaGen And Rebif from EMDSerono; and interferon plb' such as Betaferon from Schering and Betaseron from Berlex. More preferably, the other active substance is selected from the group consisting of: (b) a DHODH inhibitor, such as leflunomide, teriflunomide or international patent application No. WO2008/077639 and WO200900696. The compound; (c) an immunomodulator such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; (e) Alpha 4 integrin antibodies, such as Natalizumab (Tysabri); (f) (χ4 integrin antagonists such as R-1295, TBC-4746, CDP-323, ELND-002, felastast ( Firategrast) or TMC-2003; (g) corticoids and glucocorticoids such as prednisone or methylprednisolone, fluticasone, mometasone ) or beta-metasone; (h) fumarate, such as 5G-72; (i) anti-TNF alpha antibody, such as English 198 201130839 risximab (Infliximab), adamudan Anti-Adalimumab or Certolizumab pegol (j) soluble TNF a receptors, such as etanercept; (k) anti-CD20 monoclonal antibodies, such as rituximab (Rituximab), okrezumab (〇crelizumab), autumn Monoclonal antibody (Ofatumumab) or TRU-015; (η) anti-CD88, such as eculizumab or pexilizumab; (〇) anti-IL12R/IL23R, such as Eudragitumab ( Ustekinumab); (p) Calcineurin inhibitors, such as cyclosporine A or tacrolimus; (q) IMPDH inhibitors, such as mycophenolate morpholine B (r) cannabinoid receptor agonist, such as satex (Sativex); (s) chemokine CCR1 antagonist, such as MLN-3897 or PS-031291; (t) chemotaxis Factor CCR2 antagonists, such as INCB-8696; (u) NF-κΒ activation inhibitors, such as MLN-0415; (v) S1P receptor agonists, such as fngolimod, BAF-312, ACT128800 or Compounds described in International Patent Application No. PCT/EP2009/007348 and PCT/EP2009/008968; (w) S1P dissociation enzyme (liase) inhibition Agents such as LX2931; (X) Syk inhibitors such as R-112; (y) PKC inhibitors such as NVP-AEB071, (z) M3 antagonists such as tiotropium or aclidinium (aa) long-acting beta-adrenergic agonist, such as salmeterol, formoter〇i or indacaterol; (bb) vitamin D derivatives, Such as calcipotriol (Daivonex); (cc) phosphate II 199 201130839 酉曰 trans-IV inhibitors, such as roflunostat (r〇numiiast) or grc_4〇39; (dd) p38 inhibition Agents such as ARRY-797; (ff) ΡΙ3Κδγ inhibitor; (gg) interferon β la, such as Avonex from Biogen Idee, CinnoVex from CinnaGen, and benefit from EMD Serono Rebif; and interferon beta lb, such as Betaferon from Schering and Betaseron from Berlex. Specific examples of suitable corticosteroids and glucocorticoids which may be combined with the JAK inhibitors of the invention are prednis〇i〇ne, 曱panning nylon, dexamethasone, dexamethasone cipecilate, 秦非可特(naflocort), deflazacort, halopedone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone Triamcinolone acetonide, fluocinolone acetonide, fluocinonicie, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate , tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, contiguous methylprednisolone (methylprednisolone suleptanate), mometasone furoate, Rimesolone, prednisolone farnesylate, ciclesonide 200 201130839 (ciclesonide), butixocort propionate, RPR-106541, diproxil propionate_ (deprodone propionate), fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, butyrate propionate Betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, 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 Rigd), R_343 (from Rigel), R-112 (from Rigel), paclitaxel (piceatann〇i), 2-(2-aminoethylamino)-4-[3-(trifluoromethyl)anilino]pyrimidine-5-nonylamine, R-091 (from 1^61), 6-[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-ylamino]-2,2-diindenyl_3'4- One 虱-2H-'*·3 ratio bite [3,2-b][l,4] 11 恶 -3--3- keto benzoate ' each ' (R-406' from Ridd), 42, 4, 6-trihydroxyphenyl)-2-(4-decyloxyphenyl)ethan-1-one, N-[4-[6-(cyclobutylamino)-9H-indol-2-ylamino] Phenyl]-N-mercaptoacetamide (QAB-205 from Novartis), 2-[7-(3,4-dioxane 201 201130839 phenyl) imidazo[l,2-c]pyrimidine _ 5_ylamino]pyridine_3_formamide dihydrochloride (BAY-61-3606 'from Bayer) and AVE-0950 (from

Sanofi-Aventis). A special example of a suitable M3 antagonist (anti-cholinergic agent) which can be combined with the JAK inhibitor of the present invention is a ti〇tr〇pium salt, an oxitropium salt, and a money (£ |utr〇pium ) salt, ipratropium salt, glyc〇pyrr〇nium salt, traspium salt, revastatin vinegar (revatr〇pate), ipato 酉Espatropate, 3-[2-hydroxy-2,2·bis(2-thienyl)ethyloxy]_1_(3-phenoxypropyl)-1-nitrogenbicyclo[2.2.2]octane The salt (especially the aclidinium salt is more preferably aciidinium bromide), 1-(2-phenylethyl)-3-(9H-〇3〇5-9-ylcarbonyloxy) Small nitrogen rust bicyclo [2.2.2] octane salt, 2-sided oxy-1,2,3,4-tetrahydroquinazoline-3-carboxylic acid internal-8-methyl-8-azabicyclo P.2.1] Oct-3-yl ester salt (DAU-5884), 3-(4-phenylhydrazinopiperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropane_2 -ketone (NPC-14695), N-[l-(6-Aminoacridin-2-ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1 ( R)-cyclopentyl]-2-yl-2-phenylacetamide (J-104135), 2(R)-cyclopentyl-2-hydroxy-N-[1-[4(S)- Methylhexyl] pie bite-4 -yl]-2-phenylethylamine (J-106366), 2(R)-cyclopentyl-2-hydroxy-N-[l-(4-indolyl-3-pentenyl)-4- Piperidinyl]-2-phenylacetamide (J-104129), 1-[4-(2-aminoethyl)piperidin-1-yl]-2(R)-[3,3-di Fluorocycloindole-1(R)-yl]-2-hydroxy-2-phenylethan-1-one (Banyu-280634), Ν-[Ν-[2-[Ν-[1-(cyclohexylmethyl) )Bucking-3(R)-ylmercapto]amine-amino]ethyl]amine-mercaptoalkyl]-3,3,3-triphenylpropanamide (Banyu CPTP), 2(R) -cyclopentyl-2-hydroxy-2.phenylacetic acid 202 201130839 4-(3-Azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), UCB-101333, mark Merck, s), 7 (2_ hydroxy-2,2-diphenylethenyloxy)_9,9-dimethyl-3-oxaza rust tricyclic oxime. 3.. (2,4)]decane salt, 7-(2,2·diphenylpropanyloxy)·7,9,9-trimethyl-3-oxa-9-nitrogen tricyclic [3.3. 1.0*2,4*]decane salt, 7_transcarbyl-7,9,9·trimethyl-3-oxa-9-nitrogen tricyclo[3.3.1.0*2,4*]decane 9 _ 曱 _9-9- phthalate salt, all of which are in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally It is in the form of its pharmacologically compatible acid addition salt. Among the salts, vapor, bromine, iodide and sulfonium sulfonate are preferred. A specific example of a long-acting beta-adrenergic agonist (β2-agonist) which can be combined with the JAK inhibitor of the present invention is terbutaline sulphate or fumarate 〇〇rm〇ter〇1 fumarate, formoterol fumarate, bambuterol, pr〇cater〇1 hydrochloride, hydrochloric acid Sibenadet hydrochloride, mabuterol hydrochloride, albuterol sulphate, saibutamol suiphate, salmeterol xinafoate, cammotrol hydrochloride Carmoterol hydrochloride ), (R)-albuterol hydrochloride ' Levalbuterol hydrochloride/Levosalbutamol hydrochloride, hydrochloric acid (-)-salbutamol ((i)-Saibutamol hydrochloride), tartaric acid (R,R)- Formoterol ((R,R)-Formoterol 203 201130839 tartrate ), Arformoterol tartrate, sulfuric acid Bedordrine sulphate, darlotrol, Trantinterol hydrochloride, AZD-3199, GSK-159802, GSK_597901, GSK-678007, GSK-642444, GSK-961081, AR-C98955AA, hydrochloric acid Milveterol hydrochloride, BI-1744-CL, and the compounds described in International Patent Application No. WO2007/124898, WO2006/122788A1, WO2008/046598, and WO2008095720. Specific examples of suitable phosphodiesterase IV inhibitors which can be combined with the JAK inhibitors of the invention are benafentrine dimaleate, etazolate, denbufylline ), rolipram, cipamfylline, zardaverine, arofylline, filaminast, tipelukast, care Tofimilast, 0 picamiilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, Roflumilast, cilomilast, oglemilast, apremilast, tetomilast, non-Minist, (R)-(+)- 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-ethylidene]&lt;»bipyridine (CDP-840), N-(3,5-dichloro-4 -n ratio bite base)_2-[1-(4-fluorophenylindenyl)-5-hydroxy-1H-indol-3-yl]-2-oxoethoxyacetamide (GSK-842470), 9-( 2-fluorobenzyl)-N6-mercapto-2-(trifluoromethyl) adenine (NCS-613) N-(3,5-dioxa-4-pyridyl)-8-methoxyquinolin-5-carboxamide (D-4418), 204 201130839 3-[3_(cyclopentyloxy)-4 -Methoxy aluminyl]-6-(ethylamino)-8-isopropyl-3H-indole hydrochloride (V-11294A), 6-[3-(N,N-dimethylamine oxime) Mercapto) phenylsulfonyl]-4-(3-methoxyanilino)_8_decylquinoline_3_decylamine hydrochloride (GSK-256066), 4-[6,7-II Ethoxy-2,3-bis(methyl)naphthalen-1-yl]-1-(2-decyloxyethyl)pyridinyl-2(ih)-ketone (T-440), (-)· Trans-2-[3'-[3-(N-cyclopropylaminoindolyl)_4_sideoxy-1,4-dihydro-1,8. acridine small group]-3-fluorine Stupid-4-yl]cyclopropanedecanoic acid (mk-0873), CDC-801, UK-500001, BLX-914, 2-oxime oxycarbonyl-4-cyano-4-(3-cyclopropoxyl- 4-difluoromethoxyphenyl)cyclohexyl- ketone, cis[4-cyano-4-(3-cyclopropylmethoxy-4)difluoromethoxyphenyl)cyclohexyl-1 -Alcohol, GRC-4039, CDC-801, 5(S)-[3-(cyclopentyloxy)_4-methoxyphenyl]-3(8)-(3- mercaptobenzyl)pyridin-2-one (IPL-455903), 〇N〇-6126 (Eur Respir J 2003, 22 (Supplement 45): Abst 2557) and International Patent Application No. W003/097613, W0200 Salts as claimed in 4/058729, WO 2005/049581, WO 2005/123693, and WO 2005/123692. An example of a suitable ρΙ3Κδγ inhibitor which can be combined with the JAK inhibitor of the present invention is 2-mercapto-2-[4-[3-indolyl-2-sideoxy-8-(3-quinolinyl)-2 ,3-dihydro-1H-miso-[4,5-c]porphyrin-i-yl]phenyl]propionitrile (ΒΕΖ·235 from Novartis), CAL-101 (from Calistoga Pharmaceuticals), and N-ethyl [3-(3,4,5-Trimethoxyanilino) 0-pyridinium [2,3 carbazin-6-yl]thiourea (AEZS-126 from AeternaZentaris). The compounds of formula (I) and combinations thereof described herein are useful for the treatment of spinal proliferative disorders, leukemias, lymphoid malignancies, and solid tumors; bone marrow with 205 201130839 and organ migration-rejection reactions; and AK inhibitors have beneficial effects Immune-mediated diseases such as rheumatoid arthritis, multiple sclerosis, hair/animal disease (such as ulcerative colitis or Crohn's disease), dry eye, uveitis, allergic conjunctivitis, allergies Rhinitis, asthma, chronic obstructive pulmonary disease (10) PD), atopic dermatitis, and psoriasis. The combination of the compound of formula (1) escaped herein can also be used to treat inflammatory diseases. In one aspect, the compounds of formula (1) and combinations described herein can be used to treat spinal cord-enhanced conditions, m lymphoid malignancies, and entities in this treatment. Now. In another aspect, the compound of formula (1) described herein and , =. It can be used for; treatment of bone and organ transplant rejection; immune-mediated diseases such as osteoporosis and organ transplant rejection; and sputum and immune diseases such as bone marrow and organ transplant rejection. The treatment of Gynecological diseases and conditions is usually achieved by inhibiting the individual's Genesis S# (JAK). The a, the combination described herein can be used to inhibit the Janus kinase (JAK). ; And the difference between the group and the same pharmaceutical composition in the same pharmaceutical composition ==--open, simultaneous, concomitant or qi-' ^ all active agents will be called in close proximity or two active agents can be Take it in the morning and take it later. Or in the other side of the slaughter and two =: the agent is taken twice in the middle of the day and the other active agent is taken once per day: or: = in the drug - at the same time, or separately. Preferably; 206 201130839 ==::=. Preferably at least two and more preferably all of the active agents of the present invention are also related to the production of the invention described herein, which are useful for the treatment of susceptibility;: 卩 — 杰 杰 杰 = = Μ Μ Μ Μ Μ Μ Μ 、 、 、 、 、 、 、 、 、 Lymphatic immune system: ιγ: special = ^ is selected from the class of occupational _ inflammation, scallop sclerosis, inflammatory bowel disease = 艮宏 to _ inflammation, allergic conjunctivitis, allergic rhinitis, sexual obstructive pulmonary disease (c 〇PD), atopic dermatitis and psoriasis. Also f-s-like +, the combination product can be used for the treatment of spinal cord hyperplasia, positive blood, disease, and disease. In this aspect, the treatment is achieved by inhibiting the sputum. In another case, the combination product can treat bones _ and organ transplants reject sexual diseases and inflammatory diseases, such as bone and organ transplants, and immune-mediated diseases such as bone and organ transplantation, and the rest (4) Therapeutic treatment (4) is achieved by inhibition (m(MK). The combined product can be repressed by the nucleus. The invention also encompasses the compound of the invention and one or more other treatments 207 201130839 = combination _ way' manufacture for the delivery of disease A method of providing a method for inhibiting the 'jak' state or disease, in particular, wherein the disease is selected from the group consisting of a spinal proliferative disorder, a white disease, and a lymphoid Vulgars lead tumors; bone marrow and organ transplant rejection; immunity i: inflammatory and inflammatory diseases, such as spinal proliferative disorders, white blood and solid tumors; osteophytes and organ transplant rejection, and immune-mediated diseases. More specifically, pathological conditions or phlegm, multiple sclerosis, inflammatory disease == (_), atopic dermatitis, and cowhide: a combination of therapeutically effective amounts of the compounds described herein One or more Genus kinase is used to achieve the treatment by inhibiting the individual's side: = for a single agent to inhibit the need for an individual, the Janus kinase is effective to fine-tune the individual in need of the treatment. The compound of the compound and the group of other therapeutic agents are treated according to the condition to be treated. #蚊, the ridge of the present invention is administered by the method of 'for example, (for sugar poly: capsule, mouth 3 tablet, controlled release preparation) , fast, by Zhuang (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by 208 201130839 inhalation (in the form of dry powder, solution, dispersion, etc.). The active compound in the combination (ie, the pyrimidine of the present invention) An azole derivative) and other optionally active compounds may be co-administered in the same-p-agent composition or in different compositions intended to be separated, simultaneously, accompanied or sequentially administered by side or different routes. An embodiment of the present invention consists of a kit of dispensing parts comprising a derivative of (iv) as described herein and for simultaneous, simultaneous, separate mixing with another active compound. Book, the live Compounds rely on the treatment of spinal proliferative disorders, leukemia, lymphoid malignancies, and physical axes; bone- and material-transplantation financial responses; immune-mediated diseases and inflammatory diseases such as proliferative disorders, leukemia, lymphoid malignancies, and Tumor; bone _ and organ transplant rejection 'and plague' 丨 disease, and more specifically, for the treatment of rheumatoid (4), multiple sclerosis, inflammatory (four) material, occupational rhinitis, material , ship obstruction = disease (COPD), atopic dermatitis, and psoriasis. Another embodiment of n consists of a type of package, including the above-mentioned 吼 生 生 及 及 及 及 及 , Character therapy, septic disease, leukemia, lymphatic malignant disease, and graft rejection; immune-mediated diseases 1 ^ such as sinensis, leukemia, lymphoid == solid tumor; bone and organ transplant rejection;

Crl, more than 'sick' and more specifically 'applicable to the treatment of rheumatoid P 'hardening, inflammatory bowel disease, dry eye, uveitis, 209 201130839 inflammation, allergic rhinitis, asthma, chronic obstructive pulmonary disease CCOPD), atopic dermatitis, and pharmaceutical composition: two drugs: a compound of the present invention and a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical composition for use in two or more other treatments The medicinal treatment of the agent is easy to ameliorate the pathology or axis by inhibiting the Janus kinase (dish), such as the disease described. Loyalty/Month also relates to a pharmaceutical composition for reversing the pathological condition or disease by inhibiting the Janet kinase (jak) to σ, in particular, the squamous or disease is selected from a spinal proliferative disorder. , leukemia, and solid tumors; bone and body transplant rejection of anti-two diseases and inflammatory diseases, such as lysed proliferative diseases = anaesthesia, lymphoid malignant diseases and solid tumors; bone marrow and organ transplant rejection, and immune-mediated _, And more specifically, the condition or disease is selected from rheumatoid arthritis, multiple, intestinal disease, 'dry eye' uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (a) PD), ectopic skin f. The present invention also encompasses the use of the pharmaceutical composition of the present invention for the preparation of a medicament for the supply/oral treatment of the four diseases. In the aspect, the pharmaceutical composition can be used to treat a proliferative disease: Λ = wood corpse, sexual disease, and solid tumor. In this aspect, the oral therapy is achieved by suppressing the individual's __. In another from 210 201130839, the 'pharmaceutical composition can be used for secret bone marrow and organ should be; immune-mediated diseases as well as inflammatory diseases, such as; =: and immune-mediated diseases and treatment of the disease usually borrow It is achieved by suppression. The pharmaceutical composition can be used to inhibit Jay: to improve ======== (touch: = and inflammatory diseases, such as == multiple hair 2 = skin, chronic obstructive pulmonary disease kiss PD) ^ = skin == doctor The method comprises administering a therapeutically effective amount of a kinase as defined herein, wherein the treatment is performed by inhibiting the Gena of the individual; Therapeutic effective amount is as herein described ====: Individual treatment of treatment The present invention also provides a pharmaceutical composition comprising at least the formula (1) of 30201130839 or a pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable Accepted excipients (such as carriers or diluents). The active ingredient may comprise from 0.001% to 99% by weight, preferably from 0.01% to 9% by weight of the composition, depending on the nature of the formulation and whether it is further diluted prior to application. The composition of the composition is preferably suitable for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration. Mixture with the active compound or a salt of the compound to form a pharmaceutically acceptable excipient of the present invention, and the method of the present invention is a well-known and practically used excipient as desired. And set. The composition for oral technique and the composition may be used as a tablet, a delayed tablet, a sublingual tablet, a face, an inhalation, a Wei fluid, a dry powder inhaler or a liquid preparation (such as a mixture, an elixir, a syrup or a suspension). The liquid form, each containing a compound of the invention; the shot is prepared by methods well known in the art. The diluent from which the composition can be prepared comprises a liquid compatible with the active ingredient and a HI body, and a necessary agent. The lozenge or capsule preferably contains 001_3 〇〇 Ω; ^ (iv) (iv) unswallowed, 壬8-denier milligrams, more preferably 0.5-1000 milligrams of active or equivalent amount of a pharmaceutically acceptable salt thereof. The composition of the form (4) may be in the form of a returning liquid. The Loose Liquid can be an active compound which can be associated with, for example, a sucrose for forming a syrup. The inclusion of the insoluble active compound of the present invention == together with a suspending agent or flavoring water. Salts for use in parenteral injections may be prepared from soluble salts, which may or may not be (iv) dry and soluble in the pyrogen-free aqueous intestine injection fluid. The composition for topical administration may be in the form of an ointment, cream or lotion containing the compound of the invention; the preparation may be prepared by methods well known in the art. The amount of the active ingredient is usually in the range of _3_mg, more preferably q 5 side milligrams per day or an equivalent amount of the pharmaceutically acceptable dose can be daily- or multiple treatments, preferably 1JL 4 times The pharmaceutical formulation is preferably in unit dosage form and can be prepared by any of the methods of pharmacy. The pharmaceutical composition of the present invention which is orally administered orally can be in the form of a unit such as a capsule, a cachet or a lozenge, '3 having a predetermined amount of an active ingredient; a powder or an age; a new or trans-liquid in an aqueous liquid liquid; or an oil-in-water liquid emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of a bolus (bc &gt; lUs) (electuary) or a paste. The paper sugar concentrate formulation will generally consist of a compound or a salt in a liquid carrier containing a colorant (for example, ethanol, peanut oil, a scented liquor or a suspension or solution thereof. ^ or water) ^ when the composition is in the form of (4) Any medicine that can be used to prepare a formulation. Examples of the paving include a hard body 'moon stone gelatin, acacia, stearic acid, starch, lactose, and sucrose. The sugar is prepared by mixing 213 201130839 dispersant with a free flowing: 2 surfactant or ingredient. The active release agent (at the end or difficult) can be prepared by a mixture of difficult-to-liquid π-heart-like compounds in a suitable machine 11. The tablet is either slow or controlled. Any conventional encapsulation in the form of capsules in the form of capsules is suitable for hard (4) towels (4). The conjugate may be considered as a 'medical time' and may be considered as a pharmaceutical preparation commonly used for preparing a dispersion or suspension, such as aqueGUS gum, cellulose, oxalate or oil, and It is in a soft gelatin capsule. The dry powder composition for topical delivery to the lung by inhalation may, for example, be in the form of a capsule and an cartridge or a = (blister) form such as a laminated box for use in an inhaler or insufflator. Formulation = generally contains the compound of the present invention and an inhalation of a powder matrix (carrier material) such as lactose or starch. It is difficult to use lactose. The mother capsule or cartridge may generally contain between 2 micrograms and 150 micrograms of each &amp; therapeutically active ingredient. Alternatively, the active ingredient can be provided without excipients. The formulation for inhalation can be loaded by using a suitable inhaler device such as Genuair 8 214 201130839 (formerly known as Novolizer® SD2FL) as described in the following patent application: WO 97/000703, WO 03/ 000325 and WO 2006/008207. A typical composition for nasal delivery comprises the above-described composition for inhalation and further comprises a non-pressurized composition in the form of a solution or suspension in an inert vehicle such as water, as appropriate and conventionally shaped Agents such as buffers, antimicrobials, tonicity modifiers, and viscosity modifiers are combined and can be administered by nasal pump. Typical dermatological and transdermal formulations include conventional aqueous or non-aqueous vehicles such as creams, ointments, lotions or pastes, or in the form of medicated plasters, patches or films. Preferably, the unit is in unit dosage form, such as a lozenge, capsule or metered gas &gt; gluten, such that the patient can administer a single dose. Sex Agents: The amount of each active agent required for the treatment of the drug will vary with the particular disease. =... The individual being treated and the particular condition or reference being treated is in the form of a composition = as an example of a formulation. Phenylethyl) 1: Two, 50, each containing 1. . Capsules of mA1-AK1-, :-a pyrazin-3-ylpyrimidine-4-amine (active ingredient) Magnesium---- 5 kg - 10 kg----- 0.1 kg^---_ --- 1 kg 0.2 kg 201130839 program and loaded to the right mix. The above ingredients were sieved through a 60 mesh sieve, filled in a mixer and filled into 5 gelatin capsules. Composition Example 2 2.5 1.95 kg 9^95^- 0.4 kg Stearic acid anti-sodium butyrate per state two ~~

Active ingredient _ microcrystalline cellulose procedure, the powder is passed through a pore size of 〇·6 mm, then mixed in a suitable mixer for 20 minutes and using a 9-inch disk flat flat beveled punch machine (bevelledpunch ) compressed to 300 mg tablets. Composition Example 3 mg 0 in | (1 - phenyl-amine (active ingredient) was prepared from the following formulation 5 〇〇〇 each containing ethyl) 2 吼 吼 并 [1,5_a] pyrazine·3· Acetaminophen _4 lozenge: ι

216 201130839

All powders were mixed through a mixer having a pore size of 〇.6 20 for 20 minutes and compressed to 300 mg of tablets in a suitable machine using a 9 mm pan. The rotary 1 flat oblique knife stamping does not affect, change, or change the feed time for about 3 minutes. The group of people whose Ml A fly t is decorated with the compound, the combination or the medicine 4 is included in the scope of the present invention. Simple description of the schema] None [Key component symbol description] None

217

Claims (1)

201130839 VII. Scope of application: 1. A formula (Ο compound or its pharmaceutically acceptable salt solution or N-oxide or stereoisomer or deuterated derivative, 4 r4 Wherein m is 〇 or an integer of 1 to 3; Z represents an oxygen atom or a group NR5; w represents a nitrogen atom or a _CR3 group; X, ^ or ΐ Γ T independently represents a gas atom or a rhyme 9 group, In the case of the atomic group, the (4) face _CR9; atom; cyano 2; octagonal means hydrogen atom; dentate alkynyl; ce4 ¢ = knife ^; employed; C2-C4 cycloolefin A. / mercapto, CrQ hydroxyalkyl; C3-C1Q naphthoquinone P, chitosan, monocyclic or polycyclic fluorene), C3_Cl〇s and ]Si heterotetragonal, 3 at least one selected from 0, a 5- to 14-membered heteroaryl group of an atom; a 5- to 14-membered heterocyclic group containing at least one selected from 218 201130839 from 0, #s, and N heteroatoms; containing a monocyclic C5f9 aryl or heteroaryl direct bond a heterocyclic group or a heterocyclic group which is bonded to a 5- to 9-membered cycloalkyl or heterocyclic group. The heteroaryl or heterocyclic group contains at least one hetero atom selected from the group consisting of ruthenium, S and N; and an aza with at most 12 carbon atoms. a bicycloalkyl group or an aza-bicycloalkenyl group having up to 12 carbon atoms, wherein the alkenyl group, alkynyl group, adentyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group , heterocyclic group, bicyclic group, The hetero-bicycloalkyl group and the aza-bicycloalkenyl group are unsubstituted or substituted with one or more substituents selected from the substituents Ra, and the alkyl group is unsubstituted or substituted by one or more selected from Rb Base substitution; or heart, 112, 113, 114 and ruler 9 independently represent _ Zhang 丨 3 group, _$ 〇 1113 group, -s(o) 2Ru group, _s(0) 2 NRi3Ri4 group, _NRi3S ( 〇) 2Ri4 group, -NR13S(0)2NR14 group, -(CH2)n0R13 group, -C(0)0R13 group, -0-c(0)r13 group, _c(0)-(CH2 a n_Ri3 group, a _NRi3ri4 group, a _C(0HCH2)itNRi3R14 group, a -NR13C(〇)-(CH2)n-R14 group, a -NR13C(0)-(CH2)n-NR14R15 group, wherein each η Is 〇, 1 or 2; or in the presence of two adjacent -CR_9 groups, two adjacent _cr9 groups and their bonded carbon atoms form CrC 2 aryl or 4 to 12 as appropriate a heteroaryl group, a cycloalkyl group or a heterocyclic group containing at least one hetero atom selected from the group consisting of hydrazine, S and N, said aryl group, heteroaryl group, ring-based group and hetero The ring group is unsubstituted or one or more selected from a dentin atom, a linear or branched chain CrC6 alkyl group, Or a polycyclic c5_Cu aryl group, 5 to 14 member heteroaryl 219 containing at least one hetero atom selected from 0, S and N, 201130839 or 3 having at least 5 selected from Ο, S and N a substituted filament of a 14-mer, the capped silk, the aryl group, the heteroaryl group, and the heterocyclic substituent of the heterocyclic group are unsubstituted or have one or more selected from the group consisting of a p atom, a trans group, a cyano group, Substituted by a substituent of a straight or branched cvcw group or a crc4 haloalkyl group; a hydrogen atom, a straight or branched chain Ci_C6 alkyl group, optionally, one or more selected from the group consisting of hetero, cyano, C "C4 (tetra), Ci_C4 is substituted by a thiol group, a C3-C1G peach group, a phenyl group or a 6-membered saturated N-containing heterocyclic ring. t〇=R5 t shows -S(〇)2Rl〇基®, -S(〇)2NRi〇 Ri1 group, -C(〇)〇R10 group, _c(〇HCH2)-C(〇MCH2)n-NR丨〇Rn group; ® fly MR6riR7 money to form money atomic or linear or branched c] a _c6 alkyl group, optionally substituted by one or more substituents selected from the group consisting of a hydroxyl group and a gas-based saturated N-containing heterocyclic ring; 'R8 represents a hydrogen atom; a dentate atom; a cyano group; a linear or branched group; CVQ position; C2_Q fast base; CrC4 base a 6-group; a c3-c1G cycloalkyl group, a c3-c1G cycloalkenyl group; a radical ♦ 1 group, containing at least one selected from the group consisting of o, s and a dicentric heteroaryl; containing at least one selected from the group consisting of ruthenium and s a heterocyclic ring of 5 to 14 to 14 members of the atom; a bicyclic group containing 5 to 9 membered cycloalkyl or heterocyclic groups of a monocyclic CVC:9 aryl or hetero atom; At least one hetero atom selected from the group consisting of ruthenium, S, and ]Si. aza-bicycloalkyl group having a carbon atom or a heterocyclic ring having at most/and at most I 1 solid ruthenium 220 201130839 bicycloalkenyl group, Wherein alkenyl, alkynyl, alkenyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, bicyclo, aza-bicycloalkyl, and aza-bicyclic The alkenyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of Ra, -(CrC4 alkyl)-CN group or -(c 1 -C4 alkyl; oxime (0) ΝΙΙΕ&quot; group, wherein R 'and R' are the same or different and are selected from a hydrogen atom and a linear or branched chain CrC4 alkyl group; and the alkyl group is unsubstituted or substituted with one or more substituents selected from Rb; or the ruler 8 represents -SR13 Group, -SOR13 group, -S(0)2R1 3 group, -SCC^NRbRh group, -NRnSiOLRM group, ·NR13S(0)2NR14 group, -(CH2)nOR13 group, -C(0)0R13 group, _〇_c(〇)R13 a group, a -C(0)-(CH2)n-R13 group, a _nr13r14 group, a -C(〇HCH2)n-NR13R14 group, a -NR13C(0)-(CH2)n-R14 group or - ΝΙ113(:(〇Ηί:Η2)η·ΝΚ_14Κ15 group 'where each η is ❹^ or ], or together with the nitrogen atom to which R5 and Rs are bonded, form a 4 10 membered saturated heterocyclic group containing one or two a nitrogen atom as a hetero atom and having a straight or branched chain eve: 6 alkyl, monocyclic or polycyclic aryl, having at least one hetero atom selected from the group consisting of ruthenium, S and N, containing at least one selected Substituted from a 5 to 14 membered hetero group of a hetero atom of hydrazine, S and N, a -so2r10 group, a _c(〇MCH2)n_Ri 〇 group CXOHCHaVNRioRu group, wherein each n is oxime, wherein the alkyl group, An aryl group, a heteroaryl group, and a heterocyclic group are substituted with or substituted with a substituent of an imine atom, a cyano group, a linear group or a decyl group, or a CrQ(tetra) group, and wherein the (4) 221 201130839 Substituted or via one or more selected from the group consisting of dentate atoms, hydroxyl groups, cyanogens Substituted with a substituent of a Crc4 haloalkyl group; the restriction is that when m is 〇, R8 is not a _SR13 group, a _s〇R13 group, a -s(o)2r13 group, a _s(0)2NRi3Ri4 group Group, _NRi3S(〇)2Ri4 group, _NR13S(0)2NR14 group, -(CH2)n〇Rl3 group, _〇_c(〇)Ri3 group, -NRnRi4 group, -NRi3C(〇)_ (CH2)n_Ri4 group or -ΝΚ13(:(0)-((:Η2)η-ΝΚ_14Κ_15 group, wherein Ra is a halogen atom; cyano group; hydroxyl group; straight or branched chain Ci_C6 alkyl group; CrC4_alkyl group ;crC4 alkoxy; Cl_C4 hydroxyalkyl; Cr〇^ alkyl or q-C7 cycloalkenyl, which is unsubstituted or substituted with one or more substituents selected from the substituent Re; monocyclic or polycyclic C5 a Ci4 filament which is unsubstituted or substituted with one or more substituents selected from the substituents Re; 5 to 14 fluorene-containing aryl groups containing at least one hetero atom selected from 0, S and N, which are not Substituted or substituted with a substituent derived from a substituent Re; a 5 to 14 membered heterocyclic group containing at least one hetero atom selected from 0, S and N, which is unsubstituted or selected from - or a plurality selected from Substituent substitution of substituent Re; SR10 group Bu SOR10 group; Na) 2Ri〇 Group; _8(〇)2 is taken as a group; -NR10S(O)2Rn is a group m; _NRi〇s(〇)2NR&quot;group; -(CH2)n〇RlO 1-II » -C(O)〇R10 ^ ||J ; .