CN109776522B - Substituted heteroaryl compounds, compositions and uses thereof - Google Patents

Abstract

Substituted heteroaryl compounds, compositions thereof, and their use are disclosed. The compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I). The invention also provides pharmaceutical compositions comprising the compounds, which compounds and pharmaceutical compositions can modulate the activity of protein kinases, particularly Aurora kinases and JAK kinases, for the prevention, treatment and alleviation of diseases or disorders mediated by protein kinases, particularly JAK kinase activity.

Description

Substituted heteroaryl compounds, compositions and uses thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to novel substituted pyrimidine compounds serving as protein kinase activity inhibitors, a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds and the pharmaceutical composition in treatment of various diseases. More specifically, the compounds of the present invention may act as inhibitors of the activity or function of Aurora kinases (including Aurora-A, Aurora-B and Aurora-C), FLT3 kinase (also known as FLK-2 kinase), FLT4 kinase, and the JAK kinase family (including JAK1, JAK2, JAK3, and TYK 2).

Background

The protein kinase family comprises a large class of structurally related enzymes that control various signal transduction processes within cells, and typically contain a similar 250-300 amino acid catalytic domain that catalyzes the phosphorylation of target protein substrates. Many diseases are reported to be associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include benign and malignant proliferative disorders, disorders resulting from inappropriate activation of the immune system, allograft rejection, graft-versus-host disease, autoimmune disorders, inflammatory disorders, bone disorders, metabolic disorders, neurological and neurodegenerative disorders, cancer, cardiovascular disorders, allergy and asthma, alzheimer's disease and hormone-related disorders. Accordingly, there have been a great deal of effort in the field of medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

Kinases can be classified into families by phosphorylated substrates (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Tyrosine phosphorylation is one of the central events that regulates various biological processes such as cell proliferation, migration, differentiation, and survival. Several families of receptor and non-receptor tyrosine kinases control these events: catalyzing the transfer of phosphate from ATP to tyrosine residues of specific cellular protein targets. Currently, motifs generally corresponding to the above-mentioned kinase families have been identified (Hanks et al, FASEB J.,1995,9, 576-596; Knighton et al., Science,1991,253, 407-414; Garcia-Bustos en al. EMBO J.,1994,13: 2352-2361). Examples of kinases in the protein kinase family include, but are not limited to, Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, crrafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, 4, Erk, Flt-3, Flt-4, Fak, fes, fgfrfl, FGFR2, FGFR3, FGFR 8, FGFR5, Fgr, fpps, Frk, Fyn, Hck, JAK-1R, INS-R, KDR, Lck, Lyn, MEK, p38, pkr, PIK, PDGFR, PIK, PYK2, Tie, tiape, Tie, zype, zs, zyes-70, and the like.

Among them, the Aurora kinase family is a class of serine/threonine kinases that are key regulators of mitosis and are essential for the precise and equal separation (segtion) of genomic material from mother cell to daughter cell. Members of the Aurora kinase family include three classes of related kinases, known as Aurora-A, Aurora-B and Aurora-C (also known as Aurora-1, Aurora-2, and Aurora-3).

Aurora-a is widely expressed and regulates cell cycle events occurring from late S to M, including centrosome maturation, mitotic entry, centrosome separation, bipolar spindle assembly, chromosomal alignment on the equatorial plate, cytokinesis and mitotic termination. The Aurora-A protein level and kinase activity are increased from the G2 stage to the M stage, and the activity reaches a peak in the early-middle stage. Once activated, Aurora-a mediates a variety of functions through interaction with a variety of substrates, including the centrosome protein (centrosome), the transforming acidic coiled-coil protein, cdc25b, Eg5, and centromeric protein a. Aurora-a overexpression is an essential feature of Aurora-a-induced tumorigenesis.

Aurora-B is a chromosomal protein that plays a key role in precise chromosomal segregation, cytokinesis, protein localization to the centromere and centromere, proper microtubule-centromere attachment, and regulation of mitotic checkpoints. Aurora-B localizes first to the chromosome during the promoiety and then to the internal centromere region between sister chromatids during the promoiety and metaphase (zeitin SG, et al, j.cell biol., 2001; 155: 1147-. Aurora-B is involved in establishing the orientation of chromosomes, where sister centromeres are linked to the opposite pole of a bipolar spindle via bi-oriented attachment. The primary role of Aurora-B in mitotic stages is to repair incorrect microtubule-centromere attachment (Hauf S, et al, j.cell biol.,2003,161: 281-. In the case of Aurora-B inactivation, mitosis is impaired, leading to an increase in the number of aneuploid cells, gene instability and tumorigenesis (Weaver BA, et al, Cancer Cell,2005,8: 7-12). Aurora-B inhibition causes abnormal centromere-microtubule attachment, failure to achieve chromosomal bio-orientation, cytokinesis failure (Goto H, et al., J biol. chem.,2003,278: 8526-. The large polyploidy caused by repeated cycles of abnormal mitosis, excluding cytokinesis, ultimately leads to apoptosis (Hauf S, et al, J.Cell biol.,2003,161: 281-94; Ditchfield C, et al, J.Cell biol.,2003,161: 267-80; Giet R, et al, J.Cell biol., 2001; 152: 669-82; Murata-Hori M, Curr.biol.,2002,12: 894-.

Aurora overexpression is proved to be closely related to various malignant proliferative diseases, such as rectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, ovarian cancer, liver cancer, gastric cancer and the like, and the interest in developing Aurora inhibitors for cancer treatment is stimulated. In normal cells, Aurora-A inhibition causes centrosome separation defects and cytokinesis failure that slow but not block mitosis, unipolar mitotic spindles (Marumoto T, et al., J.biol.chem.,2003,278: 51786-. Among three human pancreatic Cancer cell lines (Panc-i, m Α PaCa-2dnsu.86.86), Aurora-a inhibitors showed encouraging anti-tumor effects, with results showing that Aurora-a inhibitors are able to inhibit the growth of tumor cells and, nearly total elimination of tumorigenicity in mouse xenografts (Hata T, et al, Cancer res, 2005,65: 2899-.

FLT3(Flt3, FMS-related tyrosine kinase 3), also known as FLK-2 (fetal liver kinase 2) and STK-I (human stem cell kinase 1), is a member of the receptor tyrosine kinase (RTK-III) family (Gtirewalt DL et al, Nat. Rev. cancer,2003,3: 650-. FLT3 is a transmembrane protein, composed of four domains, including an extracellular ligand-binding domain composed of five immunoglobulin-like structures, a Transmembrane (TM) domain, a Juxtamembrane (JM) domain, and a cytoplasmic C-terminal Tyrosine Kinase (TK) domain. (Agnes F, et al Gene, l994,145: 283-33288; Scheijen B, et al Oncogene,2002,21: 3314-3333).

The ligand for FLT3 was cloned in 1993 and was shown to be a type I transmembrane protein expressed in hematopoietic bone marrow microenvironment cells including bone marrow fibroblasts and other cells (Lyman SD, et al, Cell,1993,75, 1157-1167). Both membrane bound and soluble forms activate the tyrosine kinase activity of the receptor and stimulate progenitor cell growth in bone marrow and blood. Ligand-receptor binding induces receptor dimerization and activation of the kinase domain; it then autophosphorylates and catalyzes the phosphorylation of substrate proteins of various signal transduction pathways, such as signal transduction and transcriptional activator protein 5(STAT5), RAS/mitogen-activated protein kinase (RAS/MAPK), phosphoinositide 3-kinase (PI3K), Src homologous and collagen gene (SHC), SH 2-containing inositol-5-phosphatase (SHIP) and cytoplasmic tyrosine phosphatase with 2 Src-homology 2(SH2) domains (SHP2), which play an important role in cell proliferation, differentiation and survival (Dosil M., et al., mol. cell biol.,1993,13:6572-6585.Zhang S, biochem. Biophys. Res. Commun., l. 999,254: 440. Achain. 445). In addition to hematopoietic cells, the FLT3 gene is also expressed in the placenta, gonads and brain (Maroc N, et al., Oncogene,1993,8: 909-.

FLT3 is also associated with hematopoietic disorders that precede malignant proliferative disorders, such as thrombocythemia, polycythemia vera, Myelofibrosis (MF), chronic congenital myelofibrosis (IMF), Polycythemia (PV), precancerous myelodysplastic syndrome, hematological malignancies including, but not limited to, leukemia, (non-hodgkin's lymphoma), hodgkin's disease (also known as hodgkin's lymphoma), and myelomas, e.g., Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL), Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Neutrophilic Leukemia (CNL). FLT3 was overexpressed at various levels in 70-100% of Acute Myeloid Leukemia (AML) and in a high percentage of Acute Lymphoblastic Leukemia (ALL) (Griffin JD, et al, Haematol J.,2004,5: 188-. In the blast crisis, it is also overexpressed in smaller subtypes of Chronic Myelogenous Leukemia (CML). Studies have shown that the B lineage leukemia cells ALL and AML frequently co-express FLT3, causing autocrine or paracrine signaling cycles of constitutive activation of FLT3 (Zheng R, et al. In addition, FLT3 ligand was expressed at high levels in the cell serum of patients with langerhans cell histocytosis and systemic lupus erythematosus, further showing that FLT3 is closely associated with dendritic cell signaling dysregulation in autoimmune diseases.

There is increasing evidence that many types of leukemia and myeloproliferative syndromes have mutations in tyrosine kinases. FLT3 mutation is one of the most frequent mutations in AML, occurring in approximately 1/3 patients. Two types of mutations of FLT3 are described in leukemia patients. These include a series of Internal Tandem Duplications (ITDs) occurring in the self-inhibitory proximal membrane domain (Nakao M, et al., Leukemia,1996,10: 1911-. Internal tandem replication (ITD) mutations in the JM domain contribute to about 17-34% of activating mutations of FLT3 in AML. Low frequency mutations of FLT3-ITD were also detected in myelodysplastic syndrome (MDS) (Yokota S., et al, Leukemia, l997,11: 1605-. Both the FLT3-ITD and FLT3-Asp835 mutations are involved in FLT3 autophosphorylation and in the phosphorylation of downstream targets (Mizuki M, et al, Blood,2000,96: 3907-.

Currently, the FLT3 inhibitors in the research have entered clinical trials as monotherapies in some or all relapsed or refractory AML patients with FLT3 mutations. Collectively, these data indicate that FLT3 can be used to develop therapeutic targets for kinase inhibitors for the treatment of AML and other related diseases.

Janus kinases (JAKs) are intracellular non-receptor type tyrosine kinases that transduce cytokine mediated signals through the JAK-STAT pathways. The JAK family plays an important role in cytokine-dependent regulation of proliferation and cellular functions involved in immune responses. Cytokines bind to their receptors and cause receptor dimerization, which can promote the cross-phosphorylation of JAKs and also the phosphorylation of specific tyrosine motifs within cytokine receptors. STATs that recognize these phosphorylation motifs are aggregated on receptors and then activated during JAK-dependent tyrosine phosphorylation. Upon activation, STATs dissociate from receptors, dimerize, and translocate to the nucleus, bind to specific DNA sites, and alter transcription.

Currently, there are four known mammalian JAK family members: JAK1(Janus kinase-1), JAK2(Janus kinase-2), JAK3(Janus kinase, leukocytes, JAKL, L-JAK and Janus kinase-3) and TYK2 (protein tyrosine kinase 2). JAK1, JAK2 and TYK2 are widely expressed, whereas JAK3 is reported to be preferentially expressed in Natural Killer (NK) cells, but not in other T cells.

JAK1 is essential for the signaling of certain type I and type II cytokines. It is important for signaling with the gamma common chain (IFN-. gamma.) interferon of the type I cytokine receptor, as well as for signaling by members of the IL-10 family of type II cytokine receptors. Genetic biological studies have shown that JAK1 is functionally and physiologically associated with type I interferons (e.g., IFNalpha), type II interferons (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes. Furthermore, characterization of tissues derived from JAK1 knockout mice demonstrates a key role for this kinase in the IFN, IL-IO, IL-2/IL-4 and IL-6 pathways.

JAK1 expression in cancer cells can cause atrophy of individual cells, potentially allowing them to escape the tumor and metastasize to other parts of the body. The elevated levels of cytokines that transduce signals through JAK1 are implicated in a number of immune and inflammatory diseases. JAK1 or JAK family kinase inhibitors may be useful in the modulation or treatment of these diseases (Kisseleva et al, 2002, Gene 285: 1-24; Levy et al, 2005, Nat. Rev. mol. cell biol.,3: 651-662). Human monoclonal antibodies targeting the IL-6 pathway (Tocilizumab) were approved by the european commission for the treatment of moderate to severe rheumatoid arthritis (Scheinecker et al, 2009, nat. rev. drug discov.,8: 273-.

JAK2 is involved in signaling by members of the type II cytokine receptor family (e.g., interferon receptors), the GM-CSF receptor family, and the gp130 receptor family. JAK2 signals are activated downstream of the prolactin receptor. Studies have shown that an acquired activation of the JAK2 mutation (JAK2V617F) is prevalent in myeloproliferative diseases such as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. The mutant JAK2 protein is capable of activating downstream signals in the absence of cytokine stimulation, resulting in spontaneous growth and/or hypersensitivity to cytokines, which are thought to play a promoting role in the processes of these diseases. More mutations or translocations that cause dysfunction of JAK2 can be found in other malignancies (Ihle j.n.and Gilliland d.g., curr. opin. gene. dev.,2007,17: 8; Sayyah j.and Sayeski p.p., curr. oncol. rep.,2009,11: 117). JAK2 inhibitors have been described as having an effect on proliferative diseases (Santos et al, Blood,2010,115: 1131; Barosi g.and Rosti v., curr.opin.hematosol, 2009,16:129, atalah e.and Versotvsek s., exp.rev.anticancer ther.,2009,9: 663).

JAK3 is only associated with the common gamma cytokine receptor chain present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes. JAK3 is expressed primarily in immune cells and transduces signals through tyrosine phosphorylation activation of interleukin receptors. Since JAK3 is mostly restricted to expression in hematopoietic stem cells, its role in cytokine signaling is more stringent compared to other JAKs. Mutations in JAK3 result in Severe Combined Immunodeficiency (SCID) (O' Shea et al, 2002, Cell,109(suppl.): S121-S131). Based on their role in modulating lymphocytes, targeting JAK3 and JAK 3-mediated pathways has been used to treat immunosuppressive indications (e.g., transplant rejection and rheumatoid Arthritis) (Baslund et al, 2005, Arthritis & rhematic 52: 2686-.

TYK2 is associated with IFN- α, IL-6, IL-10 and IL-12 signaling. Biochemical studies and knockout mice have revealed an important role for TYK2 in immunity. TYK 2-deficient mice are able to grow and reproduce, but exhibit a variety of immunodeficiencies, mainly high sensitivity to infection and defects in tumor surveillance. Conversely, inhibition of TYK2 may improve the ability to fight allergic, autoimmune and inflammatory diseases. In particular, targeting TYK2 appears to be an innovative strategy for the treatment of IL-12-, IL-23-or type I IFN-mediated diseases. Such diseases include, but are not limited to, rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis, inflammatory bowel disease, uveitis, sarcoidosis, and cancer (Shaw, M.et al, Proc. Natl.Acad.Sci., USA,2003,100, 11594-.

The european commission has recently approved fully human monoclonal antibodies (usekinumab) targeting the p40 subunit common to both IL-12 and IL-23 cytokines for the treatment of moderate to severe plaque psoriasis (Krueger et al, 2007, n.engl.j.med.,356: 580-92; Reich et al, 2009, nat. rev.drug discov.,8: 355-356). In addition, antibodies targeting both the IL-12 and IL-23 pathways were tested in clinical trials for the treatment of Crohn's disease (Mannon et al, N.Engl. J.Med.,2004,351: 2069-79).

In dysregulation, JAK-mediated responses can affect cells positively or negatively, leading to over-activation of malignancies, or immune and hematopoietic deficiencies, respectively, suggesting utility for JAK kinase inhibitors. The JAK/STAT signaling pathway has been implicated in a number of proliferative and Cancer-related processes, including cell cycle progression, apoptosis, angiogenesis, infiltration, Metastasis and immune system evasion (Haura et al, Nature Clinical Practice Oncology,2005,2(6), 315-. In addition, the JAK/STAT signaling pathway plays an important role in hematopoietic stem cell generation and differentiation, dual regulation of pro-and anti-inflammatory, and immune response (O' Sullivan et al, Molecular Immunology,2007,44: 2497).

Thus, the JAK/STAT pathway, and in particular all four members of the JAK family, is thought to play a role in the pathogenesis of asthma responses, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. The JAK/STAT pathway also plays a role in inflammatory diseases of the eye (diseases)/diseases (conditions) including, but not limited to, iritis, uveitis, scleritis, conjunctivitis and slow hypersensitivity reactions. It may be useful to antagonize a specific cytokine-related disease or a disease associated with a mutation or polymorphism in the JAK/STAT pathway by using various forms of JAK kinases (O' Sullivan et al, mol. Immunol,2007,44: 2497; Murray j., Immunol,2007,178:2623) for cytokines to antagonize different selective JAK kinases within the family.

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation. Rheumatoid arthritis patients taking JAK inhibitors show inhibition of JAK1 and JAK3 module signals elicited by a variety of cytokines that are important for lymphocyte function, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 (Fleischmann, r., et al, "Placebo-controlled trial of tofacitinib mongerapy in rhematoid arthritis," n.engl.j.med.,2012,367, 495-. It is speculated that small molecule Inhibitors that directly inactivate specific JAK isoforms may not only alleviate the clinical symptoms of RA, but may also inhibit the over-regulation of many pro-inflammatory cytokines that contribute to the exacerbation of RA disease ("Inhibitors of JAKs for the treatment of inflammatory disorders: ratiometric and clinical data." clin.invest.,2012,2(1), 39-47).

Sustained activation of STAT3 or STAT5 has been demonstrated to be present in many solid tumors, including breast, pancreas, prostate, ovary, and liver cancers, as well as in a large number of hematologic tumors, including lymphomas and leukemias. In this regard, inactivation of JAK/STAT signals in hematological tumors can inhibit cell proliferation and/or induce apoptosis. Although STAT3 in tumor cells can be activated by many kinases, JAK2 is still considered to be the most important upstream activator, which can activate STAT3 in human tumor Cell lines derived from various solid tumors (Mohamad Bassam Sonbol, Belal Firwana, Ahmad Zarzour, Mohamad Morad, Vissal Rana and Ramon V.Tiu, Therapeutic Advances in Hematology 2013,4(1), 15-35; Hedvat M, Huszar D, Hernnrma A, Gozgit J M, Schroeder A, Shhyser A, et al cancer 2009,16(6): 487-97). Therefore, inhibition of JAK kinases plays a beneficial role in the treatment of these diseases.

It is clearly known that protein kinase inhibitors have gathered much attention as novel immunosuppressive, anti-inflammatory dual acting drugs and anti-cancer drugs. Therefore, new or improved agents inhibiting protein kinases such as Aurora kinase, FLT3 kinase, FLT4 kinase and JAK kinase have long been needed, which are useful as immunosuppressive and antitumor agents for organ transplantation, and also for the prevention and treatment of autoimmune diseases (e.g., multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, crohn's disease, polycythemia vera, essential thrombocythemia, myelofibrosis, autoimmune thyroid disease, alzheimer's disease), diseases involving overactivated inflammatory responses (e.g., eczema), allergy, chronic obstructive pulmonary disease, bronchitis, cancer (e.g., prostate cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, multiple myeloma) and immune responses induced by other therapies (e.g., rash, contact dermatitis or diarrhea), and the like. The compounds, compositions, and methods described in one or more embodiments of the present invention directly correspond to one or more of these needs and other objectives.

Disclosure of Invention

The present invention provides a class of compounds that inhibit, modulate and/or modulate the activity of one or more protein kinases, such as JAK kinase, FLT3 kinase, FLT4 kinase and Aurora kinase, for the treatment of one or more of proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and complications thereof. The invention also provides processes for preparing these compounds, methods of using these compounds to treat the above-mentioned disorders in mammals, especially humans, and pharmaceutical compositions containing these compounds. The compounds and compositions thereof of one or more embodiments of the present invention have a promising clinical application prospect. The compounds of one or more embodiments of the present invention have better pharmacological activity, pharmacokinetic properties, physicochemical properties, and lower toxicity than existing compounds of the same class. In particular, the compounds of one or more embodiments of the present invention exhibit good inhibitory activity against target kinases and optimized kinase selectivity, good absorption and high bioavailability in pharmacokinetic studies in animals; and the compound of one or more embodiments of the invention has no cardiotoxicity and good safety. Thus, the compounds according to one or more embodiments of the present invention have more excellent drugability.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I), or a prodrug thereof,

wherein the content of the first and second substances,

w is a saturated monocyclic heterocyclylene group or a saturated monocyclic C of 4 to 7 atoms₅-C₇Carbocyclyl optionally substituted with 1, 2, 3, 4 or 5R²Substituted by a group;

t is C₆-C₁₂Aryl or heteroaryl of 5 to 12 atoms, wherein T is optionally substituted by 1, 2, 3, 4 or 5R³Substituted by a group;

a is heteroaryl consisting of 9 atoms which is optionally substituted, which is one of the substructures shown by the following formula (A-1), (A-2), (A-3), (A-4), (A-5) or (A-6):

wherein each V₁And V₂Independently is CR⁴Or N;

each U₁、U₂And U₃Independently is CR⁴Or N;

each U₄And U₆Independently is CR⁴、N、NR⁵O or S;

U₅independently is CR⁴O or S;

wherein, the V₁、V₂、U₃、U₄、U₅And U₆At least one of which is not CR⁴；

Z is H, C₁-C₁₂Alkyl radical, C₃-C₁₂Cycloalkyl or a heterocyclic group of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₃-C₁₂Cycloalkyl and heterocyclyl consisting of 3 to 12 atoms are independently optionally substituted by 1, 2, 3, 4 or 5R⁹Substituted by a group;

R¹is H, F, Cl, Br, I, NO ₂、N₃、CN、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₃-C₁₂Cycloalkyl or a heterocyclic group of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₃-C₁₂Cycloalkyl and heterocyclyl consisting of 3 to 12 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group;

each R²And R³Independently F, Cl, Br, I, NO₂、CN、N₃、OH、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (C)₁-C₄Alkylene group) - (C₃-C₁₂Cycloalkyl), - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-12 atoms), - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), - (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms), - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-O(CR⁶R⁷)_n-R^c、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-N(R^c)C(＝O)NR^aR^b、-N(R^c)S(＝O)_mNR^aR^b、-C(＝O)N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (C)₁-C₄Alkylene group) - (C₃-C₁₂Cycloalkyl), - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-12 atoms), - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl) and- (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms) independently optionally substituted by 1, 2, 3, 4 or 5R⁹Substituted by a group;

each R⁴Independently H, F, Cl, Br, I, NO₂、N₃、CN、C₁-C₁₂Alkyl radical, C ₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-O(CR⁶R⁷)_n-R^c、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-N(R^c)C(＝O)NR^aR^b、-N(R^c)S(＝O)_mNR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bOr two adjacent R⁴Together with the carbon atom to which they are attached, form C₃-C₁₂A carbocyclic ring or a heterocyclic ring of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, C₃-C₁₂The carbocycle and the heterocycle of 3-12 atoms are independently optionally substituted with 1, 2, 3, 4 or 5R⁹Substituted by a group;

each R⁵Independently absent or H, C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclyl of 3 to 12 atoms and heteroaryl of 5 to 12 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group;

each R⁶And R⁷Independently H, F, Cl, Br, I, NO ₂、N₃、CN、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclyl of 3 to 12 atoms or heteroaryl of 5 to 12 atoms, or R⁶、R⁷Together with the carbon atom to which they are attached, form C₃-C₁₂A carbocyclic ring or a heterocyclic ring of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, C₃-C₁₂The carbocycle and the heterocycle of 3-12 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group;

each R⁸Independently is C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (C)₁-C₄Alkylene group) - (C₃-C₁₂Cycloalkyl), - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-12 atoms) or- (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms) wherein each R is⁸Independently optionally substituted by 1, 2 or 3R⁹Substituted by a group;

each R⁹Independently F, Cl, Br, I, CN, NO₂、N₃、-NH₂、-OH、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclyl consisting of 3 to 12 atoms, heteroaryl consisting of 5 to 12 atoms, -NH (C) ₁-C₁₂Alkyl), -NH (CH)₂)_n-(C₃-C₁₂Cycloalkyl), -NH (CH)₂)_n-(C₆-C₁₂Aryl), -NH (CH)₂)_n- (heterocyclic group consisting of 3 to 12 atoms), -NH (CH)₂)_n- (5-12 atom constituting heteroaryl), -N (C)₁-C₁₂Alkyl radical)₂、-N[(CH₂)_n-(C₃-C₁₂Cycloalkyl radicals]₂、-N[(CH₂)_n-(C₆-C₁₂Aryl radical)]₂、-N[(CH₂)_n- (3-12 atom constituting heterocyclic group)]₂、-N[(CH₂)_n- (5-12 atom constituting heteroaryl)]₂、-O(C₁-C₁₂Alkyl), -O (CH)₂)_n-(C₃-C₁₂Cycloalkyl), -O (CH)₂)_n-(C₆-C₁₂Aryl), -O (CH)₂)_n- (3-12 atom constituting heterocyclic group) or-O (CH)₂)_n- (5-12 atom constituting heteroaryl);

each R^a、R^bAnd R^cIndependently H, C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, - (C)₁-C₄Alkylene group) - (C₃-C₆Cycloalkyl), 3-6 heterocyclic group, - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-6 atoms), C₆-C₁₂Aryl, - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), heteroaryl of 5 to 12 atoms or- (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms), or R^a、R^bAnd together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4 to 7 atoms in which each of the above C' s₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, - (C)₁-C₄Alkylene group) - (C₃-C₆Cycloalkyl), 3-6 heterocyclic group, - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-6 atoms), C₆-C₁₀Aryl, - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), heteroaryl of 5 to 12 atoms, - (C) ₁-C₄Alkylene) - (heteroaryl of 5-12 atoms) and a heterocycle of 4-7 atoms optionally substituted with 1,2, 3 or 4 substituents independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆Substituted with a substituent of alkylamino;

each n is independently 0, 1,2, 3 or 4; and

each m is independently 1 or 2.

In some embodiments, W is one of the following heterocyclylene groups formed by heterocyclic compounds:

wherein each heterocyclic group formed by the heterocycles represented by the formulae (W-1) to (W-23) is independently optionally substituted by 1 or 2Or 3R²Substituted by a group; wherein each R is²Have the meaning as described in the present invention.

In some embodiments, W is one of the following substructures:

wherein each of the sub-structural formulae represented by the above formulae (W-31) to (W-67) is independently optionally substituted by 1,2 or 3R²Substituted by a group; wherein each R is²Have the meaning as described in the present invention.

In some embodiments, T is phenyl or heteroaryl of 5-6 atoms, wherein T is optionally substituted with 1,2, 3, or 4R³Substituted by a group; wherein each R is³Have the meaning as described in the present invention.

In some embodiments, T is phenyl, pyridyl, pyridonyl, pyrimidinyl, pyrimidinonyl, pyridazinyl, pyrazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiazolyl, isothiazolyl, tetrazolyl, triazolyl, thienyl, pyrazolyl, oxadiazolyl, thiadiazolyl, or triazinyl, wherein T is optionally substituted with 1,2, or 3R ³Substituted by a group; wherein each R is³Have the meaning as described in the present invention.

In some embodiments, a is a 9 atom heteroaryl group that is one of the substructures shown below:

wherein, in the sub-structural formula of A, hydrogen on each CH is independently and optionally substituted by R⁴Substituted by radicals, each hydrogen on NH independently being optionally substituted by R⁵Substituted by a group; wherein each R is⁴And R⁵Have the meaning as described in the present invention.

In some embodiments, Z is H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or heterocyclyl consisting of 4 to 7 atoms, wherein each of said C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl and heterocyclyl consisting of 4 to 7 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Have the meaning as described in the present invention.

In some embodiments, Z is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or cyclobutyl.

In some embodiments, R¹Is H, F, Cl, Br, NO₂、N₃、CN、C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₃-C₆Cycloalkyl or heterocyclyl consisting of 4 to 7 atoms, wherein each of said C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₃-C₆Cycloalkyl and heterocyclyl consisting of 4 to 7 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Have the meaning as described in the present invention.

In some embodiments, each R is²And R³Independently F, Cl, Br, NO₂、CN、N₃、OH、C₁-C₄Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl, phenyl, heterocyclyl of 4-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁸、R⁹、R^a、R^b、R^cN and m have the meanings given in the description.

In some embodiments, each R is⁴Independently H, F, Cl, Br, NO₂、CN、N₃、C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bOr two adjacent R⁴Together with the carbon atom to which they are attached, form C₃-C₆A carbocyclic ring or a heterocyclic ring of 4 to 7 atoms, wherein each of said C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, C ₃-C₆The carbocycle and the heterocycle of 4-7 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁸、R⁹、R^a、R^b、R^cN and m have the meanings given in the description.

In some embodiments, each R is⁴Independently H, F, Cl, Br, N₃CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, (CR)⁶R⁷)_nC(＝O)OR^cOr- (CR)⁶R⁷)_nC(＝O)NR^aR^bOr two adjacent R⁴Together with the carbon atom to which they are attached, form C₄-C₆A carbocyclic ring or a heterocyclic ring of 4 to 7 atoms, wherein each of said methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₄-C₆The carbocycle and the heterocycle of 4-7 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁹、R^a、R^b、R^cAnd n has the meaning described in the present invention.

In some embodiments, each R is⁵Independently absent or H, C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C ₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl of 4-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁸、R⁹、R^a、R^b、R^cN and m have the meanings given in the description.

In some embodiments, each R is⁵Independently absent or H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, - (CR)⁶R⁷)_nC(＝O)OR^cOr- (CR)⁶R⁷)_nC(＝O)NR^aR^bWherein each of the methyl group, ethyl group, n-propyl group, isopropyl group, sec-propyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and-CH group₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁹、R^a、R^b、R^cAnd n has the meaning described in the present invention.

In some embodiments, each R is⁶And R ⁷Independently H, F, Cl, Br, CN, C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl of 4 to 7 atoms or heteroaryl of 5 to 6 atoms, or R⁶、R⁷Together with the carbon atom to which they are attached, form C₃-C₆A carbocyclic ring or a heterocyclic ring of 4 to 7 atoms in which each of said C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, C₃-C₆The carbocycle and the heterocycle of 4-7 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Having the structure of the inventionMeaning.

In some embodiments, each R is⁸Independently is C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (C)₁-C₃Alkylene group) - (C₃-C₆Cycloalkyl), - (C)₁-C₃Alkylene) - (heterocyclic group consisting of 4-7 atoms), - (C)₁-C₃Alkylene) -phenyl or- (C)₁-C₃Alkylene) - (heteroaryl of 5-6 atoms) wherein each R is⁸Independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Have the meaning as described in the present invention.

In some embodiments, each R is ⁹Independently F, Cl, Br, CN, N₃、-NH₂、-OH、C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, -NH (C)₁-C₆Alkyl), -NH (CH)₂)_n-(C₃-C₆Cycloalkyl), -NH (CH)₂)_n-phenyl, -NH (CH)₂)_n- (heterocyclic group consisting of 4 to 7 atoms), -NH (CH)₂)_n- (5-6 atom constituting heteroaryl), -N (C)₁-C₆Alkyl radical)₂、-N[(CH₂)_n-(C₃-C₆Cycloalkyl radicals]₂、-N[(CH₂)_n-phenyl radical]₂、-N[(CH₂)_n- (4-7 atom-constituting heterocyclic group)]₂、-N[(CH₂)_n- (5-6 atom constituting heteroaryl)]₂、-O(C₁-C₆Alkyl), -O (CH)₂)_n-(C₃-C₆Cycloalkyl), -O (CH)₂)_n-phenyl, -O (CH)₂)_n- (4-7 atoms)Heterocyclyl) or-O (CH)₂)_n- (5-6 atom constituting heteroaryl); wherein each n has the meaning described in the present invention.

In some embodiments, each R is^a、R^bAnd R^cIndependently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl consisting of 4 to 6 atoms, phenyl, heteroaryl consisting of 5 to 6 atoms, - (C)₁-C₂Alkylene group) - (C₃-C₆Cycloalkyl), - (C)₁-C₂Alkylene) - (heterocyclic group consisting of 4-7 atoms), - (C)₁-C₂Alkylene) -phenyl or- (C)₁-C₂Alkylene) - (heteroaryl of 5-6 atoms), or R^a、R^bAnd together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl radical, wherein each of the above methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C ₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl consisting of 4 to 6 atoms, phenyl, heteroaryl consisting of 5 to 6 atoms, - (C)₁-C₂Alkylene group) - (C₃-C₆Cycloalkyl), - (C)₁-C₂Alkylene) - (heterocyclic group consisting of 4-7 atoms), - (C)₁-C₂Alkylene) -phenyl or- (C)₁-C₂Alkylene) - (5-6 atom-constituting heteroaryl), azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄Substituted by a substituent of alkylamino.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable excipients, carriers, vehicles.

In other embodiments, the pharmaceutical composition of the invention further comprises an additional therapeutic agent selected from at least one of a chemotherapeutic agent, an antiproliferative agent, a phosphodiesterase 4(PDE4) inhibitor, a β 2-adrenoceptor agonist, a corticosteroid, a non-steroidal GR agonist, an anticholinergic agent, an antihistamine, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, a drug for treating atherosclerosis, a drug for treating pulmonary fibrosis.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention, treatment or amelioration of a protein kinase mediated disease.

In some embodiments, the protein kinase mediated disease of the invention is a JAK-mediated disease, FLT 3-mediated disease, FLT 4-mediated disease, or Aurora-mediated disease.

In other embodiments, the protein kinase-mediated disease of the invention is a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, transplant rejection, or cancer.

In yet other embodiments, the protein kinase-mediated disease of the invention is a cancer (e.g., colorectal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, gastric cancer, esophageal cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, head and neck cancer, cancer of the CNS (central nervous system), glioblastoma, non-small cell lung cancer, cervical cancer, testicular tumor, lymphoma, multiple myeloma, malignant lymphoma, small cell lung cancer, neuroblastoma, neuroendocrine tumor, medullary thyroid cancer, melanoma, retinoblastoma, uterine cancer, ovarian cancer, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), primary macroglobulinemia, monocytic leukemia, and the like, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, atherosclerosis, pulmonary fibrosis, polycythemia vera, essential thrombocythemia, myelofibrosis, chronic obstructive pulmonary disease, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, allergic diseases of the respiratory tract, sinusitis, eczema, measles, food allergies, insect venom allergies, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, organ transplant rejection, tissue transplant rejection, or cell transplant rejection.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for modulating the activity of a protein kinase.

In some embodiments, the protein kinase of the invention is at least one of JAK kinase, FLT3 kinase, FLT4 kinase Aurora kinase.

In other embodiments, the protein kinase of the invention is at least one of JAK1 kinase, JAK2 kinase, JAK3 kinase, TYK2 kinase, Aurora-a kinase, Aurora-B kinase, FLT3 kinase, FLT4 kinase.

In yet another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

Biological test results show that the compound provided by the invention can be used as a better protein kinase inhibitor, especially as a JAK kinase inhibitor, such as JAK1 kinase and JAK2 kinase inhibitors.

Any of the embodiments of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any of the embodiments of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict each other.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied, unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2) ^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classified and encompassed within the examples.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure that may be substituted is replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the scenario where the heterocyclic group is substituted with an alkyl and the scenario where the heterocyclic group is not substituted with an alkyl.

The term "unsubstituted" means that the specified group bears no substituents.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, CN, N ₃、-NO₂、-OH、-SH、-NH₂、-(CR⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-O(CR⁶R⁷)_n-R^c、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-N(R^c)C(＝O)NR^aR^b、-N(R^c)S(＝O)_mNR^aR^b、-C(＝O)N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸、-(CR⁶R⁷)_nS(＝O)_mNR^aR^bAlkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylthio, alkylamino, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like, wherein each R is independently selected from the group consisting of⁶、R⁷、R⁸、R^a、R^b、R^cM and n have the definitions as described in the rest of the present application.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… … independently" and "… … independently" and "… … independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "M-M₁"or" M-M of a ring atom₁"consisting of atoms" means that the cyclic group consists of M-M₁A ring member including carbon atoms and/or heteroatoms such as O, N, S, P, wherein M-M₁Denotes M and M₁And M to M₁An integer in between. For example, "heteroaryl of 6 to 10 atoms" means that it includes heteroaryl of 6, 7, 8, 9 or 10 ring atoms.

The term "one or more" includes 1, 2, 3, 4, 5 or 6. Y1 to Y2 in the term "of Y1 to Y2 carbon atoms" means Y1 and Y2, and integers between Y1 to Y2, for example, "1 to 20 carbon atoms" represents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

The term "alkyl" or "alkyl group" as used herein, means a saturated, straight or branched chain, monovalent hydrocarbon radical containing 1 to 20 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 2 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 2 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 2, 2-dimethylbutyl (neopentyl, -CH)₂CH(CH₃)₂CH₃) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkylene" denotes a saturated divalent or polyvalent hydrocarbon radical resulting from the removal of two or more hydrogen atoms from a saturated straight or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 (1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. In some embodiments, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains 1 to 4 carbon atoms; in other embodiments, the alkylene group contains from 0 to 4 carbon atoms; in still other embodiments, the alkylene group contains from 0 to 3 carbon atoms; in still other embodiments, the alkylene group contains 1 to 3 carbon atoms; in still other embodiments, the alkylene group contains from 0 to 2 carbon atoms; in still other embodiments, the alkylene group contains 1 to 2 carbon atoms. Alkylene having 0 carbon atoms means that alkylene is absent and is directly a single bond. Examples of alkylene groups include, but are not limited to, methylene (-CH) ₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like.

The term "heteroalkyl" denotes an alkaneOne or more (1, 2, 3, 4, 5 or 6) heteroatoms may be inserted into the radicals, where alkyl and heteroatoms have the meaning according to the invention. Heteroalkyl groups are attached to other groups through carbon atoms. Unless otherwise specified, a heteroalkyl group contains from 1 to 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, in other embodiments from 1 to 8 carbon atoms, in other embodiments from 1 to 6 carbon atoms, in other embodiments from 1 to 4 carbon atoms, and in other embodiments from 1 to 3 carbon atoms. Examples of "heteroalkyl" include, but are not limited to, -CH₂OCH₃、-CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₃、-CH₂SCH₃、-CH₂N(CH₃)₂、-CH₂OCH₂(CH₃)₂、-CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃And the like.

The term "heteroalkylene" refers to a saturated divalent or polyvalent hydrocarbyl radical resulting from the removal of two or more hydrogen atoms from a heteroalkyl radical. Heteroalkylidene is attached to another group through a carbon atom. Unless otherwise specified, a heteroalkylene group contains 1-12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. In some embodiments, the heteroalkylene group contains 1 to 6 carbon atoms; in other embodiments, the heteroalkylene group contains 1 to 4 carbon atoms; in still other embodiments, the heteroalkylene group contains 1 to 3 carbon atoms. Examples of heteroalkylene groups include, but are not limited to, -CH ₂OCH₂-、-CH₂CH₂OCH₂CH₂-、-CH₂CH₂OCH₂-、-CH₂SCH₂-、-CH₂N(CH₃)CH₂-、-CH₂OCH₂(CH₃)CH₂-、-CH₂CH₂NHCH₂-、-CH₂CH₂NHCH₂CH₂-and so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 (2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In some embodiments, alkenyl groups contain 2 to 8 carbon atoms; in other embodiments, alkenyl groups contain 2 to 6 carbon atoms; in still other embodiments, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And so on. The alkenyl group may be optionally substituted with one or more substituents described herein.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein the alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH) ₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH) ₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more (1, 2, 3, 4, 5 or 6) halogen atoms, examples of which include, but are not limited to, difluoroethyl (-CH)₂CHF₂,-CF₂CH₃,-CHFCH₂F) Trifluoroethyl (-CH)₂CF₃,-CF₂CH₂F,-CFHCHF₂) Trifluoromethyl (-CF)₃) Trifluoromethoxy (-OCF)₃) And the like.

The terms "hydroxyalkyl" and "hydroxyalkoxy" mean alkyl or alkoxy, as the case may be, substituted with one or more (1, 2, 3, 4, 5, or 6) hydroxy groups, where "hydroxyalkyl" and "hydroxyalkyl" may be used interchangeably, and examples include, but are not limited to, hydroxymethyl (-CH)₂OH), hydroxyethyl (-CH)₂CH₂OH,-CHOHCH₃) Hydroxypropyl group (-CH)₂CH₂CH₂OH,-CH₂CHOHCH₃,-CHOHCH₂CH₃, -hydroxymethoxy (-OCH)₂OH), and the like.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or polyvalent, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms. Carbobicyclic groups include spirocarbocyclic, fused carbobicyclic, and bridged carbobicyclic groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. In some embodiments, carbocyclyl contains 3 to 12 carbon atoms; in other embodiments, carbocyclyl contains 3 to 8 carbon atoms; in other embodiments, carbocyclyl contains 5 to 7 carbon atoms; in other embodiments, carbocyclyl contains 3 to 6 carbon atoms; in other embodiments, carbocyclyl contains 4 to 6 carbon atoms. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms. In some embodiments, cycloalkyl groups contain 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms.In some embodiments, cycloalkyl is C comprising 7 to 12 carbon atoms₇-C₁₂Cycloalkyl, which further comprises C₇-C₁₂Spirobicycloalkyl radical, C₇-C₁₂Fused bicycloalkyl and C₇-C₁₂Bridged bicycloalkyl; in other embodiments, cycloalkyl is C containing 8 to 11 carbon atoms₈-C₁₁Cycloalkyl, which further comprises C₈-C₁₁Spirobicycloalkyl radical, C₈-C₁₁Fused bicycloalkyl and C₈-C₁₁Bridged bicyclic alkyl. Examples of cycloalkyl groups include, but are not limited to: c₃-C₆Cycloalkyl specifically refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a mono-, bi-or tricyclic ring system containing 3 to 12 (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, at least one of which is selected from one or more of carbon, nitrogen, sulfur, oxygen, phosphorus and/or silicon atoms, which is monovalent or multivalent, saturated or partially unsaturated, and which is not aromatic. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH ₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Heterocyclyl includes saturated heterocyclyl (i.e., heterocycloalkyl) and partially unsaturated heterocyclyl. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinylAlkyl, oxacycloheptyl, thiacycloheptyl, oxazepine

Radicals (e.g. 1, 4-oxaza)

1, 2-oxaza

Alkyl), diazepine

Radicals (e.g. 1, 4-diazepine)

1, 2-diazepines

Basic), dioxa

Radicals (e.g. 1, 4-dioxa)

1, 2-dioxan

Basic), a sulfur aza

Radicals (e.g. 1, 4-thiazepine)

1, 2-thiaza radical

Indolyl), indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, 2-azaspiro [4.4]Nonanyl, 1, 6-dioxaspiro [4.4 ]]Nonanyl, 2-azaspiro [4.5 ]]Decyl, 8-azaSpiro [4.5 ]]Decyl, 7-azaspiro [4.5 ]]Decyl, 3-azaspiro [5.5 ]]Undecyl, 2-azaspiro [5.5]Undecyl, octahydro-1H-isoindolyl, octahydrocyclopenta [ c]Pyrrolyl, hexahydrofuro [3,2-b ] groups]Furyl and dodecahydroisoquinolinyl, and the like. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 1, 1-dioxoisothiazolinone-2-yl, pyrrolidin-2-one-1-yl, imidazolidin-2-one-1-yl, oxazolidin-2-one-3-yl, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholinyl, 1-dioxotetrahydrothienyl, and 1, 1-dioxotetrahydro-2H-thiopyranyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

In some embodiments, heterocyclyl is a 3-8 atom heterocyclyl and refers to a monovalent or polyvalent, saturated or partially unsaturated, nonaromatic, monocyclic ring of 3-8 ring atoms wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 8 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxacycloheptyl, oxazepanyl, thiazepanyl, and the like

Radical diaza

Radical, sulfur nitrogen hetero

And the like. In heterocyclic radicals of-CH₂Examples of-group substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl, and the like. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 8 atoms may be optionally substituted by one or more substituents as described herein.

In other embodiments, heterocyclyl is a 4-7 atom heterocyclyl and refers to a monovalent or polyvalent, saturated or partially unsaturated, nonaromatic, monocyclic ring of 4-7 ring atoms wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, 1-dioxoisothiazolidin-2-yl, pyrrolidin-2-on-1-yl, imidazolidin-2-on-1-yl, oxazolidin-2-on-3-yl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, piperazinyl, Homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl

Radical diaza

Radical and sulfur aza

And (4) a base. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.

The terms "heterocyclylene" and "heterocyclylene" are used interchangeably herein and refer to a divalent, saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, at least one of which is selected from one or more of carbon, nitrogen, sulfur, oxygen, phosphorus and/or silicon atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, a heterocyclylene is a 4-7 atom heterocyclylene, meaning a divalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic ring of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH ₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Said 4-7 atom heterocycle ring may be optionally substituted with one or more substituents as described herein.

In other embodiments, a heterocyclylene is a 4 atom heterocyclylene, meaning a divalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 4 ring atoms in which at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 4-atom heterocycle ring may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. The 4-membered heterocyclylene may be optionally substituted with one or more substituents described herein.

In other embodiments, a heterocyclylene is a 5 atom heterocyclylene, meaning a divalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 5 ring atoms in which at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocycle ring may be carbon-based or nitrogen-based, and-CH ₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. The 5-membered heterocyclic ring may be optionally substituted with one or more substituents described herein.

In other embodiments, a heterocyclylene is a 6 atom heterocyclylene, meaning a divalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 6 ring atoms in which at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 6 atom heterocycle ring may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. The 6-membered heterocyclylene may be optionally substituted with one or more substituents described herein.

In other embodiments, a heterocyclylene is a 7 atom heterocyclylene, meaning a divalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 7 ring atoms in which at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 7-atom heterocycle ring may be carbon-based or nitrogen-based, and-CH ₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound.The 7-atom heterocyclic ring may be optionally substituted with one or more substituents described herein.

The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, wherein at least one ring atom is selected from one or more of carbon, nitrogen, sulfur, oxygen, phosphorus, and/or silicon atoms. Unless otherwise indicated, heterocycloalkyl can be carbon or nitrogen based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterobicycloalkyl groups include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, and tetrahydrothianyl

Radicals (e.g. 1, 4-oxaza)

1, 2-oxaza

Alkyl), diazepine

Radicals (e.g. 1, 4-diazepine)

1, 2-diazepines

Basic), dioxa

Radicals (e.g. 1, 4-dioxa)

1, 2-dioxan

Basic), a sulfur aza

Radicals (e.g. 1, 4-thiazepine)

1, 2-thiaza radical

Yl), 2-azaspiro [4.4]Nonanyl, 1, 6-dioxaspiro [4.4 ]]Nonanyl, 2-azaspiro [4.5 ]]Decyl, 8-azaspiro [4.5 ]]Decyl, 7-azaspiro [4.5 ]]Decyl, 3-azaspiro [5.5 ]]Undecyl, 2-azaspiro [5.5]Undecyl, octahydrocyclopenta [ c]Pyrrolyl, octahydro-1H-isoindolyl, hexahydrofuro [3,2-b ]]Furyl, hexahydrofuro [2,3-b ]]Furyl and dodecahydroisoquinolinyl. The heterocycloalkyl group can be optionally substituted with one or more substituents described herein.

In some embodiments, heterocycloalkyl is a heterocycloalkyl consisting of 4 to 7 atoms, and refers to a monovalent or polyvalent, saturated heterocyclic group containing 4 to 7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms. Unless otherwise indicated, heterocycloalkyl can be carbon or nitrogen based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocycloalkyl groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, hexakis Hydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl

Radical diaza

Radical and sulfur aza

And (4) a base. The heterocycloalkyl group of 4 to 7 atoms may be optionally substituted with one or more substituents as described herein.

The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and 1,2,3, 4-tetrahydronaphthyl is a carbocyclyl group of 10 atoms.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (e.g., N in 3, 4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl). The heterocyclyl, heterocyclylene, heterocycloalkyl, heteroalkyl, heteroalkylene, heteroaryl groups described herein may contain 1,2,3,4, 5, or 6 heteroatoms selected from O, S, N, P and/or Si.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "azido" or "N₃"represents an azide structure. Such groups may be linked to other groups, e.g. to a methyl group to form azidomethane (Men)₃) Or linked to a phenyl group to form azidobenzene (PhN)₃)。

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 (6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes aromatic, non-inclusive mono-, bi-and tricyclic ring systems containing 5 to 12 (5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, and at least one ring system contains one or more (1, 2, 3, 4, 5 or 6) heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus and/or silicon, wherein each ring system contains a ring of 5, 6 or 7 atoms, and one or more attachment points are attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-12 atom composed of 1, 2, 3, or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is 5-10 atom composed of 1, 2, 3, or 4 heteroatoms independently selected from O, S and N. In still other embodiments, heteroaryl is 5-6 atom consisting of heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S and N. The heteroaryl group is optionally substituted with one or more substituents described herein.

Examples of 5-12 atom-composed heteroaryl groups include, but are in no way limited to, the following bicyclic heteroaryl groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [4,3-c ] pyridyl, pyrazolo [3,4-b ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, pyrazolyl, and the like, Imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, [1,2,4] triazolo [4,3-a ] pyridinyl, imidazo [1,2-c ] pyrimidinyl, 1H-benzo [ d ] [1,2,3] triazolyl, 3H-imidazo [4,5-b ] pyridinyl, 1H-pyrrolo [2,3-b ] pyridinyl, 1H-benzo [ d ] imidazolyl, 1H-pyrazolo [3,2-b ] pyridinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, purinyl, and the like. Examples of heteroaryl groups of 5-12 atoms also include monocyclic heteroaryl groups of 5-6 atoms, examples of which include, but are not limited to, monocyclic rings, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridonyl, pyrimidinyl (e.g., 2-pyrimidinyl, pyrimidinyl), 4-pyrimidinyl, 5-pyrimidinyl), pyrimidinonyl, pyrimidinedionyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl, 3-pyrazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), pyrazolinonyl, isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, and 1,3, 5-triazinyl, and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO₂H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl"Or "acyloxy", represents- (C ═ O) -.

The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. Wherein, in some embodiments, the alkylamino group is one or two C₁-C₁₂The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C₁-C₆The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, alkylamino is one or two C₁-C₄The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In still other embodiments, the alkylamino group is one or two C₁-C₃The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-ethylpropyl-2-amino, and the like.

The term "arylamino" denotes an amino group substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

The term "aminoalkyl" includes C substituted with one or more amino groups₁-C₁₂A straight or branched alkyl group. In some embodiments, aminoalkyl is C substituted with one or more amino groups₁-C₁₂An alkyl group; in other embodiments, aminoalkyl is C substituted with one or more amino groups₁-C₆"lower aminoalkyl", in other embodiments, aminoalkyl is C substituted with one or more amino groups₁-C₄An alkyl group; in still other embodiments, aminoalkyl is C substituted with one or more amino groups₁-C₃An alkyl group. Examples of aminoalkyl radicalsExamples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

As described herein, a substituent that describes a ring system formed on a ring with a bond to the center (as shown in formula b) represents a substituent that is alternatively substituted at all substitutable positions on the ring system. For example, the substituent R represented by the formula b may be substituted at all positions on the ring D which may be substituted, as shown in formulas c to e.

As described herein, the ring system formed by the attachment of two linkages to the center of the ring (as shown in formula i) means that both linkages can be attached to the rest of the molecule at any point on the ring system that is attachable and the two ends of the attachment (end points Q and Q') can be interchanged. Formula i represents that any two possible attachment positions on the G ring can be attached to the rest of the molecule.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyl formate (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH ₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-silyl)Benzenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, which are formed by reaction with amino groups, or which are obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, bisulfates, salts of sodium, potassium, sodium, potassium, sodium, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺(C₁-C₄Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitableNon-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, e.g. halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

As used herein, "inflammatory disease" refers to any disease, disorder or condition of excessive inflammatory symptoms, host tissue damage or loss of tissue function due to excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.

By "specific defense system" is meant that components of the immune system respond to the presence of a particular antigen. Examples of inflammation arising from specific defense system responses include classical responses to foreign antigens, autoimmune diseases, and delayed hypersensitivity responses (mediated by T-cells). Chronic inflammatory diseases, rejection of transplanted solid tissues and organs (such as rejection of kidney and bone marrow transplants), and Graft Versus Host Disease (GVHD) are other examples of specific defense systems against inflammatory reactions.

As used herein, "autoimmune disease" refers to any collection of diseases of tissue damage associated with humoral or cell-mediated responses to the body's own components.

As used herein, "allergy" refers to any symptom of developing an allergy, tissue damage, or loss of tissue function. As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia, or lymphoproliferative disorder (lymphoproliferative disorders). More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, testicular tumor, bladder cancer, hepatoma (hepatoma), breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, medullary thyroid cancer, melanoma, retinoblastoma, liver cancer (hepatoma), anal cancer, penile carcinoma, acute myelogenous leukemia, acute lymphocytic leukemia, Chronic Myelogenous Leukemia (CML), Chronic lymphocytic leukemia and head and neck cancer.

Description of the Compounds of the invention

The compounds disclosed by the invention can be used as inhibitors of the activity of protein kinases, particularly JAK kinase, FLT4 kinase, FLT3 kinase and Aurora kinase. Compounds that are inhibitors of protein kinases are useful in the treatment of diseases associated with inappropriate protein kinase activity, particularly inappropriate JAK kinase, FLT4 kinase, FLT3 kinase and Aurora kinase activity, for example in the treatment and prevention of JAK kinase, FLT4 kinase, FLT3 kinase and Aurora kinase mediated diseases involving signaling pathways. Such diseases include proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and complications thereof. In particular, the compounds of the invention may be used to treat diseases such as cancer (colorectal, Hodgkin's lymphoma, non-Hodgkin's lymphoma, gastric, esophageal, breast, lung, liver, prostate, pancreatic, thyroid, bladder, kidney, brain, head and neck, CNS (central nervous system) cancer, glioblastoma, non-small cell lung, cervical, testicular, lymphoid, multiple myeloma, malignant lymphoma, small cell lung, neuroblastoma, neuroendocrine, medullary thyroid, melanoma, retinoblastoma, uterine cancer, ovarian, acute myelogenous leukemia, acute lymphocytic leukemia, Chronic Myelogenous Leukemia (CML), chronic lymphocytic leukemia, primary macroglobulinemia, monocytic leukemia, Sezary syndrome, prostate cancer, infectious mononucleosis, colitis, pancreatitis, atherosclerosis, pulmonary fibrosis, polycythemia vera, primary thrombocythemia, myelofibrosis, Chronic Obstructive Pulmonary Disease (COPD), asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, allergic diseases of the respiratory tract, sinusitis, eczema, measles, food allergies, insect venom allergies, inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, organ transplant rejection, tissue transplant rejection, cell transplant rejection, and the like.

In some embodiments, the compounds of the present disclosure exhibit strong inhibitory activity against one or more protein kinases.

In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I), or a prodrug thereof,

wherein the content of the first and second substances,

w is a saturated monocyclic heterocyclylene group or a saturated monocyclic C of 4 to 7 atoms₅-C₇Carbocyclyl optionally substituted with 1, 2, 3, 4 or 5R²Substituted by a group;

t is C₆-C₁₂Aryl or heteroaryl of 5 to 12 atoms, wherein T is optionally substituted by 1, 2, 3, 4 or 5R³Substituted by a group;

a is heteroaryl consisting of 9 atoms which is optionally substituted, which is one of the substructures shown by the following formula (A-1), (A-2), (A-3), (A-4), (A-5) or (A-6):

wherein each V₁And V₂Independently is CR⁴Or N;

each U₁、U₂And U₃Independently is CR⁴Or N;

each U₄And U₆Independently is CR⁴、N、NR⁵O or S;

U₅independently is CR⁴O or S;

wherein, the V₁、V₂、U₃、U₄、U₅And U₆At least one of which is not CR⁴；

Z is H, C₁-C₁₂Alkyl radical, C₃-C₁₂Cycloalkyl or a heterocyclic group of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₃-C₁₂Cycloalkyl and heterocyclyl consisting of 3 to 12 atoms are independently optionally substituted by 1, 2, 3, 4 or 5R ⁹Substituted by a group;

R¹is H, F, Cl, Br, I, NO₂、N₃、CN、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₃-C₁₂Cycloalkyl or a heterocyclic group of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₃-C₁₂Cycloalkyl and heterocyclyl consisting of 3 to 12 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group;

each R²And R³Independently F, Cl, Br, I, NO₂、CN、N₃、OH、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (C)₁-C₄Alkylene group) - (C₃-C₁₂Cycloalkyl), - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-12 atoms), - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), - (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms), - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-O(CR⁶R⁷)_n-R^c、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-N(R^c)C(＝O)NR^aR^b、-N(R^c)S(＝O)_mNR^aR^b、-C(＝O)N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (C)₁-C₄Alkylene group) - (C₃-C₁₂Cycloalkyl), - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-12 atoms), - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl) and- (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms) independently optionally substituted by 1, 2, 3, 4 or 5R⁹Substituted by a group;

each R ⁴Independently H, F, Cl, Br, I, NO₂、N₃、CN、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-O(CR⁶R⁷)_n-R^c、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-N(R^c)C(＝O)NR^aR^b、-N(R^c)S(＝O)_mNR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bOr two adjacent R⁴Together with the carbon atom to which they are attached, form C₃-C₁₂A carbocyclic ring or a heterocyclic ring of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, C₃-C₁₂The carbocycle and the heterocycle of 3-12 atoms are independently optionally substituted with 1, 2, 3, 4 or 5R⁹Substituted by a group;

each R⁵Independently absent or H, C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nC(＝O)R⁸、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₁-C₁₂Hydroxyalkyl radical, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclyl of 3 to 12 atoms and heteroaryl of 5 to 12 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group;

Each R⁶And R⁷Independently H, F, Cl, Br, I, NO₂、N₃、CN、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclyl of 3 to 12 atoms or heteroaryl of 5 to 12 atoms, or R⁶、R⁷Together with the carbon atom to which they are attached, form C₃-C₁₂A carbocyclic ring or a heterocyclic ring of 3 to 12 atoms, wherein each of said C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic ring of 3-12 atomsRadical, 5-12 atoms of heteroaryl, C₃-C₁₂The carbocycle and the heterocycle of 3-12 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group;

each R⁸Independently is C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C₆-C₁₂Aryl, heterocyclic group of 3-12 atoms, heteroaryl of 5-12 atoms, - (C)₁-C₄Alkylene group) - (C₃-C₁₂Cycloalkyl), - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-12 atoms) or- (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms) wherein each R is⁸Independently optionally substituted by 1, 2 or 3R⁹Substituted by a group;

each R⁹Independently F, Cl, Br, I, CN, NO₂、N₃、-NH₂、-OH、C₁-C₁₂Alkyl radical, C₁-C₁₂Heteroalkyl group, C₂-C₁₂Alkenyl radical, C₂-C₁₂Alkynyl, C₃-C₁₂Cycloalkyl radical, C ₆-C₁₂Aryl, heterocyclyl consisting of 3 to 12 atoms, heteroaryl consisting of 5 to 12 atoms, -NH (C)₁-C₁₂Alkyl), -NH (CH)₂)_n-(C₃-C₁₂Cycloalkyl), -NH (CH)₂)_n-(C₆-C₁₂Aryl), -NH (CH)₂)_n- (heterocyclic group consisting of 3 to 12 atoms), -NH (CH)₂)_n- (5-12 atom constituting heteroaryl), -N (C)₁-C₁₂Alkyl radical)₂、-N[(CH₂)_n-(C₃-C₁₂Cycloalkyl radicals]₂、-N[(CH₂)_n-(C₆-C₁₂Aryl radical)]₂、-N[(CH₂)_n- (3-12 atom constituting heterocyclic group)]₂、-N[(CH₂)_n- (5-12 atom groups)To heteroaryl groups)]₂、-O(C₁-C₁₂Alkyl), -O (CH)₂)_n-(C₃-C₁₂Cycloalkyl), -O (CH)₂)_n-(C₆-C₁₂Aryl), -O (CH)₂)_n- (3-12 atom constituting heterocyclic group) or-O (CH)₂)_n- (5-12 atom constituting heteroaryl);

each R^a、R^bAnd R^cIndependently H, C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, - (C)₁-C₄Alkylene group) - (C₃-C₆Cycloalkyl), 3-6 heterocyclic group, - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-6 atoms), C₆-C₁₂Aryl, - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), heteroaryl of 5 to 12 atoms or- (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms), or R^a、R^bAnd together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4 to 7 atoms in which each of the above C' s₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, - (C)₁-C₄Alkylene group) - (C₃-C₆Cycloalkyl), 3-6 heterocyclic group, - (C)₁-C₄Alkylene) - (heterocyclic group consisting of 3-6 atoms), C ₆-C₁₀Aryl, - (C)₁-C₄Alkylene group) - (C₆-C₁₂Aryl), heteroaryl of 5 to 12 atoms, - (C)₁-C₄Alkylene) - (heteroaryl of 5-12 atoms) and a heterocycle of 4-7 atoms optionally substituted with 1,2, 3 or 4 substituents independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆Substituted with a substituent of alkylamino;

each n is independently 0, 1,2, 3 or 4; and

each m is independently 1 or 2.

In some embodiments, W is one of the following heterocyclylene groups formed by heterocyclic compounds:

wherein each heterocyclic group formed by the heterocycles represented by the formulae (W-1) to (W-23) is independently optionally substituted by 1,2 or 3R²Substituted by a group; wherein each R is²Have the meaning as described in the present invention.

In some embodiments, W is one of the following substructures:

wherein each of the sub-structural formulae represented by the above formulae (W-31) to (W-67) is independently optionally substituted by 1,2 or 3R²Substituted by a group; wherein each R is²Have the meaning as described in the present invention.

In some embodiments, T is phenyl or heteroaryl of 5-6 atoms, wherein T is optionally substituted with 1,2, 3, or 4R³

Substituted by a group; wherein each R is³Have the meaning as described in the present invention.

In some embodiments, T is phenyl, pyridyl, pyridonyl, pyrimidinyl, pyrimidinonyl, pyridazinyl, pyrazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiazolyl, isothiazolyl, tetrazolyl, triazolyl, thienyl, pyrazolyl, oxadiazolyl, thiadiazolyl, or triazinyl, wherein T is optionally substituted by 1, 2 or 3R³Substituted by a group; wherein each R is³Have the meaning as described in the present invention.

In some embodiments, a is a 9 atom heteroaryl group that is one of the substructures shown below:

wherein, in the sub-structural formula of A, hydrogen on each CH is independently and optionally substituted by R⁴Substituted by radicals, each hydrogen on NH independently being optionally substituted by R⁵Substituted by a group; wherein each R is⁴And R⁵Have the meaning as described in the present invention.

In some embodiments, Z is H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl or heterocyclyl consisting of 4 to 7 atoms, wherein each of said C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl and heterocyclyl consisting of 4 to 7 atoms are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Have the meaning as described in the present invention.

In some embodiments, Z is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or cyclobutyl.

In some embodiments, R¹Is H, F, Cl, Br, NO₂、N₃、CN、C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₃-C₆Cycloalkyl or heterocyclyl consisting of 4 to 7 atoms, wherein each of said C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₃-C₆Cycloalkyl and heterocyclyl consisting of 4 to 7 atomsIndependently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is ⁹Have the meaning as described in the present invention.

In some embodiments, each R is²And R³Independently F, Cl, Br, NO₂、CN、N₃、OH、C₁-C₄Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl, phenyl, heterocyclyl of 4-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁸、R⁹、R^a、R^b、R^cN and m have the meanings given in the description.

In some embodiments, each R is⁴Independently H, F, Cl, Br, NO₂、CN、N₃、C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_n-N(R^c)C(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸、-N(R^c)S(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bOr two adjacent R⁴Together with the carbon atom to which they are attached, form C₃-C₆A carbocyclic ring or a heterocyclic ring of 4 to 7 atoms, wherein each of said C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, C ₃-C₆The carbocycle and the heterocycle of 4-7 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁸、R⁹、R^a、R^b、R^cN and m have the meanings given in the description.

