CN106749268B - Heteroaromatic compounds and their use in medicine - Google Patents

Abstract

The invention discloses a heteroaromatic compound and application thereof in medicines, and particularly provides a heteroaromatic compound or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition containing the compound; the invention also discloses application of the compound or the pharmaceutical composition thereof in preparing medicines and application thereof in treating autoimmune diseases or proliferative diseases.

Description

Heteroaromatic compounds and their use in medicine

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a heteroaromatic compound with protein kinase inhibitory activity, a pharmaceutical composition containing the heteroaromatic compound, and application of the heteroaromatic compound or the pharmaceutical composition containing the heteroaromatic compound in medicines.

Background

Janus kinases (JAKs) belong to the tyrosine kinase family, consisting of JAK1, JAK2, JAK3 and TYK 2. JAKs play an important role in cytokine signaling. JAK1, JAK2 and TYK2 can inhibit multiple gene expression, whereas JAK3 only plays a role in granulocytes. Cytokine receptors typically function as heterodimers and are therefore not generally a JAK kinase interacting with cytokine receptors.

Each JAK associates preferentially with the intracytoplasmic portion of a discrete cytokine receptor (annu. rev. immunol.1998,16, pp.293-322). JAKs are activated upon ligand binding and initiate signaling by phosphorylating cytokine receptors, which themselves lack intrinsic kinase activity. This phosphorylation creates docking sites on the receptor for other molecules called STAT proteins (signal transducers and activators of transcription), and phosphorylated JAKs bind to a variety of STAT proteins. STAT proteins, or STATs, are DNA binding proteins that are activated by phosphorylation of tyrosine residues and function both as signaling molecules and transcription factors, and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive groups (j.

Genetic biological studies have shown that JAK1 functions by interacting with cytokine receptors such as IFNalpha, IFNgamma, IL-2, IL-6, and JAK1 knockout mice die due to loss of LIF receptor signaling. The characteristic tissues of JAK1 knockout mice are observed, and JAK1 is found to play an important role in cell pathways such as IFN, IL-10, IL-2/IL-4, IL-6 and the like.

Genetic biological studies have shown a link between JAK2 and the single chain, IL-3 and interferon gamma cytokine receptor families. In response, JAK2 knockout mice died of anemia. Kinase-mediated JAK2 mutations are associated with myeloproliferative disorders in humans, including polycythemia vera, idiopathic thrombocythemia, chronic idiopathic myelofibrosis, myelogenic tissue transformation with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, and the like.

JAK3 specifically acts on the gamma cytokine receptor chain, which is present in cytokine receptors such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK3 plays an important role in the growth, proliferation and mutation of lymphocytes, and serious immune deficiency can be caused by abnormality. It has now been examined that JAK3 protein levels in XSCID populations are severely reduced or are deficient in their common gamma chain gene, showing that the immunosuppressive effect is due to blocking signaling through the JAK3 pathway. Animal studies have shown that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but also constitutively requires JAK3 to maintain T cell function. Based on their role in regulating lymphocytes, JAK3 and JAK 3-mediated pathways are used to modulate the indications for immunosuppression. JAK3 has been implicated in the mediation of many abnormal immune responses, such as allergy, asthma, autoimmune diseases such as suppression of transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic malignancies such as leukemia, lymphoma.

JAK3 inhibitors are useful therapeutics as immunosuppressive agents for: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia and other conditions where immunosuppression is appropriate.

Non-hematopoietic expression of JAK3 has also been reported, although the functional significance is unclear (j. immunol.,2002,168: 2475-2482). Since bone marrow transplantation for SCID is curative (Blood,2004,103:2009-2018), it appears that JAK3 is unlikely to have the necessary non-redundant function in other tissues or organs. Therefore, in contrast to other targets for immunosuppressive drugs, the restricted distribution of JAK3 is attractive. Active agents acting on molecular targets with expression limited to the immune system may lead to optimal efficacy: the toxicity ratio. Thus, in theory, targeting JAK3 would provide immunosuppression in situations where it is needed (i.e., on cells actively involved in the immune response) without causing any effect outside of these cell populations. Although in various STATs ^-/-Defective immune responses have been described in strains (J.Investig.Med.,1996,44: 304-311; Curr.Opin.cell biol.,1997,9:233-239), but the widespread distribution of STATs and the fact that these molecules lack enzymatic activity that can be targeted with small molecule inhibitors have contributed to their non-selectivity as key targets for immunosuppression.

TYK2 acts on the receptor complexes of type I interferons, IL-6, IL-10, IL-12, IL-23 and other cytokines. In agreement, primary cells derived from TYK 2-deficient humans present obstacles to signaling in type I interferons, IL-6, IL-10, IL-12, IL-23.

Bruton's Tyrosine Kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. BTK plays a crucial role in B-cell signaling pathways that link cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

B-cells signal through the B-cell receptor (BCR) and can produce a wide range of biological line production, which in turn depends on the developmental stage of the B-cell. The magnitude and duration of the BCR signal must be precisely adjusted. Disorganized BCR-mediated signaling can lead to deregulated B-cell activation and/or the formation of pathogenic autoantibodies, leading to multiple autoimmune and/or inflammatory diseases. Mutations in BTK in humans result in the production of X-chain immunoglobulin blood (XLA). This disease is associated with impaired maturation of B-cells, reduced immunoglobulin production, impaired T-cell independent immune responses and a marked attenuation of sustained calcium signaling upon BCR stimulation.

The effects of BTK on allergic disorders and/or autoimmune and/or inflammatory diseases have been demonstrated in BTK-deficient mouse models. For example, in a standard murine preclinical (preclinical) model of Systemic Lupus Erythematosus (SLE), BTK deletion has been shown to significantly alter disease progression.

There is a large body of evidence demonstrating the role of B-cells and the human immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Inhibition of BTK activity can be used to treat allergic disorders and/or autoimmune and/or inflammatory diseases, such as SLE, rheumatoid arthritis, multiple vasculitis (multiple vasculitides), Idiopathic Thrombocytopenic Purpura (ITP), myasthenia gravis, allergic rhinitis, and asthma. In addition, BTK has been reported to play a role in apoptosis, and thus, methods of inhibiting BTK activity are useful in the treatment of cancer, as well as in the treatment of B-cell lymphoma and non-leukemias.

Epidermal Growth Factor Receptor (EGFR) is a receptor type tyrosine kinase, a multifunctional glycoprotein widely distributed on cell membranes of various tissues of human bodies, and is an avian erythroblastic leukemia virus (v-erb-b) oncogene homolog. Human EGFR/HER1/ErbB-1 and HER-2(human epidemal growth factor receptor-2)/ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4, etc. are assigned to the HER/ErbB family and belong to Protein Tyrosine Kinases (PTKs). They are all single polypeptide chains, encoded by genes located on different chromosomes. EGFR and the like are over-expressed in tumors of epithelial origin, such as head and neck squamous cell carcinoma, breast cancer, rectal cancer, ovarian cancer, prostate cancer, non-small cell lung cancer and the like, and the expression of the EGFR and the like is related to phenomena such as cancer cell proliferation, metastasis and the like.

At present, acquired drug resistance in the tumor drug treatment process becomes a world problem and is also a reason for ineffective tumor treatment. EGFR-TKI drug (erlotinib or gefitinib) is a very important target drug in the treatment of advanced non-small cell lung cancer, but the clinical application is limited by the appearance of acquired drug resistance, so that the development mechanism of the acquired drug resistance needs to be actively explored. The mechanism of acquired drug resistance of EGFR-TKI drugs is not completely clarified at present. Existing studies have shown that the development of EGFR-TKI acquired resistance may be primarily associated with two mechanisms: secondary exon T790M mutation and MET secondary amplification.

The T790M mutation is a point mutation in the EGFR 20 exon and is one of the more currently recognized mechanisms of drug resistance. T790M is located at the entrance of the binding pocket of EGFR and ATP, and the size of its side chain directly affects the binding ability of EGFR and ATP. The T790M mutation sterically blocks the EGFR inhibitor's interaction with the ATP binding site, increasing the affinity of EGFR for ATP, and thus rendering the cell resistant to EGFR inhibitors. Originally, T790M was found only in NSCLC patient specimens that failed treatment, but was subsequently found in specimens that were not treated with any treatment, so it is presently believed that this mutation is also present in TKI-untreated tumor tissue, but is found in only a few clonal cells that were selected after treatment due to their resistance to TKI.

Accordingly, there is a need to provide compounds that inhibit protein kinases for the treatment of diseases such as autoimmune diseases, inflammatory diseases and cancer.

Summary of the invention

The heteroaromatic compounds of the invention are effective in inhibiting the activity of protein kinases including, but not limited to: ab, Akt, ALK, A-Raf, B-Raf, Brk, BLK, BTK, BMX, Cdk, CDK, CHK, C-Raf-1, Csk, EGFR, EphA, EphB, EGFR T790, Erk, Fak, FGFR, Flt, Fms, Frk, Fyn, Gsk3.alpha, Gsk3.beta, HCK, Her/Erbb, IGF1, IKK.beta, Irak, Itk, JAK, Jnk, Kdr, Kit, LCK, MAP2K, MAP4K, MAPKAPPK, Met, MLK, Pp, PDG, FRA, Pipk, Pink, Pik, TXK, Rock, TXK, YK, TXK, TK, TXK, TK. In particular, the compound has stronger inhibition effect on BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M. Such compounds would play a potential role in the treatment of autoimmune and/or inflammatory diseases and/or cancer.

The compound of the invention has an inhibitory effect on the activity of protein kinase. It is further desirable that the compounds of the invention have multiple inhibitory functions and may inhibit BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M. In particular, the compounds and pharmaceutically acceptable pharmaceutical compositions of the present invention are effective as BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M inhibitors.

In one aspect, the invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound represented by formula (III):

wherein each L¹，Cy，L²，R²，R³，R⁴，W¹，W²，R^5xAnd R^5aHave the meaning as described in the present invention.

In some of these embodiments, L is¹is-O-, -N (R)^1a)-，-S(＝O)_p-，-C(＝O)-，-C(＝O)-N(R^1a)-，-S(＝O)_p-N(R^1a)-，-(CR^mR^w)_g-or- (CR)^mR^w)_n-CR^1a＝CR^1a-(CR^mR^w)_n-；

Wherein each R^1a，R^m，R^wP, g and n have the meanings given in the description.

In some of these embodiments, L is²Is a bond, -O-, -N (R)^1a)-，-CH₂-N(R^1a)-，-CH(CH₃)-N(R^1a)-，-C(CH₃)₂-N(R^1a)-，-C(＝O)-N(R^1a) -or-S (═ O)_p-N(R^1a)-；

Wherein each R^1aAnd p has the meaning as described in the present invention.

In some of these embodiments, each R is ^1aIndependently of one another is hydrogen, deuterium, C_1-3Alkyl radical, C_2-4Alkenyl or C_2-4Alkynyl.

In some of these embodiments, Cy is C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, C_2-10Heterocyclic radical, C_6-10Aryl or C_1-9A heteroaryl group; cy is independently optionally substituted with one or more R^ySubstituted;

wherein each R^yHave the meaning as described in the present invention.

In some of these embodiments, each R is^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylamino radical C_1-6Alkylamino or halogeno C_1-6An alkyl group.

In some of these embodiments, R is²Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl.

In some of these embodiments, each R is³And R⁴Independently are hydrogen, deuterium, fluorine,chlorine, bromine, iodine, cyano, carboxyl, - (CR)^mR^w)_n-NR^m1R^w1，C_1-6Alkyl, halo C_1-6Alkyl or C_2-10Heterocyclyl radical C_1-6An alkyl group;

wherein each n, R^m，R^m1，R^wAnd R^w1Have the meaning as described in the present invention.

In some of these embodiments, each R is^mAnd R^wIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C_1-6Alkyl, cyano-substituted C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_2-10Heterocyclyl or C_2-10Heterocyclyl radical C _1-6An alkyl group.

In some of these embodiments, each R is^m1And R^w1Independently of one another is hydrogen, C_1-6Alkyl, cyano-substituted C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_6-10Aryl radical, C_1-9Heteroaryl group, C_2-10Heterocyclyl or C_2-10Heterocyclyl radical C_1-6An alkyl group.

In some of these embodiments, R is^m1、R^w1Together with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 12 atoms.

In some of these embodiments, each W is¹And W²Independently is N or CR^5y；

Wherein each R^5yHave the meaning as described in the present invention.

In some of these embodiments, each R is^5xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkylamino radical, C_1-6Alkylamino radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkylamino radical, C_1-6Alkylthio, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl, hydroxy-substituted C_1-6Alkylamino, cyano-substituted C_1-6Alkyl, cyano-substituted C_1-6Alkoxy, cyano-substituted C_1-6Alkylamino or amino substituted C_1-6An alkyl group; each R^5xIndependently optionally substituted by one or more R¹³Substituted;

wherein each R¹³Have the meaning as described in the present invention.

In some of these embodiments, each R is^5yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkylamino radical, C_1-6Alkylamino radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkylamino radical, C_1-6Alkylthio, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy-substituted C_1-6Alkyl, hydroxy-substituted C_1-6Alkylamino, cyano-substituted C_1-6Alkyl, cyano-substituted C_1-6Alkoxy, cyano-substituted C_1-6Alkylamino or amino substituted C_1-6An alkyl group; each R^5yIndependently optionally substituted by one or more R¹³Substituted;

wherein each R¹³Have the meaning as described in the present invention.

In some of these embodiments, R is^5aIs heteroarylalkyl or heteroarylcycloalkyl; r^5aIndependently optionally substituted by one or more R¹⁴，R^14xOr R^14ySubstituted;

wherein each R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In some embodiments, each n is independently 0, 1, 2, 3, or 4.

In some of these embodiments, g is 1, 2, 3, or 4.

In some embodiments, each p is independently 0, 1 or 2.

In some of these embodiments, each R is¹³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, cyano-substituted C_1-6alkyl-C (═ O) -, C_1-6Alkylamino, halogeno C_1-6Alkyl, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group.

In some of these embodiments, each R is¹⁴Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, cyano-substituted C_1-6alkyl-C (═ O) -, C_1-6Alkylamino, halogeno C_1-6Alkyl, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group.

In some of these embodiments, each R is^14xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, cyano-substituted C_1-6alkyl-C (═ O) -, C_1-6Alkylamino, halogeno C_1-6Alkyl, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group.

In some of these embodiments, each R is^14yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C _1-6alkyl-C (═ O) -, cyano-substituted C_1-6alkyl-C (═ O) -, C_1-6Alkylamino, halogeno C_1-6Alkyl, hydroxy-substituted C_1-6Alkyl or cyano-substituted C_1-6An alkyl group.

In some embodiments, when R is^14xAnd R^14yWhen attached to the same carbon atom, R^14xAnd R^14yOptionally forming a ring of 3-8 atoms together with the carbon atoms.

In still other embodiments, Cy is C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl radical, C_2-6Heterocyclic radical, C_6-10Aryl or C_1-6A heteroaryl group; cy is independently optionally substituted with one or more R^ySubstituted;

wherein each R^yHave the meaning as described in the present invention.

In still other embodiments, Cy is cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, indenyl, naphthyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pentazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; or each Cy is independently of the substructure:

cy is independently optionally substituted with one or more R^ySubstituted;

wherein each R^yHave the meaning as described in the present invention.

In still other embodiments, each R is ^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylamino radical, C_1-3Alkylamino radical C_1-4Alkylamino or halogeno C_1-3An alkyl group.

In other embodiments, the present invention relates to a compound of formula (V) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound of formula (V):

wherein each L¹，R²，R³，R⁴，R^5x，R^5yAnd R^5aHave the meaning as described in the present invention.

In still other embodiments, L is¹is-O-, -S-or- (CH)₂)-。

In still other embodiments, R is²Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-3Alkyl radical, C_2-4Alkenyl or C_2-4Alkynyl.

In still other embodiments, each R is³And R⁴Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxyl, - (CR)^mR^w)_n-NR^m1R^w1，C_1-3Alkyl, halo C_1-3Alkyl or C_2-10Heterocyclyl radical C_1-3An alkyl group;

wherein each n, R^m，R^m1，R^wAnd R^w1Have the meaning as described in the present invention.

In still other embodiments, each R is^mAnd R^wIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C_1-4Alkyl, cyano-substituted C_1-4Alkyl, halo C _1-3Alkyl radical, C_1-3Alkoxy radical C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_2-10Heterocyclyl or C_2-10Heterocyclyl radical C_1-3An alkyl group.

In still other embodiments, each R is^m1And R^w1Independently of one another is hydrogen, C_1-4Alkyl, cyano-substituted C_1-4Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_2-10Heterocyclic ringsRadical or C_2-10Heterocyclyl radical C_1-3An alkyl group.

In still other embodiments, R is^m1、R^w1Together with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 12 atoms.

In still other embodiments, R is^5aIs C_1-9Heteroaryl C_1-6Alkyl or C_1-9Heteroaryl C_3-8A cycloalkyl group; each R^5aIndependently optionally substituted by one or more R¹⁴，R^14xOr R^14ySubstituted;

wherein each R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, R is^5aIs C_1-6Heteroaryl C_1-4Alkyl or C_1-6Heteroaryl C_3-6A cycloalkyl group; each R^5aIndependently optionally substituted by one or more R¹⁴，R^14xOr R^14ySubstituted;

wherein each R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, R is^5aIs pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, triazinylmethyl, triazinylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, pyridylcyclopropyl, pyrimidylcyclopropyl, thiazolylmethyl, thiazolylethyl or thiazolylpropyl; each R ^5aIndependently optionally substituted by one or more R¹⁴，R^14xAnd R^14ySubstituted;

wherein each R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, the present invention relates to a compound represented by formula (V-a) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-a):

wherein:

y is CH or N;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, the present invention relates to a compound represented by formula (V-b) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-b):

wherein:

y is CH or N;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, the present invention relates to a compound of formula (V-c) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (V-c):

Wherein:

each Y is independently CH or N;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, the present invention relates to a compound represented by formula (V-d) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-d):

wherein:

each T²And T³Independently CH or N;

T¹is-O-, -S-or-NH-;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In still other embodiments, each R is^5xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-5Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkoxy radical, C_1-3Alkoxy radical C_1-4Alkylamino radical, C_1-4Alkylamino radical, C_1-3Alkylamino radical C_1-3Alkyl radical, C_1-4Alkylamino radical C_1-4Alkylamino radical, C_1-4Alkylthio, halo C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkylamino, cyano-substituted C_1-4Alkyl, cyano-substituted C_1-4Alkoxy, cyano-substituted C_1-4Alkylamino or amino substituted C _1-4An alkyl group; each R^5xIndependently optionally substituted by one or more R¹³Substituted;

wherein each R¹³Have the meaning as described in the present invention.