〇.C(〇)R10 ^ m . -C(〇MCH2)n-R10 group, group; 〇i〇Rn group; -C(0)-(CH2)n-NR1〇Rll ; -NR1〇C(0)-(CH2)n-R11 ^ -NR1〇C(0HCH2)n-NRllRl2 group, wherein each n is 〇, 1 or 2 宽 Rb is cyano; CrC4 卣 基; Ci_C4 Alkoxylate; c] _c far-burning 222 201130839; C3-C7 cycloalkyl or c3_c7 substituted filaments selected from the substituent Re; single more containing at least - ship-substituted, s substituent substitution, base, Unsubstituted or by- or a plurality of selected 5 S14 member heteroaryls; containing at least one substituent selected from the group consisting of: Glutamic acid: a substituent, or a plurality of substituents selected from the group Re, Tuan; tear 1G group; · group; -s(o)2NR1〇Rll group; ·ΝΚι〇8(〇)2Κιι group; view ^(9) view&quot; group, Yang 2) wind. Group; _C(0)0R1. a group; _o c(o)R10 group; -C(0HCH2)n-R1 fluorene group; _NRi〇Rn group; -QOHCHURn group; _NRi〇c(〇)_(CH2)n_Rii group or - Nrwohchuru group, wherein each 4〇, u2; Rio, Rii and R!2 each independently represent a hydrogen atom, a cyano group, a straight or branched chain (Vc6 alkyl, Cl-c4i alkyl, C]_C4 hydroxyalkyl ,Ci_C4 alkoxycarbonyl, CVC7 cycloalkyl, phenyl, 5 to 6 membered monocyclic heteroaryl containing 2 or 3 heteroatoms selected from N, fluorene and S, containing hydrazine, 2 or 3 nitrogen atoms a 5- to 6-membered heterocyclic group containing a monocyclic cvq aryl group or a heteroaryl group directly bonded to a bicyclic group of a 5- to 6-membered cycloalkyl group or a heterocyclic group, wherein the heteroaryl group or heterocyclic group contains 1, 2 or 3 nitrogen atoms, said dentate alkyl group, hydroxyalkyl alkoxy group Ik group, cycloalkyl group, phenyl group, heteroaryl group, heterocyclic group and bicyclic group are unsubstituted or substituted by one or more selected from a substituent of the group Rc is substituted, and the alkyl group is unsubstituted or substituted with one or more substituents selected from the substituent Rd; 223 201130839 Rc is a south atom, a hydroxyl group, a cyano group, a straight chain or a branched chain ^ —^alkyl 'Clf4 4 alkyl' Crc4 alkoxy, Cl- C4 hydroxyalkyl, c3-c7 cycloalkyl, stupid, 5 to 6 membered monocyclic heteroaryl containing 2 or 3 nitrogen atoms, 5 to 6 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms a C3-C7 heterocycloalkyl ketone group having 1, 2 or 3 nitrogen atoms which is unsubstituted or substituted by one or more dentate atoms, and the heteroaryl or heterocyclic ring And heterocycloalkyl ketone groups are unsubstituted or substituted by one or more straight or branched chain Ci_c3 alkyl; Rd is cyano 'CrC4 south alkyl, crC4 alkoxy, CrC4 hydroxyalkyl, CrC7 ring burn a phenyl group having 5 to 6 membered monocyclic heteroaryl groups having 1, 2 or 3 nitrogen atoms, containing 5 to 2 ring members of 1, 2 or 3 nitrogen atoms or containing 1, 2 or 3 a CrC7 heterocycloalkyl ketone group of a nitrogen atom, the phenyl group being unsubstituted or substituted by one or more halogen atoms, and the heteroaryl group, heterocyclic group and heterocycloalkyl ketone group are unsubstituted or Substituted by one or more linear or branched bonds C1-C3 alkyl; Re is a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain (^-(^alkyl or CrC4 dentate; R13, R丨) 4 and R1S each independently represent a hydrogen atom, a cyano group, Chain or branched chain crC6 alkyl, crc: 4 haloalkyl, Ci_C4 hydroxyalkyl, crc4 alkoxycarbonyl, CrQ cycloalkyl, monocyclic or polycyclic C5_Cl4 aryl, containing at least one selected from the group consisting of ruthenium, S and N a 5 to 14 membered heteroaryl group of a hetero atom, or a 5 to 14 membered heterocyclic group containing at least one hetero atom selected from the group consisting of 0, S and N, wherein the haloalkyl group, the hydroxyalkyl group, the alkoxycarbonyl group, the ring The alkyl, aryl, heteroaryl and heterocyclic groups are unsubstituted or substituted with one or more substituents selected from substituents of substituent 224 201130839 Ra, and the alkyl group is optionally one or more One compound selected from Rb is used to treat pathological conditions or diseases that are easily ameliorated by inhibition of Janus _ kmase. 2. The compound of claim 3, which is not a reverse _5. cyano_3_[6_(4-hydroxycyclohexylamino)pyridin-2-yl]pyrazole[l,5 -a]pyridine, trans-5-cyano-3_[6-(4.hydroxycyclohexyl-al曱amino)pyridin-2-yl]pyrazolo[l,5-a]pyridine, trans-5- Cyano-3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)acridin-2-yl]pyrazolo[i,5_a]npyridyl, 5-cyano- 3-[6-(piperidin-4-ylamino)pyridin-2-yl]pyrazolo[l,5-a] η than bite, 5-cyano-3-[6-(methyl(piperidyl) Acryl-4(amino)pyridin-2-yl]pyrazole [l,5-a]pyridine, 5-cyano·3·[6-(1-(2-cyanoethenyl)piperidin Pyridin-3-ylamino)acridin-2-yl]pyrazolo[l,5-a]pyridine, (and)-5-cyano-3-[6-(l-(2-cyano) Mercapto)piperidin-3-ylamino) σ-pyridyl]oxazolo[l,5-a]pyridine and W-5-cyano·3-[6_(Α^-mercapto-1-( 2-cyanoethyl fluorenyl) 0 唆 基 胺 ) ) α 比 唾 & 唾 1 1 1 1 1 1 1 1 1 1 1 1 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及 以及6-(1-hydroxydecylcyclopentylamine carbaryl-2-yl)pyrazolo[l,5-a]&lt;bite, 225 201130839 3-[6-(4-hydroxymethylpiperidine) _丨基Pyridin-2-yl]pyrazolo[i,5-a]pyridine, 3-[6-(3-hydroxycyclohexylamino)π-pyridin-2-yl]pyrazolo[i,^]pyridine , trans-3-[6-(4-hydroxycyclohexylmethylamino)pyridin-2-yl]pyrazolo[l,5-a], bite, 3-[6-(1-ethoxycarbonyl) Acridine_4·ylamino)pyridine-2-yl]pyrazolo[l,5-a]n ratio bite, trans-3-[6-(4-aminocyclohexylamino)π-pyridinium_2 · carbazino[i,5_a]a than pyridine, trans-3-[6-(4-hydroxycyclohexylamino)n-pyridin-2-yl]pyrazolo[i,5-a]pyridine , 3-[6-(tetrahydro-4//-piperidin-4-ylamino)pyridin-2-yl]pyrazolo[l,5-a] °, 3-[6-( N-methylcyclohexylamino)acridine_2_yl]pyrazolox pyridine, 3·[6-(3- thiol-l-yl-yl)pyrene-2-yl]B Than 峻 乂 乂 乂 比 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 H 、 、 、 、 、 、 H 、 、 H H 、 H 、 H H H 、 H H 、 H 、 H 6-Tetramethyl Bing-4-ylamino) Bite_2-yl] &lt;7 than saliva[l,5-a]a than bite, 3-[6-(2-phenylpropene- 2-amino)pyridin-2-yl]n-pyrazolo[丨,5_a]吼〇定, (5)_3·[6-(1-phenylethylamino)pyrene~2_yl]η ratio Salivation, 3-[6-(1-phenylmethylamine-based base-2)-π Compared with 嗤[i,5-a]° ratio bite, (iS}-3-[6-(l-cyclohexylethylamine base ratio σ _2_2_ kibbi. Sit and [1,5_&amp;]0 to 226 201130839 pyridine, (1^-3-[6-(1-decyloxypropan-2-ylamino)atb bit-2-yl] ° ratio 圭[ l,5-a]n is more than bite, 3-[6-(nonylamino)π is more than 唆-2-yl]0 than saliva[l,5-a]0 than bite, 3-[6-(aniline Base) σ is more than 唆-2-yl]0 than salivation [l,5-a]D is more than bite, 3-[6-(° is more than -3-ylamino) π than -2-yl] π Sit with β and [1,5-a]° than bite, 3_[6_(° is more than 唆-4-ylamino)π than 唆-2-yl]ntbσ and [1,5-a]atti σ, -3-3-[6-(4-Amino- succinylamino) 10 is more than -2-yl]-5- disordered base ratio σ sit and [l,5_a] ° specific, 5-cyano -〇S)-3-[6-(l-phenylethylamine-based pyridin-2-yl)oxazolo[l,5-a] 0 is more than bite, 5-ranyl-3-[6-( 4-light-butyrylamino) ° bite-2-yl] 11 to 11 sits and [1,5-&amp;] ° ratio biting, 5-cyano-3-[6-(N-methyl- (3-hydroxypropyl)amino group; Kb pyridine-2-yl]« sits at 0 and [l,5-a]n ratio bite, 3-[6-(3-aminomethylhexylamino)α Slightly bite, 5-cyano-3-[6-(N-mercapto-N-(2-methylamino) than [bit-2-yl]^- disordered 吼11 Ethylamino)acridin-2-yl] 0 is more than squat and [l,5-a]nH: lake, 5-disorgano-3-[6-((1-ethoxylated)咬-3-ylamino)D is more than 唆-2-yl] 0 than spit [1,5-&amp;] bite, :- 3- [6-(2-aminoethylamino) π ratio Bite-2-yl]-5-wearing! The base is more than π and [1,5-a] 0 is bite, (iS)-5-disorder -3-[6-(2- 曱 0 base 0 ratio Lozen-1-base) 0 to bit-2-yl] mouth ratio 227 201130839 0 sit and [l,5-a]4b bite, (and)-5-cyano_3-[6-(2- Mercaptopyridinyl benzylidene-2-yl]indolozolo[l,5-a]pyridine, 5-cyanoethyl-indole-(4-hydroxybutyl)amino)D-pyridyl- 2-yl]pyrazolo[l,5-a]pyridine, 5-cyano-3-[6-(3-hydroxypropylamino)pyridin-2-yl]pyrazolo[l,5-a] 0 Specific bite, (S)-5-cyano-3-[6-(1-(ethoxycarbonyl)piperidin-3-ylamino)D-pyridyl-2-yl]° carbazole [l,5 -a] ° pyridine, trans-3-[6-(4-acetamidocyclohexylamino)pyridin-2-yl]carbazolo[l,5-a] ° ratio, anti-3 -[6-(4-oxasulfonylaminocyclohexylamino) ° pyridine-2-yl; Bizozolo[l,5-a&gt; than bite, 3-[6-(3-(2-oxo-oxy D)-l-but-1-yl)aniline) ° leaner base] 11 azole and U , 5-a]%b bit, 3-[6-(N-cyclohexylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine, 3-[6-(N-(2 - mercaptocyclohexyl)amino) ° pyridine-2-yl]D than oxazolo[l,5-a] ° bite, 3-[6-(4-acetamidoanilino) ° pyridine -2-yl]D-pyrazolo[1,5-a] ° than pyridine, 3-[6-(3-acetamidoanilino) ° ratio 1^2-yl]1•bizozolo[1 , 5-a] acridine, 3-[6-((3-methylaminocarbonyl)anilino)π-pyridyl-2-yl]°-azolo[l,5_a] ° ratio bite, 228 201130839 3- [6-(3-Phenyl-N-methylamino)0 is more specific than sputum and [1,5-a]11 is pyridine, 3-[6-(Ν-ί ^_propyl propylamino)° than biti-2-yl]ntbβ sits and [1,5-a]11 is pyridine, (S)-3-[6-(l-phenylethylamino)0 ratio咬-2-yl]-5- 曱 ° ° 并 and [lj-a] 1 ^ bite, 3-[6-(ΰ辰ιι^-4-ylamino) π than bit-2-yl ]π is sitting at 0 and [1, 3_[6_(Big -4-amino-amino) atb唆-2-yl]-5-mono-yl ntb π sits and [1,5-a] 0 bites, 3-[6-(1-Ethyl-based brigade-4-ylamino)att bit-2-yl]attie sit and [1,5- a) mouth bite, 5-cyano-3-[6-((l-ethinyl)piperidin-3-ylamino)"pyridin-2-yl]indole[l,5-a ]° ratio σ, (S)-5-murine-3-[6-(pyrylene-3-ylamino)ntb唆-2-yl]ntb α sits and [l,5-a]n ratio bite. 3. The compound according to claim 1 or 2, which is not a compound of the following formula (I) or a salt or solvate thereof: wherein Ri, R2 and 4 each represent a hydrogen atom; W represents - CR3 group; Z represents a group -NR5; VX, Y and T each represent a group -CR9, wherein R9 represents a hydrogen atom; R3 represents anthracene, halogen, C!_4 alkyl, halo-Ci-4 alkyl, meso-Cu Alkyl, R27-Q-4 alkyl halogen, cyano, -C(0)-NR24R24, -C(0)R25, 229 201130839 -C(0)0R25, -OR24, -S(0)2R25,- S(0)2NR24R24, -NR24R24, NHCOR24, -NCCm alkyl)cor24, -NHCONR24R24, -N(Cm alkyl)conr24r24, -nhc(o)or35, -NKm alkyl)c(o)or35, -NHS (0) 2R25, NKm alkyl)S(0)2R25 or Cy!, wherein Cyjtlt is substituted with one or more substituents selected from R28; R5 represents a nitrogen atom, a C 4 alkyl group, a halogen group Ci- a 4-alkyl group, a trans-based Ci-4 alkyl group or a Q_4 alkyl group, which is substituted with a group selected from the group consisting of a cyano group, a hydroxyl group or a Cy group, wherein Cy is optionally substituted by one or more R28 groups; a group - (CR6R7 m-R8 represents (: μ4 alkyl, Cm haloalkyl, hydroxy Ci-4 alkyl, R2irC) _4 alkyl, -CONR209R209, _CO R210, -C(O)〇R210, -S(O)2R210, -SO2NR209R209 or Cy3' wherein Cy3 is optionally substituted by one or more R212; or r5 together with r8 and the nitrogen atom to which it is bonded form a Cy4 group a group wherein Cy4 is optionally substituted by one or more R212; each R_24 independently represents a gas or a ruler 25, and each R25 independently represents a Cm alkyl group, a halo C-4 alkyl group, a C a-4 alkoxy Cm alkane a group, a hydroxy CM alkyl group, a cyano Ci-4 alkyl group, a CyrCM alkyl group or a Cyi, wherein Cyi is optionally substituted by one or more R28' each R35 independently represents a Ci-4 alkyl group, a functional group Ci·4 a group, a Ci4 alkoxy Cm alkyl group, a hydroxy cM alkyl group, a cyano Cm alkyl group or a cyi-ci-4 alkyl group, wherein Cyi is optionally substituted by one or more; each R28 independently represents Ci-4 Affiliation, halo-based Cl. 4 leumino, Cl. 4 alkoxy CM alkyl, hydroxy cM alkyl, cyano Cm alkyl, dentate or hydroxy; 230 201130839 R27 represents cyano, -C(0)- NR24R24, -c(o)r25, -c(o)or25, OR24, -S(0)2R25, -S(0)2NR24R24, -NR24R24, -NHCOR24, -N(CM alkyl)COR24, -NHCONR24R24, Alkyl)CONR24R24, -NHC(0)0R25, -ΝβΜ alkyl)c(o)or25, -NHS(0)2R25 , N(Cm alkyl)S(0)2R25 or Cy!, wherein Cy! is optionally substituted with one or more substituents selected from R28; each R2G9 independently represents hydrogen or r21Q; each R2H) independently represents an alkane a base, a functional group of Q-4 alkyl, a hydroxy Cm alkyl group, a R^uC!·4 alkyl group or a Cy5, wherein Cy5 is optionally substituted with one or more substituents selected from R213; R211 represents a dentate, milk Base·, _C0NR214R214, _COR&gt;215, _C(0)0R215, -OR214, -S02R215, -S02NR214R214, -NR214R214, -NHCORzwNCCm alkyl)COR214, -NHCONR2 decyl)CONR214R214, -NHC(0)0R215, - NKm alkyl)C(0)0R215, -NHS(0)2R215, N(CM alkyl)S(0)2R215 or Cy5' wherein Cy5 is optionally substituted with one or more substituents selected from r213; each R212 Independently indicating a Q_4 alkyl group, a halogenated Cm alkyl group, a via group Ci_4, a R211-Ci_4 alkyl group or R_212, meaning any of the meanings described for Κ·211; each R213 independently represents a Cm alkyl group, Q-4 Halogenated group, Ci-4 alkoxy group C _4 alkyl group, benzyl group, cyano Ci_4 alkyl group, halogen, cyano group, -CONR216R216, _C〇R217, -C(0)0R217, -OR216, • OCONR216R216, _S(〇)2R217, _S0 2NR216R216, _NR216Rm, • NHCOR216, -N(Cm alkyl)COR216, -NHCONR^R^'-NCCw 231 201130839 alkyl)conr216r216, -NHC(0)0R217, _N(Ci 4 alkyl)C(0)0R217, -NHS(0)2R217, NCCm alkyl)S(〇)2R217; each R2〗4 independently Represents hydrogen or R215; _ each R215 independently represents cM alkyl, halo cM alkyl, cM methoxyoxy C 4 alkyl, hydroxy C 4 alkyl, cyano Ci 4 alkyl, Cy5_Ci 4 alkyl or Cys Wherein Cys is optionally substituted by one or more R213; each R·2]6 independently represents hydrogen or R217; each Κπ independently represents CM alkyl, haloQ 4 alkyl, oxyindole-4 alkyl , hydroxyalkyl or cyano Ci 4 alkyl; *Cy] represents a 3 to 7 membered monocyclic ring which is a saturated, partially unsaturated or aromatic carbocyclic ring, and optionally contains 1 to 3 independently selected from N , S and 〇 of the hetero atom 'the ring of the ring is bonded to the molecule via any available C or N material = the rest 'and wherein - or a plurality of C or S ring atoms oxidize as appropriate to form a CO, so or so2 group a single ring of 3 to 7 members which is a saturated, partially unsaturated or aromatic reverse coat 'and optionally contains 1 to 3 independently selected from N, s and scorpion' wherein the ring is via any available C Atom bonding to a molecule C〇: or more... ring original her _^^^^ member ^ or 8 to 12 members of the double ring is saturated, part from N, S in months, π anaesthesia, including 1 to 4 independently selected key points And heteroatoms, wherein said any of the available sub-232 201130839 is recorded as 姊 or partially shouted and 3 to its condition as saturated, partially unsaturated or aromatic 5 Γ, heterocyclic fused 'where Cy4 The case contains a hetero atom of N, &quot; and C); and wherein Cy-4 == oxidizes to form a CO, so or s〇2 group; ^ or S original Cy5 represents a 3 to 7 member single ring or 8 to 12 : or an aromatic carbocyclic ring, and optionally containing a hetero atom of 0, wherein the ring is bonded to the remainder of the molecule via any N atom 1 - or a plurality of atoms are oxidized as appropriate to form CO, SO Or the S02 group. $衣 - The material described in item 1 to item 3 of item circumference. Where T is not a -CR9 group. 5. A compound as described in any one of the claims, wherein a hydrogen atom, a dentate atom, a thiol group, a nitrogen group, a straight bond or a mcrC4 self-alkyl group, a w-substituent group, or (d). a ring-based or -NRR group; wherein R, and R" are the same or different and each represents a gas atom, a straight or branched chain C-C6 alkyl, a crC4-alkyl or a crc4 hydroxyalkyl group; R2, R3, and R4 is the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain Ci&lt;:6 alkyl group, a CrG tooth alkyl group, a CrCt hydroxyalkyl group or a (:3-(:1() ring). Alkyl % Rs represents a hydrogen atom, a straight or branched chain, optionally substituted by - or a plurality of cycloalkyl groups selected from the group consisting of woven, cyano, CrC4, CrC4, or CVCh). Substituent; 233 201130839 r6 and r7 are the same or different and each represents a hydrogen atom, a straight bond or a branched chain CrC6 alkyl group, a CVQ functional group or a CrC4 burned; R9 represents a hydrogen atom, a halogen atom, a trans group, a cyano group, Straight or branched chain CrC6 alkyl, CrC4 dentate or CrC4 trans-group; R8 represents a hydrogen atom, a straight or branched chain Cii, a CrQ _ alkyl 'CVC4 hydroxyalkyl group, a CrC1 () cycloalkyl group, a c6_Ci aryl group, a 5- to (tetra)heteroaryl group containing 1, 2 or 3 hetero atoms selected from N, fluorene and S, containing 2 or 3 hetero atoms selected from N, fluorene and s 5 to heterocyclic group, -L-Het-R,", _L_A, _A_s〇2_R,, A s(10)..., _a_a,, -ALC(0)NR'R- , .aL-CN , -AC(〇)- Het--L-CN , -AC(〇VNR,R" ' +C(〇)z_A",_a_c(〇) r,,,,_a c〇2 r, =;=c base c Γ means straight key or Branching chain c, -in view of the silk group "and heteroaryl and heteroaryl unsubstituted ❹ /, yl, transyl, aryl, benzyl, linear or branched chain, and wherein the Crc4 alkoxy The substituent is taken as "J; is an f chain or a branched chain CrQ alkyl group, V Het represents 0 or NriV, an atom, a straight chain or a branched chain wherein RIV is a nitrogen alkyl group, a 4 fluorenyl group, a CrC4 i alkyl group or a c 丨-c4 hydroxy 234 201130839 base, ^ to ^), ^? A, ', the same or different and each table * ring martenal naphthenic, group, ^, base, C6_C丨0 aryl or 5 to 10 members An aryl group, a plurality of which are selected from the group consisting of an anthracene, an aryl group, and a heteroaryl group which is unsubstituted or a- or a group or a fluorene VC p =, a secret, a cyano group, a linear or branched chain crc6 alkene or an alkoxy group thereof. Substituent substitution, chain or hydrogen shoulder, dentate atom, secret, cyano, straight-NR, R"-based temple I C6 alkyl, CrC4 halo, crc 4 hydroxyxyl or linear or sub-L 2 R, and R, the same or different and each represents a hydrogen atom, and R!, r 1-(:6 alkyl, CrC4 haloalkyl or crc4 hydroxyalkyl, A&quot And A, &quot; 3 R4, Rule 5, R6, R7, R8, L·, Het, A, A, and 6 are as defined above. A compound according to any one of the claims, wherein the Crc is a 'straight or branched chain CrC6 base, Ci-C4_alkyl, one selected from N, two, CrCl0% alkyl, C6-C10 An aryl group, a 5 to 10 membered heteroaryl group containing 2 or 3 or 3 or more hetero atoms of white and S, containing 5 to 10 of the hetero atom of the sulphonium, sulphur, and S 10 member heterocyclic group, -ac(〇kt 二", _Α·Α, ,, -Ac(0)-R,", group, ^^, _A-C(0)Z-L_CN or -AC(0 zL-Het-R, a group Crcf_ ^ which is 々 1 or 2 and R ... represents a linear or branched chain CrC3 alkyl group, an aryl group, and a urethral group, and wherein the cyclodyl group, heterocyclic group, group, f The ruthenium is unsubstituted or substituted by - or a plurality of selected from a halogen atom, a hydroxyl group, C6,;, Ci; C4, ^ L is a linear or branched chain CrC3 alkyl group, 235 201130839 'where R1V is a hydrogen atom , the direct bond mosquito A is β 丨, 1 &lt;: 4 _ alkyl or CrC4 hydroxyalkyl, the heterocyclic group is the same or each represents CrCl. Cycloalkyl, 5 to 10 heterocyclic, "two to a 10-membered heteroaryl group, substituted with a cycloalkyl group, an atom, a hydrazine group, a cyanide rac or one or more a substituent selected from the group consisting of a south group or a branched chain (four) or a c-o3 alkoxy Z is a compound according to any one of the two claims, wherein the center thereof is as claimed in the patent application. A compound as defined in any one of the preceding claims, wherein the compound is a compound of any one of the following claims, wherein: = Γ Γ r r r r ' C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C 5 to 6 membered monocyclic heteroaryl groups of ruthenium and 8 heteroatoms '5 to 7 membered heterocyclic groups containing 2 or 3 hetero atoms selected from N, oxime and s, or (αΐ2)η〇κ a group wherein ^ is 〇 or 1 and R represents a linear or branched CVQ alkyl group or a Ci C4 haloalkyl group; wherein the haloalkyl group, cycloalkyl group, stupid group, heteroaryl group and heterocyclic group are not Substituted or substituted with one or more substituents selected from Ra; and the alkyl group is unsubstituted or substituted with one or more substituents selected from Rb; Ra is a halogen atom; cyano; hydroxy; straight chain or a branched chain (^ gastric alkyl, Cr'C4 dentate, CrC4 alkoxy, CVC7 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the substituent Re; phenyl, Unsubstituted Substituted by one or more substituents selected from substituent Re; 5 to 6 membered monocyclic 236 containing 1, 2 or 3 heteroatoms selected from N, fluorene and S; 201130839 Heteroaryl 'unsubstituted or Substituted by one or more substituents selected from the substituent Re; 6-membered saturated N-containing heterocyclyl ring which is unsubstituted or substituted with one or more substituents selected from the substituent Re; -C(〇) a 〇R, a group or a C(〇HCH2)nR" group, wherein η is 〇 or Rb is cyano; Crc4 functional alkyl; CrC4 alkoxy; C3_C7 cycloalkyl 'unsubstituted or via one or Substituted by a plurality of substituents selected from the substituent Re; the phenyl group is unsubstituted or substituted with one or more substituents selected from the substituent Re; and contains 1, 2 or 3 selected from N, oxime and S a 5- to 6-membered monocyclic heteroaryl group of a hetero atom which is unsubstituted or substituted with one or more substituents selected from the substituent Re; 6-membered saturated N-containing heterocyclyl ring which is unsubstituted or subjected to a Or a plurality of substituents selected from the substituent Re; -C(0)0R, a group or ((OMCHm, a group, wherein n is fluorene or 1; a halogen atom, a thiol group, a cyano group, a linear chain) Or branched chain CrC6 alkyl CrC4 _alkyl; R' is a hydrogen atom 'straight or branched chain CrC6 alkyl, Crc4_alkyl, C3-C7 cycloalkyl, phenyl, containing 1, 2 or 3 selected from n, 〇 and s 5 to 6 membered monocyclic heteroaryl of a hetero atom, or 5 to 6 membered saturated N-containing heterocyclyl ring; and R, _NH 2 , cyano, straight or branched crc6 alkyl, Ci_c4 consists of an alkyl group, CH: a 7-cycloalkyl group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl group containing 1, 2 or 3 hetero atoms selected from N, 0 and S, or a 5 to 6 membered saturated N-containing heterocyclic ring; Wherein the cycloalkyl, phenyl, heteroaryl and heterocyclic groups are unsubstituted or substituted by one or more selected from the group consisting of a hydroxyl group, a cyano group, a linear or branched chain Ci-Ce alkyl group or a Ci_C4 tooth alkyl group. Substituted. 237 201130839 9 The cyano group, the linear or branched chain CrC household A 4 炫, phenyl, containing i, 2 or 3 ^ 0CrC4 New Zealand, from the ring _ A 3 selected from the ring 5, 6 membered monocyclic heteroaryl groups of N, oxime and s, or ', ', which are produced by 、, - 甘飞 5 to 6 members of saturated N-containing heterocyclic ring; The aryl group and the heterocyclic group are unsubstituted or substituted with a plurality of substituents selected from the group consisting of a hydroxyl group, a cyano group, and a fluorenyl group. ^ Branched Cl_Q wire or (1_^, as described in the scope of claim 1 of the patent, which has the formula r4 Z Formula (IC) ?8 wherein m is 0 or an integer from 1 to 3; Z represents an oxygen atom or an NR5 group; W represents a nitrogen atom or a _Cr3 group; and / in the =: a stand-alone surface * a gas atom Or a group, wherein 'X is R裘- represents a nitrogen atom' and the other represents a _CR9 group; a chain group c^, an atom, a thiol group, a nitrogen group, a straight chain or a branched soil 14 alkyl group , c]-c4 hydroxyalkyl, crc10 cycloalkane 238 201130839 or -NR, R, | groups; wherein R' and R" are the same or different and each represents a hydrogen atom, a direct bond or a branched bond Cr^6 , G-C4 functional group or (^-〇4 is burned; R2, R3 and R4 are the same or different and each represents a halogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain Cl-C: 6 alkane a group, a CrC4-alkyl group, a Crc4 hydroxyalkyl group or a C3-C1() ring-based group; R·5 represents a hydrogen atom, a direct bond or a bond C--C6 alkyl group, which is unsubstituted or has one or more Substituted from a substituent selected from the group consisting of a hydroxyl group, a cyano group, a CrQ haloalkyl group, a crC4 group via an alkyl group, a CrC1()cycloalkyl group, a phenyl group, an acridinyl group or a 6-membered saturated N-containing heterocyclic ring; R·6 and R7 is the same or different and each represents a hydrogen atom, a linear or branched chain CrQ a group, a CrC4 haloalkyl group or a Crc4.alkyl group; R9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched QQ alkyl group, a CrC4 haloalkyl group, a C]-C4 hydroxyalkyl group 4_NR, R, , group R. wherein R, and R" are the same or (d) and each of the filaments, the money or the branching bond Ci-〇6, the C1-C4 tooth-based or CpC4 is burned. π仏 represents a straight chain or a branched chain a crC6 alkyl group, a Ci_C4 tooth-burning base, a base of 2 or 3 selected from n, q and 8 and 5 to 6 membered monocyclic heteroaryl groups, containing 1, 2 or 3 selected from N, 5 to 7 members of the scorpion _ 〇: 2 or 1 is a straight or branched bond or wherein the haloalkyl, cycloalkyl, stupid is unsubstituted or one or more selected from Ra # = κ group &lt;substituent substitution; and the calcination 239 201130839 Kiri - or a plurality of self-help substituents substituted; base c: heart fc: t = base; linear or branched chain burned or warp- or a plurality of selected from; ^===== one or more selected from the group consisting of a substituent "=heteroaryl", a 5- to 6-membered single ring of a heteroatom of a pottery: ^Changzheng or one or more Substituted i-rings selected from substituted *(10), unsubstituted or via- or poly-based Its unsubstituted selection::;: oxygen $; C3-C7 ring-burning; phenyl, which is unsubstituted or substituted with a substituent of - or Re; contains 2 or 3 selected from N, ^ from a 5- to 6-membered monocyclic hybrid yarn of the substituent Re, which is substituted with a substituent of a hetero atom of S and a substituent such as a substituent; 6 贞 saturated or plural selected from substituted or substituted by one or more selected from a cyclyl ring which is unsubstituted or a -C(〇HCH2)nR" group substituted with a towel substituent; -C(9)0R' Re is a halogen atom, a thiol group, a cyanide group, or a 1 ' group or Crc4 dentate alkyl; straight or branched chain CrC6 alkane R' is hydrogenogen + 'straight or branched c c3'c7 cycloalkyl, phenyl, containing hydrazine, 2 or hexadecyl 'Crc4 _alkyl, - 5 to 6 membered monocyclic heteroaryls of a hetero atom: 3 selected from N, 0 and S ring-based rings; and 5 to 6 members saturated with N-containing 240 201130839 R is · νή; 2, an aryl group, a halophilic alkyl group, a C3-C7m^i, ^ or a branched bond Ci-Q alkyl group, a CrC4 0 and a hetero atom of S, a 5 to 6 group having a U or 3 selected from N, and an N-containing heterocyclic group a ring; wherein the hetero or 5- to 6-membered saturated ring group is unsubstituted or via an f group, a base group, a heterofilament, and a heterochain Cr C6 yard or c = solid, cyano, linear or branched U. As claimed in the patent "Hi-based substitution. In the compound of the formula (I-c), the compound of the formula wherein the NR5 group is represented by 12 Z. t ^ ^ 烧基, 〇^7 环广子, murine, linear or branched chain CrQ is different and each table Rn group 'the towel R, and R, 'the same or burnt base; Rl car exchange good table: / Straight or branched chain CrC6 alkyl, Cl-Q halogen. Preferably, the residual atom or the singularity of the residue; Ri preferably represents a compound of the hydrogen atom as in the range of any of the formulas, wherein the alkyl group or the c3-c halogen atom, the alkyl group, the linear chain or the branched chain Ci_C6 Ci-c3@&amp; .7R, and R2 preferably represents a hydrogen atom or a linear or branched chain 3, and I more preferably represents a hydrogen atom. A compound according to any one of the claims of the invention, which is characterized in that it is a calcination, a sulfhydryl group, a dentate atom, a cyano group, a straight chain or a branched chain C "C6 branching bond cY"; R3 is preferably A hydrogen atom, a cyano group or a straight chain or a cycline or a cyano group. The compound of any one of the claims, wherein the gas atom, the acne atom, the cyano group, the straight Key or branching key CA 241 201130839 Burning base or C3_(]7 loop wire; R4 recording Yang A liver or money or branched chain CrC3 alkyl; R4 preferably represents a hydrogen atom. Further 鸠16. The compound described in the above paragraph, wherein the pot is a hydrogen atom, a linear or branched C1_Q filament, which is optionally selected from two or two selected from the group consisting of a base group, a CrC4 self-combustible group, a CrC4 hydroxyl wire or a C3_C7, burnt soil. The substituent is substituted for 'R5 preferably a face hydrogen atom or a straight or branched bond CrC3 alkyl group; Rs more preferably represents a hydrogen atom. 17· (4) The compound of any of the claims, H and RJ standing wire 4 Xuan or straight thief sub-domain CA burning fc = and R7 preferably independently represent a hydrogen atom or a direct bond or a branched chain both violent. S ί I 8 in any of items 8 to 17 represents a straight or branched chain C "C ^ group, (4) tooth 2 s eve 3 private 7% alkyl "phenyl", containing 1, 2 or 3 a 5- to 7-membered heterocyclyl' or _(CH2)n〇R group selected from N, 〇 wherein η is a sub-group, and R represents a straight or branched chain Cl_C6 alkyl or (d) or warp, Ring filament, phenyl and heterocyclic groups unsubstituted or via - or oxime from the secret group. C ^ 素 atom atom; nitrogen base; warp group; linear or branched chain CrC6 alkane a group comprising 2 or 3 selected from N, 0 and S selected from the group consisting of 75 to 6 members of a monocyclic heteroaryl group which is unsubstituted or substituted by one or more, from dentate atoms, minus cyanide Substituent, straight or branched chain CrC6 alkyl or 242 201130839 Cl_C4 substituent substituted by a dentate group; -C(0)0R, a group or -C(〇HCH2)n-R', a group wherein n is 〇 Or 1, Rb is cyano; CrC: 4 haloalkyl; CrC4 alkoxy; C3_C7 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from a dentate atom, a hydroxyl group or a cyano group; a phenyl group which is unsubstituted or has one or more selected from the group consisting of a dentate atom, a hydroxyl group, and a cyano group. Substituted by a substituent of a straight or branched chain CrC6 alkyl group, a _C(〇)〇R' group or a -C(〇)-(CH2)nR, a group wherein n is 〇 or R' is a hydrogen atom, straight a chain or branched chain of a CrC6 alkyl group, a CrC4 4 alkyl group or a C3_C7 cycloalkyl group; and is a cyano group, a linear or branched chain CrC6 alkyl group, a CrC4 haloalkyl group or a C3-Cy^alkyl group, or a Chain or branched chain CrC6 alkyl, CrC4 haloalkyl, rCg alkyl 'stupyl' containing 1, 2 or 3 5 to 6 membered monocyclic heteroaryl groups selected from N, oxime and s = heteroatoms, containing 2 or 3 5 to 7 fluorene heterocyclic n(CH2)nC)R groups selected from N and S heteroatoms, wherein η is 0 or 1 and R represents a linear or branched C "C6 alkyl group" Or a haloalkyl group; wherein the i alkyl group, the cycloalkyl group, the phenyl group and the heterocyclic group are unsubstituted or substituted, or a plurality of substituents selected from Ra; and the unsubstituted or one or a plurality of substituents selected from Rb, wherein Rb is as defined above; Ra is a halogen atom; a cyano group; a hydroxyl group; a straight or branched chain 243 201130839; a C1-C4 halogen group; a complex, a hetero atom 5 Up to 6 members have a single school:] or 3 from N, 〇 And S is selected from the group consisting of an atom, a gas, a gas, a 'substituent or a group of a plurality of CA letters, a linear or branched chain or a group (four), a group of two or cm (four) w The base R'丨 is -NH2, cyanide, the ancient margin or the (5) ring. Straight bond or branch key (4) wire, CrC4, please refer to the compound mentioned in the patent system, C c9r=R ^ from face, county, cyano or linear or branched chain CA burning base ^ record money atom, (4) The original chain 匸丨·. The alkyl group, or the term X-cutler-9, represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain CrC:6 alkyl group or a _NH 2 group; preferably represents a hydrogen atom, a halogen atom, or a linear chain. Or a branched chain (^-(:3 alkyl or -NH2 group. 