In some embodiments, each R is⁴Independently H, F, Cl, Br, N₃CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, (CR)⁶R⁷)_nC(＝O)OR^cOr- (CR)⁶R⁷)_nC(＝O)NR^aR^bOr two adjacent R⁴Together with the carbon atom to which they are attached, form C₄-C₆A carbocyclic ring or a heterocyclic ring of 4 to 7 atoms, wherein each of said methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₄-C₆The carbocycle and the heterocycle of 4-7 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁹、R^a、R^b、R^cAnd n has the meaning described in the present invention.

In some embodiments, each R is⁵Independently absent or H, C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C ₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (CR)⁶R⁷)_n-OR^c、-(CR⁶R⁷)_n-NR^aR^b、-(CR⁶R⁷)_nOC(＝O)R⁸、-(CR⁶R⁷)_nC(＝O)OR^c、-(CR⁶R⁷)_nC(＝O)NR^aR^b、-(CR⁶R⁷)_nS(＝O)_mR⁸Or- (CR)⁶R⁷)_nS(＝O)_mNR^aR^bWherein each of C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₁-C₆Hydroxyalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl of 4-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁸、R⁹、R^a、R^b、R^cN and m have the meanings given in the description.

In some embodiments, each R is⁵Independently absent or H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, - (CR)⁶R⁷)_nC(＝O)OR^cOr- (CR)⁶R⁷)_nC(＝O)NR^aR^bWherein each of the methyl group, ethyl group, n-propyl group, isopropyl group, sec-propyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and-CH group₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl are independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁶、R⁷、R⁹、R^a、R^b、R^cAnd n has the meaning described in the present invention.

In some embodiments, each R is⁶And R ⁷Independently H, F, Cl, Br, CN, C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, phenyl, 4-7 atomsOr a heteroaryl group of 5 to 6 atoms, or R⁶、R⁷Together with the carbon atom to which they are attached, form C₃-C₆A carbocyclic ring or a heterocyclic ring of 4 to 7 atoms in which each of said C₁-C₄Alkyl radical, C₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, C₃-C₆The carbocycle and the heterocycle of 4-7 atoms are independently optionally substituted with 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Have the meaning as described in the present invention.

In some embodiments, each R is⁸Independently is C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, - (C)₁-C₃Alkylene group) - (C₃-C₆Cycloalkyl), - (C)₁-C₃Alkylene) - (heterocyclic group consisting of 4-7 atoms), - (C)₁-C₃Alkylene) -phenyl or- (C)₁-C₃Alkylene) - (heteroaryl of 5-6 atoms) wherein each R is⁸Independently optionally substituted by 1, 2 or 3R⁹Substituted by a group; wherein each R is⁹Have the meaning as described in the present invention.

In some embodiments, each R is ⁹Independently F, Cl, Br, CN, N₃、-NH₂、-OH、C₁-C₆Alkyl radical, C₁-C₆Heteroalkyl group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, heterocyclyl consisting of 4 to 7 atoms, heteroaryl consisting of 5 to 6 atoms, -NH (C)₁-C₆Alkyl), -NH (CH)₂)_n-(C₃-C₆Cycloalkyl), -NH (CH)₂)_n-phenyl, -NH (CH)₂)_n- (4-7 atoms)Constituent heterocyclyl), -NH (CH)₂)_n- (5-6 atom constituting heteroaryl), -N (C)₁-C₆Alkyl radical)₂、-N[(CH₂)_n-(C₃-C₆Cycloalkyl radicals]₂、-N[(CH₂)_n-phenyl radical]₂、-N[(CH₂)_n- (4-7 atom-constituting heterocyclic group)]₂、-N[(CH₂)_n- (5-6 atom constituting heteroaryl)]₂、-O(C₁-C₆Alkyl), -O (CH)₂)_n-(C₃-C₆Cycloalkyl), -O (CH)₂)_n-phenyl, -O (CH)₂)_n- (4-7 atom constituting heterocyclic group) or-O (CH)₂)_n- (5-6 atom constituting heteroaryl); wherein each n has the meaning described in the present invention.

In some embodiments, each R is^a、R^bAnd R^cIndependently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl consisting of 4 to 6 atoms, phenyl, heteroaryl consisting of 5 to 6 atoms, - (C)₁-C₂Alkylene group) - (C₃-C₆Cycloalkyl), - (C)₁-C₂Alkylene) - (heterocyclic group consisting of 4-7 atoms), - (C)₁-C₂Alkylene) -phenyl or- (C)₁-C₂Alkylene) - (heteroaryl of 5-6 atoms), or R^a、R^bAnd together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl radical, wherein each of the above methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, C ₁-C₄Heteroalkyl group, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl consisting of 4 to 6 atoms, phenyl, heteroaryl consisting of 5 to 6 atoms, - (C)₁-C₂Alkylene group) - (C₃-C₆Cycloalkyl), - (C)₁-C₂Alkylene) - (heterocyclic group consisting of 4-7 atoms), - (C)₁-C₂Alkylene) -phenyl or- (C)₁-C₂Alkylene) - (5-6 atom-constituting heteroaryl), azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, CN, N₃、-OH、-NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄Substituted by a substituent of alkylamino.

In some embodiments, the present invention relates to compounds, or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, of one of the following, but in no way limited to these compounds:

stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) are included within the scope of the present invention unless otherwise indicated.

The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

The compounds of formula (I) may exist in different tautomeric forms, and all such tautomers, such as those described herein, are included within the scope of the present invention.

The compounds of formula (I) may be present in the form of salts. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In other embodiments, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).

Pharmaceutically acceptable acid addition salts may be formed by reaction of a compound of formula (I) with an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, and phosphoric acids, and the like.

Organic acids from which salts can be derived include, for example, acetic, propionic, glycolic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, and sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H、¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotopically enriched compounds can be used for metabolic studies (use) ¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The pharmaceutical composition of the invention Agents include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable excipients, carriers, and vehicles. In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

In another aspect, the invention relates to a method of treating a disease or disorder modulated by one or more protein kinases, such as JAK kinase, FLT3 kinase, FLT4 kinase and Aurora kinase, comprising administering to a mammal an effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the disease or disorder is selected from a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, transplant rejection, or cancer.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention disclosed herein for the treatment of a disease or disorder selected from a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, transplant rejection or cancer.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the treatment of a disease or disorder selected from a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, transplant rejection or cancer.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention disclosed herein for the preparation of a medicament for modulating the activity of a protein kinase that is at least one of JAK1 kinase, JAK2 kinase, JAK3 kinase, TYK2 kinase, Aurora-a kinase, Aurora-B kinase, FLT3 kinase, FLT4 kinase; in particular, inhibiting the activity of a JAK kinase, for example, the activity of JAK1 kinase and/or JAK2 kinase.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound disclosed herein, or as listed in the examples; and at least one of pharmaceutically acceptable adjuvants, excipients, carriers, and solvents. The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect inhibition of a protein kinase in a biological sample or patient.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

The pharmaceutical compositions disclosed herein can be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) can be extracted and then administered to a patient in the form of a powder or syrup. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.

The term "pharmaceutically acceptable excipient" as used herein refers to a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected which may aid in the manufacture of stable dosage forms. Certain pharmaceutically acceptable excipients that facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient may be selected. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and may provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and at least one of a pharmaceutically acceptable adjuvant, excipient, carrier, vehicle, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, granules and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and lyophilized powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

In some embodiments, the compounds disclosed herein can be formulated in oral dosage forms. In other embodiments, the compounds disclosed herein may be formulated in an inhalation dosage form. In other embodiments, the compounds disclosed herein can be formulated for nasal administration. In still other embodiments, the compounds disclosed herein can be formulated for transdermal administration. In still other embodiments, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. patent No. 6,350,458.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.

Coloring and flavoring agents may be used in all of the above dosage forms.

The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (f: (f))

CyDex,Lenexa,KS)。

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

In some embodiments, the pharmaceutical composition is provided as a ready-to-use sterile solution. In other embodiments, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In still other embodiments, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In still other embodiments, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In some embodiments, the pharmaceutical composition is formulated as a sterile emulsion ready for use.

The disclosed pharmaceutical compositions may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In some embodiments, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In some embodiments, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In still other embodiments, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Aerosols can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art

The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.

For treatment of the eye, or other organs such as the mouth and skin, the composition may be applied as a topical ointment or cream. When formulated as an ointment, the disclosed compounds may be used with a paraffinic or water soluble ointment base. Alternatively, the disclosed compounds may be formulated as a cream with an oil-in-water cream base or an oil-in-water base.

Use of the Compounds and compositions of the invention

The present invention provides methods of using the disclosed compounds and pharmaceutical compositions for treating, preventing, or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by the behavior of one or more protein kinases, such as JAK kinases (including JAK1, JAK2, JAK3, and TYK2 kinases), FLT4 kinase, FLT3 kinase (also known as FLK-2) or Aurora kinases (including Aurora-A, Aurora-B and Aurora-C), or a disease or disorder mediated or otherwise affected by the behavior of one or more protein kinases, such as JAK kinases (including JAK1, JAK2, JAK3, and TYK2 kinase), FLT4 kinase, FLT3 kinase (also known as FLK-2), or Aurora kinases (including Aurora-A, Aurora-B and Aurora-C).

The JAK kinase can be a wild-type and/or mutant of JAK1, JAK2, JAK3, or TYK2 kinase.

In some embodiments, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for treating, preventing or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase behavior or a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase behavior. In other embodiments, the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate JAK2 kinase behavior. In some embodiments, the disease, disorder, or one or more symptoms of the disease or disorder are associated with inappropriate JAK3 kinase behavior.

In some embodiments, the invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in treating, preventing or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate FLT3 kinase behavior or a disease or disorder mediated or otherwise affected by inappropriate FLT3 kinase behavior.

In some embodiments, the invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in treating, preventing or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate FLT4 kinase behavior or a disease or disorder mediated or otherwise affected by inappropriate FLT4 kinase behavior.

In some embodiments, the invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in treating, preventing, or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate Aurora-a kinase behavior or a disease or disorder mediated or otherwise affected by inappropriate Aurora-a kinase behavior. In other embodiments, the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate Aurora-B kinase behavior. In some embodiments, the disease, disorder, or one or more symptoms of the disease or disorder are associated with inappropriate Aurora-C kinase activity.

By "inappropriate JAK kinase behavior" is meant JAK kinase behavior that occurs in a particular patient that deviates from normal JAK kinase behavior. Inappropriate JAK kinase behavior can be expressed in the form of, for example, abnormal increases in activity, or deviations in the time point and control of JAK kinase behavior. This inappropriate kinase behavior results, for example, from inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinases. Accordingly, the present invention provides methods of treating these diseases and disorders.

Consistent with the above description, such diseases or disorders include, but are not limited to: primary macroglobulinemia, monocytic leukaemia, Sezary syndrome, infectious mononucleosis, colitis, pancreatitis, atherosclerosis, pulmonary fibrosis, myeloproliferative diseases, such as polycythemia vera (PCV), essential thrombocythemia, Idiopathic Myelofibrosis (IMF); leukemias, e.g., myeloid leukemias including Chronic Myeloid Leukemia (CML), imatinib-resistant CML forms, Acute Myeloid Leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as Acute Lymphoblastic Leukemia (ALL), myeloma; cancers include colorectal cancer, hodgkin lymphoma, non-hodgkin lymphoma, gastric cancer, esophageal cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, head and neck cancer, cancer of the CNS (central nervous system), glioblastoma, non-small cell lung cancer, cervical cancer, testicular tumor, lymphoid cancer, multiple myeloma, malignant lymphoma, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, medullary thyroid cancer, melanoma, retinoblastoma, uterine cancer, and ovarian cancer, among others; and inflammatory diseases or disorders associated with immune dysfunction, immunodeficiency, immune modulation, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease including crohn's disease and Ulcerative Colitis (UC), Systemic Lupus Erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and Chronic Obstructive Pulmonary Disease (COPD), and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

In one aspect, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in the prevention and/or treatment of a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, transplant rejection or cancer in a mammal (including a human).

In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of suffering from a disease disclosed herein, comprising administering a condition treating effective amount or a condition preventing effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In another aspect, provided herein is a method of treating a mammal suffering from or at risk of suffering from a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, transplant rejection, or cancer.

In one method of therapeutic aspects, the invention provides methods of treating and/or preventing a mammal susceptible to or suffering from a proliferative disease comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular examples, the proliferative disease is selected from cancer (e.g., a solid tumor such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL), and multiple myeloma.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of a proliferative disease. In particular embodiments, the proliferative disease is selected from the group consisting of cancer (e.g., a solid tumor such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL), and multiple myeloma.

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of a proliferative disease. In particular examples, the proliferative disease is selected from cancer (e.g., solid tumor, uterine leiomyosarcoma, or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL, or CLL), and multiple myeloma.

In another aspect, provided herein is a method of treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, the method comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In a particular example, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of autoimmune diseases. In a particular embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for treating or preventing an autoimmune disease. In a particular embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.

In another aspect, provided herein is a method of treating and/or preventing a mammal susceptible to or suffering from an allergic disease, the method comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of allergic diseases. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an allergic disease. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.

In another aspect, provided herein is a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular embodiments, the inflammatory disease is selected from inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of an inflammatory disease. In particular embodiments, the inflammatory disease is selected from inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an inflammatory disease. In particular embodiments, the inflammatory disease is selected from inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.

In another aspect, provided herein is a method of treating and/or preventing a mammal susceptible to or suffering from transplant rejection comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular examples, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, provided herein is a class of compounds disclosed herein for use in the treatment and/or prevention of transplant rejection. In particular embodiments, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, provided herein is a class of compounds disclosed herein, or a pharmaceutical composition comprising a compound disclosed herein, for use in the preparation of a medicament for treating or preventing transplant rejection. In particular examples, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.

In another aspect, provided herein is a class of compounds disclosed herein for use as a medicament, particularly for use as a medicament in the treatment and/or prevention of the aforementioned diseases. Also provided is the use of a compound disclosed herein for the manufacture of a medicament for the treatment and/or prevention of the aforementioned diseases.

One particular embodiment of the present methods comprises administering to a subject having inflammation an effective amount of a compound disclosed herein for a time sufficient to reduce the level of inflammation in the subject, and preferably to stop the progression of the inflammation. Particular embodiments of the method comprise administering to a subject suffering from or susceptible to bone rheumatoid arthritis an effective amount of a compound disclosed herein for a time sufficient to reduce or prevent, respectively, inflammation of the joints of said subject, and preferably to stop the progression of said inflammation.

Another particular embodiment of the method comprises administering to a subject having a proliferative disease an effective amount of a compound of the disclosure for a time sufficient to reduce the level of the proliferative disease in the subject and preferably to stop the progression of the proliferative disease. Particular embodiments of the method comprise administering to a subject having cancer an effective amount of a compound disclosed herein for a time sufficient to reduce or prevent, respectively, the signs of cancer in said subject, and preferably to stop the progression of said cancer.

Combination therapy

The compounds of the present invention may be administered as the sole active agent or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are identified as safe and effective for such combination administration.

In one aspect, the invention provides a method of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the disclosure and one or more therapeutically active agents. In some embodiments, the combination comprises one or two additional therapeutic agents.

Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and antiproliferative agents; an anti-inflammatory agent; and an immunomodulator or immunosuppressant.

In another aspect, the invention provides products comprising a compound of the invention and at least one other therapeutic agent, formulated for simultaneous, separate or sequential administration in therapy. In some embodiments, the treatment is of a disease or condition mediated by one or more protein kinase, such as JAK kinase, FLT4 kinase, FLT3 kinase, or Aurora kinase activity. The products provided by the combined preparation include compositions comprising a compound disclosed herein and other therapeutic agent in the same pharmaceutical composition, or in different forms, e.g., a kit.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents. In some embodiments, the pharmaceutical composition may comprise a pharmaceutically acceptable adjuvant, excipient, carrier, adjuvant, or vehicle as described above.

In another aspect, the invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound disclosed herein. In some embodiments, the kit comprises means for separately holding the compositions, such as a container, a separate bottle, or a separate foil box. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.

The invention also provides the use of a compound of the invention in the treatment of a disease or condition mediated by protein kinase activity, wherein the patient has been previously (e.g. within 24 hours) treated with another therapeutic agent. The invention also provides the use of other therapeutic agents in the treatment of diseases and conditions mediated by protein kinase activity, such as JAK kinase, FLT4 kinase, FLT3 kinase and Aurora kinase, in which a patient has been previously (e.g. within 24 hours) treated with a compound of the invention.

The compounds disclosed herein may be administered as a single active ingredient or as, for example, an adjuvant, co-administered with other therapeutic agents.

In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent and/or an antiproliferative agent. Known chemotherapeutic agents include, but are not limited to, other therapeutic or anti-cancer drugs that may be used in combination with the compounds of the present invention, surgery, radiation therapy (a few examples are gamma radiation, neutron beam radiation, electron beam radiation, proton therapy, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (paclitaxel, docetaxel, etc.), platinum derivatives (cisplatin), carboplatin (carboplatin), biological response modifiers (interferons, interleukins), tumor necrosis factor (TNF, TRAIL receptor targets), hyperthermia and cryotherapy, agents to mitigate any adverse effects (e.g., anti-emetics), and other approved chemotherapeutic drugs including, but not limited to, alkylating drugs (mechlorethamine), chlorambucil (chlorembucil), cyclophosphamide (cyclophosphamide)Amines (cyclophosphamide), melphalam (melphalam), ifosfamide (ifosfamide)), antimetabolites (methotrexate), pemetrexed (pemetrexed), etc., purine and pyrimidine antagonists (6-mercaptopurine (6-mercaptoprine), 5-fluorouracil (5-fluoroouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), spindle inhibitors (vinblastine), vincristine (vincetine), vinorelbine (vinorelbine), podophyllotoxin (etoposide), irinotecan (irinotecan), topotecan (topotecan), antibiotics (doxorubicin (doruxobicin), bleomycin (bleomycin), mitomycin (mitomycin), semicarbazide (carmustine), cytostatine (carmotene (CDK), cytosin (CDK-amide), cytostasin (KSP), and cytostasin (CDK-inhibitors) Hormones (tamoxifen), leuprolide, flutamide, megestrol, dexamethasone, etc.). Anti-angiogenic agents (avastin, etc.). Mabs (belimumab), brentuximab, cetuximab (cetuximab), gemtuzumab (gemtuzumab), ipilimumab (ipilimumab), ofatumumab, panitumumab (panitumumab), ranibizumab (ranibizumab), rituximab (rituximab), tositumomab (tositumomab), trastuzumab (trastuzumab). Kinase inhibitors (imatinib), sunitinib (sunitinib), sorafenib (sorafenib), erlotinib (erlotinib), gefitinib (gefitinib), dasatinib (dasatinib), nilotinib (nilotinib), lapatinib (lapatinib), crizotinib (crizotinib), ruxolitinib, vemurafenib, vandetanib, pazopanib, and the like). Drugs inhibit or activate cancer pathways such as mTOR, the HIF (hypoxia inducible factor) pathway, and others. A broad forum for cancer treatment http://www.nci.nih.gov/FAD approved oncology drug listhttp:// www.fda.gov/cder/cancer/druglist-rame.htmAnd merck manual, eighteenth edition, 2006, all of which are incorporated by reference. In other embodiments, the compounds of the invention may bind to cytotoxic anticancer agents. Such an anticancer agent mayFound in the Merck index of the thirteenth edition (2001). These anticancer agents include, but are in no way limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin D, daunorubicin, doxorubicin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine. Other suitable cytotoxic agents for use in combination with the compounds of the present invention include, but are not limited to, those compounds which are generally recognized for use in the treatment of neoplastic diseases, as described in: goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition,1996, McGraw-Hill.); these anti-cancer agents include, but are in no way limited to, aminoglutethimide (aminoglutethimide), L-asparaginase, azathioprine, 5-azacytidine, cladribine (cladribine), busulfan (busufan), diethylstilbestrol, 2' -difluorodeoxycytidylcholine, docetaxel, erythrohydroxynonanyladenine (erythrohydroxynonyladenine), ethinylestradiol, 5-fluorouracil deoxynucleoside, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate (fludarabphospate), flumethyltestosterone (fluoxymetasone), flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interferon, medroxyprogesterone acetate, megestrol acetate, mellan (mellan), mitotane (mitane), paclitaxel, pentostatin (totriptine), N-acetyl-cysteine L (palatinomycin), nitrosurea (paminomycin L), and cysteine (paminomycin L), nitrosamine (paminomycin L) phosphate (cysteine(s), and cysteine (meprobamate (palatinomycin L), teniposide (teniposide), testosterone propionate, thiotepa (thiotepa), trimethylmelamine, uridine, and vinorelbine.

Other suitable cytotoxic anticancer agents for use in combination with the compounds of the present invention include newly discovered cytotoxic agents including, but not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), capecitabine (capecitabine), macrolide antineoplastics and natural or synthetic derivatives thereof, temozolomide (temozolomide) (Quinn et al, j.clin. Oncology,2003,21(4), 646-.

In still other embodiments, the compounds of the invention may bind to a signal transduction inhibitor. Signal transduction inhibitors target the EGFR family, such as EGFR, HER-2 and HER-4(Raymond et al, Drugs,2000,60 (supply. l), 15-23; Harari et al, Oncogene,2000,19(53),6102-6114) and their respective ligands. Such agents include, but are in no way limited to, antibody therapies such as trastuzumab (trastuzumab), cetuximab (cetuximab), ipilimumab (ipilimumab) and pertuzumab (pertuzumab). Such therapies also include, but are in no way limited to, small molecule kinase inhibitors such as imatinib (imatinib), sunitinib (sunitinib), sorafenib (sorafenib), erlotinib (erlotinib), gefitinib (gefitinib), dasatinib (dasatinib), nilotinib (nilotinib), lapatinib (lapatinib), crizotinib (crizotinib), ruxolitinib, vemurafenib, zonantanib, papanib, afatinib (afatinib), amuvanib, axitinib (axitinib), bosutinib (bosutinib), brivatinib, canertinib, cabozantinib, celandinib, cediranib (cediranib), daraflavicularinib, dasatinib, coritinib, coriertinib, saratinib, coriertinib (coridinib), coriertinib, cori, et al, j.med.chem.2008,51,5522), BZE235, and so forth.

In some embodiments, the compounds disclosed herein may also be co-administered with other drugs. Such other drugs include, immunosuppressants, immunomodulators, other anti-inflammatory agents, for example, drugs for the treatment or prevention of acute or chronic rejection of allo or xenografts, inflammatory, autoimmune diseases; or chemotherapeutic agents, such as malignant cell antiproliferative agents. For example, the compounds disclosed herein may be combined with the following active ingredients: calcineurin inhibitors, such as cyclosporin a or FK 506; mTOR inhibitors, such as rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981, etc.; a corticosteroid; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspergualin or an immunosuppressive homolog, analog or derivative thereof; PKC inhibitors, such as those described in WO 02/38561 or WO 03/82859, e.g., the compounds of examples 56 or 70; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or ligands thereof; other immunomodulatory compounds, such as recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or mutants thereof, such as at least an extracellular portion of CTLA4 linked to a non-CTLA 4 protein sequence or mutants thereof, such as CTLA4Ig (e.g., designated ATCC 68629) or mutants thereof, such as LEA 29Y; adhesion molecule inhibitors, such as LFA-1 antagonists, ICAM-1 or-3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or chemotherapeutic agents, such as paclitaxel, gemcitabine, cisplatin, doxorubicin, or 5-fluorouracil; or an anti-infective agent.

Where the compounds disclosed herein are administered in combination with other immunotherapeutic/immunomodulator, anti-inflammatory, chemotherapeutic or anti-infective therapies, the dosage of the immunosuppressant, immunomodulator, anti-inflammatory, chemotherapeutic or anti-infective compound administered in combination will, of course, vary depending on the type of combination employed, e.g., whether it is a steroid or calcineurin inhibitor, the particular drug employed, the condition being treated, etc.

In one aspect, the invention provides a composition comprising a compound of the disclosure and beta₂-a combination of adrenergic receptor agonists. Beta is a₂Examples of-adrenoceptor agonists include salmeterol, salbutamol, formoterol, salmeterol, fenoterol, carmoterol, eltanolate, naminterol, clenbuterol, pirbuterol, flubuterol, reproterol, prometrol, indacaterol, terbutaline, and salts thereof, such as the xinafoate salt of salmeterol (1-hydroxy-2-naphthoate), the sulfate or free base of salbutamol, or the fumarate salt of formoterol. In some embodiments, long-acting beta₂Adrenergic receptor agonists, such as compounds which provide effective bronchodilation for 12 hours or more, are preferred.

β₂-the adrenoceptor agonist may form a salt form with a pharmaceutically acceptable acid. The pharmaceutically acceptable acid is selected from the group consisting of sulfuric acid, hydrochloric acid, fumaric acid, hydroxynaphthoic acid (e.g., 1-or 3-hydroxy-2-naphthoic acid), cinnamic acid, substituted cinnamic acids, triphenylacetic acid, sulfamic acid, sulfanilic acid, 3- (1-naphthyl) acrylic acid, benzoic acid, 4-methoxybenzoic acid, 2-or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, and 4-phenylbenzoic acid.

In another aspect, the invention provides a combination comprising a compound of the disclosure and a corticosteroid. Suitable corticosteroids are those that are administered orally and inhaled, and prodrugs thereof that have anti-inflammatory activity. Examples include methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), S-fluoromethyl 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17 β -thiocarboxylate, S-fluoromethyl 6 α,9 α -difluoro-17 α - [ (2-furancarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androsta-1, 4-diene-17 β -thiocarboxylate (fluticasone furoate), 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-3-oxo-17 α -propionyloxy-androsta-1, 4-diene-17 β -carbothioic acid S- (2-oxo-tetrahydrofuran-3S-yl) ester, 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-3-oxo-17 α - (2,2,3, 3-tetramethylcyclopropylcarbonyl) oxy-androsta-1, 4-diene-17 β -carbothioic acid S-cyanomethyl ester and 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - (1-ethylcyclopropylcarbonyl) oxy-3-oxo-androsta-1, s-fluoromethyl 4-diene-17 β -thiocarboxylate, beclomethasone esters (such as 17-propionate or 17, 21-dipropionate), budesonide (budesonide), flunisolide (flunisolide), mometasone esters (such as mometasone furoate), triamcinolone acetonide (triamcinolone acetonide), rofleponide (rofleponide), ciclesonide (ciclesonide) (16 α,17- [ [ (R) -cyclohexylmethylene ] bis (oxy) ] -11 β, 21-dihydroxy-pregna-1, 4-diene-3, 20-dione), butocort propionate (butixocort propionate), RPR-106541 and ST-126. Preferred corticosteroids include fluticasone propionate (fluticasone propionate), 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17 β -carbothioic acid S-fluoromethyl ester, 6 α,9 α -difluoro-17 α - [ (2-furancarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androsta-1, 4-diene-17 β -carbothioic acid S-fluoromethyl ester, 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-3-oxo-17 α - (2,2,3, 3-tetramethylcyclopropylcarbonyl) oxy-androsta-1, 4-diene-17 β -carbothioic acid S-cyanomethyl ester and 6 α,9 α -difluoro-11 β -hydroxy-16 α -methyl-17 α - (1-methylcyclopropylcarbonyl) oxy-3-oxo-androsta-1, 4-diene-17 β -carbothioic acid S-fluoromethyl ester. In some embodiments, the corticosteroid is S-fluoromethyl 6 α,9 α -difluoro-17 α - [ (2-furancarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androsta-1, 4-diene-17 β -thiocarboxylate.

In another aspect, the invention provides a combination comprising a compound of the disclosure and a non-steroidal GR agonist. Non-steroidal compounds with glucocorticoid agonistic activity that are selective for transcriptional inhibition (as compared to transcriptional activation) and are useful in combination therapy include those encompassed by the following patents: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO 04/026248, WO 03/061651 and WO 03/08277. Further non-steroidal compounds are covered in WO 2006/000401, WO 2006/000398 and WO 2006/015870.

In another aspect, the present invention provides a combination comprising a compound of the present disclosure and non-steroidal anti-inflammatory drugs (NSAID's). Examples of NSAID's include cromolyn sodium, nedocromil sodium (nedocromil sodium), Phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (e.g., montelukast), iNOS inhibitors, trypsin and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g., adenosine 2a receptor agonists), cytokine antagonists (e.g., chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors. Among them, iNOS (inducible nitric oxide synthase) inhibitors are preferably administered orally. Examples of iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. CCR3 inhibitors include those disclosed in WO 02/26722.

In some embodiments, the invention relates to the use of the disclosed compounds in combination with phosphodiesterase 4(PDE4) inhibitors, particularly in an inhaled dosage form. The PDE 4-specific inhibitors useful in this aspect of the invention may be any compound known to inhibit the PDE4 enzyme or found to be useful as a PDE4 inhibitor, which are only PDE4 inhibitors and are not compounds that inhibit other members of the PDE family, such as PDE3 and PDE 5. The compounds include cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [ 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol ]; also included are cis-4-cyano-4- [3- (cyclopropoxy) -4-methoxyphenyl ] cyclohexane-1-carboxylic acid (also known as silox) and salts, esters, prodrugs, or physical forms thereof, which is disclosed in U.S. patent No. 5,552,438, issued 09/03, 1996, which patent and the compounds disclosed therein are incorporated by reference in their entirety.

In another aspect, the present invention provides a combination comprising a compound of the present disclosure and an anticholinergic agent. Examples of anticholinergics are those compounds which act as muscarinic receptor antagonists, in particular those which act as M1 or M3 receptor antagonists, M ₁/M₃Or M₂/M₃Dual receptor antagonists or M₁/M₂/M₃Compounds which are pan-antagonists of the receptor. Exemplary compounds for inhalation administration include ipratropium (e.g., as bromide, CAS 22254-24-6, to

Sold under the trade name), oxitropium (e.g., as bromide, CAS 30286-75-0) and tiotropium (e.g., as bromide, CAS 136310-93-5), to

Sold under trade name); also of interest are revatoxate (e.g., as the hydrobromide salt, CAS 262586-79-8) and LAS-34273 as disclosed in WO 01/04118. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromide CAS 133099-07-7, to

Sold as trade name), oxybutynin (CAS 5633-20-5, and

sold under the trade name of Tourethrin (CAS 15793-40-5)), tolterodine (CAS 124937-51-5, or its tartrate CAS 124937-52-6, to

Sold under the trade name) or otiminium (e.g., as bromide, CAS 26095-59-0, to

Sold under the trade name),trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or its succinate CAS 242478-38-2, compound YM-905, to

Sold under the trade name).

In another aspect, the invention provides a combination comprising a compound disclosed herein and an antagonist of H1. Examples of H1 antagonists include, but are not limited to, amxanthene (amelexanox), sisimizole (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (bropheriramine), cetirizine (cetirizine), levocetirizine (levocetirizine), efletirizine (efletirizine), chlorpheniramine (chlorpheniramine), clemastine (clintine), cyclizine (cyclizine), caristine (carebastine), cyproheptadine (procetyline), carbinoxamine (carbinoxamine), descarboethoxy loratadine (descarboethoxyloratoridine), doxylamine (doxylamine), dimethylhexidipine (mepiquin), clemastine (fenadine (e), clemastine (fenadine), clemastine (e (fenadine), fenadine (fenadine), clemastine (doxylamine), clemastine (fenadine), clemastine (meplate (meperidine), clemastine (e), clemastine (e), clemastine (, Minoxidine (meclizine), norastemizole (norastemizole), olopatadine (olopatadine), piperazines (picumast), pyrilamine (pyrilamine), promethazine (promethazine), terfenadine (terfenadine), tripelennamine (tripelenamine), temastine (temelastine), isobutylazine (trimeprazine), and triprolidine (triprolidine), with cetirizine (cetirizine), levocetirizine (levocetirizine), efletirizine (efletirizine), and fexofenadine (fexofenadine) being preferred. In other embodiments, the invention provides a combination comprising a compound disclosed herein and an antagonist (and/or inverse agonist) of H3. Examples of H3 antagonists include those disclosed in WO 2004/035556 and WO 2006/045416. Other histamine receptor antagonists useful in combination with the disclosed compounds include H4 receptor antagonists (and/or inverse agonists), such as those disclosed in jablonewski et al, j.med.chem.,2003,46: 3957-.

In yet another aspect, the invention provides a pharmaceutical composition comprising a compound of the disclosure, together with a PDE4 inhibitor and beta₂-a combination of adrenergic receptor agonists.

In a further aspect, the invention provides a combination comprising a compound disclosed herein, in combination with an anticholinergic and a PDE-4 inhibitor.

The combinations described above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with a pharmaceutically acceptable excipient or carrier represents a further aspect of the invention.

The individual compounds of these combinations may be administered sequentially or simultaneously in the form of separate or combined pharmaceutical preparations. In one embodiment, the compound components are administered simultaneously in a combined pharmaceutical formulation. Suitable dosages of known therapeutic agents will be readily understood by those skilled in the art.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein in combination with another therapeutically active agent.

In some embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a chemotherapeutic agent.

In some embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and an antiproliferative agent.

In some embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a phosphodiesterase 4(PDE4) inhibitor.

In other embodiments, the invention provides pharmaceutical compositions comprising a combination of a compound of the disclosure and a β 2-adrenoceptor agonist.

In other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a corticosteroid.

In other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a non-steroidal GR agonist.

In other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and an anticholinergic.

In still other embodiments, the present invention provides pharmaceutical compositions comprising a combination of a compound disclosed herein and an antihistamine.

In still other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and an anti-inflammatory agent.

In still other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and an immunomodulator.

In still other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a drug for atherosclerosis.

In still other embodiments, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a drug for the treatment of pulmonary fibrosis.

In the field of medical oncology, it is common practice to treat cancer patients with a combination of different treatment modalities. In surgical oncology, one or more other co-therapeutic modalities added to the compositions of the invention may be, for example, surgery, radiation therapy, chemotherapy, single transduction inhibitors or modulators (e.g., kinase inhibitors or modulators), and/or monoclonal antibodies.

The compounds disclosed herein may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, especially antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; an antiestrogen; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; (ii) histone deacetylase inhibitors; compounds that induce a cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antineoplastic antimetabolite; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; targeting, A compound that reduces or inhibits the activity of a protein or lipid phosphatase; gonadorelin agonists; an antiandrogen; methionine aminopeptidase inhibitors; a bisphosphonate; a biological response modifier; an anti-proliferative antibody; heparanase inhibitors; ras oncogenic subtype inhibitors; a telomerase inhibitor; a proteasome inhibitor; agents for treating hematological tumors; compounds that target, decrease or inhibit Flt-3 activity; an Hsp90 inhibitor; temozolomide

And calcium folinate.

The term "aromatase inhibitor" as used herein, refers to a compound that inhibits estrogen production, i.e., a compound that inhibits the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to: steroids, in particular atamestane (atamestane), exemestane (exemestane) and formestane (formestane); and, in particular, non-steroids, in particular aminoglutethimide (aminoglutethimide), lotemide (rogethimide), pirglutethimide (pyriglutethimide), trostane (trilostane), testolactone (testolactone), ketoconazole (ketoconazole), fluconazole (vorozole), fadrozole (fadrozole), anastrozole (anastrozole) and letrozole (letrozole). Exemestane can be marketed, e.g. under the trademark Emametan

Is administered in the form of (1). Formestane (formestane) is commercially available, e.g. under the trade mark

Is administered in the form of (1). Fadrozole is commercially available, e.g., under the trademark fadrozole

Is administered in the form of (1). Anastrozole (anastrozole) may be commercially available, for example under the trade mark

Is administered in the form of (1). Letrozole is commercially available, e.g. under the trade mark

Or

Is administered in the form of (1). Aminoglutethimide (aminoglutethimide) is commercially available, for example under the trademark Aminoglutethimide

Is administered in the form of (1). The combination of the invention comprising aromatase inhibitor chemotherapeutic agents is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

The term "antiestrogen" as used herein, refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen (tamoxifen), fulvestrant (fulvestrant), raloxifene (raloxifene) and raloxifene hydrochloride (raloxifenehydrochloride). Tamoxifen (tamoxifen) is commercially available, e.g. under the trademark tamoxifen

Is administered in the form of (1). Raloxifene hydrochloride is commercially available, for example under the trademark Raloxifene hydrochloride

Is administered in the form of (1). Fulvestrant may be in the form of a dosage form as disclosed in US 4,659,516 or may be commercially available, for example under the trade mark fulvestrant

Is administered in the form of (1). The present invention includes combinations of antiestrogen chemotherapeutic agents particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological effects of androgens, including, but not limited toBicalutamide (trade name)

) The dosage form may be prepared according to US patent US 4,636,505.

The term "gonadorelin-type agonist" as used herein includes, but is not limited to abarelix (abarelix), goserelin (goserelin) and goserelin acetate. Goserelin is disclosed in US patent 4,100,274 and is commercially available, for example under the trade mark Gosselin

Is administered in the form of (1). Abarelix (abarelix) can be prepared in a dosage form according to the method disclosed in US patent 5,843,901.

The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan (topotecan), gimatecan (gimatecan), irinotecan (irinotecan), camptothecin (camptothecan) and analogs thereof, 9-nitrocamptothecin (9-nitrocamptothecin), and the macromolecular camptothecin conjugated compound PNU-166148 (compound a1 in WO 99/17804). Irinotecan can be marketed, e.g. under the trademark irinotecan

Is administered in the form of (1). Topotecan is available commercially as, for example, trademark and

is administered in the form of (1).

The term "topoisomerase II inhibitor" as used herein includes, but is not limited to, anthracyclines, such as doxorubicin (doxorubicin), in the form of liposomes, under the trade name Doxorubicin

Daunorubicin (daunorubicin); epirubicin (epirubicin); idarubicin (idarubicin); naemophilus naproxen (nem)orubicin); anthraquinones mitoxantrone (mitoxantrone) and losoxantrone (losoxantrone); etoposide (etoposide) and teniposide (teniposide), which are podophyllotoxin types. Etoposide can be commercially available, e.g., under the trademark Etoposide

Is administered in the form of (1). Teniposide can be commercially available, e.g., under the trademark VM

Is administered in the form of (1). Doxorubicin is commercially available, for example, under the trademark adriamycin

Or

Is administered in the form of (1). Epirubicin is available commercially, e.g. under the trademark epirubicin

Is administered in the form of (1). Idarubicin is commercially available, e.g. under the trademark Irpex

Is administered in the form of (1). Mitoxantrone is commercially available, e.g. under the trademark Etherquinone

Is administered in the form of (1).

The term "microtubule active agent" refers to microtubule stabilizing agents, microwave destabilizing agents and microtubule polymerization inhibitors. Including, but not limited to, taxanes such as paclitaxel (paclitaxel) and docetaxel (docetaxel); vinca alkaloids, such as vinblastine (vinblastine), especially vinblastine sulfate, vincristine, especially vinblastine sulfate and vinorelbine (vinorelbine); discodermolides; colchicine; and epothilones and derivatives thereof, e.g. ebooks Mycin B or D or a derivative thereof. Paclitaxel may be commercially available, e.g., under the trademark Taxol

Is administered in the form of (1). Docetaxel can be marketed, e.g. under the trademark docetaxel

Is administered in the form of (1). Vinblastine sulphate is available commercially, e.g. under the trade name VINBLASTIN

Is administered in the form of (1). Vincristine sulfate is commercially available, e.g., under the trademark vinblastine

Is administered in the form of (1). Discodermolide is obtainable according to the method disclosed in US patent US 5,010,099. Also included are derivatives of the epothilone class disclosed in WO 98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247, with epothilone A and/or B being particularly preferred.

The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), melphalan (melphalan) or nitrosourea (nitrosourea, such as BCNU or carmustine). Cyclophosphamide is available commercially, e.g. under the trade mark

Is administered in the form of (1). Ifosfamide may be commercially available, e.g. under the trade mark ifosfamide

Is administered in the form of (1).

The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to a compound that inhibits histone deacetylase and has antiproliferative activity. Which include the compounds disclosed in WO 02/22577, especially N-hydroxy-3- [4- [ [ (2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl ] -amino ] methyl ] phenyl ] -2E-2-propenamide, N-hydroxy-3- [4- [ [ [2- (2-methyl-1H-indol-3-yl) -ethyl ] -amino ] methyl ] phenyl ] -2E-2-propenamide and pharmaceutically acceptable salts thereof. Particularly included are suberoylanilide hydroxamic acid (SAHA).

The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil (5-fluorouracil) or 5-FU; capecitabine (capecitabine); gemcitabine (gemcitabine); DNA demethylating agents such as 5-azacytidine (5-azacytidine) and decitabine (decitabine); methotrexate (methotrexate) and edatrexate (edatrexate); and folic acid antagonists such as pemetrexed (pemetrexed). Capecitabine may be marketed, e.g. under the trademark Capecitabine

Is administered in the form of (1). Gemcitabine may be commercially available, e.g. under the trade mark Gemcitabine

Is administered in the form of (1). The term also includes the monoclonal antibody trastuzumab (trastuzumab), which is commercially available, e.g., under the trademark TETRASTUzumab

Is administered in the form of (1).

The term "platinum compound" as used herein includes, but is not limited to, carboplatin (carboplatin), cis-platinum (cis-platinum), cisplatin (cissplatinum) and oxaliplatin (oxaliplatin). Carboplatin can be commercially available, e.g., under the trademark TEFLON

Is administered in the form of (1). Oxaliplatin may be marketed, e.g. under the trademark oxaliplatin

Is administered in the form of (1).

The term "compound targeting/reducing the activity of a protein or lipid kinase, or the activity of a protein or lipid phosphatase, or other anti-angiogenic compound" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine inhibitors, or lipid kinase inhibitors, e.g. as described in

a) Compounds that target, decrease or inhibit Platelet Derived Growth Factor Receptor (PDGFR) activity; compounds that target, decrease or inhibit PDGFR activity, particularly compounds that inhibit the PDGF receptor, include N-phenyl-2-pyrimidine-amine derivatives such as imatinib (imatinib), SU101, SU6668, GFB-111, and the like;

b) compounds that target, decrease or inhibit Fibroblast Growth Factor Receptor (FGFR) activity;

c) compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor-1 (IGF-1R); compounds that target, decrease or inhibit IGF-1R activity, particularly compounds that inhibit IGF-1 receptor activity, include those disclosed in patent WO 02/092599;

d) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family;

e) compounds that target, decrease or inhibit the activity of the Axl receptor tyrosine kinase family;

f) compounds that target, decrease or inhibit the activity of the c-Met receptor;

g) compounds that target, decrease or inhibit the activity of Kit/SCFR receptor tyrosine kinases;

h) compounds that target, decrease or inhibit the activity of C-kit receptor tyrosine kinases (part of the PDGFR family); compounds that target, decrease or inhibit the activity of the C-Kit receptor tyrosine kinase family, especially compounds that inhibit the C-Kit receptor, including imatinib (imatinib), and the like;

i) Compounds that target, decrease or inhibit the activity of the c-Abl family and their gene fusion products, such as BCR-Abl kinase; compounds that target, reduce or inhibit c-Abl family members and their gene fusions include N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, PD180970, AG957, NSC 680410, PD173955 from ParkeDavis

j) A compound that targets, reduces or inhibits the activity of a member of the Raf family, a member of the MEK, SRC, JAK, FAK, PDK and Ras/MAPK family, a member of the PI (3) kinase family, or a member of the PI (3) kinase-associated kinase family, and/or a member of the cyclin-dependent kinase family (CDK) in protein kinase c (pkc) and silk/threonine kinases; in particular those staurosporine derivatives disclosed in US patent 5,093,330, such as midostaurin (midostaurin); further examples of compounds also include, UCN-01; saffingol (safingol); BAY 43-9006; bryostatin 1; piperacillin (Perifosine); imofosine (llmofosine); RO 318220 and RO 320432; GO 6976; isis 3521; LY333531/LY 379196; isoquinoline compounds, such as those disclosed in WO 00/09495; FTIs; PD 184352; or QAN697 (a P13K inhibitor);

k) Compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors; compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate

Or a tyrphostin; the tyrosine phosphorylation inhibitor is preferably low molecular weight (Mr)<1500) A compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the group consisting of benallyldinitriles or S-arylbenpropionitrile or bis-substrate quinolines, further selected from the group consisting of tyrphostin A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44(+) enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and adaphostin (4- { [ (2, 5-dihydroxyphenyl) methyl]Amino } -benzoic acid adamantane esters, NSC 680410, adaphortin); and

I) compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family (homo-or heterodimers of EGFR, ErbB2, ErbB3, ErbB 4) in receptor tyrosine kinases; compounds which target, reduce or inhibit the epidermal growth factor receptor family are in particular compounds, proteins or antibodies which inhibit members of the EGF receptor family (such as EGF receptor, ErbB2, ErbB3, ErbB4, or substances which bind EGF or EGF-related ligands), in particular compounds, proteins or mabs which are generally or specifically disclosed in the following documents: WO 97/02266 (as example 39), EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688 and WO 97/38983, WO 96/30347 (as CP 358774), WO 96/33980 (as compound ZD 1839), WO 95/03283 (as compound ZM105180), trastuzumab (herceptin), cetuximab, Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and the 7H-pyrrolo- [2,3-d ] pyrimidine derivatives disclosed in WO 03/013541.

In addition, anti-angiogenic compounds include compounds with other mechanisms of activity (e.g., not associated with protein or lipid kinase inhibition), such as thalidomide

And TNP-470.

The compound that targets, decreases or inhibits protein or lipid kinase activity is a phosphatase-1 inhibitor, a phosphatase 2A inhibitor, a PTEN inhibitor or a CDC25 inhibitor, such as okadaic acid or a derivative thereof.

The compound inducing the cell differentiation process is retinoic acid, alpha-, gamma-or-tocopherol, alpha-, gamma-or-tocotrienol.

The term "cyclooxygenase inhibitors" as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives thereof, such as celecoxib

Rofecoxib

Etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, e.g. 5-methyl-2- (2 '-chloro-6' -fluoroanilino) phenylacetic acid orLumi Coxib

The term "bisphosphonate" as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is commercially available, for example under the trade name Etidronic acid

Is administered in the form of (1). The chlorophosphonic acids are commercially available, for example under the trade name Chlorophosphonic acid

Is administered in the form of (1). Telophosphonic acid is available commercially, for example under the trade name TELUPHOSPHONIC ACID

Is administered in the form of (a); pamidronic acid (Pamidronic acid) is commercially available, for example under the trade name adata^TM(AREDIA^TM) Is administered in the form of (a); alendronic acid is available commercially, for example under the trade name

Is administered in the form of (a); ibandronic acid is available commercially, for example under the trade name ibandronic acid

Is administered in the form of (a); risedronic acid is commercially available, for example under the trade name risedronic acid

Is administered in the form of (a); zoledronic acid is commercially available, for example under the trade name Zoledronic acid

Is administered in the form of (1).

The term "mTOR inhibitor" refers to a compound that inhibits the mammalian target of rapamycin (mTOR), having antiproliferative activity, such as sirolimus (sirolimus,

) Everolimus (CERTICAN)^TM) CCI-779 and ABT 578.

The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the degradation of heparan sulfate. This term includes, but is not limited to PI-88.

The term "biological response modifier" as used herein refers to lymphokines or interferons, such as interferon gamma.

The term "inhibitor of Ras oncogenic subtype (e.g., H-Ras, K-Ras or N-Ras) as used herein refers to compounds that target, decrease or inhibit Ras oncogenic activity, e.g.," farnesyl transferase inhibitors "such as L-744832, DK8G557 or R115777 (Zarnestra).

The term "telomerase inhibitor" as used herein refers to compounds that target, decrease or inhibit telomerase activity. A compound that targets, reduces or inhibits telomerase activity refers in particular to a compound that inhibits the telomerase receptor, such as, for example, telomerase.

The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit methionine aminopeptidase activity include bengamide or derivatives thereof.

The term "proteasome inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of the proteasome. Compounds that target, decrease or inhibit proteasome activity include PS-341 and MLN 341.

The term "matrix metalloproteinase inhibitor" or "MMP inhibitor" as used herein includes, but is not limited to, collagen peptide and non-peptide inhibitors, tetracycline derivatives, such as the hydroxamic acid peptide inhibitor batimastat (batimastat) and its oral bioequivalent homolog marimastat (marimastat, BB-2516), primastat (prinomastat, AG3340), metamastat (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ 996.

The term "agent for treating hematological tumors" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors. Compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-b-D-arabinofuranosyl cytosine (ara-c) and bisufan; and ALK inhibitors, such as compounds that target, decrease, or inhibit anaplastic lymphoma kinase.

Compounds targeting, decreasing or inhibiting the FMS-like tyrosine kinase receptor (Flt-3R) especially refer to compounds, proteins or antibodies inhibiting members of the Flt-3 receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN 518.

The term "HSP 90 inhibitor" as used herein includes, but is not limited to, compounds that target, decrease or inhibit the endogenous atpase activity of HSP 90; compounds that degrade, target, reduce or inhibit HSP90 client proteins through the ubiquitin proteosome enzymatic pathway. Compounds that target, decrease or inhibit the endogenous atpase activity of HSP90 refer in particular to compounds, proteins or antibodies that inhibit the endogenous atpase activity of HSP90, e.g., 17-allylamino, 17-demethoxygeldanamycin (17AAG), other geldanamycin related compounds, gibberellins and HDAC inhibitors.

The term "anti-proliferative antibody" as used herein includes, but is not limited to, trastuzumab (HERCEPTIN)^TM) trastuzumab-DM 1, erlotinib (TARCEVA)^TM) Bevacizumab (AVASTIN)^TM) Rituximab (rituximab)

PR064553(anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments (so long as they have the desired biological activity). For the treatment of Acute Myeloid Leukemia (AML), the disclosed compounds can be used in combination with standard leukemia therapies, especially in combination with therapies for the treatment of AML. In particular, the compounds disclosed herein may be used with, for example, farnesyl transferase inhibitors and/or other drugs used in the treatment of AML, such as daunorubicin, doxorubicinThe combination of the administration of the combination of the agents selected from the group consisting of mycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC 412.

The compounds disclosed herein may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, especially other anti-malarial agents. Such antimalarial agents include, but are not limited to, proguanil (proguanil), proguanil (chlorproquine), trimethoprim (trimethoprim), chloroquine (chloroquine), mefloquine (mefloquine), lumefantrine (lumefantrine), atovaquone (atovaquone), pyrimethamine-sulfanilamide (pyrimethamine-sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinidine (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfonamides, artemisinin, arterfine (artelene), artemisia methyl ether, artesunate, primaquine, inhaled NO, L-arginine, predynetriaminol (NO), erythropoietin (rythrone agonist), glitazone, levo-active, and ppa.

The compounds disclosed herein may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, for example, other therapeutic agents for the treatment of leishmaniasis, trypanosomiasis, toxoplasmosis, and cerebral cysticercosis. Such agents include, but are not limited to chloroquine sulfate, atovaquone-proguanil, artemether-lumefantrine, quinine sulfate, artesunate, quinine, doxycycline, clindamycin (clindamycin), meglumine antimony (meglumenaline antimonite), sodium stibogluconate (sodium stibogluconate), miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycin), eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsol (mesoprorol), prednisolone (prednisolone), benzimidazole, sulfadiazine, pyrimethamine, sulfamethoxazole, neomycin, azithromycin (traminon), dexamethasone, beta-quinolones, beta-aminobenzophenones, and benzoquinolones, Sulfadiazine and pyrimethamine.

The structure of The active ingredient, as determined by The code number, generic name or trade name, and its preparation, is known from The current version of The standard work "The Merck Index" (e.g. m.j.o 'Neil et al, "The Merck Index', 13 th edition, Merck Research Laboratories, 2001) or from databases (e.g. Patents International (e.g. IMS World Publications)).

The compounds described above, which can be used in combination with the compounds disclosed in the present invention, can be prepared and administered by those skilled in the art according to the methods described in the above documents.

The compounds disclosed herein may also be combined with a therapeutic procedure to enhance the therapeutic effect. For example, hormone therapy or special radiation therapy is administered. The compounds disclosed herein are particularly useful as radiosensitizers, particularly for the treatment of tumors that are weakly sensitive to those radiation treatments.

"combination" means a fixed combination or a kit of parts for the combined administration in the form of a single dosage unit, wherein a compound disclosed in the invention and a combination partner may be administered separately at the same time or may be administered separately within certain time intervals, in particular such that the combination partners show a cooperative, e.g. synergistic, effect. The terms "co-administration" or "co-administration" and the like as used herein are intended to encompass administration of the selected combination partner to a single individual in need thereof (e.g., a patient), and are intended to encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination" as used herein denotes a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the compounds disclosed herein, and the combination partner are administered to the patient simultaneously, in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound disclosed herein, and the combination partner are both administered to a patient as separate entities simultaneously, together or sequentially with no specific time limits, wherein the mode of administration provides therapeutically effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

Method of treatment

In some embodiments, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.

In some embodiments, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered orally. In other embodiments, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by inhalation. In yet another embodiment, the presently disclosed compounds or compositions comprising the presently disclosed compounds may be administered intranasally.

In some embodiments, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In some embodiments, the administration is once daily. In yet other embodiments, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or together with them in pharmaceutical compositions.

For an individual of about 50-70kg, the disclosed pharmaceutical compositions and combinations may be in unit dosage form containing from about 1-1000mg, or from about 1-500mg, or from about 1-250mg, or from about 1-150mg, or from about 0.5-100mg, or from about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend upon the species, weight, age and condition of the individual to whom it is administered, the disorder or disease being treated (disease) or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disorder or disease.

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro in the form of solutions, e.g. aqueous solutions, and also enterally, parenterally, especially intravenously, in vivo, e.g. in the form of suspensions or aqueous solutions.

In some embodiments, a therapeutically effective dose of a compound of the present disclosure is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg, from about 20mg to about 500mg, or from about 25mg to about 250mg of the principal active ingredient or a combination of principal ingredients per dosage unit form. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide about 10mg,20mg,25mg,50mg,100mg,250mg,500mg,1000mg or 2000mg of the primary active ingredient.

In addition, the compounds disclosed herein may be administered in the form of a prodrug. In the present invention, a "prodrug" of a disclosed compound is a functional derivative that, when administered to a patient, is ultimately released in vivo. When administering the compounds disclosed herein in the form of a prodrug, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、D₂O、DMSO-d₆、CD₃OD or acetone-d₆As solvent (in ppm) TMS (0ppm) or chloroform (7.26ppm) was usedIs a reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), ddd (doublet of doublets), dddd (doublet of doublets), dt (doublet of doublets), tt (triplet of triplets), and tt (triplet of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

AcOH、HOAc、CH₃COOH acetic acid

Ac₂O acetic anhydride

BOC, Boc tert-butoxycarbonyl

(Boc)₂Di-tert-butyl O dicarbonate

BINAP 1,1 '-binaphthyl-2, 2' -bis (diphenylphosphines)

n-BuOH n-butanol

Cs₂CO₃Cesium carbonate

BSA benzenesulfonamides

CH₂Cl₂DCM dichloromethane

CDC1₃Deuterated chloroform

CH₃I iodomethane

DIEA、DIPEA、i-Pr₂NEt diisopropylethylamine

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

DMF N, N-dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

PPTs 4-Methylbenzenesulfonic acid pyridine

Et₃N, TEA Triethylamine

EtOAc, EA ethyl acetate

EtOH ethanol

Et₂O Ether

g

h hours

HCl hydrochloric acid

KOH potassium hydroxide

K₂CO₃Potassium carbonate

LAH lithium aluminum hydride

LDA lithium diisopropylamide

MeCN、CH₃CN acetonitrile

MsCl methane sulfonyl chloride

mCPBA m-chloroperoxybenzoic acid

(NH₄)₂SO₄Ammonium sulfate

NH₄Cl ammonium chloride

NaH sodium hydride

Na₂CO₃Sodium carbonate

NaOH sodium hydroxide

NaOMe sodium methoxide

Na₂SO₄Sodium sulfate

Na₂S₂O₃Sodium thiosulfate

NaHCO₃Sodium bicarbonate

NaOAc ammonium acetate

Ti(Oi-Pr)₄Tetraisopropyl titanate

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NIS N-chlorosuccinimide

MeOH methanol

mL, mL

Pd(OAc)₂Palladium acetate

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium

Pd/C Palladium/carbon

Pd(OH)₂Palladium hydroxide/carbon

PE Petroleum ether (60-90 deg.C)

PTSA para-toluenesulfonic acid

PDC pyridine dichromate

RT, RT, r.t. Room temperature

Rt Retention time

Raney Ni Raney nickel

t-BuONa sodium tert-butoxide

THF tetrahydrofuran

TFAA trifluoroacetic anhydride

TFA trifluoroacetic acid

TBAF tetrabutylammonium fluoride

Ti(Oi-Pr)₄Tetra (isopropyl titanate)

TsCl 4-tosyl chloride

Xantphos 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene

Typical synthetic procedures for preparing the disclosed compounds of the present invention are shown in the following synthetic schemes 1-2. Each Z, A, ring W, ring T, R unless otherwise stated¹、R²、R³、R⁴And R⁵Having the definitions as described in the present invention. Each p, q, and t is independently 0, 1, 2, 3, 4, or 5; each s is independently 0 or 1; each of PG and PG¹Independently a protecting group.

Synthesis scheme 1:

has the formula (A)8) The disclosed compounds of the present invention of the structure shown can be prepared by the general synthetic methods described in scheme 1, with reference to the examples for specific procedures. In FIG. 1, heteroaryl Compounds: (1) And substituted heterocyclic compounds (a)2) In the presence of a base, e.g. triethylamine, diisopropylWith the aid of phenylethylamines to give substituted hetaryl compounds ( 3). The protecting group in the compound (3) can be removed under acidic condition, such as trifluoroacetic acid, hydrogen chloride in ethyl acetate solution, to obtain compound (A)4). Then, the compound (A), (B), (C4) With substituted dichloropyrimidines (5) Reaction to give a compound (6). Compound (A) to (B)6) And substituted heteroaryl compounds (A), (B), (C), (7) In the presence of a base, such as diisopropylethylamine, triethylamine, over a suitable Pd catalyst, such as Pd (OAc)₂、Pd₂(dba)₃Under the catalysis of (A), the reaction is carried out to obtain a catalyst with the formula (A)8) A protein kinase inhibitor of the structure shown.

Synthesis scheme 2:

has the formula (A)8) The disclosed compounds of the present invention of the structure shown can be prepared by the general synthetic methods described in scheme 2, with reference to the examples for specific procedures. In FIG. 2, substituted dichloropyrimidines (I), (II)5) And optionally substituted heterocyclic compounds (C:9) In the presence of a base, such as triethylamine or diisopropylethylamine, (substituted compounds)10). Compound (A) to (B)10) And substituted heteroaryl compounds (A), (B), (C), (7) In the presence of a base, such as diisopropylethylamine, triethylamine, over a suitable Pd catalyst, such as Pd (OAc)₂、Pd₂(dba)₃Under the catalysis of (A), the reaction is carried out to obtain a compound (A)11). Compound (A) to (B)11) The protecting group in (A) can be removed under acidic condition, such as trifluoroacetic acid, hydrogen chloride in ethyl acetate, to obtain compound (A) 12). Compound (A) to (B)12) And a heteroaryl compound (a)1) Under the action of a base, such as triethylamine or diisopropylethylamine, to obtain a compound having the formula (A)8) A protein kinase inhibitor of the structure shown.

Examples

Example 16- (4- ((5-chloro-2- (pyrazolo [1, 5-a))]Pyridin-6-ylamino) pyrimidin-4-yl) (methyl) amino Yl) piperidin-1-yl) nicotinonitrile

Step 1) N- (diphenylmethylene) pyrazolo [1,5-a]Pyridin-6-amines

In N₂To 6-bromopyrazolo [1,5-a ] under protection]Pyridine (1g,5.0754mmol), Pd₂(dba)₃Toluene (25mL) was added to a mixture of (403.5mg,0.4406mmol), BINAP (312.4mg,0.5017mmol), t-BuONa (982.6mg,10.22mmol) and benzophenone imine (1.842g,10.17 mmol). The reaction mixture was heated to 80 ℃ and stirred for 6.5 hours, after the reaction was complete, the reaction was quenched with water (80 mL). The resulting mixture was extracted with EtOAc (100 mL. times.3) and the combined organic phases were extracted with anhydrous Na₂SO₄Dry, filter and concentrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 15/1) to afford the title compound as a yellow solid (1.42g, 94% yield).

MS(ESI,pos.ion)m/z:298.05[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.02(s,1H),7.83(d,J＝2.3Hz,1H),7.78-7.74(m,2H),7.50(t,J＝7.3Hz,1H),7.42(t,J＝7.5Hz,2H),7.31(ddd,J＝14.3,7.0,4.2Hz,4H),7.19(dt,J＝5.3,4.5Hz,2H),6.65(dd,J＝9.3,1.7Hz,1H),6.40(d,J＝2.0Hz,1H)。

Step 2) pyrazolo [1,5-a]Pyridin-6-amines

EtOAc solution of hydrogen chloride (20mL,60mmol,3M) was added to N- (diphenylmethylene) pyrazolo [1,5-a]Pyridine-6-amine (1.42g,4.77mmol), and the resulting mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was washed with water (50 mL. times.2), and the combined aqueous layers were saturated with Na ₂CO₃The aqueous solution was adjusted to pH 10, and the resulting mixture was extracted with a mixed solvent of DCM/MeOH (10/1(v/v),150mL × 4). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH)₃Purified with MeOH (7M)) (v/v) ═ 100/1)The title compound was obtained as a yellow solid (510mg, 80% yield).

MS(ESI,pos.ion)m/z:134.20[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.98(d,J＝0.7Hz,1H),7.77(d,J＝2.1Hz,1H),7.37(d,J＝9.3Hz,1H),6.74(dd,J＝9.3,1.4Hz,1H),6.41(d,J＝2.0Hz,1H),3.40(s,2H)。

Step 3) (1- (5-cyanopyridin-2-yl) piperidin-4-yl) (methyl) carbamic acid tert-butyl ester

To a solution of tert-butyl methyl (piperidin-4-yl) carbamate (620mg,2.88mmol), 6-chloro-3-cyanopyridine (200mg,1.44mmol) in DMF (20mL) was added K₂CO₃(600mg,4.32 mmol). After stirring the reaction system at 120 ℃ for 2 hours, it was cooled to room temperature and concentrated under reduced pressure. DCM (40mL) was added to the resulting residue, and the resulting solution was washed with water (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (100% DCM) to give the title compound as a white solid (394mg, 86% yield).

MS(ESI,pos.ion)m/z:316.8[M+H]⁺；

¹H NMR(300MHz,CDCl₃)(ppm):1.45(s,9H),1.55-1.69(m,2H),1.80-1.74(m,2H),2.70(s,4H),2.91-3.01(m,1H),4.51-4.56(m,3H),6.61(d,J＝9Hz,1H),7.60(dd,J＝2.4Hz,J＝9Hz,1H),8.40(d,J＝2.4Hz,1H)。

Step 4) (6- (4- (methyl) amino) piperidin-1-yl) nicotinonitrile

To a solution of tert-butyl (1- (5-cyanopyridin-2-yl) piperidin-4-yl) (methyl) carbamate (430mg,1.36mmol) in dichloromethane (40mL) was added trifluoroacetic acid (2.33g,20.4mmol) and the reaction stirred at 50 ℃ for 6 h, then cooled to room temperature and concentrated under reduced pressure. To the resulting residue was added DCM (40mL) for dilution, and washed successively with 1M aqueous sodium hydroxide solution (30mL), saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (265mg, yield 100%). MS (ESI, pos. ion) M/z 216.9[ M + H ] ]⁺。

Step 5)6- (4- ((2, 5-dichloropyrimidin-4-yl) (methyl) amino) piperidin-1-yl) nicotinonitrile

To a solution of 2,4, 5-trichloropyrimidine (185mg,1.02mmol) and (6- (4- (methyl) amino) piperidin-1-yl) nicotinonitrile (265mg,1.224mmol) in isopropanol (40mL) was added triethylamine (206mg,2.04 mmol). The resulting reaction was stirred at 80 ℃ for 2 hours, cooled to room temperature, and concentrated under reduced pressure. To the resulting residue were added DCM (50mL) and water (30mL), the layers were separated, the organic phase was separated, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 8/1) to give the title compound as a white solid (266mg, 72% yield).