In still other embodiments, each R is^5yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-5Alkyl radical, C_2-6Alkenyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkoxy radical, C_1-3Alkoxy radical C_1-4Alkylamino radical, C_1-4Alkylamino radical, C_1-3Alkylamino radical C_1-3Alkyl radical, C_1-4Alkylamino radical C_1-4Alkylamino radical, C_1-4Alkylthio, halo C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkylamino, cyano-substituted C_1-4Alkyl, cyano-substituted C_1-4Alkoxy, cyano-substituted C_1-4Alkylamino or amino substituted C_1-4An alkyl group; each R^5yIndependently optionally substituted by one or more R¹³Substituted;

wherein each R¹³Have the meaning as described in the present invention.

In still other embodiments, each R is¹³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkoxy radical C_1-4Alkyl radical, C_1-3alkyl-C (═ O) -, cyano-substituted C_1-3alkyl-C (═ O) -, C_1-3Alkylamino, halogeno C_1-3Alkyl, hydroxy-substituted C_1-3Alkyl or cyano-substituted C _1-3An alkyl group.

In still other embodiments, each R is¹⁴Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkoxy radical C_1-4Alkyl radical, C_1-3alkyl-C (═ O) -, cyano-substituted C_1-3alkyl-C (═ O) -, C_1-3Alkylamino, halogeno C_1-3Alkyl, hydroxy-substituted C_1-3Alkyl or cyano-substituted C_1-3An alkyl group.

In still other embodiments, each R is^14xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkoxy radical C_1-4Alkyl radical, C_1-3alkyl-C (═ O) -, cyano-substituted C_1-3alkyl-C (═ O) -, C_1-3Alkylamino, halogeno C_1-3Alkyl, hydroxy-substituted C_1-3Alkyl or cyano-substituted C_1-3An alkyl group.

In still other embodiments, each R is^14yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkoxy radical C_1-4Alkyl radical, C_1-3alkyl-C (═ O) -, cyano-substituted C_1-3alkyl-C (═ O) -, C_1-3Alkylamino, halogeno C_1-3Alkyl, hydroxy-substituted C_1-3Alkyl or cyano-substituted C_1-3An alkyl group.

In other embodiments, when R is ^14xAnd R^14yWhen attached to the same carbon atom, R^14xAnd R^14yOptionally forming a ring of 3-6 atoms together with the carbon atoms.

In another aspect, the present invention includes, but is in no way limited to, a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having one of the following structures:

one aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating autoimmune disease.

Another aspect of the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the manufacture of a medicament for the prevention, treatment or alleviation of an autoimmune disease or a proliferative disease in a patient.

In some embodiments, the autoimmune disease described herein is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, or lymphoma.

In some embodiments, the proliferative disease of the invention is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the preparation of a medicament for inhibiting or modulating protein kinase activity in a biological sample.

In some embodiments, the protein kinase is BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR, or EGFR T790M.

One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating autoimmune disease.

Another aspect of the invention relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for the prevention, treatment or treatment of an autoimmune disease or a proliferative disease in a patient, and for lessening the severity thereof.

In some embodiments, the autoimmune disease described herein is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, or lymphoma.

In some embodiments, the proliferative disease of the invention is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for inhibiting or modulating protein kinase activity in a biological sample.

In some embodiments, the protein kinase is BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR, or EGFR T790M.

In one aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula (III) or (V).

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (III) or (V).

The foregoing has outlined only certain aspects of the present invention and is not intended to be limited in these or other respects to the details described herein.

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. One 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 found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

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 that has two or more chiral neutrals 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-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, 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 may be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Inter)science,New York,1981)；Principles of AsymmetricSynthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(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 (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. 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, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be 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. Wherein said substituent may be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amido, sulfonyl, aminosulfonyl, and the like.

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 "or" C_1-6Alkyl "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. Unless otherwise indicated, the manner in which the linker structural formula is written does not imply any orientation of the linker. 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. For example, of the formula Cy, each via L ¹And L²Attached to the rest of the molecule, when Cy is an aryl or heteroaryl group, this is understood to be an "aryl group"Or "heteroaryl" represents an attached arylene group or heteroarylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in one embodiment, the alkyl group contains 1 to 8 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

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) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 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 optionally be mono-substitutedOne or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, 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) Allyl (CH)₃-CH ═ CH-), oxo butenyl (CH)₃-C (═ O) -CH ═ CH-) and the like.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp triple bond.

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. 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) And so on.

The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy groups have the meaning described herein, examples of which include, but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.

The term "alkoxyalkoxy" denotes an alkoxy group substituted by one or more alkoxy groups, wherein the alkoxy groups have the meaning as described herein.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, -CH₂F，-CHF₂，-CF₃，-CH₂Cl，-CH₂CF₃，-CH₂CH₂CF₃，-OCH₂F，-OCF₃And the like.

The terms "cyano-substituted alkyl", "cyano-substituted alkoxy" or "cyano-substituted alkylamino" mean that an alkyl group, an alkoxy group or an alkylamino group is substituted with one or more cyano groups.

The term "hydroxy-substituted alkyl" or "hydroxy-substituted alkylamino" means that the alkyl group or alkylamino group is substituted with one or more hydroxy groups, examples of which include, but are not limited to, -CH ₂OH，-CH₂CH₂OH，-CH₂CH₂CH₂OH，-CH₂C(CH₃)₂OH，-NHCH₂CH₂OH，-NHCH(OH)CH₂OH and the like.

The term "alkylthio" refers to C_1-10A linear or branched alkyl group is attached to a divalent sulfur atom, the alkyl group having the meaning as described herein.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkenyl" denotes mono-, bi-or tricyclic mono-, systems containing 3 to 12 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms, which are monovalent or polyvalent, non-aromatic, and contain at least one carbon-carbon double bond.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein no aromatic ring is included in the monocyclic, bicyclic, or tricyclic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl groups may be carbon-based or Nitrogen radical, 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 heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 2-pyrrolidinyl), 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl, thiomorpholinyl, (1-oxo) -thiomorpholinyl, (1, 1-dioxo) -thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, tetrahydropyridinyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents as described herein. 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 this variable recites "heterocyclyl", it is to be understood that this "heterocyclyl" represents an attached heterocyclylene group.

The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein heterocyclyl and alkyl groups have the meaning as indicated in the present invention.

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.

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 (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

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

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 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 comprises a ring of 3 to 7 atoms with one or more attachment points 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, indenyl, naphthyl and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl, 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, 1,3, 5-triazinyl, pyrimidinonyl, pyridonyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), and the like.

The term "pyrazolyl" refers to 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 1H-pyrazol-5-yl.

The term "heteroarylalkyl" denotes an alkyl group substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl groups have the meaning as described herein, examples of which include, but are not limited to, pyridin-2-ylmethyl, pyridin-2-ylethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-2-ylethyl, pyrimidin-2-ylpropyl, pyrimidin-4-ylmethyl, pyrimidin-5-ylmethyl, thiazol-2-ylmethyl, thiazol-4-ylmethyl, thiazol-5-ylmethyl, imidazol-2-ylethyl, pyrazin-2-ylmethyl, and so on.

The term "heteroarylcycloalkyl" means a cycloalkyl group substituted with one or more heteroaryl groups, wherein the cycloalkyl and heteroaryl groups have the meaning as set forth herein, and examples include, but are not limited to, (pyridin-2-yl) cyclopropyl, (pyridin-3-yl) cyclopropyl, (pyridin-4-yl) cyclopropyl, (pyrimidin-2-yl) cyclopropyl, (pyrimidin-4-yl) cyclopropyl, (pyrimidin-5-yl) cyclopropyl, and the like.

The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO ₂H。

The term "alkylamino" or "Alkylamino "includes" N-alkylamino "and" N, N-dialkylamino "in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C_1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "alkoxyalkylamino" means an alkylamino group substituted with one or more alkoxy groups, wherein the alkoxy and alkylamino groups have the meaning as described herein.

The term "alkylaminoalkylamino" means that an alkylamino group is substituted with one or more alkylamino groups, wherein the alkylamino group has the meaning as described herein. Examples of such include, but are not limited to-NHCH₂NHCH₃，-NHCH₂NHCH₂CH₃，-NHCH₂CH₂N(CH₃)₂，-N(CH₃)CH₂CH₂NHCH₂CH₃And the like.

The term "alkylaminoalkyl" denotes an alkyl group substituted with one or more alkylamino groups, wherein alkyl and alkylamino groups have the meaning as described herein.

The term "aminoalkyl" or "amino-substituted alkyl" includes C substituted with one or more amino groups_1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups_1-6"lower aminoalkyl" radicals.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (III) or (V). 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 the ester can be used as the precursor in the prior inventionThe medicines include esters of benzene, aliphatic (C)_1-24) 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.Sympossium Series, Edward B.Roche, ed., Bioversible arrays in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature review Drug Discovery,2008,7,255-270, and S.J.Herer et al, Prodrugs of Pharmaceutical and pharmaceuticals, Journal of chemical Chemistry,2008,51, 2328-5.

"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, descriptive acceptable salts in detail in pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate Salts, tartrates, citrates, succinates, malonates or they can be obtained by other methods described in the literature, for example by 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, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺(C_1-4Alkyl 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 suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as 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.

As used herein, "autoimmune disease" or "autoimmune disease" refers to any disease of the collection of tissue damage associated with humoral or cell-mediated responses to the body's own components. Examples of autoimmune diseases include lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid diseases, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia and lymphoma.

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 (such as 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 stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (livercancer), bladder cancer, 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, hepatic carcinoma (hepatoma), anal cancer, penile cancer and head and neck cancer.

The term "biological specimen" as used herein refers to a specimen outside a living body, including, but in no way limited to, cell culture or cell extraction; biopsy material obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, or other living tissue liquid material and extracts thereof. Inhibiting or modulating kinase activity in a biological sample, particularly BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR, or EGFR T790M kinase activity, can be used for a variety of uses well known to those skilled in the art. Such uses include, but are in no way limited to, blood transfusion, organ transplantation, biological specimen storage, and biological identification.

Description of the Compounds of the invention

The compounds and pharmaceutical compositions thereof of the present invention have potential utility in the treatment of autoimmune diseases or cancer.

In one aspect, the present invention relates to a heteroaromatic compound or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

Wherein each X, X¹，X²，X³And R¹Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound represented by formula (II):

wherein each X, X³，R⁰，R¹，L¹，Cy，L²，L³，R²，R³And R⁴Having the structure as in the inventionThe above meanings are given.

In some embodiments, the present invention relates to a compound of formula (IIa) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (IIa):

wherein:

each Z¹、Z²And Z³Independently is N or CR^y；

Each R^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylamino radical C_1-6Alkylamino or halogeno C_1-6An alkyl group;

wherein each X, X³，R⁰，R¹，L¹，L²，L³，R²，R³And R⁴Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound of formula (IIb) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (IIb):

Wherein:

m is 0, 1 or 2;

q is 0, 1, 2 or 3;

wherein each X, X³，R¹，L¹，L³，R²，R³And R⁴Have the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound represented by formula (III):

wherein:

each W¹And W²Independently is N or CR^5y；

Wherein each L¹，Cy，L²，R²，R³，R⁴，R^5x，R^5yAnd R^5aHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IV) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound represented by formula (IV):

wherein:

each V, Z²And Z³Independently is N or CR^y；

Each R^yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylamino radical C_1-6Alkylamino or halogeno C_1-6An alkyl group.

Wherein each L¹，R²，R³，R⁴，R^5x，R^5yAnd R^5aHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (V) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound represented by formula (V):

wherein each L¹，R²，R³，R⁴，R^5x，R^5yAnd R^5aHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound represented by formula (V-a) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-a):

wherein:

y is CH or N;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound represented by formula (V-b) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-b):

wherein:

Y is CH or N;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound represented by formula (V-c) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-c):

wherein:

each Y is independently CH or N;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In some embodiments, the present invention relates to a compound represented by formula (V-d) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound represented by formula (V-d):

wherein:

each T²And T³Independently CH or N;

T¹is-O-, -S-or-NH-;

s is 0, 1, 2, 3 or 4;

each R^5x，R^5y，R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In some of these embodiments, X is N or CR^x；

Wherein R is^xHave the meaning as described in the present invention.

In some of these embodiments, each X is ¹And X²Independently of one another is N, CR⁰Or CR^x1(ii) a Provided that X is¹And X²At least one of which is CR^x1；

Wherein each R⁰And R^x1Have the meaning as described in the present invention.

In some of these embodiments, each R is^x1Independently the sub-formulae:

each R^x1Independently optionally substituted by one or more R⁵Substitution;

wherein each R⁵Have the meaning as described herein;

wherein each L¹，Cy，L²，L³，R²，R³And R⁴Have the meaning as described in the present invention.

In some of these embodiments, X is³Is CR or N;

wherein R has the meaning as described herein.

In some embodiments, R is hydrogen, deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, carboxy, alkyl, alkoxy, alkenyl, or alkynyl; r is optionally substituted with one or more R⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, each R is^xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; each R^xIndependently optionally substituted by one or more R⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, each R is⁰Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro Amino, carboxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; each R⁰Independently optionally substituted by one or more R⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, R is¹Is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, fused bicyclic, fused heterobicyclic, spirobicyclic or spiroheterobicyclic; r¹Further substituted by one or more R^5aSubstituted; r¹Optionally substituted by one or more R⁵、R^5xOr R^5ySubstituted;

wherein each R⁵、R^5x、R^5yAnd R^5aHave the meaning as described in the present invention.

In some of these embodiments, each L is¹Independently is-O-, -N (R)^1a)-，-S(＝O)_p-，-C(＝O)-，-C(＝O)-N(R^1a)-，-S(＝O)_p-N(R^1a)-，-(CR^mR^w)_g-or- (CR)^mR^w)_n-CR^1a＝CR^1a-(CR^mR^w)_n-; each L¹Independently optionally substituted by one or more R⁵Substitution;

wherein each R^1a，R^m，R^w，R⁵P, g and n have the meanings given in the description.

In some of these embodiments, each L is²Independently a bond, -O-, -N (R)^1a)-，-CH₂-N(R^1a)-，-CH(CH₃)-N(R^1a)-，-C(CH₃)₂-N(R^1a)-，-C(＝O)-N(R^1a) -or-S (═ O)_p-N(R^1a) -; each L²Independently optionally substituted by one or more R⁵Substitution;

wherein each R^1a，R⁵And p has the meaning as described in the present invention.

In some of these embodiments, each L is³Independently is-C (═ O) -or-S (═ O)O)₂-。

Wherein some embodiments are, each Cy is independently cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, fused bicyclic, fused heterobicyclic, spirobicyclic, or spiroheterobicyclic; each Cy is independently optionally substituted with one or more R ⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, each R is²Independently hydrogen, deuterium, fluoro, chloro, bromo, iodo, cyano, alkyl, alkenyl or alkynyl; each R²Independently optionally substituted by one or more R⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, each R is³And R⁴Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, carboxyl, - (CR)^mR^w)_n-NR^m1R^w1An alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fused bicyclic alkyl, fused heterobicyclic alkyl, spirobicyclic alkyl, spiroheterobicyclic, or spiroheterobicyclic alkyl group; each R³And R⁴Independently optionally substituted by one or more R⁵Substitution;

wherein each n, R⁵，R^m，R^m1，R^wAnd R^w1Have the meaning as described in the present invention.

In some embodiments, each n is independently 0, 1, 2, 3, or 4.

In some of these embodiments, g is 1, 2, 3, or 4.

In some embodiments, each p is independently 0, 1 or 2.

In some of these embodiments, each R is^1aIndependently hydrogen, deuterium, alkyl, alkenyl or alkynyl; each R^1aIndependently optionally by one or moreR⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, each R is^mAnd R^wIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, cyano-substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl; each R^mAnd R^wIndependently optionally substituted by one or more R⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, each R is^m1And R^w1Independently hydrogen, alkyl, cyano-substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl; each R^m1And R^w1Independently optionally substituted by one or more R⁵Substitution;

wherein each R⁵Have the meaning as described in the present invention.

In some of these embodiments, R is^m1、R^w1Together with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 12 atoms.

In some of these embodiments, each R is⁵Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylacyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, NH (NH) ₂-C(═ O) -, alkyl-N (R)⁶)-C(＝O)-，NH₂-S(＝O)₂-, alkyl-N (R)⁶)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)⁶)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R⁶) -alkyl-, aryl-alkyl-N (R)⁶) -C (═ O) -, alkyl-C (═ O) -N (R)⁶) -, alkyl-N (R)⁶) -C (═ O) -alkyl-N (R)⁶) -, alkyl-S (═ O)₂-, alkyl-S (═ O)₂-alkyl-, - (CH)₂)_n-N(R⁶)-(CH₂)_n-S(＝O)_p-R⁷，-(CH₂)_n-N(R⁶)-(CH₂)_n-N(R⁶)-S(＝O)_p-R⁷，-(CR⁸R⁹)_n-COOR¹⁰Or R¹¹R¹²N-C (═ O) -alkyl-; each R⁵Independently optionally substituted by one or more R¹³Substituted;

wherein each R⁶，R⁷，R⁸，R⁹，R¹⁰，R¹¹，R¹²And R¹³Have the meaning as described in the present invention.