20. The compound according to any one of claims 1 to 19 wherein the compound has the formula d-c) And m is 0, 1 or 2; W represents a nitrogen atom or a -CR3 group ' is preferably a -CR3 group; Z represents an NR5 group + X and Y independently represents an atmosphere atom or a -CR9 group, wherein X and At least one of Y represents a nitrogen atom 'and the other represents a -CR9 group; Ri represents a hydrogen atom or a -NH2 group, 244 201130839 R.2 represents a nitrogen atom or a direct bond or a branch bond C^-C^ R_3 represents a hydrogen atom, a cyano group or a linear or branched chain ^^-heart group; R4 represents a hydrogen atom or a straight or branched bond CrC3 alkyl group; R5 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group R6 and R7 independently represent a hydrogen atom or a straight or branched chain CrC3 alkyl group, Rs represents a straight or branched chain CrC6 alkyl group; crc4 haloalkyl group; C3-C7 cycloalkyl group 'the cycloalkyl group is not Substituting or substituting one or more substituents selected from a dentate atom and a substituent via a substituent, the phenyl group is unsubstituted or substituted with one or more halogen atoms; -(CH2)n-〇R group a group, wherein η is 〇 or 1 and R represents a linear or branched chain CrC3 group; a thiol group, which is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; a hydroperylpyranyl group which is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; and a piperidinyl group which is unsubstituted or subjected to one or Substituted by a plurality of substituents selected from the group consisting of: a straight or branched chain crc3 alkyl group; a halogen atom; a pyridyl group which is unsubstituted or substituted with one or more cyano groups; 1,2,4-triazole And C(a)-(CH2)n-R'' group 'where ^ is 〇 or 1 and R, is · 2, cyano, straight or branched chain CrC6 alkyl, CrC4 halane Or a cycloalkyl group; and R9 represents a hydrogen atom, a halogen atom, a linear or branched chain CrC3 alkyl group 245 201130839 or a -nh2 group. 21 · Patent Application No. 20 a compound wherein r8 represents a linear or branched chain CrC6 alkyl group; CrC4-alkyl group; C3-C7 cycloalkyl group, said cycloalkyl group being unsubstituted or substituted by one or more selected from a halogen atom and a hydroxyl group a phenyl group which is unsubstituted or substituted with one or more halogen atoms; a -(CH2)n-〇R group wherein η is 0 or 1 and R represents a linear or branched chain CrC3 alkane a pyridyl group, which is unsubstituted or substituted with one or more substituents selected from a dentate atom and a hydroxyl group; a tetrahydropyranyl group which is unsubstituted or subjected to one or Substituting a plurality of substituents selected from a halogen atom and a hydroxyl group; and a piperidinyl group substituted with one or more substituents, wherein the substitution is at least on the ring nitrogen of the nannyyl group, The substituent is selected from the group consisting of: a straight or branched chain Crc3 alkyl group; a halogen atom; a pyridyl group which is unsubstituted or substituted with one or more cyano groups; 1,2,4-triazolyl; a C(0)-(CH2)nR" group, wherein n is 〇 or 1 and R, is -NH2, cyano, straight or branched Crc6 alkyl, crC4 haloalkyl or C3-C7 cycloalkyl. 22. The compound of claim 1, wherein m is 0, 1 or 2 in the compound of formula (I); W represents a nitrogen atom or a -CR3 group, preferably a _Cr3 group; 246 201130839 Z represents an nr5 group; X and Y independently represent a nitrogen atom or a _CR9 group, when the combination of ^ and Y represents a t atom, the other represents a _^9 group, and τ represents a -CR9 group. R1 represents a hydrogen atom or a _NH2 group; R2 represents a hydrogen atom or a straight or branched chain crc3 alkyl group; R3 represents a hydrogen atom, a cyano group or a linear or branched chain crc3 alkyl group; R4 represents a hydrogen atom or a straight chain or Branched chain crc3 alkyl; Rs represents a hydrogen atom or a straight or branched chain alkyl group; R6 and R7 independently represent an argon atom or a straight or branched alkyl group, and g is a straight or branched chain CrC6 alkyl group; CrC: 4 _alkyl; CrC7 cycloalkyl, the cycloalkyl group is unsubstituted or substituted by one or more via groups; phenyl, the phenyl group is unsubstituted or substituted by one or more _ atomic atoms; (CH2)n-OR group 'wherein η is 0 or 1 and R represents a linear or branched CpC:3 alkyl group; and piperidinyl 'the piperidinyl group is unsubstituted or Or a plurality of substituents selected from the group consisting of: - than the bite group, the π is unsubstituted or substituted with one or more cyano groups; and the -C(0)-(GH2)rrR group η is 〇 or 1 and r, is a known, cyano, straight or branched chain Ci-C6 alkyl, Q-C4 ialkyl or (cyclopentaalkyl; and R9 represents a hydrogen atom, a halogen atom or a straight Chains or branched chains - Alkyl. 247 201130839 23. The compound of claim 22, wherein R'' is cyano, straight or branched chain CrC6 alkyl, CrQ haloalkyl or C3- C7 Cycloalkyl. 24. The compound of claim 1, which has the formula (Ia): Wherein m is 0, 1 or 2; W represents a nitrogen atom or a -CR3 group, preferably a -CR3 group; X represents a nitrogen atom or a -CR9 group; K represents a hydrogen atom or a -nh2 group R2 represents an argon atom or a linear or branched Crc3 alkyl group; R3 represents a hydrogen atom, a cyano group or a linear or branched Crc3 alkyl group; R4 represents a hydrogen atom or a straight or branched chain Crc3 alkyl group; R5 represents hydrogen Aromatic or linear or branched chain CrC3 alkyl; R6 and R7 independently represent a fluorene atom or a straight or branched chain crc3 alkyl group, 248 201130839 R8 represents a straight or branched chain Ci_C6 alkyl; cvc4 haloalkyl; c3-c7 a cycloalkyl group which is unsubstituted or substituted with one or more hydroxyl groups; a styl group which is unsubstituted or substituted with one or more i atom atoms; -(CH2)n-OR group a group wherein η is 0 or 1 and R represents a linear or branched chain CrC3 alkyl group; and a piperidinyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of: a group which is unsubstituted or substituted with one or more cyano groups; and a -C(〇MCH2)n-R'' group wherein η is 〇 or 1 and Rm is cyano, a straight or branched chain Ci-C6 alkyl group, C--C4-alkyl or acryl group; and R9 represents a hydrogen atom, a halogen atom or a linear or branched chain. 25. The compound according to claim 24, wherein: m is 0 or 1; Ri represents a hydrogen atom; R2 represents a hydrogen atom; R3 represents a hydrogen atom or a cyano group; R4 represents a hydrogen atom; and Rs represents a hydrogen atom or a straight or branched chain Ci_C3 alkyl; Re and R7 independently represent a hydrogen atom or a straight or branched chain C"C3 alkyl; ~ &amp; represents a straight or branched chain CrC:6 炫;CrC4 functional base;CrC a cycloalkyl group which is unsubstituted or substituted with or a poly-aryl group; the phenyl group is unsubstituted or substituted with one or more halogen atoms; 249 201130839 - (CHA-OR based a group wherein η is 〇 or 1 and the 尺 represents a linear or branched Q-C3 alkyl group; and a piperidinyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of: pyridine a pyridyl group which is unsubstituted or substituted with one or more cyano groups; and a -C(0)-(CH2)nR" group, wherein n is fluorene or 1 and R, is a cyano group, a straight bond Or a branched chain CpC3 alkyl group or a CrC4 theater group; and R9 represents a hydrogen atom, a halogen atom or a linear or branched chain CrC3 alkyl group. 1 of the compound having the formula (I-b): Wherein m is 0, 1 or 2; X represents a nitrogen atom or a -CR9 group; (R represents a hydrogen atom or a -NH2 group; R2 represents a hydrogen atom or a straight or branched chain Ci_C3 alkyl group; R4 a hydrogen atom or a straight or branched chain; 250 201130839 R5 represents a nitrogen atom or a straight or branched chain Crc3 alkyl; R0 and independently represent a halogen atom or a straight or branched chain Ci&lt;:3 a group, Rs represents a straight or branched chain Ci-C6 alkyl group; CrC4^alkyl group; CrC7 cycloalkyl group, said cycloalkyl group being unsubstituted or substituted by one or more hydroxyl groups; phenyl group, said phenyl group Substituted or substituted with one or more dentate atoms; - (CHJn-OR group 'where η is 0 or 1 and R represents a straight or branched bond Cj-C: 3 alkyl; and a bite base' The thiol group is unsubstituted or substituted with one or more substituents selected from the group consisting of pyridyl, unsubstituted or substituted with one or more cyano groups; and -C(0)-(CH2) a nR" group, wherein !! is 〇 or 1 and Han, is a cyano group, a straight or branched chain CrC6 alkyl group, a CrC4 haloalkyl group or a c3_c^^ yl group; and R9 represents a hydrogen atom, a halogen atom or A compound according to claim 26, wherein m is 0 or 1; X represents a gas atom; Ri represents a gas atom; R2 represents a hydrogen atom; and R. 4 represents hydrogen. Atom or a straight or branched bond Crc3 alkyl; R5 represents a hydrogen atom or a straight or branched chain; R6 and R7 independently represent a hydrogen atom or a straight or branched chain CrC3 alkyl group, 251 201130839 R8 represents a straight chain or a branch a chain crc6 alkyl; a C3-C7 cycloalkyl group which is unsubstituted or substituted with one or more hydroxy groups; a phenyl group which is unsubstituted or substituted with one or more dentate atoms; And a piperidinyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of pyridyl groups which are unsubstituted or substituted by one or more cyano groups; a C(0)-(CH2)nR" group, wherein η is 〇 or i and R, is a cyano group, a straight or branched chain CpC; a decyl group or a crc3 dentate group; and R9 represents a hydrogen atom, a halogen An atomic or linear or branched chain CrC3 alkyl group. 28. A compound as described in the scope of claim 2, which is the following 3-{4-[( Hexylmethyl)amino]pyrazine-5-indoleonitrile; 3-[4-(phenylmethylamino)-pyridyl]pyrazole tl,5 is pyridinium 3-{4-[(2,2 -dimethylpropyl)amino]methanol_2_yl}対対咐咐-5-carbonitrile; 'Bis-mercaptoethyl]amino}cyclohexyl) Bar 3-{4-[(Cyclopropyl -5-phthalonitrile; methyl)amino]__2·kibbi oxime and D,5 external ratio 唆252 201130839 AK1-stupyl ethyl»bizozolo[ι,5_β]° pyridine _3_ propyl pyrimidine 4-amine; 3-{6-[(cyclohexylmethyl)amino]σ-pyridin-2-yl" is 嗤[Ik]pyridine-5-phthalonitrile; 3-{6-[(2,2 -dimercaptopropyl)amino]°°biti-2-yl}&lt;1 than saliva[1,5-rush ratio 唆-5-曱 guess; 3-{6-[(3-fluoro alum Amino group] is more than 唆-2-yl}1 2 3 嗤[1,5-&lt;3]° ratio biting _5-phthalonitrile; 3-[6-(clum amide group pyridine) _ yl]pyrazolo[1,5-α]pyridine_5-phthalonitrile; M6-{[(1S&gt;1-stupyl]amino}pyridine-2-yl)pyrazolo[ΐ,5- α]pyridine-5-phthalonitrile; 3-(4_{[(3Λ)·Ηcyanoethyl)° acridin-3-yl]amino}pyrimidin-2-yl)pyrazolo[1,5 -α]pyridine-5-phthalonitrile; 3-(4-{[()-1-ethenylpiperidine-3-yl]amino}-indolyl-2-yl)pyrazolo[1,5 -α]η than bite_5_carbonitrile; 3-(4-{咖)-1-(5·cyanoacridin-2-yl) benzylidene]amino}Nursing base)D is more than °[1,5_外比咬_5 _ carbonitrile; ... 3-(4-{') small (3,3,3 three gas propylene base) brigade bite _3_ base] amine taunting base) n than bite and [1,5 Kun than bite 5曱 1 ; Μ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ Benzonitrile; 2 3 field (4_((reverse)········································· (S)-N-(l-phenethyl) 々_( π is more than p,5_a) π is more than 嘻3 base) gnaws winter 4- 201130839 amine; Aminobenzyl 2·吼π sits and [1,5♦ than 嗓_3· base mouth bite _4_amine; M(2,2-dimethylpropyl)_2_pyrazole [丨, 5 division Pyrazinylpyrimidine 3-oxo-3-{(3Λ)-3-[(2-pyrazole-indolyl-3-pyrimidin-4-yl)amino]-bite-l-yl} Nitrile; 6-{(3 external 3-[(2-, 坐 Π, 冲 嗪 嗪 _ _ _ ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) [1,5·φ比azine-3_yl·^[(10)_1(3,3,3trifluoropropenyl)β辰唆_3_基]carcinoma-4-amine; 3_{(3 outer 3· [Methyl (2·Caihe ,5·嗓嗓_3·基射冰基) Amino]Nanyl-1-yl}-3-sided oxypropionitrile; 私基] π bottom bit-1-yl}-3-side oxypropyl Nitrile; 〜3_{'3_[(5-fluoro-2·(四)和[1,5_啦嘻·3·基克-4-基) 私基]派咬-1-基}_3-lateral oxypropyl Nitrile; 5-fluoro-2·(tetra) and [Elephantyl [[10] propyl) piperidin-3-yl]pyrimidine _4_amine; - rat base) called 2 phase reading [1,5♦嗓Fluorine 2. Base) can do money D field 254 201130839 -3-yl) oxapyridin-4-amine; 'N4_(4,4_difluorocyclohexyl> 2 (four) and [u kiss coffee · base) money-4 ,5-diamine;. .嘻:=:::气*2-yl)ethyl)-2 he and _ secret 2:= yeah, 5 phase. 3·fine,. (slightly corrected to base) (R -3·Sideoxy_3_(3_(6·((4) and (1)(tetra))))))))))); Base -3_(3_(6-10 than salivary m[1,5♦ than biting J 1 -amino)piperidin-1-yl)propanenitrile; "(R)·3-Sideoxy-3-(3_( 2 嗤 嗤 υ υ υ 唆 唆 唆 唆 4 4 4 4 4 4 4 4 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- Specific bite _3· base) bleed _4_ylamino) 0 bottom -1-yl)-3-sided oxypropionitrile; 3-(3-(5-gas-2-(吼嗤和[ ΐ, 5_φ than pyridine _3_ base) Acridine-4-ylamino)piperidin-1-yl)-3-oxopropanenitrile; 3_(4_fluoro_3_(6-tetrazolo[1,5-a]pyridine-3-yl) Pyrazin-2-ylamino)piperidin-1-yl)-3-oxopropanonitrile; 3-(4-methyl-3-(6-(pyrazolo{1,5-a]pyridine·3 _ yl)pyrazine _2-ylamino) brigade-1-yl)-3-oxopropanenitrile; (1-(low 1,2,4-triazol-3-yl)pyrazine _ 3_基)_6_(carbazolo[1,5_&amp;]pyridin-3-yl)pyrazin-2-amine; 255 201130839 (1 (4H 1'2'4-two "sitting-3-yl") π定_3_基)-2-(πΗ:β生和[l,5-a] 0 is more than -3-yl) σσ定_4_amine; Α4(3Λ)-1-(aminoethyl hydrazine) ) fl 啶 _ _ 如 如 如 如 如 如 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 Or deuterated derivatives. 29. A compound according to any one of the preceding claims, wherein said therapeutic tc is carried out by inhibiting a Janus kinase. The compound according to any one of the preceding claims, wherein the pathological condition or disease is selected from the group consisting of myd〇proliferative dis〇rder, leukemia, lymphoid malignant disease, and solid tumor, A bone graft rejection; and an immune mediated disease, or wherein the pathological condition or disease is selected from the group consisting of an inflammatory disease. 31. The compound of claim 3, wherein the scientific condition or disease is selected from the group consisting of a lysogenic condition, a leukemia, a lymphopathy, and a solid tumor, and wherein the treatment is by inhibition Janus taught to do it. 32. * The compound of claim 3, wherein the disease is selected from the group consisting of bone marrow and organ transplant rejection; and an immune-mediated disease, 乂lr·, or VIII: a pathological condition or The disease is selected from inflammatory diseases. 33. If you mention the towel, please refer to the compound mentioned in the patent scope, and repeat the pathology and skin! ^ _ ', the disease or disease is selected from rheumatoid arthritis 256 201130839 (rheumatoid a coffee tis), multiple sclerosis (caffe (4) (10), inflammatory bowel disease: dry eye, uveitis, allergies Conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease ((; 11_〇15 her_· disease; COi&gt;D), atopic dermatitis, and psoriasis. 34. -Special application for encirclement] To the syllabus of any of the sects of the Qing Dynasty, it is turned into a medicine for the treatment of a disease according to any one of the items from the Qing Dynasty to the 33rd item. Dry dysentery 35. The individual of the first term of the applicant for the pathological condition or the disease described in item 29 or item 29 to the item of the item is administered as a therapeutically effective amount of the compound as described in the patent application scope. Or a pharmaceutical composition comprising a compound according to any one of the items 1 to 28, and a pharmaceutically acceptable diluent or carrier. The method of the individual's Jieshou scale, the hair body is administered with a therapeutically effective amount, as in the application for patent scope, item 1, item 28 The compound, or a pharmaceutical composition according to any one of the above items, wherein the compound of the formula (I) is a pharmaceutical composition; Or its pharmaceutically acceptable compound or compound or stereoisomeric M-money mosquito, ^ / Fen 257 201130839 r4 Wherein T represents ·(:% group and R9 is as defined in claim 1 of the patent scope, trade, \, 丫, and ruler 1 to 38. as defined in item 8 of the patent application scope. a compound of the formula, wherein Y 39. as claimed in the specification, denotes N, and X and T _ 7 = the compound described, wherein - 5 to 7 members of the nitrogen atom are in the group R8 represents: a substituent substitution, wherein the three conditions of the ', less ^^; 3: i are the "no: 40. a pharmaceutical composition" on the ring nitrogen of the heterocyclic group, which includes The scope of the patent range from &lt;• the 39th item of the towel to the compound and the diluent or carrier of the medicinal. 41. A combination product comprising 〇) as claimed in the third to the 39th A compound according to any one of the preceding claims; and (ϋ) alternatively - 丨 258 201130839 The following compounds: a) a dihydrofolate reductase inhibitor such as Methotrexate or CH·1504; b) DH0DH Inhibitors such as leflumite (mieflum), teriflunomide or international patent application W020 a compound as described in WO 08/077639 and WO20092696; c) an immunomodulator such as Glatiramer acetate or Laquinimod; d) DNA synthesis and repair inhibitors such as mitre Mitoxantrone or ciadribine; e) anti-α4 integrin antibodies, such as Natalizumab (Tysabri); f) α4 integrin antagonists, such as R_1295, TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; g) Corticoids and glucocorticoids such as prednis〇ne or sputum nylon ( Methylprednisolone), fluticasone (mometasone or beta-metasone; h) fumarate 'such as nicotine; 0 anti-TNFa antibody' such as infliximab, Ada Imalinrnmab or Cert〇lizumab pegol; 259 201130839 j ) Soluble TNF cx receptors, such as etanercept (f) hanercept; k) , CD20 monoclonal antibodies, such as rituximab Anti-π-), Austria Gefdizumab, Qfatumumab or TRU-015; l) anti-CD52, such as alemtuzumab; m) anti-CD25, such as daclizumab; η Anti-CD88, such as ecuHzumab or pexilizumab; 〇) anti-IL12R/IL23R ' such as ustekinumab; P) calcineurin Inhibitors, such as cyclosporine A or tacr〇limus; q) IMPDH inhibitors, such as mycophenolate mophetyl; r) cannabinoid receptors An agonist, such as santix (Sativex); s) a chemokine CCR1 antagonist, such as MLN_3897 or PS-031291; t) a chemokine CCR2 antagonist, such as INCB 8696; u) NF-κΒ activation inhibitor , such as MLN 〇 415; v) S1P receptor agonists, such as fingolimod (fmg〇lim〇d), BAF-312, ACT128800 or international patent application No. PCT/EP2009/007348 and pCT/Ep2 〇〇9/〇〇8968: a compound described in p; w) S1P dissociates from S# inhibitors, such as LX2931; X) Syk Agents, such as R-U2; 260 201130839 y) PKC inhibitors, such as NVP-AEB071; z) M3 antagonists such as tiotropium or acridinium; aa) long-acting beta-adrenergic stimuli Sexual agonists, such as formoterol; bb) vitamin D bamboo organisms such as caicjp〇tri〇i (Davonex); cc) squaric acid diacetate IV inhibition Agents such as roflumilast or GRC-4039; dd) p38 inhibitors such as ARRY_797; ee) MEK inhibitors such as ARRY-142886 or ARRY-438162; ff) ΡΙ3Κδγ inhibitors; gg) interference The prime 'includes interferon β la ' such as Avonex from Bi〇gen Idec, Sinux (αηη〇Vex) from CinnaGen, and from EMD Se·. Rebif, as well as interferon p lb, such as Betafer〇n from Schering and Betaseron from Β_χ; and (6) interferon alpha 'such as Sumifenm MP; it is used to treat the human or animal body simultaneously, separately or sequentially. n\42. The combination product of claim 41, which is used for two days: on or in order to treat a pathological condition or disease as claimed in claim 1 or 29. • The combination described in item 41 or item 42 of Lifan, 261 201130839, which comprises (i) a compound as claimed in any one of claims 37 to 39; and (ii) another a compound selected from the group consisting of: a. DHODH inhibitors such as those described in leflunomide, territory or international patent application No. WO2008/077639 and WO20092696; b. immunomodulators, Such as glatiramer acetate or laquinimod; c. anti-α4 integrin antibody, such as natalizumab (Tysabri); d. a4 integrin antagonist, such as r]295, TBC-4746, CDP-323, ELND-002, filrastat or TMC 2〇〇3; e. corticosteroids and glucocorticoids such as prednisone or methylprednisolone, fluticasone, mometasone or betatapine; f. a diacate such as; g. anti-TNF a anti-ft 'such as infliximab, adalimumab tocilizumab; h. soluble TNF a receptor, such as etanercept; l. anti-CD2 〇 Strain antibody such as rituximab, okuxumab oxazumab or TRU-015; j. anti-CD88, such as Aizuzhudan Anti- or pegizumab; k. anti-IL12R/IL23R 'such as Eudragitumab; U-Tube neuron meal, such as cyclosporin A or tacrolimus; .V, m. IMPDH inhibitor 'such as mycophenolate morpholinoline; η. cannabis-like receptor agonist, such as stilfibrate. Chemokine CCR1 antagonist, such as MLN_3897 or 262 201130839 PS-031291; p. chemokine CCR2 antagonism Agents such as INCB_8696; q. NF-κΒ activation inhibitors, such as MLN_〇415; r. SIP receptor agonists, such as fingolimod, BAF 312, ACT128800 or international patent application pCT/Ep2〇〇 a compound described in 9/〇〇7348 and PCT/EP2009/008968; s. SIP dissociation inhibitor, such as [χ2931; t. Syk inhibitor, such as r_112; U.PKC inhibitor] such as NVP- AEB071; v. M3 antagonist, such as tiotropium or adiponium; w. long-acting beta-adrenergic agonist, such as formoterol; X. vitamin D derivative, such as calcipotriol (达力士 y. Acidic diacetate IV inhibitor, such as roflumilast or GRc_4〇39; z. p38 inhibitor, such as ARRY 797; aa.PI3K5y BB. Interferon beta la, such as Afon from Bi〇gen Idec from CinnaGen, Syracuse and Liby from EMD Ser〇n〇, and CC. Interferon pib' such as from Schering2 beta From the Beyle of Berlex. 263 术 263 201130839 IV. Designated representative map: (1) The designated representative figure of the case: Figure (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. : Formula (1) The compound of 201130839 can be further here to reflux Commercially available in a solvent such as dimethyl ketoamine, reacted with a peptone such as hydrogen = 'subsequent addition of an alkylating agent such as methyl iodide to obtain = (in the formula (5)), (I_e) Or ((4) a compound. In the specific case of P, the R9 residue is a sulfo group &lt; (5)), such as) a compound of "two private" can be further used at ambient temperature, such as palladium / anaesthesia 1, suitable catalyst ' In a solvent such as ethanol or methanol, react with the Wei under the large orphan pressure to make a compound of R9 or (1-f). JW ί - In specific cases, the residue of R6, R7 or R8 contains Combination of formula (5)), ^) force (i_f) of an amine moiety functionalized with a suitable protecting group such as a second butyl group (BQC) or benzene oxysulfate (CBZ) {Greene&gt;s Protective Groups in Organic The protecting group of the amine moiety is removed under AT. 047169754(R). The corresponding free amine can then be further functionalized under standard conditions to give the corresponding decylamine, sulfonamide, urea and I alkylation and An arylated amine. [Embodiment] The synthesis of the compound of the present invention and the intermediate used therein is By the following examples (1·47) (including preparation examples (preparation M1)), ^^ is given in a certain order to provide a clear enough and complete explanation of the invention to those skilled in the art, but should not It is considered to limit the basic aspect of its subject matter as stated in the previous section of this specification. Preparation 1 110 201130839 2-Ethyl-based 4-methoxycarcinoma bite a) 4-methoxy-2-[[trimethyldecyl)ethynyl]pyrimidine To the dried resealable Schwek tube, a 2_chlorobutyroxine spray (2.60 g, Π·99 mmol), ethynyl trimethyl Wei (3.G5) , 21.58 妓 ear), tetrahydrogen (24 ml: and = U2.53 ml, millimolar). Make the Schrank pipe pass two times: the man emptying and the gas backfill cycle, then add (four) _ (❹ money '0.72 millimoles) and dichlorobis(triphenyl scale) butterfly (10) g 'G .72 millimoles). Three more emptyings were carried out. After the helium gas cycle, the Schlenk tube was sealed, the mixture was mixed and the mixture was added in a 9 (rc oil bath. After Μ hours, the mixture was removed and the solvent was removed under the pigment. The residue was dissolved in a mixture of EtOAc and EtOAc (EtOAc)EtOAc. The residue was purified to give the crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (s, 9H), 3 7 (s 3H) 6.4 (d, lH), 8.1 (d, 1H). ' ' b) 2-B-Butyl-4-methoxy bite 111 201130839 at room temperature Tetrabutylammonium fluoride (0.97 ml of a 1 Μ tetrahydrofuran solution '0.97 mmol) was added to the stirred 4-methoxy-2-[(trimethyldecyl)ethynyl]pyrimidine (Preparation la, 〇.2) Indole, 0.97 mmol, in tetrahydrofuran (1.4 mL) and acetic acid (56 L). After 5 minutes, a 10% aqueous solution of potassium carbonate was added to the reaction mixture and the mixture was extracted with dioxane. The organic layer was separated, dried (MgSO.sub.4) and evaporated. The residue was purified by flash chromatography eluting elut elut elut elut LRMS (m/z): 135 (M+l)+. !H-NMR δ (300 MHz, CDC13): 3.1 (s, 1H), 4.0 (s 3H) 6.7 (d, 1H), 8.4 (d, 1H). ' 2 ' Preparation 2 2,4,6-trimethyl benzoic acid 1 -amino 4 · cyano e than pyridine Νη2 at 0 °c will be 0-(2,4,6_triphenylsulfonyl- can be prepared, as described in 19Τ7, 1; 2. η grams, ι〇 收 (such as waterless gas (21 liters) solution was added dropwise to millimolar) alkali nitrile (1.05 g, 10.1 mmol) in anhydrous dioxins, and the mixture was stirred at week temperature for 3 hours. (1 ml) diethyl ether was added to the mixture and the bell was collected by filtration. Then, the powder was formed into a few 201130839, washed with a key and dried in a vacuum to give a white solid. The title compound (3.03 g, 94%). LRMS (m/z): 120 (M+l)+, 199 (M-Ι)·. H-NMR δ (300 MHz, CD3OD): 2.2 (s, 3H ), 2.6 (s, 6H), 6.9 (bs, 2H), 8.3 (d, 1H), 8.9 (d, 1H). ' ' Preparation 3 3-(4-Hydroxy-base-mouth bit-2-yl)0 Than Jun, 丨l,5-a]°tb bite guess a) 3-(4-Methoxypyrimidin-2-yl)pyrazolo- gamma oxime is acetonitrile at 6 °C for 2 hours, and 2,4,6-dimethylbenzoic acid ι-amine group Ice cyanide was added in portions to the stirred 2-ethynyl-4-methoxy pyrimidine (preparation lb, 2 54 g, 18.94 mmol) than bite rust (preparation 2 ' 12.10 g, 37.88 mmol) And a suspension of cesium carbonate (3.93 g, 28.43 mmol) in anhydrous dimethyl decylamine (47 ml) and the resulting mixture was allowed to stand at ambient temperature for 48 hours. The solvent was evaporated and methylene chloride was added to the residue. The solid formed was filtered and the filtrate was evaporated to dryness. The title compound (3.51 g, 74%). LRMS (m/z): 252 (M+l)+. 'H-NMR δ (300 MHz, CDC13): 4.1 (s, 3H), 6.6 (d, 1H), 7.0 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.8 (s , 1H), 9.1 (s, '1H). 'b) 3-(4-Phase-Bite-2-yl)0 is more than [1,5_&lt;|]1» than bite_5_phthalonitrile 113 201130839 chlorotridecyl decane (0.61 ml, 4.83 Millol) and sodium iodide (0.72 g ' 4.83 mmol) were added to the stirred 3_(4-methoxy-t-t- 2 yl) anthracene and [ΐχpyridinonitrile (preparation 3a, 0.14 g) , 0.54 moles of acetonitrile (η ml) in suspension and at 7〇. The mixture was heated in a sealed tube and allowed to stand overnight. The mixture is then cooled and the solvent is evaporated. Water (4 ml) and a 10% aqueous sodium thiosulfate solution (5 ml) were added to the residue and the suspension was stirred for 20 min. The suspension was filtered and the precipitate was dried in vacuo to give the title compound, which was used in the next step. LRMS (m/z): 238 (M+l)+. b-NMR δ (300 MHz, DMS0-4): 6.3 (d, 1H), 7.5 (d 1H), 8.1 (d, 1H), 9, 0 (s, 1H), 9.1 (s, ih), 9.1 (d, 1H). ' Preparation 4 2-» is more than [1,5-&lt;|]?1 than 唆_3_ base mouth 唆4_ol a) 3-(4-methoxyheptan-2-yl) than saliva and bite according to the experimental procedure as described in Preparation 3a, from 2-ethynyl-4-pyrimidine (preparation lb) and The hydrazine hydrazone was obtained as a solid (49%) and then purified by flash chromatography (4:1 hexane/ethyl acetate). LRMS (m/z): 227 (M+l) + 〇 ^-NMR δ (300 MHz, CDC13): 4.1 (s, 3H), 6.5 (dd, 1H), 114 201130839 8.6 (dd,1H),8·6 6·9 (t,1H), 7.4 (dd, 1H), 8.5 (dd, 1H), 1H), 8.7 (s, 1H). 'b) 2-pyrazolo[1&gt;5-dip pyridine-3-ylpyrimidin-4-ol-addition of 48% aqueous hydrogen bromide (19.5 ml)-pyrimidine-2-yl)carbazole [Μ················································································· The title compound (0.28 vouch, 9 ^°, obtained LRMS (m/z): 213 (M+l) +.)) in the form of bismuth bromide. B block base n bite a) 2_gas [(trimethyldecyl)ethynyl]pyridine obtained as an oil from 2,6-dipyridinium and ethynyltrimethylnonane according to the experimental procedure as described in Preparation la ( 38%) was then purified by flash chromatography (hexane to 30:1 hexanes / ethyl acetate). LRMS (m/z): 210 (M+l)+. b) 2-Ga-6-B fast radical &quot;Bite bite according to the experimental procedure as described in Preparation lb, bit by 2-chloro-6-[(trimethylglycosyl)ethynyl]°fcb (Preparation 5a) An oil (29%) was obtained which was purified by flash chromatography (hexane to 10:1 hexanes / ethyl acetate). H-NMR δ (300 MHz, CDC13): 3.2 (s, 1H), 7.3 (d, 1H), 7.4 (d, 1H), 7.6 (t, 1H). Preparation 6 3-(6-Gapyridin-2-yl)pyrazoloindole 1,5-«] acridine-5-carbonitrile According to the experimental procedure as described in Preparation 3a, from 2_gas-6-ethynylpyridine (Preparation 5b) and 2,4,6-trimethylbenzenesulfonic acid 1-amino-4-ylcyanopyridinium ( Preparation 2) A solid (30%) was obtained which was subsequently purified by flash chromatography (99: i-chloromethane/methanol). LRMS (m/z): 255 (M+l)+. Ο ^-NMR δ (300 MHz, CDC13): 6.9-7.1 (m, 1H), 7.2-7.3 1H), 7.5-7.8 (m, 2H), 8.4-8.7 (m, 2H), 9.0-9.1 (m , 1H) 〇Preparation of 7 H4-丨(3 and)-Brididine_3_ylamino]pyrimidine_2-yl}pyrazoloindole 15 but pyridine-5-carbonitrile 116 201130839 a) (3i〇-3-{[2-(5-Cyano-n-azolo[l,5-a]acridin-3-yl)pyrimidin-4-yl]amino}piperidin-1 - tert-butyl formate (3P--3-aminopiperidine-1-decanoic acid tert-butyl ester (1.49 g, 7.46 mmol) was added to the stirred 3-(4-hydroxypyrimidine-2- Pyrazolo[1,5-β]pyridine-5-phthalonitrile (preparation 3b, 0.70 g, 2.98 mmol), hexafluorophosphate (benzotriazol-1-yloxy) gin Amino) scales (1.71 grams, 3.88 millimoles) and 1,8-diazabicyclo [5.4.0]undec-7-ene (0.67 grams, 4.48 millimoles) in dimethylformamide The resulting mixture was stirred in a solution (15 ml) for 16 hours at room temperature. The solvent was then removed under reduced pressure and the residue was dissolved in a mixture of dichloromethane and aqueous sodium hydrogen carbonate. The layers were dried (MgSO4) and evaporated in vacuo.jjjjjjjjjjjjjjjjjjjjjjjjjjjj C-18 cerium oxide, water/acetonitrile/sterol as an eliminator [with 0.1% v/v citric acid buffer] 0% to 100%) repurified The title compound (0.83 g, 66%) and 3-(4-(1Η-benzo[d][l,2,3]triazol-1-yloxy)pyrimidin-2- as the main reaction by-product were obtained. Base) carbazole [1,5-ί^pyridin-5-indolecarbonitrile (0.10 g). LRMS (m/z): 420 (M+l)+, 418 (M-1)-.]H- NMR δ (300 MHz, CDC13): 0.7-0.9 (m, 4H), 1. 5 (s, 9H), 1.0-1.7 (m, 2H), 1.7-1.9 (m, 2H), 2.0-2.1 (m , IH), 5.0 (bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8. 6 (d, 1H), 8.8 (s, 1H), 9.1 ( t, 1H). b) 3-{4-[(3i〇-piperidin-3-ylamino)pyrimidin-2-yl}oxazolo[1,5-ύτ] 117 201130839 Pyridine-5-carbonitrile Trifluoroacetic acid (0.61 ml, 7.97 mmol) was added to the stirred (8) _3_(2_(5-cyanopyrazoloindole, 5·α]pyridine-3-yl)pyrimidin-4-ylamino) The solution of pyridine-1 -carboxylic acid tert-butyl ester (preparation 7a, 0.12 g, 0.27 mmol) in dichloromethane (4 ml) was stirred at room temperature for 4 hours, then 4% aqueous sodium bicarbonate was added. And solid sodium bicarbonate until the pH is basic and the mixture is further extracted with dichloromethane. The title compound (0.06 g, 62%) LRMS (m/z): 320 (M+l)+, 318 (M-1). 'H-NMR δ (300 MHz, CDC13): 0.8-0.9 (m, 4H), 1.5 (s, 9H), 1.8-2.3 (m, 5H), 5.7 (bs, 1H), 6.3 (d, 1H) , 7.0 (dd, 1H), 8.2 (d, 1H), 8.6 (d, 1H), 8.7 (s, 1H), 9.1 (bs, 1H) ° Preparation 8 (1^)-3-(4-(A (piperidin-3-yl)aminopyrimidin-2yl)pyrazoloindole [1,5-α]pyridine-5-carbonitrile a) (and)-3-((2-(5-fluorocarbazolo[1,5-α]acridin-3-yl)pyrimidin-4)yl)(methyl)amino)tripidine-1 _ tert-butyl formate added sodium hydride (60% mineral oil dispersion, 1 〇 2 mg, 2.55 mM 118 201130839 ears) to the cooled (〇.〇(10))_3_{[2_(5_cyanoguanidine) Salic (1) pyridin-3-yl)pyrimidin-4-yl]amino}piperidinyl-indole-carboxylic acid tert-butyl ester (preparation 7a, 0.83 g, 1.98 mmol) of #,-dimercaptocarboxamide (5 liters) of the solution and the reaction mixture was stirred at the same temperature for 3 minutes. Add Sunder Armor 7 (0.135 * liter, 2.17 mmol) and cake reaction mixture 2 at room temperature. The vacuum is condensed to distribute the silk between water and acetic acid. The organic layer was separated, EtOAc (EtOAc m. LRMS (m/z): 434 (M+l)+. b) (Λ)-3·(4·(methyl(Bistidyl-3-yl)amino)pyrimidine 2yl)pyrano[l,5-a]nit^-5-A guess according to preparation 7b In the experimental procedure described, the base σ ratio σ sits and [1,5-α]β is more than β -3-yl) oxime-4-yl)(methyl)amino group) Tributyl ester (Preparation 8a) gave a pale orange solid (π%). LRMS (m/z): 334 (M+l)+. iH-NMR δ (400 MHz, DMSO 〇j 9 (m, Qiu, 2.3-2.5 (m, 2H), 2.7 (t, 1H), 2.8-3.1 (m, 5H), 6.6 (bs, 1H), 7.3 (dd, 1H), 8.3 (d, 1H), 8.8 (s, 1H), 8.9-9.0 (m, 2H). Preparation 9 2,4,6-trimethylbenzenesulfonic acid 1-aminopyrazine Xiao Yan, 119 201130839 ,?