¹H NMR(300MHz,CDCl₃)(ppm):8.42(d,J＝2.4Hz,1H),8.09(s,1H),7.62(dd,J＝2.1Hz,J＝9.3Hz,1H),6.66(d,J＝9Hz,1H),5.66-4.73(m,1H),4.56-4.64(m,2H),3.06(s,3H),3.10-3.00(m,2H),1.96-1.91(m,2H),1.87-1.74(m,2H)。

Step 6)6- (4- ((5-chloro-2- (pyrazolo [1, 5-a)]Pyridin-6-ylamino) pyrimidin-4-yl) (methyl) amino) Piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) (methyl) amino) piperidin-1-yl) nicotinonitrile (156mg,0.4295mmol), pyrazolo [1, 5-a)]Pyridin-6-amine (66.2mg,0.497mmol), BINAP (26.5mg,0.0426mmol), Cs₂CO₃(273.8mg,0.8403mmol) and Pd (OAc)₂(11.3mg,0.0503mmol) to the mixture was added anhydrous 1, 4-dioxane (10 mL). The reaction mixture was placed in a sealed tube, degassed and charged with N₂Multiple times, then stirred under microwave irradiation at 150 ℃ for 1.5 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to obtain the crude product as a green solid (120 mg). The crude product was recrystallized from MeOH (6mL), filtered, and the resulting filter cake was washed with MeOH (3mL) and dried under reduced pressure to give the title compound as a pale green solid (90mg, 46% yield).

MS(ESI,pos.ion)m/z:460.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.29(s,1H),8.42(d,J＝2.1Hz,1H),8.01(s,1H),7.87(d,J＝2.2Hz,1H),7.61(dd,J＝9.0,2.3Hz,1H),7.46(d,J＝9.3Hz,1H),6.95(dd,J＝9.4,1.6Hz,1H),6.79(s,1H),6.65(d,J＝9.1Hz,1H),6.47(d,J＝1.9Hz,1H),4.66(ddd,J＝15.9,8.1,4.0Hz,1H),4.58(d,J＝13.6Hz,2H),3.12(t,J＝12.0Hz,2H),3.06(s,3H),1.96(d,J＝10.6Hz,2H),1.81(qd,J＝12.3,4.1Hz,2H)。

Example 26- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) -3-ethylpiperidin-1-yl) nicotinonitrile

Step 1) 2-Chloropropional

To a suspension of propionaldehyde (5.00g,86.11mmol) in chloroform (50mL) at 0 deg.C was added pyrrolidine-2-carboxylic acid (1.98g,17.24mmol) and NCS (12.67g,94.82 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, then allowed to warm to room temperature and stirred overnight, then n-hexane (100mL) was added to the mixture and stirring was continued for 30 minutes. After completion of the reaction, the reaction mixture was filtered, the filtrate was washed with water (100 mL. times.2), and the organic phase was washed with anhydrous Na₂SO₄Drying and filtering to obtain filtrate which is 150mL of colorless solution and is directly used for the next reaction without treatment.

GC-MS m/z(EI):92.0[M]⁺。

Step 2) 7-bromo-3-methylimidazo [1,2-a]Pyridine compound

To a colorless solution (150mL) obtained in the previous reaction was added 4-bromopyridin-2-amine (2.00g,11.57 mmol). The resulting mixture was heated to reflux and stirred overnight, after the reaction was complete, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH)₃MeOH solution (3M)) (v/v) ═ 100/1 to 50/1 to 30/1) to give the title compound as a brown viscous liquid (0.76g, 31% yield).

MS(ESI,pos.ion)m/z:211.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.79(d,J＝1.3Hz,1H),7.74(d,J＝7.2Hz,1H),7.38(s,1H),6.94(dd,J＝7.2,1.8Hz,1H),2.46(s,3H)。

Step 3) N- (diphenylmethylene) -3-methylimidazo [1,2-a ]Pyridin-7-amines

To 7-bromo-3-methylimidazo [1,2-a ]]Pd was added to a suspension of pyridine (0.76g,3.60mmol) in dry toluene (20mL)₂dba₃(0.34g,0.37mmol), BINAP (0.47g,0.76mmol), benzophenone imine (1.33g,7.33mmol) and t-BuONa (0.70g,7.32 mmol). The reaction mixture was degassed and charged with N₂Multiple times, then heating to 85 ℃, and stirring overnight after the reaction is finished. After the reaction was complete, the reaction mixture was diluted with water (40mL) and the resulting solution was extracted with EtOAc (50 mL. times.5). The combined organic phases are washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound as a brown liquid (1.12g, 100% yield).

MS(ESI,pos.ion)m/z:312.0[M+H]⁺。

Step 4) 3-methylimidazo [1,2-a ]]Pyridin-7-amines

To N- (diphenylmethylene) -3-methylimidazo [1,2-a]To a suspension of pyridin-7-amine (1.12g,3.60mmol) in DCM (30mL) was added a solution of hydrogen chloride in EtOAc (30mL,90mmol, 3M). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (30mL) and the resulting mixture was washed with EtOAc (80 mL). The separated aqueous phase is saturated with Na₂CO₃The aqueous solution was adjusted to pH 10, and then extracted with DCM (40mL × 2) and a DCM/MeOH mixed solvent (10/1(v/v),50mL × 3) in that order. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH) ₃MeOH solution (3M)) (v/v) ═ 30/1 to 20/1 to 10/1) to afford the title compound as a brown liquid (0.40g, 76% yield).

MS(ESI,pos.ion)m/z:148.2[M+H]⁺。

Step 5) (S) -N- (1-benzylpiperidin-4-ylidene) -1-phenylethylamine

A solution of 1-benzylpiperidin-4-one (30.06g,158.8mmol) and (1S) -1-phenylethylamine (28.92g,238.7mmol) in toluene (300mL) was warmed to reflux, the reaction was stirred for 46 hours, and a water separator was installed to remove the water of reaction. After the reaction is finished, the system is cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was used in the next step without further purification.

Step 6) 1-benzyl-3-ethyl-N- ((R) -1-phenylethyl) piperidin-4-amine

In that^–To a solution of (S) -N- (1-benzylpiperidin-4-ylidene) -1-phenylethylamine (46.35g,158.5mmol) in THF (250mL) at 10 deg.C was added dropwise a solution of LDA in tetrahydrofuran (125mL, 2M). The reaction was stirred at room temperature for 2 hours under a nitrogen atmosphere. Thereafter, iodoethane (20.5mL,255mmol) was added to the above reaction system, and after completion of the addition, the mixture was stirred for 2 hours. Cooling the system to^–Ethanol (250mL) and sodium borohydride (9.62g,254mmol) were added at 78 ℃. Maintenance of the resulting reaction mixture^–Stirring at 78 deg.C for 15 min, transferring to^–Stir at 10 ℃ overnight. After completion of the reaction, water (500mL) was added for quenching, followed by extraction with ethyl acetate (200 mL. times.3). The combined organic phases were washed with saturated brine (300mL) and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/3 to 1/1 to 100% EtOAc) to afford the title compound as a yellow oil (12.50g, 24.5% yield).

MS(ESI,pos.ion)m/z:323.4[M+H]⁺。

Step 7) 3-Ethyl-N- ((R) -1-phenylethyl) piperidin-4-amine

To a solution of 1-benzyl-3-ethyl-N- ((R) -1-phenylethyl) piperidin-4-amine (12.50g,38.76mmol) in 1, 2-dichloroethane (200mL) at 0 deg.C was added dropwise 1-chloroethyl chloroformate (5.0mL,46 mmol). After the reaction was stirred for 30 minutes, the temperature was raised to reflux and stirring was continued for 1 hour. After completion of the reaction, the reaction system was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (200 mL). The resulting mixture was warmed to reflux and stirred overnight, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanolic ammonia (3M)/DCM ═ 1/30 to 1/10) to afford the desired product as a brown oil (6.15g, 68.3% yield).

MS(ESI,pos.ion)m/z:233.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.35-7.27(m,4H),7.24-7.21(m,1H),3.96(q,J＝6.6Hz,1H),3.10-3.00(m,2H),2.41(td,J＝12.3,2.6Hz,1H),2.14-2.07(m,2H),2.00-1.94(m,1H),1.86-1.80(m,1H),1.32(d,J＝6.6Hz,3H),1.17-0.95(m,3H),0.81(t,J＝7.5Hz,3H)。

Step 8) 3-Ethyl-4- (((R) -1-phenylethyl) amino) piperidine-1-carboxylic acid tert-butyl ester

To a solution of 3-ethyl-N- ((R) -1-phenylethyl) piperidin-4-amine (6.15g,26.5mmol) in dichloromethane (100mL) at 0 deg.C was added triethylamine (9.2mL,66mmol) and Boc₂O (9.1mL,40 mmol). The reaction was stirred at room temperature overnight and, after completion of the reaction, concentrated under reduced pressure to give the title compound as a brown oil (8.80g, 100% yield). The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:333.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.36-7.20(m,5H),3.96-3.89(m,2H),2.68(s,1H),2.06-1.97(m,2H),1.79(s,1H),1.44(s,9H),1.33(d,J＝6.5Hz,3H),1.27-0.96(m,5H),0.84(t,J＝7.4Hz,3H)。

Step 9) 4-amino-3-ethylpiperidine-1-carboxylic acid tert-butyl ester acetate

To a solution of tert-butyl 3-ethyl-4- (((R) -1-phenylethyl) amino) piperidine-1-carboxylate (8.80g,26.5mmol) in acetic acid (100mL) was added palladium hydroxide on carbon (0.90 g). The reaction system was warmed to 70 ℃ and stirred overnight in a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through a celite funnel, and the filtrate was concentrated under reduced pressure to obtain the objective product as a yellow oil (7.63g, yield 100%). The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:173.2[M^–55]⁺。

Step 10) tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate

To a solution of 4-amino-3-ethylpiperidine-1-carboxylic acid tert-butyl ester acetate (6.04g,26.5mmol) in ethanol (100mL) were added 2,4, 5-trichloropyrimidine (4.85g,26.4mmol) and triethylamine (14.7mL,105 mmol). The reaction system was stirred at room temperature for 12 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/8) to give the title compound as a white solid (4.80g, 48.3% yield).

MS(ESI,pos.ion)m/z:375.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.00(s,1H),5.27(d,J＝8.7Hz,1H),4.31-4.10(m,1H),4.10-3.98(m,2H),3.00-2.84(m,1H),2.56(s,1H),2.05-1.92(m,1H),1.55-1.50(m,1H),1.45(s,9H),1.40-1.38(m,2H),1.24-1.10(m,1H),0.91(t,J＝7.5Hz,3H)。

Step 11)4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino 3-ethylpiperidine-1-carboxylic acid tert-butyl ester

To a suspension of tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate (0.40g,1.07mmol) in anhydrous 1, 4-dioxane (10mL) was added 3-methylimidazo [1,2-a ]Pyridin-7-amine (0.31g,2.10mmol), Pd (OAc)₂(0.049g,0.22mmol), BINAP (0.14g,0.22mmol) and Cs₂CO₃(0.70g,2.16 mmol). The reaction mixture was placed in a sealed tube, degassed and charged with N₂Multiple times, and stirring at 150 ℃ for 1 hour under microwave irradiation. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1 to 20/1) to afford the title compound as a yellow liquid (0.40g, 77% yield).

MS(ESI,pos.ion)m/z:485.9[M+H]⁺。

^{4 2}Step 12) 5-chloro-N- (3-ethylpiperidin-4-yl) -N- (3-methylimidazo [1, 2-a)]Pyridin-7-yl) pyrimidines Pyridine-2, 4-diamines

To 4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester (0.41g,0.84mmol)To DCM (20mL) was added a solution of hydrogen chloride in EtOAc (20mL,60.0mmol, 3.0M). The reaction system was stirred overnight at room temperature, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in DCM (20mL) and saturated Na₂CO₃The aqueous solution (20mL) was diluted and the resulting mixture was stirred at room temperature for 15 minutes. After standing, the organic layer was separated, and the aqueous layer was extracted successively with DCM (30 mL. times.3) and a mixed solvent of DCM/MeOH (10/1(v/v),30 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH) ₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1 to 20/1) to afford the title compound as a yellow solid (0.26g, 80% yield).

MS(ESI,pos.ion)m/z:385.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.95(d,J＝1.6Hz,1H),7.93(s,1H),7.74(d,J＝7.4Hz,1H),7.30(s,1H),7.07-7.02(m,2H),5.12(d,J＝8.6Hz,1H),4.01-3.90(m,1H),3.31-3.23(m,1H),3.18-3.10(m,1H),2.88-2.78(m,1H),2.52-2.46(m,1H),2.44(s,3H),2.20-2.12(m,1H),1.65-1.61(m,1H),1.48-1.39(m,2H),1.24-1.14(m,1H),0.90(t,J＝7.5Hz,3H)。

Step 13)6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

To 5-chloro-N⁴- (3-ethylpiperidin-4-yl) -N²- (3-methylimidazo [1,2-a ]]To a suspension of pyridin-7-yl) pyrimidine-2, 4-diamine (0.10g,0.26mmol) in EtOH (10.0mL) was added 6-chloropyridine-3-carbonitrile (0.073g,0.52mmol) and TEA (0.11mL,0.79 mmol). The resulting mixture was warmed to reflux and stirred overnight, after the reaction was complete, concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1) to give the title compound as a yellow solid (87mg, 69% yield).

MS(ESI,pos.ion)m/z:488.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.40(d,J＝2.1Hz,1H),8.13(s,1H),7.95(s,1H),7.76(d,J＝7.3Hz,1H),7.60(dd,J＝9.0,2.3Hz,1H),7.30(s,1H),7.12(s,1H),6.99(s,1H),6.64(d,J＝9.0Hz,1H),5.10(d,J＝8.2Hz,1H),4.64-4.52(m,1H),4.44-4.34(m,1H),4.28-4.16(m,1H),3.36-3.22(m,1H),3.00-2.86(m,1H),2.44(s,3H),2.34-2.25(m,1H),1.74-1.66(m,1H),1.58-1.42(m,2H),1.37-1.28(m,1H),1.00(t,J＝7.4Hz,3H)。

Example 3 6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) -3-ethylpiperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N⁴- (3-ethylpiperidin-4-yl)_-N ²- (3-methylimidazo [1,2-a ]]To a suspension of pyridin-7-yl) pyrimidine-2, 4-diamine (0.13g,0.34mmol) in DCM (10.0mL) was added 6-chloropyridazine-3-carbonitrile (0.095g,0.68mmol) and TEA (0.15mL,1.10 mmol). The reaction was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH) ₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1) to afford the title compound as a yellow solid (0.12g, 73% yield).

MS(ESI,pos.ion)m/z:489.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.20(s,1H),7.95(s,1H),7.76(d,J＝7.4Hz,1H),7.41(d,J＝9.6Hz,1H),7.29(s,1H),6.95-6.83(m,2H),5.12(d,J＝8.1Hz,1H),4.80-4.65(m,1H),4.50-4.37(m,1H),4.32-4.19(m,1H),3.48-3.33(m,1H),3.09-2.95(m,1H),2.50-2.30(m,4H),1.80-1.67(m,1H),1.65-1.47(m,2H),1.38-1.28(m,1H),0.98(t,J＝7.1Hz,3H)。

Example 46- (4- ((5-chloro-2- (imidazo [1, 2-a))]Pyridin-7-ylamino) pyrimidin-4-yl) amino) piperazine Pyridin-1-yl) pyridazine-3-carbonitrile

Step 1) (1- (6-Cyanopyridazin-3-yl)) Piperidin-4-yl) carbamic acid tert-butyl ester

To a solution of tert-butyl piperidin-4-ylcarbamate (1.40g,6.99mmol) and 6-chloropyridazine-3-carbonitrile (967.4mg,6.93mmol) in ethanol (20mL) was added triethylamine (976.2mg,9.65 mmol). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was slurried with a mixed solvent of ethanol and water (10mL/1mL) for 0.5 hour, and filtered to give the title compound as a pale brown solid (2.13g, yield 100%).

MS(ESI,pos.ion)m/z:304.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.83(d,J＝9.7Hz,1H),7.36(d,J＝9.7Hz,1H),6.89(d,J＝7.3Hz,1H),4.40(d,J＝13.4Hz,2H),3.67^–3.56(m,1H),3.24–3.12(m,2H),1.84(d,J＝10.1Hz,2H),1.39(s,9H),1.35–1.31(m,2H)。

Step 2)6- (4-Aminopiperidin-1-yl) pyridazine-3-carbonitrile

To a suspension of tert-butyl (1- (6-cyanopyridazin-3-yl) piperidin-4-yl) carbamate (2.03g,6.69mmol) in DCM (15mL) was added a solution of hydrogen chloride in ethyl acetate (4M,15mL,60 mmol). The reaction system was stirred at room temperature for 0.5 hour, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (30mL), and the resulting solution was adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (250mL × 3). The combined organic phases were washed with brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an orange solid (1.20g, 88.2% yield).

MS(ESI,pos.ion)m/z:204.2[M+H]⁺。

Step 3)6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To a suspension of 6- (4-amino-1-piperidine) pyridazine-3-carbonitrile (1.20g,5.90mmol) and 2,4, 5-trichloropyrimidine (1.50g,8.18mmol) in EtOH (30mL) was added triethylamine (1.74g,17.20 mmol). The reaction mixture was stirred at room temperature for 4 hours, after completion of the reaction, the reaction was quenched with water (50mL) and extracted with EtOAc (250 mL. times.3). The combined organic phases were washed with brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as an orange solid (1.06g, 51.3% yield).

MS(ESI,pos.ion)m/z:349.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.05(s,1H),7.45(d,J＝9.6Hz,1H),6.89(d,J＝9.6Hz,1H),5.39(d,J＝7.5Hz,1H),4.56(d,J＝13.7Hz,2H),4.47–4.34(m,1H),3.37–3.23(m,2H),2.25(dd,J＝12.6,2.8Hz,2H),1.60(dd,J＝12.0,3.7Hz,2H)。

Step 4) 7-Bromoimidazo [1,2-a ]]Piperidine derivatives

To a suspension of 4-bromopyridin-2-amine (5.26g,30.40mmol) in water (50mL) was added 2-chloroacetaldehyde (40% [ w/w ] in water, 15.24g,77.66 mmol). The reaction mixture was stirred at 100 ℃ for 4 hours, and after completion of the reaction, the pH was adjusted to 10 with a saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (100mL × 3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/100) to afford the title compound as a yellow liquid (5.93g, 100% yield).

MS(ESI,pos.ion)m/z:197.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.00(d,J＝7.2Hz,1H),7.82(d,J＝0.8Hz,1H),7.61(s,1H),7.57(s,1H),6.90(dd,J＝7.2,1.7Hz,1H)。

Step 5) N- (diphenylmethylene) imidazo [1,2-a]Pyridin-7-amines

To 7-bromoimidazo [1,2-a ]]To a solution of pyridine (5.50g,27.91mmol) and benzophenone imine (10.00g,55.19mmol) in toluene (200mL) was added Pd₂(dba)₃(97%, 1.30g,1.38mmol), BINAP (1.70g,2.73mmol) and t-BuONa (5.40g,56.19 mmol). The reaction system was stirred at 100 ℃ for 2 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a brown oil (8.00g, 96% yield).

MS(ESI,pos.ion)m/z:298.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.84(d,J＝7.1Hz,1H),7.75(d,J＝7.4Hz,2H),7.51–7.45(m,2H),7.43–7.38(m,3H),7.31–7.22(m,3H),7.18–7.15(m,2H),6.88(d,J＝0.8Hz,1H),6.30(dd,J＝7.1,1.9Hz,1H)。

Step 6) imidazo [1,2-a]Pyridin-7-amines

To a solution of N- (diphenylmethylene) imidazo [1,2-a ] pyridin-7-amine (8.00g,26.9mmol) in DCM (25mL) was added a solution of hydrogen chloride in EtOAc (50mL,150mmol, 3M). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (50mL) and adjusted to pH 10 with saturated aqueous sodium carbonate solution, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a brown solid (2.93g, 82% yield).

MS(ESI,pos.ion)m/z:134.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.74(d,J＝7.2Hz,1H),7.31(d,J＝1.0Hz,1H),7.23(s,1H),6.61–6.56(m,1H),6.21(dd,J＝7.2,2.2Hz,1H),4.19(s,2H)。

Step 7)6- (4- ((5-chloro-2- (imidazo [1, 2-a))]Pyridin-7-ylamino) pyrimidin-4-yl) amino) piperidine- 1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (110.0mg,0.31mmol) and imidazo [1,2-a ]]To a suspension of pyridin-7-amine (62.0mg,0.47mmol) in 1, 4-dioxane (25mL) was added Pd (OAc)₂(25.0mg,0.11mmol), BINAP (52.3mg,0.08mmol) and Cs₂CO₃(213.8mg,0.66 mmol). The resulting reaction mixture was stirred at 120 ℃ overnight, and after completion of the reaction, it was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to give the title compound as a beige solid (109.4mg, 77.9% yield).

MS(ESI,pos.ion)m/z:446.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.23(s,1H),8.00(d,J＝7.3Hz,1H),7.97(s,1H),7.53(s,1H),7.46–7.43(m,2H),7.05(s,1H),6.90(d,J＝9.6Hz,1H),6.76(dd,J＝7.3,1.4Hz,1H),5.24(d,J＝7.0Hz,1H),4.57(d,J＝13.1Hz,2H),4.49–4.37(m,1H),3.54–3.44(m,2H),2.36(dd,J＝12.5,2.7Hz,1H),1.73–1.50(m,2H)。

Example 5 6-(4-((2-([1,2,4]Triazolo [4,3-a]Pyridin-7-ylamino) -5-chloropyrimidin-4-yl) amino Yl) -3-ethylpiperidin-1-yl) nicotinonitrile

Step 1) N- (diphenylmethylene) - [1,2,4]Triazolo [4,3-a]Pyridin-7-amines

To 7-bromo- [1,2,4]Triazolo [4,3-a]To a suspension of pyridine (930.9mg,4.70mmol) and benzophenone imine (1.70g,9.38mmol) in toluene (40mL) was added Pd₂(dba)₃(217.7mg,0.24mmol), BINAP (293.4mg,0.45mmol) and t-BuONa (908.4mg,9.45 mmol). The reaction was stirred at 100 ℃ overnight, after completion of the reaction, the reaction was quenched by addition of water (50mL), and the resulting mixture was extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a brown solid (1.66g, 46.3% yield).

MS(ESI,pos.ion)m/z:299.2[M+H]⁺。

Step 2) [1,2,4]]Triazolo [4,3-a]Pyridin-7-amines

To a solution of N- (diphenylmethylene) - [1,2,4] triazolo [4,3-a ] pyridin-7-amine (942.8mg,3.16mmol) in 1, 4-dioxane (30mL) was added dropwise an aqueous solution of HCl (30mL,120mmol, 4M). The reaction mixture was stirred at room temperature overnight, after completion of the reaction, the pH was adjusted to 10 with saturated aqueous sodium carbonate solution, and the resulting mixture was extracted with dichloromethane (250mL × 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow solid (162.0mg, 38.2% yield).

MS(ESI,pos.ion)m/z:135.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.46(d,J＝14.8Hz,1H),7.82(dd,J＝14.5,7.3Hz,1H),6.52–6.43(m,1H),6.41–6.30(m,1H)。

Step 3)4- ((2- ([1,2, 4)]Triazolo [4,3-a]Pyridin-7-ylamino) -5-chloropyrimidin-4-yl) amino) - 3-ethylpiperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate and [1,2,4]Triazolo [4,3-a]To a suspension of pyridin-7-amine (148.6mg,1.11mmol) in 1, 4-dioxane (15mL) was added Pd (OAc)₂(65.6mg,0.29mmol), BINAP (190.6mg,0.29mmol) and Cs₂CO₃(759.7mg,2.33 mmol). The reaction mixture was placed in a sealed tube, degassed and charged with N₂Multiple times, then stirred under microwave irradiation at 150 ℃ for 2 hours. After completion of the reaction, the reaction was directly concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a yellow solid (210.8mg, yield 38.8%).

MS(ESI,pos.ion)m/z:472.9[M+H]⁺。

^{2 4}Step 4) N- ([1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) -5-chloro-N- (3-ethylpiperidin-4-yl) pyrimidine Pyridine-2, 4-diamines

To a solution of tert-butyl 4- ((2- ([1,2,4] triazolo [4,3-a ] pyridin-7-ylamino) -5-chloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate (201.9mg,0.43mmol) in DCM (10mL) was added a solution of HCl in EtOAc (10mL,40mmol, 4M). The reaction system was stirred at room temperature for 0.5 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (30mL) and adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (250mL × 3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/5) to give the title compound as a beige solid (91.8mg, 57.7% yield).

MS(ESI,pos.ion)m/z:372.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃+CD₃OD)(ppm):8.65(s,1H),8.38(s,1H),8.00(d,J＝7.4Hz,1H),7.84(s,1H),6.79(dd,J＝7.4,1.8Hz,1H),4.11–4.04(td,J＝11.1,4.3Hz,1H),3.28–3.26(m,2H),3.15(td,J＝13.0,3.2Hz,2H),2.87(t,J＝12.5Hz,1H),2.25–1.99(m,4H),1.67–1.61(m,1H),0.82(t,J＝7.5Hz,3H)。

Step 5)6- (4- ((2- ([1,2, 4)]Triazolo [4,3-a]Pyridin-7-ylamino) -5-chloropyrimidin-4-yl) amino Yl) -3-ethylpiperidin-1-yl) nicotinonitrile

To N²-([1,2,4]Triazolo [4,3-a]Pyridin-7-yl) -5-chloro-N⁴- (3-ethylpiperidin-4-yl) pyrimidine-2, 4-diamine (37.9mg,0.102mmol) and 6-chloronicotinonitrile (29.0mg,0.209mmol) in EtOH (10mL) were added to a suspension of Et₃N (33.8mg,0.334 mmol). The reaction system was stirred under reflux overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a beige solid (28.6mg, 59.2% yield).

MS(ESI,pos.ion)m/z:474.8[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.68(s,1H),8.45(s,1H),8.42(d,J＝1.9Hz,1H),8.00–7.99(m,2H),7.62(dd,J＝9.0,2.2Hz,1H),7.32(s,1H),6.80(d,J＝6.9Hz,1H),6.66(d,J＝9.0Hz,1H),5.19(d,J＝8.4Hz,1H),4.65(d,J＝13.1Hz,1H),4.43(d,J＝13.5Hz,1H),4.21(qd,J＝10.6,4.2Hz,1H),3.38–3.31(m,1H),2.92(dd,J＝13.6,10.9Hz,1H),2.35–2.29(m,1H),1.77–1.71(m,1H),1.41(t,J＝7.3Hz,1H),1.39–1.30(m,2H),1.02(t,J＝7.5Hz,3H)。

Example 6 6- (4- ((5-chloro-2- (imidazo [1, 2-a))]Pyridin-7-ylamino) pyrimidin-4-yl) amino) -3- Ethylpiperidin-1-yl) nicotinonitrile

Step 1)4- ((5-chloro-2- (imidazo [1, 2-a)]Pyridin-7-ylamino) pyrimidin-4-yl) amino) -3-ethylpiperazine Pyridine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate (202.4mg,0.5393mmol), imidazo [1,2-a]Pyridin-7-amine (91.4mg,0.686mmol), BINAP (32.8mg,0.0527mmol), Cs₂CO₃(351.4mg,1.079mmol)、Pd(OAc)₂(12.3mg,0.0548mmol) and 1, 4-dioxane (25mL) were added to a sealed tube. The reaction mixture was heated to 150 ℃ and stirred for 4 hours, after the reaction was completed, it was concentrated under reduced pressure, and the resulting residue was diluted with water (50 mL). The resulting mixture was extracted with a mixed solvent of DCM/MeOH (10/1(v/v),80 mL. times.4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a pale yellow solid (105mg, 41% yield).

MS(ESI,pos.ion)m/z:471.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.02-7.97(m,2H),7.95(s,1H),7.54(s,1H),7.45(s,1H),6.95(d,J＝6.9Hz,1H),5.11(d,J＝8.6Hz,1H),4.09(d,J＝14.9Hz,3H),3.03(s,1H),2.13(dd,J＝12.9,3.4Hz,1H),1.78-1.55(m,6H),1.48(s,9H),0.94(t,J＝7.5Hz,3H)。

^{4 2}Step 2) 5-chloro-N- (3-ethylpiperidin-4-yl) -N- (imidazo [1, 2-a)]Pyridin-7-yl) pyrimidine-2, 4-bis Amines as pesticides

EtOAc solution of hydrogen chloride (16mL,24mmol,1.5M) was added to 4- ((5-chloro-2- (imidazo [1, 2-a)]Pyridin-7-ylamino) pyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester (105mg,0.2225 mmol). The reaction system was stirred at room temperature for 4 hours, and after the reaction was completed, it was concentrated under reduced pressure. The residue was saturated with Na ₂CO₃Aqueous solution (20mL) was diluted, and the resulting mixture was extracted with a mixed solvent of DCM/MeOH (10/1(v/v),50 mL. times.4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and reducedAnd (5) concentrating under pressure. The resulting residue was purified by preparative thin layer chromatography to give the title compound as a pale yellow solid (70mg, yield 85%).

Step 3)6- (4- ((5-chloro-2- (imidazo [1, 2-a))]Pyridin-7-ylamino) pyrimidin-4-yl) amino) -3-ethyl PIPERIDIN-1-YL) NICOTHILE

To 5-chloro-N⁴- (3-ethylpiperidin-4-yl) -N²- (imidazo [1, 2-a)]Pyridin-7-yl) pyrimidine-2, 4-diamine (70mg,0.1882mmol) in EtOH (10mL) was added 6-chloropyridine-3-carbonitrile (33.8mg,0.244mmol) and DIPEA (92.4mg,0.715 mmol). The reaction mixture was warmed to reflux and stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a pale yellow solid (32mg, 36% yield).

MS(ESI,pos.ion)m/z:474.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.40(d,J＝2.0Hz,1H),8.32(s,1H),8.04(d,J＝7.4Hz,1H),7.96(s,1H),7.67(s,1H),7.59(dd,J＝9.0,2.2Hz,1H),7.55(d,J＝1.2Hz,1H),7.46(s,1H),7.16(d,J＝6.3Hz,1H),6.64(d,J＝9.1Hz,1H),5.15(d,J＝8.5Hz,1H),4.57(d,J＝12.8Hz,1H),4.39(d,J＝13.5Hz,1H),4.26(ddd,J＝19.2,10.5,4.2Hz,1H),3.38(t,J＝11.7Hz,1H),3.10-3.01(m,1H),2.31(d,J＝9.4Hz,1H),1.72(ddd,J＝14.0,7.4,3.1Hz,1H),1.47(ddd,J＝15.9,15.0,6.2Hz,2H),1.39-1.30(m,1H),1.00(t,J＝7.5Hz,3H)。

Example 76- (4- ((2- ([1,2, 4)]Triazolo [4,3-a]Pyridin-7-ylamino) -5-chloropyrimidin-4-yl) amino 3-ethylpiperidin-1-yl) -3-pyridazine-carbonitrile

To N²-([1,2,4]Triazolo [4,3-a]Pyridin-7-yl) -5-chloro-N⁴- (3-ethylpiperidin-4-yl) pyrimidine-2, 4-diamine (35.8mg,0.096mmol) and 6-chloropyridazine-3-carbonitrile (27.6mg,0.198mmol) in EtOH (10mL) were added to a suspension of Et ₃N (46.0mg,0.455 mmol). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a beige solid (39.5mg, 86.5% yield).

MS(ESI,pos.ion)m/z:475.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.69(s,1H),8.49(s,1H),8.01(d,J＝6.5Hz,1H),8.00(s,1H),7.45(d,J＝9.6Hz,1H),7.23(s,1H),6.91(d,J＝9.6Hz,1H),6.79(dd,J＝7.3,1.5Hz,1H),5.22(d,J＝8.3Hz,1H),4.84(d,J＝11.7Hz,1H),4.46(d,J＝13.2Hz,1H),4.32–4.19(m,1H),3.55–3.43(m,2H),2.41(dd,J＝13.2,3.3Hz,1H),1.82–1.72(m,1H),1.59–1.52(m,2H),1.37–1.33(m,1H),1.02(t,J＝7.5Hz,3H)。

Example 86- (4- ((5-chloro-2- ((2-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) amino) -3-ethylpiperidin-1-yl) pyridazine-3-carbonitrile

Step 1) tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) (methyl) amino) -3-ethylpiperidine-1-carboxylate

To a solution of tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate (1.31g,3.49mmol) in tetrahydrofuran (30mL) at 0 deg.C was added sodium hydride (60% suspended in mineral oil, 98.6mg,2.47mmol) and the resulting reaction was stirred at 0 deg.C for 30 minutes. Methyl iodide (0.2mL,3mmol) was added dropwise to the reaction system. The resulting mixture was allowed to warm to room temperature and the reaction was stirred for 8 hours. The reaction was quenched with water (50mL) and extracted with EtOAc (100 mL. times.3). The combined organic phases were concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10) to afford the title compound as a white solid (662.3mg, 48.7% yield).

MS(ESI,pos.ion)m/z:389.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.05(s,1H),4.36-4.29(m,2H),3.04(s,3H),2.86-2.79(m,1H),2.42-2.36(m,1H),1.86-1.83(m,1H),1.78-1.63(m,2H),1.48(s,9H),1.45-1.38(m,1H),1.27-1.24(m,1H),1.03-0.93(m,1H),0.89(t,J＝7.3Hz,3H)。

Step 2) 7-bromo-2-methylimidazo [1,2-a ]Pyridine compound

To 4-bromopyridin-2-amine (1.08g,6.24mmol) in H₂To a solution of O (20mL) was added 1-bromo-2, 2-dimethoxypropane (5.59g,30.5mmol) and 4-methylbenzenesulfonic acid (209.4mg,1.216 mmol). The reaction mixture was heated to reflux and stirred for 12 hours, after the reaction was complete, with saturated Na₂CO₃The aqueous solution was adjusted to pH 10, and the resulting mixture was extracted with EtOAc (100mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 3/1) to give the title compound as a yellow solid (750mg, 57% yield).

MS(ESI,pos.ion)m/z:211.1[M+H]⁺。

Step 3) N- (diphenylmethylene) -2-methylimidazo [1,2-a]Pyridin-7-amines

Reacting 7-bromo-2-methylimidazo [1,2-a ]]Pyridine (750mg,3.5535mmol), Pd₂(dba)₃(304.6mg,0.3326mmol), BINAP (216.7mg,0.3480mmol), t-BuONa (703.5mg,7.320mmol) and benzophenone imine (1.30g,7.17mmol) were dissolved in toluene (20 mL). The reaction was warmed to 80 ℃ and stirred overnight, then diluted with water (80 mL). The resulting mixture was extracted with EtOAc (100 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to give the title compound as a yellow solid (580mg, 52.4% yield).

MS(ESI,pos.ion)m/z:311.95[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.77-7.71(m,3H),7.49(t,J＝7.3Hz,1H),7.41(t,J＝7.5Hz,2H),7.32-7.23(m,3H),7.19-7.11(m,3H),6.79(d,J＝1.1Hz,1H),6.23(dd,J＝7.1,1.9Hz,1H),2.37(s,3H)。

Step 4) 2-methylimidazo[1,2-a]Pyridin-7-amines

Reacting N- (diphenylmethylene) -2-methylimidazo [1,2-a ]]Pyridin-7-amine (580mg,1.863mmol) was added to a solution of hydrogen chloride in EtOAc (20mL,30mmol,1.5M), and the resulting mixture was stirred at room temperature for 7 h, then washed with water (50 mL. times.2). The combined aqueous phases were saturated with Na₂CO₃The aqueous solution was adjusted to pH 10, and the resulting mixture was extracted with a mixed solvent of DCM/MeOH (10/1(v/v),150mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (7M) (v/v) ═ 40/1) to give the title compound as a light yellow solid (90mg, 33% yield).

MS(ESI,pos.ion)m/z:148.20[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.73(d,J＝7.2Hz,1H),7.05(s,1H),6.56(d,J＝1.6Hz,1H),6.19(dd,J＝7.2,2.2Hz,1H),3.91(s,2H),2.34(s,3H)。

Step 5)4- ((5-chloro-2- ((2-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) Amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) (methyl) amino) -3-ethylpiperidine-1-carboxylate (208mg,0.5343mmol), 2-methylimidazo [1,2-a ] and]pyridin-7-amine (70mg,0.47561mmol), Pd (OAc)₂(11.5mg,0.0512mmol), BINAP (28.6mg,0.0459mmol) and Cs₂CO₃(316.7mg,0.9720mmol) of the mixture was dissolved in 1, 4-dioxane (15 mL). The resulting mixture was warmed to reflux and stirred overnight, after the reaction was complete, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (140mg, 58% yield).

MS(ESI,pos.ion)m/z:500.3[M+H]⁺。

^{4 4 2}Step 6) 5-chloro-N- (3-ethylpiperidin-4-yl) -N-methyl-N- (2-methylimidazo [1, 2-a)]Pyridine-7- Yl) pyrimidine-2, 4-diamines

Reacting 4- ((5-chloro)-2- ((2-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester (140mg,0.2800mmol) was added to a solution of hydrogen chloride in EtOAc (20mL,60mmol,3M), the resulting mixture was stirred at room temperature for 1 hour, and after completion of the reaction, concentrated under reduced pressure. The residue was saturated with Na₂CO₃The aqueous solution was diluted (40mL) and extracted with a mixed solvent of DCM/MeOH (10/1(v/v),50 mL. times.6). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed by preparative thin layer chromatography (DCM/NH)₃Purified with MeOH (7M)) (v/v) ═ 10/1) to give the title compound as a pale yellow solid (105mg, 93% yield).

MS(ESI,pos.ion)m/z:400.0[M+H]⁺。

Step 7)6- (4- ((5-chloro-2- ((2-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) Yl) amino) -3-ethylpiperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N⁴- (3-ethylpiperidin-4-yl) -N⁴-methyl-N²- (2-methylimidazo [1, 2-a)]TEA (96.8mg,0.957mmol) was added to a solution of pyridin-7-yl) pyrimidine-2, 4-diamine (105mg,0.2626mmol) and 6-chloropyridazine-3-carbonitrile (44.6mg,0.320mmol) in ethanol (10 mL). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (DCM/MeOH (v/v) ═ 10/1) to afford the title compound as a light yellow solid (38mg, yield 28.8%).

MS(ESI,pos.ion)m/z:503.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.22(s,1H),7.97(s,1H),7.91(t,J＝9.3Hz,2H),7.44(d,J＝9.6Hz,1H),7.19(s,1H),7.12(d,J＝6.6Hz,1H),6.91(d,J＝9.7Hz,1H),4.79(d,J＝12.3Hz,1H),4.64(d,J＝13.8Hz,1H),4.52(td,J＝11.4,3.9Hz,1H),3.29(t,J＝12.0Hz,1H),3.07(s,3H),2.86-2.77(m,1H),2.47(s,3H),2.14(d,J＝10.1Hz,1H),1.93-1.76(m,2H),1.59-1.50(m,1H),1.15-1.05(m,1H),0.94(t,J＝7.5Hz,3H)。

Example 96- (4- ((2- ([1,2, 4)]Triazolo [1,5-a]Pyridin-6-ylamino) -5-Chloropyrimidin-4-yl) (methyl) amino) piperidin-1-yl) nicotinonitrile

Step 1) N- (diphenylmethylene) - [1,2,4]Triazolo [1,5-a]Pyridin-6-amines

To 6-bromo- [1,2,4]Triazolo [1,5-a]To a solution of pyridine (700mg,3.5350mmol), benzophenone imine (1.28g,7.06mmol) and t-BuONa (680mg,7.076mmol) in toluene (50mL) were added BINAP (221mg,0.3549mmol) and Pd₂(dba)₃(167mg,0.17690 mmol). The resulting mixture was degassed for 5 minutes and charged with N₂Then, it was stirred at 100 ℃ for 4 hours. After the reaction was complete, the reaction was quenched with water (100mL), extracted with EtOAc (100 mL. times.3), and the combined organic phases were extracted with anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 5/1 to 1/1) to afford the title compound as a yellow solid (1.01g, 95.8%).

MS(ESI,pos.ion)m/z:299.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.21(s,1H),8.04(d,J＝1.2Hz,1H),7.79-7.73(m,2H),7.50(dd,J＝8.4,2.9Hz,2H),7.42(t,J＝7.5Hz,2H),7.31(t,J＝6.2Hz,3H),7.14(dd,J＝7.7,1.7Hz,2H),7.03(dd,J＝9.4,2.0Hz,1H)。

Step 2) [1,2,4]]Triazolo [1,5-a]Pyridin-6-amines

To N- (diphenylmethylene) - [1,2,4] triazolo [1,5-a ] pyridin-6-amine (1.01g,3.39mmol) in DCM (15mL) was added a solution of hydrogen chloride in EtOAc (16mL,48mmol, 3M). The reaction system was stirred at room temperature for 4 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (15mL) and adjusted to pH 10 with saturated aqueous sodium bicarbonate solution, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1 to 20/1) to give the title compound as a yellow solid (430mg, 94.7% yield).

MS(ESI,pos.ion)m/z:135.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.17(s,1H),8.02(d,J＝1.4Hz,1H),7.56(d,J＝9.4Hz,1H),7.19(dd,J＝9.4,2.0Hz,1H),5.24(s,2H)。

Step 3)6- (4- ((2- ([1,2, 4)]Triazolo [1,5-a]Pyridin-6-ylamino) -5-chloropyrimidin-4-yl) (methyl) Yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) (methyl) amino) piperidin-1-yl) nicotinonitrile (500mg,1.377mmol), [1,2,4]Triazolo [1,5-a]Pyridin-6-amine (222mg,1.6550mmol) and Cs₂CO₃(1.35g,4.14mmol) 1, 4-dioxane (10mL) Pd (OAc) was added₂(62mg,0.2762mmol) and BINAP (171.5mg,0.2754 mmol). The reaction mixture was degassed for 5 minutes and charged with N₂And then reacted in a microwave at 150 ℃ for 2 hours. After the reaction was finished, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 5/1 to 1/1) and by preparative thin layer chromatography (DCM/MeOH (v/v) ═ 10/1) to give the title compound as a pale yellow solid (566mg, yield 89.2%).

MS(ESI,pos.ion)m/z:461.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.53(d,J＝1.5Hz,1H),8.42(d,J＝2.2Hz,1H),8.27(s,1H),8.04(s,1H),7.68(d,J＝9.5Hz,1H),7.62(dd,J＝9.0,2.3Hz,1H),7.33(dd,J＝9.5,2.0Hz,1H),7.08(s,1H),6.66(d,J＝9.1Hz,1H),4.68(ddd,J＝11.9,7.9,3.9Hz,1H),4.61(d,J＝14.1Hz,2H),3.13(t,J＝11.9Hz,2H),3.07(s,3H),1.98(d,J＝10.2Hz,2H),1.84(qd,J＝12.3,4.1Hz,2H)。

Example 106- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

Step 1)4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridine-7-yl) amino) pyrimidin-4-yl) (methyl) Amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) (methyl) amino) -3-ethylpiperidine-1-carboxylate (450mg,1.16mmol) and 3-methylimidazo [1,2-a ] ]To a solution of pyridin-7-amine (200mg,1.36mmol) in 1, 4-dioxane (8mL) were added palladium acetate (51mg,0.227mmol), BINAP (141mg,0.226mmol) and cesium carbonate (735mg,2.56 mmol). The reaction mixture was placed in a sealed tube, degassed and charged with N₂Multiple times, then stirred under microwave irradiation at 150 ℃ for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and then filtered. The filter cake was washed with DCM (20 mL. times.2), the resulting filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (NH)₃Purified with MeOH (7M)/DCM (v/v) ═ 1/50 to give the title compound as an orange oil (390mg, 67.5% yield).

MS(ESI,pos.ion)m/z:500.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.21(s,1H),7.96(s,2H),7.80(d,J＝6.7Hz,1H),7.28(s,1H),4.27(d,J＝9.0Hz,2H),3.05(s,3H),2.86(s,1H),2.61(s,4H),2.43(s,2H),1.91-1.88(m,1H),1.78-1.63(m,3H),1.48(s,9H),1.41(t,J＝6.2Hz,1H),0.88-0.86(m,3H)。

^{4 4 2}Step 2) 5-chloro-N- (3-ethylpiperidin-4-yl) -N-methyl-N- (3-methylimidazo [1, 2-a)]Pyridine-7- Yl) pyrimidine-2, 4-diamines

To 4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester (391mg,0.782mmol) in DCM (20mL) was added hydrogen chloride in EtOAc (10mL,30mmol, 3M). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20mL) and adjusted to pH 10 with saturated aqueous sodium bicarbonate, then extracted with EtOAc (50mL × 3). The combined organic phases were washed with saturated brine (50 mL. times.3) and anhydrous Na ₂SO₄Drying, filtration and concentration under reduced pressure gave a yellow solid (300mg, 87.9% yield).

MS(ESI,pos.ion)m/z:200.8[(M+H)/2]⁺。

Step 3)6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) Yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

To 5-chloro-N⁴- (3-ethylpiperidin-4-yl) -N⁴-methyl-N²- (3-methylimidazo [1,2-a ]]TEA (78mg,0.771mmol) was added to a solution of pyridin-7-yl) pyrimidine-2, 4-diamine (101mg,0.253mmol) and 6-chloronicotinonitrile (52mg,0.375mmol) in ethanol (20 mL). The reaction system is heated to 80 ℃ and stirred for 8 hours, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by preparative thin layer chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a yellow solid (40mg, 31.6% yield).

MS(ESI,pos.ion)m/z:502.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.94(s,1H),8.49(d,J＝1.9Hz,1H),8.31-8.23(m,2H),8.15(s,1H),7.86-7.83(m,1H),7.37(s,1H),7.29(s,1H),7.01(d,J＝9.1Hz,1H),4.69-4.59(m,2H),4.41(s,1H),2.97(s,3H),2.72(t,J＝12.3Hz,1H),2.42(s,3H),1.95(d,J＝11.7Hz,1H),1.82-1.75(m,2H),1.43(s,1H),1.05(s,1H),0.87(t,J＝7.3Hz,3H)。

Example 116- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) (methyl) amino) -3-ethylpiperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N⁴- (3-ethylpiperidin-4-yl) -N⁴-methyl-N²- (3-methylimidazo [1,2-a ]]TEA (78mg,0.771mmol) was added to a solution of pyridin-7-yl) pyrimidine-2, 4-diamine (100mg,0.250mmol) and 6-chloropyridazine-3-carbonitrile (53mg,0.380mmol) in ethanol (20 mL). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound The material was a yellow solid (86mg, 68% yield).

MS(ESI,pos.ion)m/z:503.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.91(s,1H),8.29-8.23(m,2H),8.15(s,1H),7.84(d,J＝9.7Hz,1H),7.41(d,J＝9.8Hz,1H),7.35(s,1H),7.28(s,1H),4.71(d,J＝26.9Hz,2H),4.44(s,1H),3.26(s,2H),2.97(s,3H),2.42(s,3H),1.98(d,J＝11.6Hz,1H),1.93–1.74(m,2H),1.43(s,1H),1.06(s,1H),0.87(t,J＝7.2Hz,3H)。

Example 126- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (100.4mg,0.29mmol) and 3-methylimidazo [1,2-a ]]To a solution of pyridin-7-amine (64.2mg,0.44mmol) in 1, 4-dioxane (8mL) was added Pd (OAc)₂(6.8mg,0.03mmol), BINAP (18.0mg,0.03mmol) and cesium carbonate (281.5mg,0.86 mmol). Reaction system at 100 ℃ and N₂Stirring for 2 hours under protection, and after the reaction is finished, concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40 to 1/20) to give the title compound as a white solid (83.4mg, yield 63.1%).

MS(ESI,pos.ion)m/z:461.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.56(s,1H),8.22(s,1H),8.12(d,J＝7.4Hz,1H),8.05(s,1H),7.88(d,J＝9.7Hz,1H),7.46(d,J＝9.8Hz,1H),7.17(s,1H),7.12(dd,J＝7.4,1.9Hz,1H),7.07(d,J＝7.7Hz,1H),4.68-4.65(m,2H),4.44-4.37(m,1H),3.28-3.21(m,2H),2.40(s,3H),2.10-2.07(m,2H),1.74-1.63(m,2H)。

Example 136- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-6-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

Step 1) 2-Chloropropional

To a suspension of propionaldehyde (20.00g,344.4mmol) in chloroform (200mL) at 0 deg.C was added pyrrolidine-2-carboxylic acid (7.93g,68.9mmol) and NCS (50.58g,378.8 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, then allowed to warm to room temperature and stirred overnight, and n-hexane (400mL) was added to the mixture and stirring was continued for 30 minutes. After completion of the reaction, the reaction mixture was filtered, the filtrate was washed with water (100 mL. times.2), and the organic phase was washed with anhydrous Na ₂SO₄Drying and filtering to obtain 600mL of colorless solution (0.57mol/L, yield 100%) which is used in the next reaction without treatment.

GC-MS m/z(EI):92.0[M]⁺。

Step 2) 6-bromo-3-methylimidazo [1,2-a ]]Pyridine compound

To the colorless solution from the previous reaction (120mL,0.57mol/L,68.40mmol) was added 5-bromopyridin-2-amine (3.00g,17.36 mmol). The resulting mixture was heated to reflux and stirred for 20 hours, after the reaction was completed, concentrated under reduced pressure. The resulting residue was taken up in DCM (50mL) and saturated Na₂CO₃The aqueous solution (50mL) was diluted and stirred for 30 min. The organic layer was separated, the aqueous layer was extracted with DCM (100mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (DCM (100%) to DCM/NH₃Purified with MeOH (3M) (v/v) ═ 200/1 to 100/1) to afford the title compound as a brown solid (1.50g, 41% yield).

MS(ESI,pos.ion)m/z:211.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.02(s,1H),7.50(d,J＝9.5Hz,1H),7.41(s,1H),7.21(dd,J＝9.5,1.7Hz,1H),2.47(s,3H)。

Step 3) N- (diphenylmethylene) -3-methylimidazo [1,2-a]Pyridin-6-amines

To a suspension of 6-bromo-3-methylimidazo [1,2-a ] pyridine (1.50g,7.11mmol) in dry toluene (35mL) was added

Pd₂(dba)₃(0.65g,0.71mmol), BINAP (0.89g,1.43mmol), t-BuONa (1.38g,14.32mmol) and benzophenone imine (2.58g,14.2 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 85 ℃ and stirred overnight. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with EtOAc (100mL), and the resulting filtrate was washed with water (50 mL. times.2) and anhydrous Na ₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound as a brown oil (2.21g, 100% yield).

MS(ESI,pos.ion)m/z:312.3[M+H]⁺。

Step 4) 3-methylimidazo [1,2-a ]]Pyridin-6-amines

To N- (diphenylmethylene) -3-methylimidazo [1,2-a]To a suspension of pyridin-6-amine (2.21g,7.10mmol) in DCM (50.0mL) was added a solution of hydrogen chloride in EtOAc (50mL,150mmol, 3M). The reaction system was stirred at room temperature for 3 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (50mL) and extracted with ethyl acetate (50 mL. times.2). The aqueous phase was saturated with Na₂CO₃The aqueous solution was adjusted to pH 10, and then extracted with DCM (100mL × 3) and a mixed solvent of DCM/MeOH (10/1(v/v),100mL × 3) in this order. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1 to 10/1) to afford the title compound as a dark green solid (0.45g, 43% yield).

MS(ESI,pos.ion)m/z:148.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.44(d,J＝9.4Hz,1H),7.33-7.28(m,2H),6.76(dd,J＝9.4,2.1Hz,1H),3.46(s,2H),2.38(s,3H)。

Step 5)6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a)]Pyridin-6-yl) amino) pyrimidin-4-yl) amino Yl) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl group) To a suspension of pyridazine-3-carbonitrile (70mg,0.20mmol) in anhydrous 1, 4-dioxane (5.0mL) was added 3-methylimidazo [1,2-a ] ]Pyridin-6-amine (46mg,0.31mmol), Pd (OAc)₂(6mg,0.028mmol), BINAP (16mg,0.025mmol) and Cs₂CO₃(0.20g,0.61 mmol). Degassing the obtained mixture for several times and charging N₂Then heated to reflux and stirred for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1 to 20/1) to give a crude product as a brown solid. The crude product was diluted with EtOAc (2mL), the resulting mixture was stirred at room temperature for 30 min, then filtered, and the resulting solid was dried under reduced pressure to give the title compound as a pale green solid (25mg, 27% yield).

MS(ESI,pos.ion)m/z:461.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃+CD₃OD)(ppm):8.54(s,1H),7.89(s,1H),7.47(d,J＝9.7Hz,1H),7.44(d,J＝9.7Hz,1H),7.28(s,1H),7.21(d,J＝9.3Hz,1H),6.90(d,J＝9.6Hz,1H),4.46–4.38(m,2H),4.29–4.21(m,1H),3.26–3.17(m,2H),2.44(s,3H),2.20–2.14(m,2H),1.61–1.53(m,2H)。

Example 146- (4- ((5-chloro-2- ((3-cyclopropylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) 7-bromo-3-iodoimidazo [1,2-a]Pyridine compound

To a solution of 7-bromoimidazo [1,2-a ] pyridine (5.93g,30.1mmol) in DMF (60mL) was added NIS (9.19g,40.8 mmol). The reaction mixture was stirred at 100 ℃ for 1 hour, then cooled to room temperature, quenched with water (50mL), and extracted with DCM (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10) to give the title compound as a white solid (8.45g, 86.9% yield).

MS(ESI,pos.ion)m/z:323.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.02(d,J＝7.3Hz,1H),7.83(d,J＝1.2Hz,1H),7.69(s,1H),7.05(dd,J＝7.3,1.7Hz,1H)。

Step 2) 7-bromo-3-cyclopropylimidazo [1,2-a]Pyridine compound

7-bromo-3-iodoimidazo [1,2-a]Pyridine (7.04g,21.80mmol) and potassium tetrafluorocyclopropane (3.87g,26.20mmol) were suspended in a mixed solvent of toluene (100mL) and water (10mL) and Pd (OAc) was added₂(493.4mg,2.20mmol), n-butyldi (1-adamantyl) phosphine (1.17g,3.26mmol) and Cs₂CO₃(21.31g,65.40 mmol). The reaction mixture was stirred at 110 ℃ overnight, then cooled to room temperature, quenched with water (50mL), and the resulting mixture extracted with DCM (250 mL. times.3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as a pale yellow solid (2.57g, 49.7% yield).

MS(ESI,pos.ion)m/z:237.2[M+H]⁺。

Step 3) 3-cyclopropyl-N- (diphenylmethylene) imidazo [1,2-a]Pyridin-7-amines

To 7-bromo-3-cyclopropylimidazo [1,2-a]Pd was added to a solution of pyridine (2.52g,10.60mmol) and benzophenone imine (2.64g,14.60mmol) in toluene (40mL)₂(dba)₃(461.8mg,0.50mmol), BINAP (626.9mg,0.96mmol) and t-BuONa (1.92g,20.00 mmol). The reaction mixture was stirred at 100 ℃ overnight. Then cooled to room temperature and quenched by addition of water (50 mL). The resulting mixture was extracted with EtOAc (100 mL. times.3), and the combined organic phases were washed with saturated brine (100mL), anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/4) to give the title compound as a black oil (1.04g, 29.0% yield).

MS(ESI,pos.ion)m/z:338.4[M+H]⁺。

Step 4) 3-Cyclopropylimidazo[1,2-a]Pyridin-7-amines

To 3-cyclopropyl-N- (diphenylmethylene) imidazo [1,2-a]A solution of pyridin-7-amine (1.02g,3.02mmol) in 1, 4-dioxane (30mL) was added dropwise to a solution of hydrogen chloride in EtOAc (30mL,120mmol, 4M). The resulting mixture was stirred at room temperature overnight and, after completion of the reaction, saturated Na was added₂CO₃The aqueous solution was adjusted to pH 10. The resulting mixture was extracted with DCM (250 mL. times.6). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a light brown oil (333.7mg, 63.7% yield).

MS(ESI,pos.ion)m/z:174.3[M+H]⁺。

Step 5)4- ((5-chloro-2- ((3-cyclopropylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate (359.3mg,1.04mmol) and 3-cyclopropylimidazo [1,2-a ]]To a suspension of pyridin-7-amine (148.7mg,0.86mmol) in 1, 4-dioxane (20mL) was added Pd (OAc)₂(38.7mg,0.17mmol), BINAP (109.4mg,0.17mmol) and Cs₂CO₃(575.1mg,1.76 mmol). The reaction system was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a yellow oil (389.5mg, 93.7% yield).

MS(ESI,pos.ion)m/z:484.4[M+H]⁺。

^{2 4}Step 6) 5-chloro-N- (3-cyclopropylimidazo [1, 2-a)]Pyridin-7-yl) -N- (piperidin-4-yl) pyrimidine-2, 4- Diamines

To a solution of tert-butyl 4- ((5-chloro-2- ((3-cyclopropylimidazo [1,2-a ] pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidine-1-carboxylate (383.9mg,0.79mmol) in dichloromethane (10mL) was added a solution of hydrogen chloride in ethyl acetate (10mL,40mmol, 4M). The reaction system was stirred at room temperature for 0.5 hour, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (30mL) and adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (250mL × 3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow oil (278.3mg, 91.4% yield).

MS(ESI,pos.ion)m/z:384.4[M+H]⁺。

Step 7)6- (4- ((5-chloro-2- ((3-cyclopropylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

To 5-chloro-N²- (3-Cyclopropylimidazo [1, 2-a)]Pyridin-7-yl) -N⁴- (piperidin-4-yl) pyrimidine-2, 4-diamine (350.9mg,0.91mmol) and 6-chloropyridazine-3-carbonitrile (130.6mg,0.92mmol) in EtOH (20mL) suspension ₃N (186.3mg,1.84 mmol). The reaction was stirred at room temperature overnight, then quenched by addition of water (30mL) and extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a beige solid (85.3mg, 19.2% yield).

MS(ESI,pos.ion)m/z:487.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.58(s,1H),8.18(d,J＝7.3Hz,1H),7.97(s,1H),7.43(d,J＝3.3Hz,1H),7.41(s,1H),7.05(s,1H),6.90(d,J＝9.6Hz,1H),5.32(d,J＝6.8Hz,1H),4.64(s,1H),4.50(d,J＝13.8Hz,

2H),3.79–3.76(m,1H),3.65–3.62(m,1H),2.40(d,J＝14.0Hz,2H),2.03–1.99(m,3H),1.85–1.80(m,2H),0.85–0.82(m,2H),0.77–0.72(m,2H)。

Example 15 6- (4- ((5-chloro-2- ((3-cyclopropylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) -3-ethylpiperidin-1-yl) pyridazine-3-carbonitrile

Step 1)4- ((5-chloro-2- ((3-cyclopropylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino 3-ethylpiperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate (388.4mg,1.04mmol) and 3-cyclopropylimidazo [1,2-a ]]To a suspension of pyridin-7-amine (149.4mg,0.86mmol) in 1, 4-dioxane (20mL) was added Pd (OAc)₂(42.5mg,0.19mmol), BINAP (110.1mg,0.17mmol) and Cs₂CO₃(564.5mg,1.73 mmol). The reaction system was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a yellow oil (402.2mg, 91.1% yield).

MS(ESI,pos.ion)m/z:512.3[M+H]⁺。

^{2 4}Step 2) 5-chloro-N- (3-cyclopropylimidazo [1, 2-a)]Pyridin-7-yl) -N- (3-ethylpiperidin-4-yl) pyrimidine Pyridine-2, 4-diamines

To a solution of tert-butyl 4- ((5-chloro-2- ((3-cyclopropylimidazo [1,2-a ] pyridin-7-yl) amino) pyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylate (392.3mg,0.77mmol) in DCM (10mL) was added a solution of hydrogen chloride in ethyl acetate (10mL,40mmol, 4M). The reaction system was stirred at room temperature for 0.5 hour, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (30mL), and the resulting mixture was adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (250mL × 3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow oil (305.8mg, 96.9% yield).

MS(ESI,pos.ion)m/z:412.4[M+H]⁺。

Step 3)6- (4- ((5-chloro-2- ((3-cyclopropylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) -3-ethylpiperidin-1-yl) Pyridazine-3-carbonitriles

To 5-chloro-N²- (3-Cyclopropylimidazo [1, 2-a)]Pyridin-7-yl) -N⁴- (3-ethylpiperidin-4-yl) pyrimidine-2, 4-diamine (263.3mg,0.64mmol) and 6-chloropyridazine-3-carbonitrile (92.8mg,0.66mmol) in EtOH (20mL) suspension ₃N (157.8mg,1.56 mmol). The reaction was stirred at room temperature overnight, then quenched by addition of water (30mL) and extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a beige solid (96.6mg, 29.3% yield).

MS(ESI,pos.ion)m/z:515.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.47(s,1H),8.17(d,J＝6.9Hz,1H),8.11–8.08(m,1H),7.95(s,1H),7.42(d,J＝9.5Hz,1H),7.12(s,1H),6.89(d,J＝9.5Hz,1H),5.22(d,J＝7.7Hz,1H),4.68(d,J＝10.6Hz,1H),4.49(d,J＝9.6Hz,1H),4.42–4.37(m,1H),3.71–3.57(m,1H),3.44–3.39(m,1H),2.02–1.99(m,2H),1.68–1.62(m,4H),1.10(d,J＝6.1Hz,3H),1.01(t,J＝7.0Hz,4H),0.76–0.71(m,2H)。

Example 16 6- (4- ((5-chloro-2- ((2, 3-dimethylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate

To a solution of 2,4, 5-trichloropyrimidine (2g,10.904mmol) in ethanol (50mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (2.62g,13.1mmol) and triethylamine (2.21g,21.8 mmol). The reaction mixture was stirred at room temperature overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/20 to 1/10) to give the title compoundCompound was a white solid (3.2g, 85% yield). MS (ESI, pos. ion) M/z 347.3[ M + H ]]⁺。

Step 2) 7-bromo-2, 3-dimethylimidazo [1,2-a]Pyridine compound

To a solution of 4-bromopyridin-2-amine (2.02g,11.7mmol) in ethanol (20mL) was added 3-bromobutan-2-one (2.62g,17.4 mmol). The reaction was warmed to 80 ℃ and stirred overnight, then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20mL) and washed with saturated NaHCO ₃The aqueous solution was adjusted to pH 10. The resulting mixture was washed with saturated brine (50 mL. times.3). Anhydrous Na for separated organic phase₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/7) to give the title compound as a yellow solid (1.6g, 61% yield).

MS(ESI,pos.ion)m/z:225.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.67(d,J＝1.3Hz,1H),7.65(d,J＝7.2Hz,1H),6.90-6.86(m,1H),2.41(s,3H),2.37(s,3H)。

Step 3) N- (diphenylmethylene) -2, 3-dimethylimidazo [1,2-a]Pyridin-7-amines

To 7-bromo-2, 3-dimethylimidazo [1,2-a ]]To a solution of pyridine (1.6g,7.10mmol) and benzophenone imine (2.67g,14.7mmol) in 1, 4-dioxane (20mL) was added BINAP (890mg,1.43mmol), Pd₂(dba)₃(653mg,0.713mmol) and t-BuONa (1.41g,14.7 mmol). The reaction system was stirred at 85 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a brown solid (1.8g, 78% yield).

MS(ESI,pos.ion)m/z:326.4[M+H]⁺。

Step 4) 3-methylimidazo [1,2-a ]]Pyridin-7-amines

To N- (diphenylmethylene) -2, 3-dimethylimidazo [1,2-a]To a solution of pyridin-7-amine (1.8g,5.50mmol) in DCM (10mL) was added a solution of hydrogen chloride in EtOAc (20mL,60mmol, 3M). The obtained reaction system is stirred at room temperature overnight, and the reaction is finishedAfter completion, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20mL) and adjusted to pH 10 with saturated aqueous sodium bicarbonate, then extracted with EtOAc (50mL × 3). The combined organic phases were washed with saturated brine (50 mL. times.3) and anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography ((NH)₃Purified with MeOH (7M))/DCM (v/v) ═ 1/20) to give the title compound as a brown solid (300mg, 34% yield).