In some of these embodiments, each R is^5xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylacyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, NH (NH) ₂-C (═ O) -, alkyl-N (R)⁶)-C(＝O)-，NH₂-S(＝O)₂-, alkyl-N (R)⁶)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)⁶)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R⁶) -alkyl-, aryl-alkyl-N (R)⁶) -C (═ O) -, alkyl-C (═ O) -N (R)⁶) -, alkyl-N (R)⁶) -C (═ O) -alkyl-N (R)⁶) -, alkyl-S (═ O)₂-, alkyl-S (═ O)₂-alkyl-, - (CH)₂)_n-N(R⁶)-(CH₂)_n-S(＝O)_p-R⁷，-(CH₂)_n-N(R⁶)-(CH₂)_n-N(R⁶)-S(＝O)_p-R⁷，-(CR⁸R⁹)_n-COOR¹⁰Or R¹¹R¹²N-C (═ O) -alkyl-; each R^5xIndependently optionally substituted by one or more R¹³Substituted;

wherein each R⁶，R⁷，R⁸，R⁹，R¹⁰，R¹¹，R¹²And R¹³Have the meaning as described in the present invention.

In some of these embodiments, each R is^5yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylacyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, NH (NH) ₂-C (═ O) -, alkyl-N (R)⁶)-C(＝O)-，NH₂-S(＝O)₂-, alkyl-N(R⁶)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)⁶)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R⁶) -alkyl-, aryl-alkyl-N (R)⁶) -C (═ O) -, alkyl-C (═ O) -N (R)⁶) -, alkyl-N (R)⁶) -C (═ O) -alkyl-N (R)⁶) -, alkyl-S (═ O)₂-, alkyl-S (═ O)₂-alkyl-, - (CH)₂)_n-N(R⁶)-(CH₂)_n-S(＝O)_p-R⁷，-(CH₂)_n-N(R⁶)-(CH₂)_n-N(R⁶)-S(＝O)_p-R⁷，-(CR⁸R⁹)_n-COOR¹⁰Or R¹¹R¹²N-C (═ O) -alkyl-; each R^5yIndependently optionally substituted by one or more R¹³Substituted;

wherein each R⁶，R⁷，R⁸，R⁹，R¹⁰，R¹¹，R¹²And R¹³Have the meaning as described in the present invention.

In some of these embodiments, each R is^5aIndependently is heteroarylalkyl or heteroarylcycloalkyl; each R^5aIndependently optionally substituted by one or more R¹⁴，R^14xOr R^14ySubstituted;

wherein each R¹⁴，R^14xAnd R^14yHave the meaning as described in the present invention.

In some of these embodiments, each R is⁶，R⁷，R⁸，R⁹And R¹⁰Independently hydrogen, deuterium, alkyl, alkenyl or alkynyl.

In some of these embodiments, each R is¹¹And R¹²Independently hydrogen, deuterium, alkyl, cyano-substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl.

In some of these embodiments, R is¹¹、R¹²Together with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 12 atoms.

In some of these embodiments, each R is¹³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (═ O) -, cyano-substituted alkyl-C (═ O) -, alkylamino, NH ₂-S(＝O)₂-, alkyl-N (R)^13a)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)^13a)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R^13a) -alkyl-, haloalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, arylalkoxy or heteroaryl;

wherein each R^13aHave the meaning as described in the present invention.

In some of these embodiments, each R is¹⁴Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (═ O) -, cyano-substituted alkyl-C (═ O) -, alkylamino, NH₂-S(＝O)₂-, alkyl-N (R)^13a)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)^13a)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R^13a) -alkyl-, haloalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, arylalkoxy or heteroaryl;

wherein each R^13aHave the meaning as described in the present invention.

In some of these embodiments, each R is^14xIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (═ O) -, cyano-substituted alkyl-C (═ O) -, alkylamino, NH₂-S(＝O)₂-, alkyl-N (R) ^13a)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)^13a)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R^13a) -alkyl-, haloalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, arylalkoxy or heteroaryl;

wherein each R^13aHave the meaning as described in the present invention.

In some of these embodiments, each R is^14yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (═ O) -, cyano-substituted alkyl-C (═ O) -, alkylamino, NH₂-S(＝O)₂-, alkyl-N (R)^13a)-S(＝O)₂-，NH₂-S(＝O)₂-alkyl-, alkyl-N (R)^13a)-S(＝O)₂-alkyl-, alkyl-S (═ O)₂-N(R^13a) -alkyl-, haloalkyl, hydroxy-substituted alkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, arylalkoxy or heteroaryl;

wherein each R^13aHave the meaning as described in the present invention.

In some embodiments, when R is^14xAnd R^14yWhen attached to the same carbon atom, R^14xAnd R^14yOptionally forming a ring of 3-12 atoms together with the carbon atoms.

In some of these embodiments, each R is^13aIndependently hydrogen, deuterium, alkyl, alkenyl or alkynyl.

The invention also encompasses the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product for the treatment of autoimmune diseases or proliferative diseases, including those described herein. The compounds of the invention are also useful in the manufacture of a medicament for the reduction, prevention, control or treatment of a disorder mediated by BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M.

The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c) or formula (V-d) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The invention also encompasses a method of treating an autoimmune disease or a proliferative disease, or a condition responsive thereto, in a subject, comprising treating the subject with a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c), or formula (V-d).

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, racemates, nitroxides, hydrates, solvates, metabolites, metabolic precursors, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.

Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of the intermediates used in the preparation or purification of the compounds of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c) or formula (V-d), or isolated enantiomers of the compounds of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c) or formula (V-d).

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, 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, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

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

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 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 e.g. "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 measurement of drug or substrate tissue distribution, or forIn radiotherapy of patients.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c) or formula (V-d) can be prepared by conventional techniques known to those skilled in the art or by employing suitable isotopically labelled reagents as described in the examples and preparations of the invention in place of the original used unlabelled reagents.

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 considered as a substituent of the compound represented by formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c) or formula (V-d). 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). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

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

The present invention provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof. 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 a compound of formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c), or formula (V-d) 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), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c), or formula (V-d). 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.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which 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 to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to 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. 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 provide alternative functions, depending on how many such excipients are 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. sup. 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 invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, 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, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted 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 one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, 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.

Exemplary pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oil; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; a phosphate buffer solution; emulsifiers, such as tweens; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting; a stabilizer; an antioxidant; a preservative; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

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 methylparaben and methylparaben, 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. Pat. 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 or preservative agents 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 buffering agents include, but are not limited to, phosphates and citrates 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 adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid suitable complexing agents include, α cyclodextrin, 35 β -cyclodextrin, β -hydroxypropyl-cyclodextrin, β -cyclodextrin Polyether- β -cyclodextrin and sulfobutyl ether 7- β -cyclodextrin (C)

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 one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, 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 yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, 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 one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, 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,1986,3(6), 318.

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 JAK kinase behavior, including JAK1, JAK2, JAK3, or TYK2, or a disease or disorder mediated or otherwise affected by JAK kinase behavior, including JAK1, JAK2, JAK3, or TYK 2.

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

In one embodiment, 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 another embodiment, the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate JAK2 kinase behavior.

In yet another embodiment, the disease, disorder, or one or more symptoms of the disease or disorder are associated with inappropriate JAK3 kinase behavior.

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: 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 myeloma; cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, and renal cancer; 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, or transplant rejection 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, or transplant rejection.

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., 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 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.

The invention also provides methods of treating, preventing, or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by a BTK kinase or a disease or disorder mediated or otherwise affected by a BTK kinase using the disclosed compounds and pharmaceutical compositions.

The present invention provides methods of treating rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and/or asthma, with the compounds of the present invention and pharmaceutically acceptable salts, solvates, and mixtures thereof being the sole active agent administered to a patient, and further includes methods of treating rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and/or asthma, wherein the compounds of the present invention and pharmaceutically acceptable salts, solvates, and mixtures thereof are administered to a patient in combination with one or more other active agents.

The compounds and pharmaceutical compositions disclosed herein are kinase inhibitors, including Btk inhibitors. These inhibitors are useful for treating one or more diseases in a mammal that respond to kinase inhibition, including diseases that respond to inhibition of Btk and/or inhibition of B-cell proliferation. Without wishing to be bound by any particular theory, it is believed that the interaction of the compounds of the present invention with Btk results in the inhibition of Btk activity and thus the pharmaceutical use of these compounds. Accordingly, the invention includes a method for treating a mammal, e.g., a human, having a disease that responds to inhibition of Btk activity and/or inhibition of B-cell proliferation, the method comprising: administering to a mammal having such a disease an effective amount of at least one chemical entity provided herein. Effective concentrations can be determined experimentally, for example, by measuring the blood concentration of the compound, or theoretically, by calculating bioavailability. In addition to Btk, other kinases that may also be affected include, but are not limited to, other tyrosine kinases and serine/threonine kinases.

Insofar as Btk is associated with disease, alleviation, prevention, and prophylactic treatment of disease and disease symptoms are within the scope of the invention.

Immune, autoimmune and inflammatory diseases that may be treated or prevented with the compounds of the invention include rheumatic diseases (e.g., rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, teratogenic arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis, and spondylitis), glomerulonephritis (with or without nephrotic syndrome), autoimmune blood system disorders (e.g., hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis, and autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), host versus graft disease, allograft rejection, chronic thyroiditis, Graves ' disease, scleroderma, diabetes (types I and II), autoimmune diseases, inflammatory bowel disease, and inflammatory bowel disease, Active hepatitis (acute and chronic), pancreatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, sunburn, vasculitis (e.g., Behcet's disease), chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic steatorrhea (idiopathetic spe), cachexia, sarcoidosis, Guillain-Barr syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, silicosis, chronic inflammatory lung disease (e.g., chronic obstructive pulmonary disease), and other inflammatory or obstructive diseases of the respiratory tract.

In some embodiments, the disorder responsive to inhibition of Btk activity and/or B cell and/or myeloid cell activity is cancer, bone disease, allergic disease, and/or autoimmune and/or inflammatory disease and/or acute inflammatory response.

The invention encompasses methods of treating a patient suffering from cancer, bone disorders, allergic disorders, and/or autoimmune and/or inflammatory disorders and/or acute inflammatory responses by administering an effective amount of a compound of the present invention and pharmaceutically acceptable salts, solvates, and mixtures thereof.

In some embodiments, conditions and diseases that may be affected using the compounds of the present invention include, but are not limited to:

allergic diseases including but not limited to eczema, allergic rhinitis or rhinitis, hay fever, bronchial asthma, urticaria (hives), and food allergies and other atopic conditions;

autoimmune and/or inflammatory diseases, including but not limited to psoriasis, Crohn's disease, irritable bowel syndrome, Sjogren's syndrome, tissue transplant rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitis), autoimmune hemolytic diseases and thrombocytopenic states, goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic Idiopathic Thrombocytopenic Purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes (type 1), septic shock, myasthenia gravis, ulcerative colitis, aplastic anemia, Coeliac disease, Wegener's granulomatosis, Crohn's disease, inflammatory bowel, And other diseases in which the cells and antibodies are caused by and directed against the subject's own tissues;

Acute inflammatory reactions including, but not limited to, skin sunburn, pelvic inflammatory disease, inflammatory bowel disease, urethritis, uveitis, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, and cholecystitis;

cancers, including but not limited to hematological malignancies such as B-cell lymphoma, and acute lymphoblastic leukemia, acute myeloid leukemia, chronic and acute lymphocytic leukemia, hairy cell leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, and other diseases characterized by cancers of the blood or lymphatic system; and

bone diseases, including but not limited to osteoporosis.

Btk is a known inhibitor of lymphoma B cell apoptosis. Defective apoptosis contributes to the pathogenesis and drug resistance of human leukemias and lymphomas. Accordingly, there is also provided a method of promoting or inducing apoptosis of cells expressing Btk comprising contacting the cells with a compound of the invention and pharmaceutically acceptable salts, solvates and mixtures thereof.

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 one embodiment, 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 one embodiment, the treatment is for a disease or condition mediated by JAK kinase activity. In one embodiment, the treatment is for a disease or condition mediated by BTK 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 one embodiment, the pharmaceutical composition may comprise a pharmaceutically acceptable 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 one embodiment, 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 JAK or BTK 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 JAK or BTK kinase activity, wherein 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 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 β₂-a combination of adrenergic receptor agonists β₂Examples 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 ₂Adrenoceptor agonists, e.g. to provide effective bronchodilationCompounds that span up to 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), butoconazole propionate (buticortpropionate), 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, WO04/005229, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO04/026248, WO 03/061651 and WO 03/08277. Further non-steroidal compounds are covered in WO 2006/000401, WO2006/000398 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 WO93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. CCR3 inhibitors include those disclosed in WO 02/26722.

In one embodiment, the invention relates to the use of the disclosed compounds in combination with a phosphodiesterase 4(PDE4) inhibitor, 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 administration by inhalation include ipratropium (e.g., as bromide, CAS22254-24-6,

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

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 CAS133099-07-7, to

Sold under the trade name), oxybutynin (CAS 5633-20-5,

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

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

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

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 another embodiment, 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, in combination with a PDE4 inhibitor and β₂-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 one embodiment, the pharmaceutical compositions provided herein comprise a combination of a compound disclosed herein and a phosphodiesterase 4(PDE4) inhibitor.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of the disclosure in combination with a β 2-adrenoceptor agonist.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of the disclosure in combination with a corticosteroid.

In another embodiment, the invention provides a pharmaceutical composition comprising a combination of a compound of the present disclosure and a non-steroidal GR agonist.

In another embodiment, the present invention provides a pharmaceutical composition comprising a combination of a compound of the present disclosure and an anticholinergic.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present disclosure in combination with an antihistamine.

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 for inducing cell differentiation processes (ii) a 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; a compound that targets, reduces or inhibits protein or lipid phosphatase activity; 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, lotemide, pirglutethimide, trilostane, troostimide,

Testolactone, ketoconazole, fluconazole, fadrozole, anastrozole and 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 US4,659,516 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 to, bicalutamide (trade name)

) The dosage form may be prepared according to US patent US4,636,505.

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, e.g., under the trademark TEFLON

Is administered in the form of (1).

The term "topoisomerase II inhibitors" as used in the present invention"includes, but is not limited to, anthracyclines, such as doxorubicin (doxorubicin), its liposomal formulation, under the trade name doxorubicin

Daunorubicin (daunorubicin); epirubicin (epirubicin); idarubicin (idarubicin); naproxubicin (nemorubicin); 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 TEPA

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

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 Mitraxantrone

Is administered in the form of (1).

The term "microtubule active agent" refers to microtubule stabilizing agents, microwave destabilizing agents and microtubule polymerization inhibitorsAnd (4) preparing the preparation. 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, such as epothilone B or D or derivatives 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 may be sold commercially, for example under the trade mark vinblastine sulphate

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 epothilone class derivatives disclosed in WO98/10121, 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 Pl (3) kinase family, or a member of the Pl (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 AG213, tyrphostin AG1748, 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, EP0520722, EP 0566226, EP 0787722, EP 0837063, US 5,747,498, WO 98/10767, WO97/30034, WO 97/49688 and WO 97/38983, WO 96/30347 (as CP 358774), WO96/33980 (as compound ZD 1839), WO 95/03283 (as compound ZM105180), trastuzumab (herceptin), cetuximab, Iressa, Tarcek, 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, such as 5-methyl-2- (2 '-chloro-6' -fluoroanilino) phenylacetic acid or lumiracoxib.

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 theTreatment 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 of the present disclosure may be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs used in the treatment of AML, such as daunorubicin, doxorubicin, 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 its 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, eds. ' The Merck Index ', 13 th edition, Merck Research Laboratories, 2001) or from databases such as The 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 one embodiment, 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 one embodiment, 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 another embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound 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 one embodiment, 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 one embodiment, the administration is once daily. In yet another embodiment, 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 adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.

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 in the same pharmaceutical composition.

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 on the species, weight, age and condition of the individual, the disease (disorder) or illness (disease) being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (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 one embodiment, 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

In general, the compounds of the invention can be prepared by the processes described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V-a), formula (V-b), formula (V-c) or formula (V-d). 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. 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 HaoLiyu chemical Co., Ltd., Qingdao Tenglong chemical reagent Co., Ltd., and Qingdao Kaihua 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. The test conditions of the nuclear magnetic resonance hydrogen spectrum are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature₃，d₆-DMSO，CD₃OD or d₆Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet ), t (triplet, triplet), q (quatet, quartet), m (multiplet ), br (broadpede, broad), dd (doublet of doublets), ddd (doublet of doublets ), dt (doublet of triplets, doublet of triplets). Coupling constants are expressed in hertz (Hz).

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

The purity of the compound is characterized in the following way: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.