+ NH, Obtained as a white solid from pyrazine and 0-(2,4,6-trimethylphenylsulfonyl)hydroxylamine (prepared as described in 咐 咐, 1977, i) according to the experimental procedure as described in Preparation 2. (75%). 〇H-NMR δ (400 MHz, DMSO-^6): 2.2 (s, 3H), 2.5 (s&gt; 6H), 6.8 (s, 2H), 8.7 (d, 2H), 9.2 (d, 2H), 9.6 (s, 2H) ° Preparation 10 2-(° ratio saliva [1,5_α] 〇 嗓 _3_ base) 咬 bit-4-ol a) 3-(4-methoxy-mouth bite-2_yl)0 is more than 嗤[l,5-&lt;i]* is called according to the experimental procedure as described in Preparation 3a, from 2-ethynyl Alkylpyrimidine (preparation lb) and 1,4,6-trimercaptobenzenesulfonic acid 1-aminopyridin-1- rust (Preparation 9) gave a solid (43%). LRMS (m/z): 228 (M+l)+ °^-NMR δ (400 MHz, CDC13): 4.1 (s, 3H), 6.6 (d, 1H) 8.0 (d, 1H), 8.4 (dd, 1H), 8.5 (d, 1H), 8.8 (s, 1H), lO.o (s, 1H). ' 120 201130839 b) 2 decathiazole [l,5-ap-pyridin-3-yl)pyrimidin-4-ol according to the experimental procedure as described in Preparation 4b, from 3-(4-methoxypyrimidine- 2-yl)pyrazolo[1,5-α]pyrazine (Preparation 10a) afforded (83%). LRMS (m/z): 214 (M+l)+, 212 (M-1)-. ^-NMR δ (300 MHz, DMSO-t/6): 6.4 (d, 1H), 8.2 (d, 1H), 8.2 (s, 1H), 9.0 (dd, 1H), 9.0 (s, 1H), 9.9 (d, 1H). Preparation 11 (jR)-_/V-(taste·bit-3-yl)-2-(n is more than 嗤[l,5-ii]10 than 嗓&quot;-3-yl) shouting -4- a) (Λ)-3_(2·(α-pyrazolo[1,5-ίΐ]«pyrazin-3-yl)pyrimidin-4-ylamino) piperidine-1-carboxylic acid tert-butyl ester according to Preparation of the experimental procedure described in 7a from 2-(pyrazolo[1,5-β]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and (3 and)-3-aminopiperazine The third butyl pyridine-1-decanoate was obtained (50%) and then purified by flash chromatography (dichloromethane to 97·3 dichloromethane / decyl alcohol). LRMS (m/z): 396 (M+l)+. b) (Bit-3-yl)_2-(β is more than [1,5-β]1* than 嗓_3_)) bite-4-amine 121 201130839 according to the experiment as described in Preparation 7b Procedure, consisting of (and) _3_(2_(d than saliva[1,5-α]pyrazin-3-yl))-pyridin-4-ylamino) decyl _1_carboxylic acid 笫二^一^厂The title (preparation 11a) and trifluoroacetic acid were obtained (91%). LRMS (m/z): 296 (M+l)+. H-NMR δ (400 MHz, CDC13): 1.6-1.7 (m, 2H), 1.7^9 (m, 3H), 2.7-3.0 (m, 4H), 3.2-3.3 (m, 1H), 5.5 ( Bs, 1H), 6 2 (d 1H), 8.0 (d, 1H), 8.2 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H) 10 〇 / 1H). ,.(s, Preparation 12 甲基methyl-7V-[(3i?)·Pyridinyl _3·yl]_2_吼 并 并pyridinium pyrimidine-4-amine a) (3i?)-3-[methyl(2-啦峻和[ι,5_α]η比嗓_3_ylpiperidine·4 amine] travel bite-1-carbohydrate third vinegar) As described in Preparation 8a, the experimental procedure consists of (and) _ 夂 唑 并 并 1 1 1 1 1 1 1 -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- (Preparation 1 la) and iodomethylation (9%), followed by reverse phase layer ^^ from Waters C-18 cerium oxide, water/acetonitrile/methanol as the leaching agent [〇.1% v /v formic acid buffer] 5% to 50%) purified. 122 201130839 LRMS (m/z): 410 (M+l)+. 1)) #-Methyl-^[(31?)_piperidin-3-yl]-2-pyrazolo[1,5_«]pyrazin-3-ylpyrimidin-4-amine according to Preparation 7b The experimental procedure consists of (3 and)-3-[mercapto(2-pyrazolo[1,5-α]pyrazin-3-ylpyrimidin-4-yl)amino]piperidin-1- Tert-butyl formate (preparation 12a) and trifluoroacetic acid afforded (94%). LRMS (m/z): 310 (M+l)+. Preparation 13 5-Gas-2-ethynyl-4-methoxypyrimidine a) 5-Actyl-4-decyloxy-2-[(tridecyldecyl)ethynyl]pyrimidine according to the experimental procedure as described in Preparation la, from 2,5-diox-4-decyloxy Mouth (as prepared in (10) 2006, 47, 4415) and ethynyl tridecyl decane (4 4 %), followed by flash chromatography (dichloromethane to 4:6 dichloromethane / hexane) purification. LRMS (m/z): 241 (M+l)+. h-NMR δ (300 MHz, CDC13): 0.1 (bs, 9 Η), 3.8 (bs, 3H), 8.1 (s, 1H). b) 5-Ga-2-ethynyl-4-methoxypyrimidine according to the experimental procedure as described in Preparation lb, from 5-chloro-4-methoxy 123 201130839 -2-((trimethyldecyl) Ethyl acetyl pyrimidine (Preparation 13a) gave a grey solid (78%) which was purified by flash chromatography (9:1 hexane/ethyl acetate). LRMS (m/z): 169 (M+l)+. !H-NMR δ (300 MHz, CDC13): 3.1 (s, 1H), 4.1 (s, 3H), 8.4 (s, 1H). Preparation 14 5-Gas-2-1* ratio 峻[1,5-έΐ]π than 嗓-3-yl-bend-4-ol a) 3-(5-Gas-4-methoxy-mouth II-yl) Β 峻 并 [1,5-&lt;|] 0 嗓 according to the experimental procedure as described in Preparation 3a, by 5 - gas-2-ethynyl-4-methoxypyrimidine (Preparation 13b) and 1-aminopyridinium-1-indolesulfonate 1-ylide (Preparation 9) gave an orange solid (84%), Purification by flash chromatography (dichloromethane to 7:3 dichloromethane / methanol). LRMS (m/z): 262 (M+l)+. ^-NMR δ (300 MHz, CDC13): 4.2 (s, 3H), 8.0 (d, 1H), 8.5 (d, 1H), 8.5 (s, 1H), 8.7 (s, 1H), 10.0 (s, 1H). 5-Gas-2-° ratio 嗤[1,5-α]° 嗓-3- 啸 咬 -4--4- leaven according to the experimental procedure as described in Preparation 4b, from 3-(5-chloro-4) -Methoxypyrimidin-2-yl)oxazolo[1,5-beta]pyrazine (Preparation 14a) gave a green solid (62%) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Acridine-3_yl]_2_&quot;Bizozolo[1,5-&lt;ι] "Bistazin-3-ylpyrimidine-4-amine a ) (3 magic-3-[(5-chloro-2-pyrazolo[l,5-dpyrazin-3-ylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester According to the experimental procedure as described in Preparation 7a, 5-chloro-2-(pyrazolo[1,5-α]pyridazin-3-yl)pyrimidin-4-ol (Preparation 14b) and (7^) 3-Aminopiperidine 1-decanoic acid tert-butyl ester gave a yellow solid (40%) which was subsequently purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate). z): 430 (M+l)+. ^-NMR δ (300 MHz, CDC13): 1.4 (bs, 9H), 1.7 (bs, 3H), 1.9-2.1 (m, 2H), 3.4 (bs, 1H) ), 3.7 (bs, 2H), 4.3 (bs, 1H), 5.6 (bs, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H) , 9.9 (s, 1H). b) 5-Gas-Λ4(3Λ)_piperidin-3-yl]-2-pyrazolo[1,5-fl]pyrazin-3-ylpyrimidin-4-amine According to the experimental procedure as described in Preparation 7b, from 3-(5-Gas-2-(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine- Tributyl phthalate (preparation 15a) and trifluoroacetic acid afforded a yellow solid (87%). 125 201130839 LRMS (m/z): 330 (M+l)+. ^-NMR δ (300 MHz, CDC13): 1.3 (bs, 2H), 1.9 (bs, 3H), 2.9 (bs, 3H), 3.2-3.3 (m, 1H), 4.4 (bs, 1H), 5.9 ( Bs, 1H), 8.0 (d, 1H), 8.2 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 9.9 (s, 1H). Preparation of 16 2-ethynyl-5-fluoro-4-methoxypyrimidine a) 2_Ga-5-fluoro-4-methoxypyrimidine Add 2,4-dichloro-5-fluoropyrimidine to a mixture of sodium (450 mg, 19 mmol) in methanol (20 mL) (3.25 g, 19 mmol) in methanol (10 mL). The reaction mixture was stirred overnight at room temperature then partitioned between water and diethyl ether. The organic phase was separated, EtOAc m m m m m m iH-NMR δ (400 MHz, CDC13): 4.1 (s, 3H), 8·2 (s, 1H). b) S-fluoro_4_methoxy-2-[(dimethyl-propyl)ethyl group] mouth bition according to the experimental procedure as described in Preparation la, from 2-gas _5-£-4- The methoxy pyrimidine (preparation 16a) and ethynyltrimethyl decane were obtained (17%), which was subsequently purified by flash chromatography (2:8 hexanes/dichloromethane to 1% 0% hexanes). , 126 201130839 LRMS (m/z): 225 (M+l)+. b-NMR δ (400 MHz, CDC13): 0.1 (s, 9H), 3.8 (s, 3H), 8.0 (d, 1H). c) 2-ethynyl-5 fluoro-4-methoxypyrimidine according to the experimental procedure as described in Preparation lb, from 5-fluoro-4-methoxy-2-((tridecyldecyl)acetylene The pyrimidine (preparation 16b) was obtained (82%), which was subsequently purified by flash chromatography (99:1 dioxane / methanol). ^-NMR δ (400 MHz, CDC13): 3.1 (d, 1H), 4.1 (s, 3H), 8.3 (d, 1H). Preparation 17 5-Gas-2-® ratio 并[1,5_ii] Qin-3-yl keto-4-ol a) 3·(5-fluoro-4-indolylpyrimidin-2-yl)pyrazolo[l,5-ii]pyrazine according to the experimental procedure as described in Preparation 3a, from 2-ethynyl-5 -Fluoro-4-oxiranylpyrimidine (Preparation 16c) and 1,1,6-trimethylbenzenesulfonic acid 1-aminopyridazine-1-indole (Preparation 9) obtained (72%), followed by a flash Chromatography (dichloromethane to 97:3 dichloromethane / methanol) was purified. LRMS (m/z): 246 (M+l)+. H-NMR δ (400 MHz, CDC13): 4.2 (s, 3H), 8.0 (d, 1H), 8.4 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 10.0 (d , 1H). 127 201130839 b) Fluoro-2-pyrazolo[l,5-ii]pyrazin-3-ylpyrimidin-4-ol was added to a hydrogen chloride aqueous solution (13 ml of 6 Ν solution, 78 mmol) to a microwave vessel. 3-(5-Fluoro-4-oxyloxypyrimidin-2-yl)pyrazino[15 η than hydrazine (preparation of l7a, 0.38 g, 1 mmol). The crucible was subjected to microwave irradiation for 1 hour. After cooling to room temperature, an aqueous solution of sodium hydroxide was added until an alkaline pH was reached. The solid formed by filtration was dried to give the title compound (72%), which can be used in the next step without further purification. LRMS (m/z): 232 (M+l)+. ^-NMR δ (400 MHz, DMSO-J6): 8.1-8.2 (m, 3H), 9.0 (bs, 1H), 9.8 (bs, 1H). Preparation of 18 fluoro-indole 4(3Ι?)·piperidin-3-yl]-2-»biszolo[1,5_α]pyrazine·3·ylpyrimidine-4-amine a) (3 and) _3-[(5_fluoro_2_pyrazolo^5^pyrazine-3-ylpyrimidin-4-yl) amine] brigade-1-carboxylic acid tert-butyl ester according to injury The experimental procedure described in 7a consists of 5-fluoro-2-((pyrazolo[1,5-α]°pyrazine·3·yl) oxime-4-ol (preparation 17b) and (3i?)-3 - Aminopiperidine 1 -carboxylic acid tert-butyl ester gave a white solid (50%) which was subsequently purified by flash chromatography (dichloromethane to 95:5 dichloromethane / methanol). 128 201130839 LRMS (m/z): 414 (M+l)+. h-NMR δ (400 MHz, CDC13): 1.4] 5 (Jn 9H), L8 (m, 1H), 1.9-2.0 (m, 1H), 2.0.2.!, ;H) 1H), 3.6 (bs , 1H), 3.7 (bs, 1H), 4.3-4.4 (m, 1Η), 8 〇. (; 8.1 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 9.9 (d, 1H) 〇, out, b) 5-fluoro good (four)) _ brigade bite _3_ base] _2_0 than saliva and u, pyrimidine-4-amine According to the experimental procedure as described in Preparation 7b, by (Fantasy_3_(5_Fluor j-dosin [1,5-trapinazine-3-yl)--4-ylamino) brigade formate The butyl ester (preparation 18a) and trifluoroacetic acid gave a solid (94%) which was subsequently purified by flash chromatography (dichloromethane to &lt;RTIgt; LRMS (m/z): 314 (M+l)+. ^-NMR δ (400 MHz, CDC13): 1.6 (m, 1H), 1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.1 (bs, 1H), 2.8-2.9 (m, 2H), 3.3 (bs, 1H), 4.3-4.4 (m, 1H), 5.7 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H), 8.4 (dd, !H), 8.6 (s, 1H ), 9.9 (d, 1H) ° Preparation of 19 2-ethynyl-4-methoxy-5-methylpyrimidine SiMe3 a) 2-Gas-4-methoxy-5-methylpyrimidine 129 201130839 Obtained as a white solid (85%) from 2,4-dichloro-5-methylpyrimidine according to the procedure as described in Preparation 16a It was then purified by flash chromatography (hexane to 95:5 hexanes / ethyl acetate). LRMS (m/z): 159 (M+l)+. !H-NMR δ (400 MHz, CDCI3): 2.1 (d, 3H), 4.0 (s, 3H), 8.1 (d, 1 H). b) 4-methoxy-5-methyl-2-[(trimethyldecyl)ethynyl]pyrimidine according to the experimental procedure as described in the preparation of la, 2-methoxy-4-methoxy-5 -Methylpyrimidine (Preparation 19a) and ethynyltrimethyldecane afforded a yellow solid (19%). LRMS (m/z): 221 (M+l)+. ^-NMR δ (400 MHz, CDC13): 0.1 (s, 9H), 1.9 (d, 3H), 3.7 (s, 3H), 7.9 (s, 1H). c) 2-ethynyl-4-methoxy-5-mercaptopyrimidine according to the experimental procedure as described in Preparation lb, 4-methoxy-5-methyl-2-((trimethyldecyl) Ethyl acetyl pyrimidine (Preparation 19b) gave a white solid (55%) which was purified by flash chromatography (dichloromethane). LRMS (m/z): 149 (M+l)+. !H-NMR δ (400 MHz, CDCI3): 2.2 (s, 3H), 3.0 (s, 1H), 4.0 (s, 3H), 8.2 (s, 1H). Preparation of 20 3-(4-decyloxy-5-mercaptopyridin-2-yl)pyrazolo[l,5-«]pyrazine 130 201130839 NH2 a) 3-(4-Methoxy-5-methylpyrimidin-2-yl)pyrazolo[l,5-fl]pyridinium According to the experimental procedure as described in Preparation 3a, 2-ethynyl-4-methoxy-5-methylpyrimidine (Preparation 19c) and 2,4,6-trimethylsuccinyl acid 1 amine σ ratio Azide-1-rust (Preparation 9) gave a yellow solid (99%) which was subsequently purified by flash chromatography (dichlorobenzene to 95:5 dichloromethane/methanol).曰 LRMS (m/z): 242 (M+l)+. ^-NMR δ (400 MHz, CDC13): 3.0 (s, 3H), 4.2 (s, 3H) 8.0 (d, 1H), 8.3 (d, 1H), 8.4 (dd, 1H), 8.7 (s, 1H) ), l〇'〇1H). V 5 b) 3-(4-methoxy-5-methylpyrimidin-2-yl)oxazolidine (10) is added to 3_(4-methoxyl side) with 35% aqueous potassium hydroxide solution (5 ml) -5-Methylpyrimidin-2-yl)pyrazolo[l,5-fl]pyridazine (preparation of 2〇a, 〇7〇g &quot; 2_89 mmol) in ethanol (1 mL). The mixture was placed in a rhyme container and subjected to 130 〇C microwave irradiation for 1 hour. After cooling to room temperature, 1 the organic solvent was removed under reduced pressure and 5 N hydrogen chloride was used. The solid which formed was filtered, washed with water and dried to give the title compound (64%). ' LRMS (m/z): 228 (M+l)+. Also δ _ MHz, DMSO-can 3,3 (bs, 3H), 8 1H), 8.1 (bs, 1H), 9.0 (bs, 2H), 9.8 (bs, 1 η). 131 201130839 Preparation 21 5-methyl·ΛΓ-[(3 and)·piperidin-3yl]_2pyrazoloindole 15_β]pyrazineylpyrimidine-4-amine C) a) (3 and) J-[(5-methyl-2-吼君[1,5-ί!]11 is more than 嗓-3-yl-biti-4-yl)amino]bite- 1-carboxylic acid tert-butyl vinegar according to the experimental procedure as described in Preparation 7a, from 5-mercapto-2-(pyrazolo[l,5-fl]pyrazin-3-yl)pyrimidin-4-ol ( Preparation of 20b) and (3 and)-3-aminopiperidine-1 -decanoic acid tert-butyl ester afforded a yellow oil (5 8 %), which was then flashed to 30:70. /ethyl acetate) purification. LRMS (m/z): 410 (M+l)+. W-NMR δ (400 MHz, DMSO-Liu 1.2 (bs, 1H), 1.4 (bs, ❹ 1H), 1.7 (bs, 1H), 1.8 (bs, 1H), 2.1 (s, 6H), 2.0 (s , 3H), 2.8-2.9 (m, 1H), 3.4 (s, 3H), 3.9 (bs, 2H), 4.0 (q, 1H), 4.1 (bs, 1H), 8.0 (d, 1H), 8.1 ( s, 1H), 8.9 (bs, 2H), 9.8 (s, 1H). b) 5-methyl-TV- [(3 and)---------------------- 1,5-0]pyridin-3-ylpyrimidin-4-amine according to the experimental procedure as described in Preparation 7b, from (and)-3-(5-methyl-2-(pyrazolo[1,5] -α]pyrazin-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 21a) and trifluoroacetic acid afforded a yellow oil (85%). LRMS (m/z): 310 (M+l)+. 132 201130839 'H-NMR δ (400 MHz, CDCls): 1.6 (bs, 2H), 1.8 (bs, 2H), 2.1 (s, 3H), 2.7-2.9 (m, 1H), 3.2-3.3 (m, 2H), 4.4 (bs, 2H), 7.9 (d, 1H), 8.0 (s, 1H), 8.4 (d, 1H), 8.7 (s, 1H), 10.0 (s) 1H). , Preparation 22 3-bromo 1• than saliva and [1,5-ίϊ]° bite a) 0-pyrido[1,5-β]pyridine-3-carboxylic acid ethyl ester ethyl propionate (50.2 ml, 49.54 mmol) and iodinated pyridine pyridine (10.0 g, 45 mmol) ) added to potassium carbonate (8 71 g, 63.02 mmol) in a suspension of dimercaptoamine (1 ml) and simmered at the temperature; the resulting mixture was dropped for 2 hours and then poured into 100 ml. In the water. Ethyl acetate was then added and the aqueous layer was separated and washed with ethyl acetate (twice). The combined organic layers were dried with MgSO4, filtered and evaporated. The crude product was purified by EtOAcjjjjjjjj LRMS (m/z): 191 (M+l)+. !H-NMR δ (250 MHz, CDC13): 1-4 (t, 3H), 4.3 (q, 2H), 6.9 (t, 1H), 7.4 (t, 1H), 8.1 (s, 1H), 8.4 (s, 1H), 8.5 (d, 1H). 'b) ° than saliva [1,5_&lt;|] 11 to bite _3_decanoic acid 2.5 N aqueous sodium hydroxide solution (36 ml) was added to pyrazole [1,5 &lt;pyridine phthalic acid ethyl citrate ( Preparation 22a, 4.3 g, 22.6 mmoles 133 201130839 in ethanol (70 ml) and the resulting reaction mixture was heated to reflux for 1 hour. After evaporating the ethanol, the reaction mixture was acidified with a 15% aqueous hydrochloric acid solution. The solid formed was filtered, washed with EtOAc EtOAcjjjjjjj LRMS (m/z): 163 (M+1). h-NMR δ (250 MHz, DMSO 7.1 (t, 1H), 7.6 (t, 1H), 8.1 (dd, 1H), 8.4 (s, 1H), 8.9 (d, 1H), 12.5 is, 1H) . ’ c) 3-bromopyrazoloindole 1,5-α] pyridine bite bromide diimide (3. 6 g, 17 22 mmol) to sodium bicarbonate (4.34 g, 51.66 mmol) Add to a solution of hydrazine and (iv) each formic acid (preparation 22b, 2.81 g, 17.22 mmol) in fresh monomethylcarbamide (40 ml) and at 4 hours, then pour in 100 ml water: : 下,所, The suspension of two 阙 阙 Wei dry combined ^ B from the Japanese extract household 'solvent. By flash chromatography (8:2 hexane/acetic acid: EtOAc: filtered and evaporated to give the title compound (2.58 g, 76%). 1), and crude product, LRMS (m/z): 197 ( M+l)+ 〇^ 1H), 7.2 (t, 1H), }H-NMR δ (250 MHz, CDC13): 6 8 7.5(d, 1H), 7.9(s, 1H), 8.4 (d,lH Preparation of 23 3-bromocarbazole [1,5_^%嗓 134 201130839 a) π is more than [ι,5-ίΐ] η than 嗓-3-decanoic acid ethyl vinegar according to the experimental procedure as described in Preparation 22a, from 2,4,6-trimethylbenzenesulfonic acid 1 -Aminopyrazine-1-indole (Preparation 9) and ethyl propionate afforded an orange solid (28%), which was subsequently purified by flash chromatography (hexane to 4: 6 hexane / ethyl acetate). LRMS (m/z): 192 (M+l)+. b) 11 than saliva and [1,5-έϊ]σ than 嗓-3-carboxylic acid according to the experimental procedure as described in Preparation 22b, from pyrazolo[1,5-fl]pyrazine-3-carboxylic acid ethyl ester (Preparation 23a) gave a white solid (99%). LRMS (m/z): 164 (M+l)+. c) 3-bromo-ratio to saliva [1,5-&lt;ι]π 嗓 according to the experimental procedure as described in Preparation 22c, by pyrazolo[1,5-α] phenazine-3-indole The acid (Preparation 23b) gave a pale-yellow solid (69%) which was subsequently purified by flash chromatography (2:8 to 6:4 ethyl acetate). LRMS (m/z): 198 (M+l)+. Preparation 24 3-(4-Ga-5-nitropyrimidin-2-yl)oxazolo[1,5-β] 135 201130839 a) Pyrazolo[1,5-α]pyrazine_3_methacetamide: . Pyrazolo[丨,5·冲比嗓I formic acid (preparation 23b, 6.7 〇 g, 41.1 毫The lysine (5 G ml) suspension of Mohr) was heated to reflux for 7 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was combined with toluene. The obtained solid was suspended in an aqueous solution of ammonium nitrite (80 ml) and the mixture of 16 C) at the ambient temperature was aged and aged to give a beige color of the title (10.0 g, >100%). ), which was used in the next synthesis step without further purification. LRMS (m/z): 163 _1)+ 〇!H NMR δ (300 MHz, DMS〇-J6): 8.1 (d, 1H) 8 7 (s !H), 8.9 (d, 1H), 9.6 (s , 1H) 〇' .( ' b) » than saliva [l,5-d]e than azine_3_carbonitrile: crude pyrazolo[1,5-α]pyrazine·3-formamide (Preparation 2, for example, a suspension of 6 smudges of phosphonium trichloride (8 ml) is maintained after heating to reflux;; =. Then the reaction mixture is poured onto a saturated aqueous solution of sodium hydrogencarbonate (2 (8) = liter), followed by The positive value was adjusted to +7-8 by the addition of a 10% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, dried (M.sup.4) and evaporated. Purify the residue to give the title compound (3························ , DMSO-: 8.3 (d, 1H), 8 8 (s 136 201130839 1H), 9.1 (d, 1H), 9.5 (s, 1H). Freshly made red _ (G 44 grams, 8 丨 里 宅Mol) anhydrous methanol (10 ml) suspension # choose: =: 2. After hours, add methanol sodium (. == public ί reaction mixture for 48 hours. Add chlorinated money ((4) The mixture was stirred and stirred in a sealed tube. After 3 days, the mixture was concentrated to dryness to give a crystal, which was suspended in ethyl acetate and stirred overnight. The precipitate was filtered and dried in vacuo. The crude title compound was obtained as a white solid (m.m., </RTI> <RTIgt; </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MHz, DMSO-^): 8.2 (d, 1H) 8 8 d) 5-Acid-2-(* 嗤[[,5-小比嗓-3-yl) 唆4_ol Stir the crude carbazole and [1,5-&lt;3]pyridazine-3-carboindoleamine hydrochloride (preparation 24c ' 4.88 g), (Z)-3-(diamine) in a sealed tube a mixture of ethyl 2-amino enoate (8.04 g, 42.7 mmol) and triethylamine (6.25 *% liter '44.8 mmol) in ethanol (165 mL) and heated to 90 ° C . After 22 hours, the reaction mixture was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LRMS (m/z): 257 (Ml)+ ° 137 201130839 !H NMR δ (300 MHz, DMSO-i/6): 8.1 (d, 1H), 8.7 (Sj 1H), 8.8 (S, 1H), 8.9 (d, 1H), 9.9 (s, 1H) 〇' e) gas-5-nitropyrimidin-2-yl)pyrazole [l,5-n]pyrazine stirs 5_nitro in a sealed tube _2_(carbazolo[1,5-α]pyridazin-3-yl) citric-4-ol (preparation of 24d' 15 gram, 5 8 mM) phosphonium trichloride pen) suspension And heated to 9 ° ° C. After 2 hours, the mixture was concentrated in vacuo and the residue was azeotroped with toluene. The resulting solid was treated with aq. EtOAc (EtOAc m. m/z)·· 277 (M+l)+. 4 NMR δ (300 MHz, DMSO-): 8.3 (d, 1H), 9.0 (s 1H), 9·1 (d, 1H), 9.6 (s, 1H), 9.9 (s, 1H). ' Preparation of 25 5_nitro-2 decaindole and [1,5·ϋ]吼嗓-3-yl)-oxime (tetrahydro-2H-indolyl-4-yl) mouth bite-4-amine Diisopropylethylamine (2.30 ml, 13.20 mmol) and tetrahydro-2H-pentan-4-amine acetate (526 mg, 3.28 mmol) were added to the stirred 3-(4•chloro- a suspension of 5-nitropyrimidin-2-yl-carbazolo[1,5-pyrazine-rhodium, 138 201130839 24e, 0.91 g, 3.29 mmol) in tetrahydrofuran (15 ml) at room temperature The mixture was stirred for 3 hours. The solvent was evaporated and water was added. The title compound (0.785 g, 70%) was obtained. LRMS (m/z): 342 (M+l)+. Preparation 26 N-(4,4-dioxacyclohexyl)-5-deacetyl·2-(0 is more than [1,5-α]0 嗓·3·yl)pyrimidine-4-amine According to the experimental procedure as described in Preparation 25, from 3-(4-chloro-5-nitropyrimidin-2-yl)pyrazolo[l,5-α]pyrazine (Preparation 24e) and 4,4- Difluorocyclohexylamine gave a yellow solid (86%). LRMS (m/z): 376 (M+l)+. lR NMR δ (300 MHz, DMSO-^6): 1.9-2.2 (m, 8H), 4.6 (m, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.9 (s, 1H), 9.0 (d, 1H), 9.2 (s, 1H), 9.9 (s, 1H). ? Preparation 27 3-(6-Chloro 0-but-2-yl)indole 唆[1,5-α]° ratio bite 139 201130839 a) 3-(4,4,5,5-tetramethyl-Hr-dioxabor-2-yl)pyridazole[1,5-&lt;ι]π bite 4,4,4,, 4', 5, 5, 5, 5, - 8? Base 2,2,-di(1,3,2_dioxo) 〇 (1.27 g ' 5. 〇 millimolar), palladium acetate (II) (0.050 g, 0.228 mmol), tricyclohexyl Phosphine (4) 27 g, 〇.46 mmol), carbonic acid unloading (0.945 g ' 6.84 mmol) and water (〇〇 5 ml) added to 3-myrazole and pyridine (prepared to, 〇9〇) Gram, *% millimolar) diethylene glycol dimethyl S (10 liters) solution and at 1 〇〇. The mixture obtained by heating is 2 彳, hour. After cooling, the mixture was filtered (M) and dissolved in methanol. The filtrate was evaporated and the crude product was used in the next step without further purification. LRMS (m/z): 245 (M+l)+. ^ b) 3-(6·Phenylpyrazin-2-yl)pyrazolo[1,5-α]pyridine will be 2,6-dichloropyrene (0.316 g, 2.12 mmol), ginseng (II) Subpyridyl) palladium (0.097 g, 0.106 mmol), tricyclohexyl, phosphine (0.06 g, 0.212 mmol) and potassium phosphate (1.35 g, 6.36 mmol) were added to 3-(4, 4,5,5-Tetramethyl'_1,3,2-dioxabor-2-yl)pyrazin[丨,5·0^bipyridine (Preparation 27a, 0.518 g, 2.12 mmol) In a suspension of decylamine (10 ml). This mixture was subjected to microwave irradiation at 100 ° C for 40 minutes. The reaction mixture was filtered through a pad of Celite®, eluted with &lt;RTI ID=0.0&gt;&gt; The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut LRMS (m/z): 231 (M+l)+. !H-NMR 5 (250 MHz, CDC13): 7.0 (t, 1H), 7.4 (t, ifj) 8.3 (s, 1H), 8.5 (s, 1H), 8.5 (m, 2H), 8.8 (s, 1H). ' Preparation 28 (Brigade bite base) _6_(n than saliva [1 b 〇 〇 base) b 嗓 a) (i?)-3-(6-(«tboxazol[1,5-&lt;|] oxazol-3-yl)"pyrazine-2-piperidin-1-carboxylic acid tert-butyl ester Amino) tert-butyl (3)-3-aminol-l-yl-l-carboxylate (〇sl, gram) and fluorinated (0.83 g, 5.46 mol) added 3-(6-gas 吼 -2- 基 基 基 基 [ [ [1,5- rush than bite (preparation of Lb to, ^ grams, 1.82 millimoles) in dimethyl sulfoxide (2 〇 ml) solution 4: The resulting mixture was stirred for 22 hours at i〇〇°c, then poured into a mixture of 5 liters. The resulting suspension was extracted with ethyl acetate (2 times) and: the organic layer was combined with ice and the filter was applied to The title compound (0.244 g, 34%) was obtained. , um, Zhu Zhuang $ 141 201130839 LRMS (m/z): 395 (M+l)+. b) (i?)-7V-(Big -3-K)-6 (吼 并 and U, 5_ 咬 _3_ azine 2-amine to trifluoroacetic acid (0.35 ml, 4.56 亳 Mo) Add to (8)-3_(6-(t sit and [W·♦ than bite each) pyridazinylamino)pyridinium citrate tartrate (preparation 28a, 0.30 g, 〇76 mmol) The second gas simmer (1G ml) solution was stirred at ambient temperature for the night, then smashed for 24 hours under the thief. Then the secret solvent was used to dissolve the residue in the dichlorohydrin and the sodium hydroxide was used. The aqueous solution was washed with MgSO4, EtOAc (EtOAc m. LRMS (m/z): 295 (M+l)+. Preparation 29 3-(6-Gasoxazin-2-yl)"-pyrazolo-u,5_tf]π-azine oxime a) 3·(4,4,5,5·tetramethyl-l,3,2-dioxo- 2-1-yl [l,5-tf]pyridazine according to the experimental procedure as described in Preparation 27a, in 1 The σ 下 下 此 此 此 此 此 此 此 此 此 此 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 M+l)+~~synthetic step b) 3-(6-aeropyrazine-2-yl)pyrazolo[13 external ratio according to the experimental procedure as described in Preparation 27b thiol-1,3,2 - Dioxin) π than saliva [1, 5%] from 3' (4, 4, 5, 5 - 4 to obtain a yellow solid (28% yield, two steps) ^ two $ (Preparation 29 &amp; Purification by (2:8 ethyl acetate / hexane). Preparation of 30 amines by flash chromatography LRMS (m/z): 232 (M+l) + 〇 _ base) oxazine 2 _ ylamino) W-AK brigade bit base) clock than saliva and (10) exoazine called a) (Λ)_3-(6 decathiazole [1,5-α] °Bistazine-3 piperidine-1_carboxylic acid tert-butyl ester oxime (10) each amine group 0 chen _1-carboxylic acid tertidine (0.41 g, 2 〇 5 mM), ginseng (dibenzylidene) Acetone) dipalladium (〇) (〇〇34 〇〇 millimolar), 9,9· dimethyl-4,5-bis(diphenylphosphino) (〇.043八克' 〇.074爱爱Mohr) and carbonate planer (0.848 g, 2 6 mmol) added to 3_(6卞Bistazine_2·yl>Bizozolopyrene, 5♦biazine (Preparation 2%, 0.43^g' 1.86 Milliol) in dimethylformamide (1 ml) suspension and purify the mixture with argon, then heat to 1 Torr. 匚 = 143 201130839 Hold 7 small dry. Cool to ambient temperature After that, the reaction mixture was filtered with EtOAc EtOAc (EtOAc m. The title compound (0.320 g, 44%). LRMS (m/z): 396 (M+l) + .H-NMR δ (250 MHz, CDC13): 1.4 ( s, 9H), 1.8 (m, 2H), 2.0 (m, 2H), 3.5 (m, 3H), 3.7 (m, 1H), 4.1 (m, 1H), 4.8 (m, 1H), 7.8 (s , 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.4 (dd, 1H), 8.5 (s, 1H), 9.8 (d, 1H). b) (J?)-7V_(piperidine -3-yl)-6-(pyrazolo[l,5-ii]pyrazin-3-yl)pyrazin-2-amine according to the experimental procedure as described in Preparation 28b, from (π)·3-( 6-(pyrazolo[1,5-α]« than indol-3-yl) ° 嗓-2-ylamino) benzylidene-1-carboxylic acid tert-butyl ester (preparation 30a) and trifluoroacetic acid Yellow foam (99%). The crude product was used in the next step without further purification. LRMS (m/z): 296 (M+l) + 〇 Preparation 31 3-(4- Base) ° azole and [1,5-&lt;ϊ]β 嗓 Heating 2-(carbazolo[1,5-fl]pyrazin-3-yl)pyrimidin-4-ol at 110 ° C 144 201130839 (Preparation of l〇b, 150 mg, 〇, 7 mmol) 4 Ancient seedlings I, w milk chlorinated scales 0.42 ml, (four) 1 mol) solution overnight. The reaction mixture was poured onto water and cooled to ambient and was purified by the addition of 2N oxyhydrogen dioxide. Then, the ethyl acetate was added, and the organic phase was separated, washed with water, dried (MgSO.sub.4), filtered and evaporated under reduced pressure to give the title compound (17 </ RTI> </ RTI> </ RTI> 87%). In the next synthesis step. LRMS (m/z): 232 (M+l)+ 4 NMR δ (300 MHz, CDC13): 7.0 (t, 1H), 7 7.4 (d, 1H), 8.6 (dd, 2H), 8.8 (s, 1H). ' Preparation of 32 3-(4,5-dioxapyrimidin-2-yl)pyrazolo[l,5_e]pyr Obtained from 5_gas_2_(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 14b) and phosphorus oxychloride according to the experimental procedure as described in Preparation 31 Solid (57%). LRMS (m/z): 267 (M+l)+ , Preparation 33 3-(4-gasbite_2_yl)0 is more than 嗤[1,5-ύτ]η ratio bite 145 201130839 Obtaining a pale yellow solid from 2-(pyrazolo[1,5-α]pyridazin-3-yl)octan-4-ol (Preparation 4b) and phosphorus hydride as described in Preparation 31 (99%). LRMS (m/z): 231 (M+l) + NMR δ (300 MHz, CDC13): 7.0 (t, 1H), 7.1 (d, 1H), 7.4 (d, 1H), 8.6 (dd, 3H) , 8.8 (s, 1H). Preparation 34 (piperidin-3-yl)-2-(pyrazolo[l,5-a]acridin-3-yl)pyridin-4- a) (and) each (2:10-pyrazolo[1,5-pyridyl-3-yl)pyrimidin-4-ylamino) brigade-1-carboxylic acid third butyl brewing ^heated at 100 ° C 3- (4-Apyrimidin-2-yl)pyrazolo[1,5-α]pyridine (preparation 33,130 mg, 0,56 mmol) and (and)_3_aminopiperidine_1_decanoic acid A solution of tributyl vinegar (326 g, 1.63 mmol) in ethanol (5 ml) was taken overnight. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of water and water. The aqueous layer was separated and washed with a gas pattern 146 201130839 (2 times). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut LRMS (m/z): 395 (M+l)+ !H NMR δ (300 MHz, CDC13): 1.5 (s, 9H), 2.1 (m, 2H), 3.0 - 4.2 (m, 7H), 5.0 - 5.1 (m, 1H), 6.2 (d, 1H), 6.9 (t, 1H), 7.3 (d, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.7 (s, 1 H). b) (piperidin-3-yl)-2 decaprozolo[l,5-ii]pyridin-3-yl)pyrimidine-4-amine according to the experimental procedure as described in Preparation 7b, from (^)- 3-(2-(pyrazolo[1,5-α]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylic acid tert-butyl ester (preparation 34a) and trifluoroacetic acid obtained shallow Yellow oil (89%). LRMS (m/z): 295 (M+l)+, 293 (M-1)-. ^NMR δ (300 MHz, CDC13): 1.5-1.9 (m, 4H), 2.0 (td, 2H), 2.3 (bs, 1H), 2.6 - 3.0 (m, 2H), 3.2 (dd, 1H), 5.4 (bs, 1H), 6.2 (d, 1H), 6.9 (t, 1H), 7.3 (d, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.6 (d, 1H), 8.7 ( s, 1 H). Preparation 35 5-Gas-2-(pyrazolo[1,5-α]pyridin-3-yl)pyrimidin-4-ol 147 201130839 a) 3-(5-Chloro-4-methoxypyrimidin-2-yl)pyrazolo[1,5-&lt;ι] pyridine bite according to the experimental procedure as described in Preparation 3a, from 5- Gas-2-Byetyl '~4. methoxypyrimidine (Preparation 13b) and 1-aminopyridinium iodide gave a pale yellow solid (69%). After the usual work-up, the crude material was triturated with diethyl ether and the title compound was obtained, which was used in the next synthesis step without further purification. 〇 LRMS (m/z): 262 (M+l)+. b) 5-A-2-pyrazolo[l,5-flt]pyridin-3-ylpyrimidin-4-ol was prepared according to the experimental procedure as described in Preparation 4b, from 3-(5-chloro-4-inox) Pyrimidin-2-yl)oxazolo[I,5·pyridinidine (Preparation 35a) gave a dark solid (61%) 〇LRMS (m/z): 247 (M+l)+. Preparation 36 3_(4,5·二气鸣咬_2_基) According to the experimental procedure as described in Preparation 31, 5-Chloro-2-pyrazolo[1,5-α]π is obtained by substituting 3-ylchito-4-ol (Preparation 35b) and oxygenated scales. Yellow solid (84%). LRMS (m/z): 266 (M+l)+ 148 201130839 ι¥ί NMR δ (300 MHz, CDC13): 6.9 - 7.0 (m, 1H), 7.4 -7.5 (m, 1H), 8.6 (ddt, 2H), 8.6 (d, 1H), 8.7 (s, 1H). Preparation 37 gas-N-(piperidin-3-yl)-2 decapyrazolo[1,5_&lt;ι] "bipyridin-3-yl"pyrimidine-4-amine a) 〇R)-3-(5-Gas-2-(pyrazolo[l,5-ii]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-1-decanoic acid tertidine Ester according to the experimental procedure as described in Preparation 34a, from 3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-β]pyridine (Preparation 36) and (Acupoint)-3- Aminopiperidine-1-carboxylic acid tert-butyl ester gave an oil (100%). LRMS (m/z): 429 (M+l)+ NMR δ (300 MHz, CDC13): 1.8 (s, 9H), 2.1 (s, 2H), 3.0 (s, 4H), 4.0 (s, 2H) , 4.3 (s, 1H), 5.4 (bs, 1H), 6.9 (t, 1H), 7.3 - 7.4 (m, 1H), 8.2 (s, 1H), 8.5 (t, 2H), 8.7 (s, H ). 1&gt;)(/〇-5-Gas-1^-(piperidin-3-yl)-2-(»Bizozolo[1,5-&lt;1]咐1 pyridine-3-yl)pyrimidine-4 -Amine according to the experimental procedure as described in Preparation 7b, from (i〇-3-(5-chloro-2-(pyrazolo[1,5-α]pyridin-3-yl)pyrimidin-4-ylamine Tert-butyl piperidine-1-decanoate (preparation 37a) and trifluoroacetic acid to give an oil (100%). LRMS (m/z): 329 (M+l) + 149 201130839 Preparation 38 -2 -amino)aminol piperidinyl-1-ylethyl) carbamic acid tert-butyl ester Aj [(Tertidinoxycarbonyl)amino]acetic acid (65 g, 〇37 mmol), hexa-II acid (7-azabenzotrione-1-yl)tetramethyl (142 MG '〇.37 mmol" and diisopropylethylamine (five) ml, (four) 亳mole) added to turn) good (final 3 dance 6 ten than pour rushing ratio °疋_3-base) π azine _ 2-amine (preparation 28b, 100 g, 〇34 2: carbamide (2 ml) solution and spoiled the mixture overnight at ambient temperature. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; CDC13): 1.5 (s, 9 H), 1.6 - 2.2 (m, 5 H), 3.2 - 4.2 (m, 7 H), 4.8 (m, 1 H), 5.6 (s, 1 H), 6.9 (t , 1 H), 7·3 (m, 1 H), 7.7 (s, 1 H), 8.2 (m, 1 H), 8.4 (m, l H), 8.4 (m, 1 H) 〇 Preparation 39 5 - gas-2-» than bite and [1,5·έΐ]* ratio 3-yl-4- mouth bite alcohol 150 201 130 839 a) 3_(5-fluoromethoxypyrimidine:yl)pyrazole, 5-"pyridine according to the experimental procedure as described in Preparation 27b, from 3-(4,4,5,5-tetradecyl) -1,3,2-oxo-2-yl)π is more than salivation [ι,5_α]〇 ratio (preparation 27a) and 2-gas-5-fluoro-4-methoxypyrimidine (preparation 16a) Obtained solid (23%). LRMS (m/z): 245 (M+l) +. H NMR δ (400 MHz, CDC13): 4.2 (s, 3H), 6.9 - 7.0 (m, 1H), 7.3 - 7.4 (m, 1H), 8·3 (d, 1H), 8.5 - 8.6 (m, 2H), 8.7 (bs, 1H) b) 5-fluoro-2-° azole and [i, 5_fl] N-pyridyl-3-ylpyrimidin-4 alcohol according to the experimental procedure as described in Preparation 4b, from 3-(5-fluoro-4-methylmethoxypyrimidin-2-yl)pyrazolo[丨,〗^]pyridine Prepare 39a) and 48% aqueous hydrogen bromide to give a solid (74%). LRMS (m/z): 231 (M+l) + Preparation 40 5 _ fluoro [(3). Pyrazolo[:,5_α]„bipyridyl-3-pyrimidine-4-amine 151 201130839 a ) (31?)-3·[(5·Gas-2-α is more than saliva[1,5-έΖ]ππ bit-3-yl-mouth-4-yl) Amino]piperidine- 1-carboxylic acid tert-butyl ester according to the experimental procedure as described in Preparation 7a, from 5-fluoro-2-pyrazolo[1,5-indolepyridin-3-ylpyrimidin-4-ol (Preparation 39b) and 3i?)-3-Aminopiperidine-1-carboxylic acid tert-butyl ester gave an oil (88%). LRMS (m/z): 413 (M+l)+ b ) 5·gas-iV-[(3jR)-Brigade bite 3-base]_2-° ratio···-[1,5-ίΐ]α比^-3_ylpyrimidin-4-amine according to the experimental procedure as described in Preparation 7b, from (37?)-3_[(5-fluoro-2-pyrazolo[1,5-«]pyridine-3 -Pyrylpyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (preparation 40a) and trifluoroacetic acid afforded an oil (98%). LRMS (m/z): 313 (M+1). Preparation of 41 ^^[(35,4^)-4- gas brigade-3-yl]-6_β than olfactory [l,5-ii] ° ratio -3-ylpyrazin-2-amine a) (3s,4r)_4·Fluor-3-[(6-Β比峻和[1,5-ίΐ]ηη bit-3-yl 0tb--2-yl)amino]piperidin-1- Benzyl formate according to the experimental procedure as described in Preparation 28a, from 3-(6-chloropyrazine-2- 152 201130839 basal to saliva [1,5·bite (preparation 27b) and external 3_ Amine-based ice-piperidine-1-carboxylic acid benzyl ester (solids (39%) as described in w 〇 2 〇 1 〇 / 〇 16 〇〇 5. J after LRMS (m/z): 447 (M +l)+. b) ^[(I know 'external 4-fluorine bite each base') such as 嗤[1,5-α]pyridine_3_ base ° than 嗓-2-amine will be 〇, external 4-fluorine -3-[(6-oxazolo[I,5♦bipyridyl-3-ylpyrazine-2-yl)amino]pyridine-1-phenyl phthalate (preparation 41a, 229 mg, 〇51 The mixture was added to a solution of 3 N hydrochloric acid in methanol (45 ml) and the mixture was heated overnight in a pan of <RTI ID=0.0># </ RTI> </ RTI> overnight. Then a 37% aqueous hydrochloric acid solution (10 ml) was added and again at 100 t: The reaction mixture was stirred for 4 hours. After cooling to ambient temperature, water was added and the organic solvent was evaporated under reduced pressure. The obtained aqueous phase was washed with di-methane and basified by the addition of 2N aqueous sodium hydroxide. The pH was washed with EtOAc (3 mL). EtOAc (EtOAc) LRMS (m/z): 313 (M+l)+. !H NMR δ (400 MHz, CDC13): 2.0 - 2.3 (m, 2 Η), 2.9 -3.8 (m, 5 Η), 4.3 - 5.2 (m, 1 Η), 4.9 - 5.2 (m, 2 Η), 6.9 (m, 1 Η), 7.4 (m, 1 Η), 7.8 (s, 1 Η), 8.3 (s, 1 Η), 8.4 (s, 1 Η), 8.5 (m? 1 H). , Example 1 3-(4-{丨(15&gt;1_phenethyl)amino}pyrimidin-2-yl)carboxazole Bipyridine-5-phthalonitrile 153 201130839 According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-β]pyridine-5-carbonitrile (Preparation 3b) and 〇S&gt;l- Phenylethylamine afforded the monoformate (15%) which was subsequently purified by flash chromatography (99:1 dichloromethane / methanol) to give the residue by reverse phase chromatography (from Waters C-18 cerium oxide, water/acetonitrile/methanol as a dissolving agent [0.2% v/v citric acid buffer] 0% to 100%) was repurified. LRMS (m/z): 341 (M)+. ^-NMR δ (300 MHz, CD3OD): 1.6 (d, 3H), 5.3 (bs, 1H), 5.5 (bs, 1H), 7.1 (d, 1H), 7.2 (t, 1H), 7.4 (t, 2H), 7.5 (d, 2H), 8.1 (d, 1H), 8.5 (bs, 1H), 8.6 (s, 1H), 8.7 (d, 1H). 〇 Example 2 3-{4-[(cyclohexylmethyl)amino]pyrimidin-2-yl}oxazolo[l,5-iippyridin-5-carbonitrile 154 201130839 according to the experimental procedure as described in Preparation 7a-2-Based to saliva and [1,5 rushing than biting 5_indene nitrile (prepared by 3, (4, melanamine to obtain monoformate (22 %), followed by reverse phase and ring-based C-18 cerium dioxide 'water / acetonitrile / methanol as the dissolution: [(: from 5% hydrazine buffer] 5% to 50%) 1 % v/v LRMS (m/z): 333 (M)+. 'H-NMR δ (300 MHz, 00300):!.!.! (m,5H), 1.9-1.9 (m, 2H), (3, m) (d, 1H), 7.2 (d, , 8.8(d,1H), 9.1 Example 3 3-[4_(phenylamino) shouting · 2_ base] saliva and [Μ♦ than 唆5 a guess Obtained according to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyridin-2-yl)pyrazolo[l,5-pyridinium-5-indolecarbonitrile (Preparation 3b) and phenylmethylamine. Monoformate (8%), followed by reverse phase chromatography (from C-18 cerium oxide, water/acetonitrile/sterol) as a dissolving agent [via 〇1% v/v citrate buffer] 5% to 50%) purified. LRMS (m/z): 327 (M+l)+, 325 (M-1)' 〇^-NMR δ (300 MHz, CDC13): 4.7 (bs, 2H), 6.3 (d, 1H) 155 201130839 6.9 (d, 1H), 7.3-7.4 (m, 1H), 7.4 (d, 4H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.0 (bs, 1H). Example 4 3-{4_[(2,2-Dimethylpropyl)amino]pyrimidin-2-yl}oxazolo[1,5_ύτ]吼 pyridine-5-carbonitrile According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 3b) and (2,2- The di- propyl propylamine afforded a yellow solid (11%) which was purified by flash chromatography (10:1 hexane/ethyl acetate to 100% ethyl acetate). LRMS (m/z): 307 (M+l)+, 305 (M-1)·. !H-NMR δ (300 MHz, CDC13): 1.1 (s, 9H), 3.3 (s, 2H) 〇5.2 (bs, 1H), 6.3 (d, 1H), 7.0 (d, 1H), 8.3 (d , 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.2 (bs, 1H). Example 5 3-(4_{[(lS)_2-methoxy-1-methylethyl]amino}pyrimidin-2-yl)° ratio 嗤[1,5_έφ ratio bite_5_A please 156 201130839 According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 3b) and [(15&gt;2) -Methoxy-1-methylethyl]amine afforded a yellow solid (10%) elute elute elute z): 309 (M+l)+, 307 (Ml)_. b-NMR δ (300 MHz, CDC13): 1.4 (d, 3H), 3·4 (s, 3H), 3.5 (d, 2H) , 4.2 (m, 1H), 5.1 (bs, 1H), 6.2 (d, 1H), 7.0 (dd, 1H), 8.2 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1 (s, 1H). Example 6 3-{4-[(Cyclopropylmethyl)amino]pyrimidin-2-yl}oxazolo[1,5-α]«pyridin-5-carbonitrile According to the experimental procedure as described in Preparation 7a, from 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 3b) and (cyclopropylmethyl) The amine was obtained as a pale-yellow solid (15%), then purified by flash chromatography (l ( hexane/ethyl acetate to 100% ethyl acetate). 157 201130839 LRMS (m/z): 291 (M+l ), 289 (Ml). ^-NMR δ (300 MHz, CDC13): 0.4 (m, 2H), 0.7 (m, 2H), 1.2 (m, 1H), 3.3 (bs, 2H), 5.1 ( Bs, 1H), 6.2 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.1 (s, 1H). Example 7 3 -{4-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}"pyrazolo[1,5-ύτ] 0 than bite-5-A guess According to the experimental procedure as described in Preparation 7a, from 3-(4-carboxy-carto-2-yl)pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 3b) and (2,2 , 2-Trifluoroethyl)amine obtained as a pale yellow solid (10%), which was subsequently purified by flash chromatography (10:1 to 1:1 hexane/ethyl acetate). 〇 LRMS (m/z): 319 (M+l)+, 317 (M-1)-. ^-NMR δ (300 MHz, CDC13): 4.2 (m, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 7.0 (dd, 1H), 8.3 (d, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.0 (s, 1H). Example 8 - 7V-(1-Phenylethyl)-2-pyrazolo[l,5-ii]pyridin-3-ylpyrimidin-4-amine 158 201130839 Obtained solid (5%) ° LRMS (m/z): 316 (M+) according to the experimental procedure as described in Preparation 7a from pyridin-3-ylpyrimidin-4-ol (Preparation 4b) and u. l) +. h-NMR δ (300 MHz, CD3〇D): u (d &amp; 1H), 6.4 (bs, 1H), 7.0 (t, 1H), 7.2-7.3 (m, 2H), 7.3 (t, 2H) , 7.i (d, 2H), 8.0 (d, 2H), 8.5 (s, 1H), 8.5 (d, 1 H). Example 9 (cyclohexylmethyl)amino group] (4)_2_yl} 3-(6-gas pyridyl-2-yl)carbonitrile under the armpit (preparation 6'30 mg, 〇1?(4)^里[1,5-啦咬_5- well, () 35 units Stem and hexyl decylamine (46 microliters 0.35 house Moule) and three in the dimethyl sulphate (0.5 ml) in the middle of the day, the day into the private please 〇 · 36 pens Moore) &quot;, Japanese people% open" The composition was heated for 20 hours. Then A heart is added with water and the resulting material is dried and dried in a vacuum. The title compound (13 mg &apos; 33%) was obtained as a yellow foam. LRMS (m/z): 332 (M+l)+. ^-NMR δ (300 MHz, CDC13): 1.1 (m, 1H), 1.2-1.4 (m, 3H), 1.5-1.8 (m, 5H), 1.9 (m, 2H), 3.2 (m, 2H), 4.7 (bs, 1H), 6.3 (d, 1H), 6.9-7.0 (m, 2H), 7.5 (t, 1H), 8.4 (s, 1H), 8.5 (d, 1H), 9.1 (s, 1H) . Example 10 3-{6-[(2,2-Dimethylpropyl)amino]pyridin-2-yl}pyrazolopyridin-5-carbonitrile The dried resealable Schlank tube was charged with 3_(6-chloropyridine·2_ fluorenyl)-based azole and [丨,5·^]pyridine·5-indoleonitrile (preparation 6, 30 mg) , 0.12 mmol, (2'2-dipropyl)amine (14 μl, 〇12 mmol), cesium carbonate (77 mg '0.24 mmol), u, _ 联二蔡_2 , 2,_diylbis(diphenylphosphine)Ο^g) and toluene (1.5 ml). The Schrank tube was subjected to three evacuations - a cycle of backfilling with argon and (9) (5 mg) of salicylic acid. Re-order, emptying - after recycling with chlorine back, the Schlenk tube was capped and placed in a 120 C oil wipe and mixed for 16 hours. The mixture was then cooled and ethyl acetate was added. The organic layer was washed with water, dried (MgSQ4) and the solvent was evaporated. The title compound (13 mg, 34%) eluted elute LRMS (m/z): 306 (M+1)+. ^-NMR δ (300 MHz, CDC13): 1.0 (s, 9H), 3.2 (d, 2H), 4.7 (bs, 1H), 6.3 (d, 1H), 6.9-7.0 (m, 2H), 7.5 ( t, 1H), 8.4 (bs, 1H), 8.5 (d, 1H), 9.1 (bs, 1H). Example 11 3-{6-[(3-Fluorobenzyl)aminobibupyridin-2-yl"-pyrazolo[l,5-flp-pyridyl-5-曱 guess According to the experimental procedure as described in Example 10, from 3-(6-chloropyridin-2-yl)-benzazolo[1,5-α]acridin-5-indolecarbonitrile (Preparation 6) and (3- The fluorophenylhydrazinium amine gave a yellow solid (57%) which was subsequently purified by flash chromatography (dichloromethane to 250:1 dichloromethane / methanol). LRMS (m/z): 344 (M+l)+. H-NMR δ (300 MHz, CDC13): 4.7 (bs, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 6.9 (d, 1H), 7.0 (t, 2H), 7.0-7.3 (m, 2H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H), 8.4 (s, 1H), 8.5 (d, 1H), 8.8 (bs, 1H). Example 12 161 201130839 3-[6-(Benzylaminobutyryl-2-yl)oxazolo[1,5-α]αpyridin-5-carbonitrile Obtained from 3-(6-chloropyridin-2-yl)pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 6) and benzylamine according to the experimental procedure as described in Example 10. 1 Yellow solid (33%) then purified by flash chromatography (100% dichloromethane to 300:1 dichloromethane / methanol). LRMS (m/z): 326 (M+l)+. ^-NMR δ (300 MHz, CDC13): 4.6 (d, 2H), 5.0 (bs, 1H), 6.3 (d, 1H), 6.9 (dd, 1H), 7.0 (d, 1H), 7.2-7.3 ( m, 1H), 7.3-7.5 (m, 5H), 8.4 (s, 1H), 8.5 (d, 1H), 8.9 (bs, 1H). Example 13 3-(6-{[(lS)-l-phenethyl]aminopyridin-2-yl)oxazolo[1,5_α]咐·〇 Bite-5-carbonitrile According to the experimental procedure as described in Example 10, from 3-(6-apyridin-2-yl-carbazolo[1,5-fl]acridin-5-indolecarbonitrile (Preparation 6) and (8)-1- Phenylethylamine 162 201130839 Obtained as a yellow solid (39%) then purified by flash chromatography (dichloromethane to 350:1 dioxane/methanol) LRMS (m/z): 340 (M+l) +. iH-NMR δ (300 MHz, CDC13): 1.7 (d, 3H), 4.9_5.0 (m, 1H), 5.0 (bs, 1H), 6.2 (d, 1H), 6.9 (dd, 1H) , 7.0 (d 1H), 7.2-7.3 (m, 2H), 7.3-7.5 (m, 4H), 8.4 (s, 1H), 8.5 (d, 1H) 8 9 (s, 1H) 〇,.,, Example 14 Pyrazolo[1 bite-5-carbonitrile 3-(4-{[(3i?)-l-(cyanoethyl)) biting i group] amine group} bite _2 base) ... d...π-~汴匕, and the solvent was evaporated under vacuum 1f7. Purification of the crude product by flash chromatography (EtOAc to EtOAc (EtOAc:EtOAc) Compound (20 mg, 27%). LRMS (m/z): 388 (M+l)+, 386 (M-1)-. b-NMR δ (300 MHz, CDC13, 2:1 mixture of rotamers): 1.7-1.9 (m, 4H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H), 2.9- 3.0 (m, 1H), 3.3-3.4 (m, 1H), 3. 5 (d, 1H), 3.5-3.6 (m, 1H), 4.1 (bs, 1H), 4.6 (d, 1H), 6.3 ( d, 1H), 6.4 (d, 1H, minor rotamer), 7.0 (d,1H), 7.1 (d, 1H, minor rotamer), 8.2 (d, 1H), 8.3 (d , 1H, minor rotamer), 8.5 (d, 1H), 8.6 (d, 1H, minor rotamer), 8.7 (s, 1H, minor rotamer), 8.8 (s, 1H), 9.0 (s, 1H). Example 15 3-(4-{[(3 and)-1-Ethylpiperidin-3-yl]amino}pyrimidin-2-yl)carbazolo[1,5-&lt;ϊ]0 bite -5-carbonitrile Add triethylamine (44 μl, 0.32 mmol), acetic anhydride (8.2 μl, 〇.〇9 mmol) and dihydropyridin-4-amine (1.2 mg, 0.01 mmol) To the stirred 3-{4-[(3Pho-piperidin-3-ylamino)pyrimidin-2-yl}pyrazolo[1,5-α]pyridine-5-carbonitrile (Preparation 7b, 40 A solution of milligrams, 0.06 millimoles in dichloromethane (0.5 ml) and stirred at ambient temperature 164 201130839 mixture was mixed for 20 hours' then partitioned between dichloromethane and 4% aqueous sodium bicarbonate. The organic layer was separated, washed with water and brine, dried (MgSO.sub.4) and evaporated. The crude product was purified by EtOAc EtOAc (EtOAc) )+, 361. ^-NMR δ (300 MHz, CDC13): 0.7-0.9 (m, 2H), 1.9 (d, 2H), 2.1 (d, 1H), 2.2 (s, 3H), 3.2 - 3.5 (m, 1H), 3.6 (bs, 1H), 3.8 (bs, 1H), 4.3 - 4.5 (m, 1H), 5.0 (bs, 1H), 6.2 - 6.3 (m, 1H), 7.0 (t, 1H), 8.3 (dd, 1H), 8.6 (t, 1H), 8.8 (d, 1H), 9.1 (d, 1H). 'Example 16 3-(4-{[(3))-l-(5-fluoropyridine-2-yl) 唆3-3-yl]aminopyrimidin-2-yl)0 than bite [1] ,5-ίΐ]0 than 唆-5-carbonitrile Add 6-gas nicotinic nitrile (0.04 g, 0.29 mmol) and to ethylamine (0.15 ml '1.08 mmol) to the mixed 3-{4-[(3/?)-tours- 3-mercapto]pyrimidin-2-yl}pyrazolo[1,5-α]pyridine-5-carbonitrile (preparation 7b, 0·11 g '〇·24 mmol) of chylorrhea (3.3 ml) The solution was stirred in a solution at 165 201130839 for 20 hours at 50 °C. The reaction mixture was then cooled to ambient temperature and dichloromethane and 4% aqueous sodium bicarbonate were added. The organic layer was separated and washed with water and brine, dried (MgSO4) and evaporated in vacuo. The title compound (0.07 g, 71%) was obtained as a pale yellow solid (yield: m/z): 422 (M+) l) +, 420 (M-1)·. !H-NMR δ (300 MHz, CDCls): 1.3-1.4 (m, 1H), 1.8 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.3 (m, 1H), 3.2-3.5 ( m, 2H), 4.0-4.1 (m, 1H), 4.5-4.6 (m, 1H), 5.0 (bs, 1H), 6.3 (bs, 1H), 6.7 (d, 1H), 7.0 (dd, 1H) , 7.6 (dd, 1H), 8.3 (d, 1H), 8.4 (bs, 1H), 8.6 (d, 1H), 8.8 (s, 1H), 9.0 (s, 1H). Example 17 3-(4-{[(3Λ)·1·(3,3,3-trifluoropropionyl)piperidin-3-yl]amino}pyrimidin-2-yl)n is 嗤[ΐ ,5-ύτ]» than bite-5-carbonitrile 3,3,3 trifluoropropionic acid (0.03 ml, 0.29 mmol), bismuth hexafluorophosphate [(dimethylamino) (3Η-[1,2,3]triazolo[4,5-b ] acridine-3-yloxymethylene]-#-mercaptomethylammonium (0.12 g, 0.30 mmol) and diiso 166 201130839 propylethylamine (0.21 mL, 1.21 mmol) added to Stirring 3-{4-[(3 and)-°Chen-3-ylamino]carcinoma-2-yl}!! than saliva [1,5_冲比唆_5· carbonitrile (preparation) 7b, 0.11 g, 0.24 mol, in a solution of dimethylformamide (3 ml) and stirring the mixture at room temperature for 20 hours. The reaction mixture was then partitioned between dioxane and 4% hydrogen carbonate. The organic layer was separated. The organic layer was washed with a 4% aqueous solution of hydrogen sulphate, dried (MgS04) and evaporated in vacuo. Purified by flash chromatography (200:1 to 10:1 m/methanol) The title compound (0.02 g, 19%) eluted elute (m/z): 430 (M+l)+, 428 (M-1)-. !H-NMR δ (300 MHz, CDC13): 1.9-2.0 (m, 1 H), 3.0-3.2 (m, 2H), 3.3-3.5 (m, 4H), 3.6-3.8 (m, 1H), 3.9 (d, 1H), 4.1-4.3 (m, 1H), 4.5 (d, 1H), 5.0 (bs, 1H), 6.3 (dd, 1H), 6.9-7.0 (m, 1H), 8.2-8.3 (m, 1H), 8.6 (t, 1H), 8.7 (d, 1H), 9.1 (bs, 1H). Example 18 3-{4_[[(3 and)_1(cyanocarbonyl)piperidine-3-yl](methyl)amino]pyrimidin-2-yl}pyrazolo[i, 5-ii]pyridine-5-carbonitrile 167 201130839 According to the experimental procedure as described in Example 14, from (and) _3_(4 gas methyl (cytidine) amino) pyridine-2-yl)pyrazolo[l,5-a]pyridin Bite-5-carbonitrile (preparation 8b) and 3-[(2,5-di- oxo-pyridinyl)oxy]_3_sideoxypropionitrile (prepared as described in BE 875054 (A1)) Yellow solid (52%) was purified by flash chromatography (dichloromethane to 9:1 dichloromethane / methanol). 〇 LRMS (m/z): 401 (M+l)+. W-NMR δ (300 MHz, CDC13, 2:1 mixture of rotamers): 1.7-1.9 (m, 4H), 2.1-2.2 (m, lH), 2 3_2 5 (m, m), 2.9- 3.0 (m,1H),3.1 (s,3H, minor rotamer), 3 2 (s 3H major rotamer), 3.3-3.4 (m,1H), 3.5 (d,1H), 3.6 _3^ 1H), 4.2 (bs, 1H), 4.5 (d, 1H), 6.2 (d, ijj), 6.5 (d, ih, minor rotamer), 7.1 (d, 1H), 7.2 (d , 1H, minor rotatory isomers) 8 2 (d,1H), 8.3 (d,1H, minor rotamers), 8 5 (d,m), (4) 11^, minor rotamers ), 8.7 (3, 111, minor rotamer), 8 8 (3 1) 1H), 9.0 (s, 1H). Example 19 3-(4·((trans)-4-hydroxycyclohexylamino)peridinyl)pyrazolo[Μπ]pyridine-5-carbonitrile 168 201130839 Anti--4-aminocyclohexanol (85 g, ο.% 亳 benzo _, 2, 3) tris-sitoxy 2 [1,5-β] acridine _5_A The nitrile (by-product of Preparation 7a, 1〇5亳二摩尔) was taken in a solution of '······················· The mixture was partitioned between Ethyl Acetate and Ethyl Acetate. The crude layer was purified by flash chromatography (dichloromethane to I). The title compound (66 mg, 67%) was obtained as a yellow solid. </ RTI> </ RTI> RMS (m/z): 335 _1)+. ^-NMR δ (400 MHz, DMSO-^): 〇.4-〇.6 (m 3H) 1.0-U (m, 3H), 1.2-1.3 (m, 2H), 2.3 (d, 1H), 2.7 (bs? 1H); im(7SQ!H)im5 1H),6'5 (d,1H),6·6 (dj 1Ηλ 12 ^ 1H), 7.9 (s, 1H), 8.1 (bs, 1H), 8.2 (d, 1H) 〇 Example 20 #-(cyclohexylmethyl)·2_ton saliva U,5_«] flavon-3-yl-4-amine ~-Alcohol (G II test sequence ring t = amine 169 201130839 acid salt (16%), followed by reverse phase chromatography (from Waters C-18 cerium oxide, water / acetonitrile / decyl alcohol as dissolution) Purification [5% to 50% by 0.1% v/v citric acid buffer) LRMS (m/z): 309 (M+l) + ^-NMR δ (300 MHz, CD3OD): 0.8-1.0 ( m, 1H), 1.0-1.2 (m, 2H), 1.2-1.4 (m, 4H), 1.7-1.8 (m, 4H), 1.9 (d, 2H), 6.4 (bs, 1H), 7.8-8.1 ( m, 2H), 8.4-8.6 (m, 1H), 8.7 (bs, 2H), 10.0 (bs, 1H). Example 21 phenethyl)-2-(»比唑和[l,5-ii]吼Pyrazin-3-yl)pyrimidine-4-amine According to the experimental procedure as described in Preparation 7a, from 2-(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and (6)-1-Phenylethylamine A solid (38%) was obtained which was subsequently purified by flash chromatography (dichlorohexane to &lt;RTI ID=0.0&gt;&gt; , LRMS (m/z): 317 (M.l)+. iH-NMR δ (300 MHz, CD3OD): 1.1-1.2 (m, 1H), 1.6 (d, 3H), 5.3 (bs, 1H), 7.1-7.2 (m, 1H), 7.3-7.4 (m, 2H) ), 7.4 (d, 2H), 7.9 (bs, 1H), 8.1 (d, 1H), 8.6 (d, 2H), 9.6 (bs, 1H). 170 201130839 Example 22 TV-Benzyl-2-pyrazolo[l,5w]pyrazin-3-ylpyrimidin-4-amine Monodecanoic acid was obtained from 2-(pyrazolo[1,5-β]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and benzylamine according to the experimental procedure as described in Preparation 7a Salt (48%), followed by reverse phase chromatography (from Waters C-18 cerium oxide, water / acetonitrile / decyl alcohol as eliminator [0.1% Wv citrate buffer] 5% to 50%) purification. LRMS (m/z): 303 (M+1). ^-NMR δ (300 MHz, CD3OD): 4.7 (s, 2H), 6.4 (bs, 1H), 7.2-7.3 (m, 1H), 7.3-7.5 (m, 4H), 8.0 (bs, 1H), 8.1 (bs, 1H), 8.5 (bs, 1H), 8.6 (bs, 2H), 9.7 (bs, 1H). Example 23 7V-(2,2-Dimercaptopropyl)-2-α is more than [l,5-ii]n ratio eQin-3-yl-biti-4-amine According to the experimental procedure as described in Preparation 7a, from 2-(pyrazolo[1,5-α]pyrazin-3-yl)pyrimidin-4-ol (Preparation 10b) and 2,2-Dimercaptopropyl 1-Amine was obtained from 171 201130839 (43%), then purified by flash chromatography (98:2 to 95:5 dichloromethane/methanol). LRMS (m/z): 283 (M+l)+. 'H-NMR δ (300 MHz, CDC13): 1.0 (s, 9H), 3.2 (bs, 2H), 5.1 (bs, 1H), 6.3 (d, 1H), 8.0 (d, 1H), 8.3 (d , 1H), 8.4 (d, 1H), 8.7-8.8 (m, 1H), 10.0 (bs, 1H) ° Example 24 3-Alkyloxy-3-{(3J?)-3-indole (2-azole And 丨1,5-&lt;|】pyridazin-3-ylpyrimidin-4-yl)amino group] brigade-l-yl}propionitrile ❹ according to the experimental procedure as described in Example 14, from (and) _ (piperidinyl-3-yl)-2-(吼 并[1,5-α]pyrazine _3_yl) pyridine _4 • Amine (preparation 11b) and 3-[(2,5-di- oxo-purinyl)-yloxypropanenitrile (prepared as described in BE 875054 (A1)) to give a solid (55%), then purified by flash chromatography, i. m. m. m. ~ LRMS (m/z): 363 (M+l)+. lH-NMR δ (400 MHz, CDC13, i:i mixture of rotamers): 1.7-2.0 (m, 6H), 2.1-2.2 (m, 2H), 3.4 (s, 2H, rotamer 1 ), 3.6 0, 2H, rotamer 2), 4.2-4.4 (m, 1H), 5.0 (bs, 172 201130839 1H), 6.3 (d, 1 Η, rotamer 丨), 6 3 (d, m, rotamer 2), 8.0 (d, 1H, rotamer 1), 8 0 (d, m, rotamer 2), 8·3 (d, 1 Η, rotamer 1) , 8.3 (d, 1 Η, rotamer 2), 8.4 (dd, 1H, rotamer 1), 8.5 (dd, 1H, rotamer 2), 8.7 (s, 1H, rotamer 1), 8.7 (s, 1H, rotamer 2), 1 〇〇 (s, 丨H). Example 25 6_{(3Λ)-3-[(2-«比唾和[n小比嗪_3ylpyrimidin-4-yl)amino group] Bite bite-l-base} According to the experimental procedure as described in Example 16, from (and) _#_(Brigade-3_base)-2, ten 嗤 嗤 Π, 5 ♦ 比 各 ) ) 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺- Gas was taken to give the solid (23%), which was then purified by flash chromatography (di. m. m. LRMS (m/z): 398 (M+l)+. bNMR δ (200 MHz, CDC13): u (m, 4H), 3 3 3 6 eg, 2H), 3.8-4.3 (m, 2H), 4.4 (m, 1H), 5·〇 (bs, 1H) 6 3 (dm), 6.7 (d,1H), 7.6 (dd,1H), 8.0 (d, 1H), 8.3 (d, Qiu, 8 3_8:5 (4) 2H), 8.7 (s,1H), 10.0 (s , 1H). 'Example 26 173 201130839 2-pyrazolo[ΐ,5-α]pyrazine_3_yl~_[(3 幻小卩,^·Trifluoropropenyl) brigade bite _3-基]Bite bite- 4-amine F According to the experimental procedure as described in Example η, solids were obtained from (8) good (biting each base &gt; 2-(tetra) and (iv)_3_yl) money glacial amine (preparative immortal) and 3,3,3-difluoropropionic acid ( 12%), followed by purification from fish methyl chloride to 9:1 di-methane/methanol). Stomach w LRMS (m/z): 406 (M+l)+. (4) tender δ (働MHz, CDCl3, 旋转 mixed with rotamers ^ 718 (m, m), mo (m, 2H), 2 hearts 2, (m, 2H), 2 6 (s, H, mainly Rotamer is ^.^, 吼: underneath the isomer), j 3.2 (m,1H), 3.3-3.4 (m,1H),3.8-3.9 (m,1H),4 3 (bs, 1H ), 4.9 (bs, 1H, minor rotamer), μ (bs, m, major rotamer), 6.3 (d, 1H, minor rotamer), 6 3 (d ih main rotation) Isomer), .8.0 ((1,111), major rotamer) 8 〇 ((1'111 minor rotamer), 8.3 (d, m, major rotamer), 8 j(4)m , minor rotamer), 8.4 ((1,111, major rotamer 84 minor rotamer), 8.7 (s, m, minor rotamer) 』.7 (s, ' Both major rotamers), 10.0 (s, 1 H). 174 201130839 Example 27 3-{(3 and)-3-indolylmethyl (2-»bisoxazolo[1,5-α]&quot; Azin-3-ylpyrimidin-4-yl)amino group] 唆-1-yl}-3-lateral oxypropyl According to the experimental procedure as described in Example 14, from methyl-tV-[(3/?)-piperidin-3-yl]-2-pyrazolo[1,5-β]pyrazine-3- Pyrimidine-4-amine (preparation 12b) and 3-[(2,5-di- oxetyrridin-1-yl)oxy]-3-oxo-propanonitrile (such as BE875054 (A1) The preparation) was obtained (76%). LRMS (m/z): 377 (M+1)+. b-NMR δ (400 MHz, CDC13, 2:1 mixture of rotamers): 1.2-1.4 (m, 2H) 1.7-2.2 (m, 4H), 3.1 (s, 2H, major rotamer) , 3.1 (s, 2H, minor rotamer), 3.1-3.3 (m, 1H) 3.5 (s, 3H, minor rotamer), 3.6 (s, 3H, major rotamer), 3.7-3.9 (m, 2H), 6.4 (d, 1H), 6.4 (d, 1H), 8.0 (d, 1H), 8.0 (d, 1H), 8.3 (d, 1H), 8.3 (d, 1HX 8.4 (dd, 1H), 8.4 (dd, 1H), 8.7 (s, 1H), 8.7 (s, 1H), 9.9 (s, 1H), 9.9 (s, 1H). Example 28 3-{(3i〇- 3-[(5-Chloro-2-oxazolo[l,5-ap-pyridazin-3-ylpyrimidin-4-yl)amino]]-唆-yl}-3-lateral oxypropyl 175 201130839 According to the experimental procedure described in Example 14, the chlorinated amine was occluded from the mouth of the chlorinated chloroform of the chlorinated hydrazine (I 5 [ I I I I I I I I I ( ( ( ( ( ( ( ( ( ( ( Preparation (10)) and O 3 —[(2'5_H*^n ratio 唆-1_yl)oxy]_3_sideoxypropionitrile (prepared as described in BE 875054 (A1)) gave a white solid (61%) Purified by flash chromatography (dichloromethane to 9:1 dichloromethane/methanol). LRMS (m/z): 397 (M.sup.1)+..H-NMR δ (300 MHz, CDC13): 1.7-2.0 (m, 2H), 2.2 (bs 2H), 3.3-3.5 (m, 2H), 3.6 (s, 2H), 3.8 (bs, 1H), 4.4 (bs, 2H) 5.4 (bs, 1H) , 8.0 (bs, 1H), 8.3 (s, 1H), 8.4 (bs, 1H), 8.8 (s 1H), 9.9 (s, 1H). 'Example 29 ❹ 3-{(3Λ)_3-[(5 -fluoro-2-pyrazolo[1,5·α]pyrazin-3-ylpyrimidinyl I))amino-1 piperidin-1-yl}-3-oxopropanenitrile According to the experimental procedure as described in Example 14, '(Xi-5-fluoro, 176 201130839 pyridine-3-yl)-2 decapyrido[I,5-exoazine _3_yl) shrine _4 -amine (preparation (10)) and 3-[(2,5-di-oxypyrrolidinium-yl)oxy]_3_oxoxypropanenitrile (prepared as described in BE 875054 (A1)) gave a white solid (62%), followed by flash chromatography (difluoroanthracene to 8:2 difluorodecane/methanol) to purify LRMS (m/z): 381 (M+l)+. δ (400 MHZ, CDC13, 1:1 mixture of rotamers m: 1-7-2.0 (m, 4H), 2.1-2.25 (m, 1H), 3.3-3.4 (m, 3.4-3.6 (m, 1H), 3.6 (s, 2H), 3.8-3.9 (m, 1H), 4.3-4.4 (m 1H) 5.1 (t, 1H), 8.0 (d, 1H, rotamer 2 ), 8 〇 (d, m, rotamer 1), 8.1 (〇1, 1 rotamer 2), 8.2 (41 rotamer '8.4 (d, lH, rotamer 2) ), 8.4 (d, lH, rotamer 1) 8 6 (s 1H, rotamer 2), 8.7 (s, lH, rotamer 0,990 m Example 30 ' 5-fluoro-2-carbazole And 丨1,5-β]«pyrazine_3_yl_τγ_[(3Λ) small (3,3,3 tripropionyl) trace bit-3-yl] shout bite-4-amine - according to the experimental procedure as described in the example, by (external 5_qizhongchen bite-3_base)·2·(吼唆[I,5♦biazine_3_yl) cancer biting glacial amine ( Preparation of 3 乂 '3-trifluoropropionic acid gave a white solid (42%) which was then purified by flashing with ssssssssss. 177 201130839 LRMS (m/z): 424 (M+l)+. b-NMR δ (400 MHz, CDC13, 1:1 mixture of rotamers): 1.7-1.8 (m, 2H), 1.8-2.0 (m, 4H), 2.1-2.2 (m, 1H), 3.3- 3.4 (m, lH, rotamer 1), 3.4-3.5 (m, lH, rotamer 2), 3.6 (d, 1H, rotamer 1), 3.9 (d, 1H, rotational isomerism 2), 4.2 (d, 1H, rotamer 1), 4.4 (bs, 1H, rotamer 2), 5.1 (d, 1H, rotamer 1), 5.2 (d, 1H, rotation Isomer 2), 8.0 (d, 1H, rotamer 1), 8.0 (d, 1H, rotamer 2), 8.1 (d, 1H, rotamer 1), 8.2 (d, 1H , rotamer 2), 8.4 (d, 1H, rotamer 1), 8.4 (d, 1H, rotamer 2), 8.6 (s, 1H, rotamer 1), 8.7 (s , 1H, rotamer 2), 9.9 (s, 1H, rotamer 1), 9.9 (bs, 1H, rotamer 2). Example 31 3-{(3U)-3-[(5 _Mercapto-2-pyrazoloindole 1,5-α]pyrazin-3-ylpyrimidin-4-yl)amino]britan-1-yl}-3-lateral oxypropyl According to the experimental procedure as described in Example 14, 5-methyl-indole 4 (37〇-^0chen-3-yl)-2-1^ spit [1,5-α]πΛβ Qin-3- Base oxime 4-amine (preparation 21b) and 3-[(2,5-di-branched sigma ratio succinyl-1-yl)oxy]-3- oxo-propion (eg ΒΕ875054 (Α1) Prepared as described above, obtained as a white solid (45%), then purified by recrystallization from ethanol from 178 201130839. LRMS (m/z): 377 (M+l) +. b-NMR δ (400 MHz, DMSO - is a 1:1 mixture of rotamers): 1.6-1.7 (m, 2H), 1.8 (bs, 2H), 2.1 (s, 3H), 2.1-2.2 (m, 1H, rotamer 2 ), 2.6-2.8 (m, 1H, rotamer 1), 3.0-3.2 (m, 1H), 3.4 (s, 2H), 3.7 (d, 1H, rotamer 2), 3, 8 ( d, 1H, rotamer l), 3.9_4.2 (m, 1H, rotamer 2), 4.3 (bs, 1H, rotamer 1), 6.6 (d, 1H, rotamer 2), 6.7 (d, 1H, rotamer 1) 8.0 (bs, 1H, rotamer 2), 8.1 (bs, 1H, rotamer 1), 8.8 (s, 1H, rotamer 2), 〇 (s, 1H, rotamer 1), 8.9 (bs, 1Η), 9.8 (s, 1H, rotamer 2), 9.8 (s, 1H, rotation Example 1). Example 32 (S)-"V-(1 _(5-Fluor&quot;bipyridin-2-yl)ethyl)-2-(0-pyrazolo[1,5·α]"Biazine -3_base) bite-4-amine 3-(4-Azinopyrimidin-2-yl)pyrazolo[1,5-α]pyrazine (Preparation 3, 170 mg, 0.61 mmol), (8)-1-(5-fluoropyridine) in a microwave oven -2-yl) Ethylamine (85 mg, 0.61 mmol, as described in WO2006/82392A1) and diisopropylethylamine (122 μL, 0.70 mmol) at 179 201130839 In the case of dimercaptocaramine (5 ml), it is separated from the organic phase, and the organic phase is separated. The more the ice is used, the more it is dried (MgS〇4) and concentrated, and the obtained = wash strip, 15%^5〇 %) '^b ^ Jinghua oral (9 * g ' 4%). To a solution of the title compound (in a free form of '9 mg, 0.027 mmol) in ethanol (2 ml), by a solution of EtOAc (1) mg (0.027 mmol) in ethanol (5 mL) 'The solvent was subsequently evaporated to prepare an anti-enedodiate salt. The resulting solid was dried under vacuum in an oven to give the desired succinic acid LRMS (m/z): 336 (M+l) + b NMR δ (400 MHz, CDC13, fumarate ): 1.6 (d, 3H), 5.9 - 6.1 (m, 1H), 6.2 - 6.4 (m, 1H), 7.4 (dd, 2H), 8.0 (d, 1H), 8.2 (d, 1H), 8.4 ( Dd, 2H), 8.7 (s, 1H), 1〇·〇(s, 1H). Example 33 #-((5-Fluoroacridin-2-yl)methyl)_2 decapyrazolo[l,5-fl]pyridazin-3-yl)pyrimidin-4-amine 180 201130839 According to the preparation of 7a as described in the preparation of 7a, the actual ratio of oxazol-3-yl) 唆 唆 _ _ _ ( ( 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由 由The phase chromatography is better than the bite-2-1) decylamine obtained by the dream of oxidation, water/acetonitrile/methanol as the solvate from C-18 〇% to 100%). a/〇v/v formic acid buffer] LRMS(m/z): 322 (lang) '32()(M_ly. lR NMR δ (400 MHz, CDC13)· 4 7 6.4 (m, 1H), 7.4 (d, 2H), 8.0 (d, 1H) , 8.3 M plus, 2H), 6 3 _ 8.7 (s, 1H), 10.00 (d5 ih) 〇,.(,1H),8.4 (dd, 2H), Example 34 3-(4,5-Dichloropyrimidin-2-yl)pyrazolofl is mg, 0.26 mmol, (5_Fluoropibit), (Preparation 32, 0.26 mmol) And a mixture of diisopropylethylamine (5) and amine (33 mg in tetrahydrofuran (3 ml) was heated to '^. Then the solvent was evaporated under reduced pressure and maintained by reverse phase: L: The broad 8 cerium dioxide 'water / acetonitrile / methanol as a solvent: two from Waters formic acid buffer] 0% to 100%) purified crude product, get the title = human j ° / QV / v 181 201130839 mg, 39% LRMS (m/z): 356 (M+l) + lR NMR δ (300 MHz, CDC13): 4.8 - 5.0 (m5 2H), 6 η (b 1H), 7.4 (d, 2H), 8.0 ( d,1H), 8.3 (s,1H),8.4 (dd,1H)',8 6 S 1H),8.7 (s,1H),9.8 (s,1H). ' '(s' Example 35 o 2- (&quot;比峻和[1,5-a]》Biazin-3-yl)-V-(tetrahydro-2 and -pyramidin-4,5-diamine*) ο Add 10%/carbon (0.392 grams, 0.37 millimoles) to base-2- (such as sitting and [1,5♦ than 嗓基基) good (tetrahydrogen α 喃 _4_ base-4 - Mixing the amine (preparation of 25 '0.785 g, 2.31 mmol) in ethanol (5 〇 $ liter) and mixing the mixture at ambient temperature in a hydrogen atmosphere for 2 hours, filtering the mixture via Cdite® and using B__ The cake was combined; the liquid and the washing liquid were obtained to obtain a light green solid (0,670 g, 94%). Not ba LRMS (m/z): 312 (M+l) + 4 NMR δ (300 MHz , DMSO-wood): 1.6 (峨2H), 3, (t &gt; 2H), 4, (d; 2H), 4, .43 (m, 1H; J; s^; 182 201130839 8.8 (dd, 1H), Example 36-4,5-Diamine with (4,4-difluorocyclohexyl)·2_((tetra) and U,5♦azine-3-ylnen According to the experimental procedure as described in Example 35, #_(4,4-difluorocyclohexyl)-5 nitro-2-(oxazolo[1,5-α]pyrazine-3-yl)pyrimidine (Preparation 26) gave an off-white solid (87%). LRMS (m/z): 346 (M+l)+. lU NMR δ (300 MHz, DMS〇-^6); \ η 2H), 2.0-2.2 (m, 6H), 4.3 (m, 1H), 5.0 (s, 2H), 6.4 (d, 1H), 7.7 (s, 1H), 8.0 (d, 1H), 8.6 (s, 1H), 8.8 (d, 1H), 9.8 (s, 1H). Example 37 (8)-5-Gas·ΛΚ1-(5-Fluoro)pyridin-2-yl)ethyl)_2·bibazole[1,5-&lt;1] pyridazin-3-yl)pyrimidine-4 -amine 183 201130839 According to the experimental procedure as described in Example 34, from 3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-α]pyrazine (Preparation 32) and (6)-1-(5) -Fluoropyridin-2-yl)ethylamine (prepared as described in WO2006/82392) gave a solid (57%). LRMS (m/z): 370 (M+l) + 屯 NMR δ (300 MHz, CDC13): 1.7 (d, 3H), 5.4 - 5.6 (m, 1H), 6.6 - 6.8 (m, 1H), 7.3 - 7.5 (m, 2H), 7.9 - 8.1 (m, 1H), 8.3 (s, 1H), 8.3 - 8.5 (m, 1H), 8.5 - 8.6 (m, 1H), 8.7 (s, 1H), 9.9 (s, 1 H). Example 38 (i?)-3-Sideoxy-3-(3-(6-(«Bizozolo[1,5-α] «Biazin-3-yl)°pyrazine-2-ylamino )Brigade bite-1-base) C. At the ambient temperature, (and) Α^-(派σ定-3-yl)-6-(ntt*n sits and [1 184 201130839 azine-3-yl)pyrazin-2-amine (Preparation 30b, 0.23 g, 0.78 mmol, 3-[(2,5-di- oxy oxime σ σ-1 -yl)oxy]-3- oxo-propion (as in ΒΕ875054 (Α1)) A solution of 0.17 g, 0.94 mmol, and triethylamine (0.13 mL, 0.94 mmol) in dichloromethane (10 mL) was stirred overnight. The title compound (0.158 g, 38%) eluted elute LRMS (m/z): 363 (M+l)+. h-NMR δ (400 MHz, DMS0-4): 1.7 (m, 2 Η), 1.8 (m, 1H), 2.1 (m, 1H), 3.2 (m, 2H), 4.3-3.5 (m, 5H), 6.9 (s, 1H), 7.9 (s, 1H), 8.0 (d, 1H), 8.3 (s, 1H), 8.8 (m, 2H), 9.8 (s, 1H). Example 39 (and)-3-Sideoxy-3-(3-(6-(n-bi-azolo[1,5-ii]acridin-3-yl)-pyrazine-2-ylamino) Brigade Bite-1-base) C. According to the experimental procedure as described in Example 38, from (i?)-7V-(piperidin-3-yl)-6-(pyrazolo[1,5-α]pyridin-3-yl)pyrazine- 2-Amine (Preparation 28b) and 3-[(2,5-di-oxalyloxa-1-yl)oxy]-3-oxo-propanonitrile (as described in 185 201130839 BE 875054 (A1) Preparation) A pale green solid (5%) was obtained, which was subsequently purified by flash chromatography (95:5 dichloromethane / methanol). LRMS (m/z): 362 (M+l)+. ^-NMR δ (400 MHz, DMSO-^6): L6 (m? 2H), L8 (m? 1H), 2.1 (m, 1H), 3.2 (m, 1H), 4.4-3.6 (m, 5H) , 4.5 (s, 1H), 6.9 (m, 1H), 7.0 (t&gt; 1H), 7.4 (t, 1H), 7.8 (m&gt; 1H), 8.3 (s, 1H), 8.4 (m, 1H), 8.6 (s, 1H), 8.7 (d, 1H). Example 40 W-3-Alkyloxy_3_(3_(2_(pyrazolo(5,5-pyridine)-3-pyrimidin-4-ylamino))-)-propanonitrile According to the experimental procedure as described in Example 38, from (10) good (piperidine sulfhydryl) &gt; 2 (° 嗤 and [1,5_ ticky) money + amine (preparation 34) and 3_[(2 , 5-Bistoxypyrrolidine oxime) oxy] prepared on the side of the oxygen oxo 75054 (9)) to obtain a solid (41%) = recrystallized as acetonitrile to purify. The error is derived from LRMS (m/z): 362 (M+l)+. !H NMR δ (300 MHz, CDC13): 1.5 - 2.1 (m, 4m . 