MS(ESI,pos.ion)m/z:162.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.53(d,J＝7.2Hz,1H),6.61(d,J＝1.5Hz,1H),6.30-6.26(m,1H),2.31(s,3H),2.29(s,3H)。

Step 5)4- ((5-chloro-2- ((2, 3-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidine-1-carboxylic acid tert-butyl ester

To 3-methylimidazo [1,2-a ]]Pyridine-7-amine (112mg,0.691mmol) and tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate (200mg,0.576mmol) in 1, 4-dioxane (20mL) was added BINAP (72mg,0.115mmol), Pd (OAc)₂(25mg,0.115mmol) and Cs₂CO₃(376mg,1.15 mmol). The reaction system was stirred at 100 ℃ overnight and after the reaction was complete, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH)₃Purified with MeOH (7M)/DCM (v/v) ═ 1/30) to give the title compound as a yellow solid (150mg, 55.2% yield).

MS(ESI,pos.ion)m/z:472.5[M+H]⁺。

^{2 4}Step 6) 5-chloro-N- (2, 3-dimethylimidazo [1, 2-a)]Pyridin-7-yl) -N- (piperidin-4-yl) pyrimidin-2, 4-diamines

To 4- ((5-chloro-2- ((2, 3-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (150mg,0.317mmol) in DCM (20mL) was added hydrogen chloride in EtOAc (20mL,60mmol, 3M). The reaction mixture was stirred at room temperature overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20mL), And adjusted to pH 10 with saturated aqueous sodium bicarbonate, followed by extraction with EtOAc (50mL × 3). The combined organic phases were washed with saturated brine (50 mL. times.3) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure, and the resulting residue was purified by preparative chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a yellow solid (90mg, 76.2% yield).

MS(ESI,pos.ion)m/z:372.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.04(s,1H),7.90(s,1H),7.71(s,1H),6.96(s,1H),4.28(s,1H),3.34-3.29(m,2H),3.19-3.14(m,2H),2.37(s,6H),2.22-2.17(m,2H),1.91-1.86(m,2H)。

Step 7)6- (4- ((5-chloro-2- ((2, 3-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N²- (2, 3-dimethylimidazo [1, 2-a)]Pyridin-7-yl) -N⁴- (piperidin-4-yl) pyrimidine-2, 4-diamine (87mg,0.234mmol) and 6-chloronicotinonitrile (53mg,0.379mmol) in EtOH (10mL) was added TEA (85mg,0.840 mmol). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH)₃Purified with MeOH (7M)/DCM (v/v) ═ 1/20) to give the title compound as a yellow solid (60mg, 54% yield).

MS(ESI,pos.ion)m/z:475.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.01(d,J＝1.5Hz,1H),7.95(s,1H),7.67(d,J＝7.3Hz,1H),7.44(d,J＝9.6Hz,1H),7.04(s,1H),6.90(d,J＝9.6Hz,1H),6.84(dd,J＝7.3,2.0Hz,1H),5.21(d,J＝7.0Hz,1H),4.55-4.50(m,2H),4.44-4.40(m,1H),3.51-3.46(m,2H),2.36(s,6H),2.37-2.31(m,2H),1.60-1.57(m,2H)。

Example 17 6- (4- ((5-chloro-2- ((3-methyl- [1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

Step 1)6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

To a solution of 2, 5-dichloro-N- (3-ethylpiperidin-4-yl) pyrimidin-4-amine (806.2mg,2.93mmol) in ethanol (20mL) was added TEA (0.6mL,4mmol) and 6-chloropyridine-3-carbonitrile (487.4mg,3.52 mmol). The reaction mixture was heated to reflux and stirred for 3 hours, after completion of the reaction, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5 to 1/3) to give the title compound as a white solid (182.0mg, 17% yield).

MS(ESI,pos.ion)m/z:377.2[M+H]⁺。

Step 2) N- (diphenylmethylene) -3-methyl- [1,2,4]Triazolo [4,3-a]Pyridin-7-amines

To 7-bromo-3-methyl- [1,2, 4%]Triazolo [4,3-a]To a solution of pyridine (945mg,4.46mmol) and benzophenone imine (1.22g,6.72mmol) in 1, 4-dioxane (20mL) was added BINAP (558mg,0.896mmol), Pd₂(dba)₃(410mg,0.448mmol) and t-BuONa (861mg,8.96 mmol). The reaction was stirred at 85 ℃ for 4 hours, after the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:313.4[M+H]⁺。

Step 3) 3-methyl- [1,2,4]Triazolo [4,3-a]Pyridin-7-amines

To N- (diphenylmethylene) -3-methyl- [1,2,4]Triazolo [4,3-a]To a solution of pyridin-7-amine (1.4g,4.48mmol) in DCM (10mL) was added a solution of hydrogen chloride in EtOAc (20mL,60mmol, 3M). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (20mL), and the resulting mixture was adjusted to pH 10 with saturated aqueous sodium bicarbonate solution, followed by extraction with EtOAc (50mL × 3). The combined organic phases were washed with saturated brine (50mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH) ₃MeOH solution (7M)/DCM (v/v) ═ v1/20) to afford the title compound as a brown solid (176mg, 27% yield).

MS(ESI,pos.ion)m/z:149.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.57(d,J＝7.4Hz,1H),6.48(d,J＝1.4Hz,1H),6.39-6.35(m,1H),2.54(s,3H)。

Step 4)6- (4- ((5-chloro-2- ((3-methyl- [1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile (80mg,0.212mmol) and 3-methyl- [1,2,4]Triazolo [4,3-a]To a solution of pyridin-7-amine (40mg,0.270mmol) in 1, 4-dioxane (20mL) was added BINAP (26mg,0.041mmol), Pd (OAc)₂(9mg,0.040mmol) and Cs₂CO₃(138mg,0.424 mmol). The reaction was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH)₃Purified with MeOH (7M)/DCM (v/v) ═ 1/20 to give the title compound as a yellow solid (45mg, 43.4% yield).

MS(ESI,pos.ion)m/z:489.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.41(d,J＝2.1Hz,1H),8.36(s,1H),7.98(s,1H),7.74(d,J＝7.4Hz,1H),7.61(dd,J＝9.0,2.3Hz,1H),7.36(s,1H),6.89(d,J＝6.5Hz,1H),6.65(d,J＝9.1Hz,1H),5.18(d,J＝8.4Hz,1H),4.62(d,J＝13.0Hz,1H),4.41(d,J＝13.4Hz,1H),4.27–4.16(m,1H),3.39–3.28(m,1H),2.95(dd,J＝13.5,10.9Hz,1H),2.70(s,3H),2.34–2.28(m,1H),1.59–1.44(m,2H),1.39–1.28(m,2H),1.01(t,J＝7.5Hz,3H)。

Example 18 6- (4- ((5-chloro-2- (imidazo [1, 2-b))]Pyridazin-7-ylamino) pyrimidin-4-yl) amino) piperazines Pyridin-1-yl) nicotinonitrile

Step 1)3,4, 5-Trichloropyridazine

4, 5-dichloropyridazin-3-one (20.06g,122.3mmol) and POCl₃(117mL,1280mmol) of the mixture was stirred at reflux for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and then a mixed suspension of water and ice (100mL) was added. The resulting mixture was saturated with Na ₂CO₃The aqueous solution was adjusted to pH 10 and then extracted with EtOAc (250mL × 3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/30) to give the title compound as a white solid (17.80g, 79.3% yield).

¹H NMR(400MHz,CDCl₃):(ppm)9.12(s,1H)。

Step 2)5, 6-dichloropyridazin-4-amine

3,4, 5-Trichloropyridazine (17.79g,96.99mmol) and NH₃A mixture of THF solution (250mL,750mmol,3M) was placed in a sealed tube, stirred at 125 ℃ for 5 hours, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to afford the title compound as a white solid (4.01g, 25% yield).

MS(ESI,pos.ion)m/z:164.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.60(s,1H),4.89(s,2H)。

Step 3) 5-chloro-6-hydrazinopyridazin-4-amine

A mixture of 5, 6-dichloropyridazin-4-amine (4.01g,24.5mmol) and hydrazine hydrate (80% [ w/w ] aq. solution, 26.20g,419mmol) was stirred at 90 ℃ for 3 hours, then cooled to room temperature, water (20mL) was added and a yellow solid precipitated which was filtered to collect the filter cake as the title compound as a yellow solid (3.51g, 90% yield).

MS(ESI,pos.ion)m/z:160.1[M+H]⁺。

Step 4) 4-chloropyridazine-3, 5-diamine

To a suspension of 5-chloro-6-hydrazinopyridazin-4-amine (3.51g,22.0mmol) in ethanol (50mL) was added RayleighNickel (7.26 g). The mixture was placed in an autoclave and then heated at 55 ℃ and 3MPa H ₂After stirring for 3 hours, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a brown solid (1.80g, yield 57%).

MS(ESI,pos.ion)m/z:145.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)7.98(s,1H),6.28(s,2H),6.04(s,2H)。

Step 5) pyridazine-3, 5-diamine

To a suspension of 4-chloropyridazine-3, 5-diamine (6.00g,41.50mmol) in EtOH (150mL) were added NaOH solid (1.67g,41.75mmol) and Pd/C (mass fraction% (% 10%, 660.0 mg). The resulting suspension is at room temperature and H₂The atmosphere was stirred overnight and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound as a red-brown solid (4.50g, 98% yield).

MS(ESI,pos.ion)m/z:111.2[M+H]⁺。

Step 6) imidazo [1,2-b]Pyridazin-7-amines

Pyridazine-3, 5-diamine (1.53g,13.9mmol) and 2-chloroacetaldehyde (40% [ w/w ]]Aqueous solution, 4.32g,22.0mmol) in water (50mL) was stirred at 100 deg.C overnight, then cooled to room temperature, washed with saturated Na₂CO₃The aqueous solution was adjusted to pH 10. The resulting mixture was extracted with DCM (250 mL. times.3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a brown oil (668.9mg, yield 35.9%).

MS(ESI,pos.ion)m/z:135.2[M+H]⁺。

Step 7)6- (4- ((5-chloro-2- (imidazo [1, 2-b))]Pyridazin-7-ylamino) pyrimidin-4-yl) amino) piperidine- 1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (176.4 m)g,0.50mmol) and imidazo [1,2-b ]]To a suspension of pyridazin-7-amine (83.6mg,0.62mmol) in 1, 4-dioxane (20mL) was added Pd (OAc)₂(23.6mg,0.10mmol), BINAP (63.7mg,0.10mmol) and Cs₂CO₃(332.5mg,1.00 mmol). The reaction was stirred at 100 ℃ for 7.5 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50) to give the title compound as a beige solid (65.0mg, 28.8% yield).

MS(ESI,pos.ion)m/z:447.4[M+H]⁺；

¹H NMR(600MHz,CDCl₃And CD₃OD)(ppm):8.62(s,1H),8.44–8.35(m,2H),8.35(s,1H),7.96(s,1H),7.83(s,1H),7.64(dd,J＝9.0,2.3Hz,1H),7.57(s,1H),6.72(d,J＝9.0Hz,1H),4.44(d,J＝13.0Hz,2H),4.37–4.32(m,1H),3.36–3.29(m,2H),2.25(d,J＝12.1Hz,2H),1.63–1.56(m,2H)。

Example 196- (4- ((5-chloro-2- (imidazo [1, 2-b))]Pyridazin-7-ylamino) pyrimidin-4-yl) amino) piperazines Pyridin-1-yl) pyridazine-3-carbonitrile

Step 1)4- ((5-chloro-2- (imidazo [1, 2-b)]Pyridazin-7-ylamino) pyrimidin-4-yl) amino) piperidin-1-ylmethane Tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate (743.7mg,2.14mmol) and imidazo [1,2-b ]]To a suspension of pyridazin-7-amine (314.8mg,2.35mmol) in 1, 4-dioxane (50mL) was added Pd (OAc)₂(112.3mg,0.50mmol), BINAP (311.4mg,0.49mmol) and Cs₂CO₃(1.37g,4.12 mmol). The reaction system was stirred at 100 ℃ for 7 hours, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a yellow solid (157.1mg, 16.5% yield).

MS(ESI,pos.ion)m/z:445.4[M+H]⁺。

^{2 4}Step 2) 5-chloro-N- (imidazo [1, 2-b)]Pyridazin-7-yl) -N- (piperidin-4-yl) pyrimidine-2, 4-diamines

To a solution of tert-butyl 4- ((5-chloro-2- (imidazo [1,2-b ] pyridazin-7-ylamino) pyrimidin-4-yl) amino) piperidine-1-carboxylate (143.2mg,0.32mmol) in DCM (10mL) was added a solution of hydrogen chloride in ethyl acetate (10mL,40mmol, 4M). The reaction system was stirred at room temperature for 0.5 hour, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (10mL), and adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (100mL × 3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow oil (111.0mg, 100% yield).

MS(ESI,pos.ion)m/z:345.0[M+H]⁺。

Step 3)6- (4- ((5-chloro-2- (imidazo [1, 2-b))]Pyridazin-7-ylamino) pyrimidin-4-yl) amino) piperidine- 1-yl) pyridazine-3-carbonitrile

To 5-chloro-N²- (imidazo [1,2-b ]]Pyridazin-7-yl) -N⁴- (piperidin-4-yl) pyrimidine-2, 4-diamine (95.7mg,0.28mmol) and 6-chloropyridazine-3-carbonitrile (96.3mg,0.69mmol) in EtOH (20mL) suspension were added Et₃N (192.0mg,1.90 mmol). The reaction was stirred at room temperature overnight, and after completion of the reaction, water (30mL) was added to quench the reaction. The resulting mixture was extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a beige solid (45.8mg, 36.8% yield).

MS(ESI,pos.ion)m/z:448.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃And MeOH-d₄)(ppm):8.51(d,J＝1.3Hz,1H),8.36(s,1H),7.87(s,1H),7.74(s,1H),7.48(s,1H),7.41(d,J＝9.7Hz,1H),6.93(d,J＝9.7Hz,1H),4.46(d,J＝13.8Hz,2H),4.38–4.26(m,1H),2.22(dd,J＝12.3,1.4Hz,3H),1.97–1.86(m,1H),1.60–1.51(m,3H)。

Example 206- (4- ((5-chloro-2- ((3-methyl- [1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (70mg,0.199mmol) and 3-methyl- [1,2,4]Triazolo [4,3-a]BINAP (25mg,0.040mmol), Pd (OAc) were added to a solution of pyridin-7-amine (37mg,0.249mmol) in 1, 4-dioxane (20mL)₂(8mg,0.039mmol) and Cs₂CO₃(130mg,0.398 mmol). The reaction system was heated to 105 ℃ and stirred overnight, after the reaction was complete, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ((MeOH/DCM (v/v) ═ 1/20) to give the title compound as a yellow solid (30mg, yield 32.5%).

MS(ESI,pos.ion)m/z:462.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.86(s,1H),8.34(s,1H),8.25(d,J＝7.4Hz,1H),8.10(s,1H),7.88(d,J＝9.7Hz,1H),7.45(d,J＝9.7Hz,1H),4.68-4.64(m,2H),4.59-4.55(s,1H),4.42-4.38(m,1H),2.61(s,3H),2.10-2.05(m,2H),2.02-1.98(m,1H),1.72-1.67(m,2H)。

Example 216- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-b)]Pyridazin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) nicotinonitrile

Step 1) 3-methylimidazo [1,2-b ]]Pyridazin-7-amines

To pyridazine-3, 5-diamine (0.80g,7.30mmol) was added a solution of 2-chloropropionaldehyde in chloroform and n-hexane (70.0mL,39.9mmol, 0.57M). The reaction system was warmed to 80 ℃ and stirred overnight, then concentrated under reduced pressure. The residue was saturated with Na₂CO₃Aqueous solution (20mL) was diluted, and the resulting mixture was extracted sequentially with DCM (50 mL. times.3) and a mixed solvent of DCM/MeOH (10/1(v/v),50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH) ₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1 to 20/1) to afford the title compound as a yellow solid (0.37g, 34% yield).

MS(ESI,pos.ion)m/z:149.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.97(d,J＝2.6Hz,1H),7.27(s,1H),6.97(d,J＝2.6Hz,1H),3.95(s,2H),2.48(s,3H)。

Step 2)6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-b)]Pyridazin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidin-1-yl) nicotinonitrile

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (0.15g,0.43mmol) in anhydrous 1, 4-dioxane (10.0mL) was added 3-methylimidazo [1,2-b]Pyridazin-7-amine (0.098g,0.66mmol), Pd (OAc)₂(0.021g,0.095mmol), BINAP (0.056g,0.089mmol) and Cs₂CO₃(0.28g,0.87 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then heated to 100 ℃ and stirred for reaction for 5 hours, after the reaction was completed, the mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1 to 30/1 to give the crude product (0.14g, 70% yield). The crude product was subjected to preparative thin layer chromatography (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 40/1) to give the title compound as a yellow solid (32mg, 16% yield).

MS(ESI,pos.ion)m/z:461.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.51-8.35(m,3H),7.98(s,1H),7.61(dd,J＝9.0,2.3Hz,1H),7.43(s,1H),7.16(s,1H),6.65(d,J＝9.0Hz,1H),5.25(d,J＝7.3Hz,1H),4.49-4.39(m,2H),4.39-4.28(m,1H),3.38-3.25(m,2H),2.53(s,3H),2.31-2.20(m,2H),1.60-1.54(m,2H)。

Example 226- (4- ((5-chloro-2- ((3, 6-di)Methylimidazo [1,2-a ]]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) 4-bromo-3-methylpyridine 1-oxy Compound

To a solution of 4-bromo-3-methylpyridine hydrochloride (10g,47.966mmol) in DCM (200mL) at 0 deg.C was added mCPBA (11.69g,57.58 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight, after completion of the reaction, concentrated under reduced pressure. The obtained residue was dissolved in water (250mL), adjusted to pH 8 to 9 with saturated aqueous sodium carbonate solution, and then extracted with dichloromethane (250mL × 3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to afford the title compound as a yellow solid (4.68g, 51.9% yield).

MS(ESI,pos.ion)m/z:188.2[M+H]⁺。

Step 2) 4-bromo-N- (tert-butyl) -5-methylpyridin-2-amine

To a solution of 4-bromo-3-methylpyridine 1-oxo compound (4.68g,24.9mmol) and 2-methylpropan-2-amine (9.10g,124mmol) in DCM (200mL) at 0 deg.C was added 4-toluenesulfonic anhydride (16.2g,49.6 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour, then allowed to warm to room temperature and stirred overnight. After the reaction was completed, it was diluted with water (250mL), and the resulting mixture was extracted with DCM (250 mL. times.3). The combined organic phases were washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 100/1 to 50/1) to give the title compound as a yellow solid (1.35g, 22.3% yield).

MS(ESI,pos.ion)m/z:243.2[M+H]⁺。

Step 3) 4-bromo-5-methylpyridin-2-amine

To a solution of 4-bromo-N- (tert-butyl) -5-methylpyridin-2-amine (2.35g,9.67mmol) in toluene (12mL) was added 2,2, 2-trifluoroacetic acid (12 mL). The reaction mixture was stirred at 70 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The residue was dissolved in water (250mL), and the mixture was adjusted to pH 8 to 9 with saturated aqueous sodium bicarbonate solution, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50) to afford the title compound as a yellow solid (1.43g, 79.1% yield).

MS(ESI,pos.ion)m/z:187.2[M+H]⁺。

Step 4) 7-bromo-3, 6-dimethylimidazo [1,2-a]Pyridine compound

To a solution of 4-bromo-5-methylpyridin-2-amine (1.5g,8.0mmol) and 2-chloropropionaldehyde (140mL,80mmol) in ethanol (100mL) was added 4-methylbenzenesulfonic acid (280mg,1.626 mmol). The reaction system is heated to 100 ℃ and stirred for reaction overnight, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1 to 50/1) to give the title compound as a yellow solid (820mg, 45% yield).

MS(ESI,pos.ion)m/z:225.2[M+H]⁺。

Step 5) N- (diphenylmethylene) -3, 6-dimethylimidazo [1,2-a]Pyridin-7-amines

To 7-bromo-3, 6-dimethylimidazo [1,2-a ]]Pyridine (820mg,3.6431mmol), benzophenone imine (991mg,5.469mmol) and t-BuONa (700.5mg,7.289mmol) in 1, 4-dioxane (50mL) was added BINAP (227mg,0.3645mmol) and Pd ₂(dba)₃(172mg,0.1822 mmol). The resulting mixture was degassed for 5 minutes and refilled with N₂Then, the mixture was stirred at 105 ℃ for 4 hours, and after the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow solid (667mg, yield 56.26%).

MS(ESI,pos.ion)m/z:326.4[M+H]⁺。

Step 6)3, 6-dimethylimidazo [1,2-a]Pyridin-7-amines

To N- (diphenylmethylene) -3, 6-dimethylimidazo [1,2-a]Pyridin-7-amine (667mg,2.050mmol) in DCM (20mL) was addedTo this was added a solution of hydrogen chloride in EtOAc (11mL,33mmol, 3M). The reaction was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The resulting residue was dissolved in water (15mL), and adjusted to pH 10 with saturated aqueous sodium bicarbonate solution, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 20/1 to 10/1) to afford the title compound as a yellow solid (270mg, 81.71% yield). MS (ESI, pos.ion) M/z 162.2[ M + H ]]⁺。

Step 7)6- (4- ((5-chloro-2- ((3, 6-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (0.15g,0.43mmol) in n-BuOH (5.0mL) was added 3, 6-dimethylimidazo [1,2-a ] ]Pyridin-7-amine (0.086g,0.53mmol) and DIPEA (0.14g,1.05 mmol). The reaction mixture was placed in a sealed tube, degassed and charged with N₂After stirring for 48 hours at 150 ℃ several times, the reaction mixture was concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (DCM/MeOH (v/v) ═ 100/1 to 50/1 to DCM/(NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 20/1 to 10/1 to 2/1) to give the crude product. The crude product was subjected to preparative thin layer chromatography (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 40/1) to give the title compound as a pale yellow solid (62mg, 30% yield).

MS(ESI,pos.ion)m/z:475.2[M+H]⁺；

¹H NMR(400MHz,MeOH-d₄)(ppm):8.26(s,1H),8.24(s,1H),8.16(s,1H),8.15-8.13(m,1H),7.69(d,J＝9.7Hz,1H),7.33(d,J＝9.7Hz,1H),4.71-4.54(m,3H),3.44-3.34(m,2H),2.54(s,3H),2.32(s,3H),2.23-2.14(m,2H),1.84-1.71(m,2H)。

Example 23 6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) nicotinonitrile

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (0.15g,0.43mmol) in anhydrous 1, 4-dioxane (10.0mL) was added 3-methylimidazo [1,2-a ™ ]]Pyridin-7-amine (0.10g,0.67mmol), Pd (OAc)₂(0.020g,0.090mmol), BINAP (0.055g,0.088mmol) and Cs₂CO₃(0.30g,0.93 mmol). In N₂The reaction mixture was heated to 100 ℃ under protection and stirred overnight, after the reaction was complete, concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1) to give the title compound as a pale yellow solid (95mg, 48% yield).

MS(ESI,pos.ion)m/z:460.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.41(d,J＝2.2Hz,1H),8.14(d,J＝1.6Hz,1H),7.96(s,1H),7.75(d,J＝7.4Hz,1H),7.60(dd,J＝9.0,2.3Hz,1H),7.28(s,1H),7.11(s,1H),6.85(dd,J＝7.4,1.9Hz,1H),6.65(d,J＝9.1Hz,1H),5.21(d,J＝7.2Hz,1H),4.47-4.32(m,3H),3.42-3.29(m,2H),2.44(s,3H),2.32-2.23(m,2H),1.62-1.51(m,2H)。

Example 24 6- (4- ((5-chloro-2- ((6-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

Step 1) 7-bromo-6-methylpyrazolo [1,2-a]Pyridine compound

An aqueous solution of 4-bromo-5-methylpyridin-2-amine (880mg,4.7049mmol) and 2-chloroacetaldehyde (8mL,% by mass ═ 40%) was placed in a 25mL sealed tube. The reaction mixture was heated to 100 ℃ and stirred for 20 hours, after the reaction was complete, saturated Na was added₂CO₃The resulting mixture was adjusted to pH 10 with an aqueous solution, and extracted with a mixed solvent of DCM/MeOH (10/1(v/v),100mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM)Purification with/MeOH (v/v) ═ 100/1) afforded the title compound as a yellow solid (780mg, 78.5% yield).

MS(ESI,pos.ion)m/z:211.2[M+H]⁺。

Step 2) N- (diphenylmethylene) -6-methylimidazo [1,2-a]Pyridin-7-amines

Reacting 7-bromo-6-methylimidazo [1,2-a ]]Pyridine (780mg,3.6956mmol), benzophenone imine (816.4mg,4.506mmol), t-BuONa (713.6mg,7.426mmol), BINAP (232.5mg,0.3734mmol) and Pd₂(dba)₃(334.8mg,0.3656mmol) was dissolved in 1, 4-dioxane (20 mL). The reaction mixture was warmed to 100 ℃ and kept under N₂The mixture was extracted with a mixed solvent of DCM/MeOH (10/1(v/v),100 mL. times.3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 80/1) to give the title compound as a yellow solid (710mg, 61.7% yield).

MS(ESI,pos.ion)m/z:312.1[M+H]⁺。

Step 3) 6-methylimidazo [1,2-a ]]Pyridin-7-amines

Reacting N- (diphenylmethylene) -6-methylimidazo [1,2-a ]]Pyridin-7-amine (710mg,2.280mmol) was added to a solution of hydrogen chloride in EtOAc (20mL,20mmol, 1M). The reaction mixture was stirred at room temperature overnight, and after completion of the reaction, the mixture was washed with water (40 mL. times.2). The combined aqueous phases were adjusted to pH 12 with NaOH powder. The resulting mixture was extracted with a mixed solvent of DCM/MeOH (10/1(v/v),100 mL. times.5). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified (7M) MeOH (v/v) ═ 80/1 to give the title compound as a yellow solid (320mg, 95.36% yield).

MS(ESI,pos.ion)m/z:148.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃+CD₃OD)(ppm):7.77(s,1H),7.30(s,1H),6.69(s,1H),2.15(s,3H)。

Step 4)6- (4- ((5-chloro-2- ((6-methylimidazole)And [1,2-a ]]Pyridin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidin-1-yl) pyridazine-3-carbonitrile

Reacting 6-methylimidazo [1,2-a ]]Pyridin-7-amine (203.4mg,1.382mmol), 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (497.8mg,1.421mmol), DIPEA (0.8mL,5mmol), and n-BuOH (6mL) were placed in a 25mL sealed tube. The reaction mixture was heated to 150 ℃ and stirred for 2 days. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (DCM/(NH) ₃Purified with MeOH (7M)) (v/v) ═ 80/1) to give the title compound as a white solid (11.4mg, 1.79% yield).

MS(ESI,pos.ion)m/z:461.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.45(s,1H),8.39(d,J＝2.6Hz,1H),8.33(s,1H),7.98(d,J＝2.5Hz,1H),7.93(s,1H),7.89(d,J＝9.7Hz,1H),7.44(d,J＝9.8Hz,1H),4.63-4.51(m,3H),2.19(s,3H),2.05-1.91(m,4H),1.74-1.64(m,2H)。

Example 256- (4- ((5-chloro-2- ((3-methyl- [1,2, 4)]Triazolo [4,3-b]Pyridazin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 6-hydrazinopyridazin-4-amine

To a solution of 5-chloro-6-hydrazinopyridazin-4-amine (5.02g,31.3mmol) in ethanol (60mL) were added Pd/C (10% by mass, 503mg) and NaOH (1.25g,31.3 mmol). The mixture was placed in an autoclave and at room temperature and 2MPa H₂Stirring was continued overnight, after completion of the reaction, filtration was carried out, and the filtrate was concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (7M) (v/v) ═ 30/1) to give the title compound as a yellow solid (1.3g, 33% yield).

MS(ESI,pos.ion)m/z:126.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.91(d,J＝2.3Hz,1H),7.16(s,1H),6.02(d,J＝2.3Hz,1H),5.97(s,2H)。

Step 2) 3-methyl- [1,2,4]Triazolo [4,3-b]Pyridazin-7-amines

To a solution of 6-hydrazinopyridazin-4-amine (5.02g,31.3mmol) in EtOH (30mL) was added Et₃N (2.43g,24.0mmol) and acetic anhydride (1.22g,12.2 mmol). The reaction system was stirred at 90 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (7M) (v/v) ═ 30/1) to give the title compound as a yellow solid (400mg, 33.6% yield). MS (ESI, pos.ion) M/z 150.3[ M + H ] ]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.14(d,J＝2.2Hz,1H),6.63(s,1H),6.26(s,2H),2.46(s,3H)。

Step 3)6- (4- ((5-chloro-2- ((3-methyl- [1,2, 4)]Triazolo [4,3-b]Pyridazin-7-yl) amino) pyrimidines- 4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (100mg,0.286mmol) and 3-methyl- [1,2,4]Triazolo [4,3-b]BINAP (35mg,0.056mmol), Cs and/or the like were added to a solution of pyridazin-7-amine (65mg,0.436mmol) in 1, 4-dioxane (20mL)₂CO₃(138mg,0.424mmol) and Pd (OAc)₂(12mg,0.053 mmol). The reaction system is heated to 105 ℃ and stirred for reaction overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to give the title compound as a yellow solid (65mg, 49.1% yield).

MS(ESI,pos.ion)m/z:462.5[M+H]⁺；

HRMS(ESI,pos.ion)m/z:462.1675[M+H]⁺,C₂₁H₂₀ClN₁₁[M+H]⁺The theoretical values of (A) are: 462.1592, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.05(s,1H),8.64-6.48(m,2H),8.49(d,J＝2.0Hz,1H),8.09(s,1H),7.85(dd,J＝9.1,2.1Hz,1H),7.20(d,J＝7.7Hz,1H),7.01(d,J＝9.1Hz,1H),4.59-4.54(m,2H),4.36-4.22(m,1H),3.13-3.05(m,2H),2.60(s,3H),2.03-1.98(m,2H),1.69-1.59(m,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):158.91,157.32,156.86,153.25,152.61,144.80,144.42,142.14,140.00,132.96,118.77,106.50,105.57,102.33,94.88,48.67,43.82,30.46,9.18。

example 266- (4- ((5-chloro-2- ((6,7,8, 9-tetrahydrobenzo [4,5 ]]Imidazo [1,2-a ]]Pyridin-3-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) 3-bromo-6, 7,8, 9-tetrahydrobenzo [4,5 ]]Imidazo [1,2-a ]]Pyridine compound

To a solution of 4-bromopyridin-2-amine (1.94g,11.21mmol) and 2-chlorocyclohexanone (2.62g,19.76mmol) in n-BuOH (25mL) was added 4-methylbenzenesulfonic anhydride (400.9mg,2.11 mmol). The reaction mixture was stirred at 150 ℃ overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in water (30mL), adjusted to pH 10 with saturated aqueous sodium carbonate solution, and then extracted with dichloromethane (100mL × 3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/8) to give the title compound as a yellow solid (2.33g, 82.7% yield).

MS(ESI,pos.ion)m/z:251.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.71(d,J＝9.0Hz,2H),7.66(d,J＝7.1Hz,1H),6.87(dd,J＝7.1,1.6Hz,1H),2.83(t,J＝5.9Hz,2H),2.75–2.68(m,2H),2.03–1.88(m,4H)。

Step 2) N- (diphenylmethylene) -6,7,8, 9-tetrahydrobenzo [4,5]]Imidazo [1,2-a ]]Pyridin-3-amines

To 3-bromo-6, 7,8, 9-tetrahydrobenzo [4,5]]Imidazo [1,2-a ]]Pyridine (2.28g,9.08mmol) and benzophenone imine (2.48g,13.69mmol) in 1, 4-dioxane (40mL),adding Pd₂(dba)₃(424.5mg,0.46mmol), BINAP (596.9mg,0.91mmol) and t-BuONa (1.75g,18.21 mmol). The reaction was stirred at 100 ℃ overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 2/1) to give the title compound as a yellow solid (1.29g, 40.4% yield).

MS(ESI,pos.ion)m/z:352.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.75(d,J＝7.2Hz,2H),7.54(d,J＝7.1Hz,1H),7.48(d,J＝7.2Hz,1H),7.41(t,J＝7.4Hz,2H),7.29–7.26(m,3H),7.19–7.16(m,2H),6.84(d,J＝1.3Hz,1H),6.29(dd,J＝7.1,1.9Hz,1H),2.78(t,J＝5.8Hz,2H),2.66(t,J＝5.8Hz,2H),1.99–1.83(m,4H)。

Step 3)6,7,8, 9-Tetrahydrobenzo [4,5]]Imidazo [1,2-a ]]Pyridin-3-amines

To a solution of N- (diphenylmethylene) -6,7,8, 9-tetrahydrobenzo [4,5] imidazo [1,2-a ] pyridin-3-amine (1.25g,3.56mmol) in 1, 4-dioxane (35mL) was added dropwise a solution of hydrogen chloride in EtOAc (35mL,140mmol, 3M). The reaction mixture was stirred at room temperature overnight, after completion of the reaction, adjusted to pH 10 with saturated sodium carbonate powder, then extracted with dichloromethane (250mL × 6), and the combined organic phases were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a brown solid (666.0mg, 100% yield).

MS(ESI,pos.ion)m/z:188.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.49(d,J＝7.2Hz,1H),6.58(d,J＝1.6Hz,1H),6.24(dd,J＝7.2,2.0Hz,1H),3.75(s,2H),2.70(t,J＝5.8Hz,2H),2.60(t,J＝5.9Hz,2H),1.94–1.75(m,4H)。

Step 4)6- (4- ((5-chloro-2- ((6,7,8, 9-tetrahydrobenzo [4,5 ]]Imidazo [1,2-a ]]Pyridin-3-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (69.7mg,0.20mmol) and 6,7,8, 9-tetrahydrobenzo [4,5 ] -c]Imidazo [1,2 ] s-a]To a suspension of pyridin-3-amine (73.1mg,0.39mmol) in 1, 4-dioxane (8mL) was added Pd (OAc)₂(9.4mg,0.04mmol), BINAP (98%, 28.0mg,0.04mmol) and Cs₂CO₃(98%, 137.8mg,0.41 mmol). The reaction system was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to give the title compound as a beige solid (59.1mg, 59.3% yield).

MS(ESI,pos.ion)m/z:501.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:501.2022[M+H]⁺,C₂₅H₂₆ClN₁₀[M+H]⁺The theoretical values of (A) are: 501.2030, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.56(s,1H),8.09(s,1H),8.05(d,J＝7.5Hz,1H),8.03(s,1H),7.87(d,J＝9.7Hz,1H),7.44(d,J＝9.7Hz,1H),7.14(dd,J＝7.3,1.6Hz,1H),7.03(d,J＝7.7Hz,1H),4.63(d,J＝12.4Hz,2H),4.48–4.31(m,1H),3.26(t,J＝12.5Hz,2H),2.74–2.56(m,4H),2.06(d,J＝11.0Hz,2H),1.92–1.76(m,4H),1.74–1.64(m,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):159.1,158.2,153.8,131.6,123.7,111.6,107.0,100.4,48.7,44.3,30.9,24.9,23.5,22.8,20.1。

example 276- (4- ((5-chloro-2- ((2-methylimidazo [1, 2-a))]Pyridin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (0.15g,0.43mmol) in anhydrous 1, 4-dioxane (10mL) was added 2-methylimidazo [1,2-a]Pyridin-7-amine (0.097g,0.66mmol), Pd (OAc)₂(0.020g,0.087mmol), BINAP (0.055g,0.089mmol) and Cs ₂CO₃(0.30g,0.92 mmol). Pumping out air from the reaction mixture, introducing nitrogen for many times, heating to 100 ℃, stirring for reaction for 3 hours,then concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1 to 30/1) to give the crude product. The resulting crude product was stirred in EtOAc (3mL), filtered, and the collected filter cake was dried under reduced pressure to give the title compound as a white solid (95mg, 48% yield).

MS(ESI,pos.ion)m/z:461.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:461.1716[M+H]⁺,C₂₂H₂₂ClN₁₀[M+H]⁺The theoretical values of (A) are: 461.1712, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.51(s,1H),8.26(d,J＝7.3Hz,1H),8.08-8.01(m,2H),7.88(d,J＝9.7Hz,1H),7.49-7.40(m,2H),7.06(dd,J＝7.4,1.9Hz,1H),7.02(d,J＝7.8Hz,1H),4.70-4.58(m,2H),4.45-4.32(m,1H),3.29-3.20(m,2H),2.24(s,3H),2.12-2.01(m,2H),1.77-1.62(m,2H)；

¹³C NMR(100MHz,DMSO-d₆):159.11,158.21,157.26,153.81,145.85,142.40,137.78,131.58,128.82,126.16,117.94,111.63,108.73,107.14,104.63,100.49,48.68,44.33,30.91,14.81。

example 28 6- (4- ((5-chloro-2- ((2- (difluoromethyl) imidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) 7-Bromoimidazo [1,2-a ]]Pyridine-2-carboxylic acid ethyl ester

To a suspension of 4-bromopyridin-2-amine (6.00g,34.7mmol) in EtOH (100mL) was added p-toluenesulfonic acid hydrate (1.32g,6.94mmol) and ethyl 3-bromo-2-oxopropanoate (10.14g,52.00 mmol). The mixture was placed in a sealed tube and then heated to 100 ℃ and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was saturated with Na₂CO₃Aqueous solution (50mL) and water (30 mL). The resulting mixture was sequentially subjected to DCM (100 mL. times.3) extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/5 to 1/2) to give the title compound as a light yellow solid (3.80g, 40% yield).

MS(ESI,pos.ion)m/z:269.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.15(s,1H),8.00(d,J＝7.2Hz,1H),7.86(s,1H),6.97(dd,J＝7.2,1.7Hz,1H),4.45(q,J＝7.1Hz,2H),1.43(t,J＝7.1Hz,3H)。

Step 2) 7-Bromoimidazo [1,2-a]Pyridine-2-carbaldehyde

At-78 ℃ and N₂Protected to 7-bromoimidazo [1,2-a ]]To a suspension of pyridine-2-carboxylic acid ethyl ester (3.50g,13.0mmol) in dry DCM (80mL) was added diisobutylaluminum hydride (18.50mL,18.50mmol, 1.0M). The mixture was stirred at-78 deg.C overnight, after completion of the reaction, it was moved to 0 deg.C and quenched by the sequential addition of water (0.75mL), 15% aqueous NaOH (0.75mL) and water (2 mL). The resulting mixture was stirred at room temperature for 15 minutes, and Et was then added thereto₂O (50mL), EtOAc (50mL) and Mg monohydrate₂SO₄(20g) Stirring was continued for 15 min, and filtration was performed, the resulting filter cake was washed with EtOAc (200mL), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/5) to give the title compound as a pale yellow solid (1.50g, 51% yield).

MS(ESI,pos.ion)m/z:225.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):10.14(s,1H),8.13(s,1H),8.04(d,J＝7.2Hz,1H),7.89(s,1H),7.02(dd,J＝7.2,1.7Hz,1H)。

Step 3) 7-bromo-2- (difluoromethyl) imidazo [1,2-a]Pyridine compound

To 7-bromoimidazo [1,2-a ]]To a suspension of pyridine-2-carbaldehyde (1.45g,6.44mmol) in dry DCM (30mL) was slowly added diethylaminosulfur trifluoride (8.50mL,64.3 mmol). The resulting mixture was stirred at-78 ℃ for 15 minutes, then allowed to warm to room temperature and stirred overnight. The reaction system is cooled to 0 ℃ and then saturated NaHCO is added in turn ₃The reaction was quenched with aqueous solution (20mL) and water (50 mL). The resulting mixture was extracted with DCM (50 mL. times.4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/5) to give the title compound as a pale yellow solid (0.55g, 35% yield).

MS(ESI,pos.ion)m/z:247.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.01(d,J＝7.2Hz,1H),7.83(s,1H),7.79(s,1H),6.98(dd,J＝7.2,1.7Hz,1H),6.84(t,J＝52.0Hz,1H)；

¹⁹F NMR(376MHz,CDCl₃)(ppm):–114.23。

Step 4)2- (difluoromethyl) -N- (diphenylmethylene) imidazo [1,2-a]Pyridin-7-amines

To 7-bromo-2- (difluoromethyl) imidazo [1,2-a]To a suspension of pyridine (0.50g,2.0mmol) in anhydrous 1, 4-dioxane (20mL) was added BINAP (0.26g,0.416mmol6), Pd₂(dba)₃(0.19g,0.21mmol), t-BuONa (0.40g,4.18mmol) and benzophenone imine (0.74g,4.07 mmol). The reaction mixture was degassed several times and purged with nitrogen, then warmed to 105 ℃ and stirred overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/3 to 1/1) to give the title compound as a brown liquid (0.60g, 85% yield).

MS(ESI,pos.ion)m/z:348.2[M+H]⁺。

Step 5)2- (difluoromethyl) imidazo [1,2-a]Pyridin-7-amines

To 2- (difluoromethyl) -N- (diphenylmethylene) imidazo [1,2-a]To a suspension of pyridin-7-amine (0.53g,1.50mmol) in DCM (20mL) was added HCl in EtOAc (20.0mL,60.0mmol, 3.0M). The reaction system was stirred at room temperature for 30 minutes, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in DCM (20mL) and saturated Na ₂CO₃The aqueous solution (20mL) was diluted and the mixture was stirred at room temperature for 15 min. After standing, the organic layer was separated, and the aqueous layer was extracted successively with DCM (50 mL. times.2) and a mixed solvent of DCM/MeOH (10/1(v/v),50 mL. times.2). For combined organic phasesDried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 20/1) to afford the title compound as a yellow solid (0.12g, 43% yield).

MS(ESI,pos.ion)m/z:184.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.86(d,J＝7.3Hz,1H),7.54(s,1H),6.78(t,J＝55.8Hz,1H),6.65(d,J＝1.8Hz,1H),6.35(dd,J＝7.3,2.2Hz,1H),4.00(s,2H)；

¹⁹F NMR(376MHz,CDCl₃)(ppm):–113.93。

Step 6)6- (4- ((5-chloro-2- ((2- (difluoromethyl) imidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (0.10g,0.29mmol) in anhydrous 1, 4-dioxane (10mL) was added 2- (difluoromethyl) imidazo [1,2-a [, 2-b ] and]pyridin-7-amine (0.064g,0.35mmol), Pd (OAc)₂(0.016g,0.070mmol), BINAP (0.038g,0.061mmol) and Cs₂CO₃(0.20g,0.61 mmol). The reaction mixture was degassed and charged with N₂Multiple times, then stirred at 105 ℃ for 3 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1) to give a white solid. The resulting white solid was stirred in EtOAc (5mL) for 0.5 h, filtered and dried under reduced pressure to give the title compound as a white solid (70mg, 49% yield).

MS(ESI,pos.ion)m/z:497.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:497.1550[M+H]⁺；C₂₂H₂₀ClF₂N₁₀[M+H]⁺The theoretical values of (A) are: 497.1524, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.70(s,1H),8.42(d,J＝7.4Hz,1H),8.22(s,1H),8.07(s,1H),8.03(s,1H),7.89(d,J＝9.7Hz,1H),7.45(d,J＝9.8Hz,1H),7.21(dd,J＝7.5,2.0Hz,1H),7.08(d,J＝7.8Hz,1H),7.04(t,J＝52.0Hz,1H),4.71-4.59(m,2H),4.46-4.34(m,1H),3.29-3.20(m,2H),2.11-2.02(m,2H),1.76-1.64(m,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):158.62,157.62,156.83,153.31,146.14,138.93,131.12,129.66,128.37,126.93,117.46,113.55,112.01,111.16,108.63,104.67,100.18,56.02,48.21,43.86,30.41,18.56；

¹⁹F NMR(376MHz,DMSO-d₆)(ppm):–112.19。

example 296- (4- ((5-chloro-2- ((3, 8-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) N- (diphenylmethylene) -3, 8-dimethylimidazo [1,2-a]Pyridin-7-amines

To 7-bromo-3, 8-dimethylimidazo [1,2-a ]]Pyridine (995mg,4.4207mmol), benzophenone imine (1.61g,8.89mmol) and t-BuONa (850mg,8.845mmol) in 1, 4-dioxane (30mL) was added BINAP (276mg,0.4432mmol) and Pd₂(dba)₃(209mg,0.22139 mmol). The reaction mixture was degassed for 5 minutes and charged with N₂Then, it was stirred at 100 ℃ for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1 to 50/1) to give the title compound as a yellow solid (522mg, yield 36.29%).

MS(ESI,pos.ion)m/z:326.4[M+H]⁺。

Step 2)3, 8-dimethylimidazo [1,2-a]Pyridin-7-amines

To N- (diphenylmethylene) -3, 8-dimethylimidazo [1,2-a]To a solution of pyridin-7-amine (522mg,1.604mmol) in DCM (15mL) was added a solution of hydrogen chloride in EtOAc (16mL,48mmol, 3M). The reaction system was stirred at room temperature for 4 hours, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (15mL) and saturated carbonic acid was used The aqueous sodium hydrogen solution was adjusted to pH 10 and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1 to 20/1) to give the title compound as a yellow solid (234mg, yield 90.49%). MS (ESI, pos.ion) M/z 162.3[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.54(d,J＝7.2Hz,1H),7.18(s,1H),6.37(d,J＝7.2Hz,1H),3.77(s,2H),2.38(s,6H)。

Step 3)4- ((5-chloro-2- ((3, 8-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidine-1-carboxylic acid tert-butyl ester

To 3, 8-dimethylimidazo [1,2-a ]]Pyridin-7-amine (175mg,1.0856mmol), tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate (415mg,1.195mmol) and Cs₂CO₃(1.06g,3.25mmol) of 1, 4-dioxane (20mL) was added Pd (OAc)₂(25mg,0.1114mmol) and BINAP (68mg,0.1092 mmol). The reaction system was degassed for 2 minutes and charged with N₂Then, it was stirred at 105 ℃ for 4 hours. After the reaction was finished, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1 to 20/1) to give the title compound as a pale yellow solid (438mg, yield 85.48%).

MS(ESI,pos.ion)m/z:472.2[M+H]⁺。

^{2 4}Step 4) 5-chloro-N- (3, 8-dimethylimidazo [1, 2-a)]Pyridin-7-yl) -N- (piperidin-4-yl) pyrimidin-2, 4-diamines

To a solution of tert-butyl 4- ((5-chloro-2- ((3, 8-dimethylimidazo [1,2-a ] pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidine-1-carboxylate (438mg,0.928mmol) in DCM (12mL) was added a solution of hydrogen chloride in EtOAc (6mL,18.0mmol, 3M). The reaction system was stirred at room temperature for 2 hours, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (20mL), and the mixture was adjusted to pH 8 to 9 with saturated aqueous sodium bicarbonate. Then concentrated under reduced pressure and the resulting residue purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1 to 20/1) to afford the title compound as an off-white solid (256mg, 74.18% yield).

MS(ESI,pos.ion)m/z:372.4[M+H]⁺；

1H NMR(400MHz,DMSO-d₆)(ppm):8.61(s,1H),7.97(d,J＝7.4Hz,1H),7.86(s,1H),7.23(s,1H),7.17(d,J＝7.3Hz,1H),6.68(d,J＝7.9Hz,1H),3.95-3.82(m,1H),3.45(dt,J＝29.1,5.1Hz,2H),2.92(d,J＝12.3Hz,2H),2.42(s,3H),2.38(s,3H),1.72(d,J＝10.0Hz,2H),1.44(qd,J＝12.0,3.9Hz,2H)。

Step 5)6- (4- ((5-chloro-2- ((3, 8-dimethylimidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N²- (3, 8-dimethylimidazo [1, 2-a)]Pyridin-7-yl) -N⁴To a solution of- (piperidin-4-yl) pyrimidine-2, 4-diamine (100mg,0.2689mmol) in ethanol (10mL) was added 6-chloropyridazine-3-carbonitrile (56.5mg,0.405mmol) and TEA (54.5mg,0.539 mmol). The reaction mixture was stirred at room temperature overnight, after completion of the reaction, it was filtered, and the filter cake was rinsed with EtOH (50mL × 3) to give the title compound as a pale yellow solid (98mg, yield 76.73%).

MS(ESI,pos.ion)m/z:475.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.78(s,1H),8.10(d,J＝7.2Hz,1H),7.91(s,1H),7.85(d,J＝9.6Hz,1H),7.38(t,J＝8.7Hz,2H),7.32(s,1H),6.89(d,J＝7.7Hz,1H),4.56(d,J＝12.3Hz,2H),4.21(s,1H),3.05(t,J＝12.5Hz,2H),2.43(s,3H),2.41(s,3H),1.94(d,J＝11.8Hz,2H),1.69-1.53(m,2H)。

Example 306- (4- ((5-chloro-2- ((3- (difluoromethyl) - [1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 4-bromo-2-hydrazinopyridine

To a suspension of 4-bromo-2-fluoropyridine (6.00g,34.1mmol) in EtOH (60mL) was added hydrazine hydrate (21.0mL,346mmol,% by mass ═ 80%). The reaction mixture was heated to 75 ℃ and stirred overnight, then cooled to room temperature and quenched with aqueous NaOH (25mL,4M) and water (200 mL). The resulting mixture was cooled to 0 ℃ and stirred for 15 minutes, then filtered. The filter cake was washed with water (100mL) and dried under reduced pressure to give the title compound as a yellow solid (4.60g, 71% yield).

MS(ESI,pos.ion)m/z:188.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.92(d,J＝5.4Hz,1H),6.98(d,J＝1.4Hz,1H),6.81(dd,J＝5.4,1.6Hz,1H),5.89(s,1H),3.78(s,2H)。

Step 2) 7-bromo- [1,2,4]Triazolo [4,3-a]Pyridine-3-carboxylic acid ethyl ester

To a suspension of 4-bromo-2-hydrazinopyridine (4.60g,24.5mmol) in MeOH (60mL) was added ethyl glyoxylate (5.99g,29.3 mmol). The reaction was heated to 60 ℃ and stirred for 2 hours, then cooled to room temperature and concentrated under reduced pressure. DCM (60mL) was added to the resulting residue, which was then cooled to 0 ℃ and iodobenzene diacetic acid (10.26g,31.85mmol) was added portionwise. The resulting mixture was allowed to warm to room temperature and stirred overnight, then diluted with DCM (200 mL). The resulting mixture was washed with water (50 mL. times.2), anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5) to give the title compound as a white solid (5.10g, 77% yield).

MS(ESI,pos.ion)m/z:270.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.03(d,J＝7.3Hz,1H),8.14(s,1H),7.19(dd,J＝7.4,1.7Hz,1H),4.58(q,J＝7.1Hz,2H),1.51(t,J＝7.1Hz,3H)。

Step 3) (7-bromo- [1,2,4 ]]Triazolo [4,3-a]Pyridin-3-yl) methanol

At 0 deg.C, to produce 7-bromo- [1,2,4 ]]Triazolo [4,3-a]To a suspension of pyridine-3-carboxylic acid ethyl ester (3.40g,12.6mmol) in dry THF (100.0mL) was added DIBAL-H (51.0mL,51mmol,1.0M) slowly. The reaction was stirred at 0 ℃ for 1.5 h, then quenched by the sequential addition of water (2mL), 15% aqueous NaOH (2mL), water (5mL) and DCM (200 mL). The resulting mixtureThe mixture was allowed to warm to room temperature and stirred for 15 minutes, and anhydrous MgSO was added ₄And stirring was continued for 15 minutes, followed by filtration. The filter cake was washed with a mixture of DCM/MeOH (10/1(v/v),500 mL. times.4). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1 to 20/1) to afford the title compound as a white solid (1.30g, 45% yield).

MS(ESI,pos.ion)m/z:228.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.42(d,J＝7.3Hz,1H),8.16(d,J＝0.7Hz,1H),7.18(dd,J＝7.3,1.7Hz,1H),5.74(t,J＝5.8Hz,1H),4.97(d,J＝5.8Hz,2H)。

Step 4) 7-bromo- [1,2,4]Triazolo [4,3-a]Pyridine-3-carbaldehyde

At 0 deg.C, to (7-bromo- [1,2, 4)]Triazolo [4,3-a]Pyridin-3-yl) methanol (1.30g,5.70mmol) was suspended in dry DCM (50mL) and dess-martin oxidant (2.90g,6.84mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the filter cake was rinsed with DCM (100 mL). The filtrate was sequentially washed with saturated NaHCO₃Aqueous solution (60 mL. times.2) and saturated Na₂S₂O₃Washed with an aqueous solution (60 mL. times.2) and then with anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1) to afford the title compound as a yellow solid (1.25g, 97% yield).

MS(ESI,pos.ion)m/z:226.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):10.25(s,1H),9.05(d,J＝7.2Hz,1H),8.56(d,J＝0.9Hz,1H),7.52(dd,J＝7.3,1.8Hz,1H)。

Step 5) 7-bromo-3- (difluoromethyl) - [1,2,4]Triazolo [4,3-a]Pyridine compound

To 7-bromo- [1,2,4 ] at-78 DEG C]Triazolo [4,3-a]To a suspension of pyridine-3-carbaldehyde (1.28g,5.66mmol) in dry DCM (50mL) was added DAST (7.50mL,56.8 mmol). The reaction was stirred at-78 ℃ for 15 minutes and then allowed to warm to room temperature overnight. Then the reaction system is cooled to 0 ℃ and saturated Na is added ₂CO₃Aqueous solution (10mL) and water (10mL) and the resulting mixture was stirred for an additional 15 minutes. The resulting mixture was extracted sequentially with DCM (50 mL. times.3) and the mixed solvent DCM/MeOH (10/1(v/v),50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM) to give the title compound as a pale yellow solid (0.71g, 51% yield).

MS(ESI,pos.ion)m/z:248.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.23(d,J＝7.3Hz,1H),8.09(s,1H),7.24(t,J＝51.7Hz,1H),7.11(dd,J＝7.0,1.9Hz,1H)；

¹⁹F NMR(376MHz,CDCl₃)(ppm):–117.12。

Step 6)3- (difluoromethyl) - [1,2,4]Triazolo [4,3-a]Pyridin-7-amines

To 7-bromo-3- (difluoromethyl) - [1,2,4 ]]Triazolo [4,3-a]To a suspension of pyridine (0.71g,2.90mmol) in anhydrous 1, 4-dioxane (40mL) were added benzophenone imine (1.05g,5.79mmol), Pd₂(dba)₃(0.26g,0.29mmol), BINAP (0.37g,0.59mmol) and t-BuONa (0.56g,5.86 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then heated to 105 ℃ and stirred for reaction for 3 hours, and after the reaction was completed, the mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1 to 20/1) to afford the title compound as a yellow solid (0.24g, 46% yield).

MS(ESI,pos.ion)m/z:185.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.23(d,J＝7.4Hz,1H),7.54(t,J＝51.7Hz,1H),6.65(dd,J＝7.4,2.0Hz,1H),6.47(d,J＝1.7Hz,1H),6.32(s,2H)；

¹⁹F NMR(376MHz,DMSO-d₆):(ppm):–117.09。

Step 7)6- (4- ((5-chloro-2- ((3- (difluoromethyl) - [1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-bis)Chloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (0.12g,0.34mmol) was added to a suspension of 3- (difluoromethyl) - [1,2,4 ] dioxane (10mL)]Triazolo [4,3-a]Pyridin-7-amine (85mg,0.46mmol), Pd (OAc)₂(22mg,0.096mmol), BINAP (52mg,0.0837mmol) and Cs₂CO₃(0.24g,0.73 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 105 ℃ and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1) to give 0.11g of a yellow solid. The resulting yellow solid was stirred in MeOH (5mL) for 1 hour, then filtered, and the collected filter cake was dried under reduced pressure to give the title compound as a light yellow solid (0.11g, 64% yield).

MS(ESI,pos.ion)m/z:497.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:497.1536[M+H]⁺；C₂₂H₂₀ClF₂N₁₀[M+H]⁺The theoretical values of (A) are: 497.1524, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.04(s,1H),8.54(d,J＝1.2Hz,1H),8.51(d,J＝2.1Hz,1H),8.48(d,J＝7.5Hz,1H),8.12(s,1H),7.86(dd,J＝9.1,2.4Hz,1H),7.65(t,J＝51.7Hz,1H),7.29(dd,J＝7.5,1.9Hz,1H),7.21(d,J＝7.8Hz,1H),7.03(d,J＝9.1Hz,1H),4.67-4.52(m,2H),4.44-4.30(m,1H),3.20-3.09(m,2H),2.08-1.99(m,2H),1.73-1.59(m,2H)；

¹³C NMR(100MHz,DMSO-d₆):159.43,157.87,157.38,153.81,153.08,152.65,141.46,140.47,139.28,124.29,119.22,111.94,109.89,106.99,105.88,96.48,95.36,49.19,44.30,30.98；

¹⁹F NMR(376MHz,DMSO-d₆)(ppm):–117.42。

example 31 6- (4- ((5-chloro-2- ((2, 3-dimethylimidazo [1, 2-a))]Pyridin-6-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 6-bromo-2, 3-dimethylimidazo [1,2-a]Pyridine compound

To a suspension of 5-bromopyridin-2-amine (4.00g,23.12mmol) in EtOH (60mL) was added 3-bromobutan-2-one (10.0mL,95.4mmol) and p-toluenesulfonic acid hydrate (0.89g,4.68 mmol). The reaction mixture was placed in a sealed tube and then heated to 100 ℃ and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (50mL) and DCM (100mL), adjusted to pH 10 with aqueous NaOH (2M) and extracted with dichloromethane (100mL × 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/5 to 1/2) to give the title compound as a yellow solid (1.43g, 28% yield).

MS(ESI,pos.ion)m/z:225.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.92(d,J＝0.9Hz,1H),7.39(d,J＝9.4Hz,1H),7.15(dd,J＝9.4,1.8Hz,1H),2.41(s,3H),2.38(s,3H)。

Step 2) N- (diphenylmethylene) -2, 3-dimethylimidazo [1,2-a]Pyridin-6-amines

To 6-bromo-2, 3-dimethylimidazo [1,2-a ]]Pyridine (1.40g,6.22mmol) in 1, 4-dioxane (40mL) suspension, adding benzophenone imine (2.25g,12.4mmol), Pd₂(dba)₃(0.58g,0.63mmol), BINAP (0.78g,1.25mmol) and t-BuONa (1.21g,12.59 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 105 ℃ and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 2/1) to give the title compound as a brown liquid (2.03g, 100% yield).

MS(ESI,pos.ion)m/z:326.3[M+H]⁺。

Step 3)2, 3-dimethylimidazo [1,2-a ]]Pyridin-6-amines

To N- (diphenylmethylene) -2, 3-dimethylimidazo [1,2-a]To a suspension of pyridin-6-amine (2.03g,6.24mmol) in DCM (50mL) was added a solution of hydrogen chloride in EtOAc (60mL,180mmol, 3M). The resulting reaction system was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting residue was diluted with DCM (50mL) and water (30mL) and the resulting mixture was adjusted to pH 10 with 10% aqueous NaOH. The separated organic phase and the aqueous phase were extracted successively with DCM (50 mL. times.5) and a mixed solvent of DCM/MeOH (10/1(v/v),100 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH) ₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1) to afford the title compound as a brown solid (0.50g, 50% yield).

MS(ESI,pos.ion)m/z:162.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.29(d,J＝1.4Hz,1H),7.18(d,J＝9.4Hz,1H),6.74(dd,J＝9.4,2.0Hz,1H),4.77(s,2H),2.25(s,3H),2.23(s,3H)。

Step 4)6- (4- ((5-chloro-2- ((2, 3-dimethylimidazo [1, 2-a)]Pyridin-6-yl) amino) pyrimidine-4- Yl) amino) piperidin-1-yl) nicotinonitrile

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (105mg,0.30mmol) in anhydrous 1, 4-dioxane (10mL) was added 2, 3-dimethylimidazo [1,2-a ]]Pyridin-6-amine (75mg,0.47mmol), Pd (OAc)₂(14mg,0.062mmol), BIANP (37mg,0.060mmol) and Cs₂CO₃(0.22g,0.69 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 105 ℃ and stirred for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 100/1 to 50/1) to give 0.11g of a pale green solid. The solid obtained is chromatographed by preparative thin layer chromatography (DCM/NH)₃Further purified with MeOH (3M) (v/v) ═ 30/1) to give the title compound as a pale green solid (55mg, 39% yield).

MS(ESI,pos.ion)m/z:474.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:474.1925[M+H]⁺；C₂₄H₂₅ClN₉[M+H]⁺474.1916;

¹H NMR(400MHz,CDCl₃)(ppm):8.55(s,1H),8.41(d,J＝2.1Hz,1H),7.97(s,1H),7.62(dd,J＝9.0,2.3Hz,1H),7.51(d,J＝9.5Hz,1H),7.08(dd,J＝9.4,1.3Hz,1H),6.80(s,1H),6.64(d,J＝9.0Hz,1H),5.16(d,J＝7.6Hz,1H),4.42-4.33(m,2H),4.31-4.20(m,1H),3.22-3.13(m,2H),2.43(s,3H),2.41(s,3H),2.20-2.12(m,2H),1.60-1.51(m,2H)；

¹³C NMR(100MHz,CDCl₃)(ppm):159.04,158.18,157.11,153.17,152.79,139.99,126.96,120.63,118.58,116.42,115.78,113.47,105.78,105.59,96.47,77.24,77.03,76.82,47.90,43.55,31.58,13.08,8.63。

example 32 6- (4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) (2,4, 6-Trimethylbenzenesulfonyl) Oxycorbamic acid tert-butyl ester

Et was added dropwise to a solution of 2,4, 6-trimethylbenzenesulfonyl chloride (54.98g,251.4mmol) and tert-butyl N-hydroxycarbamate (33.44g,251.1mmol) in EtOAc (100mL) at-10 deg.C₃N (32.27g,318.9 mmol). The reaction mixture was warmed to 0 ℃ and stirred for 1 hour, then quenched with water (100mL) and extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL) and anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound as a yellow solid (73.01g, 92.1% yield).

¹H NMR(400MHz,CDCl₃)(ppm):7.63(s,1H),7.01(s,2H),2.70(s,6H),2.34(s,3H),1.34(s,9H)。

Step 2)1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate

Trifluoroacetic acid (200mL) was cooled to 0 ℃ and thenTo this was added dropwise tert-butyl (2,4, 6-trimethylbenzenesulfonyl) oxycarbamate (55.18g,175.0mmol) at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 2.5 hours, then quenched with water (400mL), and extracted with DCM (400 mL). The organic phase was cooled to 0 ℃ and 4-bromopyridin-2-amine (30.33g,175.3mmol) was added dropwise thereto. After the addition was complete, the resulting mixture was stirred at 0 ℃ for 1 hour and then filtered. The obtained filter cake was treated with Et₂O (50mL × 2) rinse afforded the title compound as a white solid (67.94g, 100% yield).

MS(ESI,pos.ion)m/z:188.0[C₅H₇BrN₃]⁺。

Step 3) 7-bromo-2-methyl- [1,2,4]Triazolo [1,5-a]Pyridine compound

To a solution of 1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (67.94g,175.0mmol) and acetic anhydride (71.53g,700.7mmol) in EtOH (200mL) was added p-toluenesulfonic acid hydrate (6.67g,35.1 mmol). After the addition was complete, the reaction mixture was placed in a sealed tube and stirred at 100 ℃ for 24 hours, then cooled to room temperature and quenched with water (100 mL). The resulting mixture was adjusted to pH 10 with saturated aqueous sodium carbonate solution, and then extracted with dichloromethane (500mL × 3). The combined organic phases were washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/14) to give the title compound as a yellow solid (2.14g, 5.8% yield).

MS(ESI,pos.ion)m/z:212.1[M+H]⁺。

Step 4) N- (diphenylmethylene) -2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-7-amines

To 7-bromo-2-methyl- [1,2, 4%]Triazolo [1,5-a]To a solution of pyridine (2.14g,10.09mmol) and benzophenone imine (2.75g,15.17mmol) in 1, 4-dioxane (40mL) was added Pd₂(dba)₃(467.0mg,0.51mmol), BINAP (95%, 664.4mg,1.01mmol) and t-BuONa (1.94g,20.19 mmol). The reaction was stirred at 100 ℃ overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound As a yellow solid (2.56g, 81.2% yield).