The following acronyms are used throughout the invention:

HPLC high performance liquid chromatography; h₂O water; MeOH, CH₃OH methanol; CD (compact disc)₃OD deuterated methanol; EtOH, ethanol; HCOOH formic acid; CH (CH)₃CN, MeCN acetonitrile; DCM, CH₂Cl₂Dichloromethane; CHCl₃Chloroform, chloroform; CDCl₃Deuterated chloroform; cyclohexane; CDI N, N' -carbonyldiimidazole; cs₂CO₃Cesium carbonate; DAST diethylaminosulfur trifluoride; DCC dicyclohexylcarbodiimide; DMSO dimethyl sulfoxide; DIEA, DIPEA N, N-diisopropylethylamine; DMF N, N-dimethylformamide; DME dimethyl ether; et (Et)₃N,TEA,NEt₃Triethylamine; EtOAc ethyl acetate; PE petroleum ether; EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; HOBT 1-hydroxybenzotriazole; HATU 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; LiOH lithium hydroxide; sodium NaH hydride; NaOH hydroxide Sodium; NaHCO 2₃Sodium bicarbonate; na (Na)₂SO₄Sodium sulfate; KOH potassium hydroxide; KI potassium iodide; k₂CO₃Potassium carbonate; KOAc potassium acetate; HCl hydrogen chloride; h₂SO₄Sulfuric acid; TFA trifluoroacetic acid; THF tetrahydrofuran; Pd/C palladium on carbon; SEMCl2- (trimethylsilyl) ethoxymethyl chloride; TsCl tosyl chloride; pd (dppf) Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; xanthphos 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene; X-Phos 2-dicyclohexylphos-2, 4, 6-triisopropylbiphenyl; DBU 1, 8-diazabicyclo [5.4.0]Undec-7-ene; g, g; mg; mol; mmol millimole; h hours; min; l liter; mL, mL; r.t, RT room temperature; rt retention time; HEPES hydroxyethylpiperazine ethanethiosulfonic acid; brij-35 dodecyl polyglycol ether; DTT dithiothreitol; EDTA ethylene diamine tetraacetic acid; EGFR epidermal growth factor receptor; BTK bruton tyrosine kinase; EGFR T790M epidermal growth factor receptor T790M mutant; peptide 22 labeled with Peptide FAM-P22 fluorescein; ATP triphosphate adenosine; 96-well plate; 384-well plate 384 well plate; staurosporine; coating reagent #3# 3.

Synthesis method 1

Compound 1 can be prepared by synthesis method one, wherein X ¹，X³，X，Z¹，Z²，Z³And R¹Have the meaning as described in the present invention. Reacting compound 1-1 with SEMCl under the action of alkali (such as sodium hydride, potassium tert-butoxide, etc.) to obtain compound 1-2; the compound 1-2 and the compound 1-3 react to generate the compound 1-4 by catalysis of metal (such as copper (0), copper (I), copper (II), palladium (0), Ni (0) and the like) and catalysis of alkali (such as potassium carbonate, cesium carbonate, potassium phosphate and the like); reacting compound 1-4 with iodinating agent in polar solvent (such as DMSO, DMF, acetone, etc.) to obtain compound 1-5; compounds 1-5 and Compounds R¹-B(OH)₂Carrying out Suzuki cross-coupling reaction under the catalysis of transition metal to obtain compounds 1-6;carrying out catalytic hydrogenation on the compounds 1-6 to obtain compounds 1-7; reacting the compound 1-7 with acyl chloride under the action of alkali (such as triethylamine, diisopropylethylamine, potassium carbonate, etc.) to generate a compound 1-8; after the compounds 1-8 react under acidic conditions (such as trifluoroacetic acid, hydrogen chloride and the like), the solvent is concentrated, and then the reaction is carried out under alkaline conditions (such as ethylenediamine, triethylamine, sodium hydroxide, sodium bicarbonate and the like) to obtain the target compound 1.

Synthesis method II

Compound 2 can be prepared by synthesis method two, wherein X¹，X³，X，L¹，Z¹，Z²，Z³，R¹，R²，R³And R⁴Have the meaning as described in the present invention. The compound 1-2 and the compound 2-1 react to generate the compound 2-2 under the action of alkali (such as potassium carbonate, cesium carbonate, potassium phosphate and the like) by catalysis of metal (such as copper (0), copper (I), copper (II), palladium (0), Ni (0) and the like) to generate the compound 2-2; reacting compound 2-2 with iodinating agent in polar solvent (such as DMSO, DMF, acetone, etc.) to obtain compound 2-3; the aniline compound is obtained by catalytic hydrogenation of the compound 2-3, and then reacts with acyl chloride under the action of alkali (such as triethylamine, diisopropylethylamine, potassium carbonate and the like) to generate a compound 2-4; compound 2-4 and compound R ¹-B(OH)₂Carrying out Suzuki cross-coupling reaction under the catalysis of transition metal to obtain a compound 2-5; after the compound 2-5 reacts under acidic conditions (such as trifluoroacetic acid, hydrogen chloride and the like), the solvent is concentrated, and then the reaction is carried out under alkaline conditions (such as ethylenediamine, triethylamine, sodium hydroxide, sodium bicarbonate and the like) to obtain the target compound 2.

Synthesis method III

The compound 3 can be prepared by a third synthesis method, wherein X, X³，R⁵And R^5aHave the meaning as described in the present invention. Reacting compound 3-1 with SEMCl under the action of alkali (such as sodium hydride, potassium tert-butoxide, etc.) to obtain compound 3-2; reacting the compound 3-2 with a brominating reagent in a polar solvent (such as DMSO, DMF, acetone, etc.) to obtain a compound 3-3; reacting the compound 3-3 with a compound N- (3-hydroxyphenyl) acrylamide to obtain a compound 3-4; reacting the 1H-pyrazole-4-boronic acid pinacol ester derivative 3-5 with a compound 3-6 to obtain a compound 3-7; reacting the compound 3-4 with the compound 3-7 to obtain a compound 3-8; after the compound 3-8 reacts under acidic conditions (such as trifluoroacetic acid, hydrogen chloride and the like), the solvent is concentrated, and then the reaction is carried out under alkaline conditions (such as ethylenediamine, triethylamine, sodium hydroxide, sodium bicarbonate and the like) to obtain the target compound 3.

Examples

Example 1

N- (3- ((7- (1- (pyridine-2-methylene) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of the Compound 2- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

Sodium hydride (60%, 51mg,1.28mmol) was added to a solution of 1H-pyrazole-4-boronic acid pinacol ester (100mg,0.52mmol) in N, N-dimethylformamide (6mL) under ice-bath, and after stirring at room temperature for 30 minutes, 2- (bromomethyl) pyridine hydrobromide (160mg,0.63mmol) was added, and stirring at room temperature was continued for 20 hours, followed by addition of a saturated ammonium chloride solution (15mL) and quenching, extraction with dichloromethane (20mL × 3), drying over anhydrous sodium sulfate, removal of the solvent, and column chromatography of the concentrate (eluent: PE/v) ═ 2/1) was performed to obtain 76mg of a pale yellow oil with a yield: 51.70. MS (ESI, pos.ion) M/z:286.20[ M +1 EtOAc% > (ESI, pos.]⁺。

Step 2: synthesis of compound 2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

2-bromo-5H-pyrrolo [2,3-b ] pyrazine (300mg,1.52mmol) was dissolved in N, N-dimethylformamide (8mL), sodium hydride (60%, 91.3mg,2.28mmol) was added under ice bath, stirring was continued at this temperature, after 30min, 2- (trimethylsilyl) ethoxymethyl chloride (404. mu.L, 2.26mmol) was added, and stirring was continued at room temperature for 12H. Quenched with water (20mL), extracted with dichloromethane (30mL × 2), concentrated and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 270mg of a yellow oil, yield: 54.3 percent.

MS(ESI,pos.ion)m/z:330.10[M+1]⁺。

And step 3: synthesis of compound 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

To a solution of 2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (0.51g,1.53mmol) in dichloromethane (26mL) was added N-bromosuccinimide (0.29g,1.59mmol) at room temperature and stirred at room temperature for 30H. The solvent was concentrated and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 5/1) to give 560mg of a white solid, yield: 89.4 percent.

MS(ESI,pos.ion)m/z:408.0[M+1]⁺。

And 4, step 4: synthesis of compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To a mixture of 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (0.30g,0.73mmol), N- (3-hydroxyphenyl) acrylamide (0.15g,0.92mmol), cesium carbonate (0.36g,1.10mmol), cuprous iodide (0.16g,0.84mmol) and N, N-dimethylglycine (0.08g,0.81mmol) was added 1, 4-dioxane (5mL), protected with nitrogen, reacted at 115 ℃ for 5 hours, cooled to room temperature, filtered through celite column, rinsed with dichloromethane, concentrated, isolated (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 260mg of light yellow oil, yield: 72.59 percent.

MS(ESI,pos.ion)m/z:491.1[M+1]⁺。

And 5: synthesis of the compound N- (3- ((7- (1- (pyridin-2-methylene) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (30mg,0.06mmol) in 1, 4-dioxane (3mL) was added in sequence 2- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (22mg,0.07mmol), potassium carbonate (13mg,0.09mmol), Pd (dppf) Cl₂(6mg,0.01mmol) and water (0.75mL) in N₂The reaction was refluxed for 6 hours under protection, stopped, cooled to room temperature, quenched with saturated brine (8mL), extracted with dichloromethane (10mL × 3), and extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 1/1) afforded 21mg of a brown solid, yield: 60.22 percent.

MS(ESI,pos.ion)m/z:568.30[M+1]⁺。

Step 6: synthesis of the compound N- (3- ((7- (1- (pyridine-2-methylene) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To N- (3- ((7- (1- (pyridin-2-methylidene) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) ]Pyrazin-2-yl) oxy) phenyl) acrylamide (250mg,0.44mmol) in dichloromethane (6mL) was added trifluoroacetic acid (2mL), stirred at room temperature for 5 hours, directly concentrated, dissolved in tetrahydrofuran (6mL), and adjusted to pH with saturated sodium bicarbonate solution>7, stirred at room temperature for 12 hours, and then saturated brine (20mL), methylene chloride (20mL × 3) were added to the mixture to extract the mixture, followed by extraction with anhydrous Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 1/1) afforded 66mg of a white solid, yield: 34.26 percent.

MS(ESI,pos.ion)m/z:438.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.12(s,1H),10.22(s,1H),8.51(d,J＝4.6Hz,1H),8.20(s,1H),8.14(s,1H),8.13(s,1H),7.91(s,1H),7.74(td,J₁＝7.7Hz,J₂＝1.4Hz,1H),7.63(s,1H),7.43(d,J＝8.2Hz,1H),7.36(t,J＝8.1Hz,1H),7.29(dd,J₁＝7.2Hz,J₂＝5.1Hz,1H),7.05(d,J＝7.8Hz,1H),6.90(dt,J₁＝16.2Hz,J₂＝8.1Hz,1H),6.39(dd,J₁＝17.0Hz,J₂＝10.2Hz,1H),6.21(m,1H),5.73(m,1H),5.40(s,2H)。

Example 2

N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.40g,6.73mmol) in DMF (40mL) was added 2- (bromomethyl) pyridine hydrobromide (2.5g,9.9mmol), Cs₂CO₃(3.91g,12.0mmol) and KI (0.41g,2.4mmol) and reacted at 70 ℃ for 10h, the reaction was concentrated under reduced pressure to remove DMF, water (40mL) was added, dichloromethane (50mL × 3) was extracted, and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 1.3g of a yellow oil, yield: 65 percent.

MS(ESI,pos.ion)m/z:300.1[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Reacting N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.51g,1.0mmol), 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.5g,2mmol), Pd (dppf) Cl₂(0.05g,0.07mmol) and K₂CO₃(0.21g,1.5mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 120 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄Dried and concentratedThe crude product was isolated and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 40/1) to give 0.25g yellow oil, yield: 42 percent.

MS-ESI:(ESI,pos.ion)m/z:582.1[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (0.25g,0.43mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), and the reaction was stirred at room temperature for 8H. The reaction was concentrated under reduced pressure, THF (15mL) and TEA (2mL) were added, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane (30mL × 3) was extracted, the mixture was washed with a saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated, and the concentrated crude product was purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 30/1), whereby 0.05g of a yellow solid was obtained, yield: 30 percent.

MS-ESI:(ESI,pos.ion)m/z:452.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.19(s,1H),10.23(s,1H),8.50(d,J＝4.1Hz,1H),8.14(d,J＝17.7Hz,2H),7.93(d,J＝2.8Hz,1H),7.73(d,J＝1.6Hz,1H),7.63(s,1H),7.40(d,J＝8.2Hz,1H),7.34(d,J＝8.1Hz,1H),7.28(d,J＝2.0Hz,1H),7.03(d,J＝7.8Hz,1H),6.88(dd,J₁＝8.0Hz,J₂＝1.6Hz,1H),6.36(d,J＝10.2Hz,1H),6.20(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.71(dd,J₁＝10.2Hz,J₂＝1.7Hz,1H),5.29(s,2H),2.29(s,3H)。

Example 3

N- (3- ((7- (3- (difluoromethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazole-3-carbaldehyde

To a solution of 4-bromo-1H-pyrazole-3-carbaldehyde (1.01g,5.77mmol) in DMF (40mL) was added 2- (bromomethyl) pyridine hydrobromide (2g,7.91mmol), Cs₂CO₃(6.6g,20mmol) and KI (1g,5.96mmol) and reacted at 70 ℃ for 10h, the reaction was concentrated under reduced pressure to remove DMF, water (30mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 0.7g of a yellow oil, yield: 50 percent.

MS(ESI,pos.ion)m/z:266.1[M+1]⁺。

Step 2: synthesis of the compound 2- ((4-bromo-3- (difluoromethyl) -1H-pyrazol-1-yl) methyl) pyridine

A solution of DAST (0.7g,0.6mL,5mmol) in DCM (1mL) was slowly added to a solution of 4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazole-3-carbaldehyde (0.51g,1.9mmol) in DCM (20mL) at-20 deg.C, then the reaction was stirred at room temperature overnight, the reaction was added to ice water (20mL), dichloromethane (30mL × 3) was extracted, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give 0.3g of a yellow oil, yield: 50 percent.

MS(ESI,pos.ion)m/z:288.1[M+1]⁺。

And step 3: synthesis of the compound 2- ((3- (difluoromethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

2- ((4-bromo-3- (difluoromethyl) -1H-pyrazol-1-yl) methyl) pyridine (0.31g,1.1mmol), pinacol diboron (0.5g,2mmol), KOAc (0.31g,3.2mmol) and Pd (dppf) Cl₂(0.08g,0.1mmol) were mixed, DMSO (10mL) was added, the mixture was reacted at 80 ℃ overnight, the reaction mixture was cooled, water (20mL) was added, methylene chloride (30mL × 3) was added and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/3) to give 0.12g of yellow oily substanceSubstance, yield: 33 percent. MS (ESI, pos.ion) M/z 336.3[ M +1 ]]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3- (difluoromethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.15g,0.31mmol) in 1, 4-dioxane (20mL) was added 2- ((3- (difluoromethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.12g,0.36mmol), Pd (dppf) Cl₂(0.03g,0.04mmol) and K₂CO₃(0.07g,0.5mmol), and then H was added₂O (5mL) was purged with nitrogen, the reaction mixture was cooled, water (20mL) and methylene chloride (30mL × 3) were added to the cooled reaction mixture, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 50/1) to give 0.06g yellow oil, yield: 32 percent.

MS-ESI:(ESI,pos.ion)m/z:618.5[M+1]⁺。

And 5: synthesis of the compound N- (3- ((7- (3- (difluoromethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

N- (3- ((7- (3- (difluoromethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (0.06g,0.1mmol) was dissolved in dichloromethane (15mL), TFA (3mL,38.7mmol) was added at 0 ℃, and the reaction was stirred at room temperature for 8H. The reaction solution was concentrated under reduced pressure, THF (15mL) and TEA (3mL) were added, and the reaction was further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane (30mL × 3) was extracted, the mixture was washed with a saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated, and the concentrated crude product was purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 30/1), whereby 0.01g of a yellow solid was obtained, yield: 20 percent.

MS-ESI:(ESI,pos.ion)m/z:488.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.33(s,1H),10.24(s,1H),8.51(d,J＝4.7Hz,1H),8.37(s,1H),8.20(s,1H),7.95(d,J＝2.8Hz,1H),7.81-7.75(m,1H),7.66(s,1H),7.41(d,J＝8.1Hz,1H),7.35(t,J＝8.1Hz,1H),7.33-7.29(m,1H),7.16(s,1H),7.15(s,1H),6.91(dd,J₁＝8.1Hz,J₂＝1.4Hz,1H),6.38(dd,J₁＝17.0Hz,J₂＝10.2Hz,1H),6.20(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.72(dd,J₁＝10.2Hz,J₂＝1.6Hz,1H),5.44(s,2H)。

Example 4

N- (3- ((7- (1- (pyridin-2-ylmethyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of the compound 2- ((4-bromo-3- (trifluoromethyl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of 4-bromo-3- (trifluoromethyl) -1H-pyrazole (1.01g,4.7mmol) in DMF (40mL) was added 2- (bromomethyl) pyridine hydrobromide (1.76g,6.96mmol), Cs₂CO₃(5.3g,16mmol) and KI (0.4g,2mmol) and reacted at 100 ℃ for 10h, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 1.2g yellow oil, yield: 83 percent. MS (ESI, pos.ion) M/z 308.1[ M +1 ]]⁺。

Step 2: synthesis of the compound 2- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) methyl) pyridine

2- ((4-bromo-3- (trifluoromethyl) -1H-pyrazol-1-yl) methyl) pyridine (0.51g,1.7mmol), pinacol diboride (0.75g,3.0mmol), KOAc (0.50g,5.1mmol) and Pd (dppf) Cl₂(0.12g,0.16mmol) and DMSO (10mL) is added, thenThe reaction mixture was cooled, water (20mL) and methylene chloride (30mL × 3) were added to extract the reaction mixture, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 0.4g yellow oil, yield: 70 percent.

MS-ESI:(ESI,pos.ion)m/z:354.4[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (1- (pyridin-2-ylmethyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Reacting N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.4g,0.82mmol), 2- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) methyl) pyridine (0.42g,1.2mmol), Pd (dppf) Cl₂(0.08g,0.1mmol) and K₂CO₃(0.17g,1.2mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 120 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 40/1) to give 0.19g yellow oil, yield: 37 percent.

MS-ESI:(ESI,pos.ion)m/z:636.5[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (1- (pyridin-2-ylmethyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

N- (3- ((7- (1- (pyridin-2-ylmethyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (0.25g,0.43mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), and the reaction was stirred at room temperature for 8H. The reaction was concentrated under reduced pressure, THF (15mL) and TEA (2mL) were added, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane (30mL × 3) was extracted, the mixture was washed with a saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated, and the concentrated crude product was purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 30/1), whereby 0.05g of a yellow solid was obtained, yield: 30 percent.