2H), 3.3 - 3.6 (m, 2H), 3.8 (d, 1H), 4.0 - 4.3 (m,: .1 (d, (m, 1H), 4.9 - 5.2 (m, 1H) 6.2 (t, 1H), 6.9 (d, 1H), 73 (t , 1 h)5 201130839 8.3 (d, 1H), 8.5 (d, 2H) , 8.7 (d, 1H). Example 41 (i〇-3-(3-(5-Gas-2 bisazolo[1,5-α]&quot;bipyridin-3-yl)pyrimidin-4-yl Amino) brigade bite-1-yl)-3-lateral oxycaline According to the experimental procedure as described in Example 38, from (7^)-5-chloro-indolyl-3-yl)-2-(pyrazolo[1,5-β]pyridin-3-yl)pyrimidine 4-Amine (Preparation 37b) and 3-[(2,5-di-oxyl"pyrrolidin-1-yl)oxy]-3-oxo-propanenitrile (as described in BE 875054 (A1)) Prepared) to obtain a white solid (41%), followed by reverse phase chromatography (from Waters C-18 sulphur dioxide, water/acetonitrile/nonanol as the eliminator [0.1% v/v citric acid) Buffer] 0% to 100%) purified. LRMS (m/z): 396 (M+l)+ lU NMR δ (300 MHz, DMSO-i/6): 1.5-1.9 (m, 3H), 2.0 (s, 1H), 2.7 (dd, 1H) , 2.9 - 3.2 (m, 1H), 3.7 (dd, 1H), 3.9 - 4.2 (m, 2H), 4.3 (d, 1H), 4.7 (d, 1H), 7.0 - 7.2 (m, 2H), 7.5 (dd, 1H), 8.3 (d, 1H), 8.4 (d, 1H), 8.7 (d, 1H), 8.8 (t, 1H). Example 42 〇R&gt;7V-(l-(4H-l,2,4-triazol-3-yl)piperidin-3-yl)-2-(pyrazolo[l,5_d] mouth bite-3 -base) mouth bite-4-amine 187 201130839 Ο In the move (: under the paste of the red base) _2 Liu Butterfly 1 &gt; 5 outside the beer _3 · base) biting the winter amine (preparation 34, 2 grams, 1 〇 1 millim) and 3 desert , 2,4-triterpene (75 mg, 〇51 mmol), such as Li Qing CW Qing 200 cut (four) is a mixture of μ heated overnight. By reverse phase chromatography into τmill preparation) cerium dioxide 'water / acetonitrile / The crude mixture was purified by decyl alcohol as a solution from Waters (C-18 0% to 100%) to give I Ο·1% v/v formic acid buffer (96 mg, 52%). Title of color solid LRMS (m/z): 362 (M+l)+. 1,5 (d, 1H), 1.7 (ms, 1H), 3.0 (m, 1H), 3.4 (bs, say), 7.G (t, 1H), ' 8.2 (s, 1H), 8.5 (m , !H NMR δ (300 MHz, DMSO-^6). 1H), 1.8 (m, 1H), 2.0 (m, 1H), 2.8 (cut, (m, 1H), 3.7 (m, 1H), 4.2 (m, 2H), 6.3 7.3 (m, 1H), 7.4 (m, 1H), 8.1 (m, 1H) 1H), 8.6 (s, 1H), 8.8 (d, 1H). Example 43] Salivation [ι,5-&lt;ι]π ratio 7V-[(3 and)-1-(aminoethenyl)piperidine-3, pyridine-3-ylpyrazin-2-amine 201130839 Add the diwei test (4Μ, Η) of hydrochloric acid to (2_sideoxy·2·{(Μ)·3·[(6_吼吼和(1)5 but than bite 4 嗓%嗓2 base) amine a mixture of piperidine-ι-yl}ethyl)aminocarbamic acid tert-butyl ester (preparation 38, 88 mg, 〇23 mmol) in methanol (3 liters) and at ambient temperature 麟,Time. Then, the yellow solid which was immersed in a volume and dried over a helium was evaporated, washed with (10) and dried to give the title compound mg (95%). LRMS (m/z): 352 (M+l)+. Example 44 W-3_(3-(5·Fluoroindole-((,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Propiononitrile ~ Press ", as in the experimental procedure described in Example 38, from 5-fluorochun [(3 and 唆 唆 唆 ]] _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -amine (preparation 40 A solid (68%) was obtained from EtOAc (m.p.). LRMS (m/z): 380 (M+l)+. lH NMR δ (400 MHz, OUSO-d6): 1.5 - 1.7 (m, 1 Η), 1.8 (bs, 1H), 2.1 (d, 1H), 2.6 - 2.7 (m, 1H), 2.7 - 2.9 (m , 1H), 3.1 (td, 1H), 3.6 (bs, 1H), 3.8 (bs, 1H), 3.9 - 4.0 (m, 1H), 4.1 (q, 2H), 4.7 (d, 1H), 7.0 ( t, 1H), 7.4 - 7.5 (m, 1H), 7.5 - 7.6 (m, 1H), 8.2 (d, 1H), 8.4 (d, 1H), 8.8 (t, 1H). Example 45 3-((3s,4r)-4-fluoro-3-(6-(pyrazolo[1,5-&lt;|]pyridin-3-yl)pyrazin-2-ylamino)piperidine _1·yl)-3-oxopropiononitrile According to the experimental procedure as described in Example 38, from jV-[(3s,4r)-4-fluorooxazol-3-yl]-6-» 嗤[[,5-^] 吼-3 - 吼 -2 -2 - amine (preparation 41) and 3-[(2,5-one-oxyl phloate-1-yl))-based group]_3_sideoxy-propion (eg ΒΕ875054 (Α1) Prepared as described) to obtain a green solid (47%), which was subsequently purified by flash chromatography (di-hexanes to 93:7 methane / methanol). LRMS (m/z): 381 (M+l)+. b NMR δ (400 MHz, CDC13, 1:1 mixture of rotamers): 1.9 _ 2.3 (m, 2H), 2.9 _ 3.8 (m, 5H), 4.3 _ 5.2 (m, 4H), 6.9 (m , 1H), 7.4 (m, 1H), 7.8 (s, 1H, rotamer A), 7.9 (s, 190 201130839 1H, rotamer B), 8.2 (d, lH, rotamer rotation) Isomer A), 8.3 (s, 1H, rotamer B), 8^), 8.3 (s, 1 Η, isomer Β), 8.4 (s, 1 Η), 8.5 (d, 1 Η, rotation Isoproportionation (d, 1 Η, rotation 1 Η, rotamer Β), Α Α, 8.0 (d, Example 46 3-((3r,4r)-4-methyl-3-(6-(pyrazole) And [1,5 览-2-ylamino) bistidin-1-yl)-3-oxoxypropionitrile-based azine Example 47 Pyridyl)-6-(pyrazolo(/?), /V-(l-(4H-l,2,4-tris-s-3)yl][1,5-&lt;|]pyridine- 3-yl)pyrazine-2-amine Pharmacological Activity In Vitro JAK Kinase Assay Compounds were screened for their ability to modulate human JAK2 and jAK3 using assays as indicated below. 5 substances inhibit JAK1, using the baculovirus expression system, enabling the catalytic domain of human xia 1 (Xian 85〇_1154), 191 201130839 JAK2 (aa826-1132), JAK3 (aa795-1124) and Tyk2 (aa 871-1187) The N-terminal GST-fusion protein was expressed and purchased from Carna Biosciences ° using the biotinylated peptide poly(GT)-biotin (CisBio) as a substrate to characterize the enzyme activity. The peptide concentration in the reaction was 60 nM for JAK1, 20 nM for JAK2, 140 nM for JAK3 and 50 nM for Tyk2. The degree of acidification was detected by time-resolved fluorescence energy transfer (TR-FRET). IC The IC50 of the compound was measured for each kinase in the reaction mixture containing enzyme, ATP, and peptide in 8 mM MOPS (pH 7.0), 10 mM MgCl 2 , 0.05% β-mercaptoethanol, 0.45 mg/ml BSA. The ATP concentration in the reaction was 3 μΜ for JAK1, 0.2 μΜ for JAK2, 0.6 μΜ for JAK3, and 1.8 μΜ for Tyk2. The enzyme reaction was carried out for 30 minutes at room temperature. Next, 20 μl of quenching detection buffer (50 〇 containing 0.115 μg/ml of phosphotylin phosphorylation (ΡΤ66)-cryptate (CisBio) and variable concentration of SA-XL665 (CisBio) was used. mM HEPES, 0.5 M KF, EDTA 0·25 Μ, 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 acid GST: glutathione-S-transferase MOPS: 3-(N-morphine) propionic acid 192 201130839 BSA: Bovine serum albumin ATP Glandular cans of acid EDTA: ethylenediaminetetraacetic acid HEPES: 4-(2-hydroxyethyl) piperazine ethanesulfonic acid Table 1 describes the ic50 values for certain exemplary compounds described in the present invention. In Table 1, "A" indicates that the IC50 value is less than 0.1 μΜ ( ΙΟΟηΜ), B indicates that the IQo value is in the range of Μ. 1 μΜ (1 〇〇nM ) to 1 μΜ, and C indicates that the IC50 value is higher than 1 μΜ. Table 1 _Example No. IC5〇JAK3 (μΜ) IC5〇JAK2 (μΜ) ICsoJAKl (μΜ) 5 AAB —7 BAC 14 AAB 19 AAB 21 —One AAA 25 AAB 27 -- AAB 30 ---- AAB 35 —— BA B--- L· 37 A _____ AA Muscle 丄 3 see, 柳 钩 JA JAiU, JAK2 and effective inhibitors of jak3 kinase. The IC5 enthalpy of the preferred heteroaryl-ketone derivatives, JAK2 and 3 kinases of the invention (e.g. less than 1 μΜ above, preferably less than Μ 5 μΜ for each JAK kinase), combination 193 201130839. Combinations of the invention may optionally include one or more other active agents known to be useful in the treatment of spinal cord proliferative disorders (such as true plethora, thrombocytopenia or myelofibrosis), leukemia, lymphoid malignancy. Diseases and solid tumors; bone marrow and organ transplant rejection; and immune-mediated diseases, more specifically, wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory 0 disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (C〇pd), atopic dermatitis and psoriasis, the active substance such as: (a) two Hydrogen folate reductase inhibitors, such as Methotrexate or CH-1504; (b) DHODH inhibitors, such as leflunomide, teriflun〇mide or international patent applications a compound as described in WO2008/077639 and WO20092696; (c) an immunomodulator such as Glatiramer acetate (Copaxone) , Laquinimod or Imiquimod; (d) DNA synthesis and repair inhibitors, such as Mitoxantrone or Cladribine; (e) Anti-α4 integration Antibody, such as Natalizumab (Tysabri); (f) α4 integrin antagonists such as R-1295, TBC-4746, CDP-323, ELND-002, Filatgrast or TMC-2003; (g) Corticoids and glucocorticoids, such as prednisone or methylprednisolone, fluticasone, and mometasone 194 201130839 (mometasone) Or beta-metasone; (h) anti-butanyl diphosphate, such as GW2; (i) anti-TNFα antibodies, such as infliximab, adalimumab or Certolizumab pegol; (j) Soluble TNFα receptors, such as etanercept; (k) anti-CD20 monoclonal antibodies, such as Rituximab, Akezhu Monoclonal antibody (〇crelizumab), atorvazumab (Ofatumumab) or TRU-015; (1) anti-CD52, such as alemtuzumab; (m) anti-CD25, such as daclizumab; (η) anti-CD88, such as eculizumab or peculiar beads Monoclonal antibody (pexilizumab); ( 〇) anti-IL12R/IL23R, such as ustekinumab; (p) _ weekly phosphatase inhibitor (Calcineurin), such as cyclosporine A or cyclosporine A Tacrolimus; (q) MPdh inhibitors such as myCOphenolate mophetyl; (steroidal marijuana receptor agonists such as satex; S s a chemokine CCR1 antagonist, such as MLN-3897 or PS-031291; (t) a chemokine CCR2 antagonist, such as iNCB-8696; (u) an NF-κΒ activation inhibitor such as MLN-0415; (v) SIP receptor agonists, such as those described in flngolimod, BAF-312, ACT 128800 or International Patent Application No. PCT/EP2009/007348 and PCT/EP2009/008968; (w) S1P dissociation enzyme (liase) inhibitor such as LX2931; (X) Syk inhibitor, such as R-112; (y) PKC inhibitor, such as NVP-AEB071; (z) M3 antagonist Anti-agents, such as tiotropium or aclidinium; (aa) long 195 201130839 efficacious beta-adrenergic agonist's such as salmeter(l), formoterol ( Formoterol) or indacaterol; (bb) vitamin D bamboo organisms such as caicip〇trj〇i (Daivonex); (cc) phosphodiesterase IV inhibitor, Such as roflumilast or GRC-4039; (dd) p38 inhibitors such as ARRY-797; (ee) MEK inhibitors such as ARRY-142886 or ARRY-438162; (ff) Π3Κδγ inhibitors; Interferon, including interferon 01 &amp;, such as from 6丨 (^111 (16 (; Afoona (human ¥ 〇 1 ^), CinnoVex from CinnaGen) and Libby from EMD Serono (Rebif), as well as interferon beta ib, such as Betaferon from Schering and Betaseron from Berlex; and (hh) interferon alpha, such as Sumiferon MP ° Usually, the other active substance is not methotrexate. Preferably, the other active substance is selected from the group consisting of: (b) a DHODH inhibitor such as leflunomide, teriflunomide or international patent application No. WO2008/077639 and No. WO2009021696 The compound described; (c) an immunomodulator such as Glatiramer acetate (Copaxone), Laquinim〇d or Imiquimod; e) anti-α4 integrin antibodies, such as natalizumab, (Natalizumab) (Tysabri); (f) α4 integrin pickup, such as R-1295, TBC-4746, CDP-323, ELND-002, non Firategmst or TMC-2003; ( g ) corticosteroids (c〇rtic〇id ) and glucocorticoids such as prednis〇ne 196 201130839 or methylprednisolone , fluticasone, mometasone or beta-metasone; (h) fumarate, such as 5G-/2; (i) anti-TNF alpha antibodies, such as Yingli Infliximab, Adalimumab or Safran (Certolizumab pegol); (j) soluble tnF a receptor, such as etanercept; (k) anti-CD20 monoclonal antibody, such as rituximab (Rituximab), okuximab (〇 creiiZUmab), ovalimumab (〇fatumumab) or TRU-015; (η) anti-CD88, such as eculizumab or pexilizumab; (〇) anti-IL12R/IL23R, such as Ustekinumab; (p) calcineurin inhibitors such as cyclosporine A or tacrolimus; (q) IMPDH inhibitors such as Mycophenolate mophetyl; (r) cannabinoid receptor agonist, such as satex (Sativex); (s) chemokine CCR1 antagonist, such as MLN-3897 or PS-031291 (1) chemokine CCR2 antagonists, such as INCB-8696; (u) NF-κΒ activation inhibitors, such as MLN-0415; (v) S1P receptor agonists such as fingolimod (flng〇lim〇d) ), a compound described in BAF-312 'ACT 128800 or International Patent Application No. PCT/EP2009/007348 and PCT/EP2009/008968 (w) S1P dissociating enzyme (liase) inhibitor, such as LX2931; (X) Syk inhibitor, such as R-112; (y) PKC inhibitor, such as NVP-AEB071; (z) M3 antagonist, such as tiotropium (ti〇tr〇pium) or adidium (aclidinium); (aa) long-acting beta-adrenergic stimulating effect 197 201130839 Qi J such as 々, salmeterol, formoterol or Indacaterol; (bb) Vitamin D derivatives such as calciP〇tri〇l (Daivonex); (cc) phosphodiacetase 1V inhibitors such as roflule (Roflumilast or GRC-4039; (dd) p38 inhibitors such as ARRY-797; (ee) ARRY-438162; (ff) ΡΙ3Κδγ inhibitor; (gg) interferon β la, such as from Βί〇_ IdeC Avonex, CinnoVex from CinnaGen, and Rebif from EMDSerono; and interferon Plb' such as Betafer〇n from Schering and from Berlex Betaceron. More preferably, the other active substance is selected from the group consisting of: (b) j) HODH inhibitors, such as leflunomide, teriflunomide or international patent application No. WO2008/077639 and WO20091696 (c) an immunomodulator such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod; Anti-α4 integrin antibodies, such as Natalizumab (Tysabri); (1) α4 integrin antagonists, such as R-1295, TBC-4746, CDP-323, ELND-002, Filatgrast or TMC-2003; (g) cortic〇id and glucocorticoid, such as prednis (me) or methylprednisolone, penticosone (f|uticasone), Mometasone or beta-metasone; (h) anti-butyric acid vinegar 'such as 5G-/2; (i) anti-TNF alpha antibody, such as English 198 201130839 risuximab (Infliximab), Adalimumab or certolizumab (Certolizumab pe Gol); (j) soluble TNFα receptor, such as etanercept; (k) anti-CD20 monoclonal antibody, such as rituximab (Rituximab), okrezumab (〇crelizumab), Ortamuumab or TRU-015; (η) anti-CD88, such as eculizumab or pexilizumab; (〇) anti-IL12R/IL23R, such as Eudragit (ustekinumab); (p) Calcineurin inhibitors such as cyclosporine A or tacrolimus; (q) IMPDH inhibitors, such as mycophenolic acid? Mycophenolate mophetyl; (steroidal cannabinoid receptor agonist, such as santix (Sativex); (s) chemokine CCR1 antagonist, such as MLN-3897 or PS-031291; (1) chemokine CCR2 antagonists, such as INCB-8696; (u) NF-κΒ activation inhibitors, such as MLN-0415; (v) S1P receptor agonists, such as fingolimod (flng〇lim〇d), BAF-312 , ACT 128800 or the compounds described in International Patent Application No. PCT/EP2009/007348 and PCT/EP2009/008968; (w) S1P dissociation (liase) inhibitors, such as LX2931; (X) Syk inhibitors, such as R-112; (y) PKC inhibitors, such as NVP-AEB071; (z) M3 antagonists such as tiotropium (ti〇tlOpium) or Aclidinium; (as) long-acting beta-adrenergic agonist, such as salmeterol, formoter〇1 or indacaterol; a vitamin D derivative, such as calcipotriol (Davonex); (cc) acid II 199 201130839 chymase IV inhibitors such as roflumilast or GRC-4039; P38 inhibitors, such as ARRY_797; (ff) ΡΙ3Κδγ inhibitors; interferon P la' such as Afoona from Biogen Idee ( ) CinnoVex from CinnaGen and Libby from EMD Serono ( Rebif); and interferon p lb, such as Betaferon from Schering and Betaseron from Berlex. Specific examples of corticosteroids and glucocorticoids which may be combined with the JAK inhibitors of the invention are predniS〇l〇ne, sputum nylon, dexamethasone, dexamethasone cipecilate, Qin Feikete. (najQ〇c〇rt), defjazacort, halopedone acetate, budesonide, beclomethasone dipropionate, hydrocortisone , triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitate Dexamethasone palmitoate ), tipredane, hydrocortisone aceponate, prednicarbate, alclometasoi'ie dipropionate, halometasone, · Continued gypsum nylon (methylprednisolone suleptanate), mometasone furoate (mometasone fur) Oate), rimexolone, prednisolone farnesylate, ciclesonide 200 201130839 (ciclesonide), butixocort propionate, RPR-106541, propionic acid Deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, butyrate propionate Betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, Betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate And hydrocortisone probutate ° can be combined with the present invention Specific examples of suitable Syk kinase inhibitors for J AK inhibitor combinations are fosfamatinib (from Rigel), ruler-348 (from 1^4), 1^_343 (from 1^61), 11- 112 (from Rigel), paclitaxel (?丨(^ station grab 11〇1), 2-(2-aminoethylamino)-4-[3-(trifluoromethyl)anilino]pyrimidine-5-carboxamide, R-091 (from 1 ^61),6-[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-one- 2H-σ ratio bite [3,2-b][1,4] π aceton-3-ketophthalate (R-406' from Rigel),! #,&quot;-Trihydroxyphenyl)-2-(4-decyloxyphenyl)ethan-1-one, N-[4-[6-(cyclobutylamino)-9H-indol-2-yl Amino]phenyl]-N-methylacetamide (QAB-205 from Novartis), 2-[7-(3,4-dimethoxy 201 201130839 phenyl)-salt [1,2- c] squirting j-based amino group p than biting _3_methyl-dihydrochloride (BAY-61-3606 'from Bayer) and AVE_〇950 (from Sanofl-Aventis) ° can be compared with the suppressing side of the present invention Specific examples of suitable M3 antagonists (anti-cholinergic agents) for combination are tiotropium 〇i〇tr〇pium) salts, oxitropium salts, mutotox (tetra) salts, and isopropyl Ipratropium salt, giyc〇pyrr〇nium salt, tr〇Spium salt, revatropate, jastolamine (js^atn) Pate), 3- [2-hydroxy-2- 2 only (2_thienyl)ethyloxy] small (3-phenoxypropyl)-1-nitrogenbicyclo[222]octane salt (especially aclidinium salt) More preferably, adiidium bromide, 1-(2-phenylethyl)-3-(9H--9-ylcarbonyloxy)-1·azepinebicyclo[2·2.2]octane salt , 2-sided oxy-1,2,3,4-tetrahydro hydrazine _3_A Nalodiyl azabicyclo[3.2.1]oct-3-yl ester (DAU-5884), 3-(4-benzylpiperidin-1-yl)-1-cyclobutyl-1-hydroxyl -1-phenylpropan-2-one (NPC_14695), N-[l-(6-aminopyrene-But-2-ylmethyl) brigade ·4_yl]_2(R)_[3,3 -dioxane _1(8)-cyclopentyl]-2-hydroxy-2-phenylethylamine (J-104135), 2(8)-cyclopentyl-2-hydroxy-N-[1-[4(S)-己 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基-4-Big bite base]-2-phenylethylamine (J-104129), 1-[4-(2-aminoethyl) TB-1-yl]-2(R)-[3f3- Dioxocyclopentanyl-l(R)-yl]_2-pyridyl-2-phenylidene-1-one (Banyu-280634), Ν_[Ν-[2-[Ν-[1-(cyclohexylmethyl) Piperidine-3(R)-ylmethyl]aminoindenyl]ethyl]amine-mercaptopurinyl]_3 3,3_triphenylpropanamide (Banyu CPTP), 2(R)-ring Amyl-2-hydroxy-2-phenylacetate 202 201130839 M3-azabicyclo[Uo]hexyl-3-yl)_2_butyne vinegar (Ranbaxy 364057), UCB-101333, Merck's 0rM3, 7- -(2-hydroxy-2,2-diphenylethenyloxy)_9,9-diindenyloxa-9-nitrogen tricyclo[3.3.1.0(2,4)]decane Salt, 7-(2,2-diphenylpropanyloxy)_7,9,9-trimethyloxa-9-nitrogen tricyclic guanidine 3.1.0*2,4*]decane salt , 7-Hydroxy-7,9,9-dimethyl-3-oxa-9-azinium tricyclo[3 3 j 〇*2,4*]decane 9_methyl_9Η -9-A The acid ester salts, all of which are in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and, where appropriate, their pharmacologically compatible acid addition salts. form. Among the salts, vapor, bromine, iodide and methanesulfonate are preferred. A specific example of a long-acting ρ-adrenergic agonist (β2-agonist) which can be combined with the JAK inhibitor of the present invention is terbutaline sulphate or fumarate 〇〇rm〇ter〇1 fumarate, fumarate fumarate, bambuterol, procaterol hydrochloride (pr〇cater) Hydrochloride1 hydrochloride ), sibenadet hydr〇chi〇ride, mabuterol hydrochloride, albuterol sulphate, salbutamol sulphate, salmeterol sulmeterol Xinafoate ), carmoterol hydrochloride, (R)-albuterol hydrochloride, Levalbuterol hydrochloride/Levosalbutamol hydrochloride, hydrochloric acid (-)-salbutamol ((1)_Salbutamol hydrochloride), Tartaric acid (R,R)-formoterol ((jgR^pormoterol 203 201130839 tartrate ), formoterol tartrat (Arform〇ter〇i tartrat) e), Bedordrine sulphate, indacaterol, Trantinterol hydrochloride, AZD-3199, GSK-159802, GSK-5979 (H, GSK-678007, GSK-642444, GSK) -961081, AR-C98955AA, Milveterol hydrochloride, BI-1744-CL, and International Patent Application No. WO2007/124898, WO2006/122788A1, WO2008/046598, and WO2008095720 A specific example of a suitable acid-breaking diesterase inhibitor which can be combined with a JAK inhibitor of the present invention is benafentrine dimaleate, etazolate, Denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tyros Tipelukast, tofimilast, piciamilast, tolafentrine, mesopram, drotaverine hydrochloride, larry Liri Milast ), roflumilast, cilomilast, 〇giemiiast, apremilast, tetomilast, non-Minist, (R)- (+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)_2_phenethyl]n ratio bite (CDP-840), N-(3,5-J chloride- 4 "pyridyl"_2-[1·(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoethoxyacetamide (GSK-842470), 9- (2-fluorophenylindenyl)-N6-mercapto-2-(trifluoromethyl)adenine (NCS-613), N-(3,5-dichloro-4-° ratio) 1.8- Methoxy 啥琳_5_ 曱 胺 (D-4418), 204 201130839 3-[3-(cyclopentyloxy)-4-methoxybenzyl]]6-(ethylamino)-8 -isopropyl-3H-indole hydrochloride (V-11294A), 6-[3-(N,N-dimethylaminecarbamyl)phenylphenyl] sylylene (3-methoxyanilinyl) )_8_methylquinoline each meglumine hydrochloride (GSK-256066), 4-[6,7-diethoxy-2,3-bis(methyl)naphthalen-1-yl]-1 -(2-methoxyethyl). Bipyridine 02(1H)-ketone (τ_44〇), (a)_trans_2-[3'-[3-(Ν-cyclopropylaminoindolyl)_4_sideoxy_ι,4_dihydrogen ·1,8·pyridin-1-yl]_3_fluorobiphenyl-4·yl]cyclopropanecarboxylic acid (MK-〇873), CDC-801, UK_5G()001, BLX-914, 2-oxime oxycarbonyl _ 4-cyano-4(3-cyclopropanomethoxy-4-difluorodecyloxyphenyl)cyclohexanone, cis[4-cyano-4_(3_cyclopropylmethoxybutane) Methoxyphenyl)cyclohexan-1-ol, GRC_4039, CDC-8 (U, 5(SM3-(cyclopentyloxy)-4-methoxyphenyl]_3(s)-(3-indenyl) Benzyl) piperidin-2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22 (Supp. 45): Abst 2557) and International Patent Application No. W003/097613, No. WO2004/058729 a salt as claimed in WO 2005/049581, WO 2005/123693, and WO 2005/23692. An example of a suitable ρΐ3Κδγ inhibitor which can be combined with the JAK inhibitor of the present invention is 2-methyl-2- [4-[3-Methyl-2-oxo-8-(3-quinolinyl)-2,3-dihydro-1H-flavored salido[4,5-c]porphyrin-1_yl Phenyl]propionitrile (BEZ-235 from Novartis), CAL-101 (from Calistoga Pharmaceuticals), and N-ethyl scratch [3-(3,4,5) -Trimethoxyaminoamine carbazino[2,3-b]indol-6-yl]thiourea (AEZS-126 'from AeternaZentaris). The compounds of formula (I) and combinations thereof described herein are useful in therapy Spinal cord proliferative disorders, leukemia, lymphoid malignancies, and solid tumors; bone marrow to 205 201130839 and organ transplant rejection; and the use of immunosuppressive diseases with 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 (CODD), atopic dermatitis and Psoriasis. The compounds of the formula (1) and combinations thereof described herein can also be used for the treatment of inflammatory diseases. Ο 、 In the sputum, the compounds of the formula (1) and combinations described herein can be used to treat T-proliferative disorders, leukemias, lymphoid malignancies. And the entity = 杳 is in this state, the silk (4) is realized by the Janus stimulation of the inhibition surface. In another aspect, the compound of the formula (1) and the group mouth described herein can be used for treatment. Bone marrow and organ transplant rejection; immune-mediated diseases such as osteophytes and organ transplant rejection and sputum-related diseases such as bone and organ transplant rejection. The treatment of these diseases and conditions is usually achieved by inhibiting the individual's Gena. The compounds of formula (1) and the compositions described herein are useful for inhibiting the Janus kinase (JAK). The active compound of the disc can be administered in the same composition as the same or (iv) pathway, simultaneously, concomitantly or sequentially. A T all active ship _ or the day of the butterfly is extremely eager to heal. Or t-t two active agents can be taken in the afternoon and other active agents in one day. Or in another embodiment - or two active agents may be taken every 3: two: = the active agent is taken once per ounce, which is carried out simultaneously with the -: person in each of the pleasures, or separately. Preferably 206 201130839 All active agents will be taken at the same time. More than #5小ία will be administered as a mixture.胄 胄 and more preferably all active agents, the present invention also a group of compounds described herein and/or a plurality of other therapeutic agents a... for use in the treatment of nanoenzymes (JAK) for the improvement of pathological conditions or diseases, in particular I := The pathological condition or disease is selected from the disease of the spine hyperplasia and the solid tumor; the bone metastasis = disease, lymphoid malignant disease _ sexual second disease, lymphoid malignant disease and sputum, r · White blood reactions to the condition; and immune-mediated diseases. J special mouth 2 and organ 2 plant rejection disease is selected from rheumatoid arthritis, pathological conditions or dry eye, uveitis, allergic disease, inflammatory bowel disease, :=_), Atopic dermatitis to: Ϊ: In the - state, the combination of products can be used for treatment = disease, leukemia, lymphatic malignant disease and "the treatment of the disease is the use of age-old repentance #激" &amp;Middle's sample, the combination product can be used for household itch = _ _ to achieve. In another state of immune-mediated disease and hair transplant rejection; rejection; and immune-mediated: and organ transplant rejection Responsive diseases such as bone marrow and organ transplantation s-kinase = ^ usual # is achieved by _ individual Gena (JAK) 、), and the product can be used to inhibit the Janus kinase. The invention also encompasses the compounds of the invention and Or a variety of other treatments 207 201130839 The use of a combination of these diseases or a combination of agents for the manufacture of a therapeutic agent. Q to provide a treatment for inhibition of the Janus kinase (JAK) Or a method of disease, in particular, wherein the disease is Diseases are selected from hyperplasia, leukemia, lymphatic (4) money 11 official transplant dissatisfaction; immune II, /, disease and inflammatory diseases, such as spinal proliferative disorders, white blood 1 , .. malignant disease and physical shop; bone _ and 11 official transplant rejection Two: and immune-mediated diseases. More specifically, the pathological condition or hyperthyroidism is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, eye, uveitis, allergic conjunctivitis, allergic rhinitis _, ectopic Sexual dermatitis is a method comprising administering a therapeutically effective amount of a compound described herein in combination with one or more other therapeutic agents. In particular, the filament is achieved by inhibiting the Janus kinase of the individual. The invention also provides a method of inhibiting a Janus kinase in an individual in need thereof, comprising administering to the individual an individual in need of the treatment! A combination of a compound described herein and one or more other therapeutic agents. Depending on the nature of the condition to be treated, the active compound of the combination of the invention may be administered by any suitable route, for example, orally (in syrups, elixirs, capsules, buccal bonds, controlled release formulations, Rapidly dissolving the preparation, etc.); topical (in the form of a cream, ointment, lotion, nasal spray or aerosol) · by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by 208 201130839 Inhalation (in the form of dry powder, solution, dispersion, etc.). The active compound in the combination (i.e., the pyrazole derivative of the present invention) and other optionally active compounds may be co-administered in the same-f pharmaceutical composition or intended to be used in the same or different routes. The sequential dose is administered in a different composition. The invention of the present invention consists of a kit of parts, which includes the derivative of the present invention and the synchronization of Chen and another activation contract, which are used in combination or in sequence. In the specification, the active compound depends on treatment (4) hypertrophic charm, leukemia, lymphoid malignant disease = and solid tumor; face and device (4) _ differential; immune-mediated and inflammatory diseases, such as lysing proliferative disorders, leukemia , 雍巴心isheng f disease and solid tumors; bone marrow and organ transplant rejection of γ-related diseases, and more specifically 'applicable to treatment class === sclerosis, inflammatory bowel disease, dry eye, grapes Inflammation, neonatal rhinitis, asthma, chronic obstructive pulmonary disease (C〇PD), atopic dermatitis, and psoriasis. Further, the embodiment consists of a package comprising, for example, a compound suitable for treating a spinal cord hyperplasia, said active compound and entity _, a blood-borne disease, a lymphoid malignant disease, and a state Official transplant rejection; immune-mediated diseases such as ridge-proliferative disorders, autologous blood disorders, lymphoid malignancies, and solid tumors. Cups and immune-mediated diseases, official transplant rejection; arthritis, multiple Harder, more general, for the treatment of rheumatoid arthritis, inflammatory bowel disease, dry eye, uveitis, 209 201130839 asthma, chronic obstructive pulmonary disease skin sputum. Allergic conjunctivitis, allergic rhinitis, (COPD), ectopic dermatitis, and bovine pharmaceutical compositions The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable diluent or _. Inventive Compounds and Medicines Further Provided by the Invention Acceptable diluent or carrier _ and 4 days of m compound and medical pathology of good disease or: wrong touch to change = r disease or disease 4 drugs == (two) jin said pathological conditions or The disease is selected from, lymphoid malignant diseases such as (4) _; 'white 1' mediated diseases and inflammatory diseases such as: 2: transplant rejection; and immunization: c tumor; bone marrow and organ pathology in the organ 4 Sexual disease 'and more specifically' its sclerosis, dysentery t is selected from rheumatoid arthritis, multiple f. The present invention also encompasses the pharmaceutical composition of the present invention for use in 4 for oral therapy Use of a medicament for disease. In the L sample, the pharmaceutical composition can be used for the treatment of a spinal proliferative disorder, leukemia, lymphoid malignant disease, and a physical axis. In this aspect, the treatment is to suppress Jian Zhijie by Φ __ to achieve. In another state 210 201130839 sample 'medicine composition can secrete bone marrow and should; immune-mediated diseases and hair disease, such as transplant rejection; and immune-mediated transplant rejection Μ for example (4) and organs such diseases as well The treatment of the form is usually achieved by the use of a drug. The pharmaceutical composition can be used to inhibit Gener's two treatments by inhibiting the pathology of Jayneskin (jak): the pathology or disease, in detail, The disease or disease in Lizhong is selected from the group consisting of spinal proliferative disorders, leukemia, and solid tumors; bone marrow and organ transplant rejection: disease, === inflammatory disease, such as spinal proliferative disorder, white blood I = == and solid tumors; bones and organs transplant rejection of the disease ^. Guided disease 'and more specifically 'the disease is inflammation: from rheumatoid arthritis, multiple sclerosis, inflammation, snarl a heart, uveitis, allergic conjunctivitis, allergic nasal skin == lung disease (c〇pD), atopic dermatitis and pharmaceutical composition details „Taiwan treatment effective amount of the enzyme enzyme as defined in this article achieve. Peach, / σ ^ by the inhibition of the individual's Gena's prescription - the inhibition of the needy individual's Genus kinase therapy effective Jin Eryi (four) face (four) face-to-face treatment of individual treatment A pharmaceutical composition as defined. The test month also provides a pharmaceutical composition which comprises at least formula (1) 吼唆 211 Ο Ο 201130839 ii 'pharmaceutically acceptable salt as a component and a medically acceptable 2 excipients (such as residual or diluent) The active ingredient may comprise from 0.0G1% to 99% by weight, preferably (4)% by weight to 9〇f' of the substance, and whether it is further diluted before application. The composition of the composition is preferably suitable for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration. The remainder of the compound with the active compound forms the pharmaceutical form of the present invention. The acceptable excipients are themselves well known and the excipients actually used will depend on the method of administration of the composition. The compositions for oral administration may be in the form of lozenges, delayed-type squeezing agents, lingual IS. a compound in the form of an inhaled aerosol, an inhaled solution, a dry powder inhaler = body weight (such as a mixture, a syrup or a fresh liquid); the formulation can be used to prepare a dilution of the composition by the technique The agent comprises a sword compatible with the active ingredient. If necessary, the coloring agent or flavoring capsule should preferably contain _1_3 〇〇〇 mg, more preferably 〇5 gram active knives or an equivalent amount of the pharmaceutically acceptable salt thereof. The liquid composition in a palatable form can be The reading of the solution or suspension may be the dissolution of the active compound with, for example, a solvent associated with _ _, the insoluble active compound or its "study together with the suspending agent or flavoring agent associated with water. ^ Parenteral compositions can be prepared from soluble salts, which may be 212 201130839 or may be undried and soluble in parenteral injection fluids. ", 1, w or other suitable combination for local administration. The formula can be used in any form, and all forms include a compound of the square wire which is well known in the art of the formula or the lotion; the _ can be used as the effective agent, usually in the range of 1 mg per 曰_ Activity or equivalent · H = G.5, 1000: r can be used in a single dosage form, and can be used in the form of a pharmaceutical composition suitable for oral administration. Objects, individual, early, such as glue The capsule, sachet (caehet) has a predetermined amount of m8} 5 ^ 0 feed impurities; powder or age; solution or liquid in water = liquid; or oil-in-water liquid emulsion Or an oil liquid ritual. The active ingredient may also be in the form of a bolus,:: (electuary) or paste. y syrup syrup formulation will generally consist of a compound or a salt in a liquid carrier containing a toner (eg Ethanol, peanut oil, eucalyptus oil or a suspension or solution thereof. / or water) When the composition is in the form of a tablet, any pharmaceutical carrier which is usually used in the formulation may be used. Examples of the carrier include Stearin = body talc, gelatin, acada, stearic acid deer and sucrose. The sugar can be processed by 213 201130839, which can be compressed or arrogant by means of the situation and - or more. (d) (iv) may be prepared by the use of an active ingredient in a suitable machine in the form of a viscous agent, a lubricant, an inert diluent, a lubricant, a surfactant or a free-flowing form such as a powder or granule. =_ can be obtained by molding a liquid-like compound (tetra) compound in a suitable machine. The tablet may optionally be D-coat or closed and may be provided to provide a slow or controlled release of the active ingredient of the towel. When the field, and the composition is in the form of a capsule, any conventional encapsulation is suitable, such as the use of the above fine in the turn of the hard division. #组合物为软明f二C, consider any medical music commonly used in the preparation of dispersions or suspensions, such as aqueGUS gum, fiber sulphate or oils and soften them together Gelatin capsule towel. ' = a dry powder composition that is delivered locally to the lungs by inhalation can be, for example, a cold-cold capsule and an eartridge or a bllster, such as a laminated box, for use in an inhaler The compound of the present invention and the powder base (carrier substance) are preferably used as the final product. It is difficult to use lactose. Or the cartridge can generally contain between 2 micrograms and 15 micrograms. Sexual ingredients. Alternatively, the active ingredient can be provided in the absence of the agent. And the formulation may be packaged by the use of a suitable inhaler, which is described in the following special case (10) She 8 214 201130839 (formerly known as Novolizer 9 SD2FL): WO 97/000703, 03/000325 and WO 2006/008207. A typical composition for nasal delivery comprises the above-described composition for inhalation and further comprises a non-pressurized composition in the form of a solution or suspension in an inert vehicle such as water, as appropriate and conventionally shaped Agents such as buffers, antimicrobials, tonicity modifiers, and viscosity modifiers are combined and can be administered by nasal pump. '' Typical skin and transdermal formulations include conventional aqueous or non-aqueous A vehicle, such as a cream, ointment, lotion or paste, or in the form of a medicated plaster patch or film. 