MS(ESI,pos.ion)m/z:313.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.23(d,J＝7.2Hz,1H),7.78(d,J＝7.4Hz,2H),7.54(t,J＝6.3Hz,1H),7.45(t,J＝7.3Hz,2H),7.31(d,J＝7.0Hz,3H),7.17(d,J＝6.3Hz,2H),6.85(s,1H),6.45(dd,J＝7.2,2.0Hz,1H),2.53(s,3H)。

Step 5) 2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-7-amines

To N- (diphenylmethylene) -2-methyl- [1,2,4]Triazolo [1,5-a]A solution of pyridin-7-amine (2.56g,8.19mmol) in 1, 4-dioxane (80mL) was added dropwise an aqueous solution of hydrogen chloride (80mL,320mmol, 4M). The reaction was stirred at room temperature overnight and then Na was added₂CO₃The powder was adjusted to pH 10 and extracted with DCM (250mL × 9). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a brown oil (560.1mg, 46.1% yield).

MS(ESI,pos.ion)m/z:149.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.19(d,J＝7.3Hz,1H),6.66(d,J＝2.3Hz,1H),6.36(dd,J＝7.3,2.3Hz,1H),4.16(s,2H),2.52(s,3H)。

Step 6)4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate (967.7mg,2.79mmol) and 2-methyl- [1,2,4]Triazolo [1,5-a]To a suspension of pyridin-7-amine (410.2mg,2.77mmol) in 1, 4-dioxane (40mL) was added Pd (OAc)₂(129.6mg,0.58mmol), BINAP (98%, 362.4mg,0.57mmol) and Cs₂CO₃(98%, 1.84g,5.53 mmol). The reaction system was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 3/1) to give the title compound as a pale yellow solid (567.5mg, 44.4% yield).

MS(ESI,pos.ion)m/z:459.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)(ppm):8.30(d,J＝7.4Hz,1H),8.13(s,1H),7.95(s,1H),7.63(s,1H),7.02(d,J＝6.9Hz,1H),5.26(d,J＝7.3Hz,1H),4.22–4.14(m,1H),4.09(s,2H),3.08(s,2H),2.55(s,3H),2.15–2.07(s,2H),1.52–1.45(m,11H)。

^{2 4}Step 7) 5-chloro-N- (2-methyl- [1,2,4]]Triazolo [1,5-a]Pyridin-7-yl) -N- (piperidin-4-yl) pyrimidines Pyridine-2, 4-diamines

To tert-butyl 4- ((5-chloro-2- ((2-methyl- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidine-1-carboxylate (207.3mg,0.45mmol) in DCM (10mL) was added a solution of hydrogen chloride in EtOAc (10mL,40mmol, 4M). The reaction system was stirred at room temperature for 0.5 hour, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (10mL), and adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (100mL × 3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/5) to give the title compound as a light yellow solid (162.1mg, 100% yield).

MS(ESI,pos.ion)m/z:359.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.30(d,J＝7.4Hz,1H),8.07(d,J＝1.9Hz,1H),7.96(s,1H),7.14(s,1H),7.08(dd,J＝7.4,2.1Hz,1H),5.26(d,J＝7.4Hz,1H),4.17–4.03(m,1H),3.49(s,1H),3.16(dt,J＝6.1,3.5Hz,2H),2.91–2.80(m,2H),2.55(s,3H),2.12(dd,J＝11.5,2.1Hz,2H),1.49(dd,J＝11.9,3.4Hz,2H)。

Step 8)6- (4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) nicotinonitrile

To 5-chloro-N²- (2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) -N⁴- (piperidin-4-yl) pyrimidine-2, 4-diamine (143.7mg,0.40mmol) and Et₃6-Chloronicotinonitrile (112.4mg,0.81 mmol). The reaction was stirred at room temperature overnight, then quenched with water (30mL) and extracted with DCM (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a beige solid (127.3mg, 69.0% yield).

MS(ESI,pos.ion)m/z:461.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:461.1694[M+H]⁺,C₂₂H₂₂ClN₁₀[M+H]⁺The theoretical values of (A) are: 461.1717, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.87(s,1H),8.62(d,J＝7.0Hz,1H),8.51(s,1H),8.28(s,1H),8.08(s,1H),7.86(d,J＝8.6Hz,1H),7.26(d,J＝6.5Hz,1H),7.12(d,J＝6.7Hz,1H),7.02(d,J＝8.8Hz,1H),4.56(d,J＝11.7Hz,2H),4.36(s,1H),3.14(t,J＝12.1Hz,2H),2.37(s,3H),2.01(d,J＝10.3Hz,2H),1.72–1.56(m,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):163.5,159.4,157.9,157.3,153.8,153.1,152.3,142.5,140.5,128.2,119.3,108.0,107.0,105.5,98.7,95.3,49.0,44.3,31.0,14.7。

example 33 6- (4- ((5-chloro-2- ((2-methylimidazo [1, 2-b))]Pyridazin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

Step 1) 2-methylimidazo [1,2-b ]]Pyridazin-7-amines

To a solution of pyridazine-3, 5-diamine (509mg,4.62mmol) in EtOH (20mL) was added p-toluenesulfonic acid hydrate (156mg,0.905mmol) and 1-bromopropan-2-one (1.56g,11.4 mmol). The reaction was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH)₃Purified with MeOH (7M)/DCM (v/v) ═ 1/30) to give the title compoundAs a yellow solid (467mg, 68.2% yield).

MS(ESI,pos.ion)m/z:149.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.41(d,J＝1.9Hz,1H),7.94(s,1H),7.25(s,2H),6.89(s,H),2.35(s,3H)。

Step 2)6- (4- ((5-chloro-2- ((2-methylimidazo [1, 2-b)]Pyridazin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (101mg,0.288mmol) and 2-methylimidazo [1,2-b ]]BINAP (36mg,0.057mmol), Cs and/or the like were added to a solution of pyridazin-7-amine (65mg,0.438mmol) in 1, 4-dioxane (15mL)₂CO₃(189mg,0.580mmol) and Pd (OAc)₂(13mg,0.057 mmol). The reaction system is heated to 105 ℃ and stirred for reaction overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to give the title compound as a yellow solid (55mg, yield 41.3%).

MS(ESI,pos.ion)m/z:462.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:462.1666[M+H]⁺；C₂₁H₂₁ClN₁₁[M+H]⁺The theoretical values of (A) are: 462.1592, respectively;

¹H NMR(600MHz,DMSO-d₆)(ppm):9.84(s,1H),8.60(s,1H),8.43(s,1H),8.08(s,1H),7.88(d,J＝9.4Hz,1H),7.81(s,1H),7.45(d,J＝9.4Hz,1H),7.13(d,J＝6.8Hz,1H),4.63(s,2H),4.36(s,1H),3.22(t,J＝12.3Hz,2H),2.31(s,3H),2.04(d,J＝10.8Hz,2H),1.69(d,J＝10.8Hz,2H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):158.62,157.53,156.88,153.32,141.88,138.76,138.39,131.75,131.12,128.38,117.46,112.00,111.19,106.11,105.00,48.21,43.82,30.38,14.41。

example 34 6- (4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-6-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) (2,4, 6-Trimethylbenzenesulfonyl) Oxycorbamic acid tert-butyl ester

Et was added dropwise to a solution of 2,4, 6-trimethylbenzenesulfonyl chloride (54.98g,251.4mmol) and tert-butyl N-hydroxycarbamate (33.44g,251.1mmol) in EtOAc (100mL) at-10 deg.C₃N (32.27g,318.9 mmol). The reaction mixture was warmed to 0 ℃ and stirred for 1 hour, then quenched with water (100mL) and extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL) and anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound as a yellow solid (73.01g, 92.1% yield).

¹HNMR(400MHz,CDCl₃)(ppm):7.63(s,1H),7.01(s,2H),2.70(s,6H),2.34(s,3H),1.34(s,9H)。

Step 2)2- ((aminooxy) sulfonyl) -1,3, 5-trimethylbenzene

To tert-butyl (2,4, 6-trimethylbenzenesulfonyl) oxycarbamate (29.00g,91.95mmol) was added pre-cooled 2,2, 2-trifluoroacetic acid (60mL) at 0 ℃. The reaction was stirred at 0 ℃ overnight and then quenched with water (180 mL). The resulting mixture was extracted with DCM (250 mL). The organic layer was used in the next reaction without further purification.

Step 3) (1, 2-diamino-5-bromopyridin-1-ium) 2,4, 6-trimethylbenzenesulfonate

A solution of 2- ((aminooxy) sulfonyl) -1,3, 5-trimethylbenzene from the previous step in DCM was cooled to 0 ℃ and then 5-bromopyridin-2-amine (5.00g,28.9mmol) was added thereto. The mixture was stirred at 0 ℃ for 1 hour, and after completion of the reaction, it was concentrated under reduced pressure to give 11.2g of a pale yellow viscous liquid (yield in two steps 100%). The crude product was used directly in the next reaction without purification.

Step 4) 6-bromo-2-methyl- [1,2,4]Triazolo [1,5-a]Pyridine compound

To (1, 2-diamino-5-bromopyridin-1-ium) 2,4, 6-trimethylbenzenesulfonate (13.47g,34.69mmol) of Ac₂To the O (70mL) suspension was added p-toluenesulfonic acid hydrate (1.37g,7.21 mmol). The reaction mixture was placed in a sealed tube and heated to 100 ℃ and stirred for 24 hours, after the reaction was completed, the reaction was quenched with water (30mL), and then concentrated under reduced pressure. The resulting residue was diluted with water (50mL), adjusted to pH 10 with saturated aqueous sodium carbonate solution, and extracted with EtOAc (200mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/5) to afford the crude product as a yellow solid (3.90 g). The crude product was dissolved in DCM (50mL) and triethyloxonium tetrafluoroborate (22.0mL,22mmol,1.0M) was added thereto. The resulting mixture was stirred at room temperature overnight, after the reaction was complete, it was filtered and the filter cake was rinsed with DCM (50 mL). The filtrate was saturated with Na ₂CO₃Aqueous solution (50.0mL) was washed, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (0.85g, 12% yield).

MS(ESI,pos.ion)m/z:212.0[M+H]⁺。

Step 5) N- (diphenylmethylene) -2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-6-amines

To 6-bromo-2-methyl- [1,2, 4%]Triazolo [1,5-a]To a suspension of pyridine (0.84g,4.00mmol) in anhydrous 1, 4-dioxane (20mL) was added Pd₂(dba)₃(0.36g,0.40mmol), BINAP (0.49g,0.79mmol), benzophenone imine (1.45g,8.02mmol) and t-BuONa (0.77g,8.01 mmol). The reaction mixture was degassed and purged with nitrogen several times, heated to 105 ℃ and stirred overnight, and after the reaction was completed, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2 to 1/1 to EtOAc 100%) to afford the title compound as a brown liquid (0.34g, 27% yield).

MS(ESI,pos.ion)m/z:313.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.97-7.92(m,1H),7.76(d,J＝7.5Hz,2H),7.51(t,J＝7.3Hz,1H),7.47-7.37(m,3H),7.36-7.28(m,3H),7.14(dd,J＝7.4,1.7Hz,2H),6.99(dd,J＝9.3,1.8Hz,1H),2.53(s,3H)。

Step 6) 2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-6-amines

To N- (diphenylmethylene) -2-methyl- [1,2,4]Triazolo [1,5-a]To a suspension of pyridin-6-amine (0.34g,1.10mmol) in 1, 4-dioxane (10mL) was added an aqueous solution of hydrogen chloride (10mL,40mmol, 4.0M). The reaction was stirred at room temperature overnight and then Na was added₂CO₃The aqueous solution was adjusted to pH 10, and extracted with DCM (50mL × 3) and a mixed solvent of DCM/MeOH (10/1(v/v),50mL × 3) in that order. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH) ₃Purified with MeOH (3M)) (v/v) ═ 50/1 to 30/1 to give the title compound as a light yellow solid (50mg, 31% yield).

MS(ESI,pos.ion)m/z:149.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.93(d,J＝1.9Hz,1H),7.42(d,J＝9.4Hz,1H),7.12(dd,J＝9.4,2.1Hz,1H),5.13(s,2H),2.36(s,3H)。

Step 7)6- (4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-6-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To a suspension of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (0.11g,0.32mmol) in 1, 4-dioxane (10mL) was added 2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-6-amine (54mg,0.36mmol), Pd (OAc)₂(16mg,0.072mmol), BINAP (40mg,0.065mmol) and Cs₂CO₃(0.21g,0.64 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then heated to 105 ℃ and stirred for reaction for 3 hours, and after the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (20mL) and water (20mL) and stirred for 10 min. After standing, the organic layer was separated, and the aqueous layer was successively extracted with DCM (50 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (DCM/NH)₃Purified with MeOH (3M) (v/v) ═ 50/1 to 30/1) to give the crude product. CoarseThe product was chromatographed by preparative thin layer chromatography (DCM/NH)₃Further purified with MeOH (3M) (v/v) ═ 20/1) to give the title compound as a grey solid (45mg, 30% yield).

MS(ESI,pos.ion)m/z:462.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:462.1658[M+H]⁺；C₂₁H₂₁ClN₁₁[M+H]⁺462.1664;

¹H NMR(600MHz,CDCl₃)(ppm):9.48(s,1H),7.97(s,1H),7.55(d,J＝9.4Hz,1H),7.46(d,J＝9.6Hz,1H),7.31-7.27(m,1H),6.99(s,1H),6.90(d,J＝9.6Hz,1H),5.24(d,J＝7.2Hz,1H),4.64-4.53(m,2H),4.40-4.30(m,1H),3.45-3.36(m,2H),2.55(s,3H),2.35-2.27(m,2H),1.67-1.64(m,2H)；

¹³C NMR(150MHz,CDCl₃)(ppm):163.75,158.35,157.41,157.18,153.25,147.92,130.72,129.26,128.15,124.93,118.05,116.79,115.02,109.82,105.73,48.45,43.76,31.52,14.50。

example 35 6- (4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)2- ((aminooxy) sulfonyl) -1,3, 5-trimethylbenzene

2,2, 2-trifluoroacetic acid (60mL) was cooled to 0 ℃ and tert-butyl (2,4, 6-trimethylbenzenesulfonyl) oxycarbamate (29.00g,91.95mmol) was added dropwise thereto. The reaction was stirred at 0 ℃ overnight and then quenched with water (180 mL). The layers were separated and the aqueous layer was extracted with DCM (90 mL. times.2). The combined organic layers were used in the next step without further purification.

Step 2)1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate

A solution of 2- ((aminooxy) sulfonyl) -1,3, 5-trimethylbenzene from the previous step in DCM (180mL) was cooled to 0 ℃ and 4-bromopyridin-2-amine (6.00g,34.7mmol) was added thereto. The mixture was stirred at 0 ℃ for 1 hour and then concentrated under reduced pressure to give the crude product as a white solid (13.50g) which was used in the next step without further purification.

MS(ESI,pos.ion)m/z:188.1,190.1[M₁]⁺；

MS(ESI,neg.ion)m/z:199.1[M₂]^–。

Step 3) 7-bromo-2-methyl- [1,2,4]Triazolo [1,5-a]Pyridine compound

To 1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (13.00g,33.48mmol) of Ac ₂To a solution of O (50mL) was added p-toluenesulfonic acid (1.30g,7.55 mmol). The reaction mixture was placed in a sealed tube and heated to 100 ℃ with stirring overnight. After the reaction was completed, the reaction was quenched with water (200mL), adjusted to pH 9 with aqueous NaOH (1M), and extracted with DCM (80mL × 3). The combined organic phases were washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/6) to afford the title compound as a white solid (4.90g, overall yield 69.0% from step 1) to step 3). MS (ESI, pos.ion) M/z 212.0[ M + H ]]⁺。

Step 4) N- (diphenylmethylene) -2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-7-amines

To 7-bromo-2-methyl- [1,2, 4%]Triazolo [1,5-a]Pd was added to a solution of pyridine (4.40g,20.7mmol) and benzophenone imine (5.64g,31.1mmol) in anhydrous 1, 4-dioxane (60mL)₂(dba)₃(952.2mg,1.04mmol), BINAP (1.29g,2.07mmol) and Cs₂CO₃(13.52g,41.50 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 4 hours and after the reaction was complete, concentrated under reduced pressure. The resulting residue was diluted with water (200mL) and DCM (100 mL). The separated aqueous layer was extracted with DCM (100 mL. times.2). The combined organic phases were washed with water (100 mL. times.2) and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5 to 1/2) to give the title compound as a brown oil (6.4) 8g, 100% yield).

MS(ESI,pos.ion)m/z:313.1[M+H]⁺。

Step 5) 2-methyl- [1,2,4]Triazolo [1,5-a]Pyridin-7-amines

To a solution of N- (diphenylmethylene) -2-methyl- [1,2,4] triazolo [1,5-a ] pyridin-7-amine (6.48g,20.7mmol) in DCM (25mL) was added a solution of HCl in EtOAc (80mL,240mmol, 3M). The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was diluted with water (100 mL). The resulting mixture was adjusted to pH 9 with aqueous NaOH (1M) and then extracted with DCM (50mL × 3). The combined organic phases were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/200 to 1/30) to afford the title compound as a yellow solid (1.45g, 47.2% yield).

MS(ESI,pos.ion)m/z:149.2[M+H]⁺。

Step 6)4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidine-4- Yl) amino) piperidine-1-carboxylic acid tert-butyl ester

To 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (1.50g,4.32mmol) and 2-methyl- [1,2,4]Triazolo [1,5-a]To a solution of pyridin-7-amine (641.2mg,4.33mmol) in 1, 4-dioxane (30mL) was added Cs₂CO₃(2.82g,8.66mmol)、Pd(OAc)₂(195.4mg,0.87mmol) and BINAP (536.2mg,0.86 mmol). The obtained reaction system is stirred overnight at 100 ℃ under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2 to 3/1) to give the title compound as a yellow solid (1.36g, 68.6% yield).

MS(ESI,pos.ion)m/z:459.3[M+H]⁺。

^{2 4}Step 7) 5-chloro-N- (2-methyl- [1,2,4 ]]Triazolo [1,5-a]Pyridin-7-yl) -N- (piperidin-4-yl) pyrimidines Pyridine-2, 4-diamines

To 4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (1.36g,2.96mmol) in DCM (10mL)To the solution was added a solution of hydrogen chloride in EtOAc (30mL,90mmol, 3M). The reaction system was stirred at room temperature for 1 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (10mL) and adjusted to pH 9 with aqueous NaOH (1M), followed by extraction with dichloromethane (25mL × 3). The combined organic phases were concentrated under reduced pressure. The residue obtained was chromatographed over a silica gel column (MeOH/DCM (v/v) ═ 1/5 to (NH)₃MeOH solution (7M))/DCM (v/v) ═ 1/10)) to afford the title compound as a yellow solid (613.4mg, 57.7%).

MS(ESI,pos.ion)m/z:359.2[M+H]⁺。

Step 8)6- (4- ((5-chloro-2- ((2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N²- (2-methyl- [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) -N⁴- (piperidin-4-yl) pyrimidine-2, 4-diamine (300.2mg,0.84mmol) and 6-chloropyridazine-3-carbonitrile (118.1mg,0.85mmol) in EtOH (15mL) were added TEA (129.2mg,1.28 mmol). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50) to give the title compound as a yellow solid (146.4mg, 37.9% yield).

MS(ESI,pos.ion)m/z:462.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:462.1673[M+H]⁺,C₂₁H₂₁ClN₁₁[M+H]⁺The theoretical values of (A) are: 462.1664, respectively;

¹H NMR(600MHz,CDCl₃)(ppm):8.84(s,1H),8.54(d,J＝7.4Hz,1H),7.99(s,1H),7.51-7.46(m,2H),6.98(d,J＝9.6Hz,1H),6.48(d,J＝7.0Hz,1H),4.73-4.63(m,1H),4.46(d,J＝13.4Hz,2H),3.45(t,J＝11.7Hz,2H),2.71(s,3H),2.37-2.29(m,2H),1.71(dt,J＝14.6,7.3Hz,2H)；

¹³C NMR(150MHz,CDCl₃)(ppm):161.6,158.6,158.2,157.2,151.8,145.4,144.8,141.5,131.0,129.7,116.3,112.5,111.0,107.4,98.7,49.8,43.1,30.6,11.9。

example 36 6-(4-((5-chloro-2- ((3-methylimidazo [1, 2-c)]Pyrimidin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) pyridazine-3-carbonitriles

Step 1) pyrimidine-4, 6-diamine

6-bromopyrimidin-4-amine (1.01g,5.80mmol) and aqueous ammonia (25mL) were placed in a sealed tube and the mixture was stirred at 125 ℃ overnight, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/15) to afford the title compound as a yellow solid (0.46g, 72% yield).

MS(ESI,pos.ion)m/z:111.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.82(s,1H),6.10(s,4H),5.39(s,1H)。

Step 2) 3-methylimidazo [1,2-c]Pyrimidin-7-amines

To pyrimidine-4, 6-diamine (342.0mg,3.10mmol) and NaHCO₃(286.0mg,3.40mmol) in EtOH (20mL) was added a solution of 2-chloropropionaldehyde (0.57M,57mmol) in chloroform and n-hexane (1/2(v/v),100 mL). The reaction mixture was placed in a sealed tube and stirred at 85 ℃ overnight, after the reaction was complete, cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a brown oil (80.0mg, 17.4% yield).

MS(ESI,pos.ion)m/z:149.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.84(s,1H),7.09(s,1H),6.46(s,2H),6.26(s,1H),2.40(s,3H)。

Step 3)4- ((5-chloro-2- ((3-methylimidazo [1, 2-c)]Pyrimidin-7-yl) amino) pyrimidin-4-yl) amino) Piperidine-1-carboxylic acid tert-butyl ester

To tert-butyl 4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidine-1-carboxylate (451.8mg,1.30 mmol) and 3-methylimidazo [1,2-c ]]To a suspension of pyrimidin-7-amine (190.4mg,1.28mmol) in 1, 4-dioxane (40mL) was added Pd (OAc)₂(59.5mg,0.26mmol), BINAP (98%, 172.4mg,0.27mmol) and Cs₂CO₃(98%, 866.8mg,2.61 mmol). The reaction system was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a yellow solid (60.5mg, 10.1% yield).

MS(ESI,pos.ion)m/z:459.2[M+H]⁺。

^{2 4}Step 4) 5-chloro-N- (3-methylimidazo [1, 2-c)]Pyrimidin-7-yl) -N- (piperidin-4-yl) pyrimidine-2, 4-di Amines as pesticides

To a solution of tert-butyl 4- ((5-chloro-2- ((3-methylimidazo [1,2-c ] pyrimidin-7-yl) amino) pyrimidin-4-yl) amino) piperidine-1-carboxylate (54.9mg,0.12mmol) in DCM (5mL) was added a solution of hydrogen chloride in ethyl acetate (5mL,20 mmol). The reaction system was stirred at room temperature for 0.5 hour, and after the reaction was completed, it was concentrated under reduced pressure. The resulting residue was dissolved in water (10mL), and adjusted to pH 10 with saturated aqueous sodium carbonate solution, followed by extraction with dichloromethane (100mL × 3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/5) to give the title compound as a light yellow solid (30.4mg, yield 70.8%).

MS(ESI,pos.ion)m/z:359.2[M+H]⁺。

Step 5)6- (4- ((5-chloro-2- ((3-methylimidazo [1, 2-c)]Pyrimidin-7-yl) amino) pyrimidin-4-yl) amino Yl) piperidin-1-yl) pyridazine-3-carbonitrile

To 5-chloro-N²- (3-methylimidazo [1, 2-c)]Pyrimidin-7-yl) -N⁴- (piperidin-4-yl) pyrimidine-2, 4-diamine (30.4mg,0.085mmol) and Et₃To a solution of N (135.2mg,1.34mmol) in EtOH (10mL) was added 6-chloropyridazine-3-carbonitrile (24.2mg,0.173 mmol). The reaction was stirred at room temperature overnight, quenched after the reaction was complete by addition of water (30mL) and extracted with DCM (50 mL. times.3). The combined organic phases are used as saturated foodWashed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a beige solid (27.7mg, 70.8% yield).

MS(ESI,pos.ion)m/z:462.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:462.1666[M+H]⁺，C₂₁H₂₁ClN₁₁[M+H]⁺The theoretical values of (A) are: 462.1670, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.58(s,1H),9.14(s,1H),8.12(d,J＝13.9Hz,2H),7.90(s,1H),7.24(s,1H),7.13(s,1H),6.65(s,1H),5.47(s,1H),5.33(s,2H),4.64(s,2H),2.27(s,3H),1.72(s,2H),1.45(s,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):174.8,160.1,159.0,157.3,153.6,146.4,139.2,131.6,130.1,128.8,117.9,111.7,106.9,93.3,48.9,44.3,35.6,25.6。

example 376- (4- ((5-chloro-2- ((2-methylimidazo [1, 2-b)]Pyridazin-7-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (201mg,0.575mmol) and 2-methylimidazo [1,2-b ]]To a solution of pyridazin-7-amine (135mg,0.911mmol) in 1, 4-dioxane (20mL) were added BINAP (72mg,0.115mmol) and Cs₂CO₃(375mg,1.15mmol) and Pd (OAc)₂(26mg,0.115 mmol). The reaction system is heated to 105 ℃ and stirred for reaction overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ((MeOH/DCM (v/v) ═ 1/30) to give the title compound as a yellow solid (112mg, 42.2% yield).

MS(ESI,pos.ion)m/z:461.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:461.1722[M+H]⁺,C₂₂H₂₂ClN₁₀[M+H]⁺Has a theoretical value of461.1639；

¹H NMR(600MHz,DMSO-d₆)(ppm):9.81(s,1H),8.59(d,J＝2.2Hz,1H),8.50(d,J＝2.1Hz,1H),8.43(s,1H),8.06(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.79(s,1H),7.12(d,J＝7.8Hz,1H),7.02(d,J＝9.1Hz,1H),4.55(d,J＝12.3Hz,2H),4.36-4.29(m,1H),3.11(t,J＝12.5Hz,2H),2.30(s,3H),1.99(d,J＝13.5Hz,2H),1.67-1.60(m,2H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):158.88,157.50,156.82,153.21,152.54,142.14,139.92,138.78,138.23,131.50,118.68,111.84,106.45,106.34,104.88,94.81,48.36,43.73,30.41,14.44。

Example 386- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) imidazo [1, 2-a)]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)2- (7-Bromoimidazo [1,2-a ]]Pyridin-2-yl) acetic acid ethyl ester

To a solution of 4-bromopyridin-2-amine (8.00g,46.2mmol) in ethanol (100mL) was added ethyl 4-bromo-3-oxo-butyrate (23.22g,111.1 mmol). The reaction mixture was refluxed overnight, and after completion of the reaction, it was concentrated under reduced pressure, and the resulting residue was diluted in water (50 mL). The resulting mixture was adjusted to pH 10 with saturated aqueous sodium carbonate solution and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5 to 1/2) to give the title compound as a yellow solid (3.02g, 23% yield).

MS(ESI,pos.ion)m/z:283.0[M+H]⁺。

Step 2)1- (7-Bromoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol

In N₂Protection and reaction at-78 deg.C to 2- (7-bromoimidazo [1,2-a ]]Ethyl pyridin-2-yl) acetate (2.45g,8.65mmol) in tetrahydrofuran (50mL) was added dropwise methyl magnesium bromide (3.0M in diethyl ether, 28.8mL,86.4 mmol). Reaction mixtureThe mixture was transferred to 0 ℃ and stirred overnight. After the reaction was complete, the reaction was quenched by addition of water (80mL) and extracted with EtOAc (40 mL. times.3). The combined organic phases were concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1 to 2/1) to afford the title compound as a tan solid (0.45g, 19% yield).

MS(ESI,pos.ion)m/z:269.0[M+H]⁺。

Step 3)1- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-2-yl) -2-methylpropan-2-ol

To 1- (7-bromoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol (450.0mg,1.67mmol) and benzophenone imine (457.2mg,2.52mmol) in 1, 4-dioxane (15mL) was added Pd₂(dba)₃(154.4mg,0.17mmol), BINAP (105.1mg,0.17mmol) and Cs₂CO₃(1.09g,3.35 mmol). The reaction system is heated to 100 ℃ and stirred for 6 hours under the protection of nitrogen, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was diluted with water (20mL), and the resulting mixture was extracted with DCM (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product as a brown solid (617 mg).

MS(ESI,pos.ion)m/z:370.1[M+H]⁺。

Step 4)1- (7-aminoimidazo [1, 2-a)]Pyridin-2-yl) -2-methylpropan-2-ol

To 1- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-2-yl) -2-methylpropan-2-ol (617.8mg,1.67mmol) in DCM (5mL) was added hydrogen chloride in EtOAc (20mL, 3M). The reaction system was stirred at room temperature for 1 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (15mL) and adjusted to pH 9 with aqueous NaOH (1M), then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (MeOH/DCM (v/v) ═ 1/50 to 1/10 to (NH) ₃Purified with MeOH (7M)/DCM (v/v) ═ 1/10) to give the title compound as a yellow solid (343.2mg, step 3) to step 4) in 33% yield over two steps.

MS(ESI,pos.ion)m/z:206.1[M+H]⁺。

Step 5)6- (4- ((5-chloro-2- ((2- (2-hydroxy)2-methylpropyl) imidazo [1,2-a]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (50.0mg,0.14mmol) and 1- (7-aminoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol (27.0mg,0.13mmol) in 1, 4-dioxane (1mL) Pd (OAc) was added₂(3.6mg,0.02mmol), BINAP (9.2mg,0.02mmol) and Cs₂CO₃(93.2mg,0.29 mmol). The reaction system is heated to 100 ℃ under the protection of nitrogen and stirred overnight, and after the reaction is finished, the reaction system is decompressed and concentrated. The residue obtained is chromatographed on a silica gel column (MeOH/DCM (v/v) ═ 1/50 to 1/10 to (NH)₃Purified with MeOH solution (7M)/DCM (v/v) ═ 1/10) to give the crude product as a yellow solid, which was further purified by preparative thin layer chromatography (MeOH/DCM (v/v) ═ 1/6) to afford the title compound as a yellow solid (8.2mg, 11% yield).

MS(ESI,pos.ion)m/z:519.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2132[M+H]⁺，C₂₅H₂₈ClN₁₀O[M+H]⁺519.2131;

¹H NMR(600MHz,CDCl₃)(ppm):8.28(s,1H),8.13(d,J＝7.3Hz,1H),7.91(s,1H),7.54(d,J＝6.0Hz,1H),7.42(d,J＝9.6Hz,1H),7.34(s,1H),6.97(d,J＝9.6Hz,1H),4.47-4.39(m,3H),3.54(t,J＝12.5Hz,2H),2.29(d,J＝12.1Hz,2H),1.98-1.93(m,1H),1.59-1.50(m,3H),1.25(s,6H)；

¹³C NMR(150MHz,CDCl₃)(ppm):158.5,157.2,156.7,152.6,141.1,130.7,129.9,128.6,126.9,116.8,110.9,110.6,110.5,107.3,95.1,69.6,48.1,43.4,38.6,31.3,28.9。

example 396- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2,4 ]]Triazolo [1,5-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 7-bromo- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxylic acid tert-butyl ester

To a solution of 1, 2-diamine-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (24.78g,63.8mmol) in pyridine (200mL) at 0 deg.C was added ethyl 2-chloro-2-oxoacetate (14.5mL,130 mmol). The reaction mixture was allowed to stand at room temperature and stirred for 30 minutes, then heated to 100 ℃ and stirred overnight, and after completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was diluted with water (300mL) and extracted with ethyl acetate (200 mL. times.3). The combined organic phases were washed with water (200mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/6 to 1/4) to give the title compound as a yellow solid (0.96g, 6.0% yield).

MS(ESI,pos.ion)m/z:270.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.51(d,J＝7.2Hz,1H),8.03(s,1H),7.28(d,J＝1.7Hz,1H),4.56(q,J＝7.1Hz,2H),1.49(t,J＝7.1Hz,3H)。

Step 2)2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

In N₂Protection and reaction at-78 deg.C to 7-bromo- [1,2,4 ]]Triazolo [1,5-a]To a solution of pyridine-2-carboxylic acid tert-butyl ester (830.0mg,3.07mmol) in tetrahydrofuran (20mL) was added dropwise methylmagnesium bromide (3.0M in diethyl ether, 5.1mL,15 mmol). The reaction mixture was allowed to warm to 0 ℃ and stirred overnight, after completion of the reaction, the reaction was quenched by addition of water (5mL) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5 to 1/1) to give the title compound as a white solid (402.2mg, 51% yield).

MS(ESI,pos.ion)m/z:256.1[M+H]⁺。

Step 3)2- (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To 2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol and benzophenone imine (429.1mg,2.37mmol) in 1, 4-dioxane (15mL) and Pd was added₂(dba)₃(143.4mg,0.16mmol), BINAP (97.6mg,0.16mmol) and Cs₂CO₃(1.02g,3.13 mmol). The reaction system is heated to 100 ℃ and stirred overnight under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was diluted with water (40mL) and extracted with DCM (30 mL. times.3). The combined organic phases were washed with water (40mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown oil (556.7 mg).

MS(ESI,pos.ion)m/z:357.2[M+H]⁺。

Step 4)2- (7-amino- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To 2- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) propan-2-ol (556.7mg,1.56mmol) in DCM (5mL) was added a solution of hydrogen chloride in EtOAc (15mL, 3M). The reaction system was stirred at room temperature for 1 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (15mL) and adjusted to pH 9 with aqueous NaOH (1M), then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50 to 1/20 to 1/10) to give the title compound as a yellow solid (220.4mg, step 3) to step 4) in 73% yield over two steps.

MS(ESI,pos.ion)m/z:193.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.23(d,J＝7.3Hz,1H),6.70(d,J＝1.6Hz,1H),6.41(dd,J＝7.3,2.1Hz,1H),4.25(s,2H),1.71(s,6H)。

Step 5)6- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [1,5-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (140.3mg,0.40mmol) and 2- (7-amino- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol (77.2mg,0.40mmol) in 1, 4-dioxane (6mL) was added Pd (OAc)₂(9.5mg,0.04mmol), BINAP (25.2mg,0.04mmol) and Cs₂CO₃(262.1mg,0.80 mmol). The reaction system is heated to 100 ℃ under the protection of nitrogen and stirred overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/50 to 1/30) to give the crude product as a pale red solid. The crude product was diluted in EtOH (6mL), then stirred and filtered. The resulting filter cake was the title compound as a white solid (104.4mg, 52% yield).

MS(ESI,pos.ion)m/z:505.5[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1974[M+H]⁺，C₂₄H₂₆ClN₁₀O[M+H]⁺The theoretical values of (A) are: 505.1974, respectively;

¹H NMR(600MHz,DMSO-d₆)(ppm):9.88(s,1H),8.68(d,J＝7.4Hz,1H),8.51(d,J＝2.0Hz,1H),8.32(d,J＝1.6Hz,1H),8.09(s,1H),7.86(dd,J＝9.1,2.2Hz,1H),7.32(dd,J＝7.5,2.1Hz,1H),7.13(d,J＝7.8Hz,1H),7.02(d,J＝9.1Hz,1H),5.08(s,1H),4.55(d,J＝12.2Hz,2H),4.41–4.31(m,1H),3.14(t,J＝12.4Hz,2H),2.01(d,J＝10.3Hz,2H),1.68–1.61(m,2H),1.53(s,6H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):172.2,159.0,157.5,156.9,153.2,152.7,151.6,142.0,140.0,128.1,118.8,107.9,106.5,105.2,99.0,94.8,68.1,48.4,43.8,30.5,29.7。

example 40 6- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) - [1,2,4 ]]Triazolo [4,3-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 4-bromo-2-hydrazinopyridine

To a solution of 4-bromo-2-fluoropyridine (6.00g,34.1mmol) in EtOH (60mL) was added hydrazine hydrate (21mL,346mmol, 80% by mass). The reaction mixture was warmed to 75 ℃ and stirred overnight, after completion of the reaction, cooled to room temperature. To the mixture was added aqueous sodium hydroxide (25.0mL,4M) and water (200mL), and the resulting mixture was stirred at 0 ℃ for 15 minutes, then filtered. The filter cake was washed with water (100mL) and dried under reduced pressure to give the title compound as a yellow solid (4.60g, 71% yield).

MS(ESI,pos.ion)m/z:188.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.92(d,J＝5.4Hz,1H),6.98(d,J＝1.4Hz,1H),6.81(dd,J＝5.4,1.6Hz,1H),5.89(s,1H),3.78(s,2H)。

Step 2) 7-bromo- [1,2,4]Triazolo [4,3-a]Pyridine-3-carboxylic acid ethyl ester

4-bromo-2-hydrazinopyridine (4.60g,24.5mmol) was suspended in MeOH (60mL), to which was added ethyl 2-oxoacetate (5.99g,29.3 mmol). The mixture was warmed to 60 ℃ and stirred for 2 hours, after the reaction was complete, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (60mL), and the resulting solution was cooled to 0 ℃ and (diacetoxyiodo) benzene (10.26g,31.85mmol) was added thereto in portions. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with DCM (200mL) and washed with water (50 mL. times.2) and anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5) to give the title compound as a white solid (5.10g, 77% yield).

MS(ESI,pos.ion)m/z:270.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.03(d,J＝7.3Hz,1H),8.14(s,1H),7.19(dd,J＝7.4,1.7Hz,1H),4.58(q,J＝7.1Hz,2H),1.51(t,J＝7.1Hz,3H)。

Step 3)2- (7-bromo- [1,2, 4)]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol

At 0 deg.C, 7-bromo- [1,2,4 ]]Triazolo [4,3-a]Pyridine-3-carboxylic acid ethyl ester (5.00g,18.5mmol) was suspended in THF (100mL), to which was added methylmagnesium bromide (18.5mL,56mmol,3.0M in THF). The reaction mixture was stirred at 0 ℃ for 1 hour, and after completion of the reaction, saturated NH was slowly added thereto₄Aqueous Cl (50mL), water (100mL) and EtOAc (200 mL). The mixture was filtered through celite, the organic layer was separated from the filtrate, and the aqueous layer was extracted with EtOAc (200 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was passed through a silica gel column Purification by chromatography (MeOH/DCM (v/v) ═ 100/1 to 50/1 to 20/1) gave the title compound as a white solid (3.0g, 63% yield).

MS(ESI,pos.ion)m/z:256.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.56(d,J＝7.4Hz,1H),7.78(s,1H),6.87(d,J＝7.4Hz,1H),1.79(s,6H)。

Step 4)2- (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol

2- (7-bromo- [1,2, 4)]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol (3.00g,11.7mmol) was suspended in 1, 4-dioxane (50mL) to which was added Pd₂(dba)₃(1.08g,1.18mmol)、BINAP(1.46g,2.36mmol)、Cs₂CO₃(7.65g,23.5mmol) and benzophenone imine (4.27g,23.56 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 105 ℃ and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was diluted with water (50mL) and DCM (50mL) and filtered through celite. The filtrate was extracted with DCM (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (100 mL. times.3). The combined organic layers were washed with saturated brine (100mL) and anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave a brown viscous liquid (6.80g) containing the title compound (4.17g, 100% yield). The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:357.4[M+H]⁺。

Step 5)2- (7-amino- [1,2,4]]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol

2- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) propan-2-ol (4.17g,11.7mmol) was suspended in DCM

To (100mL), a solution of HCl in EtOAc (100mL,300mmol,3.0M) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with water (100mL), and the mixture was adjusted to pH 10 with saturated sodium carbonate solution, followed by extraction with DCM (200mL × 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the pressure was reducedAnd (5) concentrating. The residue was subjected to silica gel column chromatography (DCM/(NH)₃Purified with MeOH (3M)) (v/v) ═ 50/1 to 25/1 to 10/1) to give the title compound as a yellow solid (0.88g, 39% yield).

MS(ESI,pos.ion)m/z:193.1[M+H]⁺；

¹H NMR(400MHz,CD₃OD)(ppm):8.49(d,J＝7.6Hz,1H),6.52(dd,J＝7.6,2.1Hz,1H),6.44(d,J＝1.4Hz,1H),1.72(s,6H)。

Step 6)6- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [4,3-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (0.12g,0.35mmol) was suspended in 1, 4-dioxane (15.0mL), and 2- (7-amino- [1,2,4 ] was added thereto]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol (0.081g,0.42mmol), Pd (OAc)₂(0.017g,0.077mmol), BIANP (0.046g,0.074mmol) and Cs₂CO₃(0.25g,0.75 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, and then, heated to 105 ℃ and stirred to react for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH) ₃Purified with MeOH (3M)) (v/v) ═ 100/1 to 50/1 to 30/1 to give the title compound as a pale yellow solid (45mg, 26% yield).

MS(ESI,pos.ion)m/z:505.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1985[M+H]⁺,C₂₄H₂₆ClN₁₀O[M+H]⁺A theoretical value of 505.1974;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.81(s,1H),8.55(d,J＝7.6Hz,1H),8.51(d,J＝1.9Hz,1H),8.37(s,1H),8.09(s,1H),7.86(dd,J＝9.1,2.3Hz,1H),7.16(d,J＝7.8Hz,1H),7.09-7.00(m,2H),4.58(d,J＝13.1Hz,2H),4.42-4.30(m,1H),3.15(t,J＝12.4Hz,2H),2.08-2.00(m,2H),1.72-1.57(m,8H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):159.44,158.05,157.33,153.81,153.08,151.75,150.76,140.47,139.52,125.84,119.23,109.66,106.97,105.38,96.82,95.34,68.77,60.21,49.18,44.32,31.02,29.34,21.22,14.55。

EXAMPLE 41 6- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) - [1,2,4 ]]Triazolo [4,3-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

Step 1)4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [4,3-a]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester

4- ((2, 5-dichloropyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester (0.30g,0.80mmol) was suspended in 1, 4-dioxane (20mL), and 2- (7-amino- [1,2,4 ] was added thereto]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol (0.19g,0.98mmol), Pd (OAc)₂(0.038g,0.17mmol), BINAP (0.10g,0.17mmol) and Cs₂CO₃(0.54g,1.66 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then, heated to 100 ℃ and stirred for reaction for 3 hours, and then the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 100/1 to 50/1) to give the title compound as a pale yellow solid (0.36g, 85% yield).

MS(ESI,pos.ion)m/z:531.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.45(d,J＝7.5Hz,1H),8.25(s,1H),7.94(s,1H),6.70(s,1H),5.16(d,J＝8.6Hz,1H),4.44-4.17(m,1H),4.15-3.96(m,2H),3.14-2.86(m,2H),2.78-2.55(m,1H),2.19-2.08(m,1H),1.85(s,3H),1.82(s,3H),1.74-1.64(m,1H),1.47(s,9H),1.31-1.19(m,2H),0.96(t,J＝7.4Hz,3H)。

Step 2)2- (7- ((5-chloro-4- ((3-ethylpiperidin-4-yl) amino) pyrimidin-2-yl) amino) - [1,2,4 ]III Azolo [4,3-a ] s]Pyridin-3-yl) propan-2-ol

To 4- ((5-chloro-2- ((3- (2-hydroxy)Propan-2-yl) - [1,2,4]Triazolo [4,3-a]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) -3-ethylpiperidine-1-carboxylic acid tert-butyl ester (0.38g,0.72mmol) in DCM (10mL) was added hydrogen chloride in ethyl acetate (10.0mL,30mmol, 3.0M). The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10mL), then adjusted to pH 9 with saturated aqueous sodium carbonate solution, and then extracted with DCM (50mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH)₃Purified with MeOH (3M)) (v/v) ═ 50/1 to 25/1 to 10/1 to give the title compound as a yellow solid (0.18g, 58% yield).

MS(ESI,pos.ion)m/z:431.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.44(d,J＝7.5Hz,1H),8.35(s,1H),8.15(s,1H),7.83(s,1H),6.66(d,J＝5.9Hz,1H),5.21(d,J＝8.5Hz,1H),3.99-3.84(m,1H),3.25-3.15(m,1H),3.05(d,J＝12.2Hz,1H),2.84(t,J＝11.7Hz,1H),2.46(t,J＝11.4Hz,1H),2.15(d,J＝11.1Hz,1H),1.81(s,3H),1.78(s,3H),1.69-1.56(m,2H),1.50-1.36(m,2H),0.89(t,J＝7.3Hz,3H)。

Step 3)6- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [4,3-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) -3-ethylpiperidin-1-yl) nicotinonitrile

2- (7- ((5-chloro-4- ((3-ethylpiperidin-4-yl) amino) pyrimidin-2-yl) amino) - [1,2,4]Triazolo [4,3-a]Pyridin-3-yl) propan-2-ol (70mg,0.16mmol) was suspended in EtOH (10mL), to which was added 6-chloronicotinonitrile (46mg,0.33mmol) and TEA (46mg,0.45 mmol). The mixture was warmed to reflux and stirred overnight, after the reaction was complete, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH) ₃Purified with MeOH (3M)) (v/v) ═ 100/1 to 50/1 to 30/1 to give the title compound as a pale yellow solid (50mg, 58% yield).

MS(ESI,pos.ion)m/z:533.5[M+H]⁺；

HRMS(ESI,pos.ion)m/z:533.2293[M+H]⁺,C₂₆H₃₀ClN₁₀O[M+H]⁺Theoretical value of 533.2287；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.81(s,1H),8.54(d,J＝7.7Hz,1H),8.52(d,J＝1.8Hz,1H),8.36(s,1H),8.07(s,1H),7.86(dd,J＝9.1,2.1Hz,1H),7.18(d,J＝8.6Hz,1H),7.10-6.96(m,2H),4.66(d,J＝11.8Hz,1H),4.55(d,J＝12.6Hz,1H),4.29-4.15(m,1H),3.13(t,J＝12.5Hz,1H),2.78-2.65(m,1H),2.06-1.94(m,1H),1.84-1.71(m,1H),1.64(s,6H),1.61-1.51(m,2H),1.22-1.13(m,1H),0.93-0.88(m,3H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):158.85,157.57,157.37,153.25,152.70,151.29,150.30,140.07,139.09,125.40,118.82,109.19,106.45,104.94,96.31,94.85,68.30,52.65,48.14,44.13,40.97,30.87,28.87,22.37,10.93。

Example 42 6- (4- ((5-chloro-2- ((3- (2-hydroxy-2-methylpropyl) imidazo [1, 2-a)]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 4-Oxobutyric acid Ethyl ester

Ethyl 4-hydroxybutyrate (5g,37.833mmol) was suspended in DCM (100mL) and pyridinium chlorochromate (16.31g,75.66mmol) was added to it. The reaction system was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 10/1) to give the title compound as a colorless oil (2.68g, 54.4% yield).

¹H NMR(400MHz,CDCl₃)(ppm):9.77(s,1H),4.13-4.08(m,2H),2.75(t,J＝6.6Hz,2H),2.58(t,J＝6.6Hz,2H),1.22(t,J＝7.1Hz,3H)。

Step 2) 3-bromo-4-oxobutanoic acid ethyl ester

Ethyl 4-oxobutyrate (2.6g,20mmol) was suspended in DCM (50mL) and elemental bromine (3.2g,20mmol) was added dropwise thereto at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour, then water (50mL) was added and the resulting mixture was extracted with DCM (50 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 10/1) to give the title compound as a brown oil (2.7g, 65% yield).

¹H NMR(600MHz,CDCl₃)(ppm):9.52(s,1H),4.66(t,J＝6.9Hz,1H),4.18(q,J＝7.1Hz,2H),3.21(dd,J＝17.1,7.2Hz,1H),2.92(dd,J＝17.1,6.7Hz,1H),1.26(t,J＝7.1Hz,3H)。

Step 3)2- (7-Bromoimidazo [1,2-a ]]Pyridin-3-yl) acetic acid ethyl ester

Ethyl 3-bromo-4-oxobutyrate (2.7g,13mmol) was dissolved in ethanol (20mL), to which was added 4-bromopyridin-2-amine (2.2g,13 mmol)

mmol). The reaction system is heated to 60 ℃ and stirred for 3 hours, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 500/1 to 100/1) to afford the title compound as a yellow solid (1.3g, 36% yield).

MS(ESI,pos.ion)m/z:283.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.94(d,J＝7.3Hz,1H),7.81(s,1H),7.52(s,1H),6.95(d,J＝7.2Hz,1H),4.17(q,J＝7.1Hz,2H),3.90(s,2H),1.25(t,J＝7.1Hz,3H)。

Step 4)1- (7-Bromoimidazo [1,2-a ]]Pyridin-3-yl) -2-methylpropan-2-ol

To 2- (7-bromoimidazo [1,2-a ] at 0 DEG C]Ethyl pyridin-3-yl) acetate (2g,7.0641mmol) in dry tetrahydrofuran (100mL) was added dropwise methyl magnesium bromide (11.8mL,35.4mmol,3M in THF). The reaction was stirred at 0 ℃ overnight. After the reaction is finished, saturated NH is added₄The reaction was quenched with aqueous Cl (20mL), then the mixture was diluted with water (40mL) and extracted with EtOAc (60 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 100/1 to 50/1) to give the title compound as a yellow solid (250mg, yield 13.15%).

MS(ESI,pos.ion)m/z:269.3[M+H]⁺。

Step 5)1- (7- ((diphenylmethylene) amino) imidazo [1,2-a ]Pyridin-3-yl) -2-methylpropan-2-ol

To 1- (7-bromoimidazo [1,2-a ]]Pyridin-3-yl) -2-methylpropan-2-ol (150mg,0.55733mmol), benzophenone imine (152mg,0.8389mmol) and t-BuONa (107mg,1.113mmol) in 1, 4-dioxane (20mL) was added BINAP (35mg,0.05621mmol) and Pd₂(dba)₃(26.3mg,0.0279 mmol). The reaction mixture was evacuated of air for 5 minutes and purged with nitrogen several times, then warmed to 100 ℃ and stirred overnight. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 5/1 to 1/1) to give the title compound as a yellow solid (100mg, 48.56% yield).

MS(ESI,pos.ion)m/z:370.1[M+H]⁺。

Step 6)1- (7-Aminoimidazo [1, 2-a)]Pyridin-3-yl) -2-methylpropan-2-ol

To 1- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-3-yl) -2-methylpropan-2-ol (100mg,0.2706mmol) in DCM (10mL) was added hydrogen chloride in EtOAc (2mL, 4M). The reaction mixture was stirred at room temperature for 2 hours, and after completion of the reaction, it was concentrated under reduced pressure. The residue was dissolved in water (5mL) and the resulting solution was saturated NaHCO₃Adjusting the pH value of the aqueous solution to 8-9, and then concentrating the mixture under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH)₃Purified with MeOH (7M)) (v/v) ═ 20/1) to give the title compound as a yellow solid (45mg, 81.01% yield).

MS(ESI,pos.ion)m/z:206.2[M+H]⁺。

Step by stepStep 7)6- (4- ((5-chloro-2- ((3- (2-hydroxy-2-methylpropyl) imidazo [1, 2-a)]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (32mg,0.09164mmol), 1- (7-aminoimidazo [1, 2-a)]Pyridin-3-yl) -2-methylpropan-2-ol (23mg,0.11205mmol) and Cs₂CO₃(90mg,0.27623mmol) of 1, 4-dioxane (10mL) to which Pd (OAc) was added₂(2mg,0.00891mmol) and BINAP (6mg,0.00966 mmol). The reaction mixture was evacuated of air for 2 minutes and purged with nitrogen several times, then warmed to 100 ℃ and stirred for 4 hours. After the reaction was finished, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1 to 20/1) to give the title compound as a pale yellow solid (3.3mg, yield 7.0%).

MS(ESI,pos.ion)m/z:518.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:518.2186[M+H]⁺,C₂₆H₂₉ClN₉O[M+H]⁺The theoretical values are: 518.2178, respectively;

¹H NMR(600MHz,CD₃OD)(ppm):8.43(s,2H),8.26(s,1H),8.01(s,1H),7.66(d,J＝8.2Hz,1H),7.61-7.51(m,2H),7.40(s,2H),6.75(d,J＝8.4Hz,1H),5.38(t,J＝4.7Hz,1H),4.48(s,1H),4.41(s,2H),3.42(s,2H),3.05(s,2H),2.05(dd,J＝12.4,6.5Hz,2H),1.60(d,J＝9.8Hz,2H),1.29(s,6H)；

¹³C NMR(150MHz,CD₃OD)(ppm):159.2,157.3,157.1,152.8,152.7,139.9,131.1,129.9,129.7,128.9,128.6,128.4,126.1,118.7,109.7,106.1,95.8,43.5,37.0,35.8,31.9,31.4,29.7。

example 43 6- (4- ((5-chloro-2- ((3- (1-hydroxyethyl) imidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 7-Bromoimidazo [1,2-a ]]Pyridine-3-carbaldehyde

4-Bromopyridin-2-amine (10.00g,57.80mmol) was suspended in EtOH (120mL), to which was added 2-bromomalondialdehyde (13.13g,86.98mmol) and 4-methylbenzenesulfonic acid monohydrate (2.25g,11.8 mmol). The mixture was placed in a sealed tube and stirred at 100 ℃ overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (100mL) and water (100mL) and then adjusted to pH 10 with 15% aqueous sodium hydroxide. The layers were separated by standing, the organic layer was separated from the filtrate, and the aqueous layer was extracted with EtOAc (100 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10 to 1/5 to 1/3) to afford the title compound as a brown solid (12.1g, 93% yield).

MS(ESI,pos.ion)m/z:225.0[M+H]⁺。

Step 2)1- (7-Bromoimidazo [1,2-a ]]Pyridin-3-yl) ethanol

At 0 ℃, 7-bromoimidazo [1,2-a ℃]Pyridine-3-carbaldehyde (12.1g,53.8mmol) was suspended in anhydrous THF (130mL), to which methyl magnesium bromide (27.0mL,81mmol,3.0M in THF) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1 hour and, after the reaction was complete, saturated NH was used₄The reaction was quenched with aqueous Cl (50mL) and water (50 mL). The resulting mixture was allowed to stand to separate into layers, and the separated aqueous layer was extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2 to 1/2 to 1/1 to 2/1) to give the title compound as a yellow solid (3.00g, 23% yield).

MS(ESI,pos.ion)m/z:241.0[M+H]⁺。

Step 3)1- (7-Bromoimidazo [1,2-a ]]Pyridin-3-yl) ethanones

1- (7-bromoimidazo [1,2-a ] at 0 DEG C]Pyridin-3-yl) ethanol (3.00g,12.4mmol) was suspended in DCM (100mL), dess-Martin reagent (7.95g,18.7mmol) was added thereto, and the reaction was stirred at room temperature overnight. After the reaction was completed, the mixture was saturated with Na₂CO₃The aqueous solution was diluted, the mixture was allowed to stand to separate into layers, and the separated aqueous layer was extracted with DCM (100 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5 to 1/2) to give the title compound as a yellow solid (1.30g, 44% yield).

MS(ESI,pos.ion)m/z:239.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.51(d,J＝7.3Hz,1H),8.30(s,1H),7.95(d,J＝1.2Hz,1H),7.19(dd,J＝7.3,1.7Hz,1H),2.60(s,3H)。

Step 4)1- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-3-yl) ethanones

1- (7-Bromoimidazo [1,2-a ]]Pyridin-3-yl) ethanone (1.30g,5.44mmol) was suspended in anhydrous 1, 4-dioxane (40mL) to which was added Pd₂(dba)₃(0.50g,0.55mmol)、BINAP(0.68g,1.10mmol)、Cs₂CO₃(3.55g,10.89mmol) and benzophenone imine (1.98g,10.92 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 105 ℃ and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100mL) and extracted with DCM (100 mL. times.3). The combined organic phases were passed over anhydrous Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave the crude product as a red viscous liquid (3.80g) containing the desired product (1.85g, 100% yield).

MS(ESI,pos.ion)m/z:340.1[M+H]⁺。

Step 5)1- (7-Aminoimidazo [1, 2-a)]Pyridin-3-yl) ethanones

1- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-3-yl) ethanone (1.85g,5.45mmol) was suspended in DCM (50mL) to which was added a solution of HCl in EtOAc (50mL,150mmol, 3M). The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was diluted with DCM (100mL) and water (50mL) and the resulting mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide. The mixture was allowed to stand for separation, and the separated aqueous layer was extracted with DCM (200 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH) ₃Purified with MeOH (3M)) (v/v) ═ 100/1 to 50/1 to 25/1) to give the title compound as a yellow solid (0.25g, 26% yield).

MS(ESI,pos.ion)m/z:176.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.37(d,J＝7.4Hz,1H),8.15(s,1H),6.76(d,J＝1.9Hz,1H),6.49(dd,J＝7.4,2.1Hz,1H),4.26(s,2H),2.52(s,3H)。

Step 6)6- (4- ((2- ((3-acetylimidazo [1, 2-a)]Pyridin-7-yl) amino) -5-chloropyrimidin-4-yl Amino) piperidin-1-yl) nicotinonitrile

6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (0.20g,0.57mmol) was suspended in anhydrous 1, 4-dioxane (10mL), and 1- (7-aminoimidazo [1,2-a ] was added thereto]Pyridin-3-yl) ethanone (0.10g,0.57mmol), Pd (OAc)₂(0.028g,0.12mmol), BINAP (0.073g,0.12mmol) and Cs₂CO₃(0.37g,1.14 mmol). The reaction mixture was evacuated of air and purged with nitrogen several times, then warmed to 105 ℃ and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 100/1 to 50/1 to 25/1) to give the title compound as a light yellow solid (0.23g, 83% yield).

MS(ESI,pos.ion)m/z:488.1[M+H]⁺。

Step 7)6- (4- ((5-chloro-2- ((3- (1-hydroxyethyl) imidazo [1, 2-a)]Pyridin-7-yl) amino) pyrimidine- 4-yl) amino) piperidin-1-yl) nicotinonitrile

6- (4- ((2- ((3-acetylimidazo [1,2-a ] pyridin-7-yl) amino) -5-chloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (0.23g,0.47mmol) was suspended in MeOH (5mL) and DCM (5mL), to which was added sodium borohydride (0.11g,2.86 mmol). The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 100/1 to 50/1 to 20/1) to give the crude product. The crude product was stirred in methanol (2.0mL) for 30 min, filtered and the filter cake was dried under reduced pressure to give the title compound as an off-white solid (25mg, 11% yield).

MS(ESI,pos.ion)m/z:490.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:490.1868[M+H]⁺,C₂₄H₂₅ClN₉O[M+H]⁺The theoretical values are: 90.1865, respectively;

¹H NMR(600MHz,DMSO-d₆)(ppm):9.58(s,1H),8.51(d,J＝2.1Hz,1H),8.28(d,J＝7.5Hz,1H),8.23(d,J＝1.3Hz.1H),8.04(s,1H),7.85(dd,J＝9.1,2.2Hz,1H),7.27(s,1H),7.10(dd,J＝7.5,1.7Hz,1H),7.07(d,J＝7.8Hz,1H),7.02(d,J＝9.1Hz,1H),5.24(d,J＝6.0Hz,1H),5.06-5.02(m,1H),4.59-4.53(m,2H),4.40-4.35(m,1H),3.19-3.15(m,2H),2.04-2.00(m,2H),1.66-1.60(m,2H),1.56(d,J＝6.5Hz,3H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):159.38,158.17,157.27,153.83,153.12,146.66,140.47,137.82,130.13,129.79,127.50,125.47,119.30,107.62,106.96,101.13,95.20,59.86,49.06,44.28,31.03,22.02。

example 446- (4- ((5-chloro-2- ((2- (1-hydroxycyclopropyl) - [1,2,4 ]]Triazolo [1,5-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) N- (1-amino-4-bromopyridin-2 (1H) -ylidene) -1-hydroxycyclopropanecarboxamide

To a solution of 1-hydroxycyclopropanecarboxylic acid (1.03g,10.09mmol) in THF (20mL) at 0 deg.C was added DMF (1mL) and thionyl chloride (3mL,41.35 mmol). The reaction mixture was stirred at room temperature for 3 hours, and then 1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (1.96g,5.05mmol) was added to the system. The reaction mixture was stirred at rt overnight and, after completion of the reaction, filtered and the filter cake was collected to give the title compound as a yellow-green solid (1.38g, 100% yield).

MS(ESI,pos.ion)m/z:272.1[M+H]⁺。

Step 2)1- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) cyclopropanol

N- (1-amino-4-bromopyridin-2 (1H) -ylidene) -1-hydroxycyclopropanecarboxamide (1.57g,5.77mmol), DMAP (706.3mg,5.78mmol) and DIPEA (395.2mg,3.06mmol) were suspended in MeCN (10mL), to which BSA (5.6mL,22.90mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then warmed to reflux and stirred overnight, and after the reaction was completed, concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a white solid (470.2mg, 32.1% yield).

MS(ESI,pos.ion)m/z:254.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.35(d,J＝7.2Hz,1H),7.82(d,J＝1.4Hz,1H),7.08(dd,J＝7.2,1.8Hz,1H),3.94(s,1H),1.39(s,4H)。

Step 3)1- (7- ((diphenylmethylene) amino- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) cyclopropanol

To 1- (7-bromo- [1,2, 4)]Triazolo [1,5-a]To a solution of pyridin-2-yl) cyclopropanol (424.5mg,1.67mmol) and benzophenone imine (475.8mg,2.63mmol) in 1, 4-dioxane (30mL) was added Pd₂(dba)₃(80.8mg,0.09mmol), BINAP (98%, 109.5mg,0.17mmol) and Cs₂CO₃(1.12g,3.37 mmol). The reaction system is stirred for 3 hours at 100 ℃, cooled to room temperature after the reaction is finished, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (EtOAc/PE (v/v) ═ 7/3) to give the title compound as a yellow solid (142.8mg, 24.1% yield).

MS(ESI,pos.ion)m/z:355.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.22(d,J＝7.2Hz,1H),7.76(d,J＝7.6Hz,2H),7.56–7.49(m,1H),7.48–7.39(m,3H),7.30(d,J＝7.1Hz,2H),7.14(d,J＝6.1Hz,2H),6.82(d,J＝1.3Hz,1H),6.44(dd,J＝7.2,2.0Hz,1H),3.44(s,1H),1.34–1.32(m,4H)。

Step 4)1- (7-amino- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) cyclopropanol

To a solution of 1- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclopropanol (127.0mg,0.36mmol) in THF (10mL) was added dropwise an aqueous solution of HCl (4mL,16mmol, 4M). The reaction mixture was stirred at room temperature for 1 hour, then adjusted to pH 10 with sodium carbonate powder and extracted with DCM (100mL × 3). The combined organic phases are concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a yellow solid (63.5mg, 93.2% yield).

MS(ESI,pos.ion)m/z:191.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.19(d,J＝7.2Hz,1H),6.63(d,J＝1.7Hz,1H),6.35(dd,J＝7.3,2.1Hz,1H),4.18(s,2H),3.39(s,1H),1.38–1.32(m,4H)。

Step 5)6- (4- ((5-chloro-2- ((2- (1-hydroxycyclopropyl) - [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) pyridin-1-yl) nicotinonitrile 2.0mg,0.18mmol) and 1- (7-amino- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) Cyclopropanol (49.9mg,0.26mmol) was suspended in 1, 4-dioxane (10mL) to which was added Pd (OAc)₂(10.2mg,0.045mmol), BINAP (98%, 24.9mg,0.039mmol) and Cs₂CO₃(98%, 128.3mg,0.38 mmol). The reaction system is heated to 100 ℃ and stirred for 3 hours, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by flash silica column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a beige solid (24.2g, 27.1% yield).

MS(ESI,pos.ion)m/z:503.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):10.07(s,1H),8.85(d,J＝7.5Hz,1H),8.51(s,2H),8.12(s,1H),7.87(d,J＝9.0Hz,1H),7.48(d,J＝7.4Hz,1H),7.20(d,J＝7.8Hz,1H),7.03(d,J＝9.1Hz,1H),6.65(s,1H),4.57(d,J＝12.8Hz,2H),4.43–4.29(m,1H),3.20–3.06(m,2H),1.74–1.60(m,2H),1.51–1.40(m,2H),1.10(t,J＝7.2Hz,2H),0.85(t,J＝6.3Hz,2H)。

Example 45 2- (7- ((5-chloro-4- ((1- (5-cyanopyridin-2-yl) piperidin-4-ylamino) pyrimidin-2-yl) Amino) - [1,2,4]Triazole [1,5-a ]]Pyridin-2-yl) acetic acid methyl ester

Step 1)2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) acetic acid ethyl ester

To a solution of 1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (4.20g,10.8mmol) and diethyl 3-oxoglutarate (4.0mL,22mmol) in ethanol (60mL) was added sodium hydroxide (436.4mg,10.91mmol), and the reaction mixture was warmed to reflux and stirred for 5 hours. After the reaction was complete, concentrated under reduced pressure and the resulting residue was purified by flash silica gel column chromatography (EtOAc/PE (v/v) ═ 1/4) to afford the title compound as a yellow solid (2.25g, 73% yield).