MS-ESI:(ESI,pos.ion)m/z:506.4[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.41(s,1H),10.26(s,1H),8.51(d,J＝4.2Hz,1H),8.46(s,1H),8.21(s,1H),7.86(s,1H),7.78(s,1H),7.67(s,1H),7.39(d,J＝7.9Hz,1H),7.33(dd,J₁＝13.4Hz,J₂＝5.5Hz,2H),7.19(d,J＝7.8Hz,1H),6.90(d,J＝7.7Hz,1H),6.37(d,J＝10.2Hz,1H),6.20(d,J＝16.8Hz,1H),5.71(d,J＝10.5Hz,1H),5.48(s,2H)。

Example 5

N- (3- ((7- (1- (pyridin-3-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of Compound 1- (3-picolyl) -1H-pyrazole-4-boronic acid pinacol ester

3- (bromomethyl) pyridine (2.67g,15.5mmol) and 4-pyrazoleboronic acid pinacol ester (3.01g,15.5mmol) were dissolved in DMF (20mL), potassium carbonate (2.2g,16mmol) was added to the system, and the reaction was allowed to warm to 80 ℃ for 8 hours. The reaction solution was poured into water (50mL), extracted with ethyl acetate (50mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1.5) to give 280mg of a pale yellow oil, yield: 6.33 percent.

MS-ESI:(ESI,pos.ion)m/z:286.30[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7- (1- (pyridin-3-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

1- (3-picolyl) -1H-pyrazole-4-boronic acid pinacol ester (351mg,1.23mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (602mg,1.23mmol) were dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1), potassium carbonate (510mg,3.7mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (100mg,0.12mmol) were added to the system, nitrogen was replaced, and the temperature was raised to 110 ℃ for reaction for 8 hours. The reaction mixture was poured into water (20mL), extracted with ethyl acetate (20mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/8) to give 142mg of a dark brown oil, yield: 20.32 percent.

MS-ESI:(ESI,pos.ion)m/z:569.10[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (1- (pyridin-3-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (1- (pyridin-3-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine-2-yl) oxy) phenyl) acrylamide (170mg,0.30mmol) and trifluoroacetic acid (3.1mL) were dissolved in dichloromethane (15mL) and reacted at room temperature for 6h, the reaction solution was directly spun dry, the residue was dissolved in tetrahydrofuran (5mL), saturated sodium bicarbonate solution (10mL) was added and stirred at room temperature for 8h, the reaction solution was poured into water (20mL), ethyl acetate (20mL × 3) was extracted, saturated brine was washed (20mL), anhydrous sodium sulfate was dried, and the concentrated crude product was chromatographically separated and purified (eluent: CH silica gel column)₂Cl₂MeOH (v/v) ═ 10/1), yielding 40mg of a light yellow solid, yield: 30.54 percent.

MS-ESI:(ESI,pos.ion)m/z:438.40[M+1]⁺；

¹H NMR(400MHz,MeOD):(ppm)8.59(d,J＝20.6Hz,2H),8.23(s,1H),8.06(s,1H),8.01(d,J＝8.6Hz,1H),7.96(s,1H),7.92(s,1H),7.72-7.65(m,2H),7.36(dd,J₁＝14.3Hz,J₂＝6.5Hz,2H),6.93(d,J＝8.1Hz,1H),6.36-6.31(m,1H),5.73(d,J＝11.8Hz,1H),5.46(s,2H),5.33(s,1H)。

Example 6

N- (3- ((7- (1- (pyridin-4-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of the Compound 4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

4- (bromomethyl) pyridine hydrochloride (3.3g,16mmol) and 4-pyrazoleboronic acid pinacol ester (3.01g,15.6mmol) were dissolved in DMF (20mL), potassium carbonate (2.25g,16.3mmol) was added to the system, and the reaction was allowed to warm to 80 ℃ for 8 h. The reaction solution was poured into water (50mL), extracted with ethyl acetate (50mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 267mg of a pale yellow oil, yield: 6 percent.

MS-ESI:(ESI,pos.ion)m/z:286.25[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7- (1- (pyridin-4-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Compound 4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (190mg,0.67mmol) and compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (370mg,0.76mmol) were dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1), potassium carbonate (290mg,2.10mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (60mg,0.07mmol), replacing nitrogen, heating to 110 ℃ and reacting for 4 h. The reaction mixture was poured into water (20mL), extracted with ethyl acetate (20mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/5) to give 110mg of a brown oil, yield: 29.09 percent.

MS-ESI:(ESI,pos.ion)m/z:568.15[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (1- (pyridin-4-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

N- (3- ((7- (1- (pyridin-4-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine-2-yl) oxy) phenyl) acrylamide (123mg,0.22mmol) and trifluoroacetic acid (3.1mL) were dissolved in dichloromethane (15mL) and reacted at room temperature for 6h, the reaction solution was directly spun dry, the residue was dissolved in tetrahydrofuran (5mL), saturated sodium bicarbonate solution (10mL) was added and stirred at room temperature for 8h, the reaction solution was poured into water (20mL), ethyl acetate (20mL × 3) was extracted, saturated brine was washed (20mL), anhydrous sodium sulfate was dried, and the concentrated crude product was chromatographically separated and purified (eluent: CH silica gel column)₂Cl₂MeOH (v/v) ═ 10/1), yielding 7mg of a yellow solid, yield: 7.38 percent.

MS-ESI:(ESI,pos.ion)m/z:438.20[M+1]⁺；

¹H NMR(400MHz,MeOD):(ppm)8.27(s,1H),8.05(d,J＝9.4Hz,1H),8.01(s,1H),7.94(s,1H),7.67(s,1H),7.61(s,2H),7.37-7.30(m,2H),7.23-7.06(m,2H),6.92(d,J＝7.0Hz,1H),6.37-6.29(m,1H),5.72(d,J＝9.9Hz,1H),5.57(s,2H),5.32(t,J＝4.8Hz,1H)。

Example 7

N- (3- ((7- (3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of Compound (4-bromo-1H-pyrazol-3-yl) methanol

To a solution of 4-bromo-1H-pyrazole-3-carbaldehyde (6g,34.3mmol) in EtOH (100mL) at 0 deg.C was added NaBH ₄(1.9g,39mmol) and then reacted at room temperature overnight. By NH₄After quenching with Cl, concentration under reduced pressure, removal of the solvent, and separation and purification of the crude product by silica gel column chromatography (eluent: EtOAc) gave 3.3g of a white solid in yield: 50 percent.

MS(ESI,pos.ion)m/z:179.1[M+2]⁺。

Step 2: synthesis of Compound (4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazol-3-yl) methanol

To a solution of compound (4-bromo-1H-pyrazol-3-yl) methanol (3.34g,18.9mmol) in DMF (100mL) was added 2- (bromomethyl) pyridine hydrobromide (7.1g,28mmol), Cs₂CO₃(21.3g,65.4mmol) and KI (1.6g,9.5mmol) and then reacted at 70 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (30mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 7/3) to give 2.0g of the product as a yellow oil, yield: 40 percent.

MS(ESI,pos.ion)m/z:270.1[M+2]⁺。

And step 3: synthesis of Compound (1- (pyridin-2-ylmethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) methanol

The compound (4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazol-3-yl) methanol (0.51g,1.9mmol), pinacol diboron ester (0.85g,3.3mmol), KOAc (0.55g,5.6mmol) and Pd (dppf) Cl ₂(0.14g,0.19mmol) was mixed and DMSO (15mL) was added, followed by reaction at 90 ℃ overnight, the reaction mixture was cooled and then water (20mL) was added, dichloromethane (30mL × 3) was extracted, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 7/3) to give 0.3g of the product as a yellow oil, yield: 50 percent.

MS(ESI,pos.ion)m/z:316.1[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To the compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.31g,0.63mmol) in 1, 4-dioxane (20mL) was added (1- (pyridin-2-ylmethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan)Runne-2-yl) -1H-pyrazol-3-yl) methanol (0.28g,0.89mmol), Pd (dppf) Cl₂(0.05g,0.07mmol) and K₂CO₃(0.13g,0.94mmol) and then H was added₂O (5mL), replacement of nitrogen and reaction at 115 ℃ overnight, cooling the reaction mixture, addition of water (20mL), extraction with dichloromethane (30mL × 3), and application of anhydrous Na to the organic phase ₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 40/1), yielding 0.13g of product as a yellow oil, yield: 34 percent.

MS-ESI:(ESI,pos.ion)m/z:598.1[M+1]⁺。

And 5: synthesis of the compound N- (3- ((7- (3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3- (hydroxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.13g,0.22mmol) was dissolved in dichloromethane (15mL), TFA (3mL,38.7mmol) was added at 0 ℃ and the reaction was stirred at room temperature for 8h, the reaction mixture was concentrated under reduced pressure and THF (15mL) and TEA (3mL) were added, then the reaction was stirred at room temperature overnight, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate (20mL) was added after removal of the solvent, dichloromethane was extracted (30mL × 3), saturated brine was washed (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH)₂Cl₂MeOH (v/v) ═ 30/1), preparative HPLC separation afforded 0.01g of yellow solid, yield: 9.8 percent. MS-ESI (ESI, pos.ion) M/z 468.0[ M +1 ] ]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.24(s,1H),10.23(s,1H),8.50(d,J＝4.4Hz,1H),8.17(s,1H),7.98(d,J＝2.4Hz,1H),7.79-7.70(m,2H),7.57(s,1H),7.42(d,J＝8.2Hz,1H),7.35(t,J＝8.1Hz,1H),7.32-7.26(m,1H),7.04(d,J＝7.9Hz,1H),6.90(d,J＝6.8Hz,1H),6.37(d,J＝10.1Hz,1H),6.22(d,J＝15.2Hz,1H),5.74(d,J＝11.6Hz,1H),5.49(s,2H),5.35(t,J＝5.6Hz,1H),4.63(d,J＝5.5Hz,2H)。

Example 8

N- (3- ((7- (3- (methoxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- ((4-bromo-3- (methoxymethyl) -1H-pyrazol-1-yl) methyl) pyridine

NaH (0.2g,5mmol) was slowly added to a solution of (4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazol-3-yl) methanol (0.51g,1.9mmol) in THF (30mL) at 0 deg.C, stirred for 10min and CH was added₃I (0.5g,3mmol), stirring the reaction at room temperature, extracting the reaction mixture with water (30mL), dichloromethane (50mL × 3), and extracting the organic phase with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 0.5g of the product as a yellow oil, yield: 94 percent.

MS(ESI,pos.ion)m/z:284.1[M+2]⁺。

Step 2: synthesis of the compound 2- ((3- (methoxymethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

2- ((4-bromo-3- (methoxymethyl) -1H-pyrazol-1-yl) methyl) pyridine (0.5g,1.8mmol), pinacol diboron (0.85g,3.3mmol), KOAc (0.55g,5.6mmol) and Pd (dppf) Cl₂(0.14g,0.19mmol) was mixed, DMSO (10mL) was added, the reaction mixture was allowed to react at 80 ℃ overnight, water (20mL) was added after the reaction mixture was cooled, methylene chloride (30mL × 3) was extracted, and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 7/3) to give 0.4g yellow oil, yield: 70 percent.

MS(ESI,pos.ion)m/z:330.4[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3- (methoxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.33g,0.67mmol) in 1, 4-dioxane (16mL) was added 2- ((3- (methoxymethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.33g,1.0mmol), Pd (dppf) Cl₂(0.05g,0.07mmol) and K₂CO₃(0.14g,1.0mmol) and then H was added₂O (4mL), replacement of nitrogen, reaction overnight at 115 ℃ after cooling the reaction mixture, addition of water (20mL), extraction with dichloromethane (30mL × 3), and application of anhydrous Na to the organic phase₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 30/1), yielding 0.33g of product as a yellow oil, yield: 80 percent.

MS-ESI:(ESI,pos.ion)m/z:612.6[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3- (methoxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3- (methoxymethyl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.33g,0.54mmol) was dissolved in dichloromethane (15mL), TFA (3mL,38.7mmol) was added at 0 ℃ and the reaction was stirred at room temperature for 8h, the reaction mixture was concentrated under reduced pressure, THF (15mL) and TEA (3mL) were added, and the reaction was stirred at room temperature overnight, the reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution (20mL) was added after removal of the solvent, dichloromethane (30mL × 3) was extracted, a saturated brine was washed (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH)₂Cl₂MeOH (v/v) ═ 30/1), yielding 0.07g of a yellow solid, yield: 27 percent.

MS-ESI:(ESI,pos.ion)m/z:482.5[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.25(s,1H),10.24(s,1H),8.50(d,J＝4.2Hz,1H),8.19(s,1H),7.94(d,J＝2.5Hz,1H),7.79(s,1H),7.72(dd,J₁＝9.2Hz,J₂＝7.7Hz,1H),7.58(s,1H),7.41(d,J＝8.1Hz,1H),7.35(t,J＝8.1Hz,1H),7.28(dd,J₁＝6.9Hz,J₂＝5.2Hz,1H),6.96(d,J＝7.8Hz,1H),6.90(dd,J₁＝8.0Hz,J₂＝1.6Hz,1H),6.39(dd,J₁＝17.0Hz,J₂＝10.2Hz,1H),6.22(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.74(dd,J₁＝10.2Hz,J₂＝1.6Hz,1H),5.45(s,2H),4.57(s,2H),3.09(s,3H)。

Example 9

N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) phenyl) acrylamide

Step 1: synthesis of the compound 3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) aniline

The compound 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ]Pyrazine (1.51g,3.71mmol), 3-aminothiophenol (1g,0.9mL,8mmol), Pd (PPh)₃)₄(0.34g,0.29mmol) and KOBu-t (0.88g,7.4mmol) were mixed, EtOH (40mL) was added, and the mixture was refluxed overnight under nitrogen. The reaction solution was cooled and filtered through celite, the filter cake was washed with dichloromethane, the filtrate was collected, and the concentrated crude product was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 1g of a yellow oil, yield: 60 percent.

MS(ESI,pos.ion)m/z:452.4[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) phenyl) acrylamide

To a solution of 3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) aniline (0.21g,0.47mmol) in DCM (20mL) at 0 ℃ was added a solution of TEA (0.087g,0.12mL) and acryloyl chloride (0.6g,6mmol) in DCM (1mL), and the reaction was allowed to slowly return to room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 0.19g of a pale yellow solid, yield: 81 percent.

MS(ESI,pos.ion)m/z:506.1[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) phenyl) acrylamide

To the compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) thio) phenyl) acrylamide (0.51g,1.0mmol) in 1, 4-dioxane (20mL) was added 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.5g,2mmol), Pd (dppf) Cl₂(0.08g,0.1mmol) and K₂CO₃(0.21g,1.5mmol) and then H was added₂O (5mL), replacement of nitrogen and reaction at 115 ℃ overnight, cooling the reaction mixture, addition of water (20mL), extraction with dichloromethane (30mL × 3), and application of anhydrous Na to the organic phase₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 40/1) to give 0.18g yellow oil, yield: 30 percent.

MS-ESI:(ESI,pos.ion)m/z:598.3[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) thio) phenyl) acrylamide (0.15g,0.25mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), and the reaction was stirred at room temperature for 8H. The reaction mixture was concentrated under reduced pressure, THF (15mL) and TEA (2mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane (30mL × 3) was extracted, a saturated brine was washed (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was separated and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 30/1), and preparative separation by HPLC gave 0.06g of a yellow solid, yield: 30 percent.

MS-ESI:(ESI,pos.ion)m/z:468.4[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.23(s,1H),10.24(s,1H),8.53(d,J＝4.6Hz,1H),8.26(s,1H),8.13(s,1H),7.95(d,J＝2.7Hz,1H),7.87(s,1H),7.74(d,J＝1.6Hz,1H),7.62(d,J＝8.1Hz,1H),7.33(t,J＝8.0Hz,1H),7.31-7.27(m,1H),7.21(d,J＝7.7Hz,1H),7.02(d,J＝7.8Hz,1H),6.35(dd,J₁＝17.0Hz,J₂＝10.2Hz,1H),6.20(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.75-5.70(m,1H),5.33(s,2H),2.31(s,3H)。

Example 10

N- (3- ((7- (3-methyl-1- ((6- (trifluoromethyl) pyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound (6- (trifluoromethyl) pyridin-2-yl) methylmethanesulfonate

TEA (1.4g,1.9mL,14mmol) was added dropwise to a solution of (6-trifluoromethyl-pyridin-2-yl) -methanol (1.61g,9.09mmol) in DCM (20mL) at 0 deg.C, MsCl (1.2g,11mmol) was added under nitrogen, the reaction was continued at 0 deg.C, the reaction was concentrated under reduced pressure, then saturated aqueous sodium bicarbonate (40mL) was added, dichloromethane (50mL × 3) was extracted, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 7/3) to give 2.2g yellow solid, yield: 95 percent. MS (ESI, pos. ion) M/z 256.1[ M +1 ]]⁺。

Step 2: synthesis of compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) -6- (trifluoromethyl) pyridine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.00g,4.81mmol) in DMF (40mL) was added (6- (trifluoro-phenyl-ethyl-phenyl)Methyl) pyridin-2-yl) methyl methanesulfonate (1.9g,7.4mmol) and K ₂CO₃(2.5g,7.7mmol) and then reacted at 100 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 0.7g of the product as a pale yellow oil, yield: 40 percent.

MS(ESI,pos.ion)m/z:368.4[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- ((6- (trifluoromethyl) pyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To the compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.41g,0.84mmol) in 1, 4-dioxane (20mL) was added 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) -6- (trifluoromethyl) pyridine (0.5g,1mmol), Pd (dppf) Cl₂(0.09g,0.1mmol) and K₂CO₃(0.17g,1.2mmol) and then H was added₂O (5mL), replacement of nitrogen and reaction at 115 ℃ overnight, cooling the reaction mixture, addition of water (20mL), extraction with dichloromethane (30mL × 3), and application of anhydrous Na to the organic phase ₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 40/1), yielding 0.4g of yellow oil, yield: 70 percent.