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 be dictated by the particular active agent, the route of administration, the face to be treated, and the condition or condition being treated. The following formulation forms are cited as examples of formulations: Composition Example 1 According to the following formulation, 50,000 samples each containing 100 mg of good (1_ phenethyl)-2-» are compared with "sit and [ι,5 bispyrazine·3_ Keing bite _4_amine (active membrane 賫: j tongue component &gt; hydration ΐΰί7 i mdian - 5 kg - 10 kg -. - 0.1 kg - - - 1 kg 0.2 kg 215 201130839 procedure via 60 sieve The sieve was filled into the above-mentioned compounder to 5 〇, _ _ =1; and loaded to the appropriate mixed composition Example 2 was prepared from the following formula 50 各 each thanks [1, 5 things. 3. Her Phase = ^; = base · 2 - sprayed carboxymethyl temple t stearin Microcrystalline Cellulose \ 2~~--- Procedure Ο All powders were mixed through a mixer with a pore size of 0.6 mm for 20 minutes and compressed to 300 mg tablets using a 9 mm bevelled punch. Stamping Composition Example 3 5 - each containing 5 () mg of (8) ethyl)-2 oxazole and [l,5_a]n than 嗓_3_ylpyrimidine _4_amine (active ingredient present) Doubt: The activity of Knife J is _ Micro-day cellulose ^ A /| Q Qc , \ ^ — Spray-dried lactose - kg 216 201130839 Carboxymethyl starch hard fat ruminant tri-acid ^ Colloidal state Semen dioxide Procedure All powders were mixed through a mixer having a pore size of 06 mils for 20 minutes and using a 9 mm disk = then followed by a suitable bonding agent. Modifications of the compound, combination or pharmaceutical composition at the time of disintegration of the tablet are within the scope of the present invention. [Simple description of the diagram] No [Main component symbol description] No 217 201130839 VII. Patent application scope: 1 ', a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof or N-telluride or Stereoisomer or deuterated derivative, -R7)m Z where m is 〇 or an integer from 1 to 3; Ζ represents an oxygen atom or a group NR5; W represents a nitrogen atom or a _cr3 group; X group X, Y and T independently represent a nitrogen atom or a _CR9 group, and 1 X 1 T represents a nitrogen atom, and the rest Both represent _CR9 base atoms: 1 cyanide XRL, R4 and ~ each independently represent a hydrogen atom; a south block; a C chain CrQ wire; a trend: a ring from a ring; a single ring, "C4 ship base, C3_ClG ring a base; C3-C10 S and a hetero-f&amp;C, Cl4 aryl group; a 5- to MS heteroaryl group containing at least one hetero atom selected from ruthenium; containing at least one selected 218 201130839 from 〇, s, and N a heterologous c5-c9 aryl or a heteropolysaccharide; a monocyclic bicyclic group; a heterocyclic ring containing a monocyclic bicyclic group; and a heterocyclic group of 5 to 9 members; Miscellaneous: ί or heterocyclyl contains at least one selected from fluorene, s, and up to 12, aza-bicyclic alkyl having 12 carbon atoms to the town, or 12, one carbon atom Aza, bicyclol, sulphate, sulphate, sulphate, sulphate, sulphonyl, cycloalkyl, cyclo and (tetra), heterocyclyl, bicyclo, aza Suppressing that I % is unsubstituted or substituted with one or more + 1 selected from the group consisting of substituents Ra, and the alkyl group is unsubstituted or substituted with one or more substituents selected from Rb; or R 〖, I, I, I and ruler 9 independently represent _SU group, _s(10) η bis group, S(〇) 2Rl3 group, _S(0)2NR13R14 group, _nr13s(o)2r14 bis group, -nr13s(0) 2NRi4 group, _(CH2)n〇Ri3 group, _c(〇)〇Ri3 group, -〇-C(〇)r13 group, _c(〇MCH2)n_R]3 group, _NRi3Ri4 earth group, - C(〇)-(CH2)n-NR13R14 group, -NR13C(〇)-(CH2)n-R14 圏, -NR13C(〇)-(CH2)n-NR14R15 group, wherein each n is 〇, i or 2; or in the presence of two adjacent -CR9 groups, two adjacent _cr9 groups and their bonded carbon atoms optionally form a CrC12 aryl group or a 4 to 12 membered heteroaryl group, a cycloalkyl or heterocyclic group, the heteroaryl group and the heterocyclic group containing at least one hetero atom selected from the group consisting of hydrazine, S and N, the aryl group, the heteroaryl group, the cycloalkyl group and the heterocyclic group being unsubstituted Or via one or more selected from the dentate atom 'linear or branched crc6 alkyl, monocyclic or polycyclic C5_C14 aryl, Substituent substitution of 5 to 14 member heteroaryl 219 201130839 having at least one hetero atom selected from 0, S and N, or a substituent having 5 to 14 membered heterocyclic groups containing at least one hetero atom selected from the group consisting of ruthenium, S and N Wherein said alkyl group, said aryl group, said heteroaryl group and said heterocyclic group substituent are unsubstituted or one or more selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a straight chain or a branched chain^ —Substituted by a substituent of a decyl group or a Ci_c4 haloalkyl group, I represents a hydrogen atom, a linear or branched CVQ alkyl group, optionally, one or more selected from the group consisting of a hydroxyl group, a cyano group, a Cl_C4 haloalkyl group, a hydrazine hydroxyalkyl group, a C3-C1G cycloalkyl group, a phenyl group or The 6-membered saturated substituent containing a heterocyclic ring substituted with ' or Rs represents a -S(〇)2R10 group, a _s(0)2NRi〇Ru group, a -C(〇)OR10 group, _c(〇&gt (CH2)n_Ri〇 group•C^OHCH^NRioRn group; & and R7 each independently represent a hydrogen atom or a straight or branched bond, and optionally, or a plurality of selected from cyano , CK: 4 ^ shape, crc4 ship base, Cl_C4 aerobic wire, CH: 7 Wei group, phenyl group substituted with a substituent containing a N heterocyclic ring; R8 represents a hydrogen atom; a halogen atom; a cyano group; a chain or a subunit; a acetylene group; a Cl-heart heteroaryl; containing at least one heterocyclic group selected from the group consisting of hydrazine, s"" 14 to 14 members; containing a monocyclic (tetra) aryl group or 5 5 to a bicyclic group of a 5-membered cycloalkyl or heterocyclic group, which is directly bonded to a nitrogen-containing bicyclic group having at least one carbon atom selected from the group consisting of hydrazine, S, and a heteroaryl or heterocyclic group. At most '=2-220 201130839 bicycloalkenyl, of which Alkenyl, alkynyl, dentyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, bicyclo, aza-bicycloalkyl, and aza-bicycloalkenyl Substituting 'where R' and R'1 are unsubstituted or substituted by one or more substituents selected from the group consisting of Ra, alkyl)-CN or -(CrC4 alkyl)-C(0)NR'R&quot; The same or different and selected from the group consisting of a mouse atom and a straight or branched chain CrC4 alkyl; and the alkyl group is unsubstituted or substituted with one or more substituents selected from Rb; or Rs represents a -SR 3 group, -SORn group, -S(〇)2R13 group, -s(o)2nr13r14 group, -NR13S(0)2R14 group 圑, -NR13S(〇)2NR14 group, -(CH2)n〇R13 group , -C(0)0R13 group, -〇-C(〇)R13 group, -C(〇HCH2)n-R13 group, -NR13R14 group, -C(0)-(CH2)n-NR13R14 a group, a -NR13C(0)-(CH2)n-R14 group or a -NR13C(0)-(CH2)n-NR14R15 group, wherein each η is 〇, 1 or 2, or Rs together with &amp; and R5 The bonded nitrogen atoms together form a 4 to 10 membered saturated heterocyclic group containing one or two nitrogen atoms as a hetero atom and which is linear or branched QQ alkyl, monocyclic or a polycyclic C5_Ci4 aryl group having 5 to 14 membered heteroaryl groups containing at least one hetero atom selected from 0, S and N, and a 5 to 14 membered heterocyclic group containing at least one hetero atom selected from the group consisting of ruthenium, S and N, a -so2r10 group, a _c(〇MCH2)n_Ri() group or a -QOMCPyn-NRHjRn base ring, wherein each ^ is ο]*, wherein the alkyl group, the aryl group, the heteroaryl group, and the heterocyclic group are not Substituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain Ci_c6 alkyl group, or a CrC4 minus group, and the substituted group of the alkyl group 221 201130839 is substituted or One or more substituents selected from a halogen atom, a hydroxyl group, a cyano group or a Ci_c4 halogen group; the limitation is that when m is 〇, R8 is not an SR3 group, a _SORl3 group, or -S(0) 2R13 group, _s(〇)2NRi3Ri4 group, _NRi3S(〇)2Ri4 group, -NR13S(0)2NR14 group, _(CH2)nOR13 group, -0-C(0)R13 group, _NR13R14 group a group, a _NRi3C(:〇)_(CH2)n_Ri4 group or a _NR13C(0)-(CH2)n-NR14R15 group, wherein 〇Ra is a halogen atom; a cyano group; a hydroxyl group; a straight chain or a branched chain (^( ^Alkyl;CrC4 haloalkyl ;crC4 alkoxy;crC4 hydroxyalkyl; C3-C7 cycloalkyl or Q-C7 cycloalkenyl, unsubstituted or substituted with one or more substituents selected from substituent Re; monocyclic or polycyclic a C5_Ci4 aryl group which is unsubstituted or substituted with one or more substituents selected from the substituents Re; a 5- to 14-membered heteroaryl group containing at least one hetero atom selected from 0, S and N, which is unsubstituted Or substituted with a substituent selected from the substituent Re; a 5- to 14-membered heterocyclic group containing at least one hetero atom selected from o, s, and K, wherein the unsubstituted H is selected from a substituent Substituents for Re; _SRl0 group; _SORl fluorenyl®; Nacene group; -S(9)2NR1〇Rll base; pendulum 1〇s(0)2Ri1 group; -nr10s(o)2nr„ group; (CH2)nOR10 group; -C(〇)〇Ri〇 group; _〇-C(〇)Ri〇 group; -c(o)-(ch2vr10 group; 1 as group &lt; -C (O)-(CH2)n-NR10Rn; -NRl〇C(〇).(CH2)n.Rii Ma 0C(〇)f post is regarded as a 2 group, wherein each η is 0, i or 2; Rb is Cyano·' Cl-C4 halide; crc4, alkoxy; crc4, burned 222 201130839; CVC7 cycloalkyl or oxime: 7 cycloalkenyl, one of its choices Substituted from a substituent of a substituent Re; a monocyclic ring or a ring; a plurality of unsubstituted or fluorene-selected ones selected from the group consisting of substituents, ': have =- selected from 0, S, and N Miscellaneous: dif 1 at least one selected from the hetero atom of hydrazine, s, and N, 5 to yl = beheterocyclyl, unsubstituted or substituted by one or more selected from Substituent substitution; -SR10 group; withdrawal of 1 〇 group; _s(〇)2Ri〇 group. -S(O)2NR10Rn^® ; ; -NRl〇S(〇)2NRi group b (CH2)n〇 Rl. Group; _c(〇)〇Ri. Group; _〇_ 美团; -c(〇MCH2)n_Rl0 group '·娜〇Rn group ^ -C(〇HCH2)n-NR1〇Rll group; _NRi〇c(9)仰2)^^&quot; a group or a -NR10C(Q)-(CH2)n_NRllRl2 group, wherein each n is Qi or 2; rig, Rii and each independently represent a hydrogen atom, a cyano group, a straight or branched chain CrC6 alkyl group, a Crc4 halide Alkyl, Ci_c4 hydroxyalkyl, Ci-q alkoxycarbonyl, C3-C7 cycloalkyl, phenyl, 5- to 6-member singles containing 1, 2 or 3 heteroatoms selected from N, 4 〇 = and S a cycloheteroaryl group having 5 to 6 membered heterocyclic groups of 1, 2 or 3 nitrogen atoms, containing a monocyclic aryl or heteroaryl group, directly bonded to a bicyclic group of 5 to 6 membered cycloalkyl or heterocyclic groups The heteroaryl or heterocyclic group contains 1, 2 or 3 nitrogen atoms, the sulfhydryl group, the hydroxyalkyl group, the alkoxycarbonyl group, the cycloalkyl group, the phenyl group, the heteroaryl group, the heterocyclic group and the bicyclic group. Substituted or substituted with one or more substituents selected from the substituent Rc, and the leuco group is unsubstituted or substituted with one or more substituents selected from the substituent Rd; 223 201130839 Rc is a halogen atom, Light-based, cyano' linear or branched chain crC6 alkyl, Crc4 , CrC4 alkoxy 'Ci-C4 via alkyl 'C3_C7 cycloalkyl, phenyl, 5 to 6 membered monocyclic heteroaryl containing 1, 2 or 3 nitrogen atoms, containing 1, 2 or 3 nitrogen atoms a 5- to 6-membered heterocyclic group or a c3-C7 heterocyclic ketone ketone group having 1, 2 or 3 nitrogen atoms, wherein the phenyl group is unsubstituted or substituted with one or more halogen atoms, and Heteroaryl, heterocyclyl and heterocycloalkyl ketone groups are unsubstituted or substituted by one or more linear or branched CrC3 alkyl groups; Rd is a chaotic group, C!-C4 haloalkyl 'C1-C4 burned Oxy 'C1-C4 light alkyl' C3_c7 cycloalkyl, stupid, 5 to 6 membered monocyclic heteroaryl containing 1, 2 or 3 nitrogen atoms, containing 5, 2 or 3 nitrogen atoms to 5 a 6-membered heterocyclic group III or a C3-C7 heterocycloalkyl ketone group having 1, 2 or 3 nitrogen atoms which are unsubstituted or substituted by one or more functional atom atoms, and the heteroaryl a group, a heterocyclic group, and a heterocycloalkyl ketone group are unsubstituted or substituted by one or more linear or branched CrC3 alkyl groups; Re Re is a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain crc6 Alkane or C1-C4 _alkyl; or each of Rl4 and Rl5 The ground represents a hydrogen atom, a cyano group, a linear burnt: i: CrC6 alkyl, Cl-C4 haloalkyl, Cl-C4 hydroxyalkyl, C1_C4 at least - 13 s; a polycyclic Cs-C!4 aryl group containing 5 to 14 membered heteroaryl groups to the hetero atom of oxime VS and N, a ring group, and a hetero atom selected from the group consisting of 〇, S and N. To a 14-membered hetero-organic group, a heterofluorenyl group substituted with a ^=^alkyl group, a calcined oxygen group, a cycloalkyl group, an aryl group, or substituted with one or more substituents selected from the substituent 224 201130839 Ra, and The alkyl group is optionally substituted with one or more substituents selected from ribs. The compounds are useful for treating pathological conditions or diseases which are readily ameliorated by inhibition of Janus kinase. 2. A compound according to claim 1 which is not a trans-5-cyano-[6-(4-hydroxycyclohexylamino)pyridine-2-yl]biszolo[1,5 -a]1^Bite, trans-5·cyano-3-[6-(4.hydroxycyclohexyl-methylaminobutyryl-2-yl)trans-5-cyano-3-[6-( N-ethyl-N-(4-hydroxycyclohexyl)amino)ηpyridin-2-yl]σ is more than salino[i,5-a]indole, 5-cyano-3_[6-(piperider Acridine_4_ylamino)pyridine-2-yl]pyrazole π ratio, 5-cyano-3-[6-(methyl(piperidin-4-yl)amino)pyridine_2-yl ]pyrazolo[l,5-a]°tb^ X 5-cyano·3-[6-(1-(2-cyanoethyl)pyridinyl-3-ylamino) bite, 2_ Pyrazolo[1,5-a]pyridine, W-5-cyano-3-[6-(1-(2-cyanoethyl)] 唆_3_ylamino)n 唆-2-yl]11 is more than [1,5-a]e than bite and W-5-cyano-3-[6-(7V-fluorenyl-1·(2-cyanoethyl) group Biting, arylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine, and salts of the above compounds; and 3-[6-(1-hydroxymethylcyclopentylamino)pyridinium Pyridin-2-yl]pyrazolo[l,5,a&gt;tb pyridine, 225 201130839 3_[6-(4_ 曱 曱 base mouth bite-1-base) σ than bite-2-yl]0 And [l,5-a]0 ratio Pyridine, 3-[6·(3·基基氯胺胺)ϋ 咬_2_基]σ ratio 13 sits and [l,5_a]ntba fixed, anti_3·[6-(4-light base壤 基 甲 甲 ) ) & & & 2- 2- 2- 2- σ σ σ [ [ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- Base) ^ bite-2-yl] ϋ ratio ° sitting and [l,5-a]u than bite, trans-3-[6-(4•aminohexylamine base than bite _-2-yl] ° is more than η and [1,5_a]° is more than pyridine, anti-3·[6-(4-pyridyl-hexylamino). It is more than sputum-based [1,5-a] Oral pyridine, 3-[6-(four-rat-4//_旅喃-4-ylamino)0 than bite_2-yl]11 than °[1,5,3&lt;] leaf 匕口Ding, 3-[6-(N-methylcyclohexylamine) is more than 嗤[1,5-ap than 唆, 3-[6_(3- via methyl enough) -1-yl) 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2-base] 吼σ sits and [1,5-a] ° is more than the mouth, 3·[6-(2,2,6,6-tetramethyl 唆·4·ylamino)° 唆· 2·基]0°°[[,5-a]11 is more than bite, 3_[6-(2·phenylpropan-2-amino)σ is more than bite_2_base]0°°[ l,5_a]ntb bite, (*S)-3-[6-(l-phenylethylamino)σ 唆-2-yl] Sit and [1,5·&amp;] ϋ bite, 3-[6-(1·phenylhydrazinyl)° than bite-2-yl]σ 唆 and [1,5-8]0 ratio °定, (iS)-3_[6_(l-dextylethylamine) than bit-2-yl]^ is more than [1,5-a]^ ratio 226 201130839 pyridine, (8)_3-[6-(l -decyloxypropan-2-ylamino)pyridin-2-yl]pyrazolo[l,5-a]n 〇, 3-[6-(methylamino)"pyridin-2-yl ] oxazolo[l,5-a]acridine, 3-[6-(anilino) σ than bit-2-yl]atbn sits and [1,5-a]ntbn, 3_[6_(π ratio σ定_3·基胺基)atba定-2_S]atba sits and [1,5-a]atb唆, 3-[6-(11 to 11-1,4-amino group) 11 to 11^_- 2-base]|〇 is more than 11 and [1,5-&amp;]'1 to 11, trans-3-[6-(4-aminocyclohexylamino)pyridin-2-yl]-5- Cyanopyrazolo[1,5-mad]0 is more than 5-butylated, 5-cyano-indole S&gt;3-[6-(l-phenylethylamine-bipyridin-2-yl)oxazolo[l , 5-a] bite, 5-n-methyl-3-[6-(4-pyridinyl)π ratio α-but-2-yl]° than saliva [1,5-a] 0 Ding, 5-ranyl-3-[6-(N-methyl-(3-propylpropyl)amino)° ratio biti-2-yl]0 than wow [l,5-a]n ratio Bite, 3-[6-(3-Aminomethylhexylamine) ° sits on the bite-2-yl]-5-lactylium 11 and [l 5-a] 0 is more than bite, 5-disorgano-3-[6-(N-methyl-N~(2-amidino)ethylamino)° than bit-2-yl] 0 is 0 [l,5-a]ai:b 唆,5-lactyl-3-[6-((1-ethoxyxo)indan-3-ylamino)α ratio σ定-2-yl] 吼Squatting and [l,5-a]n than 唆, , 3-[6-(2-aminoethylamino) ° ratio σ定-2-yl]-5- disorder base ratio β sitting and [1 ,5-a] 0 than bite, 〇S)-5-cyano-3-[6-(2-hydroxydecylpyrrolidin-1-yl)pyridin-2-yl]pyrene 227 201130839 σ sit and [l ,5-a]4t; a, (and)-5-cyano-3-[6-(2-hydroxymethyloxaridin-1-yl; Kb-pyridine-2-yl]吼β sits and [ l,5-a]ni:b bite, 5-ranyl-3-[6-C/V~ethyl-N-(4-|^-ylbutyl)amino)0 than bit-2-yl ] 0 is more than [1,5-a]n ratio, 5-cyano-3-[6-(3-hydroxypropylamino)acridin-2-yl]oxazolo[1,5-a] Bite, (S)-5-disorganized-3-[6-(1-(ethoxyphenyl)pyrazine-3-ylamino)° ratio -2-I base]° 嗤[ 1,5-&amp;]0 is more than bite, trans-3-[6-(4-ethylamino-aminohexylamino) π than bit-2-yl] ° ratio °[1,5-a] Bite, trans-3-[6-(4-methyl sulphate), 10-bito-2-yl]ntb, and [l,5-a]n ratio bite, 3- [6-(3-(2 -Sideoxyl ratio of butyl-1-yl)anilino)11 is more than-2-yl]17 to 0 and [l,5-a]n ratio bite, 3-[6-(Ν-ί哀Hexylamino)α-pyryl]α ratio σ-and-[1,5-a]a ratio bite, 〇3-[6-(N-(2-fluorenylcyclohexyl)amino)acridin-2-yl ] carbazole [l,5-a] π ratio bite, 3-[6-(4-ethylamine basic amino group) ° bite-2-yl]0 ratio σ sit and [l,5-a] ° pyridine, 3-[6-(3-acetamidophenylamino) acridine-2-yl]»biazo[1,5-a]acridine, 3-[6-((3- Methylaminocarbonyl)anilino)pyridin-2-yl]indazolo[l,5-a] bite, 228 201130839 3-[6-(3-hydroxyphenyl-N-nonylamino)pyridine- 2-yl]pyrazolo[1,5-a]pyridine, 3-[6-(N-cyclopropylcarbonylamino)"pyridin-2-yl]«bizozolo[1,5-a] Acridine, (S)-3-[6-(l-phenylethylamino)acridin-2-yl]-5-hydroxymethylcarbazolo[l,5-a]ntb^ ' 3-[6 -(Bunker-4-ylamino)ntb唆-2-yl]ntb β sits and [1,5-a] 0 is more than bite, 3-[6-(Big 定-4-ylamino)° More than bite-2-yl]-5-fluorenyl ° ratio σ sit and [1,5-a] Π bite, 3-[6-(1-ethyl-based base 0--4-amino group) 11 More than bite-2-yl]^ is more than [l,5-a] ° bite, 5-cyano-3-[6-((l-ethylidene) Pyridine-3-ylamino) "bipyridin-2-yl] 吼σ sits and [l,5-a]^n, (S)-5-cyano-3-[6-(piperidine-3 -Amino)pyridin-2-yl]pyrazolo[1,5-a]0 is more specific. 3. The compound according to claim 1 or 2, which is not a compound of the following formula (I) or a salt or solvate thereof: wherein R1, R_2 and R4 each represent a nitrogen atom, and W represents - CR3 group; Z represents a group -NR5; X, Y and T each represent a group -CR9, wherein R9 represents a hydrogen atom; r3 represents hydrogen, halogen, c 1-4 alkyl, fluorenyl C 1-4 alkyl , thiol C 1-4 alkyl, Rr-Cw alkyl halogen, cyano, -C(0)-NR24R24, -C(0)R25, 229 201130839 -C(0)0R25' -OR24 ' -S( 0)2R25 ' -S(0)2NR24R24 '-NR24R24 '-NHCOR24, -ΝΘμ alkyl)COR24, -NHCONR24R24, -NCCm alkyl)CONR24R24, -NHC(0)OR35, -NCCm alkyl)c(〇) 〇R35, •NHS(0)2R25, N(C]_4 alkyl)S(0)2R25 or Cyi, wherein Cyi is optionally substituted with one or more substituents selected from R28; R~5 represents a hydrogen atom, a Cm alkyl group, a halogenated Cm alkyl group, a hydroxy Ci-4 alkyl group or a Cm alkyl group, which is substituted with a group selected from a cyano group, a hydroxyl group or a Cyi group, wherein Cyi is optionally substituted with one or more R28; The group -(CR6R7)m-R8 represents Cm alkyl, Cm haloalkyl, hydroxyCl-4 alkyl, R2U-C1-4 alkyl, -CONR2〇9R 209, -COR210, -C(0)OR2i〇, -S(0)2R2i〇, -SO2NR209R209 or Cy3 'wherein Cy3 is optionally substituted by one or more R212; or R5 together with R8 and the nitrogen atom to which it is bonded Forming a group together, wherein Cy4 is optionally substituted by one or more R212; each R24 independently represents hydrogen or R25; each R25 independently represents C _4 alkyl, halo Cm alkyl, decyl Cm alkyl, a hydroxy Cm alkyl group, a cyano C -4-alkyl group, a CyrCw alkyl group or a Cyi, wherein Cyi is optionally substituted by one or more R28; each R35 independently represents a Ci_4 alkyl group, a halogenated group C-4 alkyl group, and Cl. -4 alkoxy CV4 alkyl, hydroxy Cm alkyl, cyano Cw alkyl or CyrCM top group, wherein Cy! is optionally substituted by - or a plurality of R28, each R28 independently represents a Cm alkyl group, a halogen group Ci -4 alkyl, Ci-4 alkoxy CM alkyl, hydroxy (^_4 alkyl, cyano Cm alkyl, hydroxyl or thiol; 230 201130839 R27 represents cyano, _C(0)-NR24R24, -c (o) r25, -c(o)or25, -OR24, -S(0)2R25, _S(〇)2NR24R24, -NR24R24, -NHCOR24, -NCCm alkyl)C〇R24, _NHCONR24R24, -N(CM alkane Base) CONR24R24, _NHC(0)0R25, -NCC^alkyl)c(o)or25, -NHS(0)2R25, Nfw alkyl)S(〇)2R25 or cyi, wherein Cy! is optionally substituted with one or more substituents selected from r28; each R2.9 independently represents hydrogen or r210; Independently, a C1 -4 alkyl group, a dentate C 1_4 alkyl group, a via group Ci 4 alkyl group, a R 2 ii-C! 4 alkyl group or a Cy5 group, wherein Cy5 is optionally substituted with one or more substituents selected from R213; Table No., aryl group, -CONR214R214, _COR215, C(0)0R215, -〇R214, -S02R215, _so2nr214r214, -NR214R214, -NHCOR214, alkyl)CORw'-NHCONR^R^r-NiCM alkyl) CONR2I4R214, -NHC(0)0R215, -NCCm alkyl)C(0)0R215, -NHS(0)2R215, NCCm alkyl)S(0)2R215 or Cy5, wherein Cy5 is optionally selected from one or more Substituted by a substituent of r213; each R212 independently represents a Ci_4 alkyl group, a halogenated Ci_4 alkyl group, a via group Ci_4 alkyl group, a R211-C1-4 alkyl group or a ruler 212, meaning any of the meanings for the ruler 211; each R213 Independently represented by Ci-4 alkyl, Cm haloalkyl, Cm alkoxy Ci_4 alkyl, hydroxy Ci_4, cyano Cm alkyl, halogen, cyano, -CONR216R216, -COR217, -C(0)0R217 , -OR216, -OCONR216R2I6, -S( 2R217, _S〇2NR_2i6R216, _NR_216R216, -NHCORzwNCCm alkyl)COR^fNHCONRwRnr-NfM 231 Ο υ 201130839 alkyl)CONR216R216, -NHC(0)0R2]7, -N(CM alkyl)C(0)0R217, -NHS(0)2R217, n(cm alkyl)s(o)2r217; each R·2!4 independently represents hydrogen or r215; each R2!5 independently represents C!_4 alkyl, halo CM alkyl CM alkoxy CM alkyl, hydroxy Ci 4 alkyl, cyano Ci 4 alkyl, alkyl or Ch, wherein Cys is optionally substituted by one or more R213; 4 each Rm independently represents hydrogen or R217; Each R217 independently represents c&quot;alkyl, halo cM alkyl, Cl4 alkoxy cM alkyl, hydroxyalkyl or cyanohydrazine "alkyl; vanzan m Cy! is not saturated with 3 to 7 members single ring a partially unsaturated or aromatic carbon framework, and optionally containing from 1 to 3 independently selected from N, 8 and any available c or _ bond to the molecular knife and one or more of the 0 or 8 rings The atom is a C〇, S〇 or s〇2 group; the rolled shape 乂2 indicates that the 3 to 7 member single ring is saturated, partially saturated... independently: saturating two = 'ίΙΓ ring is bonded via any available c atom In the second part of the heart. "Or more than one ° ring atom oxidizes to form insufficient: the member '^ or 8 to 12 members of the double ring are saturated, and some of the heteroatoms from n, s, and 〇 are independently bonded to the rest of the molecule.状 ^ ^ oxidized by any available C atom to form a co, so or S02 base 圏; ^ or 8 ring atom 232 201130839 Cy4 is not saturated or partially unsaturated 3 to 7 i » depending on the situation and is saturated, part Unsaturated or aromatic heterocyclic ring 'Ν, S and = case】 f I a total of 1 to 4 independently selected from the sub-view _, 3, ', ', sub, and ', in the Cy4 one or more C Or the S atom depends on the condition to form a c〇, so or S〇2 group; and the second 8 original h is not a 3 to 7 member monocyclic or 8 to 12 g 镂s inflammatory unsaturated or aromatic carbon ring, And the domain, the member is saturated, partially from N, Smn, and the brother contains 1 to 4 independently selected N atom bonds, wherein the ring is oxidized to form C0, SO or s〇2 groups via any available C or atom. group. Or a compound of the formula, wherein the compound of any one of items 1 to 3 is a non-Cr9 group. ^ The compound described in any one of the patents' wherein the chain c, the second gas atom, the dentate atom, the thiol group, the cyano group, the straight chain or the branched group, the straight chain or the same or different and each represents a gas primordium a flying knife branched Ci-Q alkyl group, a CVC4 functional alkyl group or a CrC4 hydroxyalkane early, and R4 are the same or different and each represents a hydrogen atom, a halogen atom, a broad, a fl group, a straight chain or a branched chain c]_c6 炫, CK: 4 halo, q-Ci via alkyl or c3_CiG cycloalkyl; , = hydrogen atom, linear or branched C1_C6 alkyl, depending on the case, = or more selected from thief, cyano, C] _C4 halogen filament, Crc4 naval or C3-CIG cycloalkyl substituent substitution; 233 201130839 R6 and R? are the same or different and each represents a hydrogen atom, a straight or branched chain Ci-C6 alkyl, a CrC4 R or 9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain CrC6 alkyl group, a CrC4_Hyun group or a CrC4 burnt group; Ο € Rs represents a hydrogen atom, a linear chain Or a branched chain Ci_C6 alkyl, Ci_C4 halogenated group, CrC4 is burned, C3-C1() ring-based, c6_Ci. An aryl group, a 5 to 1 member heteroaryl having 丄, 2 or 3 hetero atoms selected from N, 〇 and S, containing 1, 2 or 3 heteroatoms selected from N, 〇 and s to 5 1 〇 杂环 heterocyclic, -L-Het-R, &quot;, -LA, -AS〇2-R', -A-SO-R,,,,-AA,, -ALC(0)NR*R ^ , -AL-CN , -AC(0)-Het'-L-CN , -A-C(9)-NRnc(9)Z_A,,,_A,)R,n,ac〇2_r,, 5 'AC(〇)z'L -RM,5 -AC(0)zL-CN -AC(0)z-L_Het-R' group, wherein z is 丨R ^ represents a hydrogen atom or a straight or branched chain Cl_C6 alkyl group, C=4 cvw silk 'and R'" denotes a straight or branched chain; a primary U alkyl group or a Cl_C4 hydroxyalkyl group, said heterocyclic group and a heteroaryl group: U condition "phenyl" fused, and the ring filament, heterocyclic ring thereof Base, Fang Yi ^ „Untaken— or a plurality of atoms selected from dentate atoms: a branched chain CVC6 alkyl or a CrC4 morphoxy substituent. L is a linear or branched chain crC6 alkylene, Het represents 〇 Or NRiv, and Het, denotes nrIV, wherein the atomic, linear or branched chain CK: 4 alkyl, C c odontium or /, 虱 院, 4 画 基 or CrC4 via 234 201130839 AAA and A"' Same or not And each of the groups, 5 to 10 members of the heterocyclic group, 〇f^C3-c^ alkane, said ring green, hetero-heteroaryl, a plurality of selected from halogen atoms, the United States 3: base unsubstituted or - or its + I group, chaotic, linear or branched Γ 基 ^ or (10) alkoxy substituted substituents, ^ C1 'C6^ _ or 5: di-free atom, halogen atom, hydroxyl group, cyano group , straight or branched chain cr= or different and each represents a hydrogen atom, and RR 16 , a terroir, a CrC 4 haloalkyl or a CrC 4 hydroxyalkyl group, 乂 and ^ =, 6, (10), L, -, H , 心心表6^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ a 5 to 1 G(10) aryl group containing 1, 2 or 3 hetero atoms, containing 1, on: 5 to 10 membered heterocyclic groups selected from hetero atoms of Γ0 and s, T / _A-A, -A_L_CN, -A_C (〇&gt;R,,,,圏T)zLR,",_A_c(〇)z_L. or _A c(〇)z心七七基c二中i or 2_a_R"'-face straight or branched chain Ci_c3 a aryl group, a 3,5 group thereof or a CrC3 hydroxyalkyl group, and wherein the cycloalkyl group, heterocyclic group, methoxy group The aryl group is unsubstituted or substituted with or a plurality of substituents selected from the dentate atom i, a linear or branched chain CrC6 alkyl or a crC4 alkoxy group, which is a linear or branched chain CrC3 alkylene group, 235 201130839 Et is not 〇 or NRlv, wherein rIV is a hydrogen atom, a straight or branched bond, a silyl group, a Ci_C4 radical or a Crc4 hydroxyalkyl group, and an eight' identical or different and each represents a C3-Cl〇 cycloalkyl group, 5 To 10 杂 aryl or 5 to 10 membered heteroaryl, the cycloalkyl, s:, fluorenyl and heteroaryl unsubstituted or via one or more molybdenum-based money or branches A compound of the formula (10) or a compound of any one of the following claims, wherein R5 is as defined in the scope of claim i. ~ represents a compound of the straight scarf, wherein the compound, the benzene, the chain, the silk, the (4) sister group, the (4) ring of 5 to 6 stomachs selected from the hetero atom of the hetero atom S of ruthenium, osmium and 8 5 to 『? '3 has 2 or 3 selected from Ν, 〇 and is 〇 or 1 and R represents ff ff ' or ' 偶), wherein η group; ', linear or branched chain CrC6 alkyl or 〇 1 &lt; a 4-haloalkane wherein the halogen-based or cycloalkyl group is unsubstituted or substituted with a substituent of a ruthenium-based and unsubstituted base; and the burned eight or more are selected from the group consisting of Rb取其冲珩#. As a halogen atom; a substituent substituted by a aryl group, a base; crc4 _ phenoyl; Ci&lt;:4; benzyl-linear or branched chain crc6 calcined or trans- or poly-self-substituent R = Welch' which is unsubstituted or substituted with _ or more phenyl; phenyl, which has 2 or 3 selected from N, fluorene and 3 =: substituent substituted; 5 to 6 membered monocyclic 236 201130839 Heteroaryl, which is unsubstituted or substituted with or a plurality of substituents selected from the substituent Re; 6 members are saturated with a [heterocyclic ring, which is unsubstituted or Or a plurality of substituents selected from the substituents Re; _c(〇)〇R, a group or a -C(〇MCH2)nR" group wherein ^ is 〇 or Rb is a cyano group; CrC4_alkyl; CrC4 alkoxy; C3_C7 cycloalkyl, which has not been Substituted or substituted with one or more substituents selected from the substituent Re; a phenyl group which is unsubstituted or substituted with one or more substituents selected from the substituent Re; contains 1, 2 or 3 selected from The 5 to 6 membered monocyclic heteroaryl group of the hetero atom of ruthenium, osmium, and s is unsubstituted or substituted with a plurality of substituents selected from the substituent Re; the 6-membered saturated N-containing heterocyclic ring Without substitution or by- or a plurality of substituted filaments selected from the substituent Re; _c(〇)〇r, earth cluster or -C(0)-(CH2)nR" group, wherein n is 〇 or ^ Re is a halogen atom, a thiol group, a ruthenium group, an anthraquinone group, a octadecyl group or a CVQ (tetra) group; a mouse-based direct bond or a branched chain C-heart R' is a ruthenium atom, a linear or branched chain CrQ appearance group, a CrC7 ring An alkyl group, a phenyl group, a 5- to 6-membered monocyclic heteroaryl group containing i, 2 or 3, 4, or a hetero atom of a terroir, or 5 to a ring derived from an N, S ring; Miscellaneous -NH2, cyano 'linear or branched chain fluorenyl, c3-c7 cycloalkyl, phenyl, containing 16 alkyl, Ci_C4 0 and s of the atom 5 to 6 member single ', Selected from N, and an N-containing heterocyclyl ring; wherein the cycloalkyl group or 5 to 6 members are saturated Unsubstituted or via- or a hetero-chained CiM-based W group; straight-chain or branched 237 201130839 9. The compound of claim 8, wherein R, is a cyano group Linear or branched CVC6 alkyl 'CVQ i alkyl, c3-c7 cycloalkyl, stupid, 5 to 6 membered monocyclic heteroaryl containing hydrazine, 2 or 3 heteroatoms selected from N, fluorene and 8. a 5- or 6-membered saturated N-containing heterocyclyl ring; wherein the cycloalkyl, stupid, heterologous filament is substituted or one or more selected from the group consisting of hydroxyl, cyano, straight or branched Substituted by a substituent of a CrC6 alkyl group or a Cl-C4 haloalkyl group. Ο 10. The compound of claim 1, which has the formula (i-c): r4 Formula (I-c) Wherein 111 is an anthracene or an integer from 1 to 3; Z represents an oxygen atom or an NR5 group; -w represents a nitrogen atom or a -CR3 group; and X and Y independently represent a nitrogen atom or a -CR9 group, wherein X and Y are At least one of them represents a nitrogen atom, and the other represents a -CR9 group; Ri represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain Crc6 alkyl group, a Crc4_thry group, and a Crc4 group. , C3_C(7) cyclized 238 201130839 or -NR'R&quot;group; wherein R, and R" are the same or different and each represents a hydrogen atom i straight or branched chain CrC6 alkyl, CrQ haloalkyl or crc4 hydroxyalkyl; The reverse 3 and R4 are the same or different and each represents a halogen atom, a halogen atom, a hydroxyl group, a cyano group, a linear or branched chain CrC6 alkyl group, a CrC4 haloalkyl group, a Cl-C4 hydroxydecyl group or a fluorene 3 hair 1 () fluorene. Alkyl; ^ represents an argon atom, a straight bond or a branched C1_C6 alkyl group, which has not been subjected to ~ or a plurality selected from a carboxyl group, a cyano group, a Crc4 haloalkyl group, a C1-C4 hydroxy C3, a C1Q cycloalkyl group, a fluorenyl group. Substituted with a pyridyl group or a 6-membered saturated N-containing heterocyclic group; the heart and the ruler 7 are different and each represents a hydrogen atom, a straight chain or a branch a bond CrC6 alkyl, crc4 lialkyl or crc4 hydroxyalkyl; ^ represents a hydrogen atom, a halogen atom, a trans group, a cyano group, a straight bond or a branched 16 alkyl group, a C-C4 haloalkyl group, a CrC4 hydroxyalkyl group Or -Nf^R" group. Shouting not the various hydrogen atoms, money or branched bond alkyl, Cl_C4 haloalkyl or (^(^ hydroxyalkyl; R8 means straight or branched C]-C6 alkane Base, dc halogen A ring cyclyl, phenyl, containing 2 or 3 (four) N ^ silk % 5 sag selected from N, 〇 and S, miscellaneous dinosaur 3 to 6 shell early core, including right 5 and 7 members of the heteroatoms of ^ and 8 are 5 selected from N, 〇 in the middle ... or (1) represents a straight chain; a group J_R group, a south alkyl group; a slit knife branch c - c6 alkane a group or a CrCi. wherein the dentate alkyl group, the environmental group, unsubstituted or substituted with one or more substituents selected from the group consisting of R^heteroaryl and heterocyclic group a; and the calcined 239 201130839 base is unsubstituted Or substituted by one or more substituents selected from Rb; Ra is a halogen atom; cyano; hydroxy; straight or branched C!-C6 alkyl; crc4 #丝; crc4 alkoxy; C3_C7 cycloalkyl, Not, = or one or more selected from the group consisting of substituents Re Substituted with a substituent; phenyl, unsubstituted or 1 - or more substituents selected from the substituent group Re Dimethyl; Bu and have 2 or 3 heteroatoms selected from N, 5 and a single square of the heteroatoms ^ s a heteroaryl group which is unsubstituted or substituted with - or a plurality of substituents selected from the group of substituents; 6(d) and a ring containing N, a county, a base, which is unsubstituted or one or more One selected from a substituent r-substituent; containing 1, 2 or 3 substituents selected from N, fluorene with 5 to 6 membered monocyclic heteroaryl groups, which are unsubstituted and substituted; 6-membered saturated Containing ^ generations or by - or a plurality of materials selected from the substituents Re, recording ^®^-C(0HCH2)nR^ffl, *t C(〇)〇R? such as a halogen atom, a hydroxyl group, Cyano, ^, or Crc4 haloalkyl; hard sub-branched clc6 alkane is a hydrogen atom, straight or branched c1&lt;: kc7 cycloalkyl, phenyl, containing hydrazine, 2 or 36 =^-c4 halogen A 5- to 6-membered monocyclic heteroaryl group, a 0- and S-ring-based ring of a hetero atom; and a 4 to 6-membered saturated N-containing hydrocarbon 240 201130839 R is -ΝΉ2 ' 鮝,, Α 4Α 牙县,w匕, 3弋 branched chain Cl_C6 alkyl group 'CK: 4 Ο νλΆ Μ: soil base, containing 1, 2 or 3 selected from Ν, and containing i6 members of the monocyclic heteroaryl, or 5 to 6 full Ring group not (four) base, phenyl, miscellaneous and miscellaneous ίίίΓ or multiple selected from A cyano group, a linear or branched ί ίΐ &amp; _ group of substituents. The compound of the formula ==:=, wherein the NR5 group is not represented by the 171 and the Z. The compound of the formula R, which is described in the patent application, is a non-deuterium atom, an octadecyl group, a CA cycloalkyl group; a base = or a branched chain W different and a long time 矣 h X NKR group Wherein R' and R" are the same or alkyl; R! is more than η straight or branched chain Ci_c6 alkyl, (iv) _ sub. 1 preferably a residual atom or a shed 2 group; R1 more preferably represents a hydrogen source A compound according to any one of the preceding claims, wherein the alkyl or c-bicyclic ring: a dentate 3, a cyano group, a straight chain or a branched chain is in the form of a CK:Zhao, a money atom or a branched chain, as in the aforementioned patent scope. The compound of the above-mentioned item, wherein the branched chain Crc, j^t 3 is more than an atom, a cyano group or a straight chain or a 15 group, and R3 is more preferably a hydrogen atom or a cyano group. Any compound, its atom, _ atom, cyano group, linear or branched chain crc6 241 201130839 alkyl; R4 is preferably a 4 atom or a linear or branched bond CVC3 alkyl group; more preferably represents an ammonia atom. Or a compound of any one of the claims, wherein - or more than 5 m, face or branched chain μ county, which is optionally taken by a cycloalkyl group, , the alkyl group at the CrQ, the Crc4 hydroxyalkyl group or the C3-C7 cd is substituted with the .P soil; the R5 preferably represents a gas atom or a linear or branched chain CrC3 alkyl group, and the r5 preferably represents an ammonia atom. Any of the compounds described in the scope, wherein: 7 « 7 地 地 & ^ ^ ^ atom or linear or branched chain Cl_C6 alkane CR? preferably independently represents a chlorine atom or a linear or branched chain 匕 1 7 3. Hyun base. 18. As claimed in any one of claims 8 to 17, the object 2, chain or branch chain 2 = 22 to stupid f member 'two' 2 / 3 selected from N 〇 示 示 示 示 Cl Cl 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或Substituted by one or a substituent selected from Rb; ^ is a halogen atom; a cyano group; a transradical; a linear or branched 鏠c C alkyl group; a Cl-C4 (tetra) group; containing 2 or 3 selected from N, 6 a monocyclic heteroaryl group which is unsubstituted or substituted by one or more substituents, a cyano group, a linear or branched chain Cl., or a substituent of 242 201130839 CrC4 dentate; -C(0 )0R, group Or a -C(0)-(CH2)trR" group, wherein η is 0 or 1, 1, Rb is cyano, CrC4 is haloalkyl; crc4 alkoxy; C3-C7 cycloalkyl, unsubstituted Or substituted by one or more substituents selected from the group consisting of a sulfonium atom, a hydroxyl group or a cyano group, which are unsubstituted or have one or more selected from a halogen atom, a hydroxyl group, a cyano group or a linear or branched chain Crc6. a substituent of an alkyl group; -c(0)0R, a group or _c(〇MCH2)n_R, a group wherein n is 〇 or R is a hydrogen atom, a straight or branched chain Ci_c6 alkyl, a Ci_c4 halane a C or a C;j-C7 cycloalkyl; and a c-, straight- or branched-chain CrC6 filament, a c-, or a 3 L7, or wherein R8 represents a straight or branched chain Crc6 L3C7 cycloalkyl, benzene base! 4 s of the hetero atom of the country has 12 or 3 selected from N, Ο and S 贞 money base, traitor, 2 or 3 selected from N, where n is 〇 or i and R represents mu if 'or' (CH2)n〇R group, haloalkyl; chain or branched chain crC6 alkyl or crC4 or a trans group, a phenyl group and a heterocyclic group unsubstituted or one or more _ self; The appearance of the base is not as defined above, substituting for the base, the shot is a south atom; the base; the return; the direct or branch bond (3) marry 243 201130839 base, Cl_C4 halogen group; containing 1, 2 or 3 5 to 6 membered monocyclic heteroaryl groups selected from the heteroatoms of N, 0 and S, which are unsubstituted or have one or more selected from the group consisting of dentate atoms, secret, cyano, straight or branched chain crc6 Substituted by a substituent of a CrQ haloalkyl group; a _c(〇)〇Rf group-C(0)-(CH2)nR" group, wherein n is 〇 or j, a hydrogen atom, a straight chain or a branched chain CA An alkyl group, a Ci_Q tooth or a C3_C7 cycloalkyl group; Occupying a wide range of f-NH2, cyano, linear or branched chain CrC6 alkyl, Crc4 dentate or c3_c7 cycloalkyl. A compound according to any one of the preceding claims, wherein: 9: a hydrogen atom, a halogen atom, a woven group, a cyano group or a straight two = or preferably a hydrogen atom, a * atom or a straight bond or a tributary八ΐ R9 represents a gas atom, a pixel atom, a thiol group, a cyano group, a straight bond, a branched alkyl group or a aryl group; R9 preferably represents a hydrogen atom, a linear or branched chain Cl_C3 alkyl group or _Nh2 Group. A compound according to any one of claims 1 to 19, wherein the compound has the formula (I-C) and the term m is 0, 1 or 2; W represents a nitrogen atom or _CR; a group, preferably a _CR3 group; z represents an NR5 group; x and Y independently represent a nitrogen atom or a _CR group nj, and a mechanical atom in the Y, and the other represents that R1 represents hydrogen. Atom or -NH2 group; 阌' 244 201130839 R2 represents a hydrogen atom or a straight or branched chain crc3 alkyl; R3 represents: a hydrogen atom, a cyano group or a linear or branched chain crc3 graft; R4 represents a germanium atom or a straight a chain or branched chain crc3 alkyl; R5 represents a hydrogen atom or a straight or branched chain crc3 alkyl; R6 and R7 independently represent a hydrogen atom or a straight or branched chain CrC3, and // represents a straight or branched chain C1_C6 An alkyl group; a CrC4 haloalkyl group; a C3_C7 anthracenyl group which is unsubstituted or substituted with one or more substituents selected from a permeate atom and a hydroxyl group: a phenyl group which is unsubstituted or Substituted by one or more halogen atoms; -(CH2)n-〇R group, wherein η is 0 or 1 and R represents a straight or branched chain CrC3 alkyl group; pyridyl group The pyridyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a sulfinyl atom and a hydroxy group; a tetrahydropyranyl group which is unsubstituted or one or more selected from dentate a substituent substituted with an atom and a hydroxyl group; and a piperidinyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of: a straight bond or a branched bond Cl_C3 alkyl; a halogen atom; a pyridyl group which is unsubstituted or substituted with hydrazine or a plurality of cyano groups; 1,2,4·triazolyl; and -C(0)-(CH2)iTR, a group wherein 11 is hydrazine or 1 and R&quot; is -ΝΗ2, cyano, straight or branched bond CrC6 alkyl, Cl_C4_alkyl or C3_C7 cycloalkyl; and R9 represents a halogen atom, a functional atom, a direct bond or a branched bond Cl, C3 alkyl 245 201130839 or -nh2 group. 21. The compound of claim 20, wherein R8 represents a linear or branched Crc6 alkyl group; a CrC4-alkyl group; a C3-C7 cycloalkane group; the cycloalkyl group is unsubstituted or Or a plurality of substituents selected from a pertinyl atom and a transradical; a phenyl group which is unsubstituted or substituted with one or more halogen atoms; a -(CH2)n-OR group wherein n is 0 or 1 and the scale represents a linear or branched Q-C3 alkyl group; "pyridyl, the pyridyl group is not substituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; tetrahydropyranyl And the tetrahydropyranyl group is unsubstituted or substituted with one or more substituents selected from a halogen atom and a hydroxyl group; the bottom acyl group is substituted with one or more substituents, wherein the substitution At least on the ring nitrogen of the piperidinyl group, the substituent is selected from the group consisting of: a straight or branched chain crc3 alkyl group; a halogen atom; a ratio of a thiol group to an unsubstituted or one or more a cyano group; Ο 1,2,4-triazolyl; and a -C(0)-(CH2)n·^' group, wherein ^ is 〇 or 1 and R&quot; is ·ΝΗ2 Chaos group, a direct bond or branched CrC6 ^ bond group, C1-C4 halo burn or C3_C7 cycloalkyl group. 22. The compound of claim 1, wherein m is 0, 1 or 2 in the compound of formula (I); W represents a nitrogen atom or a _Cr3 group, preferably a _CR3 group; 201130839 Z represents an NRS group; a group; when the table is not disordered, the other means that UT represents a -CR9 group; R1 represents a hydrogen atom or a -NH2 group; R2 represents a dihydrogen atom or a straight or branched chain Crc3 alkyl; R3 represents a hydrogen atom, a cyano group or a linear or branched chain q_C3 alkyl group; R4 represents a hydrogen atom or a straight or branched chain Crc3 alkyl group; soil RS represents a hydrogen atom or a straight or branched chain CrC3 alkyl group; R6 and R7 are independently The ground represents a hydrogen atom or a straight or branched chain Ci_C3 alkyl group, R8 represents a direct bond or a branched bond Ci_C6 alkyl group; CVC4 is a halogenated group; C3-C7 is a non-substituted or cyclic group. Substituted by a plurality of radicals; the phenyl 'the stupid group is unsubstituted or substituted with one or more im atoms; -(CH2)n-OR group, wherein n is 0 or 1 and the scale represents a straight chain or a branch a chain CrC3 alkyl; and a piperidinyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of pyridyl, unsubstituted or via one or more cyano groups Substituted; and -C(0)-(CH2)nR, a group 'where n is 0 or 1 and R, is -NH2, cyano, straight or branched C1-C6 leuntyl, C1-C4 halo An alkyl group or a CrC7 cycloalkyl group; and R9 represents a hydrogen atom, a halogen atom or a linear or branched chain Cl-C3 alkyl group. 247. The compound of claim 22, wherein ΪΤ is a gas group, a direct bond or a branched bond Ci_C6 alkyl, a C1-C4 halogen compound or a C3-C7 cycloalkyl group. 24. A compound as claimed in claim 1 having the formula (I-a)= Wherein m is 0, 1 or 2; W represents a nitrogen atom or a -CR3 group, preferably a -CR3 group; X represents a nitrogen atom or a -CR9 group; Ri represents a hydrogen atom or a -NH2 group R2 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group; R3 represents a halogen atom, a cyano group or a linear or branched chain heart-^alkyl group; R4 represents a ruthenium? Or a straight or branched chain CrC3 alkyl group; R5 represents a halogen atom or a linear or branched chain CrC3 alkyl group; R6 and R7 independently represent a hydrogen atom or a linear or branched chain CrC3 alkyl group, 248 201130839 R8 represents a straight chain or a branch Chain CrC6 alkyl; CrC4 _ = 斤 所 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环a C(〇HCH2)n_R" group, wherein η is 〇 or i and R ^ chain or branch bond Cl_C6 alkyl, CVQ i alkyl or c3_C7 ring; ί table atom, halogen atom or linear or branched chain Cl_C3 alkyl. According to the compound of claim 24, 1, m is 〇 or 1; Ri represents a hydrogen atom; R·2 represents a hydrogen atom; I represents a hydrogen atom or a cyano group; R4 represents a hydrogen atom R5 represents a hydrogen atom or a straight or branched chain CrC3 alkyl group; R6 and & independently represent a hydrogen atom or a straight or branched chain belly violent ^, 3 &gt; - household, ^8 surface, linear or Branched chain C "C6 alkyl; Cl_C4 halogenated group; C3-C7 = Cyclohexyl is unsubstituted or substituted by one or more hydroxyl groups. The cage group is not taken. Or a halogen atom 249 201130839 - (CH2)n-OR group, wherein η is 0 or 1 and R represents a linear or branched chain CrC3 alkyl group; and a piperidinyl group, the piperidinyl group is not Substituted or substituted with one or more substituents selected from the group consisting of: 吼0, which is unsubstituted or substituted with one or more cyano groups; and -C(0)-(CH2)n- An R&quot; group wherein n is 0 or 1 and R&quot; is a cyano, straight or branched chain crc3 alkyl or crc4_alkyl; and R9 represents a hydrogen atom, a halogen atom or a straight or branched chain crc3 alkyl group. 26. The compound of claim 1, which has the formula (Ib): Wherein m is 0, 1 or 2; X represents a nitrogen atom or a '-CR9 group; K represents a deuterium atom or a -NH2 group; R2 represents a deuterium atom or a straight or branched bond C1-C3 alkyl group; R_4 represents a nitrogen atom or a direct bond or a branched bond C1-C3 alkyl group, 250 201130839 represents a hydrogen atom or a straight or branched chain crc3 alkyl group; a burnt group, 6 and a standing atom representing a hydrogen atom or a straight or branched chain C1' C3 Aid 8 table:, + straight, or branched chain crQ alkyl; C1_C4 tooth alkyl is unsubstituted or substituted by - or a plurality of bases; benzene 7 soil; L native unsubstituted or one or Substituted by a plurality of halogen atoms; (CH2)n-OR group 'wherein or liR represents a straight or branched CrC3 alkyl group; and piperidinyl group, said bridging base is unsubstituted or one or more selected from the group consisting of Substituent substitution: pyridyl, unsubstituted or substituted by one or more cyano groups; and -C(0)-(CH2)n-R&quot; group, wherein η is 〇 or 1 and „Cyano, straight or branched chain CrQ alkyl, CrC4 _alkyl or C3_Cyt alkyl; and R9 represents a hydrogen atom, a halogen atom or a straight or branched chain Ci_C3 alkyl. The compound according to Item 26, wherein m is 0 or 1; X is a mouse atom; Ri represents an iron i atom; R2 represents a mouse atom; IU represents a hydrogen atom or a linear or branched ei-c3 alkyl group; R_5 represents a hydrogen atom or a linear or branched chain CrC3 alkyl group; R_6 and R·/ independently represent a nitrogen atom or a linear or branched chain C1-C3 炫* group, 251 201130839 ... & straight _ sub-nuclear Ci_C6 county; q_C7 Weiji's secret base is not converted or by ❹ 丝 silk; phenyl, the base is unsubstituted or substituted by a zebra atom; and the base, the brigade bite is not replaced - or the town Substituted by a substituent: a pyridyl group which is unsubstituted or one or more generations; and a -C(〇MCH2)n_R" group, wherein n is G or 丨 and R, 'is an aryl group a straight or branched chain crc:3 alkyl or Crc3 haloalkyl; and R9 represents a deuterium atom, a dentate atom or a linear or branched crc3 alkyl group. 28. A compound of the formula (4), which is one of the following compounds: 3_(4-{[(lS)_l-stupyl]amino}}}} 基 唑 唑 • [ a bite-5-曱 guess, 3-{4-[(cyclohexylmethyl)amino]pyrimidin-2-yl}pyrazolopyridine-5-method; 3-[4-(benzamide ) 唆 唆 _ _ 唆 唆 唆 唆 唆 唆 唆 ; ; 3- ; 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 5_冲比咬-5-甲猜, 3-(4-{[(15&gt;2·曱oxy-1-methylethyl)aminopyrimidin-2-yl is more than 0 sitting and [1,5 -α]° than bite-5-carbonitrile; 3-{4-[(cyclopropylmethyl)amine:yl]pyrimidin-2-yl}pyrazolopyridine-5-method; 3-{4-[ (2,2,2_difluoroethyl)amino]Nursing _2·Kibby 嗤[1,5-“] ° than bite-5-A guess; 252 201130839 '(1-stupylethyl )_2_咐^Sitting and [1,5-«|π ratio biting-3-yl-n-oxime-4-amine; Η6-[(cyclohexylmethyl)amino]pyridin-2-yl}pyrazolo[ 1,5·α]pyridine-5-carbonitrile; 3-{6-[(2,2-dipropylpropyl)amino]pyridin-2-yl}pyrazolo[1,5-α]pyridine- 5-carbonitrile; Η6-[(3-fluorobenzyl)amino]pyridin-2-yl}pyrazolo[1,5-α]pyridine-5-method, 3-[6-(benzoquinone Amine咬-2-yl]° ratio spit [1,5-α] 吼-5-carbonitrile; 3-(6-{[(15&gt;1·phenethyl)amino} acridine-2-yl "Bizozolo[1,5-branches-5-indene nitrile; 3-(4-{[(3))-1-(cyanoethenyl))-3-amino]amino} Bite_2_base) σ ratio sits and [1,5-α]σ ratio bites 5--carbonitrile; 3-(4-{[(3i?)-l-ethyl aryl η bottom bite -3- Amino group] cancer bite_2_yl) π than saliva [1,5-〇1 pyridine-5-phthalonitrile; 3-(4_{[(3 and)-1-(5 - chaotic υ) ratio咬-2-yl) π 咬 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ )-1 -(3,3,3-trifluoropropionyl)piperidine-3-yl]amino}-pyridin-2-yl)σ ratio 51 sitting and [1,5-α]° ratio bite- 5-indene nitrile; 3-{4-[[(3) 1-(cyanocarbonyl))-[3-yl](indenyl)amino]pyrimidin-2-yl}0 sits and sits [1, 5-fif]10 ratio α--5-carbonitrile; 3-(4-((trans)-4-ylcyclohexylamino))pyridin-2-yl)carbazolo[^-bipyridin-5 -carbonitrile; AK cyclohexyl)-2-pyrazolo[ΐ,5-β]pyrazine-3-ylpyrimidine4-amine; (S)-N-(l-phenylethyl)-2 Heptazo[,,,,,,,, -4- ; (2,2-Dimethylpropyl)-2-'1 is more than 唆[1,5-«]0 to 11-Qin-3-ylindol-4-amine; 3-flank-3- {(3i?)-3-[(2-0 is more than 11 sits and [1,5-&lt;3]π is more than σ-qin-3-yl 0^ 〇-4-yl)amino][alpha]-biting- L-基} 丙猜; 6- {(3i?)-3-[(2-a ratio β sits and [1,5-β]π ratio σ Qin-3-yl oxime-4-yl) amine group ] Bite bite _1_ base} to test; 2-pyrazolo[1,5-α]pyrazin-3-yl-Aq(3i?)-l-(3,3,3-trifluoropropanthene) Base) 咬--3-yl] mouth bite-4-amine, 3-{(3 magic-3-[mercapto(2-oxazolopyridin-3-ylpyrimidin-4-yl)amino] Brigade π定_1_基}_3_Sideoxy C., 3 - {(3 and)-3-[(5 - gas σ sit and [1,5-β] π than _3· base bite -4-yl) Amino] 唆 唆 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Σβββ-3-yl-n-butyl-4-yl)amino]predomin-1-yl]·-3-flank-based, 5-fluoro-2-oxazolo[1,5- α]Toxazin-3-yl-#-[(3i〇-l-(3,3,3-trifluoropropyl)pyrylene-3-yl]bite-4-amine, 3-{(37 ?)-3-[(5-Methyl-2-pyrazolo[1,5-β]pyrazin-3-ylpyrimidin-4-yl)amino] brigade bite_1_yl}_3_ side oxygen乙丙猜, (S)-N-(l-(5-fluoroacridin-2-yl)ethyl)-2-(carbazole And [1,5-a]pyridazin-3-yl)indolyl-4-amine, N-((5-fluoroacridin-2-yl)methyl)-2-(carbazolo[l, 5-a]pyridazin-3-yl)pyrimidin-4-amine; 254 201130839 5·Chloro-Ν·((5-money-2_yl)methyl)_2•((4) and ^♦ than 嗓-3- Carbium-4-amine; ', n4-(hi cyclohexyl) clock is 嗤4,5·diamine; with foot (S)-5-chloro·Ν_(1-(5·fluoro(tetra) _2_ Ethyl)ethyl)_2_(pyrazazine_3_yl)pyrimidine-4-amine; L _ J 2- (吼 并[1,5♦biazine-3_yl) This (tetrahydro-visual brigade Pyrimidine-4,5-diamine; soil (R)-3-sided oxy- 3-(3-(6-tendopyrano[1,5-oxazin-3-yl) noisy_2_ylamino ) π bottom bite-1-yl) C.; '(R)·3-sideoxy-3-(3_(6-10 than saliva[u♦ than bit I) I-amino group) α-bite- 1-())propanenitrile; '(8)·3·sideoxy·3·(3_(2)(4) and ^^唆_Heartylamino>&gt;succinyl-1-yl)propionitrile; 3- (3 -(5-fluoro-2-(吼 并 并 [i,5_a]n than bite each base) squeezing ice-ylaminopiperidin-1-yl)-3-oxo-propanonitrile; 3-(3- (5-gas-2-(such as sitting and [ΐ, 5_φ than biting _3_ base) mouth biting i-amino group) 0 bottom bit-1-yl)-3-sided oxypropionitrile; 3-(4 -Fluor-3_(6 ten than saliva (1) 5, than bite _3_ base> ; 嗔 _ _ _ -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3_基> 噪 _2 基 基 基 基 ) -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- ; ; ; ; = = = = = = = = = = = = = = = = = = = = = = = The compound of any one of the above-mentioned acceptable salts, solvates, and N-oxides, wherein: Come on. A compound according to any one of the above-mentioned patents, wherein (myelop; ri^ ^ ^ ^ Ϊ = tumor; bone marrow and organ transplant rejection; should; == sex 31: scientific condition or disease is selected A inflammatory disease. The compound of claim 30, wherein the D malignant diproliferative disorder, leukemia, lymphokine kinase is administered. The treatment is by inhibiting Janus. The compound described in the pathology of the disease, wherein the immune mediated = sputum is selected from the group consisting of bone and organ transplant rejection; and the physiology is selected from the group consisting of inflammatory diseases. The compound according to any one of the preceding claims, wherein the disease or disease is selected from the group consisting of rheumatoid arthritis 256 201130839 (rheumatoid arthritis), multiple sclerosis (severin sder〇sis), inflammatory bowel disease, dry eye, Uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, and psoriasis. 34. Types of patent applications 1 to 28 Secondary Use of a compound as described herein for the manufacture of a medicament for the treatment of a pathological condition or disease as described in claim 1 or claim 29 to item 33. A method of treating an individual suffering from a pathological condition or disease as described in any of the above-mentioned claims, or comprising administering to the individual a therapeutically effective amount of item 28 The compound described in any one of the above items, or the compound of any one of the items 1 to 28, and the diluted pharmaceutical composition of the invention. W - an individual including two 6.2 lions The method of the Genus kinase, and to the 28th item, the therapeutically effective amount of the compound as described in the first to the right of the patent application, or the diluent or carrier as claimed in the patent application. Of 257 201130839 r4 /, take the K9 group and m, z, R9 as claimed in the scope of the patent "to (10) - item: = heart to 38. If the scope of application for patents 37 indicates -CR9 group. A compound, wherein Y 39. is a compound as described in claim 37, and represents X, and X and Τ represent a _CR9 group, which represents: when a 5- to 7-membered heterocyclic group of the atom is a heterocyclic ring Substituent substituent, wherein the substitution is at least on the heterocyclic group, and the restriction is that the substitution on the ring nitrogen of the heterocyclic group is a third butoxycarbonyl group. The composition 'comprising a compound according to any one of claims to claim 39 and a pharmaceutically acceptable diluent or carrier. &amp; 41. A combination product 'which includes U) as an application A compound according to any one of claims 37 to 39; and (ii) another compound selected from the group consisting of 258 201130839: a) a dihydrofolate reductase inhibitor such as Methotrexate Or CH-1504; b) DHODH inhibitors, such as leflunomide (ief|un〇mide), Moli An amine (teriflunomide) or a compound described in International Patent Application No. WO2008/077639 and WO20092696; c) an immunomodulator such as Glatiramer acetate or Laquinimod; DNA synthesis and repair inhibitors, such as Mitoxantrone or ciadribine; e) anti-x4 integrin antibodies, such as Nataiizumab (Tysabri); f) α4 integration Antagonists such as R 1295, TBC_4746, CDP-323, ELND-002, Firategrast or TMC-2003; g) cortic〇id and glucocorticoids such as sputum Prednis〇ne or methylprednisolone, fluticas〇ne, mometasone or beta_metas〇ne; h) fumarate, such as i) anti-TNFα antibody such as inHiximab, Adalimumab or certolizumab pegol; 259 201130839 j ) Soluble TNF alpha receptors such as Ina Ethanercept; k), CD20 monoclonal antibody, such as rituximab (R-), okrezumab (Ocrelizumab), oxajuximab (〇fatum_b) or TRU-015; CD52, such as alemtuzumab; m) anti-CD25 'such as daclisumab (dadkumab); η) anti-CD88, such as eculizumab (Shenxian Brain) or pegizumab ( Pexilizumab); &lt;π 0 ) anti-1L12R/IL23R, such as ustekinumab; P) calcineurin inhibitor, such as cyclosporine A or tacrolimus Division (tacr〇limus); q) IMPDH inhibitors such as mycophenolate mophetyl; r) cannabinoid receptor agonists, such as satex (Sativex); s) chemotaxis a factor CCR1 antagonist, such as MLN_3897 or PS-031291; O t) a chemokine CCR2 antagonist, such as INCB-8696; u) an NF-κΒ activation inhibitor, such as MLN_〇415; v) a SIP receptor agonist , such as fingolimod (j^ng〇nm〇d), BAF-312, ACT128800 or International Patent Application No. PCT/EP2009/007348 and PCT/EP a compound described in 2G09/008968; w) an S1P dissociation enzyme inhibitor such as LX2931; X) a Syk inhibitor such as R-112; 260 201130839 Υ) a PKC inhibitor such as NVP-AEB071; z) M3 antagonist &amp; Agents such as 嗟 &amp; ammonium ((9) 丨 丨 )) or aclidinium; aa) long-acting beta-adrenergic agonist, such as formoterol; bb) vitamin D derived Compounds such as calcipotriol ((3) kiss this _ (Davonex); CC) acid (two) 1V inhibitors, such as roflumilast or GRC-4039; ξ, dd) P38 inhibitors' Such as arry_797; ee) MEK inhibitors, such as arry_142886 or ARRY-438162; ff) ΡΙ3Κδγ inhibitors; )) interferon' including interferon P la, such as Afoona (Αν_χ) from Biogen Idee, from ❿(10) Nuuks () and Rebif from earning S_〇, as well as interferon beta lb, such as beta-Ferling from Schering (B-ship) and Betelelon from #; Hh) interferon alpha 'such as Sumiferon MP; On or sequential use in treatment of the human or animal body. 42. If the combination product mentioned in Item 41 of the Patent Park is used, it is used for the treatment of the pathology as defined in the patent application scope t or item 29 to item 33. Learn the condition or disease. 43. The combination of the invention described in claim 41 or 42 of the patent application 261 201130839, which includes (i) a compound as claimed in any one of claims 37 to 39; Another compound selected from the group consisting of: a.DHODH inhibitors, such as leflunomide, teriflamine or the compounds described in International Patent Application No. WO2008/077639 and WO2009021696; b. Immunomodulation An expectorant, such as gramimab or ramidazole; c. an anti-α4 integrin antibody, such as natalizumab (Tysabri); d. a4 integrin antagonists, such as R_1295, TBC_4746 CDP-323, ELND., felastide or TMc 2〇〇3; e. corticosteroids and glucocorticoids, such as prednisone or methylprednisolone, Fluticasone, mometasone or betatapine; f. anti-butyrate 'sour acid, such as · gas. anti-TMF a antibody, such as infliximab, adalimumab or; ^^ beads 4, h. soluble TNF a receptor, such as etanercept; 1. anti-CD20 monoclonal antibody, such as oxacabumab or TRU-015; heart early ^ Wu Kezhu early 4 division k. anti-lUmALBR, such as Ute克单彳^早_周神__Inhibitors such as Cyclosporin A or Tucker nUMPDH inhibitors, such as mycophenolic acid 琳 酉 ;; η. Cannabis-like agonists, such as 〇. The factor CCR1 includes y such as an antagonist, such as MLN-3897 = 262 201130839 PS-031291; p. chemokine CCR2 inhibitor, such as INCB-8696; q. NF-κΒ activation inhibitor, such as MLN_〇415 r. SIP defensive agonists, such as fingolimod, baf 312, ACT 128 or international patents, please refer to pcT/Ep2_/GG7348 and PCT/EP2009/008968 a compound; s. SIP dissociation enzyme inhibitor, such as LX2931; t. Syk inhibitor, such as r_112; u. PKC inhibitor such as Nvp_AEB〇71; v. M3 antagonist, such as guanidine ammonium or adiponium; Long-acting beta-adrenergic agonist, such as formoterol; X. Vitamin D derivatives, such as calcipotriol (Darishi); y. Acid-filled diacetate IV inhibitor, such as Luo z. p38 inhibitor, such as aRRy_797; aa.PI3K5y inhibitor; bb. interferon beta la, such as Affitta from Bi〇gen Wec, Sinux from CinnaGen, and from EMDSer〇n Litby ratio, and cc. interferon pib' such as beta from Schering from Berex. 263