MS(ESI,pos.ion)m/z:284.0[M+H]⁺。

Step 2)2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) acetic acid methyl ester

At-78 deg.C under nitrogen atmosphere to 2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) acetic acid ethyl ester (1.75g,6.16mmol) in tetrahydrofuran (45mL) was added dropwise methylmagnesium bromide (10.3mL,3M in THF). The reaction mixture was stirred at-78 ℃ for 30 minutes and then moved to 0 ℃ and stirred overnight. After completion of the reaction, the reaction was quenched by addition of water (3mL) at 0 ℃ and then concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a white solid (220.0mg, 13% yield). MS (ESI, pos.ion) M/z 270.1[ M + H ]]⁺。

Step 3)2- (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) acetic acid methyl ester Esters

To 2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]To a solution of methyl pyridin-2-yl) acetate (220.0mg,0.81mmol) and benzophenone imine (196.2mg,1.08mmol) in 1, 4-dioxane (7mL) was added Pd₂(dba)₃(76.2mg,0.08mmol), BINAP (54.6mg,0.09mmol) and Cs₂CO₃(532.1mg,1.63mmol) and the reaction mixture was stirred at 100 ℃ under nitrogen for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (20mL) and then extracted with DCM (15 mL. times.2). The combined organic phases were washed with water (15 mL. times.2) and then with anhydrous Na ₂SO₄Drying, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product as brown oil. The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:371.2[M+H]⁺。

Step 4)2- (7-amino- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) acetic acid methyl ester

To a solution of methyl 2- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) acetate (301.7mg,0.82mmol) in THF (4mL) was added an aqueous solution of HCl (4mL,4M,16 mmol). The reaction system was stirred at room temperature for 2 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (3mL), and the resulting mixture was adjusted to pH 9 with saturated aqueous sodium bicarbonate. The mixture was concentrated under reduced pressure and the resulting residue was purified by flash silica column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a yellow solid (42.2mg, 25% overall yield over 2 steps).

MS(ESI,pos.ion)m/z:207.2[M+H]⁺。

Step 5)2- (7- ((5-chloro-4- ((1- (5-cyanopyridin-2-yl) piperidin-4-ylamino) pyrimidin-2-yl) amino) Base) - [1,2,4]Triazole [1,5-a ]]Pyridin-2-yl) acetic acid methyl ester

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (55.3mg,0.16mmol) and 2- (7-amino- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) acetic acid methyl ester (42.2mg,0.21mmol)1, 4-dioxane (3mL) solution Pd (OAc) ₂(4.6mg,0.02mmol), BINAP (12.4mg,0.02mmol) and Cs₂CO₃(108.3mg,0.33mmol) and the reaction mixture was stirred overnight at 100 ℃ under nitrogen. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a grey solid (14.5mg, 18% yield).

MS(ESI,pos.ion)m/z:519.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.1793；C₂₄H₂₄ClN₁₀O₂[M+H]⁺519.1772;

¹H NMR(600MHz,CDCl₃):(ppm)8.41(d,J＝1.9Hz,1H),8.34(d,J＝7.4Hz,1H),8.25(d,J＝1.7Hz,1H),7.98(s,1H),7.62(dd,J＝9.0,2.3Hz,1H),7.43(s,1H),7.02(dd,J＝7.1,1.2Hz,1H),6.66(d,J＝9.0Hz,1H),5.27(d,J＝7.3Hz,1H),4.43(d,J＝13.6Hz,2H),4.35–4.28(m,1H),3.94(s,2H),3.74(s,3H),3.33–3.27(m,2H),2.25(dd,J＝13.5,3.6Hz,2H),1.61–1.54(m,2H)。

¹³C NMR(100MHz,CDCl₃):(ppm)169.9,161.1,159.3,157.4,157.3,153.2,152.9,152.7,141.5,140.1,127.8,118.7,108.2,106.8,106.0,100.8,96.6,52.5,48.8,43.7,35.2,31.6。

example 466- (4- ((5-chloro-2- ((1-methyl-1H-benzo [ d ] imidazol-5-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) N- (diphenylmethylene) -1-methyl-1H-benzo [ d]Imidazole-5-amines

Reacting 5-bromo-1-methyl-1H-benzo [ d]Imidazole (302.3mg,1.432mmol), benzophenone imine (341.5mg,1.885mmol), t-BuONa (271.1mg,2.821mmol), BINAP (89.7mg,0.144mmol) and Pd₂(dba)₃(130.6mg,0.1426mmol) was dissolved in 1, 4-dihexacyclo (10 mL). The reaction mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere, and after completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with water (40mL), and the resulting mixture was extracted with a mixed solvent of DCM and MeOH (10/1(v/v),50 mL. times.3). The combined organic phases were passed over anhydrous Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave the crude product as a brown solid (0.446 g). The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:312.4[M+H]⁺。

Step 2) 1-methyl-1H-benzo [ d]Imidazole-5-amines

N- (diphenylmethylene) -1-methyl-1H-benzo [ d]Imidazol-5-amine (0.446g,1.43mmol) was dissolved in hydrogen chloride in EtOAc (8mL,32mmol,4M) and the reaction mixture was stirred at room temperature for 7 h. After the reaction was complete, the reaction mixture was washed with water (30mL × 2), and the combined aqueous phases were adjusted to pH 12 with sodium hydroxide powder. The mixture was dissolved in a mixture of DCM and MeOH(10/1(v/v),100 mL. times.4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH)₃Purified with MeOH (7M)) (v/v) ═ 60/1) to give the title compound as a yellow solid (100mg, 47.4% yield).

MS(ESI,pos.ion)m/z:148.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.72(s,1H),7.16(d,J＝8.5Hz,1H),7.08(d,J＝1.9Hz,1H),6.75(dd,J＝8.5,1.9Hz,1H),3.77(s,3H)。

Step 3)6- (4- ((5-chloro-2- ((1-methyl-1H-benzo [ d)]Imidazol-5-yl) amino) pyrimidin-4-yl) amino) Piperidin-1-yl) nicotinonitrile

1-methyl-1H-benzo [ d]Imidazol-5-amine (100mg,0.67944mmol), 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (182mg,0.5212mmol), Cs₂CO₃(508.7mg,1.561mmol), BINAP (34.6mg,0.0556mmol) and Pd (OAc)₂(12.8mg,0.0570mmol) of the mixture was dissolved in 1, 4-dioxane (10 mL). The reaction mixture was stirred at 100 ℃ under a nitrogen atmosphere for 4 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 50/1) to give the title compound as a white solid (54.4mg, 22.7% yield).

MS(ESI,pos.ion)m/z:460.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)(ppm):9.20(s,1H),8.49(d,J＝2.0Hz,1H),8.22(s,1H),8.06(s,1H),7.94(s,1H),7.84(dd,J＝9.1,2.3Hz,1H),7.48(dd,J＝8.7,1.5Hz,1H),7.42(d,J＝8.7Hz,1H),6.99(d,J＝9.1Hz,1H),6.88(d,J＝7.8Hz,1H),4.54(d,J＝12.1Hz,2H),4.37-4.29(m,1H),3.79(s,3H),3.10(t,J＝12.5Hz,2H),2.00(d,J＝10.6Hz,2H),1.60(qd,J＝12.5,3.8Hz,2H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):159.0,158.3,156.9,153.6,152.8,144.7,143.7,140.1,135.6,130.1,119.0,115.9,109.6,109.2,106.6,102.9,94.8,44.0,30.8,30.7。

Example 476- (4- ((5-chloro-2- ((1-methyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) amino) pyrimidines- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) N- (diphenylmethylene) -1-methyl-1H-benzo [ d][1,2,3]Triazole-5-amines

5-bromo-1-methyl-1H-benzo [ d][1,2,3]Triazole (302.3mg,1.426mmol), benzophenone imine (342.5mg,1.890mmol), t-BuONa (274.2mg,2.853mmol), BINAP (87.8mg,0.141mmol) and Pd₂(dba)₃(131.4mg,0.1435mmol) was dissolved in 1, 4-dioxane (10 mL). The reaction mixture was stirred at 100 ℃ under a nitrogen atmosphere for 6 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50mL), and the resulting mixture was extracted with a mixed solvent of DCM and MeOH (10/1(v/v),80 mL. times.3). The combined organic phases were passed over anhydrous Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave the title compound as a brown solid (445.4 mg). The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:313.2[M+H]⁺。

Step 2) 1-methyl-1H-benzo [ d][1,2,3]Triazole-5-amines

N- (diphenylmethylene) -1-methyl-1H-benzo [ d][1,2,3]Triazole-5-amine (445.4mg,1.426mmol) was dissolved in HCl in EtOAc (10mL,40mmol, 4M). The reaction mixture was stirred at room temperature overnight, and after completion of the reaction, the reaction mixture was washed with water (20 mL. times.3). The combined aqueous phases were adjusted to pH 12 with sodium hydroxide powder. The resulting solution was extracted with a mixed solvent of DCM and MeOH (10/1(v/v),100 mL. times.4), and the combined organic phases were extracted with anhydrous Na ₂SO₄Drying, filtering, and concentrating the filtrate under reduced pressure. The residue was subjected to silica gel column chromatography (DCM/(NH)₃Purified with MeOH (7M)) (v/v) ═ 100/1) to give the title compound as a yellow solid (151mg, 71.5% yield).

MS(ESI,pos.ion)m/z:149.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.30(d,J＝8.7Hz,1H),7.18(d,J＝1.8Hz,1H),6.94(dd,J＝8.7,1.9Hz,1H),4.21(s,3H),3.82(s,2H)。

Step 3)6- (4- ((5-chloro-2- ((1-methyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) amino) pyrimidin-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

1-methyl-1H-benzo [ d][1,2,3]Triazol-5-amine (64.8mg,0.437mmol), 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (147.6mg,0.4215mmol), Cs₂CO₃(301.4mg,0.9251mmol), BINAP (27.5mg,0.0442mmol) and Pd (OAc)₂(10.2mg,0.0454mmol) of the mixture was dissolved in 1, 4-dioxane (10 mL). The reaction mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere, and after completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 60/1) to give the title compound as a white solid (68.1mg, 48.6% yield).

MS(ESI,pos.ion)m/z:462.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:462.1671[M+H]⁺,C₂₁H₂₁ClN₁₁[M+H]⁺A theoretical value of 462.1670;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.51(s,1H),8.61(s,1H),8.01(s,1H),7.87(d,J＝9.7Hz,1H),7.72(s,2H),7.44(d,J＝9.7Hz,1H),6.99(d,J＝7.8Hz,1H),4.66(d,J＝13.2Hz,2H),4.45-4.34(m,1H),4.25(s,3H),3.23(t,J＝12.4Hz,2H),2.08(d,J＝11.0Hz,2H),1.69(qd,J＝12.3,3.5Hz,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):158.7,158.1,156.9,153.5,146.0,137.4,131.1,129.3,128.4,121.7,117.5,111.2,110.1,105.5,103.7,44.0,34.2,30.6。

example 486- (4- ((5-chloro-2- ((1, 2-dimethyl-1H-benzo [ d)]Imidazol-5-yl) amino) pyrimidin-4- Yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 4-bromo-N-methyl-2-nitroaniline

To 4-bromo-1-fluoro-2-nitro-benzene (1.1g,5.0mmol) and K₂CO₃To a solution of (1.28g,9.26mmol) in DCM (20mL) was added an aqueous solution of methylamine (3.5mL,% by mass: 40%). The reaction mixture was stirred at room temperature for 1.5 h, then diluted with water (50mL), the resulting mixture was extracted with DCM (80 mL. times.3), and the combined organic phases were extracted with anhydrous Na ₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave the title compound as a red solid (1.11g, 96% yield).

MS(ESI,pos.ion)m/z:231.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.31(d,J＝2.3Hz,1H),8.01(s,1H),7.52(dd,J＝9.1,2.2Hz,1H),6.75(d,J＝9.1Hz,1H),3.02(d,J＝5.1Hz,3H)。

¹Step 2) 4-bromo-N-methylbenzene-1, 2-diamine

To a solution of 4-bromo-N-methyl-2-nitroaniline (1.11g,4.80mmol) in EtOH (30mL) was added zinc powder (3.6g,55mmol) and saturated NH₄Aqueous Cl (4mL) and the reaction mixture was warmed to 60 ℃ and stirred for 1.5 hours, resulting in precipitation in the system. After the reaction was complete, filtration was carried out, the filter cake was washed with MeOH (150mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 7/1 to 4/1) to give the title compound as a brown liquid (720mg, 74.5% yield).

MS(ESI,pos.ion)m/z:201.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):6.93(dd,J＝8.4,2.2Hz,1H),6.83(d,J＝2.2Hz,1H),6.50(d,J＝8.4Hz,1H),3.34(s,3H),2.83(s,3H)。

Step 3) 5-bromo-1, 2-dimethyl-1H-benzo [ d]Imidazole

At 0 ℃ to 4-bromo-N¹Acetyl chloride (337.6mg,4.301mmol) was added dropwise to a solution of-methyl-benzene-1, 2-diamine (550mg,2.7355mmol) in pyridine (4mL) and the reaction mixture was warmed to reflux and stirred overnight. After the reaction is finished, the reaction bodyIt was concentrated under reduced pressure, the residue was diluted with water (50mL), and the resulting mixture was extracted with a mixed solvent of DCM and MeOH (10/1(v/v),80 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 125/1 to 100/1) to give the title compound as a light yellow solid (450mg, 73.1% yield).

MS(ESI,pos.ion)m/z:225.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.79(s,1H),7.32(dd,J＝8.5,1.5Hz,1H),7.12(d,J＝8.5Hz,1H),3.69(s,3H),2.58(s,3H)。

Step 4) N- (diphenylmethylene) -1, 2-dimethyl-1H-benzo [ d]Imidazole-5-amines

5-bromo-1, 2-dimethyl-1H-benzo [ d]Imidazole (450mg,1.9993mmol), benzophenone imine (482.7mg,2.664mmol), t-BuONa (388.6mg,4.044mmol), BINAP (135.2mg,0.2171mmol), Pd₂(dba)₃A mixture of (181.5mg,0.1982mmol) and 1, 4-dioxane (10mL) was warmed to 100 ℃ and the reaction was stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in water (50mL) and extracted with a mixed solvent of DCM and MeOH (10/1(v/v),50 mL. times.3). The combined organic phases were passed over anhydrous Na₂SO₄Drying, filtration and concentration of the filtrate under reduced pressure gave the title compound as a brown solid (650.6 mg). The crude product was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:326.4[M+H]⁺。

Step 5)1, 2-dimethyl-1H-benzo [ d]Imidazole-5-amines

N- (diphenylmethylene) -1, 2-dimethyl-1H-benzo [ d ] imidazol-5-amine (650.6mg,1.999mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (10mL,40mmol, 4M). The reaction mixture was stirred at room temperature overnight, after completion of the reaction, the reaction mixture was washed with water (20mL × 3), and the combined aqueous layers were adjusted to pH 12 with sodium hydroxide powder, followed by extraction with a mixed solvent of DCM and MeOH (10/1(v/v),100mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 80/1) to give the title compound as a yellow solid (190mg, 59% yield).

MS(ESI,pos.ion)m/z:162.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.04(d,J＝8.4Hz,1H),6.98(d,J＝1.9Hz,1H),6.66(dd,J＝8.4,2.0Hz,1H),3.63(s,3H),2.53(s,3H)。

Step 6)6- (4- ((5-chloro-2- ((1, 2-dimethyl-1H-benzo [ d)]Imidazol-5-yl) amino) pyrimidin-4-yl) Amino) piperidin-1-yl) nicotinonitrile

To 1, 2-dimethyl-1H-benzo [ d ]]To a solution of imidazol-5-amine (100.4mg,0.6228mmol) and 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (217.8mg,0.6237mmol) in 1, 4-dioxane (10mL) was added Cs₂CO₃(608.2mg,1.867mmol), BINAP (38.6mg,0.0620mmol), and Pd (OAc)₂(14.5mg,0.0646 mmol). The reaction mixture was stirred at 100 ℃ for 5 hours under a nitrogen atmosphere, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as an off-white solid (145.4mg, 49.3% yield).

MS(ESI,pos.ion)m/z:474.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:474.1921[M+H]⁺,C₂₄H₂₅ClN₉[M+H]⁺A theoretical value of 474.1921;

¹HNMR(400MHz,DMSO-d₆)(ppm):9.10(s,1H),8.50(d,J＝2.1Hz,1H),7.99(d,J＝1.5Hz,1H),7.92(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.46(dd,J＝8.7,1.7Hz,1H),7.32(d,J＝8.7Hz,1H),7.00(d,J＝9.1Hz,1H),6.81(d,J＝7.8Hz,1H),4.53(d,J＝13.3Hz,2H),4.37-4.27(m,1H),3.67(s,3H),3.10(t,J＝12.2Hz,2H),2.47(s,3H),1.99(d,J＝10.6Hz,2H),1.61(qd,J＝12.4,3.7Hz,2H)；

¹³CNMR(100MHz,DMSO-d₆)(ppm):159.0,158.3,156.7,153.4,152.6,152.0,142.5,140.0,135.1,131.3,118.8,114.7,108.7,108.5,106.5,102.8,94.8,43.9,30.6,29.6,13.5。

example 496- (4- ((5-chloro-2- ((1,2-dimethyl-1H-benzo [ d]Imidazol-5-yl) amino) pyrimidin-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (303.4mg,0.8664mmol), 1, 2-dimethyl-1H-benzo [ d ]]Imidazol-5-amine (145.6mg,0.9032mmol) and Cs₂CO₃(841.3mg,2.582mmol) in 1, 4-dioxane (15mL) was added BINAP (50.7mg,0.0814mmol) and Pd (OAc)₂(19.0mg,0.0846 mmol). The reaction mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere, and after completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 40/1) to give the title compound as a yellow solid (167.4mg, 40.7% yield).

MS(ESI,pos.ion)m/z:475.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:475.1870[M+H]⁺,C₂₃H₂₄ClN₁₀[M+H]⁺A theoretical value of 475.1874;

¹H NMR(600MHz,DMSO-d₆)(ppm):9.13(s,1H),8.00(d,J＝1.4Hz,1H),7.93(s,1H),7.87(d,J＝9.7Hz,1H),7.46(dd,J＝8.7,1.6Hz,1H),7.43(d,J＝9.7Hz,1H),7.33(d,J＝8.7Hz,1H),6.84(d,J＝7.7Hz,1H),4.62(d,J＝10.1Hz,2H),4.41–4.32(m,1H),3.67(s,3H),3.20(t,J＝12.3Hz,2H),2.47(s,3H),2.04(d,J＝10.8Hz,2H),1.66(qd,J＝12.6,3.8Hz,2H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):159.1,158.7,157.2,153.9,152.5,142.9,135.6,131.7,131.6,128.8,118.0,115.1,111.6,109.2,108.9,103.2,44.3,31.0,30.1,13.9。

example 506- (4- ((5-chloro-2- ((1-methyl-1H-benzo [ d)]Imidazol-5-yl) amino) pyrimidin-4-yl) amino Yl) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (285.8mg,0.82mmol) and 1-methyl-1H-benzo [ d ]]Pd (OAc) was added to a solution of imidazol-5-amine (149.1mg,1.01mmol) in 1, 4-dioxane (20mL)₂(38.3mg,0.17mmol), BINAP (98%, 106.0mg,0.17mmol) and Cs₂CO₃(98%, 554.2mg,1.67 mmol). The reaction system was stirred at 100 ℃ overnight and, after completion of the reaction, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a beige solid (233.3mg, 62% yield).

MS(ESI,pos.ion)m/z:461.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:461.1740[M+H]⁺,C₂₂H₂₂ClN₁₀[M+H]⁺A theoretical value of 461.1717;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.22(s,1H),8.24(s,1H),8.07(s,1H),7.96(s,1H),7.88(d,J＝9.7Hz,1H),7.50(dd,J＝8.7,1.6Hz,1H),7.44(dd,J＝9.2,4.4Hz,2H),6.89(d,J＝7.7Hz,1H),4.66(d,J＝12.5Hz,2H),4.47–4.33(m,1H),3.80(s,3H),3.22(t,J＝12.3Hz,2H),2.07(d,J＝10.9Hz,2H),1.67(qd,J＝12.5,3.8Hz,2H)；

¹³C NMR(100MHz,DMSO-d₆)(ppm):159.1,158.7,157.2,153.9,145.0,144.1,135.9,131.5,130.5,128.8,117.9,116.2,111.6,109.8,109.7,103.3,48.6,44.4,31.1,31.0。

example 516- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-pyrazolo [4, 5-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- (6-bromo-1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol

To 6-bromo-3H-imidazo [4,5-b ]]Pyridine (360.0mg,1.83mmol)And 1-bromopropan-2-ol (500.0mg,3.60mmol) in DMF (20mL) with addition of Cs₂CO₃(1.78g,5.46 mmol). The reaction mixture was stirred at 100 ℃ for 6 h, then cooled to room temperature, quenched by addition of water (50mL), and the resulting mixture extracted with EtOAc (80 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a white solid (0.16g, 34% yield).

MS(ESI,pos.ion)m/z:256.0[M+H]⁺。

Step 2)1- (6- ((diphenylmethylene) amino) -1H-imidazo [4,5-b]Pyridin-1-yl) propan-2-ol

To 1- (6-bromo-1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol (270.0mg,1.05mmol), benzophenone imine (380.0mg,2.10mmol), Pd₂(bda)₃To a solution of (100.0mg,0.10mmol) and BINAP (135.0mg,0.21mmol) in 1, 4-dioxane (20mL) was added t-BuONa (200.0mg,2.04 mmol). The reaction mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere, and after completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was diluted with water (20mL) and then extracted with DCM (20mL × 3), and the combined organic phases were concentrated under reduced pressure to give the title compound as a yellow solid (236.6mg, 63% yield).

MS(ESI,pos.ion)m/z:357.1[M+H]⁺。

Step 3)1- (6-amino-1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol

To 1- (6- ((diphenylmethylene) amino) -1H-imidazo [4,5-b ] at room temperature]Pyridin-1-yl) propan-2-ol (340.0mg,0.95mmol) in 1, 4-dioxane (20mL) was added dropwise HCl in EtOAc (20mL,60mmol, 3M). The reaction was stirred at room temperature overnight, after completion of the reaction, water (20ml) was added to quench the reaction, which was followed by addition of saturated Na₂CO₃The aqueous solution was adjusted to pH 10 and the resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (10mL) and MeOH (10mL) and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a brown solid (110.0mg, 60% yield).

MS(ESI,pos.ion)m/z:193.1[M+H]⁺。

Step 4)6- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-imidazo [4, 5-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To Pd (OAc)₂(15.0mg,0.065mmol), BINAP (40.0mg,0.062mmol), 1- (6-amino-1H-imidazo [4,5-b ]]Pyridin-1-yl) propan-2-ol (120.0mg,0.62mmol) and 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (100.0mg,0.29mmol) in 1, 4-dioxane (30mL) was added Cs₂CO₃(615.0mg,1.89 mmol). The reaction mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere, and after completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a white solid (25.0mg, 8% yield).

MS(ESI,pos.ion)m/z:505.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1991[M+H]⁺,C₂₄H₂₆ClN₁₀O[M+H]⁺A theoretical value of 505.1980;

¹H NMR(600MHz,DMSO-d₆)(ppm):9.41(s,1H),8.57(s,1H),8.49(s,1H),8.38(s,1H),8.26(s,1H),7.97(s,1H),7.84(d,J＝8.1Hz,1H),6.99(d,J＝9.2Hz,1H),6.89(d,J＝7.6Hz,1H),5.11(s,1H),4.47(d,J＝11.0Hz,2H),4.34(s,1H),4.17(d,J＝12.1Hz,1H),4.08–3.97(m,2H),3.05(t,J＝12.7Hz,2H),1.93(d,J＝10.1Hz,2H),1.70–1.57(m,2H),1.07(d,J＝5.4Hz,3H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):159.4,158.7,157.3,153.8,153.1,151.4,146.1,140.4,138.0,133.2,126.8,119.0,109.2,107.0,104.3,95.2,65.6,52.2,48.1,44.1,31.0,21.3。

example 52 6- (4- ((5-chloro-2- ((3- (2-hydroxypropyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol

To 6-bromo-3H-imidazo [4,5-b ]]Pyridine (360.0mg,1.83mmol) and 1-bromopropan-2-ol (500.0mg,3.60mmol) in DMF (20mL) with Cs₂CO₃(1.78g,5.46 mmol). The reaction mixture was stirred at 100 ℃ for 6 hours, after completion of the reaction, cooled to room temperature, and quenched by addition of water (50 mL). The resulting mixture was extracted with EtOAc (80 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a white solid (180.0mg, 39% yield).

MS(ESI,pos.ion)m/z:256.0[M+H]⁺。

Step 2)1- (6- ((diphenylmethylene) amino) -3H-imidazo [4,5-b]Pyridin-3-yl) propan-2-ol

To 1- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol (170.0mg,0.66mmol), benzophenone imine (240.0mg,1.32mmol), Pd₂(bda)₃To a solution of (63.0mg,0.067mmol) and BINAP (85.0mg,0.13mmol) in 1, 4-dioxane (10mL) was added t-BuONa (130.0mg,1.33 mmol). The reaction mixture was stirred at 100 ℃ under a nitrogen atmosphere for 6 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. After the residue was diluted with water (20mL), the resulting mixture was extracted with ethyl acetate (20 mL. times.3). The combined organic phases were concentrated under reduced pressure to give the title compound as a yellow solid (236.6mg, 100% yield).

MS(ESI,pos.ion)m/z:357.4[M+H]⁺。

Step 3)1- (6-amino-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol

To 1- (6- ((diphenylmethylene) amino) -3H-imidazo [4,5-b ] at room temperature]To a solution of pyridin-3-yl) propan-2-ol (340.0mg,0.95mmol) in 1, 4-dioxane (20mL) was added dropwise a solution of hydrogen chloride in ethyl acetate (20mL,60mmol, 3M). The reaction mixture was stirred at room temperature overnight, after completion of the reaction, the reaction was quenched with water (20ml), and then saturated Na was added₂CO₃The aqueous solution was adjusted to pH 10 and the resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (10mL) and MeOH (10mL) and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a brown solid (110.0mg, 60% yield).

MS(ESI,pos.ion)m/z:193.1[M+H]⁺。

Step 4)6- (4- ((5-chloro-2- ((3- (2-hydroxypropyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To Pd (OAc)₂(12.1mg,0.053mmol), BINAP (33.2mg,0.052mmol), 1- (6-amino-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol (101.2mg,0.53mmol) and 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (180.8mg,0.52mmol) in 1, 4-dioxane (30mL) was added Cs₂CO₃(431.2mg,1.32 mmol). The reaction system was stirred overnight at 100 ℃ under a nitrogen atmosphere, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a white solid (28.3mg, 11% yield).

MS(ESI,pos.ion)m/z:505.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1963[M+H]⁺,C₂₄H₂₆ClN₁₀O[M+H]⁺A theoretical value of 505.1980;

¹H NMR(600MHz,DMSO-d₆)(ppm):9.38(s,1H),8.58(s,1H),8.49(d,J＝14.5Hz,2H),8.27(s,1H),7.96(s,1H),7.85(dd,J＝9.0,1.7Hz,1H),7.01(d,J＝9.1Hz,1H),6.94(d,J＝7.5Hz,1H),5.01(d,J＝4.3Hz,1H),4.54(d,J＝11.7Hz,2H),4.37–4.25(m,1H),4.18(d,J＝9.9Hz,1H),4.12–4.02(m,2H),3.05(t,J＝12.5Hz,2H),2.03-1.98(m,2H),1.64–1.58(m,2H),1.07(d,J＝5.6Hz,3H)；

¹³C NMR(150MHz,DMSO-d₆)(ppm):159.4,158.7,157.2,153.9,153.1,146.5,142.9,140.5,137.6,134.9,133.5,130.1,119.3,117.9,107.0,95.3,65.0,50.6,44.3,40.5,31.0,21.4。

examples53 6- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-pyrrolo [3, 2-b)]Pyridin-6-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- (6-bromo-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) propan-2-ol

To 6-bromo-1H-pyrrolo [3,2-b ]]Pyridine (1.01g,5.13mmol) and 1-bromopropan-2-ol (2.14g,15.0mmol) in DMF (10mL) with addition of Cs₂CO₃(4.97g,15.3mmol) and the reaction mixture was stirred at 100 ℃ overnight. After the reaction was complete, the mixture was diluted with EtOAc (100mL) and washed with water (100mL) and anhydrous Na ₂SO₄Drying, filtering, and concentrating the filtrate. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow oil (1.22g, 93.3% yield).

MS(ESI,pos.ion)m/z:255.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.32(d,J＝1.8Hz,1H),7.80(d,J＝0.9Hz,1H),7.27(d,J＝3.3Hz,1H),6.44(d,J＝3.2Hz,1H),4.22-4.16(m,1H),4.08(dd,J＝14.5,3.3Hz,1H),3.95(dd,J＝14.5,8.0Hz,1H),3.46(s,1H),1.28(d,J＝6.3Hz,3H)。

Step 2)1- (6- ((diphenylmethylene) amino) -1H-pyrrolo [3, 2-b)]Pyridin-1-yl) propan-2-ol

To 1- (6- ((diphenylmethylene) amino) -1H-pyrrolo [3, 2-b)]To a solution of pyridin-1-yl) propan-2-ol (1.1g,4.30mmol) and benzophenone imine (935mg,5.16mmol) in 1, 4-dioxane (20mL) was added BINAP (270mg,0.433mmol), Pd₂(dba)₃(391mg,0.427mmol) and Cs₂CO₃(2.81g,8.62 mmol). The reaction mixture was stirred at 105 ℃ under nitrogen atmosphere for overnight reaction, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50mL) and extracted with DCM (100 mL. times.3). The combined organic phases were washed with saturated brine (50 mL. times.3),anhydrous Na₂SO₄Drying and concentration of the filtrate under reduced pressure gave the title compound as a brown solid (1.5g, 98% yield).

MS(ESI,pos.ion)m/z:356.1[M+H]⁺。

Step 3)1- (6-amino-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) propan-2-ol

To 1- (6- ((diphenylmethylene) amino) -1H-pyrrolo [3, 2-b)]To a solution of pyridin-1-yl) propan-2-ol (1.5g,4.20mmol) in dioxane (20mL) was added concentrated hydrochloric acid (6mL,72mmol, 12M). The reaction system was stirred at room temperature for 2 hours, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was saturated NaHCO ₃The aqueous solution was adjusted to pH 10 and concentrated again under reduced pressure. The residue was subjected to silica gel column chromatography ((NH)₃Purified with MeOH (7M))/DCM (v/v) ═ 1/20 to give the title compound as a brown solid (480mg, 59.0% yield).

MS(ESI,pos.ion)m/z:192.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.83(d,J＝1.6Hz,1H),7.23(d,J＝3.1Hz,1H),6.96(s,1H),6.29(d,J＝3.0Hz,1H),4.09(d,J＝4.5Hz,1H),3.95-3.91(m,1H),3.17(d,J＝3.0Hz,2H),1.02(d,J＝5.5Hz,3H)。

Step 4)6- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-pyrrolo [3, 2-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (101mg,0.289mmol) and 1- (6-amino-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) propan-2-ol (82mg,0.428mmol) in 1, 4-dioxane (10mL) was added Cs₂CO₃(94mg,0.288mmol), BINAP (17mg,0.027mmol) and Pd (OAc)₂(6mg,0.026 mmol). The reaction mixture was stirred at 105 ℃ for 3 hours under a nitrogen atmosphere, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/40) to give the title compound as a yellow solid (65mg, 44.6% yield).

MS(ESI,pos.ion)m/z:504.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:504.2039[M+H]⁺,C₂₅H₂₇ClN₉O[M+H]⁺A theoretical value of 504.1949;

¹H NMR(600MHz,CDCl₃)(ppm):8.44(s,1H),8.39(d,J＝1.5Hz,1H),8.02(s,1H),7.89(s,1H),7.59(dd,J＝9.0,2.0Hz,1H),6.61(d,J＝9.0Hz,1H),6.56(d,J＝2.4Hz,1H),5.14(d,J＝7.4Hz,1H),4.33(d,J＝13.4Hz,2H),4.27-4.23(m,1H),4.19(dd,J＝10.0,6.6Hz,1H),4.10(dd,J＝14.5,3.4Hz,1H),4.01(dd,J＝14.5,7.8Hz,1H),3.19(t,J＝12.6Hz,2H),2.15(d,J＝10.3Hz,2H),1.52(dd,J＝23.1,11.3Hz,2H),1.27(d,J＝6.2Hz,3H)；

¹³C NMR(150MHz,CDCl₃)(ppm):159.2,158.5,157.2,153.1,152.9,142.4,140.0,137.7,131.5,130.8,129.8,118.8,109.0,106.0,105.2,102.4,96.4,67.3,54.3,48.1,43.6,31.6,21.0。

example 546- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- (5-bromo-1H-pyrrolo [2, 3-b)]Pyridin-1-yl) propan-2-ol

To 5-bromo-1H-pyrrolo [2,3-b ] ]Pyridine (1.01g,5.13mmol) and 1-bromopropan-2-ol (2.13g,15.3mmol) in DMF (20mL) with addition of Cs₂CO₃(5.00g,15.3mmol) and the reaction mixture was stirred at 100 ℃ for 4 h. After completion of the reaction, the resulting solution was diluted with EtOAc (100mL), then washed with water (100mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the title compound as a yellow oil (1.24g, 94.8% yield).

MS(ESI,pos.ion)m/z:256.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.28(d,J＝2.0Hz,1H),8.03(d,J＝2.1Hz,1H),7.23(d,J＝3.4Hz,1H),6.40(d,J＝3.5Hz,1H),4.35-4.30(m,1H),4.26-4.20(m,1H),4.16(m,1H),3.93(d,J＝3.8Hz,1H),1.22(d,J＝6.2Hz,3H)。

Step 2)1- (5- ((diphenylmethylene) amino) -1H-pyrrolo [2,3-b]Pyridin-1-yl) propan-2-ol

To 1- (5-bromo-1H-pyrrolo [2,3-b ]]Pyridin-1-yl) propan-2-ol (1.24g,4.86mmol) and diphenylazomethine (1.04g,5.74mmol) in 1, 4-dioxane (20mL) was added BINAP (303mg,0.486mmol), Pd (OAc)₂(106mg,0.472mmol) and Cs₂CO₃(3.18g,9.76 mmol). The reaction mixture was stirred at 105 ℃ under nitrogen overnight, and after completion of the reaction, it was concentrated under reduced pressure. The resulting residue was diluted with water (50mL) and then extracted with dichloromethane (100 mL. times.3). The combined organic phases were washed with saturated brine (50mL × 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (1.70g, 98.0% yield).

MS(ESI,pos.ion)m/z:356.1[M+H]⁺。

Step 3)1- (5-amino-1H-pyrrolo [2, 3-b)]Pyridin-1-yl) propan-2-ol

To 1- (5- ((diphenylmethylene) amino) -1H-pyrrolo [2, 3-b)]To a solution of pyridin-1-yl) propan-2-ol (1.7g,4.80mmol) in 1, 4-dioxane (20mL) was added concentrated hydrochloric acid (6mL,72mol, 12M). The reaction mixture was stirred at room temperature for 3 hours, and after completion of the reaction, it was concentrated under reduced pressure. The residue was saturated NaHCO₃The aqueous solution was adjusted to pH 10 and concentrated again under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to give the title compound as a brown solid (180mg, 20.0% yield).

MS(ESI,pos.ion)m/z:192.1[M+H]⁺。

Step 4)6- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) amino group) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (59mg,0.169mmol) and 1- (5-amino-1H-pyrrolo [2, 3-b)]Pyridin-1-yl) propan-2-ol (50mg,0.261mmol) of 1, 4-dioxane (10mL) was added with Cs₂CO₃(117mg,0.359mmol), BINAP (10mg,0.016mmol) and Pd (OAc)₂(4mg,0.017 mmol). The reaction mixture was heated to reflux, then stirred under nitrogen for 2 hours, and after the reaction was completed, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ((MeOH/DCM (v/v) ═ 1/40) to give the title compound as a yellow solid (50mg, 58.7% yield).

MS(ESI,pos.ion)m/z:504.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:504.2050[M+H]⁺,C₂₅H₂₇ClN₉O[M+H]⁺The theoretical values are: 504.1949, respectively;

¹H NMR(400MHz,CDCl₃)(ppm):8.40(d,J＝1.8Hz,1H),8.30(d,J＝2.1Hz,1H),8.19(d,J＝2.2Hz,1H),7.89(s,1H),7.60(dd,J＝9.0,2.3Hz,1H),7.30(s,1H),7.19(d,J＝3.4Hz,1H),6.63(d,J＝9.0Hz,1H),6.39(d,J＝3.4Hz,1H),5.13(d,J＝7.2Hz,1H),4.40(d,J＝13.5Hz,2H),4.34-4.29(m,1H),4.26-4.14(m,3H),3.10(t,J＝11.7Hz,2H),2.17(d,J＝12.4Hz,2H),1.53-1.47(m,2H),1.22(d,J＝6.2Hz,3H)；

¹³C NMR(100MHz,CDCl₃)(ppm):159.2,158.9,157.2,153.3,152.9,144.8,140.0,137.5,130.7,129.9,121.9,120.8,118.7,105.9,104.7,99.3,96.4,67.8,54.4,48.5,43.8,31.7,20.8。

example 556- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2,4 ]]Triazolo [1,5-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) (2,4, 6-trimethylphenylsulfonyl) oxycarboxylic acid tert-butyl ester

To a solution of 2,4, 6-trimethylphenyl-1-sulfonyl chloride (20.01g,91.50mmol) and tert-butyl hydroxycarbamate (12.24g,91.93mmol) in EtOAc (200mL) at-10 deg.C was added triethylamine (15.4mL,110mmol) dropwise. After the addition was complete, the reaction mixture was warmed to 0 ℃ and stirred for 2 hours, then quenched with water (100mL) and allowed to settle into layers. The separated organic layer was washed with water (200 mL. times.3), and then concentrated under reduced pressure. The residue was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:338.2[M+23]⁺。

Step 2) O- (2,4, 6-trimethylphenylsulfonyl) hydroxylamine

To a solution of tert-butyl (2,4, 6-trimethylphenylsulfonyl) oxycarbamate (28.86g,91.50mmol) in EtOAc (200mL) was added concentrated sulfuric acid (9.0mL,164.7mmol) dropwise. After the addition was complete, the reaction mixture was warmed to 0 ℃ and stirred overnight, then quenched with saturated sodium carbonate and allowed to stand until layers separated. The separated organic layer was washed with water (300mL) and then concentrated under reduced pressure. The residue was used in the next reaction without purification.

Step 3)1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate

To a solution of O- (2,4, 6-trimethylphenylsulfonyl) hydroxylamine (19.70g,91.50mmol) in EtOAc (400mL) at 5 deg.C was added 4-bromopyridin-2-amine (7.95g,45.8 mmol). The mixture was stirred at 5 ℃ for 1 hour, then filtered, and the filter cake was washed with EtOAc (20 mL. times.3), then dried under reduced pressure to give the title compound as a white solid (13.70g, three-step reaction yield: 77%).

MS(ESI,pos.ion)m/z:188.1[M₁]⁺；

MS(ESI,neg.ion)m/z:199.1[M₂]^-。

Step 4) 7-bromo- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxylic acid ethyl ester

To a solution of 1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (3.98g,10.2mmol) in pyridine (30mL) at 0 deg.C was added ethyl 2-chloro-2-oxo-acetate (2.45mL,21.9 mmol). The reaction mixture was stirred at room temperature for 30min, then moved to 100 ℃ and stirred overnight, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/4) to give the title compound as a white solid (0.42g, 15%).

MS(ESI,pos.ion)m/z:269.9[M+H]⁺。

Step 5)2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

In N₂Protection and reaction at-78 deg.C to 7-bromo- [1,2,4 ]]Triazolo [1,5-a]To a solution of pyridine-2-carboxylic acid ethyl ester (0.30g,1.1mmol) in tetrahydrofuran (11mL) was added dropwise methylmagnesium bromide (3.0M in diethyl ether, 1.9mL,5.7 mmol). After the addition was complete, the reaction mixture was moved to 0 ℃ and stirred overnight. After the reaction was completed, the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with EtOAc (10 mL. times.2). The combined organic phases were concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to afford the title compound as a white solid (0.19g, 67%). MS (ESI, pos. ion) M/z 256.0[ M + H ] ]⁺。

Step 6)2- (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To 2- (7-bromo- [1,2, 4)]Triazolo [1,5-a]To a solution of pyridin-2-yl) propan-2-ol (0.19g,0.74mmol) and benzophenone imine (0.17g,0.94mmol) in 1, 4-dioxane (5mL) was added Pd₂(dba)₃(0.068g,0.074mmol), BINAP (0.046g,0.074mmol) and Cs₂CO₃(0.48g,1.5 mmol). The reaction system is heated to 100 ℃ and stirred overnight under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was diluted with DCM (20mL) and the resulting mixture was washed with water (15 mL. times.2). The organic phase was concentrated under reduced pressure to give the title compound as a brown oil which was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:357.1[M+H]⁺。

Step 7)2- (7-amino- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To 2- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) propan-2-ol (0.26g,0.73mmol) in DCM (5mL) was added a solution of hydrogen chloride in EtOAc (3M,2.5mL,7.5 mmol). The reaction system was stirred at room temperature for 1 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure, adjusted to pH 9 with an aqueous NaOH solution (1M), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow solid (0.12g, 86% yield over two steps).

MS(ESI,pos.ion)m/z:193.1[M+H]⁺。

Step 8)6- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [1,5-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (102.3mg,0.29mmol) and 2- (7-amino- [1,2, 4-mmol)]Triazolo [1,5-a]To a solution of pyridin-2-yl) -propan-2-ol (81.2mg,0.42mmol) in 1, 4-dioxane (8mL) was added Pd (OAc)₂(6.8mg,0.03mmol), BINAP (18.2mg,0.03mmol) and Cs₂CO₃(188.3mg,0.58 mmol). The reaction system is heated to 100 ℃ under the protection of nitrogen and stirred overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the crude product as a pale red solid. The crude product was diluted in EtOH (6mL), then stirred and filtered. The resulting filter cake was the title compound as a cream solid (138.1mg, 93.4%).

MS(ESI,pos.ion)m/z:506.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:506.1943[M+H]⁺；C₂₃H₂₅ClN₁₁O[M+H]⁺A theoretical value of 506.1932;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.88(s,1H),8.69(d,J＝7.4Hz,1H),8.31(d,J＝1.5Hz,1H),8.10(s,1H),7.89(d,J＝9.7Hz,1H),7.45(d,J＝9.8Hz,1H),7.33(dd,J＝7.5,2.0Hz,1H),7.13(d,J＝7.8Hz,1H),5.04(s,1H),4.64(d,J＝12.2Hz,2H),4.47–4.32(m,1H),3.18(d,J＝5.2Hz,2H),2.06(d,J＝12.2Hz,2H),1.76–1.65(m,2H),1.53(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)172.7,159.2,157.9,157.4,153.7,152.0,142.5,131.6,128.9,128.6,117.9,111.6,108.4,105.6,99.5,68.6,48.7,44.3,30.9,30.2。

example 566- (4- ((5-chloro-2- ((2- (2-hydroxypropyl) - [1,2, 4)]Triazole [1,5-a]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)1- (7-bromo- [1,2, 4)]Triazole [1,5-a ]]Pyridin-2-yl) propan-2-ones

In N₂Protection and reaction at-78 deg.C to 2- (7-bromo- [1,2, 4)]Triazole [1,5-a ] ]Ethyl pyridin-2-yl) acetate (1.06g,3.8mmol) in tetrahydrofuran (12mL) was added dropwise methyl magnesium bromide (3.0M in diethyl ether, 1.2mL,3.6 mmol). After the addition was complete, the reaction mixture was moved to-30 ℃ and stirred for 4 hours. After completion of the reaction, the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with EtOAc (15 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as a white solid (78.0mg, 8%).

MS(ESI,pos.ion)m/z:254.0[M+H]⁺。

Step 2)1- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To 1- (7-bromo- [1,2,4 ] at 0 DEG C]Triazole [1,5-a ]]Pyridin-2-yl) propan-2-one (100mg,0.39mmol) in EtOH (10mL) was added sodium borohydride (31.5mg,0.83 mmol). After the addition was complete, the reaction mixture was moved to 20 ℃ and stirred overnight. After the reaction was complete, the reaction was quenched by addition of a cooled saturated aqueous ammonium chloride solution and extracted with EtOAc (15 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as a white solid (99.5mg, 99%). MS (ESI, pos. ion) M/z 256.1[ M + H ] ]⁺。

Step 3)1- (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To 1- (7-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol (100mg,0.39mmol) and benzophenone imine (88.1mg,0.4 mmol)9mmol) of 1, 4-dioxane (8mL) was added Pd₂(dba)₃(35.4mg,0.04mmol), BINAP (24.3mg,0.04mmol) and Cs₂CO₃(257.1mg,0.79 mmol). The reaction system was stirred at 100 ℃ for 3 overnight, cooled to room temperature after the reaction was complete, and concentrated under reduced pressure. The resulting residue was diluted with DCM (20mL) and washed with water (15 mL. times.2). The organic phase was concentrated under reduced pressure to give the title compound as a brown liquid which was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:357.3[M+H]⁺。

Step 4)1- (7-amino- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To a solution of 1- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) propan-2-ol (139.2mg,0.39mmol) in DCM (3mL) was added dropwise a solution of HCl in EtOAc (3M,1.5mL,4.5 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was adjusted to pH 9 with aqueous NaOH (1M) solution and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow solid (69.5mg, 93% yield over two steps).

MS(ESI,pos.ion)m/z:193.2[M+H]⁺。

Step 5)6- (4- ((5-chloro-2- ((2- (2-hydroxypropyl) - [1,2, 4)]Triazole [1,5-a ]]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (52.5mg,0.15mmol) and 1- (7-amino- [1,2,4 mmol)]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol (37.2mg,0.19mmol) in 1, 4-dioxane (5mL) was added Pd (OAc)₂(3.3mg,0.02mmol), BINAP (9.1mg,0.02mmol) and Cs₂CO₃(97.5mg,0.30 mmol). The reaction system is heated to 95 ℃ under the protection of nitrogen and stirred for 6 hours, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as an off-white solid (58.9mg, 78%).

MS(ESI,pos.ion)m/z＝506.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:506.1956.[M+H]⁺；C₂₃H₂₅ClN₁₁O[M+H]⁺A theoretical value of 506.1932;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.89(s,1H),8.65(d,J＝7.4Hz,1H),8.31(s,1H),8.09(s,1H),7.88(d,J＝9.7Hz,1H),7.44(d,J＝9.7Hz,1H),7.28(dd,J＝7.4,2.0Hz,1H),7.15(d,J＝7.7Hz,1H),4.71(d,J＝4.6Hz,1H),4.64(d,J＝12.8Hz,2H),4.49–4.31(m,1H),4.16–4.02(m,1H),3.25(t,J＝20.3,8.1Hz,2H),2.78(ABX,J＝6.4,6.8,14.0Hz,2H),2.06(d,J＝11.6Hz,2H),1.79–1.58(m,2H),1.10(d,J＝6.1Hz,3H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)165.1,159.1,157.9,157.4,153.8,152.0,142.5,131.5,128.8,128.3,117.9,111.6,108.2,105.6,99.1,65.9,48.8,44.3,38.8,30.9,23.7。

example 576- (4- ((5-chloro-2- ((2- (2-hydroxypropyl) - [1,2, 4)]Triazolo [1,5-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (24.3mg,0.07mmol) and 1- (7-amino- [1,2, 4)]Triazolo [1,5-a]Add Pd (OAc) to a solution of pyridin-2-yl) propan-2-ol (18.5mg,0.10mmol) in 1, 4-dioxane (2mL)₂(1.9mg,0.01mmol), BINAP (4.8mg,0.01mmol) and Cs ₂CO₃(48.2mg,0.15 mmol). The reaction system is heated to 90 ℃ and stirred overnight under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a yellow solid (25.5mg, 73%).

MS(ESI,pos.ion)m/z:505.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1943[M+H]⁺,C₂₄H₂₆ClN₁₀O[M+H]⁺A theoretical value of 505.1980;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.87(s,1H),8.64(d,J＝7.3Hz,1H),8.51(s,1H),8.30(s,1H),8.07(s,1H),7.86(d,J＝8.7Hz,1H),7.27(d,J＝6.4Hz,1H),7.13(d,J＝7.5Hz,1H),7.01(d,J＝9.0Hz,1H),4.69(d,J＝4.3Hz,1H),4.55(d,J＝12.3Hz,2H),4.46–4.26(m,1H),4.17–4.00(m,1H),3.13(t,J＝12.6Hz,2H),2.78(ABX,J＝6.2,6.8,14.0Hz,2H),2.12–1.88(m,2H),1.76–1.54(m,2H),1.10(d,J＝5.9Hz,3H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)165.1,159.5,157.9,157.3,153.7,153.1,152.1,142.5,140.4,128.3,119.2,108.1,107.0,105.5,99.1,95.3,65.9,49.0,44.3,31.0,23.7。

example 58 2- (7- ((5-chloro-4- ((1- (6-cyanopyridazin-3-yl) piperidin-4-yl) amino) pyrimidin-2-yl) Amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) acetic acid ethyl ester

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (40.1mg,0.12mmol) and 2- (7-amino- [1,2, 4-mmol)]Triazolo [1,5-a]To a solution of methyl pyridin-2-yl acetate (33.1mg,0.16mmol) in 1, 4-dioxane (2mL) was added Pd (OAc)₂(1.8mg,0.008mmol), BINAP (5.6mg,0.009mmol) and Cs₂CO₃(94.1mg,0.29 mmol). The reaction system is heated to 100 ℃ and stirred overnight under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a beige solid (22.6mg, 38%).

MS(ESI,pos.ion)m/z:520.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:520.1757[M+H]⁺；C₂₃H₂₃ClN₁₁O₂[M+H]⁺A theoretical value of 520.1725;

¹H NMR(400MHz,CDCl₃+CD₃OD):(ppm)8.29(d,J＝7.3Hz,1H),8.21(s,1H),7.90(s,1H),7.43(d,J＝9.5Hz,1H),7.08(d,J＝6.7Hz,1H),6.93(d,J＝9.6Hz,1H),4.47(d,J＝12.8Hz,2H),4.36–4.31(m,1H),3.85(s,2H),3.67(s,3H),3.40(t,J＝12.3Hz,2H),2.25(d,J＝11.8Hz,2H),1.62–1.54(m,2H)；

¹³C NMR(150MHz,CDCl₃+CD₃OD):(ppm)169.8,160.4,158.5,153.0,152.4,142.1,130.8,130.0,129.0,127.7,116.9,110.3,108.6,106.3,99.9,52.5,43.6,34.8,31.4,29.8。

example 596- (4- ((5-chloro-2- ((2- (2-fluoropropan-2-yl) - [1,2, 4)]Triazolo [1,5-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile.

To 6- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2,4 ]) at-78 ℃ under nitrogen protection]Triazole [1,5-a ]]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (201.4mg,0.40mmol) in DCM (15mL) was added DAST (0.3mL,2.27mmol) dropwise. The reaction mixture was stirred at-78 ℃ under nitrogen for 1 hour, then warmed to room temperature and at 0 ℃ with saturated NaHCO₃The reaction mixture was adjusted to pH 9 with aqueous solution. The resulting mixture was extracted with DCM (50 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/55) to afford the title compound as a white solid (176mg, 87.0%).

MS(ESI,pos.ion)m/z:507.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:507.1825[M+H]⁺,C₂₄H₂₅ClFN₁₀[M+H]⁺A theoretical value of 507.1936;

¹H NMR(400MHz,CDCl₃):(ppm)8.42(d,J＝2.0Hz,1H),8.38(d,J＝7.4Hz,1H),8.30(d,J＝1.9Hz,1H),7.99(s,1H),7.62(dd,J＝9.0,2.2Hz,1H),7.31(s,1H),7.06(dd,J＝7.4,2.2Hz,1H),6.66(d,J＝9.1Hz,1H),5.25(d,J＝7.3Hz,1H),4.44(d,J＝13.6Hz,2H),4.37–4.27(m,1H),3.33–3.26(m,2H),2.25(d,J＝9.6Hz,2H),1.90(s,3H),1.85(s,3H),1.63–1.53(m,2H)；

¹³C NMR(150MHz,CDCl₃):(ppm)168.9(d,J＝23.3Hz)159.3(s),157.3(d,J＝12.1Hz),153.2(s),152.9(s),152.5(s),141.5(s),140.1(s),128.0(s),118.7(s),108.5(s),106.9(s),105.9(s),100.9(s),96.6(s),92.8(s),91.7(s),48.7(s),43.8(s),31.6(s),27.3(s),27.2(s)。

example 606- (4- ((5-chloro-2- ((1- (cyclopropylmethyl) -1H-benzo [ d)][1,2,3]Triazol-5-yl) amines Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

¹Step 1) N- (cyclopropylmethyl) -4-nitrophenyl-1, 2-diamine

To a solution of 2-fluoro-5-nitro-aniline (607.8mg,3.89mmol) and potassium carbonate (824.2mg,5.96mmol) in DMSO (10mL) was added cyclopropylmethylamine (376.4mg,5.29 mmol). The reaction mixture was stirred at 100 ℃ in a sealed tube. After completion of the reaction, the reaction mixture was cooled to room temperature, then diluted with water (80mL), and the resulting mixture was extracted with EtOAc (80 mL. times.3). The combined organic phases were washed with water (50mL × 5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/3) to give the title compound as a brown solid (640mg, 79.3%).

MS(ESI,pos.ion)m/z:208.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃):(ppm)7.81(dd,J＝8.8,1.7Hz,1H),7.62(d,J＝1.7Hz,1H),6.50(d,J＝8.8Hz,1H),4.41(s,1H),3.40(s,2H),3.07–3.05(m,2H),1.18–1.12(m,1H),0.62(q,J＝5.0Hz,2H),0.30(q,J＝4.8Hz,2H)。

Step 2)1- (cyclopropylmethyl) -5-nitro-1H-benzo [ d][1,2,3]Triazole compounds

To N¹- (Cyclopropylmethyl) -4-nitrophenyl-1, 2-diamine (580.0mg,2.80mmol) in acetic acid (C: (A))6mL) was added an aqueous solution of sodium nitrite (2M,3mL,6 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was saturated with Na₂CO₃The reaction mixture was adjusted to pH 8 with aqueous solution and then extracted with DCM (50mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5) to give the title compound as a yellow solid (520mg, 85.1%).

MS(ESI,pos.ion)m/z:219.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)8.97(d,J＝1.7Hz,1H),8.37(dd,J＝9.1,1.9Hz,1H),7.70(d,J＝9.1Hz,1H),4.58(d,J＝7.2Hz,2H),1.46–1.36(m,1H),0.70(q,J＝5.9Hz,2H),0.52(q,J＝5.3Hz,2H)。

Step 3)1- (cyclopropylmethyl) -1H-benzo [ d][1,2,3]Triazole-5-amines

To a solution of 1- (cyclopropylmethyl) -5-nitro-1H-benzo [ d ] [1,2,3] triazole (520mg,2.3830mmol) in MeOH (20mL) was added Pd/C (500mg, 10% by mass). The reaction mixture was stirred at room temperature overnight under 1 atmosphere of hydrogen, then filtered through celite, and the filter cake was rinsed with MeOH (50mL), and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/35) to afford the title compound as a red-brown solid (350mg, 78.0%).

MS(ESI,pos.ion)m/z:189.3[M+H]⁺。

Step 4)6- (4- ((5-chloro-2- ((1- (cyclopropylmethyl) -1H-benzo [ d) ][1,2,3]Triazol-5-yl) amino group Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (607.4mg,1.74mmol) and 1- (cyclopropylmethyl) -1H-benzo [ d][1,2,3]To a solution of triazole-5-amine (350mg,1.86mmol) in 1, 4-dioxane (20mL) was added Pd (OAc)₂(39.2mg,0.175mmol), BINAP (105.4mg,0.1693mmol) and Cs₂CO₃(1.134g,3.480 mmol). The reaction mixture was refluxed for 4 hours and then concentrated under reduced pressure. The resulting residue was chromatographed over a silica gel column (MeOH/DCM (v)/v) ═ 1/50) to give the title compound as a white solid (610mg, 70%).

MS(ESI,pos.ion)m/z:501.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:501.2003[M+H]⁺；C₂₅H₂₆ClN₁₀[M+H]⁺A theoretical value of 501.2030;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.52(s,1H),8.62(s,1H),8.51(d,J＝2.0Hz,1H),8.01(s,1H),7.85(dd,J＝9.1,2.2Hz,1H),7.80(d,J＝9.0Hz,1H),7.70(dd,J＝9.0,1.2Hz,1H),7.01(t,J＝8.6Hz,2H),4.58(d,J＝13.2Hz,2H),4.53(d,J＝7.1Hz,2H),4.42–4.31(m,1H),3.12(t,J＝12.5Hz,2H),2.03(d,J＝11.0Hz,2H),1.68–1.58(m,2H),1.39–1.29(m,1H),0.56–0.52(m,2H),0.47–0.45(m,2H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)158.9,158.0,156.7,153.4,152.6,146.0,139.9,137.3,128.5,121.6,118.7,110.2,106.4,105.5,103.6,94.8,51.8,48.4,43.8,30.6,11.2,3.8。

example 616- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-benzo [ d)]Imidazol-5-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- ((2-amino-4-nitrophenyl) amino) propan-2-ol

To a solution of 2-fluoro-5-nitro-aniline (408.6mg,2.62mmol) and potassium carbonate (714.4mg,5.17mmol) in DMSO (4mL) was added 1-aminopropan-2-ol (294.4mg,3.92 mmol). The reaction mixture was placed in a sealed tube and stirred at 100 ℃ overnight. The reaction mixture was cooled to room temperature and diluted with water (60mL) and then extracted with EtOAc (100 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/33) to afford the title compound as a brown solid (520mg, 94.1%).

MS(ESI,pos.ion)m/z:212.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)7.51(dd,J＝8.8,2.5Hz,1H),7.41(d,J＝2.5Hz,1H),6.50(d,J＝8.9Hz,1H),5.88(t,J＝5.3Hz,1H),5.15(s,2H),4.81(d,J＝4.7Hz,1H),3.89–3.83(m,1H),3.17–3.08(m,2H),1.13(d,J＝6.2Hz,3H)。

Step 2)1- (5-Nitro-1H-benzo [ d ]]Imidazol-1-yl) propan-2-ol

A mixture of 1- ((2-amino-4-nitrophenyl) amino) propan-2-ol (520mg,2.46mmol) and triethyl orthoformate (10mL) was refluxed and stirred for 5 hours, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 4/1) to give the title compound as a tan solid (310mg, 56.9%).

MS(ESI,pos.ion)m/z:222.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.54(d,J＝1.9Hz,1H),8.46(s,1H),8.17(dd,J＝8.9,2.0Hz,1H),7.87(d,J＝9.0Hz,1H),5.04(d,J＝4.9Hz,1H),4.34(dd,J＝14.2,3.4Hz,1H),4.15(dd,J＝14.2,7.6Hz,1H),4.04–3.95(m,1H),1.11(d,J＝6.2Hz,3H)。

Step 3)1- (5-amino-1H-benzo [ d ]]Imidazol-1-yl) propan-2-ol

To 1- (5-nitro-1H-benzo [ d ]]To a solution of imidazol-1-yl) propan-2-ol (310mg,1.4014mmol) in MeOH (20mL) was added (500mg, 10% by mass). The reaction mixture was stirred under hydrogen atmosphere for 8 hours, then filtered through a pad of celite, the filter cake was rinsed with methanol (50mL), and the filtrate was concentrated under reduced pressure. The residue obtained is subjected to flash column chromatography (7M) NH₃Purification in MeOH/DCM (v/v) ═ 1/20) gave the title compound as a white solid (130mg, 48.5%).

MS(ESI,pos.ion)m/z:192.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)7.86(s,1H),7.23(d,J＝8.5Hz,1H),6.76(d,J＝1.6Hz,1H),6.58(dd,J＝8.5,1.7Hz,1H),4.94(d,J＝4.4Hz,1H),4.69(s,2H),4.08–4.02(m,1H),3.98–3.91(m,2H),1.05(d,J＝5.6Hz,3H)。

Step 4)6- (4- ((5-chloro-2- ((1- (2-hydroxy)Cyclopropyl) -1H-benzo [ d]Imidazol-5-yl) amino) pyrimidin-4- Yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (206.0mg,0.59mmol) and 1- (5-amino-1H-benzo [ d ]]To a solution of imidazol-1-yl) propan-2-ol (130mg,0.68mmol) in 1, 4-dioxane (10mL) was added Pd (OAc) ₂(13.4mg,0.060mmol), BINAP (33.6mg,0.054mmol) and Cs₂CO₃(371.5mg,1.14 mmol). The reaction mixture was refluxed and stirred for 4 hours, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (176mg, 59.2%).

MS(ESI,pos.ion)m/z:504.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:504.2030[M+H]⁺；C₂₅H₂₇ClN₉O[M+H]⁺A theoretical value of 504.2027; .

¹H NMR(400MHz,DMSO-d₆):(ppm)9.18(s,1H),8.50(d,J＝2.1Hz,1H),8.21(s,1H),8.03(s,1H),7.94(s,1H),7.85(dd,J＝9.1,2.0Hz,1H),7.48–7.42(m,2H),7.01(d,J＝9.1Hz,1H),6.87(d,J＝7.8Hz,1H),4.96(d,J＝4.7Hz,1H),4.55(d,J＝12.5Hz,2H),4.39–4.31(m,1H),4.17–4.09(m,1H),4.05–3.93(m,2H),3.11(t,J＝12.5Hz,2H),2.00(d,J＝11.2Hz,2H),1.65–1.55(m,2H),1.07(d,J＝5.9Hz,3H)。

¹³C NMR(100MHz,DMSO-d₆):(ppm)158.9,158.2,156.7,153.4,152.6,144.6,143.5,139.9,135.2,129.7,118.7,115.6,109.9,109.1,106.4,102.7,94.7,65.0,51.4,48.3,43.8,30.6,20.9。

Example 62 6- (4- ((5-chloro-2- ((1- (2-hydroxy-2-methylpropyl) -1H-benzo [ d)][1,2,3]Triazole- 5-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)1- ((2-amino-4-nitro)Phenyl) amino) -2-methylpropan-2-ol

To a solution of 2-fluoro-5-nitroaniline (500mg,3.20mmol) and 1-nitro-2-methylpropan-2-ol (342mg,3.84mmol) in DMSO (6mL) was added potassium carbonate (660mg,4.78 mmol). The reaction mixture was stirred at 100 ℃ overnight, then cooled to room temperature and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with brine (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as a red solid (600mg, 83.2%).

MS(ESI,pos.ion)m/z:226.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)7.51(dd,J＝8.9,2.5Hz,1H),7.43(d,J＝2.6Hz,1H),6.57(d,J＝9.0Hz,1H),5.55(t,J＝5.4Hz,1H),5.18(s,2H),4.59(s,1H),3.13(d,J＝5.6Hz,2H),1.18(s,6H)。

Step 2) 2-methyl-1- (5-nitro-1H-benzo [ d ]][1,2,3]Triazol-1-yl) propan-2-ol

To 2-methyl-1- (5-nitro-1H-benzo [ d ]][1,2,3]To a solution of triazol-1-yl) propan-2-ol (350mg,1.55mmol) in AcOH (2mL) was added aqueous sodium nitrite (2M,2mL,4 mmol). The reaction mixture was stirred at room temperature overnight and then with NaHCO₃The pH was adjusted to 10 with aqueous solution, extracted with DCM (100mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

Title compound was obtained as a yellow solid (360mg, 98.1%).