MS-ESI:(ESI,pos.ion)m/z:650.6[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- ((6- (trifluoromethyl) pyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- ((6- (trifluoromethyl) pyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.41g,0.63mmol) was dissolved in dichloromethaneTo an alkane (15mL), TFA (5mL) was added, the reaction was stirred at room temperature for 8 hours, the reaction mixture was concentrated under reduced pressure, THF (15mL) and TEA (2mL) were added, the reaction was stirred at room temperature overnight, the reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, methylene chloride was extracted (30mL × 3), the mixture was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was separated and purified by silica gel column chromatography (eluent: CH₂Cl₂MeOH (v/v) ═ 20/1), preparative HPLC isolation gave 0.06g of yellow solid, yield: 22 percent.

MS-ESI:(ESI,pos.ion)m/z:520.5[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.19(s,1H),10.19(s,1H),8.18(d,J＝18.9Hz,2H),8.03(t,J＝7.9Hz,1H),7.95(s,1H),7.81(d,J＝7.7Hz,1H),7.63(s,1H),7.34(dt,J₁＝16.1Hz,J₂＝7.9Hz,2H),7.21(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,1H),6.41-6.29(m,1H),6.17(d,J＝16.6Hz,1H),5.69(d,J＝9.9Hz,1H),5.42(s,2H),2.31(s,3H)。

Example 11

N- (3- ((7- (3-methyl-1- (pyrimidin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound pyrimidin-2-ylmethyl methanesulfonate

TEA (2.1g,21mmol) was added dropwise to a solution of pyrimidin-2-ylmethanol (1.50g,13.6mmol) in DCM (20mL) at 0 deg.C, MsCl (1.9g,17mmol) was added under nitrogen, the reaction was continued at 0 deg.C for 1h, the reaction was concentrated under reduced pressure, then saturated aqueous sodium bicarbonate (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 7/3) to give 1.3g of a yellow oil, yield: 51 percent.

Step 2: synthesis of the compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (0.91g,4.4mmol) in DMF (25mL) was added pyrimidin-2-ylmethyl methanesulfonate (1.2g,6.4mmol) and Cs₂CO₃(2.3g,7.1mmol) and then reacted at 100 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 1.1g yellow oil, yield: 84 percent.

MS(ESI,pos.ion)m/z:301.4[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyrimidin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.41g,0.84mmol), 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidine (0.5g,1mmol), Pd (dppf) Cl₂(0.06g,0.08mmol) and K₂CO₃(0.17g,1.2mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 115 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 40/1), yielding 0.35g of yellow oil, yield: 72 percent.

MS-ESI:(ESI,pos.ion)m/z:583.7[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyrimidin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- (pyrimidin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.36g,0.62mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), reaction stirred at room temperature for 8h, concentration of the reaction solution under reduced pressure, addition of THF (15mL) and TEA (2mL), reaction stirred at room temperature overnight, concentration of the reaction solution under reduced pressure, removal of the solvent, addition of saturated aqueous sodium bicarbonate (20mL), extraction with dichloromethane (30mL × 3), washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration, and separation and purification of the concentrated crude product by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.03g of a yellow solid, yield: 14 percent.

MS-ESI:(ESI,pos.ion)m/z:453.5[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.16(s,1H),10.18(s,1H),8.74(d,J＝4.9Hz,2H),8.14(d,J＝8.5Hz,2H),7.93(d,J＝2.7Hz,1H),7.60(s,1H),7.41(dd,J₁＝10.7Hz,J₂＝5.9Hz,2H),7.32(t,J＝8.1Hz,1H),6.88(d,J＝7.8Hz,1H),6.36(dd,J₁＝17.0Hz,J₂＝10.1Hz,1H),6.19(dd,J₁＝17.0Hz,J₂＝1.8Hz,1H),5.76-5.68(m,1H),5.41(s,2H),2.27(s,3H)。

Example 12

N- (3- ((7- (1- ((4-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- (bromomethyl) -4-fluoropyridine

4-fluoro-2-methylpyridine (4.32g,4.01mL,38.9mmol), NBS (6g,33.7mmol) and AIBN (0.56g,3.4mmol) were mixed and CCl was added₄(50mL) and then heated to 80 ℃ for reaction for 3 h. The reaction solution was cooled and filtered through celite, and the crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 9/1) to give 1.3g of a brown oily product, yield: 16 percent.

MS(ESI,pos.ion)m/z:191.1[M+1]⁺。

Step 2: synthesis of the compound 4-fluoro-2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.01g,4.85mmol) in DMF (40mL) was added 2- (bromomethyl) -4-fluoropyridine (1.2g,6.3mmol), Cs₂CO₃(5.5g,17mmol) and KI (0.4g,2mmol) and then reacted at 70 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 1g of a yellow oil, yield: 65 percent.

MS(ESI,pos.ion)m/z:318.3[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (1- ((4-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.35g,0.72mmol), 4-fluoro-2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.35g,1.1mmol), Pd (dppf) Cl ₂(0.06g,0.08mmol) and K₂CO₃(0.15g,1.1mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 115 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 0.21g of a yellow oil, yield: 49 percent.

MS-ESI:(ESI,pos.ion)m/z:600.3[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (1- ((4-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Reacting a compound N- (3- ((7- (1- ((4-fluoropyridin-2-yl) methyl)) -3-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.21g,0.35mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), stirring at room temperature for 8h reaction [ reaction solution was concentrated under reduced pressure, then THF (15mL) and TEA (2mL) were added, then stirring at room temperature overnight ] reaction solution was concentrated under reduced pressure, solvent was removed, saturated aqueous sodium bicarbonate (20mL) was added, dichloromethane (30mL × 3) was extracted, saturated brine was washed (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH) ₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.03g of a yellow solid, yield: 16 percent.

MS-ESI:(ESI,pos.ion)m/z:470.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.18(s,1H),10.20(s,1H),8.54(dd,J₁＝8.8Hz,J₂＝5.7Hz,1H),8.15(d,J＝2.8Hz,2H),7.94(s,1H),7.63(s,1H),7.38(d,J＝8.2Hz,1H),7.33(t,J＝8.0Hz,1H),7.27-7.16(m,1H),6.90(dd,J₁＝9.8Hz,J₂＝2.5Hz,2H),6.36(dd,J₁＝16.9Hz,J₂＝10.1Hz,1H),6.19(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.74-5.65(m,1H),5.33(s,2H),2.30(s,3H)。

Example 13

N- (3- ((7- (1- ((6-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- (bromomethyl) -6-fluoropyridine

2-fluoro-6-methylpyridine (4.32g,38.9mmol), NBS (6g,33.7mmol) and AIBN (0.56g,3.4mmol) were mixed and CCl was added₄(50mL) and then heated to 80 ℃ for reaction for 3 h. The reaction solution was cooled and filtered through celite, and the crude product after concentration of the filtrate was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 9/1) to give 4g of yellow oil, yield: 54 percent.

MS(ESI,pos.ion)m/z:191.1[M+1]⁺。

Step 2: synthesis of the compound 2-fluoro-6- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.51g,7.26mmol) in DMF (40mL) was added 2- (bromomethyl) -6-fluoropyridine (2.1g,11mmol), Cs₂CO₃(8.3g,25mmol) and KI (0.6g,4mmol) and then reacted at 70 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 1.5g yellow oil, yield: 65 percent.

MS(ESI,pos.ion)m/z:318.3[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (1- ((6-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.41g,0.84mmol), 2-fluoro-6- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.4g,1mmol), Pd (dppf) Cl₂(0.09g,0.1mmol) and K₂CO₃(0.17g,1.2mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 115 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 0.31g of a yellow oil, yield: 62 percent.

MS-ESI:(ESI,pos.ion)m/z:600.3[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (1- ((6-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (1- ((6-fluoropyridin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.3g,0.52mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), stirring at room temperature for 8h reaction [ reaction solution was concentrated under reduced pressure, then THF (15mL) and TEA (2mL) were added, then stirring at room temperature overnight ] reaction solution was concentrated under reduced pressure, solvent was removed, saturated aqueous sodium bicarbonate (20mL) was added, dichloromethane (30mL × 3) was extracted, saturated brine was washed (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), preparative HPLC isolation gave 0.04g yellow solid, yield: 16 percent.

MS-ESI:(ESI,pos.ion)m/z:470.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.19(s,1H),10.21(s,1H),8.23-8.09(m,2H),7.93(d,J＝9.0Hz,2H),7.60(d,J＝24.0Hz,1H),7.46-7.28(m,2H),7.07(d,J＝8.0Hz,1H),6.97(d,J＝7.3Hz,1H),6.88(d,J＝4.8Hz,1H),6.44-6.34(m,1H),6.20(t,J＝15.3Hz,1H),5.71(d,J＝10.3Hz,1H),5.36(s,1H),5.27(s,1H),2.31(d,J＝8.2Hz,3H)。

Example 14

N- (3- ((7- (3-ethyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazole-3-carbaldehyde

To a solution of 4-bromo-1H-pyrazole-3-carbaldehyde (5g,28.6mmol) in DMF (150mL) was added 2- (bromomethyl) pyridine hydrobromide (11g,43.49mmol), Cs ₂CO₃(33g,101.28mmol) and KI (2.4g,14mmol), followed by reaction at 70 ℃ overnight. Cooling the reaction solution, filtering, concentrating the filtrate, separating and purifying the crude product by silica gel column chromatography (eluent: PE)EtOAc (v/v) ═ 7/3), yielding 2g of the product as a yellow oil, yield: 26.3 percent.

MS(ESI,pos.ion)m/z:268.1[M+2]⁺。

Step 2: synthesis of compound 2- ((4-bromo-3-vinyl-1H-pyrazol-1-yl) methyl) pyridine

MeLi (3.5mL,5.6mmol) (1.6M in ether) was added dropwise to a solution of methyltriphenylphosphonium bromide (2.27g,6.35mmol) in THF (35mL) at 0 deg.C, the reaction was stirred for 1H, then a solution of 4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazole-3-carbaldehyde (1.21g,4.55mmol) in THF (5mL) was slowly added dropwise, the reaction was allowed to proceed at 0 deg.C for 1H, the reaction was allowed to return to room temperature and continued for 1H, the reaction was added to a saturated aqueous ammonium chloride solution (30mL), EtOAc (50mL × 3) was extracted, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 0.26g of a yellow oil, yield: 22 percent.

MS(ESI,pos.ion)m/z:265.1[M+1]⁺。

And step 3: synthesis of the compound 2- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-vinyl-1H-pyrazol-1-yl) methyl) pyridine

The compound 2- ((4-bromo-3-vinyl-1H-pyrazol-1-yl) methyl) pyridine (0.26g,0.98mmol), pinacol diboron (0.5g,2mmol), KOAc (0.3g,3mmol) and Pd (dppf) Cl ₂(0.08g,0.1mmol) was mixed, DMSO (15mL) was added, the mixture was reacted at 90 ℃ overnight, the reaction mixture was cooled, water (20mL) was added, methylene chloride (30mL × 3) was extracted, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 0.18g of a yellow oil, yield: 59 percent.

MS(ESI,pos.ion)m/z:312.3[M+1]⁺。

And 4, step 4: synthesis of the compound 2- ((3-ethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of compound 2- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-vinyl-1H-pyrazol-1-yl) methyl) pyridine (0.29g,0.93mmol) in EtOH (20mL) was added Pd/C (10%0.03g) of substitution of H₂The reaction was then stirred at room temperature overnight. The reaction solution was filtered through celite, and the crude product after concentrating the filtrate was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 0.24g of a yellow oily product, yield: 82 percent.

MS-ESI:(ESI,pos.ion)m/z:314.3[M+1]⁺。

And 5: synthesis of the compound N- (3- ((7- (3-ethyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

To the compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.21g,0.43mmol) in 1, 4-dioxane (20mL) was added 2- ((3-ethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.18g,0.57mmol), Pd (dppf) Cl₂(0.03g,0.04mmol) and K₂CO₃(0.09g,0.7mmol) and then H was added₂O (5mL), replacement of nitrogen and reaction at 115 ℃ overnight, cooling the reaction mixture, addition of water (20mL), extraction with dichloromethane (30mL × 3), and application of anhydrous Na to the organic phase₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 0.08g of the product as a yellow oil, yield: 30 percent.

MS-ESI:(ESI,pos.ion)m/z:596.3[M+1]⁺。

Step 6: synthesis of the compound N- (3- ((7- (3-ethyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-ethyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.08g,0.14mmol) was dissolved in dichloromethane (15mL), TFA (3mL,38.7mmol) was added at 0 deg.C, and the reaction stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure, THF (15mL) and TEA (3mL) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the solvent was removed, and a saturated aqueous sodium bicarbonate solution (20mL) was added thereto Extracting with chloromethane (30mL × 3), washing with saturated sodium chloride solution (20mL), drying with anhydrous sodium sulfate, concentrating, and separating and purifying the concentrated crude product by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), preparative HPLC separation afforded 0.01g of yellow solid, yield: 18 percent. MS-ESI (ESI, pos.ion) M/z 466.3[ M +1 ]]⁺；

1H NMR(400MHz,DMSO-d₆):(ppm)12.17(s,1H),10.21(s,1H),8.50(d,J＝4.2Hz,1H),8.16(s,1H),8.09(s,1H),7.89(d,J＝2.8Hz,1H),7.72(td,J₁＝7.7Hz,J₂＝1.7Hz,1H),7.62(s,1H),7.37(dd,J₁＝23.7Hz,J₂＝8.2Hz,2H),7.31-7.25(m,1H),7.01(d,J＝7.8Hz,1H),6.88(dd,J₁＝7.9Hz,J₂＝1.5Hz,1H),6.38(dd,J₁＝16.9Hz,J₂＝10.1Hz,1H),6.19(dd,J₁＝17.0Hz,J₂＝1.8Hz,1H),5.71(dd,J₁＝10.1Hz,J₂＝1.8Hz,1H),5.30(s,2H),3.49(q,J＝10.4,5.0Hz,2H),1.10(t,J＝7.5Hz,3H)。

Example 15

N- (3- ((7- (3-methyl-1- (thiazol-5-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of 5- (chloromethyl) thiazole compound

Thiazol-5-ylcarbinol (503mg,4.37mmol) and thionyl chloride (2.59g,21.8mmol) were dissolved in dichloromethane (15mL) at room temperature and reacted for 3 h. The reaction solution was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give 512mg of a pale yellow oil, yield: 87.73 percent.

MS-ESI:(ESI,pos.ion)m/z:134.0[M+1]⁺。

Step 2: synthesis of compound 5- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) thiazole

5- (chloromethyl) thiazole (502mg,3.76mmol) and 3-methylpyrazole-4-boronic acid pinacol ester (820mg,3.94mmol) were dissolved in acetone (10mL), and Cs was added to the system ₂CO₃(402mg,1.23mmol), and the reaction was allowed to proceed for 8h at 60 ℃. The reaction was filtered and the concentrated crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give an isomer mixture as 652mg yellow oil in yield: 56.85 percent.

MS-ESI:(ESI,pos.ion)m/z:306.30[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- (thiazol-5-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound 5- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) thiazole (301mg,0.99mmol) and N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (482mg,0.98mmol) were dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1, potassium carbonate (342mg,2.48mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (70mg,0.095mmol), replacing nitrogen, heating to 110 ℃ and reacting for 6 h. The reaction solution was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/5) to give 220mg of a yellow oil, yield: 37.85 percent.

MS-ESI:(ESI,pos.ion)m/z:588.10[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- (thiazol-5-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- (thiazol-5-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (221mg,0.38mmol) and trifluoroacetic acid (5mL) were dissolved in dichloromethane (15mL) and reacted at room temperature for 8 h. Directly spin-drying the reaction solutionDissolving the residue in tetrahydrofuran (5mL), adding saturated sodium bicarbonate solution (10mL), stirring at room temperature for 20h, pouring the reaction mixture into water (20mL), extracting with ethyl acetate (20mL × 3), washing with saturated sodium chloride solution (20mL), drying with anhydrous sodium sulfate, and separating and purifying the concentrated crude product by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 10/1), yielding 25mg of a yellow solid, yield: 20.18 percent.

MS-ESI:(ESI,pos.ion)m/z:458.20[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.20(s,1H),10.23(s,1H),9.00(s,1H),8.16(s,1H),7.92(d,J＝2.7Hz,1H),7.88(s,1H),7.70(s,1H),7.55(s,1H),7.45(d,J＝8.1Hz,1H),7.36(t,J＝8.1Hz,1H),6.89(dd,J₁＝8.1Hz,J₂＝1.8Hz,1H),6.42-6.37(m,1H),6.23(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.75(dd,J₁＝10.2Hz,J₂＝1.7Hz,1H),5.56(s,2H),2.35(s,3H)。

Example 16

N- (3- ((7- (3-methyl-1- (pyrazin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- (chloromethyl) pyrazine

Pyrazin-2-ylcarbinol (103mg,0.094mmol) and thionyl chloride (546mg,4.59mmol) were dissolved in dichloromethane (15mL) at room temperature and reacted for 3 h. The reaction solution was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give 87mg of a pale yellow oil, yield: 72.34 percent.

¹H NMR(400MHz,CDCl₃):(ppm)8.78(s,1H),8.58(d,J＝1.5Hz,2H),4.72(s,2H)。

Step 2: synthesis of the compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrazine

2- (chloromethyl) pyrazine (107mg,0.83mmol) and 3-methylpyrazole-4-boronic acid pinacol ester (180mg,0.87mmol) were dissolved in acetone (10mL), and Cs was added to the system₂CO₃(402mg,1.23mmol), and the reaction was allowed to proceed for 8h at 60 ℃. The reaction was filtered and the concentrated crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) ═ 1/1) to give the isomer mixture as 189mg yellow oil in yield: 75.64 percent.