MS(ESI,pos.ion)m/z:237.0[M+H]⁺。

Step 3)1- (5-amino-1H-benzo [ d ]][1,2,3]Triazol-1-yl) -2-methylpropan-2-ol

To 1- (5-amino-1H-benzo [ d ]][1,2,3]To a solution of triazol-1-yl) -2-methylpropan-2-ol (360mg,1.52mmol) in EtOH (10mL) was added Pd/C (100mg, 10% by mass). The reaction mixture was placed in an autoclave and at 2MPa H₂And stirred at room temperature for 3 hours, then filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue obtainedPurification by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) afforded the title compound as a brown solid (300mg, yield 95.4%).

MS(ESI,pos.ion)m/z:207.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)7.53(d,J＝9.3Hz,1H),6.990–6.88(m,2H),5.15(s,2H),4.77(s,1H),4.44(s,2H),1.12(s,6H)。

Step 4)6- (4- ((5-chloro-2- ((1- (2-hydroxy-2-methylpropyl) -1H-benzo [ d)][1,2,3]Triazole-5- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (103mg,0.294mmol) and 1- (5-amino-1H-benzo [ d ] ][1,2,3]Add Pd (OAc) to a solution of triazol-1-yl) -2-methylpropan-2-ol (90mg,0.436mmol) in 1, 4-dioxane (15mL)₂(6mg,0.026mmol), BINAP (17mg,0.027mmol) and Cs₂CO₃(186mg,0.570 mmol). The reaction mixture was stirred at 100 ℃ for 3 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (90mg, 58.8%).

MS(ESI,pos.ion)m/z:520.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:520.2101[M+H]⁺；C₂₄H₂₇ClN₁₁O[M+H]⁺A theoretical value of 520.2089;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.49(s,1H),8.60(s,1H),8.01(s,1H),7.88(d,J＝9.7Hz,1H),7.75(d,J＝8.9Hz,1H),7.65(d,J＝8.8Hz,1H),7.45(d,J＝9.7Hz,1H),7.00(d,J＝7.6Hz,1H),4.82(s,1H),4.67(d,J＝12.2Hz,2H),4.54(s,2H),4.46–4.32(m,1H),3.23(t,J＝12.5Hz,2H),2.08(d,J＝10.9Hz,2H),1.73–1.65(m,2H),1.14(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)158.6,158.1,156.8,153.5,145.7,137.0,131.1,129.9,128.4,121.4,117.5,111.6,111.2,105.3,103.6,70.0,58.3,48.3,43.9,30.6,27.3。

example 636- (4- ((5-chloro-2- ((1- (cyclopropyl)Methyl) -1H-benzo [ d]Imidazol-5-yl) amino) pyrimidines Pyridin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)1- (cyclopropylmethyl) -5-nitro-1H-benzo [ d]Imidazole

To a solution of 2-fluoro-5-nitroaniline (998.3mg,6.4mmol) in DMSO (20mL) was added cyclopropylmethylamine (1.1mL,13 mmol). The reaction mixture was stirred at 120 ℃ overnight, then cooled to room temperature and triethyl orthoformate (2.5mL,32.1mmol) was added. The resulting mixture was stirred at 100 ℃ overnight, then diluted with EtOAc (100mL) and the resulting mixture was washed with water (50 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/5) to give the title compound as a yellow solid (1.03g, 74% over 2 steps).

MS(ESI,pos.ion)m/z:218.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)8.70(d,J＝1.7Hz,1H),8.22(dd,J＝9.0,1.9Hz,1H),8.20(s,1H),7.48(d,J＝8.9Hz,1H),4.07(d,J＝7.0Hz,2H),1.39–1.26(m,1H),0.76(q,J＝5.6Hz,2H),0.46(q,J＝5.2Hz,2H)。

Step 2)1- (cyclopropylmethyl) -1H-benzo [ d]Imidazole-5-amines

To 1- (cyclopropylmethyl) -5-nitro-1H-benzo [ d]To a solution of imidazole (201.3mg,0.9mmol) in EtOH (15mL) was added 10% Pa/C (99.6 mg). The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a pink solid (173.5mg, 100%). MS (ESI, pos.ion) M/z 188.2[ M + H ]]⁺。

Step 3)6- (4- ((5-chloro-2- ((1- (cyclopropylmethyl) -1H-benzo [ d)]Imidazol-5-yl) amino) pyrimidin-4- Yl) amino) piperidin-1-yl) pyridOxazine-3-carbonitriles

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (150.1mg,0.4mmol) and 1- (cyclopropylmethyl) -1H-benzo [ d]Pd (OAc) was added to a solution of imidazole-5-amine (173.5mg,0.9mmol) in 1, 4-dioxane (5mL)₂(8.8mg,0.04mmol), BINAP (26.4mg,0.04mmol) and Cs₂CO₃(275.1mg,0.8 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 4 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a pink solid (189.3mg, 88%).

MS(ESI,pos.ion)m/z:501.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:501.2038[M+H]⁺,C₂₅H₂₆ClN₁₀[M+H]⁺A theoretical value of 501.2030;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.22(s,1H),8.24(s,1H),8.16(s,1H),7.96(s,1H),7.88(d,J＝9.7Hz,1H),7.58–7.38(m,3H),6.90(d,J＝7.7Hz,1H),4.66(d,J＝12.0Hz,2H),4.50–4.24(m,1H),4.06(d,J＝7.1Hz,2H),3.24(t,J＝25.4,12.9Hz,2H),2.07(d,J＝10.8Hz,2H),1.81–1.50(m,2H),1.26–1.21(m,1H),0.65–0.47(m,2H),0.43–0.26(m,2H)。

¹³C NMR(100MHz,DMSO-d₆):(ppm)158.6,158.2,156.7,153.4,143.7,135.3,131.0,129.3,128.3,117.4,115.8,111.1,109.7,109.2,102.8,48.4,48.1,43.8,30.5,11.3,3.8。

example 646- (4- ((5-chloro-2- ((1- (2-hydroxy-2-methylpropyl) -1H-benzo [ d)]Imidazol-5-yl) amine Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 2-methyl-1- (5-nitro-1H-benzo [ d ]]Imidazol-1-yl) propan-2-ol

To a solution of 2-fluoro-5-nitroaniline (305.0mg,2.0mmol) in DMSO (3mL) was added 1-amino-2-methylpropan-2-ol (271.0mg,3.0 mmol). The reaction mixture was stirred at 120 ℃ overnight, then cooled to room temperature and triethyl orthoformate (1.1mL,10.0mmol) was added. The resulting mixture was stirred at 100 ℃ overnight, then diluted with EtOAc (100mL) and the resulting mixture was washed with water (50 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 2/1) to give the title compound as a yellow solid (435.7mg, 95% yield over two steps).

MS(ESI,pos.ion)m/z:236.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)8.55(d,J＝1.9Hz,1H),8.18(dd,J＝9.0,2.0Hz,1H),8.10(s,1H),7.51(d,J＝9.0Hz,1H),4.17(s,2H),1.33(s,6H)。

Step 2)1- (5-amino-1H-benzo [ d ]]Imidazol-1-yl) -2-methylpropan-2-ol

To a solution of 2-methyl-1- (5-nitro-1H-benzo [ d ] imidazol-1-yl) propan-2-ol (424.3mg,1.8mmol) in EtOH (25mL) was added Pa/C (99.6mg, 10% by mass). The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as an orange solid (251.8mg, 68%).

MS(ESI,pos.ion)m/z:206.0[M+H]⁺。

Step 3)6- (4- ((5-chloro-2- ((1- (2-hydroxy-2-methylpropyl) -1H-benzo [ d)]Imidazol-5-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (139.6mg,0.4mmol) and 1- (5-amino-1H-benzo [ d ] b]Add Pd (OAc) to a solution of imidazol-1-yl) -2-methylpropan-2-ol (110.1mg,0.5mmol) in 1, 4-dioxane (5mL)₂(9.2mg,0.04mmol), BINAP (25.1mg,0.04mmol) and Cs₂CO₃(263.0mg,0.8 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 4 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compoundThe title compound was a white solid (86.7mg, 42%).

MS(ESI,pos.ion)m/z:518.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:518.2190[M+H]⁺；C₂₆H₂₉ClN₉O[M+H]⁺A theoretical value of 501.2184;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.17(s,1H),8.51(d,J＝2.0Hz,1H),8.20(s,1H),8.01(s,1H),7.94(s,1H),7.85(dd,J＝9.1,2.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.43(dd,J＝8.8,1.3Hz,1H),7.01(d,J＝9.1Hz,1H),6.87(d,J＝7.8Hz,1H),4.76(s,1H),4.56(d,J＝12.9Hz,2H),4.40–4.27(m,1H),4.09(s,2H),3.11(t,J＝12.5Hz,2H),2.01(d,J＝10.7Hz,2H),1.65–1.56(m,2H),1.10(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)159.4,158.7,157.2,153.9,153.1,145.6,143.6,140.5,135.5,130.8,119.3,116.2,111.0,109.4,106.9,95.2,70.1,55.1,44.3,31.1,27.7。

example 656- (4- ((5-chloro-2- ((1-propyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) amino) pyrimidines- 4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

¹Step 1) 4-Nitro-N-propylbenzene-1, 2-diamine

To 2-fluoro-5-nitroaniline (1.00g,6.44mmol) and K₂CO₃To a solution of (1.76g,12.72mmol) in DMSO (10mL) was added propan-1-amine (0.8mL,10 mmol). The reaction mixture was stirred at 80 ℃ overnight and then concentrated under reduced pressure. The resulting residue was diluted with water (40mL) and extracted with EtOAc (100 mL. times.3). The organic phase was washed with water (10 mL. times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc/PE (v/v) ═ 1/4) to afford the title compound as a red solid (1.02g, 81.4%).

MS(ESI,pos.ion)m/z:196.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)7.83(dd,J＝8.9,2.4Hz,1H),7.62(d,J＝2.4Hz,1H),6.54(d,J＝8.9Hz,1H),4.32(s,1H),3.34(s,2H),3.19(s,2H),1.78–1.67(m,2H),1.04(t,J＝7.4Hz,3H)。

Step 2) 5-Nitro-1-propyl-1H-benzo [ d][1,2,3]Triazole compounds

To 4-nitro-N¹To a solution of (1.02g,5.24mmol) of (1.02 g) propylbenzene-1, 2-diamine in acetic acid (20mL) was added NaNO₂Aqueous solution (5.2mL,10.4 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was saturated with Na₂CO₃The pH was adjusted to 8 with aqueous solution, followed by extraction with EtOAc (150mL × 2), and the combined organic phases were washed with brine (5mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc/PE (v/v) ═ 1/10) to give the title compound as a red oil (773.0mg, 71.6%).

MS(ESI,pos.ion)m/z:207.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)8.99(d,J＝1.7Hz,1H),8.38(dd,J＝9.1,1.9Hz,1H),7.65(d,J＝9.1Hz,1H),4.67(t,J＝7.1Hz,2H),2.13–2.02(m,2H),0.99(t,J＝7.4Hz,3H)。

Step 3) 1-propyl-1H-benzo [ d][1,2,3]Triazole-5-amines

To 5-nitro-1-propyl-1H-benzo [ d][1,2,3]To a solution of triazole (773.0mg,3.75mmol) in MeOH (10mL) was added Pd/C (151.8mg, 10% by mass). Reaction mixture at 2MPa H₂The reaction kettle was stirred at room temperature overnight, then filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/15) to afford the title compound as a red solid (409.4mg, 62.0%).

MS(ESI,pos.ion)m/z:177.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):7.31(d,J＝8.7Hz,1H),7.19(d,J＝1.5Hz,1H),6.92(dd,J＝8.7,1.9Hz,1H),4.51(t,J＝7.1Hz,2H),3.82(s,2H),2.05–1.96(m,2H),0.95(t,J＝7.4Hz,3H)。

Step 4)6- (4- ((5-chloro-2- ((1-propyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) amino) pyrimidin-4- Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (783.2mg,2.24mmol) and 1-propyl-1H-benzo [ d ]][1,2,3]Add Pd (OAc) to a solution of triazole-5-amine (395.2mg,2.24mmol) in 1, 4-dioxane (20mL)₂(51.5mg,0.23mmol), BINAP (140.3mg,0.22mmol) and Cs₂CO₃(1.47g,4.52 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM ═ 1/20) to afford the title compound as a beige solid (232.4mg, 21.2%).

MS(ESI,pos.ion)m/z:490.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:490.1982[M+H]⁺；C₂₃H₂₅ClN₁₁[M+H]⁺A theoretical value of 490.1983;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.52(s,1H),8.62(s,1H),8.01(s,1H),7.88(d,J＝9.7Hz,1H),7.77(d,J＝8.9Hz,1H),7.70(d,J＝9.0Hz,1H),7.45(d,J＝9.7Hz,1H),7.00(d,J＝7.7Hz,1H),4.67(d,J＝12.1Hz,2H),4.60(t,J＝6.8Hz,2H),4.46–4.34(m,1H),3.22(t,J＝12.5Hz,2H),2.08(d,J＝8.5Hz,2H),1.96–1.87(m,2H),1.73–1.64(m,2H),0.85(t,J＝7.3Hz,3H)。

¹³C NMR(150MHz,DMSO-d₆):(ppm)158.6,158.0,156.8,153.5,145.9,137.3,131.1,128.7,128.4,121.6,117.5,111.2,110.1,105.5,103.6,49.0,48.3,43.9,30.5,22.7,11.0。

example 666- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) imidazo [1, 2-a)]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidine-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (100mg,0.286mmol) and 2- (7-aminoimidazo [1,2-a ]]Add Pd (OAc) to a solution of pyridin-3-yl) propan-2-ol (110mg,0.575mmol) in 1, 4-dioxane (20mL)₂(6mg,0.026mmol), BINAP (17mg,0.027mmol) and Cs₂CO₃(186mg,0.570 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/40) to afford the title compound as a white solid (60mg, 41.6%).

MS(ESI,pos.ion)m/z:505.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1986[M+H]⁺；C₂₄H₂₆ClN₁₀O[M+H]⁺A theoretical value of 505.1980;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.65(s,1H),8.58(d,J＝7.5Hz,1H),8.25(s,1H),8.05(s,1H),7.87(d,J＝9.7Hz,1H),7.44(d,J＝9.7Hz,1H),7.25(s,1H),7.11(d,J＝7.6Hz,1H),7.08(d,J＝7.9Hz,1H),5.32(s,1H),4.64(d,J＝12.4Hz,2H),4.48–4.32(m,1H),3.24(t,J＝12.5Hz,2H),2.07(d,J＝11.6Hz,2H),1.73–1.63(m,2H),1.59(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)174.4,158.6,157.6,156.9,153.4,145.8,131.1,130.0,129.7,128.4,126.9,117.5,111.2,107.6,104.6,66.9,48.3,43.8,30.5,29.1。

example 676- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) - [1,2, 4)]Triazolo [1,5-a]Pyridine (II) Pyridin-6-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) (2,4, 6-trimethylphenylxanthyl) oxycarboxylic acid tert-butyl ester

To a solution of 2,4, 6-trimethylphenyl-1-sulfonyl chloride (9.91g,45.3mmol) and tert-butyl hydroxycarbamate (6.10g,45.8mmol) in EtOAc (60mL) at-10 deg.C was added triethylamine (7.8mL,56mmol) dropwise. After the addition was complete, the reaction mixture was warmed to 0 ℃ and stirred for 2 hours, then quenched with water (30mL) and allowed to settle into layers. The separated organic layer was washed with water (30 mL. times.2), and then concentrated under reduced pressure. The residue was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:338.1[M+Na]⁺。

Step 2) O- (2,4, 6-trimethylphenyl-xanthoyl) hydroxylamine

To a solution of tert-butyl (2,4, 6-trimethylphenylsulfonyl) oxycarbamate (14.30g,45.3mmol) in EtOAc (60mL) was added concentrated sulfuric acid (4.5mL,83.0mmol) dropwise. After the addition was complete, the reaction mixture was warmed to 0 ℃ and stirred overnight, then quenched with saturated aqueous sodium carbonate solution and allowed to stand for separation. The separated organic layer was washed with water (60 mL. times.3), and then concentrated under reduced pressure. The residue was used in the next reaction without purification.

Step 3)1, 2-diamino-5-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate

To a solution of O- (2,4, 6-trimethylphenylsulfonyl) hydroxylamine (9.75g,45.3mmol) in EtOAc (60mL) at 5 deg.C was added 5-bromopyridin-2-amine (4.05g,23.4 mmol). The mixture was stirred at 0 ℃ for 1 h, then filtered, and the filter cake was washed with EtOAc (20 mL. times.3) and then dried under reduced pressure to give the title compound as a white solid (5.25g, 58% yield from three steps).

MS(ESI,pos.ion)m/z:188.1[M₁]⁺；

MS(ESI,neg.ion)m/z:199.1[M₂]^-。

Step 4) 3-hydroxy-3-methylbutyrate ethyl ester

To LiHMDS (1mol/L in THF,20mL,20mmol) was added EtOAc (2mL,20.5mmol) dropwise at-78 ℃. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Acetone (1.8mL,24mmol) was then added dropwise. After the addition was complete, the reaction mixture was allowed to continue and stirred for 0.5 h, then quenched with aqueous hydrochloric acid (2M,15mL,30mmol) and extracted with EtOAc (30 mL. times.2). The combined organic phases were washed with saturated NaHCO₃Washed with aqueous solution (15mL), dried over anhydrous sodium sulfate, and filteredFiltration and concentration under reduced pressure gave the title compound as a yellow oil (2.99g, 100%).

¹H NMR(400MHz,CDCl₃):(ppm)4.18–4.04(m,2H),3.66(s,1H),2.43(s,2H),1.27–1.14(m,9H)。

Step 5)1- (6-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol

To a solution of 1, 2-diamino-5-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (2.01g,5.2mmol) in methanol (20mL) was added ethyl 3-hydroxy-3-methylbutyrate (1.50g,10.3mmol) and NaOH (212.3mg,5.3 mmol). The reaction mixture was stirred at 70 ℃ overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a white solid (719.0mg, 51%).

MS(ESI,pos.ion)m/z:270.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)8.67(s,1H),7.57(s,2H),4.10(s,1H),3.06(s,2H),1.27(s,6H)。

Step 6)1- (6- ((diphenylmethylene) amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) -2-methyl Propan-2-ol

To 1- (6-bromo- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol (400.1mg,1.5mmol) and benzophenone imine (352.1mg,1.9mmol) in 1, 4-dioxane (10mL) was added Pd₂(dba)₃(136.0mg,0.15mmol), BINAP (92.3mg,0.15mmol) and Cs₂CO₃(963.5mg,3.0 mmol). The reaction system is heated to 100 ℃ and stirred overnight under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was diluted with DCM (100mL) and the resulting mixture was washed with water (30 mL. times.2). The organic phase was concentrated under reduced pressure to give the title compound as a brown oil which was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:371.2[M+H]⁺。

Step 7)1- (6-amino- [1,2,4]]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol

To 1- (6- ((diphenylmethylene) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -2-methylpropan-2-ol (548.6mg,1.5mmol) in DCM (10mL) was added a solution of hydrogen chloride in EtOAc (3M,2.5mL,7.5 mmol). The reaction system was stirred at room temperature for 1 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure, adjusted to pH 9 with an aqueous NaOH solution (1M), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow solid (288.2mg, 94% yield over two steps).

MS(ESI,pos.ion)m/z:207.2[M+H]⁺。

Step 8)6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) - [1,2, 4)]Triazolo [1,5-a]Pyridine- 6-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (148.6mg,0.4mmol) and 1- (6-amino- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol (117.0mg,0.6mmol) in 1, 4-dioxane (4mL) was added Pd (OAc)₂(10.3mg,0.04mmol), BINAP (26.3mg,0.04mmol) and Cs₂CO₃(280.4mg,0.9 mmol). The reaction system is heated to 100 ℃ under the protection of nitrogen and stirred overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as an off-white solid (182.4mg, 83%).

MS(ESI,pos.ion)m/z:519.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2141[M+H]⁺；C₂₅H₂₈ClN₁₀O[M+H]⁺A theoretical value of 519.2136;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.60(s,1H),9.56(s,1H),8.51(d,J＝1.7Hz,1H),8.03(s,1H),7.86(dd,J＝9.0,2.0Hz,1H),7.71–7.65(m,2H),7.09(d,J＝7.6Hz,1H),6.99(d,J＝9.1Hz,1H),4.560–4.54(m,3H),4.40–4.26(m,1H),3.11(t,J＝12.4Hz,2H),2.86(s,2H),2.01(d,J＝10.7Hz,2H),1.70–1.56(m,2H),1.14(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)164.1,159.5,158.0,157.3,153.8,153.0,146.9,140.4,129.9,125.7,119.2,116.9,115.1,106.9,95.3,69.7,55.3,44.3,43.1,31.0,29.7。

example 686- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) imidazo [1, 2-a)]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) Potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-ol

To a solution of ethyl 2-chloroacetate (10.0g,81.6mmol) and ethyl formate (6.65g,89.8mmol) in THF (100mL) at 0 deg.C under nitrogen was slowly added potassium tert-butoxide (1M,90mL,90 mmol). After addition was complete, the reaction mixture was stirred at room temperature for 24 hours, then filtered, and the filter cake was rinsed with THF (50mL) and dried in vacuo to afford the title compound as a yellow solid (13.0g, 84.5%).

1H NMR(400MHz,DMSO-d₆):(ppm)8.90(s,1H),3.96–3.91(m 2H),1.12(t,J＝7.0Hz,3H)。

Step 2) 7-Bromoimidazo [1,2-a]Pyridine-3-carboxylic acid ethyl ester

To a solution of potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (13.0g,68.9mmol) and 4-bromopyridin-2-amine (3.00g,17.3mmol) in ethanol (60mL) was added concentrated H₂SO₄(2 mL). The reaction mixture was stirred at 90 ℃ for 18 hours and then concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃The aqueous solution was pH 10, then extracted with EtOAc (200mL × 3). The combined organic phases were washed with brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/4) to afford the title compound as a white solid (4.6g, 99%).

MS(ESI,pos.ion)m/z:269.1[M+H]⁺；

1H NMR(400MHz,CDCl₃):(ppm)9.17(d,J＝7.3Hz,1H),8.26(s,1H),7.92(d,J＝1.1Hz,1H),7.14(dd,J＝7.3,1.6Hz,1H),4.41(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H)。

Step 3)2- (7-Bromoimidazo [1,2-a ]]Pyridin-3-yl) propan-2-ol

To ethyl 7-bromoimidazo [1,2-a ] pyridine-3-carboxylate (830.0mg,3.07mmol) in THF (20mL) at-78 ℃, methyl magnesium bromide (3M in tetrahydrofuran) was added dropwise after addition, the reaction mixture was warmed to 0 ℃ and stirred overnight, then the reaction was quenched with water (50mL) and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to afford the title compound as a yellow solid (900mg, 47.5%).

MS(ESI,pos.ion)m/z:255.0[M+H]⁺；

1H NMR(400MHz,CDCl₃):(ppm)8.55(d,J＝7.4Hz,1H),7.71(d,J＝1.2Hz,1H),7.31(s,1H),6.88(dd,J＝7.4,1.8Hz,1H),1.74(s,6H)。

Step 4)2- (7- ((diphenylmethylene) amino) imidazo [1,2-a ]Pyridin-3-yl) propan-2-ol

To 2- (7-bromoimidazo [1,2-a ]]To a solution of pyridin-3-yl) propan-2-ol (1.70g,6.70mmol) and benzophenone imine (1.41g,7.78mmol) in 1, 4-dioxane (50mL) was added Pd₂(dba)₃(610mg,0.666mmol), BINAP (410mg,0.658mmol) and Cs₂CO₃(4.31g,13.2 mmol). The reaction system is heated to 100 ℃ and stirred overnight under the protection of nitrogen, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a yellow solid (1.70g, 72.0%).

MS(ESI,pos.ion)m/z:356.1[M+H]⁺。

Step 5)2- (7-Aminoimidazo [1, 2-a)]Pyridin-3-yl) propan-2-ol

To 2- (7- ((diphenylmethylene) amino) imidazo [1,2-a]To a solution of pyridin-3-yl) propan-2-ol (900mg,2.53mmol) in 1, 4-dioxane (20mL) was added an aqueous solution of hydrochloric acid (4M,7mL,28 mmol). The reaction system is stirred for 1 hour at room temperature, after the reaction is finished, the reaction system is decompressed and concentrated, and the residue is NaHCO₃The aqueous solution (1M) was adjusted to pH 8 and then concentrated under reduced pressure. The resulting residue was chromatographed over a silica gel column ((MeOH (7M NH)₃) Purification of/DCM (v/v) ═ 1/1) to give the title compoundThe compound was a brown solid (280mg, 57.8%)

MS(ESI,pos.ion)m/z:192.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.35(d,J＝7.3Hz,1H),6.94(s,1H),6.36(dd,J＝7.5,1.8Hz,1H),6.32(s,1H),5.52(s,2H),4.46(s,1H),1.54(s,6H)。

Step 6)6- (4- ((5-chloro-2- ((3- (2-hydroxypropan-2-yl) imidazo [1, 2-a)]Pyridin-7-yl) amino group) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (80mg,0.229mmol) and 2- (7-aminoimidazo [1,2-a ]]Add Pd (OAc) to a solution of pyridin-3-yl) propan-2-ol (92mg,0.481mmol) in 1, 4-dioxane (10mL)₂(5mg,0.022mmol), BINAP (14mg,0.022mmol) and Cs₂CO₃(150mg,0.460 mmol). The reaction system is heated to 100 ℃ under the protection of nitrogen and stirred for 2 hours, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (70mg, 60.6%).

MS(ESI,pos.ion)m/z:504.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:504.2061[M+H]⁺；C₂₅H₂₇ClN₉O[M+H]⁺A theoretical value of 504.2027;

¹H NMR(600MHz,DMSO-d₆):(ppm)9.59(s,1H),8.55(d,J＝7.5Hz,1H),8.50(d,J＝2.0Hz,1H),8.23(s,1H),8.03(s,1H),7.85(dd,J＝9.1,2.1Hz,1H),7.20(s,1H),7.09–7.04(m,2H),7.00(d,J＝9.1Hz,1H),5.31(s,1H),4.55(d,J＝11.9Hz,2H),4.39–4.32(m,1H),3.15(t,J＝12.6Hz,2H),2.02(d,J＝11.5Hz,2H),1.66–1.60(m,2H),1.58(s,6H)；

¹³C NMR(101MHz,DMSO-d₆)(ppm):158.9,157.7,156.8,153.3,152.6,146.3,139.4,137.1,129.7,128.2,126.5,118.8,107.1,106.4,104.3,100.7,94.8,66.9,48.5,43.8,30.5,29.1。

example 696- (4- ((5-chloro-2- ((1- (2-hydroxy-2-methylpropyl) -1H-benzo [ d)][1,2,3]Triazole- 5-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- - (((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (100mg,0.286mmol) and 1- (5-amino-1H-benzo [ d ]][1,2,3]Add Pd (OAc) to a solution of triazol-1-yl) -2-methylpropan-2-ol (90mg,0.436mmol) in 1, 4-dioxane (6mL)₂(6mg,0.026mmol), BINAP (17mg,0.027mmol) and Cs₂CO₃(186mg,0.570 mmol). The reaction mixture was stirred at 100 ℃ for 3 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (80mg, 53.8%).

MS(ESI,pos.ion)m/z:519.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2140[M+H]⁺；C₂₅H₂₈ClN₁₀O[M+H]⁺A theoretical value of 519.2136;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.48(s,1H),8.59(s,1H),8.50(s,1H),8.00(s,1H),7.85(dd,J＝9.3,1.6Hz,1H),7.74(d,J＝9.0Hz,1H),7.65(d,J＝8.9Hz,1H),7.01(d,J＝9.2Hz,1H),6.98(d,J＝7.9Hz,1H),4.80(s,1H),4.58(d,J＝12.8Hz,2H),4.53(s,2H),4.44–4.29(m,1H),3.12(t,J＝12.5Hz,2H),2.03(d,J＝12.6Hz,2H),1.67–1.58(m,2H),1.14(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)158.9,158.1,156.8,153.5,152.7,145.7,140.0,137.1,129.9,121.4,118.8,111.6,106.5,105.2,103.5,94.8,70.0,58.3,48.5,43.9,30.7,27.3.

example 706- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) imidazo [1, 2-a)]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 7-Bromoimidazo [1,2-a ]]Pyridine-2-carboxylic acid ethyl ester

To a solution of 4-bromopyridin-2-amine (5.00g,28.9mmol) in EtOH (50mL) was added ethyl 3-bromo-2-oxopropanoate (12.02g,61.6 mmol). The reaction mixture was refluxed and stirred for 8 hours, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a light yellow solid (7.02g, 90%).

MS(ESI,pos,ion):269.1[M+H]⁺。

Step 2)7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridine-2-carboxylic acid ethyl ester

To 7-bromoimidazo [1,2-a ]]To a solution of pyridine-2-carboxylic acid ethyl ester (8.0g,30.0mmol) and benzophenone imine (8.10g,45.0mmol) in 1, 4-dioxane (100mL) was added Pd₂(dba)₃(2.76g,3.0mmol), BINAP (1.84g,3.0mmol) and Cs₂CO₃(19.60g,60.3 mmol). The reaction was refluxed and stirred under nitrogen for 6 hours, then cooled to room temperature and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as a light yellow solid (5.20g, 47%).

MS(ESI,pos,ion):370.2[M+H]⁺。

Step 3) 7-Aminoimidazo [1,2-a ]Pyridine-2-carboxylic acid ethyl ester

To ethyl 7- ((diphenylmethylene) amino) imidazo [1,2-a ] pyridine-2-carboxylate (5.03g,13.6mmol) in DCM (20mL) is added a solution of hydrogen chloride in EtOAc (3M,50mL,150 mmol). The reaction system was stirred at room temperature for 2 hours, after completion of the reaction, concentrated under reduced pressure, and the resulting residue was adjusted to pH 9 with aqueous NaOH (1M), followed by extraction with EtOAc (100mL × 4). The combined organic phases were washed with brine (100mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a light yellow solid (2.10g, 75%).

MS(ESI,pos,ion):206.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.16(d,J＝7.4Hz,1H),8.14(s,1H),6.47(d,J＝7.2Hz,1H),6.33(s,1H),5.84(s,2H),4.24(q,J＝7.0Hz,2H),1.28(t,J＝7.1Hz,3H)。

Step 4)2- (7-aminoimidazo [1, 2-a)]Pyridin-2-yl) propan-2-ol

In N₂Protection and reaction at-78 deg.C to 7-aminoimidazo [1,2-a]Ethyl pyridine-2-carboxylate (2.10g,10.2mmol) in THF (50mL) was added dropwise methyl magnesium bromide (2.0M in THF, 55mL,110 mmol). After the addition was complete, the reaction mixture was moved to 0 ℃ and stirred for 5 hours. After the reaction was complete, the reaction was quenched by addition of water (30mL) and the resulting mixture was extracted with EtOAc (60 mL. times.4). The combined organic phases were washed with brine (40mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a light yellow solid (200.5mg, 10%).

MS(ESI,pos,ion):192.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.31(d,J＝7.3Hz,1H),7.63(s,1H),7.04(s,2H),6.75(dd,J＝7.3,1.9Hz,1H),6.55(d,J＝1.2Hz,1H),1.51(s,6H)。

Step 5)6- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) imidazo [1, 2-a)]Pyridin-7-yl) amino group) Pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 2- (7-aminoimidazo [1,2-a ]]Pyridin-2-yl) propan-2-ol (90.0mg,0.47mmol) and 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (81.2mg,0.23mmol) in 1, 4-dioxane (10mL) was added Pd (OAc)₂(23.4mg,0.10mmol), BINAP (60.1mg,0.10mmol) and Cs₂CO₃(312.0mg,0.96 mmol). The reaction mixture was refluxed and stirred for 4 hours, then cooled to room temperature and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (40 mL. times.4). The combined organic phases were washed with brine (40mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a white solid (62.5mg, 26%)。

MS(ESI,pos,ion):504.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:504.2024[M+H]⁺；C₂₅H₂₇ClN₉O[M+H]⁺A theoretical value of 504.2027;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.51(s,1H),8.50(s,1H),8.30(d,J＝7.3Hz,1H),8.11(s,1H),8.02(s,1H),7.85(dd,J＝9.1,1.8Hz,1H),7.49(s,1H),7.08–7.02(m,2H),7.00(d,J＝9.3Hz,1H),4.84(s,1H),4.54(d,J＝13.5Hz,2H),4.42–4.29(m,1H),3.16(t,J＝12.5Hz,2H),2.01(d,J＝14.3Hz,2H),1.67–1.57(m,2H),1.42(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)174.8,159.5,158.2,157.2,153.7,153.1,140.4,130.1,126.7,119.3,107.6,107.0,106.6,95.2,69.2,56.5,44.3,31.1,31.0。

example 716- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) imidazo [1, 2-a)]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 2- (7-aminoimidazo [1,2-a ]]Pyridin-2-yl) propan-2-ol (45.0mg,0.24mmol)6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (42.0mg,0.12mmol) in 1, 4-dioxane (2mL) was added Pd (OAc) ₂(10.4mg,0.046mmol), BINAP (29.2mg,0.047mmol) and Cs₂CO₃(160.2mg,0.49 mmol). The reaction mixture was refluxed and stirred for 5 hours, then cooled to room temperature and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (30 mL. times.4). The combined organic phases were washed with brine (30mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a white solid (36.8mg, 31%).

MS(ESI,pos,ion):505.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:505.1976[M+H]⁺；C₂₄H₂₆ClN₁₀O[M+H]⁺A theoretical value of 505.1980;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.90(s,1H),8.46(d,J＝5.3Hz,1H),8.24(s,1H),8.07(s,1H),7.87(d,J＝9.6Hz,1H),7.66(s,1H),7.43(d,J＝9.7Hz,1H),7.29(s,1H),7.09(d,J＝7.6Hz,1H),5.27(s,1H),4.59(d,J＝12.7Hz,2H),4.50–4.34(m,1H),3.37(s,2H),2.04(d,J＝12.8Hz,2H),1.71–1.63(m,2H),1.47(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)174.9,167.4,159.1,157.9,157.4,153.6,131.6,131.2,130.1,123.0,128.7,118.0,111.6,68.4,48.5,44.1,30.8,30.8。

example 726- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) imidazo [1, 2-b)]Pyridazin-7-yl radicals Amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- (7-Aminoimidazo [1, 2-b)]Pyridazin-2-yl) -2-methylpropan-2-ol

To a solution of pyridazine-3, 5-diamine (500mg,4.54mmol) in ethanol (20mL) was added 1-bromo-4-hydroxy-4-methylpentan-2-one (1.75g,8.97 mmol). The reaction mixture was stirred at 80 ℃ for 6 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a yellow solid (520mg, 55.5%).

MS(ESI,pos.ion)m/z:207.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.41(d,J＝2.5Hz,1H),7.91(s,1H),7.18(s,2H),6.94(d,J＝2.3Hz,1H),4.81(s,1H),2.76(s,2H),1.16(s,6H)。

Step 2)6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) imidazo [1, 2-b)]Pyridazin-7-yl) amines Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (100mg,0.286mmol) and 1- (7-aminoimidazo [1,2-b ]]Pyridazin-2-yl) -2-methylpropan-2-ol (90mg,0.429mmol) in 1, 4-dioxane (10mL) Pd (OAc) was added₂(6mg,0.026mmol), BINAP (17mg,0.027mmol) and Cs₂CO₃(186mg,0.570 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (60mg, 40.4%).

MS(ESI,pos.ion)m/z:519.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2136[M+H]⁺；C₂₅H₂₈ClN₁₀O[M+H]⁺A theoretical value of 519.2136;

¹H NMR(400MHz,DMSO-d₆):(ppm):9.81(s,1H),8.58(d,J＝2.4Hz,1H),8.50(t,J＝2.3Hz,2H),8.06(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.81(s,1H),7.13(d,J＝7.8Hz,1H),6.99(d,J＝9.1Hz,1H),4.67(s,1H),4.55(d,J＝12.8Hz,2H),4.37–4.28(m,1H),3.09(t,J＝12.3Hz,2H),2.73(s,2H),2.00(d,J＝10.4Hz,2H),1.68–1.58(m,2H),1.09(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)159.4,158.0,157.3,153.8,153.0,144.5,140.4,139.0,132.0,119.2,113.5,107.3,107.0,105.4,95.3,70.0,49.0,44.3,42.9,31.0,29.8。

example 736- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl l) imidazo [1, 2-a)]Pyridine-6- Yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1)1- (6-Bromoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol

To a solution of 5-bromopyridin-2-amine (1.91g,11.0mmol) in ethanol (20mL) was added 1-bromo-4-hydroxy-4-methylpentan-2-one (2.17g,11.1 mmol). Refluxing of the reaction mixtureAnd stirred overnight, then concentrated under reduced pressure. To the concentrated residue was added water (30 mL). The residue was saturated with Na₂CO₃The aqueous solution had pH 8, and was then extracted with DCM (100mL × 2). The combined organic phases were washed with water (5mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc/PE (v/v) ═ 1/10) to afford the title compound as a yellow solid (1.44g, 48.1%).

MS(ESI,pos.ion)m/z:269.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)8.22(dd,J＝1.7,0.7Hz,1H),7.43(d,J＝9.5Hz,1H),7.37(s,1H),7.22(dd,J＝9.5,1.8Hz,1H),4.54(s,1H),2.88(s,2H),1.23(s,6H)。

Step 2)1- (6- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-2-yl) -2-methylpropan-2-ol

To 1- (6-bromoimidazo [1,2-a ]]To a solution of pyridin-2-yl) -2-methylpropan-2-ol (1.44g,5.35mmol) and benzophenone imine (1.1mL,6.60mmol) in 1, 4-dioxane (20mL) was added Pd₂(dba)₃(473.6mg,0.52mmol), BINAP (319.7mg,0.51mmol) and Cs₂CO₃(3.42g,10.50 mmol). The reaction mixture was stirred at 100 ℃ for 2 hours, then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EtOAc/PE (v/v) ═ 1/10) to give the title compound as a red solid (717.4mg, 36.3%).

MS(ESI,pos.ion)m/z:369.8[M+H]⁺。

Step 3)1- (6-Aminoimidazo [1, 2-a)]Pyridin-2-yl) -2-methylpropan-2-ol

To 1- (6- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-2-yl) -2-methylpropan-2-ol (700.0mg,1.89mmol) in DCM (15mL) was added dropwise HCl in EtOAc (3M,0.9mL,2.70 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was diluted with water (30mL) and then Na₂CO₃The pH was adjusted to 8 with aqueous solution, and the resulting mixture was extracted with DCM (200mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtainedPurification by flash column chromatography (MeOH/DCM (v/v) ═ 1/20) afforded the title compound as a black solid (94.5mg, 24.3%).

MS(ESI,pos.ion)m/z:206.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)7.53(d,J＝1.5Hz,1H),7.36(d,J＝9.4Hz,1H),7.22(s,1H),6.76(dd,J＝9.4,2.1Hz,1H),4.78(s,1H),3.41(s,2H),2.83(s,2H),1.22(s,6H)。

Step 4)6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl l) imidazo [1, 2-a)]Pyridin-6-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (117.8mg,0.34mmol) and 1- (6-aminoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol (94.0mg,0.46mmol) in 1, 4-dioxane (15mL) was added Pd (OAc)₂(10.1mg,0.045mmol), BINAP (23.1mg,0.037mmol) and Cs₂CO₃(220.0mg,0.68 mmol). The reaction mixture was stirred at 100 ℃ for 1.5 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a beige solid (147.2mg, 84.2%).

MS(ESI,pos.ion)m/z:518.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:518.2193[M+H]⁺；C₂₆H₂₉ClN₉O[M+H]⁺A theoretical value of 518.2184;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.55(s,1H),9.25(s,1H),8.49(d,J＝2.1Hz,1H),8.01(s,1H),7.92(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.71–7.64(m,2H),7.00(d,J＝3.6Hz,1H),6.98(d,J＝4.9Hz,1H),4.80(s,1H),4.51(d,J＝12.9Hz,2H),4.40–4.31(m,1H),3.05(t,J＝12.2Hz,2H),2.81(s,2H),1.96(d,J＝10.7Hz,2H),1.67–1.57(m,2H),1.13(s,6H)；

¹³C NMR(151MHz,DMSO-d₆):(ppm)158.9,157.6,156.9,153.1,152.6,140.0,137.8,130.0,124.9,118.8,115.2,113.2,112.9,106.5,104.5,94.8,69.1,48.0,43.8,40.2,30.5,29.2。

example 746- (4- ((5-chloro-2- ((3- (2-hydroxy-2-methylpropyl) - [1,2, 4)]Triazolo [4,3-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 3-hydroxy-3-methylbutyric acid

To a solution of ethyl 3-hydroxy-3-methylbutyrate (1.56g,10.7mmol) in water (20mL) was added sodium hydroxide (851.0mg,21.3 mmol). The reaction mixture was stirred at room temperature overnight, then adjusted to pH 5 with hydrochloric acid and extracted with EtOAc (50mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Title compound was obtained as a yellow oil (1.17g, 93%).

Step 2) N' - (4-bromopyridin-2-yl) -3-hydroxy-3-methylbutanoic acid hydrazine

To a solution of 3-hydroxy-3-methylbutyric acid (1.17g,9.9mmol) and 4-bromo-2-hydrazinopyridine (1.44g,7.7mmol) in THF (20mL) were added triethylamine (2.8mL,20.0mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (4.62g,12.2 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (1.66g, 75%).

MS(ESI,pos.ion)m/z:288.0[M+H]⁺。

Step 3)1- (7-bromo- [1,2, 4)]Triazolo [4,3-a]Pyridin-3-yl) -2-methylpropan-2-ol

A mixture of N' - (4-bromopyridin-2-yl) -3-hydroxy-3-methylbutanohydrazide (1.66g,5.8mmol) and acetic acid (10mL) was reacted at 180 ℃ for 40 minutes under microwave irradiation, then cooled to room temperature and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (330.4mg, 21%).

MS(ESI,pos.ion)m/z:270.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.47(d,J＝7.4Hz,1H),8.06(d,J＝1.0Hz,1H),7.07(dd,J＝7.4,1.8Hz,1H),4.69(s,1H),3.19(s,2H),1.20(s,6H)。

Step 4)1- (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [4,3-a]Pyridin-3-yl) -2-methyl Propan-2-ol

To 1- (7-bromo- [1,2, 4)]Triazolo [4,3-a]Pyridin-3-yl) -2-methylpropan-2-ol (330.4mg,1.2mmol) and benzophenone imine (445.0mg,2.5mmol) in 1, 4-dioxane (5mL) was added Pd₂(dba)₃(112.0mg,0.12mmol), BINAP (76.2mg,0.12mmol) and Cs₂CO₃(717.2mg,2.2 mmol). The reaction mixture was stirred overnight at 100 ℃ under nitrogen and then concentrated under reduced pressure. The resulting residue was dissolved in DCM (100mL) and the resulting mixture was washed with water (30 mL. times.2). The organic phase was concentrated under reduced pressure to give the title compound as a brown oil which was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:371.3[M+H]⁺。

Step 5)1- (7-amino- [1,2,4]]Triazolo [4,3-a]Pyridin-3-yl) -2-methylpropan-2-ol

To 1- (7- ((diphenylmethylene) amino) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -2-methylpropan-2-ol (453.0mg,1.2mmol) in DCM (5mL) was added a solution of hydrogen chloride in EtOAc (3M,3mL,9 mmol). The reaction system was stirred at room temperature for 1 hour, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was adjusted to pH 9 with an aqueous NaOH solution (1M), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to give the title compound as a yellow solid (252.2mg, 100% yield over two steps).

MS(ESI,pos.ion)m/z:207.2[M+H]⁺。

Step 6)6- (4- ((5-chloro-2- ((3- (2-hydroxy-2-methylpropyl) - [1,2, 4)]Triazolo [4,3-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (50.0mg,0.14mmol) and 1- (7-amino- [1,2, 4)]Triazolo [4,3-a]Pyridin-3-yl) -2-methylpropan-2-ol (180.0mg,0.87mmol) in 1, 4-dioxane (3mL) Pd (OAc) was added₂(3.2mg,0.014mmol), BINAP (8.9mg,0.014mmol) and K₂CO₃(39.2mg,0.29 mmol). The reaction mixture was stirred overnight at 100 ℃ under nitrogen and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a yellow solid (40.1mg, 54%).

MS(ESI,pos.ion)m/z:519.3[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2146[M+H]⁺；C₂₅H₂₈ClN₁₀O[M+H]⁺A theoretical value of 519.2136;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.75(s,1H),8.50(s,1H),8.33(s,1H),8.32(d,J＝7.5Hz,1H),8.07(s,1H),7.85(d,J＝9.0Hz,1H),7.15(d,J＝7.6Hz,1H),7.01(t,J＝7.4Hz,2H),4.64(s,1H),4.58(d,J＝12.7Hz,2H),4.42–4.29(m,1H),3.21–3.06(m,4H),2.03(d,J＝12.9Hz,2H),1.64(m,2H),1.19(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)159.4,158.1,157.3,153.8,153.1,150.9,144.5,140.5,139.4,130.1,124.9,119.3,109.2,107.0,96.4,95.3,70.7,49.2,44.3,38.1,31.0,29.8。

example 75 6- (4- ((5-chloro-2- ((3- (2-hydroxy-2-methylpropyl) - [1,2,4 ]]Triazolo [4,3-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (97.3mg,0.28mmol) and 1- (7-amino- [1,2, 4-mmol)]Triazolo [4,3-a]Pyridin-3-yl) -2-methylpropan-2-ol (121.3mg,0.59mmol) in 1, 4-dioxane (4mL) was addedPd (OAc)₂(7.2mg,0.032mmol), BINAP (18.8mg,0.030mmol) and K ₂CO₃(79.5mg,0.58 mmol). The reaction mixture was stirred overnight at 100 ℃ under nitrogen and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (139.4mg, 96%).

MS(ESI,pos.ion)m/z:520.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:520.2106[M+H]⁺；C₂₄H₂₇ClN₁₁O[M+H]⁺A theoretical value of 520.2089;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.76(s,1H),8.33(s,1H),8.32(d,J＝7.7Hz,1H),8.08(s,1H),7.87(d,J＝9.7Hz,1H),7.45(d,J＝9.8Hz,1H),7.16(d,J＝7.7Hz,1H),7.00(dd,J＝7.4,1.1Hz,1H),4.69-4.64(m,3H),4.46–4.33(m,1H),3.26(t,J＝12.4Hz,2H),3.11(s,2H),2.08(d,J＝10.8Hz,2H),1.77–1.62(m,2H),1.19(s,6H)；

¹³C NMR(150MHz,DMSO-d₆):(ppm)159.1,158.1,157.3,153.9,150.9,144.5,139.4,131.6,128.8,124.9,117.9,111.6,109.2,105.2,96.5,70.7,49.0,44.4,38.1,30.9,29.8。

example 76 6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) imidazo [1, 2-a)]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

Step 1) 1-bromo-4-hydroxy-4-methylpentan-2-one

To a solution of 4-hydroxy-4-methyl-pentan-2-one (20.03g,172.4mmol) in MeOH (120mL) at 0 deg.C was added Br dropwise₂(8.8mL,170 mmol). After the addition was complete, the reaction mixture was stirred for a further 3 hours, then diluted with water (200mL) and the resulting mixture was extracted with DCM (200 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Title compound was obtained as a yellow oil (32.92g, 9)7.9％)。

¹H NMR(400MHz,CDCl₃):(ppm)3.91(s,2H),2.83(s,2H),1.29(s,6H)。

Step 2)1- (7-Bromoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol

To a solution of 4-bromopyridin-2-amine (7.01g,40.5mmol) in EtOH (150mL) was added 1-bromo-4-hydroxy-4-methylpentan-2-one (15.82g,81.1 mmol). The reaction mixture was refluxed and stirred overnight, then concentrated under reduced pressure. The residue was saturated with Na₂CO₃The pH of the aqueous solution was adjusted to 8. The resulting mixture was extracted with DCM (150 mL. times.4). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to afford the title compound as a yellow solid (3.3g, 30%).

MS(ESI,pos.ion)m/z:269.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃):(ppm)7.93(dd,J＝7.1,0.4Hz,1H),7.71(d,J＝1.7Hz,1H),7.37(s,1H),6.87(dd,J＝7.1,1.9Hz,1H),4.57(s,1H),2.87(s,2H),1.22(s,6H)。

Step 3)1- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-2-yl) -2-methylpropan-2-ol

To 1- (7-bromoimidazo [1,2-a ]]To a solution of pyridin-2-yl) -2-methylpropan-2-ol (3.3g,12.0mmol) and benzophenone imine (3.11g,17.2mmol) in 1, 4-dioxane (150mL) was added Pd₂(dba)₃(1.03g,1.12mmol), BINAP (746.5mg,1.20mmol) and Cs₂CO₃(7.96g,24.4 mmol). The reaction mixture was refluxed for 5 hours under nitrogen blanket and then concentrated under reduced pressure. The resulting residue was dissolved in DCM (20mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown semi-solid which was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:370.2[M+H]⁺.

Step 4)1- (7-aminoimidazo [1, 2-a)]Pyridin-2-yl) -2-methylpropan-2-ol

1- (7- ((diphenyl)Methylene) amino) imidazo [1,2-a]Mixing of pyridin-2-yl) -2-methylpropan-2-ol (4.5g,12.0mmol) and a EtOAc solution of hydrogen chloride (4M,80mL,320mmol) was stirred at room temperature overnight and, after completion of the reaction, concentrated under reduced pressure. The residue obtained is NaHCO₃The aqueous solution was adjusted to pH 8 and then concentrated under reduced pressure. The resulting residue was dissolved in DCM (200mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (7M NH ₃Purified in MeOH/DCM (v/v) ═ 1/30) to give the title compound as a yellow solid (1.84g, 74% yield over two steps).

MS(ESI,pos.ion)m/z:206.1[M+H]⁺。

Step 5)6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) imidazo [1, 2-a)]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (203.2mg,0.58mmol) and 1- (7-aminoimidazo [1,2-a ]]Pyridin-2-yl) -2-methylpropan-2-ol (139.5mg,0.68mmol) in 1, 4-dioxane (10mL) Pd (OAc) was added₂(14.2mg,0.063mmol), BINAP (38.8mg,0.062mmol), and Cs₂CO₃(380.1mg,1.17 mmol). The reaction mixture was refluxed for 4 hours under nitrogen blanket and then concentrated under reduced pressure. The material was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/25) to afford the title compound as a light yellow solid (93.9mg, 31.2%).

MS(ESI,pos.ion)m/z:518.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:518.2186[M+H]⁺；C₂₆H₂₉ClN₉O[M+H]⁺A theoretical value of 518.2184;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.58(s,1H),8.50(d,J＝2.1Hz,1H),8.30(d,J＝7.3Hz,1H),8.18(s,1H),8.03(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.49(s,1H),7.07–7.02(m,2H),7.00(d,J＝9.2Hz,1H),4.97(s,1H),4.56(d,J＝12.8Hz,2H),4.41–4.31(m,1H),3.12(t,J＝12.5Hz,2H),2.68(s,2H),2.01(d,J＝11.0Hz,2H),1.67–1.57(m,2H),1.07(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)158.9,157.6,156.7,153.3,152.5,145.0,143.5,139.9,137.6,125.8,118.7,109.4,107.0,106.5,104.2,100.1,94.8,69.6,48.5,43.8,41.7,30.5,29.3。

example 776- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) - [1,2, 4)]Triazolo [1,5-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)1,2, 4-aminopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate

To O- (2,4, 6-trimethylphenylsulphonyl) hydroxylamine (29.53g,137.2mmol) in EtOAc (220mL) was added pyridine-2, 4-diamine (4.00g,36.7mmol) at 5 ℃. The reaction mixture was stirred at 5 ℃ for 1 h, then filtered and the filter cake was washed with EtOAc (10 mL. times.3) to afford the title compound as a yellow solid (6.90g, 58%).

MS(ESI,pos.ion)m/z:125.3[M₁]⁺.

MS(ESI,neg.ion)m/z:199.1[M₂]^-.

Step 2)1- (7-amino- [1,2,4 ]]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol

To a solution of 1,2, 4-aminopyridin-1-ium 2,4, 6-trimethylbenzenesulfonate (2.00g,6.2mmol) in (20mL) methanol (20mL) was added ethyl 3-hydroxy-3-methylbutyrate (3.60g,24.7mmol) and NaOH (493.6mg,12.3 mmol). The reaction mixture was stirred at 70 ℃ overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a yellow solid (183.2mg, 14%).

MS(ESI,pos.ion)m/z:207.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.35(d,J＝7.3Hz,1H),6.45(dd,J＝7.3,2.3Hz,1H),6.41(d,J＝1.9Hz,1H),6.08(s,2H),4.69(s,1H),2.74(s,2H),1.15(s,6H)。

Step 3)6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) - [1,2, 4)]Triazolo [1,5-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (80.0mg,0.23mmol) and 1- (7-amino- [1,2, 4-mmol)]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol (70.3mg,0.34mmol) in 1, 4-dioxane (3mL) Pd (OAc) was added₂(5.2mg,0.02mmol), BINAP (14.8mg,0.02mmol) and Cs₂CO₃(149.0mg,0.46 mmol). The reaction system is heated to 100 ℃ under the protection of nitrogen and stirred overnight, and after the reaction is finished, the reaction system is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (66.1mg, 56%).

MS(ESI,pos.ion)m/z:520.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:520.2077[M+H]⁺；C₂₄H₂₇ClN₁₁O[M+H]⁺A theoretical value of 520.2089;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.90(s,1H),8.66(d,J＝7.4Hz,1H),8.36(d,J＝1.8Hz,1H),8.08(s,1H),7.88(d,J＝9.7Hz,1H),7.43(d,J＝9.8Hz,1H),7.26(dd,J＝7.5,2.1Hz,1H),7.17(d,J＝7.8Hz,1H),4.67-4.62(m,3H),4.46–4.33(m,1H),3.22(t,J＝12.3Hz,2H),2.82(s,2H),2.06(d,J＝10.9Hz,2H),1.69(m,2H),1.14(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)164.8,159.1,157.9,157.3,153.8,151.8,142.5,131.5,128.9,128.3,117.9,111.6,108.2,105.5,99.2,69.8,48.9,44.3,42.7,30.9,29.7。

example 78 6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) - [1,2,4 ]]Triazolo [1,5-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (109.1mg,0.31mmol) and 1- (7-amino- [1,2, 4)]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol (100.1mg,0.49mmol) in 1, 4-dioxane (4mL) Pd (OAc) was added₂(7.2mg,0.03mmol), BINAP (20.3mg,0.03mmol) and K₂CO₃(87.0mg,0.63 mmol). The reaction mixture was stirred overnight at 100 ℃ under nitrogen and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (76.4mg, 47%).

MS(ESI,pos.ion)m/z:519.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2162[M+H]⁺；C₂₅H₂₈ClN₁₀O[M+H]⁺A theoretical value of 519.2136;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.89(s,1H),8.65(d,J＝7.4Hz,1H),8.50(d,J＝2.1Hz,1H),8.36(d,J＝1.8Hz,1H),8.07(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.25(dd,J＝7.5,2.1Hz,1H),7.15(d,J＝7.8Hz,1H),7.00(d,J＝9.1Hz,1H),4.62(s,1H),4.56(d,J＝13.1Hz,2H),4.39–4.30(m,1H),3.12(t,J＝12.4Hz,2H),2.82(s,2H),2.01(d,J＝10.7Hz,2H),1.69–1.58(m,2H),1.14(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)164.8,159.5,157.9,157.3,153.8,153.1,151.9,142.5,140.4,128.3,119.2,108.2,107.0,105.5,99.1,95.3,69.8,49.1,44.3,42.7,31.0,29.7.

example 79 6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) - [1,2,4 ]]Triazolo [1,5-a]Pyridine (II) Pyridin-6-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (60mg,0.17mmol) and 1- (6-amino- [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) -2-methylpropan-2-ol (50mg,0.24mmol) in 1, 4-dioxahexa-zineAddition of Pd (OAc) to the Ring (3mL)₂(4mg,0.02mmol), BINAP (11mg,0.02mmol) and Cs ₂CO₃(112mg,0.34 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as an off-white solid (69mg, 77%).

MS(ESI,pos.ion)m/z:520.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:520.2098[M+H]⁺；C₂₄H₂₇ClN₁₁O[M+H]⁺A theoretical value of 520.2089;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.61(s,1H),9.56(s,1H),8.04(s,1H),7.88(d,J＝9.7Hz,1H),7.69(d,J＝1.5Hz,1H),7.68(s,1H),7.43(d,J＝9.8Hz,1H),7.10(d,J＝7.7Hz,1H),4.65(d,J＝12.5Hz,2H),4.54(s,1H),4.44–4.32(m,1H),3.22(t,J＝12.6Hz,2H),2.85(s,2H),2.05(d,J＝11.1Hz,2H),1.74–1.64(m,2H),1.13(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)164.1,159.1,158.0,157.3,153.9,146.9,131.5,129.9,128.8,125.7,117.9,116.9,115.1,111.6,104.6,69.7,44.3,43.1,31.4,30.9,29.7。

example 80 6- (4- ((5-chloro-2- ((3- (2-hydroxy-2-methylpropyl) imidazo [1, 2-a)]Pyridin-7-yl) Amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)2- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-3-yl) acetic acid ethyl ester

To 2- (7-bromoimidazo [1,2-a ]]To a solution of pyridin-3-yl) carboxylic acid ethyl ester (4.70g,17.0mmol) and benzophenone imine (3.60g,20.0mmol) in 1, 4-dioxane (60mL) was added Pd₂(dba)₃(1.47g,1.61mmol), BINAP (1.02g,1.64mmol) and Cs₂CO₃(10.80g,33.1 mmol). The reaction mixture isStirring at 100 deg.C under nitrogen for 8 hr, and concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/1) to give the title compound as a yellow solid (4.10g, 64%).

MS(ESI,pos.ion)m/z:384.2[M+H]⁺。

Step 2)2- (7-Aminoimidazo [1, 2-a)]Pyridin-3-yl) acetic acid ethyl ester

To 2- (7- ((diphenylmethylene) amino) imidazo [1,2-a]Pyridin-3-yl) acetic acid ethyl ester (3.10g,2.53mmol) in DCM (10mL) was added hydrogen chloride in EtOAc (4N,10mL,40 mmol). The reaction system is stirred for 2 hours at room temperature, after the reaction is finished, the reaction system is decompressed and concentrated, and the obtained residue is saturated NaHCO ₃The aqueous solution was adjusted to pH 8 and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (MeOH (7 MNH)₃) Purification of/DCM (v/v) ═ 1/30) gave the title compound as a brown solid (900mg, 51.8%).

MS(ESI,pos.ion)m/z:220.2[M+H]⁺。

Step 3)1- (7-Aminoimidazo [1, 2-a)]Pyridin-3-yl) -2-methylpropan-2-ol

In N₂Protection and reaction at-78 deg.C to 2- (7-aminoimidazo [1,2-a ]]Pyridin-3-yl) acetic acid ethyl ester (900mg,3.07mmol) in tetrahydrofuran (20mL) was added methyl magnesium bromide (3.0M in ether, 15mL,45mmol) dropwise. After the addition was complete, the reaction mixture was moved to 0 ℃ and stirred for 5 hours. After completion of the reaction, the reaction was quenched with water (20mL), then concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (MeOH (7M NH)₃) Purification of/DCM (v/v) ═ 1/20) gave the title compound as a yellow solid (230mg, 27.3%).

MS(ESI,pos.ion)m/z:206.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)8.20(d,J＝7.4Hz,1H),7.10(s,1H),6.45(dd,J＝7.4,2.0Hz,1H),6.38(d,J＝2.0Hz,1H),5.93(s,2H),2.85(s,2H),1.13(s,6H)。

Step 4)6- (4- ((5-chloro-2- ((2- (2-hydroxy-2-methylpropyl) imidazo [1, 2-b)]Pyridazin-7-yl) amines Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinylNitrile

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (70mg,0.20mmol) and 1- (7-aminoimidazo [1,2-a ]]Pyridin-3-yl) -2-methylpropan-2-ol (60mg,0.29mmol) in 1, 4-dioxane (20mL) was added Pd (OAc)₂(5mg,0.022mmol), BINAP (12mg,0.019mmol) and Cs ₂CO₃(130mg,0.40 mmol). The reaction system is heated to 100 ℃ and stirred for 2 hours under the protection of nitrogen, and after the reaction is finished, the reaction system is decompressed and concentrated. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/30) to afford the title compound as a white solid (25mg, 24.1%).

MS(ESI,pos.ion)m/z:519.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.2134[M+H]⁺；C₂₅H₂₈ClN₁₀O[M+H]⁺A theoretical value of 519.213;

¹H NMR(600MHz,CDCl₃+CD₃OD)(ppm):8.22(s,1H),8.09(s,1H),7.82(s,1H),7.39(d,J＝9.2Hz,1H),7.31–7.19(m,2H),6.92(s,1H),4.41–4.37(m,3H),3.34–3.30(m,2H),2.89(s,2H),2.24–2.20(m,2H),1.53-1.49(m,2H),1.20(s,6H)；

¹³C NMR(150MHz,CDCl₃+CD₃OD):(ppm)158.5,157.3,157.2,152.7,130.8,123.0,129.9,128.6,125.5,121.8,116.9,110.6,108.9,106.3,71.2,51.7,43.5,37.1,31.3,29.0。

example 81 4- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2,4 ]]Triazolo [1,5-a]Pyridine (II) Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) benzonitrile

To 2- (7- ((5-chloro-4- (piperidin-4-ylamino) pyrimidin-2-yl) amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol (0.10g,0.25mmol) and 4-fluorobenzonitrile (36.5mg,0.30mmol) in DMSO (5mL) was added K₂CO₃(68.0mg,0.49 mmol). The reaction system is as followsAfter stirring at 100 ℃ for 8 hours, it was cooled to room temperature, quenched with water (10mL), and the resulting mixture was extracted with DCM (50 mL. times.4). The combined organic phases were washed with brine (100mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a white solid (45.0mg, 36%).

MS(ESI,pos,ion):504.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:504.2022[M+H]⁺；C₂₅H₂₇ClN₉O[M+H]⁺A theoretical value of 504.2027;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.87(s,1H),8.67(d,J＝7.4Hz,1H),8.33(d,J＝1.7Hz,1H),8.07(s,1H),7.58(d,J＝8.9Hz,2H),7.29(dd,J＝7.5,2.1Hz,1H),7.17(d,J＝7.7Hz,1H),7.08(d,J＝8.9Hz,2H),4.33–4.20(m,1H),4.04(d,J＝13.1Hz,2H),3.08(t,J＝12.3Hz,2H),1.99(d,J＝13.7Hz,2H),1.77–1.67(m,2H),1.51(s,6H)；

¹³C NMR(100MHz,DMSO-d₆):(ppm)172.7,157.9,157.4,153.7,153.4,152.0,142.4,133.8,128.6,120.6,114.8,108.4,105.6,99.4,98.2,68.6,49.1,46.9,30.6,30.1。

example 82 2- (7- ((5-chloro-4- ((1- (6-cyanopyridazin-3-yl) piperidin-4-yl) amino) pyrimidin-2-yl) Amino) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) -N-methylacetamide

Step 1)3- (methylamino) -3-oxopropanoic acid ethyl ester

To a solution of methylamine hydrochloride (2.24g,33.2mmol) in THF (50mL) was added KOH (4.09g,73.1 mmol). The reaction was cooled to 0 ℃ and ethyl 3-chloro-3-oxo-propionate (5.00g,33.2mmol) was added slowly. The reaction was warmed to room temperature and stirred overnight, then quenched with water (20mL) and extracted with EtOAc (100 mL. times.4). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/2) to give the title compound as a yellow oil (0.89g, 18.6%).

MS(ESI,pos.ion)m/z:146.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.98(s,1H),4.07(q,J＝7.1Hz,2H),3.19(s,2H),2.59(d,J＝4.6Hz,3H),1.18(t,J＝7.1Hz,3H)。

Step 2)2- (7-amino- [1,2,4 ]]Triazolo [1,5-a]Pyridin-2-yl) -N-methylacetamide

To a solution of ethyl 3- (methylamino) -3-oxopropanoate (0.49g,3.38mmol) in MeOH (20mL) were added NaOH (0.14g,3.38mmol) and 1,2,4 triaminopyridin-1-ium 2,4,6 trimethylbenzenesulphonic acid (0.50g,1.54 mmol). The reaction was refluxed overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 1/10) to afford the title compound as a yellow solid (0.12g, 39.4%).

MS(ESI,pos.ion)m/z:206.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.36(d,J＝7.3Hz,1H),7.92(s,1H),6.48(dd,J＝7.3,2.2Hz,1H),6.42(d,J＝1.8Hz,1H),6.11(s,2H),3.48(s,2H),2.60(d,J＝4.6Hz,3H)。

Step 3)2- (7- ((5-chloro-4- ((1- (6-cyanopyridazin-3-yl) piperidin-4-yl) amino) pyrimidin-2-yl) amino) Base) - [1,2,4]Triazolo [1,5-a]Pyridin-2-yl) -N-methylacetamide

To 2- (7-amino- [1,2, 4)]Triazolo [1,5-a]To a solution of pyridin-2-yl) -N-methylacetamide (0.11g,0.54mmol) in 1, 4-dioxane (5mL) was added 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (0.15g,0.43mmol), BINAP (0.031g,0.05mmol), Pd (OAc)₂(0.011g,0.05mmol) and Cs₂CO₃(0.35g,1.07 mmol). The reaction was refluxed for 1 hour and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) ═ 1/20) to afford the title compound as a yellow solid (0.12g, 43.3%).

MS(ESI,pos.ion)m/z:519.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.1874[M+H]⁺；C₂₃H₂₄ClN₁₂O[M+H]⁺The theoretical values of (A) are: 519.1884, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):9.91(s,1H),8.68(d,J＝7.5Hz,1H),8.30(d,J＝1.7Hz,1H),8.10(s,1H),7.93(d,J＝4.3Hz,1H),7.89(d,J＝9.7Hz,1H),7.45(d,J＝9.7Hz,1H),7.33(dd,J＝7.5,2.1Hz,1H),7.13(d,J＝7.8Hz,1H),4.65(d,J＝12.9Hz,2H),4.45–4.34(m,1H),3.59(s,2H),3.24(t,J＝12.1Hz,2H),2.58(d,J＝4.6Hz,3H),2.06(d,J＝10.7Hz,2H),1.71–1.69(m,2H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):168.52,168.51,162.17,159.07,157.89,157.32,153.75,152.19,142.65,131.58,128.82,128.43,117.92,111.62,108.38,105.62,98.99,48.71,44.29,36.62,30.87,26.18。

example 837- ((5-chloro-4- ((1- (5-cyanopyridin-2-yl) piperidin-4-yl) amino) pyrimidin-2-yl) amino) Radical) -N, N-dimethyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxamides

Step 1) Ethyl 2- (dimethylamino) -2-oxoacetate

To a solution of oxalyl chloride monoethyl ester (2.77g,20.3mmol) in THF (10mL) at 0 deg.C was added dropwise a solution of dimethylamine in THF (10mL,20mmol,2mol/L) and TEA (2.23g,22.0 mmol). The reaction was stirred at 0 ℃ overnight and then diluted with water (40 mL). The aqueous phase was extracted with EtOAc (50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound as a yellow-brown oil (1.316g, 45.33%) which was used in the next reaction without purification.

MS(ESI,pos.ion)m/z:146.1[M+H]⁺。

Step 2) 7-bromo-N, N-dimethyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxamides

To a suspension of 1, 2-diamino-4-bromopyridin-1-ium 2,4, 6-trimethylbenzenesulfonic acid (2.02g,5.20mmol) and sodium hydroxide (217.4mg,5.435mmol) in EtOH (20mL) was added ethyl 2- (dimethylamino) -2-oxoacetate (1.316g,9.066 mmol). The reaction was refluxed overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 4/1) to give the title compound as a white solid (446mg, 31.9%).

MS(ESI,pos.ion)m/z:269.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):8.46(d,J＝7.3Hz,1H),7.97(d,J＝1.3Hz,1H),7.21(dd,J＝7.2,2.0Hz,1H),3.25(s,3H),3.18(s,3H)。

Step 3)7- ((diphenylmethylene) amino) -N, N-dimethyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxylic acid methyl ester Amides of carboxylic acids

To 7-bromo-N, N-dimethyl- [1,2,4 ]]Triazolo [1,5-a]To a solution of pyridine-2-carboxamide (446mg,1.6574mmol) and benzophenone imine (403.4mg,2.226mmol) in 1, 4-dioxane (20mL) was added BINAP (103.5mg,0.1662mmol), Pd₂(dba)₃(146.7mg,0.1602mmol) and Cs₂CO₃(1.087g,3.336 mmol). The reaction was refluxed for 8 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with (MeOH/DCM (v/v) ═ 1/10,50 mL). The resulting mixture was filtered and the filter cake was washed with DCM (50 mL. times.2). The filtrate was concentrated under reduced pressure to give the title compound as a reddish brown solid-liquid mixture which was used directly in the next reaction without purification.

MS(ESI,pos.ion)m/z:370.2[M+H]⁺。

Step 4) 7-amino-N, N-dimethyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxamides

7- ((diphenylmethylene) amino) -N, N-dimethyl- [1,2,4]Triazolo [1,5-a]A suspension of pyridine-2-carboxamide (612.2mg,1.657mmol) and HCl in EtOAc (20mL,60mmol,3mol/L) was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was saturated with Na₂CO₃The aqueous solution was adjusted to pH 9 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3M NH)₃MeOH/DC ofM solution (v/v) ═ 1/25) to give the title compound as a pale yellow solid (298mg, 87.62%).

MS(ESI,pos.ion)m/z:206.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.46(d,J＝7.4Hz,1H),6.59(dd,J＝7.4,2.3Hz,1H),6.50(d,J＝2.0Hz,1H),6.27(s,2H),3.01(s,3H),2.99(s,3H)。

Step 5)7- ((5-chloro-4- ((1- (5-cyanopyridin-2-yl) piperidin-4-yl) amino) pyrimidin-2-yl) amino) - N, N-methyl- [1,2,4 ]]Triazolo [1,5-a]Pyridine-2-dicarboxamides

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (256.7mg,0.7351mmol) and 7-amino-N, N-dimethyl- [1,2, 4-dimethyl- [1]Triazolo [1,5-a]To a suspension of pyridine-2-carboxamide (146.4mg,0.7134mmol) in 1, 4-dioxane (20mL) was added BINAP (44.1mg,0.0708mmol), Pd (OAc)₂(17.7mg,0.0788mmol) and Cs₂CO₃(468.2mg,1.437 mmol). The reaction was refluxed overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/35) to afford the title compound as a white solid (92mg, 24.16%).

MS(ESI,pos.ion)m/z:518.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:518.1924[M+H]⁺；C₂₄H₂₅ClN₁₁O[M+H]⁺The theoretical values of (A) are: 518.1932, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.02(s,1H),8.77(d,J＝7.5Hz,1H),8.50(d,J＝2.1Hz,1H),8.46(d,J＝1.8Hz,1H),8.09(s,1H),7.85(dd,J＝9.1,2.3Hz,1H),7.38(dd,J＝7.5,2.1Hz,1H),7.17(d,J＝7.8Hz,1H),7.01(d,J＝9.2Hz,1H),4.56(d,J＝12.9Hz,2H),4.40–4.28(m,1H),3.12(t,J＝12.4Hz,2H),3.01(d,J＝9.8Hz,6H),2.01(d,J＝10.2Hz,2H),1.64(qd,J＝12.5,3.6Hz,2H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):162.21,159.10,158.95,157.38,156.89,153.33,152.65,151.08,142.87,140.02,128.58,118.82,109.45,106.53,105.33,98.87,94.87,48.65,43.85,38.02,34.70,30.51。

example 846- (4- ((5-chloro-2- ((2- (3-hydroxyazetidine-1-carbonyl) - [1,2, 4)]A triazolo [1 ] group, a triazolo [1 ], 5-a]pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) Ethyl 2- (3-hydroxyazetidin-1-yl) -2-oxocarboxylate

To a solution of azetidine-3-ol hydrochloride (800.8mg,7.309mmol) in THF (15mL) at 0 deg.C was added 2-chloro-2-oxo-acetic acid ethyl ester (1.37g,10.0mmol) and triethylamine (3mL,21.6 mmol). The mixture was stirred at 0 ℃ overnight, then diluted with water and the resulting mixture extracted with DCM (100 mL. times.3). The combined organic phases were washed with brine, anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to give the title compound as a brown solid (1.10g, 63.3%).

MS(ESI,pos.ion)m/z:174.0[M+H]⁺；

¹HNMR(400MHz,CDCl₃)(ppm):4.68–4.67(m,1H),4.66–4.65(m,2H),4.32–4.30(m,2H),3.95–3.92(m,2H),1.33(t,J＝7.1Hz,3H)。

Step 2) (7-amino- [1,2,4 ]]Triazolo [1,5-a]Pyridin-2-yl) (3-hydroxyazetidin-1-yl) methyl Ketones

To a solution of pyridin-1-ium-1, 2, 4-triamine 2,4, 6-trimethylbenzenesulfonic acid (350mg,1.079mmol) in ethanol (15mL) was added ethyl 2- (3-hydroxyazetidin-1-yl) -2-oxocarboxylate (450mg,2.5986mmol) and sodium hydroxide (51.4mg,1.29 mmol). The reaction mixture was stirred at 80 ℃ overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a light yellow solid (150.0mg, 59.6%).

MS(ESI,pos.ion)m/z:234.0[M+H]⁺。

¹HNMR(400MHz,DMSO-d₆)(ppm):8.48(d,J＝7.4Hz,1H),6.64(dd,J＝7.4,2.2Hz,1H),6.52(d,J＝1.9Hz,1H),6.31(s,2H),5.76(d,J＝6.4Hz,1H),4.74–4.65(m,1H),4.56–4.45(m,1H),4.29–4.19(m,2H),3.81–3.73(m,1H)。

Step 3)6- (4- ((5-chloro-2- ((2- (3-hydroxyazetidine-1-carbonyl) - [1,2, 4)]Triazolo [1,5- a]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To a solution of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (102.0mg,0.2913mmol) in 1, 4-dioxane (10mL) was added (7-amino- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) - (3-hydroxyazetidin-1-yl) methanone (132.8mg,0.5694 mmol). Palladium acetate (9.4mg,0.042mmol), BINAP (17.9mg,0.0287mmol) and potassium carbonate (89.0mg,0.644 mmol). The mixture was stirred at 100 ℃ under nitrogen for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a light yellow solid (79.1mg, 49.6%).

MS(ESI,pos.ion)m/z:547.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:547.1830[M+H]⁺；C₂₄H₂₄ClN₁₂O₂[M+H]⁺The theoretical values of (A) are: 547.1828, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.06(s,1H),8.79(d,J＝7.5Hz,1H),8.53(s,1H),8.11(s,1H),7.87(d,J＝9.7Hz,1H),7.45(d,J＝9.7Hz,1H),7.38(dd,J＝7.5,1.7Hz,1H),7.24(d,J＝7.6Hz,1H),5.66(d,J＝6.5Hz,1H),4.76–4.69(m,2H),4.75–4.65(m,1H),4.47–4.33(m,2H),4.29–4.17(m,2H),3.80–3.73(m,1H),3.29–3.20(m,2H),2.16–2.05(m,2H),1.80–1.66(m,2H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):159.9,159.1,158.2,157.8,157.3,153.9,151.9,143.2,131.6,129.1,128.9,118.0,111.6,110.4,105.7,99.4,63.7,61.1,58.6,49.1,44.4,30.9。

example 857- ((5-chloro-4- ((1- (6-cyanopyridazin-3-yl) piperidin-4-yl) amino) pyrimidin-2-yl) amino Radical) -N, N-dimethyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxamides

To 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (259.4mg,0.7407mmol) and 7-amino-N, N-dimethyl- [1,2, 4-dimethyl- [1]Triazolo [1,5-a]To a suspension of pyridine-2-carboxamide (146.8mg,0.7153mmol) in 1, 4-dioxane (20mL) was added BINAP (45.2mg,0.0726mmol), Pd (OAc) ₂(17.8mg,0.0793mmol) and Cs₂CO₃(471.6mg,1.447 mmol). The reaction was refluxed overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/35) to afford the title compound as a white solid (144mg, 37.46%).

MS(ESI,pos.ion)m/z:519.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:519.1870[M+H]⁺；C₂₃H₂₄ClN₁₂O[M+H]⁺The theoretical values of (A) are: 519.1885, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.03(s,1H),8.78(d,J＝7.5Hz,1H),8.46(d,J＝1.3Hz,1H),8.11(s,1H),7.88(d,J＝9.7Hz,1H),7.44(d,J＝9.7Hz,1H),7.39(dd,J＝7.5,1.8Hz,1H),7.19(d,J＝7.7Hz,1H),4.65(d,J＝12.5Hz,2H),4.46–4.32(m,1H),3.23(t,J＝12.4Hz,2H),3.01(d,J＝10.1Hz,6H),2.07(d,J＝11.1Hz,2H),1.70(qd,J＝12.4,3.2Hz,2H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):162.22,159.11,158.65,157.38,156.90,153.36,151.08,142.87,131.14,128.60,128.41,117.48,111.20,109.45,105.34,98.88,48.44,43.88,38.02,34.68,30.43。

example 867- ((5-chloro-4- ((1- (6-cyanopyridazin-3-yl) piperidin-4-yl) amino) pyrimidin-2-yl) amino Radical) -N-cyclopropyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxamides

Step 1) Ethyl 2- (cyclopropylamino) -2-oxoacetate

To a solution of cyclopropylamine (4.18g,73.2mmol) in THF (100mL) was added Et₃N (14.79g,146.4 mmol). The reaction was cooled to 0 ℃ and ethyl 2-chloro-2-oxoacetate (10.00g,73.2mmol) was then slowly added thereto. The reaction was warmed to room temperature and stirred overnight, then quenched with water (20mL) and extracted with EtOAc (100 mL. times.4). The combined organic layers were washed with saturated NaCl (100 mL. times.2), anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 1/10) to give the title compound as a yellow oil (7.90g, 68.2%).

MS(ESI,pos.ion)m/z:158.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):4.31(q,J＝7.1Hz,2H),2.86–2.75(m,1H),1.36(t,J＝7.1Hz,3H),0.89–0.80(m,2H),0.65–0.56(m,2H)。

Step 2) 7-amino-N-cyclopropyl- [1,2,4]Triazolo [1,5-a]Pyridine-2-carboxamides

To a solution of ethyl 2- (cyclopropylamino) -2-oxoacetate (2.13g,13.56mmol) in MeOH (20mL) were added NaOH (0.54g,13.56mmol) and 1,2, 4-triaminopyridin-1-ium 2,4, 6-trimethylbenzenesulfonic acid (2.00g,6.16 mmol). The reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a yellow oil (0.18g, 13.5%).

MS(ESI,pos.ion)m/z:218.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):8.54(d,J＝4.6Hz,1H),8.46(t,J＝9.7Hz,1H),6.63(dd,J＝7.4,2.2Hz,1H),6.50(d,J＝1.8Hz,1H),6.30(s,2H),2.92–2.78(m,1H),0.66–0.64(m,4H)。

Step 3)7- ((5-chloro-4- ((1- (6-cyanopyridazin-3-yl) piperidin-4-yl) amino) pyrimidin-2-yl) amino) - N-cyclopropyl- [1,2,4 ]]Triazolo [1,5-a]Pyridine-2-Carboxamides

To 7-amino-N-cyclopropyl- [1,2,4 ]]Triazolo [1,5-a]To a solution of pyridine-2-carboxamide (0.11g,0.51mmol) in 1, 4-dioxane (5mL) was added 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (0.12g,0.35mmol), BINAP (0.031g,0.05mmol), Pd (OAc)₂(0.011g,0.05mmol) and Cs₂CO₃(0.331g,1.01 mmol). The mixture was refluxed for 1 hour and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a yellow solid (0.085g, 31.8%).

MS(ESI,pos.ion)m/z:531.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:531.1876[M+H]⁺；C₂₄H₂₄ClN₁₂O[M+H]⁺The theoretical values of (A) are: 531.1884, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.02(s,1H),8.79(d,J＝7.5Hz,1H),8.60(d,J＝4.6Hz,1H),8.40(d,J＝1.4Hz,1H),8.12(s,1H),7.88(d,J＝9.7Hz,1H),7.51–7.46(m,1H),7.45(d,J＝9.8Hz,1H),7.17(d,J＝7.8Hz,1H),4.64(d,J＝12.8Hz,2H),4.39(dd,J＝7.4,3.7Hz,1H),3.23(t,J＝12.2Hz,2H),2.92–2.80(m,1H),2.05(d,J＝10.8Hz,2H),1.71–1.69(m,2H),0.74–0.64(m,2H),0.66–0.57(m,2H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):160.98,159.13,158.78,157.74,157.37,153.52,151.91,143.46,131.55,129.19,128.83,117.93,111.63,110.30,106.08,99.40,55.38,48.58,44.25,30.84,23.21,6.22。

example 876- (4- ((5-chloro-2- ((3- (3-hydroxyazetidine-1-carbonyl) - [1,2, 4)]A triazolo [4 ] group, 3-a]pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1) (Z) -4-bromo-2-hydrazono-1, 2-dihydropyridine

To a solution of 4-bromo-2-fluoropyridine (5.22g,29.7mmol) in pyridine (15mL) was added hydrazine hydrate (13.5mL,273 mmol). The mixture was stirred at 75 ℃ for 2 hours and then concentrated under reduced pressure. The resulting residue was diluted with water (10mL) and stirred for 0.5 h, and the mixture was filtered. The resulting filter cake was washed with water (1 mL. times.3) to afford the title compound as a white solid (4.61g, 82.7%).

MS(ESI,pos.ion)m/z:188.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):7.85(d,J＝5.3Hz,1H),7.71(s,1H),6.92(d,J＝1.5Hz,1H),6.70(dd,J＝5.3,1.7Hz,1H),4.20(s,2H)。

Step 2) 7-bromo- [1,2,4]Triazolo [4,3-a]Pyridine-3-carboxylic acid ethyl ester

To a solution of (Z) -4-bromo-2-hydrazono-1, 2-dihydropyridine (2.03g,10.8mmol) in methanol (30mL) was added ethyl 2-oxoacetate (2.17g,21.3 mmol). The resulting mixture was stirred at 70 ℃ for 1.5 hours and then concentrated under reduced pressure. The resulting residue was dissolved with iodophenylenediacetic acid (3.77g,11.7mmol) in DCM (25mL), then stirred at room temperature overnight and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc/PE (v/v) ═ 2/5) to give the title compound as a light yellow solid (1.27g, 43.6%).

MS(ESI,pos.ion)m/z:270.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)(ppm):9.03(d,J＝7.4Hz,1H),8.14(d,J＝0.8Hz,1H),7.19(dd,J＝7.4,1.7Hz,1H),4.58(q,J＝7.1Hz,2H),1.51(t,J＝7.1Hz,3H)。

Step 3) (7-bromo- [1,2,4]]Triazolo [4,3-a]Pyridin-3-yl) (3-hydroxyazetidin-1-yl) methanones

To a solution of ethyl 7-bromo- [1,2,4] triazolo [4,3-a ] pyridine-3-carboxylate (1.27g,4.70mmol) in ethanol (15mL) placed in a microwave tube was added azetidine-3-ol hydrochloride (1.29g,11.8mmol) and triethylamine (3.3mL,24 mmol). The reaction was stirred at 80 ℃ overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a light yellow solid (1.21g, 86.6%).

MS(ESI,pos.ion)m/z:297.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)(ppm):9.11(d,J＝7.1Hz,1H),8.38(d,J＝0.9Hz,1H),7.35(dd,J＝7.4,1.8Hz,1H),5.85(d,J＝6.2Hz,1H),4.90–4.82(m,1H),4.63–4.54(m,1H),4.41–4.32(m,2H),3.91–3.84(m,1H)。

Step 4) (7- ((diphenylmethylene) amino) - [1,2,4]Triazolo [4,3-a]Pyridin-3-yl) (3-hydroxy nitrogen Heterocyclobutane-1-yl) methanones

To a solution of (7-bromo- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) (3-hydroxyazetidin-1-yl) methanone (1.21g,4.07mmol) in 1, 4-dioxane (25mL) was added benzophenone imine (1.4mL,8.3mmol), tris (dibenzylideneacetone) dipalladium (375.4mg,0.410mmol), BINAP (255.8mg,0.4108mmol) and cesium carbonate (2.67g,8.19 mmol). The mixture was stirred at 100 ℃ under nitrogen for 3 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a crude oil (1.26g, 77.9%).

MS(ESI,pos.ion)m/z:398.1[M+H]⁺。

Step 5) (7-amino- [1,2,4]]Triazolo [4,3-a]Pyridin-3-yl) (3-hydroxyazetidin-1-yl) methyl Ketones

To (7- ((diphenylmethylene) amino) - [1,2,4]]Triazolo [4,3-a]Pyridin-3-yl) (3-hydroxyazetidin-1-yl) methanone (410.3mg,1.010mmol) in DCM (25mL) was added HCl/EtOAc (3.4mL,10 mmol). The reaction mixture was stirred at room temperature for 1 hour, then saturated NaHCO was added₃The pH of the aqueous solution was adjusted to 8. The resulting mixture was concentrated under reduced pressure and the concentrated residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a yellow solid (230.5mg, 97.9%).

MS(ESI,pos.ion)m/z:234.0[M+H]⁺。

Step 6)6- (4- ((5-chloro-2- ((3- (3-hydroxyazetidine-1-carbonyl) - [1,2, 4) ]Triazolo [4,3- a]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To a solution of 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (200.2mg,0.5717mmol) in 1, 4-dioxane (20mL) was added (7-amino- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) (3-hydroxyazetidin-1-yl) methanone (220.5mg,0.9454mmol), palladium acetate (20.2mg,0.090mmol), BINAP (39.1mg, 0.8 mmol), and potassium carbonate (161.5mg, 1.062169 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 3 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/15) to afford the title compound as a light yellow solid (133.4mg, 42.7%).

MS(ESI,pos.ion)m/z:547.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:547.1823[M+H]⁺；C₂₄H₂₄ClN₁₂O₂[M+H]⁺The theoretical values of (A) are: 547.1828, respectively;

¹H NMR(400MHz,DMSO-d₆)(ppm):10.20(s,1H),9.06(d,J＝7.6Hz,1H),8.58(s,1H),8.14(s,1H),7.89(d,J＝9.7Hz,1H),7.47(d,J＝9.7Hz,1H),7.29(dd,J＝21.7,7.6Hz,2H),4.86–4.78(m,1H),4.74–4.64(m,2H),4.62–4.55(m,1H),4.48–4.38(m,1H),4.37–4.30(m,2H),3.90–3.82(m,1H),3.32–3.25(m,2H),2.14–2.05(m,2H),1.78–1.65(m,2H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):159.1,157.6,157.4,157.4,153.7,151.0,142.5,138.4,131.6,128.9,126.7,117.9,111.9,111.7,106.1,95.6,63.9,61.4,58.7,44.3,30.9。

example 886- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [1,5-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) pyridazine-3-carbonitrile

Step 1) (2,4, 6-trimethylphenylxanthyl) oxycarboxylic acid tert-butyl ester

To 2,4, 6-trimethylTo a solution of phenyl-1-sulfonyl chloride (20g,92.9mmol) in EtOAc (200mL) was added tert-butyl hydroxycarbamate (12.21g,91.7mmol) and Et₃N (11.6g,115 mmol). The reaction mixture was stirred at 0 ℃ for 2h, then water (100mL) was added. The resulting mixture was extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next reaction without purification.

Step 2) O- (2,4, 6-trimethylphenyl-xanthoyl) hydroxylamine

To a solution of tert-butyl (2,4, 6-trimethylphenylxanthyl) oxycarbamate (28g,88.8mmol) in EtOAc (200mL) was added H₂SO₄(18.4g, mass ratio: 98%). The reaction mixture was stirred at 5 ℃ for 8h, then water (200mL) was added. The resulting mixture was washed with NaHCO₃The solid was adjusted to pH 8, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was used in the next reaction without purification.

Step 3) 1,2, 4-triaminopyrium 2, 4-trimethylbenzenesulfonate salt

To a solution of O- (2,4, 6-trimethylphenylxanthoyl) hydroxylamine (20.0g,92.0mmol) in EtOAc (200mL) was added pyridine-2, 4-diamine (4.0g,37.0 mmol). The reaction mixture was stirred at 5 ℃ for 1h, then filtered to give the title compound as a yellow solid (6.4g, 53.7%).

MS(ESI,pos.ion)m/z:125.1[M+H]⁺。

Step 4)2- (7-amino- [1,2,4 ]]Triazolo [1,5-a]Pyridin-2-yl) propan-2-ol

To a solution of 2,4, 6-trimethylbenzenesulfonic acid 1,2, 4-triaminopyridinium salt (6.4g,0.487mmol) in EtOH (50mL) was added sodium hydroxide (1.6g,39mmol) and ethyl 2-hydroxy-2-methyl-propionate (5.2g,39 mmol). The reaction mixture was stirred at 80 ℃ for 1h, then sodium hydroxide (1.6g,39mmol) and ethyl 2-hydroxy-2-methyl-propionate (5.2g,39mmol) were added once per hour with stirring, a total of three times. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a yellow solid (2.3g, 61.0%).

MS(ESI,pos.ion)m/z:193.1[M+H]⁺。

Step 5)4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [1,5-a]Pyridin-7-yl) amino Yl) pyrimidin-4-yl) amino) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester

To 2- (7-amino- [1,2, 4)]Triazolo [1,5-a]Add Pd (OAc) to a solution of pyridin-2-yl) propan-2-ol (740mg,3.8mmol) in 1, 4-dioxane (25mL)₂(90.0mg,0.38mmol), BINAP (98%, 240mg,0.38mmol) and cesium carbonate (98%, 2500mg,7.7 mmol). The reaction mixture was stirred at reflux for 2h, then concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (1.71g, 86.0%).

MS(ESI,pos.ion)m/z:521.1[M+H]⁺。

Step 6)2- (7- ((5-chloro-4- ((3-fluoropiperidin-4-yl) amino) pyrimidin-2-yl) amino) - [1,2,4]Triazole compounds And [1,5-a ]]Pyridin-2-yl) propan-2-ol

To 4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2,4 ]]Triazolo [1,5-a]Pyridin-7-yl) amino) pyrimidin-4-yl) amino) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (400mg,0.736mmol) in CH₂Cl₂Hydrochloric acid (2mL,10mmol,10mol/L) was added to the solution (15 mL). The reaction mixture was stirred at room temperature for 1h, then washed with saturated aqueous solution and the organic layer was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a white solid (290mg, 88.38%).

MS(ESI,pos.ion)m/z:421.2[M+H]⁺。

Step 7)6- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2, 4)]Triazolo [1,5-a]Pyridine-7- Yl) amino) pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) pyridazine-3-carbonitrile

To a solution of 2- (7- ((5-chloro-4- ((3-fluoropiperidin-4-yl) amino) pyrimidin-2-yl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) propan-2-ol (400mg,0.95mmol) in MeOH (20mL) was added 6-chloropyridazine-3-carbonitrile (240mg,1.71 mmol). The reaction mixture was stirred at 80 ℃ for 8 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (410mg, 82.3%).

MS(ESI,pos.ion)m/z:524.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:524.1842[M+H]⁺；C₂₃H₂₃ClFN₁₁O[M+H]⁺A theoretical value of 524.9532;

¹H NMR(400MHz,DMSO-d₆)9.92(d,J＝13.7Hz,2H),8.69(t,J＝6.9Hz,2H),8.24(dd,J＝11.5,1.7Hz,2H),8.14(d,J＝5.9Hz,2H),7.92(dd,J＝25.0,9.7Hz,2H),7.52(dd,J＝26.7,9.7Hz,2H),7.44–7.28(m,3H),7.04(d,J＝7.1Hz,1H),5.10(s,2H),4.99–4.81(m,2H),4.82–4.75(m,1H),4.68–4.59(m,1H),4.49(d,J＝12.4Hz,1H),3.34(s,1H),3.28(dd,J＝11.8,7.3Hz,2H),3.17(d,J＝5.1Hz,1H),2.17–2.08(m,2H),1.93(d,J＝10.4Hz,1H),1.74(d,J＝9.4Hz,1H),1.53(s,12H),1.22(s,1H)；

¹³C NMR(151MHz,DMSO-d₆)172.69,172.66,160.97,159.95,159.77,159.29,158.72,157.88,157.79,157.78,157.68,157.28,156.91,154.13,154.04,153.91,153.77,151.96,151.92,144.61,142.43,142.40,142.36,132.73,131.89,131.80,131.58,131.45,130.53,130.03,129.78,129.71,129.15,129.07,128.67,128.61,119.38,117.81,117.76,117.68,113.03,112.20,112.10,111.73,110.21,108.48,108.42,107.43,105.81,105.76,105.69,101.11,99.68,99.63,99.56,91.13,89.19,89.01,88.23,88.13,87.99,87.30,87.05,68.57,68.39,54.16,52.73,52.66,52.61,52.19,50.80,50.74,50.68,50.24,49.07,48.03,47.65,47.47,47.26,47.17,47.07,46.77,43.68,43.64,43.60,42.73,40.46,30.15,30.12,30.11,28.99,25.27。

example 89 6- (4- ((5-chloro-2- ((2- (2-hydroxypropan-2-yl) - [1,2,4]]Triazolo [1,5-a]Pyridine- 7-yl) amino) pyrimidin-4-yl) amino) -3-fluoropiperidin-1-yl) nicotinonitrile

To a solution of 2- (7- ((5-chloro-4- ((3-fluoropiperidin-4-yl) amino) pyrimidin-2-yl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) propan-2-ol (300mg,0.712mmol) in MeOH (15mL) was added 6-chloropyridine-3-carbonitrile (180mg,1.28 mmol). The reaction mixture was stirred at 80 ℃ for 8h, then concentrated under reduced pressure and the residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a white solid (210mg, 56.3%).

MS(ESI,pos.ion)m/z:524.4[M+H]⁺；

HRMS(ESI,pos.ion)m/z:524.1842[M+H]⁺；C₂₄H₂₄ClFN₁₀O[M+H]⁺A theoretical value of 524.9532;

¹H NMR(400MHz,DMSO-d₆)9.92(d,J＝13.7Hz,2H),8.69(t,J＝6.9Hz,2H),8.24(dd,J＝11.5,1.7Hz,2H),8.14(d,J＝5.9Hz,2H),7.92(dd,J＝25.0,9.7Hz,2H),7.52(dd,J＝26.7,9.7Hz,2H),7.44–7.28(m,3H),7.04(d,J＝7.1Hz,1H),5.10(s,2H),4.99–4.81(m,2H),4.82–4.75(m,1H),4.68–4.59(m,1H),4.49(d,J＝12.4Hz,1H),3.34(s,1H),3.28(dd,J＝11.8,7.3Hz,2H),3.17(d,J＝5.1Hz,1H),2.17–2.08(m,2H),1.93(d,J＝10.4Hz,1H),1.74(d,J＝9.4Hz,1H),1.53(s,12H),1.22(s,1H)；

¹³C NMR(151MHz,DMSO-d₆)172.69,172.66,160.97,159.95,159.77,159.29,158.72,157.88,157.79,157.78,157.68,157.28,156.91,154.13,154.04,153.91,153.77,151.96,151.92,144.61,142.43,142.40,142.36,132.73,131.89,131.80,131.58,131.45,130.53,130.03,129.78,129.71,129.15,129.07,128.67,128.61,119.38,117.81,117.76,117.68,113.03,112.20,112.10,111.73,110.21,108.48,108.42,107.43,105.81,105.76,105.69,101.11,99.68,99.63,99.56,91.13,89.19,89.01,88.23,88.13,87.99,87.30,87.05,68.57,68.39,54.16,52.73,52.66,52.61,52.19,50.80,50.74,50.68,50.24,49.07,48.03,47.65,47.47,47.26,47.17,47.07,46.77,43.68,43.64,43.60,42.73,40.46,30.15,30.12,30.11,28.99,25.27。

example 906- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-imidazo [4, 5-b)]Pyridin-6-yl) amino Yl) pyrimidin-4-yl)Amino) piperidin-1-yl) pyridazine-3-carbonitriles

Step 1)1- (6-bromo-1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol

To a solution of 6-bromo-3H-imidazo [4,5-b ] pyridine (1.50g,7.57mmol) in DMF (15mL) was added 1-bromopropan-2-ol (2.01g,11.4mmol) and cesium carbonate (3.71g,11.4 mmol). The reaction mixture was stirred at 100 ℃ overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a light yellow solid (1.12g, 57.7%).

MS(ESI,pos.ion)m/z:256.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)8.47(d,J＝2.0Hz,1H),8.45–8.43(m,2H),5.01(d,J＝5.0Hz,1H),4.29(dd,J＝14.2,3.1Hz,1H),4.12–4.06(m,1H),4.01–3.94(m,1H),1.11(d,J＝6.2Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆)(ppm):154.9,148.5,144.5,128.4,122.5,113.4,65.7,52.4,21.1。

Step 2)1- (6- ((diphenylmethylene) amino) -1H-imidazo [4,5-b]Pyridin-1-yl) propan-2-ol

To 1- (6-bromo-1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol (1.12g,4.37mmol) in toluene (20mL) was added Xantphos (256.1mg,0.4426mmol), Pd₂(dba)₃(400.3mg,0.4372mmol), t-BuONa (635.1mg,6.609mmol) and benzophenone imine (1.21g,6.68 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 6h and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a light brown solid (446.5mg, 28.6%).

MS(ESI,pos.ion)m/z:357.1[M+H]⁺。

Step 3)1- (6-amino-1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol

To 1- (6- ((diphenylmethylene) amino) -1H-imidazo [4, 5-b)]Pyridin-1-yl) propan-2-ol (446.5mg,1.253mmol) in THF (10mL) was added aqueous HCl (1.0mL,12 mmol). The reaction mixture was stirred at room temperature for 1h, then concentrated under reduced pressure and the residue obtained was taken up with saturated NaHCO₃The aqueous solution was adjusted to pH 8 and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a brown solid (117.8mg, 48.9%).

MS(ESI,pos.ion)m/z:193.2[M+H]⁺。

Step 4)6- (4- ((5-chloro-2- ((1- (2-hydroxypropyl) -1H-imidazo [4, 5-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 1- (6-amino-1H-imidazo [4, 5-b)]To a solution of pyridin-1-yl) propan-2-ol (117.8mg,0.6128mmol) in 1, 4-dioxane (15mL) was added 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (150.1mg,0.4286mmol), Pd (OAc)₂(9.8mg,0.0436mmol), BINAP (28.6mg,0.0459mmol) and cesium carbonate (210.6mg,0.6464 mmol). The reaction mixture was stirred at 100 ℃ for 3h and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/25) to afford the title compound as a pale yellow solid (120.1mg, 55.4%).

MS(ESI,pos.ion)m/z:506.1[M+H]⁺；

HRMS(ESI,pos.ion)m/z:506.1927[M+H]⁺；C₂₃H₂₅ClN₁₁O[M+H]⁺A theoretical value of 506.1932;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.40(s,1H),8.59(s,1H),8.49(s,1H),8.28(s,1H),7.98(s,1H),7.87(d,J＝9.6Hz,1H),7.43(d,J＝9.7Hz,1H),6.96(d,J＝7.4Hz,1H),5.03(d,J＝3.8Hz,1H),4.72–4.57(m,2H),4.41–4.27(m,1H),4.25–4.15(m,1H),4.14–4.02(m,2H),3.22–3.11(m,2H),2.09–1.99(m,2H),1.75–1.59(m,2H),1.08(d,J＝5.1Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆):(ppm)159.0,158.7,157.2,153.9,146.5,142.9,137.6,134.9,133.5,131.6,128.8,117.9,117.9,111.6,104.0,72.7,65.0,50.6,44.3,31.0,21.4。

example 916- (4- ((5-chloro-2- ((3- (2-hydroxyethyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)2- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) ethanol

To a solution of 6-bromo-3H-imidazo [4,5-b ] pyridine (1.50g,7.57mmol) in DMF (15mL) was added 2-bromoethanol (1.42g,11.4mmol) and cesium carbonate (3.71g,11.4 mmol). The reaction mixture was stirred at 100 ℃ for 3h and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a light yellow solid (1.06g, 57.8%).

MS(ESI,pos.ion)m/z:242.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)8.47(s,1H),8.45(d,J＝2.0Hz,1H),8.36(d,J＝2.0Hz,1H),5.03(t,J＝5.3Hz,1H),4.32(t,J＝5.4Hz,2H),3.79(q,J＝5.3Hz,2H)；

¹³C NMR(151MHz,DMSO-d₆):(ppm)147.9,146.3,144.2,136.7,129.9,113.2,59.5,46.4。

Step 2)2- (6- ((diphenylmethylene) amino) -3H-imidazo [4,5-b]Pyridin-3-yl) ethanol

To 2- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) EtOH (1.06g,4.38mmol) in toluene (20mL) was added Xantphos (256.2mg,0.4428mmol), Pd₂(dba)₃(403.2mg,0.4403mmol), t-BuONa (635.2mg,6.610mmol) and benzophenone imine (1.21g,6.68 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 6h and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a brown solid (694.4mg, 46.3%).

MS(ESI,pos.ion)m/z:343.2[M+H]⁺。

Step 3)2- (6-amino-3H-imidazo [4, 5-b) ]Pyridin-3-yl) ethanol

To 2- (6- ((diphenylmethylene) amino) -3H-imidazo [4, 5-b)]Pyridin-3-yl) ethanol (694.4mg,2.028mmol) in THF (10mL) was added aqueous HCl (1.7mL,20 mmol). The reaction mixture was stirred at room temperature for 1h, then concentrated under reduced pressure and the residue obtained was taken up with NaHCO₃The aqueous solution was adjusted to pH 8 and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a brown solid (239.5mg, 66.3%).

MS(ESI,pos.ion)m/z:179.1[M+H]⁺。

Step 4)6- (4- ((5-chloro-2- ((3- (2-hydroxyethyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 2- (6-amino-3H-imidazo [4, 5-b)]Pyridin-3-yl) ethanol (219.0mg,1.229mmol) in 1, 4-dioxane (15mL) was added 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (155.0mg,0.4426mmol), Pd (OAc)₂(10.2mg,0.0454mmol), BINAP (28.3mg,0.0454mmol) and cesium carbonate (220.4mg,0.6764 mmol). The reaction mixture was stirred at 100 ℃ for 3h and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/25) to afford the title compound as a pale yellow solid (185.3mg, 85.1%).

MS(ESI,pos.ion)m/z:492.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:492.1768[M+H]⁺；C₂₂H₂₃ClN₁₁O[M+H]⁺A theoretical value of 492.1770;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.40(s,1H),8.59(d,J＝1.4Hz,1H),8.51(d,J＝1.7Hz,1H),8.30(s,1H),7.98(s,1H),7.88(d,J＝9.7Hz,1H),7.44(d,J＝9.7Hz,1H),6.96(d,J＝7.8Hz,1H),5.00(t,J＝5.3Hz,1H),4.70–4.60(m,2H),4.41–4.32(m,1H),4.28(t,J＝5.3Hz,2H),3.82–3.75(m,2H),3.19–3.12(m,2H),2.10–2.00(m,2H),1.74–1.60(m,2H)；

¹³C NMR(101MHz,DMSO-d₆):(ppm)159.1,158.7,157.3,153.9,146.3,142.8,137.6,135.1,133.5,131.5,128.8,118.0,117.9,111.6,104.0,59.7,48.6,46.2,44.3,31.0。

Example 926- (4- ((5-chloro-2- ((3- (2-hydroxyethyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino Yl) pyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile

To 2- (6-amino-3H-imidazo [4, 5-b)]Pyridin-3-yl) ethanol (123.5mg,0.6931mmol) in 1, 4-dioxane (15mL) was added 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) nicotinonitrile (200.1mg,0.5730mmol), Pd (OAc)₂(13.6mg,0.0606mmol), BINAP (36.4mg,0.0585mmol) and cesium carbonate (286.3mg,0.8787 mmol). The reaction mixture was stirred at 100 ℃ for 3h and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/25) to afford the title compound as a pale yellow solid (95.6mg, 34.0%).

MS(ESI,pos.ion)m/z:491.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:491.1822[M+H]⁺,C₂₃H₂₄ClN₁₀O[M+H]⁺A theoretical value of 491.1818;

¹H NMR(400MHz,DMSO-d₆):(ppm)9.39(s,1H),8.59(s,1H),8.50(s,2H),8.29(s,1H),7.97(s,1H),7.85(d,J＝8.6Hz,1H),7.00(d,J＝8.8Hz,1H),6.94(d,J＝6.9Hz,1H),5.00(t,J＝5.1Hz,1H),4.61–4.49(m,2H),4.38–4.23(m,3H),3.84–3.74(m,2H),3.14–2.99(m,2H),2.06–1.93(m,2H),1.70–1.52(m,2H)。

¹³C NMR(101MHz,DMSO-d₆):(ppm)159.4,158.7,157.3,153.9,153.1,146.3,142.8,140.4,137.6,135.1,133.5,119.2,117.9,106.9,104.0,95.3,59.7,48.8,46.2,44.3,31.1。

example 936- (4- ((5-chloro-2- ((3- (2-hydroxypropyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino Yl) pyrimidine-4-Yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

Step 1)1- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol

To a solution of 6-bromo-3H-imidazo [4,5-b ] pyridine (2.50g,12.6mmol) in DMF (15mL) was added 1-bromopropan-2-ol (3.35g,19.0mmol) and cesium carbonate (6.23g,19.1 mmol). The reaction mixture was stirred at 100 ℃ overnight and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/20) to afford the title compound as a light yellow solid (1.10g, 34.0%).

MS(ESI,pos.ion)m/z:256.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)8.43(d,J＝2.4Hz,1H),8.43(s,1H),8.34(d,J＝2.0Hz,1H),5.04(d,J＝4.9Hz,1H),4.23(dd,J＝13.6,3.7Hz,1H),4.14–4.09(m,1H),4.08–4.02(m,1H),1.08(d,J＝6.1Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆):(ppm)148.0,146.4,144.2,136.5,129.8,113.2,64.9,50.8,21.3。

Step 2)1- (6- ((diphenylmethylene) amino) -3H-imidazo [4,5-b]Pyridin-3-yl) propan-2-ol

To 1- (6-bromo-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol (1.10g,4.30mmol) in toluene (15mL) was added Xantphos (253.1mg,0.4374mmol), Pd₂(dba)₃(396.8mg,0.4333mmol), t-BuONa (620.3mg,6.455mmol) and benzophenone imine (1.21g,6.68 mmol). The reaction mixture was stirred at 100 ℃ under nitrogen for 6h and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM (v/v) ═ 1/25) to afford the title compound as a brown solid (446.5mg, 29.2%).

MS(ESI,pos.ion)m/z:357.2[M+H]⁺。

Step 3)1- (6-amino-3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol

To 1- (6- ((diphenylmethylene) amino) -3H-imidazo [4, 5-b)]Pyridin-3-yl) propan-2-ol (446.5mg,1.246mmol) in THF (10mL) was added aqueous HCl (1.0mL,12 mmol). The reaction mixture was stirred at room temperature for 1h, then concentrated under reduced pressure. The residue obtained is NaHCO₃The aqueous solution was adjusted to pH 8 and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/10) to afford the title compound as a brown solid (166.6mg, 69.6%).

MS(ESI,pos.ion)m/z:193.2[M+H]⁺。

Step 3)6- (4- ((5-chloro-2- ((3- (2-hydroxypropyl) -3H-imidazo [4, 5-b)]Pyridin-6-yl) amino) Pyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile

To 1- (6-amino-3H-imidazo [4, 5-b)]To a solution of pyridin-3-yl) propan-2-ol (166.6mg,0.8667mmol) in 1, 4-dioxane (15mL) was added 6- (4- ((2, 5-dichloropyrimidin-4-yl) amino) piperidin-1-yl) pyridazine-3-carbonitrile (200.0mg,0.5711mmol), Pd (OAc)₂(15.2mg,0.0677mmol), BINAP (36.8mg,0.0591mmol) and cesium carbonate (280.3mg,0.8603 mmol). The reaction mixture was stirred at 100 ℃ for 3h and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (MeOH/DCM (v/v) ═ 1/25) to afford the title compound as a pale yellow solid (100.0mg, 34.6%).

MS(ESI,pos.ion)m/z:506.2[M+H]⁺；

HRMS(ESI,pos.ion)m/z:506.1934[M+H]⁺,C₂₃H₂₅ClN₁₁O[M+H]⁺A theoretical value of 506.1927;

¹H NMR(600MHz,DMSO-d₆):(ppm)9.43(s,1H),8.59(d,J＝1.9Hz,1H),8.39(s,1H),8.26(s,1H),7.99(s,1H),7.87(d,J＝9.7Hz,1H),7.41(d,J＝9.7Hz,1H),6.91(d,J＝8.0Hz,1H),5.09(d,J＝4.5Hz,1H),4.62–4.52(m,2H),4.44–4.35(m,1H),4.23–4.16(m,1H),4.09–3.98(m,2H),3.21–3.14(m,2H),2.04–1.97(m,2H),1.74–1.64(m,2H),1.09(d,J＝5.8Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆):(ppm)159.1,158.7,157.3,153.8,151.4,146.2,138.0,133.2,131.5,128.8,126.8,117.9,111.6,109.3,104.3,65.6,52.2,47.9,44.1,30.9,21.3。

biological assay

The LC/MS/MS system for analysis included an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate autosampler, a column oven, an Agilent G6430 three-stage quadrupole mass spectrometer with an electrospray ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table a:

TABLE A

Multiple reaction detection scan	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Temperature of drying gas	350℃
Atomizer	0.28MPa
		Flow rate of drying gas	10L/min

Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table B:

TABLE B

Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100X 4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6 mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.

Example A stability in human and rat liver microsomes

The stability of the compounds of the invention in human and rat liver microsomes can be tested by the following two methods:

the method comprises the following steps:

human or rat liver microsomes were incubated in polypropylene tubes in duplicate wells. A typical incubation mixture comprises human or rat liver microsomes (0.5mg protein/mL), the compound of interest (5. mu.M) and a total volume of 200. mu.L of NADPH (1.0mM) potassium phosphate buffer (PBS, 100mM, pH 7.4), dissolved in DMSO, and diluted with PBS to a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37 ℃ in air communication, and after 3 minutes of pre-incubation, protein was added to the mixture and the reaction was started. At different time points (0, 5, 10, 15, 30 and 60min), the reaction was stopped by adding the same volume of ice-cold acetonitrile. The samples were stored at-80 ℃ until LC/MS/MS analysis.

The linear concentration range of each target compound was determined, and then the concentration of the target compound in the human or rat liver microsome incubation mixture was determined by the LC/MS method.

Parallel incubation experiments were performed using denatured microsomes as negative control and dextromethorphan (70 μm) as positive control. Negative control, incubation at 37 ℃ and reaction termination at different time points (0,15 and 60 min); positive controls, incubated at 37 ℃ and reactions terminated at different time points (0, 5, 10, 15, 30 and 60 minutes). Positive and negative control samples were used in each assay to ensure the integrity of the microsomal incubation system.

The method 2 comprises the following steps:

in addition, stability data for the compounds of the invention in human or rat liver microsomes can also be obtained from the following assays:

human or rat liver microsomes were incubated in duplicate wells in polypropylene tubes. A typical incubation mixture comprises human or rat liver microsomes (final concentration: 0.5mg protein/mL), the compound of interest (final concentration: 1.5. mu.M) and a total volume of 30. mu.L of K-buffer solution (containing 1.0mM EDTA,100mM, pH 7.4). Compounds were dissolved in DMSO and diluted with K-buffer to give a final DMSO concentration of 0.2%. After a pre-incubation time of 10 minutes, 15. mu.L of NADPH (final concentration: 2mM) was added for the enzymatic reaction, and the whole assay was carried out in an incubation tube at 37 ℃. At various time points (0,15, 30 and 60 minutes), the reaction was stopped by the addition of 135. mu.L acetonitrile (containing IS). The supernatant was collected by centrifugation at 4000rpm for 10 minutes to remove protein and analyzed by LC-MS/MS.

In the above assay, ketanserin (1 μ M) was selected as a positive control, incubated at 37 ℃ and the reaction was terminated at different time points (0, 15, 30 and 60 min). A positive control sample was included in each assay method to ensure the integrity of the microsomal incubation system.

Data analysis

For each reaction, the concentration of compound (in percent) in human or rat liver microsome incubations was plotted as a percentage of the zero time point to infer intrinsic liver clearance in vivoDivision ratio CL_int(ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.prediction of human pathological clearance from in v and experimental experiments and in vitro methods students with their microorganisms and humans. drug Metabolism and Disposition 2001,29: 1316-1324.). Results see table 1, table 1 for experimental results of the stability of the compounds provided in the examples of the present invention in human and rat liver microparticles.

Table 1 experimental results for the stability of the compounds provided in the examples of the invention in human and rat liver microparticles

NT: no test was made

As can be seen from Table 1, the compounds of the present invention exhibited suitable stability when incubated in human and rat liver microsomes.

Example B pharmacokinetics of mice, rats, dogs and monkeys after intravenous and oral dosing of a compound of the invention Evaluation of science

The present invention evaluates the pharmacokinetic studies of the compounds of the invention in mice, rats, dogs or monkeys. The compounds of the invention were administered as aqueous solutions or 2% HPMC + 1% Tween-80 in water, 5% DMSO + 5% saline solution, 4% MC or in capsule form. For intravenous administration, animals are given a dose of about 0.5, 0.6, 1, or 2 mg/kg. For oral doses (p.o.), rats and mice were 5 or 10mg/kg, and dogs and monkeys were 10 mg/kg. Blood (0.3mL) was taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000rpm for 10 minutes. The plasma solutions were collected and stored at-20 ℃ or-70 ℃ until the LC/MS/MS analysis described above was performed. The results show that the compounds provided by the invention show good pharmacokinetic properties including better absorption and good oral bioavailability when administered intravenously or orally. The results are shown in table 2, and table 2 shows the experimental results of the pharmacological characteristics of the compounds provided in the examples of the present invention in rats.

Table 2 experimental results of pharmacological characterization of the compounds provided in the examples of the present invention in rats

NT: no test was made

As can be seen from Table 2, the compounds of the present invention exhibited very good pharmacokinetic properties including better Absorption (AUC) when administered intravenously or orally_last) And good oral bioavailability (F).

Example C kinase Activity assay

The utility of the disclosed compounds as protein kinase inhibitors can be evaluated by the following experiments.

General description of kinase assays

Kinase assays by detecting incorporation of gamma-³³Myelin Basic Protein (MBP) of P-ATP. Mu.g/ml MBP (Sigma # M-1891) Tris buffered saline (TBS; 50mM Tris pH 8.0,138mM NaCl,2.7mM KCl) was prepared in 60. mu.L/well in high binding white 384 well plates (Greiner). Incubate at 4 ℃ for 24 h. The plate was then washed 3 times with 100. mu.L TBS. Kinase reaction in a total volume of 34. mu.L of kinase buffer (5mM Hepes pH 7.6,15mM NaCl, 0.01% bovine serum albumin (Sigma # I-5506)),10mM MgCl₂1mM DTT, 0.02% TritonX-100). Compounds were dissolved in DMSO and added to each well at a final DMSO concentration of 1%. Each data was assayed in two passes, with at least two trials for each compound assay. For example, the final concentration of the enzyme is 10nM or 20 nM. Addition of unlabeled ATP (10. mu.M) and gamma- ³³P-labelled ATP (2X 10 per well)⁶cpm, 3000Ci/mmol) was started. The reaction was performed at room temperature with shaking for 1 hour. The 384 well plates were washed with 7 × PBS and 50 μ L of scintillation fluid per well was added. The results were checked with a Wallac Trilux counter. It will be apparent to those skilled in the art that this is only one of many detection methods, and that other methods are possible.

IC inhibited by the test method₅₀And/or suppression constant K_i。IC₅₀Defined as the concentration of compound that inhibits 50% of the enzyme activity under the conditions tested. IC was estimated using a dilution factor of 1/2log to generate a curve containing 10 concentration points₅₀Values (e.g., a typical curve is made by compound concentrations of 3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M, 0.03. mu.M, 0.01. mu.M, 0.003. mu.M, 0.001. mu.M, 0.0003. mu.M, 0. mu.M).

JAK1(h)

JAK1(h) in 20mM Tris/HCl pH 7.5, 0.2mM EDTA, 500. mu. M GEEPLYWSFPAKKK, 10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

JAK2(h)

JAK2(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 100. mu. M KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC, 10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, 3% was addedPhosphoric acid solution to stop the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

JAK3(h)

JAK3(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 500. mu. M GGEEEEYFELVKKKK, 10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

TYK2(h)

TYK2(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 250. mu. M GGMEDIYFEFMGGKKK,10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K _MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

FLT3(h)

FLT3(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 50. mu. M EAIYAAPFAKKK,10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

FLT4(h)

FLT4(h) at 8mM MOPS pH 7.0, 0.2mM EDTA, 50. mu. M GGEEEEYFELVKKKK,10mM magnesium acetate and [ gamma-³³P-ATP](specific Activity)Approximately 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

Aurora-A(h)

Aurora-A (h) at 8mM MOPS pH 7.0,0.2mM EDTA, 200. mu.M LRRASLG (Kemptide),10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

Aurora-B(h)

Aurora-B (h) at 8mM MOPS pH 7.0,0.2mM EDTA,30 μ M AKRRRLSSLRA,10mM magnesium acetate and [ gamma-³³P-ATP](specific activity about 500cpm/pmol, 10. mu.M or K_MValue) is present. The reaction was started after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to terminate the reaction. 10 μ L of the reaction solution was spotted on a P30 filter and washed 3 times with 75mM phosphoric acid in 5 minutes and stored in methanol solution immediately before drying and scintillation counting.

The kinase assay of the present invention was performed by Millipore corporation, UK (Millipore UK Ltd, Dundee Technology Park, Dundee DD 21 SW, UK).

Alternatively, the kinase activity of a compound can be measured by KINOMEScan (TM), which is based on the quantitative determination of the compound using an active site-directed competitive binding assay. The test is carried out by combining with three compounds, namely DNA marker enzyme, immobilized ligand and detection compound, and qPCR is carried out by DNA marker to detect the competitive capacity of the compound and the immobilized ligand.

Most experiments were carried out by culturing a kinase-labeled T7 bacteriophage strain in an E.coli host derived from BL21 strain, infecting E.coli in the logarithmic growth phase with T7 bacteriophage, incubating with shaking at 32 ℃ until lysis, centrifuging the lysate to remove cell debris, transferring the remaining kinase to HEK-293 cells, and carrying out qPCR detection with DNA labeling. Streptavidin-coated particles were treated with biotinylated small molecule ligands for 30min at room temperature to generate affinity resins for kinase assays. The ligand particles are blocked by surplus biotin and then passed through blocking Solution (SEABLOCK)^TM(Pierce), 1% bovine serum albumin, 0.05% Tween-20, 1mM DTT) washes unbound ligand to reduce non-specific binding. By binding buffer (20% SEABLOCK) at 1X^TM0.17 x phosphate buffer, 0.05% tween 20,6mM DTT), ligand affinity particles and test compound were subjected to binding reactions, all reactions were performed in 96-well plates with a final reaction volume of 0.135mL, incubated at room temperature with shaking for 1h, washing the affinity particles with washing buffer (1 x phosphate buffer, 0.05% tween 20), resuspended with elution buffer (1 x phosphate buffer, 0.05% tween 20,0.5 μ M non-biotinylated affinity ligand), incubated at room temperature with shaking for 30min, and the kinase concentration in the eluate was determined by qPCR. The kinase activity assay described herein is KINOMEscan by Discovex Rx, Albrae St.Fremont, CA 94538, USA ^TMDepartment, perform the assay. The results of kinase activity assays are shown in tables 3 and 4, table 3 shows the results of JAK1, JAK2 and Aurora-a kinase assays for the compounds provided in the examples of the present invention, and table 4 shows the results of JAK3, TYK2, Aurora-B, FLT4 and FLT3 kinase assays for the compounds provided in the examples of the present invention.

TABLE 3 JAK1, JAK2 and Aurora-A kinase assay results for the compounds of the invention

NT-not tested

TABLE 4 JAK3, TYK2, Aurora-B, FLT4 and FLT3 kinase assay results for the compounds of the invention

NT-not tested

Experiment D inhibition experiment of PMA-induced ICR mouse acute atopic dermatitis by the compound of the present invention

The experimental method comprises the following steps:

female ICR mice were randomly grouped into 4-5 control groups, and 9 groups remained.

Mu.g of PMA was dissolved in 20. mu.l of absolute ethanol, and for the model group and the administration group, each mouse was coated with 20. mu.l of PMA solution on the front and back sides of the right ear of the mouse. For the control group, the application was performed with 20. mu.l of absolute ethanol (without PMA).

For the administration group, the compound was formulated with a vehicle (ethanol/acetone (V/V) ═ 1/1), and administered 30min before and 15min after PMA molding, and 20 μ l of the compound was administered per mouse and applied to the front and back of the right ear. After 6 hours of molding, the thickness of the right ear was measured with a thickness gauge and weighed by pulling it down with an ear-pulling device, and the results of the ear thickness and ear weight of the mouse are expressed as Mean ± Sem. The results of the inhibition of the compound on the thickness of the ears and the increase in the weight of the ears in mice are shown in tables 5-1 to 5-3.

TABLE 5-1 inhibition of ear thickness and ear weight gain by Compound 68 in mice

Note: compared to the model group, "# is p <0.05," # is p < 0.01.

TABLE 5-2 inhibition of growth of ear thickness and ear weight in mice by Compounds 76 and 50

Note: compared to the model group, "# is p <0.05," # is p < 0.01.

TABLE 5-3 inhibition of ear thickness and ear weight gain in mice by Compounds 92 and 65

Note: compared to the model group, "# is p <0.05," # is p < 0.01.

As is clear from tables 5-1, 5-2 and 5-3, the compounds of the present invention have excellent inhibitory effects on the increase in thickness and weight of ears of mice induced by PMA.

As is clear from tables 3 and 4, the compounds of the present invention have inhibitory activities against JAK1, JAK2, JAK3, TYK2, Aurora-A, Aurora-B FLT4 and FLT3 kinases in kinase assays in general, and particularly have more significant inhibitory activities against JAK1 and JAK 2.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation, of the invention as described. It should be understood that the above-described embodiments are exemplary and should not be construed as limiting the present invention, and those skilled in the art may make variations, modifications, substitutions and alterations to the above-described embodiments within the scope of the present invention. Modifications within the scope of the invention or equivalents added to the claims are also possible. All publications or patents cited herein are incorporated by reference.

Claims (16)

1. A compound which is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I),

wherein the content of the first and second substances,

w is

Wherein said (W-10) is optionally substituted with 1, 2 or 3R²Substituted by a group;

t is phenyl, pyridyl or pyridazinyl, wherein T is optionally substituted with 1, 2, 3 or 4R³Substituted by a group;

a is an optionally substituted heteroaryl group of 9 atoms, which is one of the substructures shown below:

wherein, in the sub-structural formula of A, hydrogen on each CH is independently and optionally substituted by R⁴Substituted by radicals, each hydrogen on NH independently being optionally substituted by R⁵Substituted by a group;

z is H or C₁-C₆Alkyl, wherein, said C₁-C₆Alkyl is optionally substituted by 1, 2 or 3R⁹Substituted by a group;

R¹is H, F, Cl, Br, I, NO₂CN or C₁-C₁₂An alkyl group;

each R²And R³Independently F, Cl, Br, I, NO₂CN, OH or C₁-C₁₂An alkyl group;

each R⁴Independently H, F, Cl, Br, I, NO₂、CN、C₁-C₆Alkyl radical, C₁-C₆Hydroxyalkyl or- (CR)⁶R⁷)_nC(＝O)NR^aR^bWherein each of C₁-C₆Alkyl and C₁-C₆Hydroxyalkyl is independently optionally substituted with 1, 2 or 3R⁹Substituted by a group;

each R⁵Independently absent or H, C₁-C₆Alkyl or C₁-C₆Hydroxyalkyl, wherein each of said C₁-C₆Alkyl and C₁-C₆Hydroxyalkyl is independently optionally substituted with 1, 2 or 3R⁹Substituted by a group;

Each R⁶And R⁷Independently H, F, Cl, Br, I, NO₂CN or C₁-C₄Alkyl, wherein, said C₁-C₄Alkyl is optionally substituted by 1, 2 or 3R⁹Substituted by a group;

each R⁹Independently F, Cl, Br, I, CN, NO₂、-NH₂-OH or C₁-C₁₂An alkyl group;

each R^aAnd R^bIndependently is H or C₁-C₆Alkyl, wherein each of the above C₁-C₆Alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, -OH, -NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆Substituted with a substituent of alkylamino;

each n is independently 0, 1, 2, 3 or 4.

2. The compound of claim 1, wherein W is one of the following substructures:

wherein each of the sub-structural formulae represented by the above formulae (W-39) to (W-41) is independently optionally substituted by 1, 2 or 3R²Substituted by a group.

3. The compound of claim 1, wherein Z is H, methyl, ethyl, n-propyl, or isopropyl.

4. The compound of claim 1, wherein R¹Is H, F, Cl, Br, NO₂CN or C₁-C₄An alkyl group.

5. The compound of claim 1, wherein each R²And R³Independently F, Cl, Br, NO₂CN, OH or C₁-C₄An alkyl group.

6. The compound of claim 1, wherein each R⁴Independently H, F, Cl, Br, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃、-CH₂C(CH₃)₂OH or- (CR)⁶R⁷)_nC(＝O)NR^aR^bWherein each of the methyl group, ethyl group, n-propyl group, isopropyl group, sec-propyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and-CH group₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃and-CH₂C(CH₃)₂OH is independently optionally substituted by 1, 2 or 3R⁹Substituted by a group.

7. The compound of claim 1, wherein each R⁵Independently absent or H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃or-CH₂C(CH₃)₂OH, wherein each of said methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH₂OH、-CH₂CH₂OH、-CH(OH)CH₃、-C(CH₃)₂OH、-CH₂CH(OH)CH₃and-CH₂C(CH₃)₂OH is independently optionally substituted by 1, 2 or 3R⁹Substituted by a group.

8. The compound of claim 1, wherein each R⁶And R⁷Independently is H, F, Cl, Br, CN or C₁-C₄Alkyl radical, wherein said C₁-C₄Alkyl is optionally substituted by 1, 2 or 3R⁹Substituted by a group.

9. The compound of claim 1, wherein each R⁹Independently F, Cl, Br, CN, -NH₂-OH or C₁-C₆An alkyl group.

10. The compound of claim 1, wherein each R^aAnd R^bIndependently H, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, wherein each of the above methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, CN, -OH, -NH and the like ₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄Substituted by a substituent of alkylamino.

11. A compound that is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound of one of the following structures:

12. a pharmaceutical composition comprising a compound of any one of claims 1-11, further comprising at least one of a pharmaceutically acceptable adjuvant, excipient, carrier, vehicle.

13. The pharmaceutical composition of claim 12, further comprising an additional therapeutic agent selected from the group consisting of chemotherapeutic agents, antiproliferative agents, phosphodiesterase 4 inhibitors, beta 2-adrenoreceptor agonists, corticosteroids, non-steroidal GR agonists, anticholinergics, antihistamines, anti-inflammatory agents, immunosuppressive agents, immunomodulatory agents, agents for treating atherosclerosis, agents for treating pulmonary fibrosis, and combinations thereof.

14. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to any one of claims 12 to 13 in the manufacture of a medicament for the prevention, treatment or alleviation of a protein kinase mediated disease; wherein the protein kinase-mediated disease is a JAK-mediated disease, FLT 4-mediated disease, FLT 3-mediated disease, Aurora-mediated disease, autoimmune disease, inflammatory disease, transplant rejection, polycythemia vera, essential thrombocythemia, myelofibrosis, chronic obstructive pulmonary disease, asthma, systemic lupus erythematosus, lupus nephritis, psoriasis, eczema, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, organ transplant rejection, tissue transplant rejection, or cell transplant rejection.

15. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to any one of claims 12 to 13 in the manufacture of a medicament for modulating the activity of a protein kinase; wherein the protein kinase is at least one of JAK kinase, FLT3 kinase, FLT4 kinase and Aurora kinase.

16. The use of claim 15, wherein the protein kinase is at least one of JAK1 kinase, JAK2 kinase, JAK3 kinase, TYK2 kinase, Aurora-a kinase, Aurora-B kinase, FLT4 kinase, FLT3 kinase.