MS-ESI:(ESI,pos.ion)m/z:301.1[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyrazin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrazine (198mg,0.66mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (327mg,0.67mmol) was dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1), potassium carbonate (233mg,1.69mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (51mg,0.069mmol), replacing nitrogen, heating to 105 ℃ and reacting for 6 h. The reaction solution was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 208mg of a pale yellow oil, yield: 54.12 percent.

MS-ESI:(ESI,pos.ion)m/z:583.60[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyrazin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- (pyrazin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (182mg,0.31mmol) and trifluoroacetic acid (10mL) were dissolved in dichloromethane (15mL) and reacted at room temperature for 8 h. Reacting the reaction solutionDirectly spin-drying, dissolving the residue in tetrahydrofuran (5mL), adding saturated sodium bicarbonate solution (10mL), stirring at room temperature for 8h, pouring the reaction solution into water (20mL), extracting with ethyl acetate (20mL × 3), washing with saturated saline (20mL), drying with anhydrous sodium sulfate, and separating and purifying the concentrated crude product by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 10/1), yielding 14mg of a yellow solid, yield: 11.74 percent.

MS-ESI:(ESI,pos.ion)m/z:453.20[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.20(s,1H),10.21(s,1H),8.60-8.58(m,1H),8.57(d,J＝2.5Hz,1H),8.42(s,1H),8.17(s,1H),7.94(s,1H),7.71(s,1H),7.56(s,1H),7.42(d,J＝8.0Hz,1H),7.34(s,1H),6.90-6.88(m,1H),6.38(s,1H),6.22(d,J＝15.2Hz,1H),5.74(d,J＝10.0Hz,1H),5.48(s,2H),2.36(s,3H)。

Example 17

N- (3- ((7- (3-methyl-1- (thiazol-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of Compound Thiazol-2-ylmethanol

Thiazole-2-carbaldehyde (301mg,2.66mmol) was dissolved in methanol (15mL) at 0 ℃ and sodium borohydride (151mg,3.99mmol) was added to the system and reacted for 2 h. The reaction mixture was poured into water (10mL), the solvent was dried by spinning, extracted with ethyl acetate (15mL × 3), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 285mg of a pale yellow oil, yield: 93 percent.

MS-ESI:(ESI,pos.ion)m/z:116.10[M+1]⁺。

Step 2: synthesis of Compound 2- (chloromethyl) thiazole

Thiazol-2-ylcarbinol (287mg,2.49mmol) and thionyl chloride (0.9mL,10mmol) were dissolved in dichloromethane (15mL) at room temperature and reacted for 4 h. The reaction solution was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give 289mg of a pale yellow oil, yield: 86.79 percent.

And step 3: synthesis of Compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) thiazole

2- (chloromethyl) thiazole (302mg,2.26mmol) and 3-methylpyrazole-4-boronic acid pinacol ester (463mg,2.23mmol) were dissolved in acetone (10mL), and Cs was added to the system₂CO₃(1.12g,3.44mmol), heating to 60 ℃ and reacting for 6 h. The reaction solution was filtered, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 483mg of a yellow oil, yield: 70.01 percent. MS-ESI (ESI, pos.ion) M/z 306.35[ M +1 ]]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- (thiazol-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

A compound, 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) thiazole (305mg,1mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (486mg,1mmol) was dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1), potassium carbonate (345mg,2.5mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (75mg,0.1mmol), replacing nitrogen, heating to 105 ℃ and reacting for 6 h. The reaction mixture was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/9) to give 207mg of a brown oil, yield: 35.24 percent.

MS-ESI:(ESI,pos.ion)m/z:588.20[M+1]⁺。

And 5: synthesis of the compound N- (3- ((7- (3-methyl-1- (thiazol-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- (thiazol-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine-2-yl) oxy) phenyl) acrylamide (204mg,0.35mmol) and trifluoroacetic acid (5mL) were dissolved in dichloromethane (6mL) and reacted at room temperature for 6h, the reaction solution was directly dried by spinning, the residue was dissolved in tetrahydrofuran (5mL), a saturated sodium bicarbonate solution (10mL) was added, the reaction solution was stirred at room temperature for 8h, poured into water (20mL), extracted with ethyl acetate (20mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and the concentrated crude product was chromatographically separated and purified (eluent: CH silica gel column) ₂Cl₂MeOH (v/v) ═ 10/1), yielding 29mg of a yellow solid, yield: 16.35 percent.

MS-ESI:(ESI,pos.ion)m/z:458.20[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.19(s,1H),10.22(s,1H),8.15(d,J＝3.6Hz,2H),7.93(s,1H),7.74(d,J＝2.9Hz,1H),7.67-7.59(m,2H),7.40(d,J＝8.4Hz,1H),7.34(t,J＝8.0Hz,1H),6.88(d,J＝7.7Hz,1H),6.38(dd,J₁＝16.7Hz,J₂＝10.0Hz,1H),6.21(d,J＝17.3Hz,1H),5.73(d,J＝9.7Hz,1H),5.56(s,2H),2.30(s,3H)。

Example 18

N- (3- ((7- (3-methyl-1- ((2-methylthiazol-5-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 5- (chloromethyl) -2-methylthiazole

(2-methylthiazol-5-yl) methanol (304mg,2.35mmol) and thionyl chloride (0.9mL,10mmol) were dissolved in dichloromethane (15mL) at room temperature and reacted for 4 h. The reaction solution was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give 286mg of a pale yellow oil, yield: 82.32 percent.

Step 2: synthesis of Compound 2-methyl-5- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) thiazole

The compound 5- (chloromethyl) -2-methylthiazole (241mg,1.63mmol) and 3-methylpyrazole-4-boronic acid pinacol ester (340mg,1.63mmol) were dissolved in acetone (10mL), and Cs was added to the system₂CO₃(1.3g,4.0mmol), heating to 60 ℃ and reacting for 6 h. The reaction mixture was filtered, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 312mg of a yellow oil, yield: and 59.88 percent.

MS-ESI:(ESI,pos.ion)m/z:320.10[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- ((2-methylthiazol-5-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compounds 2-methyl-5- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) thiazole (376mg,1.18mmol) and N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide (570mg,1.17mmol) were dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1), potassium carbonate (400mg,2.9mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (86mg were added to the system, 0.012mmol), replacing nitrogen, heating to 105 ℃ and reacting for 6 h. The reaction mixture was poured into water (30mL), extracted with ethyl acetate (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/10) to give 236mg of a brown oil, yield: 33.29 percent.

MS-ESI:(ESI,pos.ion)m/z:602.55[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- ((2-methylthiazol-5-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- ((2-methylthiazol-5-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethyl)Silyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-2-yl) oxy) phenyl) acrylamide (182mg,0.30mmol) and trifluoroacetic acid (5mL) were dissolved in dichloromethane (5mL) and reacted at room temperature for 6h, the reaction solution was directly dried by spinning, the residue was dissolved in tetrahydrofuran (10mL), a saturated sodium bicarbonate solution (15mL) was added, the reaction solution was stirred at room temperature for 8h, poured into water (20mL), extracted with ethyl acetate (20mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and the concentrated crude product was chromatographically separated and purified (eluent: CH silica gel column)₂Cl₂MeOH (v/v) ═ 10/1), yielding 48mg of a yellow solid, yield: 24.67 percent.

MS-ESI:(ESI,pos.ion)m/z:472.20[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.16(s,1H),10.26(s,1H),8.15(s,1H),8.04(s,1H),7.90(s,1H),7.63(s,1H),7.54(s,1H),7.43(d,J＝8.3Hz,1H),7.37(t,J＝8.1Hz,1H),6.89(d,J＝8.1Hz,1H),6.44-6.36(m,1H),6.23(dd,J₁＝17.0Hz,J₂＝1.8Hz,1H),5.75(dd,J₁＝10.0Hz,J₂＝1.8Hz,1H),5.37(s,2H),2.56(s,3H),2.28(s,3H)。

Example 19

N- (3- ((7- (3-methyl-1- ((4-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2, 4-dimethylpyridine 1-oxide

HOAc (30mL) was slowly added to 2, 4-lutidine (11.1g,104mmol) with constant stirring, and H was slowly added dropwise₂O₂(16mL) and then reacted at 70 ℃ for 24 h. Cooling the reaction solution, and adding a small amount of Na ₂SO₃After quenching, stirring at room temperature for 10min, the pH was adjusted to 12 with aqueous NaOH (20%), followed by extraction with dichloromethane (50mL × 3), and the organic phase was washed with anhydrous Na₂SO₄Dried and concentrated to give 12g of a colorless oily liquid, yield: 93.9 percent.

MS(ESI,pos.ion)m/z:124.3[M+1]⁺。

Step 2: synthesis of Compound (4-methylpyridin-2-yl) methanol

To a solution of 2, 4-lutidine 1-oxide (10.11g,82.10mmol) in DCM (200mL) was slowly added TFAH (51.37g,244.6mmol) in DCM (50mL) dropwise, and the reaction was stirred at room temperature for 3.5 days. The solvent was removed by concentration under reduced pressure, MeOH (200mL) and saturated K were added₂CO₃The solution (250mL) was stirred at room temperature for 3h, concentrated under reduced pressure to remove MeOH, extracted with dichloromethane (200mL × 3), and the organic phase was extracted with anhydrous Na₂SO₄Drying and concentration gave 4g of product as a brown oil, yield: 39.6 percent.

MS(ESI,pos.ion)m/z:124.3[M+1]⁺。

And step 3: synthesis of compound (4-methylpyridin-2-yl) methylmethanesulfonate

TEA (1.9g,19mmol) was added dropwise to a solution of (4-methylpyridin-2-yl) methanol (1.50g,12.2mmol) in dichloromethane (20mL) at 0 deg.C, MsCl (1.6g,14mmol) was added under nitrogen, the reaction was continued at 0 deg.C, the reaction was concentrated under reduced pressure, then saturated aqueous sodium bicarbonate (50mL) was added, dichloromethane (60mL × 3) was extracted, and the organic phase was extracted with anhydrous Na ₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 0.7g of product as a reddish brown oil, yield: 30 percent.

MS(ESI,pos.ion)m/z:202.1[M+1]⁺。

And 4, step 4: synthesis of the compound 4-methyl-2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (0.50g,2.4mmol) in DMF (25mL) was added (4-methylpyridin-2-yl) methyl methanesulfonate (0.62g,3.1mmol) and K₂CO₃(1.3g,4.0mmol) and then reacted at 100 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 7/3) to give 0.18g of a pale yellow oilYield, yield: 24 percent.

MS(ESI,pos.ion)m/z:314.3[M+1]⁺。

And 5: synthesis of the compound N- (3- ((7- (3-methyl-1- ((4-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

4-methyl-2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.21g,0.43mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) ]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.28g,0.57mmol), Pd (dppf) Cl₂(0.03g,0.04mmol) and K₂CO₃(0.09g,0.7mmol) were mixed, 1, 4-dioxane (16mL) and water (4mL) were added, nitrogen was replaced, the mixture was heated to 120 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 40/1), yielding 0.15g of yellow oil, yield: 59 percent.

MS-ESI:(ESI,pos.ion)m/z:596.3[M+1]⁺。

Step 6: synthesis of the compound N- (3- ((7- (3-methyl-1- ((4-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Mixing compound N- (3- ((7- (3-methyl-1- ((4-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.11g,0.18mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), stirring at room temperature for 8h reaction [ reaction solution was concentrated under reduced pressure, then THF (15mL) and TEA (2mL) were added, then stirring at room temperature overnight ] reaction solution was concentrated under reduced pressure, solvent was removed, saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane was extracted (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH) ₂Cl₂/MeOH (v/v) ═ 20/1), yielding 0.04g of a yellow solid, yield: 27 percent.

MS-ESI:(ESI,pos.ion)m/z:466.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.21(s,1H),10.21(s,1H),9.11(s,1H),8.72(d,J＝5.2Hz,1H),8.18(d,J＝19.3Hz,2H),7.96(d,J＝2.8Hz,1H),7.64(s,1H),7.35(dd,J₁＝16.5Hz,J₂＝8.1Hz,2H),7.02(d,J＝5.0Hz,1H),6.88(d,J＝7.8Hz,1H),6.34(d,J＝10.2Hz,1H),6.21-6.15(m,1H),5.71(dd,J₁＝10.2Hz,J₂＝1.7Hz,1H),5.35(s,2H),2.31(s,3H)。

Example 20

N- (3- ((7- (3-isopropyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- ((4-bromo-3-isopropyl-1H-pyrazol-1-yl) methyl) pyridine

4-bromo-3-isopropyl-1H-pyrazole (310mg,1.64mmol), 2- (bromomethyl) pyridine (812mg,1.96mmol) and Cs were added at room temperature₂CO₃(1.29g,3.97mmol) was dissolved in acetone (15mL) and the reaction was allowed to warm to 60 ℃ for 8 h. Celite was filtered, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 367mg of a pale yellow liquid, yield: 79.89 percent.

MS-ESI:(ESI,pos.ion)m/z:281.15[M+1]⁺。

Step 2: synthesis of the compound 2- ((3-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

2- ((4-bromo-3-isopropyl-1H-pyrazol-1-yl) methyl) pyridine (681mg,2.43mmol), potassium acetate (721mg,7.36mmol), pinacol diboron (780mg,3.06mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (130mg,0.18mmol) were dissolved in dioxane (20mL) at room temperature, and the temperature was raised to 100 ℃ for reaction for 8H. The reaction mixture was poured into water (50mL), extracted with ethyl acetate (50mL × 3), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, and the solvent was removed, and the residue was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1), to give 198mg of a yellow oil, yield: 24.89 percent.

MS-ESI:(ESI,pos.ion)m/z:328.25[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-isopropyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound 2- ((3-isopropyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (263mg,0.80mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] at room temperature]Pyrazin-2-yl) oxy) phenyl) acrylamide (402mg,0.82mmol), potassium carbonate (271g,1.96mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (45mg,0.061mmol) is dissolved in a mixed solvent of dioxane and water (15mL, (v/v) ═ 4/1), heated to 100 ℃ and reacted for 8h, the reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) is extracted, saturated brine (15mL) is washed, dried over anhydrous sodium sulfate, the solvent is removed, and the residue is subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/10) to give 192mg of brown oil, yield: 39.17%. MS-ESI (ESI, pos.ion) M/z:610.30[ M + 1M + ESI: (ESI, pos.ion) M/z: 610.30: (M + 1)]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-isopropyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-isopropyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) was reacted at room temperature]Pyrazin-2-yl) oxy) phenyl) acrylamide (192mg,0.31mmol) and trifluoroacetic acid (5.3mL) were dissolved in dichloromethane (5mL) and reacted at room temperature for 10h, the reaction solution was directly dried by spinning, the residue was dissolved in tetrahydrofuran (5mL), a saturated sodium bicarbonate solution (5mL) was added and stirred at room temperature for 8h, the reaction solution was poured into water (20mL), dichloromethane (20mL × 3) was extracted, saturated brine (15mL) was washed, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatographySeparating, separating and purifying (eluent: CH)₂Cl₂MeOH (v/v) ═ 10/1), yielding 12mg of a light yellow solid, yield: 29.66 percent.

MS-ESI:(ESI,pos.ion)m/z:480.50[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.15(s,1H),10.18(s,1H),8.51(d,J＝3.9Hz,1H),8.16(s,1H),8.02(s,1H),7.87(s,1H),7.73(s,1H),7.61(s,1H),7.39(d,J＝8.4Hz,1H),7.34-7.26(m,2H),6.98(d,J＝7.8Hz,1H),6.87(d,J＝8.0Hz,1H),6.41-6.33(m,1H),6.23-6.15(m,1H),5.71(d,J＝11.9Hz,1H),5.31(s,2H),3.25(d,J＝6.0Hz,1H),1.11(d,J＝6.8Hz,6H)。

Example 21

(E) -N- (3- ((7- (3- (3-oxobut-1-en-1-yl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound (E) -4- (4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazol-3-yl) but-3-en-2-one

To a solution of 4-bromo-1H-pyrazole-3-carbaldehyde (5g,28.6mmol) in acetone (100mL) was added 2- (bromomethyl) pyridine hydrobromide (11g,43.5mmol), Cs ₂CO₃(33g,101.3mmol) and KI (1g,5.6mmol), followed by reaction at 100 ℃ overnight. The reaction was cooled and filtered, the filtrate was concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 4g of a pale yellow solid, yield: 45.6 percent.

MS(ESI,pos.ion)m/z:306.3[M+1]⁺。

Step 2: synthesis of Compound (E) -4- (1- (pyridin-2-ylmethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) but-3-en-2-one

The compound (E) -4- (4-bromo-1- (pyridin-2-ylmethyl) -1H-pyrazol-3-yl) but-3-en-2-one (0.49g,1.6mmol), pinacol diboron (0.75g,3.0mmol), KOAc (0.50g,5.1mmol) and Pd (dppf) Cl₂(0.12g,0.16mmol) was mixed and DMSO (10mL) was added theretoThe reaction was allowed to proceed overnight at 90 ℃ after the reaction mixture was cooled, water (20mL) and methylene chloride (30mL × 3) were added to extract the mixture, and the organic phase was extracted with anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 0.22g of a light yellow solid, yield: 37 percent.

MS-ESI:(ESI,pos.ion)m/z:354.1[M+1]⁺。

And step 3: synthesis of the compound (E) -N- (3- ((7- (3- (3-oxobut-1-en-1-yl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.21g,0.43mmol), (E) -4- (1- (pyridin-2-ylmethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-3-yl) but-3-en-2-one (0.28g,0.79mmol), Pd (dppf) Cl₂(0.03g,0.04mmo) and K₂CO₃(0.09g,0.7mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 115 ℃ and reacted overnight, the reaction mixture was cooled, water (20mL) and methylene chloride (30mL × 3) were added and extracted, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 40/1), yielding 0.14g of a light yellow oil, yield: 51 percent.

MS-ESI:(ESI,pos.ion)m/z:636.7[M+1]⁺。

And 4, step 4: synthesis of the compound (E) -N- (3- ((7- (3- (3-oxobut-1-en-1-yl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound (E) -N- (3- ((7- (3- (3-oxobut-1-en-1-yl) -1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.14g,0.22mmol) was dissolved in dichloromethane (15mL) and TFA (5mL) was added and the reaction stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure, and THF (15mL) andTEA (2mL) was then reacted at room temperature under stirring overnight, the reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, methylene chloride was extracted (30mL × 3), the mixture was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was purified by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 30/1), yielding 0.04g of a brown solid, yield: 40 percent.

MS-ESI:(ESI,pos.ion)m/z:506.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.39(s,1H),10.19(s,1H),8.53(d,J＝3.9Hz,1H),8.20(d,J＝8.5Hz,2H),8.08(s,1H),7.77(t,J＝7.1Hz,1H),7.68(d,J＝16.1Hz,1H),7.59(s,1H),7.47-7.24(m,3H),7.18(d,J＝7.5Hz,1H),6.86(d,J＝7.1Hz,1H),6.66(d,J＝16.0Hz,1H),6.36(d,J＝10.0Hz,1H),6.20(d,J＝17.0Hz,1H),5.72(d,J＝10.1Hz,1H),5.46(s,2H),2.23(s,3H)。

Example 22

N- (3- ((7- (3-methyl-1- ((6-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of the compound 2-methyl-6- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.50g,7.2mmol) in acetone (40mL) was added 2- (bromomethyl) -6-methylpyridine (2g,10.8mmol), Cs₂CO₃(5.9g,18.0mmol) and KI (0.6g,4mmol), followed by reaction at 60 ℃ overnight. The reaction solution was cooled and filtered, and the crude product after concentrating the filtrate under reduced pressure was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 1.5g of a yellow solid, yield: 66 percent.

MS(ESI,pos.ion)m/z:314.4[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7- (3-methyl-1- ((6-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.51g,1.0mmol), 2-methyl-6- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.54g,1.7mmol), Pd (dppf) Cl₂(0.05g,0.07mmo) and K₂CO₃(0.21g,1.5mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 120 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 25/1), yielding 0.48g of product as a light yellow oil, yield: 77 percent.

MS-ESI:(ESI,pos.ion)m/z:596.6[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- ((6-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- ((6-methylpyridin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.48g,0.81mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), stirring at room temperature for 8h reaction [ reaction solution was concentrated under reduced pressure, then THF (15mL) and TEA (2mL) were added, then stirring at room temperature overnight ] reaction solution was concentrated under reduced pressure, solvent was removed, saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane was extracted (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), preparative separation by HPLC gave 0.07g of yellow solid, yield: 19 percent. MS-ESI (ESI, pos.ion) M/z 466.3[ M +1 ]]⁺；

¹H NMR(400MHz,DMSO-d₆):(ppm)12.17(s,1H),10.21(s,1H),8.14(d,J＝15.0Hz,2H),7.93(s,1H),7.60(dd,J₁＝14.5Hz,J₂＝6.6Hz,2H),7.41(d,J＝7.8Hz,1H),7.34(d,J＝8.0Hz,1H),7.13(d,J＝7.6Hz,1H),6.88(d,J＝7.2Hz,1H),6.78(d,J＝7.6Hz,1H),6.36(d,J＝10.1Hz,1H),6.20(d,J＝16.8Hz,1H),5.71(d,J＝10.2Hz,1H),5.24(s,2H),2.43(s,3H),2.30(s,3H)。

Example 23

N- (3- ((7- (3-methyl-1- (pyrimidin-4-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 4- (bromomethyl) pyrimidine

To a solution of compound 4-methylpyrimidine (2.07g,22.0mmol) in THF (150mL) was added AIBN (0.36g,2.2mmol) followed by NBS (4.7g,26mmol) in THF (20mL) at 0 deg.C and then heated to 70 deg.C for reaction overnight. The reaction solution was cooled and filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give 1.5g of a reddish brown oil, yield: 39 percent.

MS(ESI,pos.ion)m/z:175.1[M+2]⁺。

Step 2: synthesis of the compound 4- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.01g,4.85mmol) in DMF (40mL) was added 4- (bromomethyl) pyrimidine (1.2g,6.9mmol), Cs₂CO₃(3.9g,12mmol) and KI (0.4g,2mmol) and then reacted at 70 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.8g of yellow oil, yield: 50 percent.

MS(ESI,pos.ion)m/z:301.2[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyrimidin-4-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.51g,1.0mmol), 4- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidine (0.8g,2mmol), Pd (dppf) Cl ₂(0.05g,0.07mmol) and K₂CO₃(0.21g,1.5mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 115 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.29g of product as a yellow oil, yield: 48 percent.

MS-ESI:(ESI,pos.ion)m/z:583.3[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- (pyrimidin-4-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound N- (3- ((7- (3-methyl-1- (pyrimidin-4-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.29g,0.5mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), stirring at room temperature for 8h reaction [ reaction solution was concentrated under reduced pressure, then THF (15mL) and TEA (2mL) were added, then stirring at room temperature overnight ] reaction solution was concentrated under reduced pressure, solvent was removed, saturated aqueous sodium bicarbonate solution (20mL) was added, dichloromethane was extracted (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH: eluent: CH) ₂Cl₂MeOH (v/v) ═ 20/1), preparative HPLC separation afforded 0.02g yellow solid, yield: 8.7 percent.

MS-ESI:(ESI,pos.ion)m/z:453.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.21(s,1H),10.21(s,1H),9.11(s,1H),8.72(d,J＝5.2Hz,1H),8.18(d,J＝19.3Hz,2H),7.96(d,J＝2.8Hz,1H),7.64(s,1H),7.35(dd,J₁＝16.5Hz,J₂＝8.1Hz,2H),7.02(d,J＝5.0Hz,1H),6.88(d,J＝7.8Hz,1H),6.34(d,J＝10.2Hz,1H),6.21-6.15(m,1H),5.71(dd,J₁＝10.2Hz,J₂＝1.7Hz,1H),5.35(s,2H),2.31(s,3H)。

Example 24

N- (2- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) pyridin-4-yl) acrylamide

Step 1: synthesis of the compound 2- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) pyridin-4-amine

Reacting 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine (2.01g,4.94mmol), 4-amino-2-hydroxypyridine (0.65g,5.9mmol), DMG (0.52g,4.9mmol), Cs₂CO₃(2.41g,7.39mmol) and CuI (0.94g,4.9mmol) were mixed, 1, 4-dioxane (40mL) was added, nitrogen was added, and the mixture was reacted at 110 ℃ overnight. Cooling the reaction solution, filtering with diatomite, and separating and purifying the crude product after vacuum concentration of the filtrate by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 15/1), yielding 0.92g of yellow solid, yield: and 43 percent.

MS(ESI,pos.ion)m/z:437.0[M+1]⁺。

Step 2: synthesis of the compound N- (2- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) pyridin-4-yl) acrylamide

To 2- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) at-10 deg.C ]Pyrazin-2-yl) oxy) pyridin-4-amine (0.71g,1.6mmol) in DCM (40mL) was added DIEA (0.43g,3.3mmol) and acryloyl chloride (0.13g,1.5mmol) in DCM (1mL)After the reaction was continued for 2 hours, the temperature was slowly returned to 0 ℃ for 1 hour, the reaction mixture was quenched with water and poured into water, DCM (50mL × 3) was extracted, the organic phase was washed with saturated brine and then with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.53g of solid product, yield: 66 percent.

MS(ESI,pos.ion)m/z:492.1[M+2]⁺。

And step 3: synthesis of the compound N- (2- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) pyridin-4-yl) acrylamide

N- (2- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) pyridin-4-yl) acrylamide (0.53g,1.1mmol), 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (0.5g,2mmol), Pd (dppf) Cl₂(0.08g,0.1mmol) and K₂CO₃(0.22g,1.6mmol) were mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 120 ℃ for overnight reaction, water (20mL) and methylene chloride (30mL × 3) were added after the reaction mixture was cooled, and the organic phase was extracted with anhydrous Na ₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.19g of yellow oil, yield: 30 percent.

MS-ESI:(ESI,pos.ion)m/z:583.2[M+1]⁺。

And 4, step 4: synthesis of the compound N- (2- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) pyridin-4-yl) acrylamide

The compound N- (2- ((7- (3-methyl-1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) pyridin-4-yl) acrylamide (0.19g,0.33mmol) was dissolved in dichloromethane (15mL) and TFA (5mL) was added and the reaction stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure, and THF (15mL) and T were addedEA (2mL), followed by stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure, the solvent was removed, a saturated aqueous sodium bicarbonate solution (20mL) was added, methylene chloride was extracted (30mL × 3), the mixture was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated crude product was purified by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 30/1), preparative HPLC separation afforded 0.02g yellow solid, yield: 13.3 percent.

MS-ESI:(ESI,pos.ion)m/z:453.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.41(s,1H),10.46(s,1H),8.58(s,1H),8.53(s,1H),8.36(s,1H),8.06(d,J＝2.6Hz,1H),7.93(d,J＝7.6Hz,1H),7.78(s,1H),7.31(s,2H),7.04(d,J＝2.0Hz,1H),6.60(dd,J₁＝7.6Hz,J₂＝2.1Hz,1H),6.45(dd,J₁＝17.0Hz,J₂＝10.1Hz,1H),6.35(dd,J₁＝17.0Hz,J₂＝1.5Hz,1H),5.92-5.85(m,1H),5.42(s,2H),2.38(s,3H)。

Example 25

N- (3- ((7- (3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of the compound 4-bromo-3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazole

Dissolving 4-bromo-3-methyl-1H-pyrazole (1.50g,9.3mmol) in tetrahydrofuran (25mL), slowly adding sodium hydride (0.47g,12.0mmol, 60%) at 0 ℃, heating to room temperature to continue reaction for 1H, slowly adding 1-methyl-2-chloromethylimidazole (1.80g,14.1mmol) to the mixed solution, replacing nitrogen, heating to 70 ℃ to react for 12H, stopping heating, cooling to room temperature, filtering with diatomite, concentrating the filtrate, adding water (30mL), extracting with dichloromethane (30mL × 3), and extracting the organic phase with anhydrous Na₂SO₄The crude product after drying and concentration was purified by preparative isolation to give 0.6g of product as a pale yellow oil, yield: 25.0 percent.

MS(ESI,pos.ion)m/z:256.0[M+1]⁺。

Step 2: synthesis of Compound 3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

4-bromo-3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazole (0.33g,1.3mmol), pinacol diboron (0.49g,1.95mmol), Pd (dppf) Cl ₂(0.09g,0.12mmol) and KOAc (0.38g,3.9mmol) were mixed, 1, 4-dioxane (25mL) was added, nitrogen was replaced, the mixture was heated to 80 ℃ to react for 13 hours, heating was stopped, the mixture was cooled to room temperature, filtered through celite, the filtrate was concentrated, water (30mL) and methylene chloride (30mL × 3) were added to extract the organic phase with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 30/1), yielding 0.22g of brown oil, yield: 56 percent.

MS(ESI,pos.ion)m/z:303.1[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.20g,0.66mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.20g,0.41mmol), Pd (dppf) Cl₂(0.03g,0.04mmol) and K₂CO₃(0.085g,0.61mmol) were mixed, 1, 4-dioxane (25mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 105 ℃ and reacted overnight, the reaction mixture was cooled, water (30mL) and methylene chloride (30mL × 3) were added and extracted, and the organic phase was extracted with anhydrous Na ₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 25/1), yielding 0.1g of brown dope, yield: 41.8 percent.

MS-ESI:(ESI,pos.ion)m/z:585.2[M+1]⁺。

And 4, step 4: synthesis of the compound N- (3- ((7- (3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Reacting N- (3- ((7- (3-methyl-1- ((1-methyl-1H-imidazol-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.1g,0.17mmol) was dissolved in dichloromethane (10mL), TFA (5mL) was added, the reaction was stirred at room temperature for 12h, THF (10mL) and TEA (5mL) were added after the reaction mixture was concentrated under reduced pressure, the reaction mixture was stirred at room temperature for 12h, the reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution (20mL) was added after the solvent was removed, dichloromethane was extracted (30mL × 3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and the concentrated crude product was isolated and purified by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 12/1), yielding 0.03g of a light yellow dope, yield: 41.1 percent.

MS-ESI:(ESI,pos.ion)m/z:455.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.27(d,J＝1.9Hz,1H),10.37(s,1H),8.17(s,1H),7.94(d,J＝2.7Hz,1H),7.72(s,1H),7.58(s,1H),7.46(d,J＝7.6Hz,2H),7.35(t,J＝8.1Hz,1H),7.31(s,1H),6.88(dd,J₁＝8.1Hz,J₂＝1.7Hz,1H),6.45(dd,J₁＝17.0Hz,J₂＝10.2Hz,1H),6.23(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.74(dd,J₁＝10.2Hz,J₂＝1.7Hz,1H),5.56(s,2H),3.75(s,3H),2.43(s,3H)。

Example 26

N- (3- ((7- (1- ((4-aminopyrimidin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of compound 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidin-4-amine

To a solution of 3-methylpyrazole-4-boronic acid pinacol ester (1.01g,4.85mmol) in DMF (40mL) was added 2-chloromethyl-4-amino-pyrimidine (1.1g,7.7mmol), Cs₂CO₃(5.5g,17mmol) and KI (0.4g,2mmol) and then reacted at 70 ℃ overnight, the reaction was concentrated under reduced pressure to remove DMF, water (40mL), dichloromethane (50mL × 3) was added and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.48g of a yellow solid, yield: 31 percent. MS (ESI, pos.ion) M/z 316.2[ M +1 ]]⁺。

Step 2: synthesis of the compound N- (3- ((7- (1- ((4-aminopyrimidin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Reacting N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) ]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.36g,0.74mmol), 2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidin-4-amine (0.35g,1.1mmol), Pd (dppf) Cl₂(0.06g,0.08mmol) and K₂CO₃(.15g,1.1mmol) was mixed, 1, 4-dioxane (20mL) and water (5mL) were added, nitrogen was replaced, the mixture was heated to 115 ℃ and reacted overnight, the reaction mixture was cooled, water (20mL) and methylene chloride (30mL × 3) were added and extracted, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 0.39g of yellow oil, yield: 89 percent.

MS-ESI:(ESI,pos.ion)m/z:598.5[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (1- ((4-aminopyrimidin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Reacting N- (3- ((7- (1- ((4-aminopyrimidin-2-yl) methyl) -3-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.39g0.65mmol) was dissolved in dichloromethane (15mL), followed by addition of TFA (5mL), stirring at room temperature for 8h, concentration of the reaction mixture under reduced pressure, addition of THF (15mL) and TEA (3mL), stirring at room temperature overnight, concentration of the reaction mixture under reduced pressure, removal of the solvent, addition of saturated aqueous sodium bicarbonate solution (20mL), extraction with dichloromethane (30mL × 3), washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration, and separation and purification of the concentrated crude product by silica gel column chromatography (eluent: CH ₂Cl₂MeOH (v/v) ═ 20/1), preparative HPLC separation afforded 0.01g of yellow solid, yield: 3.2 percent.

MS-ESI:(ESI,pos.ion)m/z:468.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.17(s,1H),10.22(s,1H),8.17(s,1H),7.96(d,J＝5.9Hz,1H),7.92(d,J＝2.7Hz,1H),7.64(s,1H),7.57(s,1H),7.42(d,J＝8.1Hz,1H),7.35(t,J＝8.1Hz,1H),6.90(dd,J₁＝8.1Hz,J₂＝1.6Hz,2H),6.87(s,1H),6.42-6.36(m,1H),6.29(d,J＝5.8Hz,1H),6.22(dd,J₁＝17.0Hz,J₂＝1.7Hz,1H),5.74(dd,J₁＝10.2Hz,J₂＝1.6Hz,1H),5.15(s,2H),2.31(s,3H)。

Example 27

N- (3- ((7- (3-methyl-1- ((5-methylpyrimidin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

Step 1: synthesis of the compound 5-methyl-2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidine

3-methyl-4-pyrazoleboronic acid pinacol ester (1.50g,7.2mmol) was dissolved in DMF (15mL), followed by the addition of 2- (chloromethyl) -5-methylpyrimidine (1.5g,11mmol), Cs in that order₂CO₃(8.2g,25mmol) and potassium iodide (0.6g,3.6 mmol). Then replacing nitrogen, heating to 70 ℃ under the protection of nitrogen, and reacting for 15 h. The heating was stopped and the reaction was cooled to room temperature. Filtering with diatomaceous earth, concentrating under reduced pressure, removing DMF from the filtrate, adding water(60mL), dichloromethane (30mL × 3) and the organic phase over anhydrous Na₂SO₄The crude product after drying and concentration was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 943mg of the product as a pale yellow oil (containing the isomers) which was purified by preparative isolation to give 645mg of a pale yellow oil, yield: 28 percent.

MS(ESI,pos.ion)m/z:315.1[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7- (3-methyl-1- ((5-methylpyrimidin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

The compound 5-methyl-2- ((3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyrimidine (0.385g,1.2mmol), N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.40g,0.82mmol), Pd (dppf) Cl₂(0.06g,0.08mmol) and K₂CO₃(0.17g,1.23mmol) were mixed, 1, 4-dioxane (16mL) and water (4mL) were added, nitrogen was replaced, the mixture was heated to 105 ℃ and reacted for 12 hours, the reaction mixture was cooled, water (30mL) and methylene chloride (30mL × 3) were added and extracted, and the organic phase was extracted with anhydrous Na₂SO₄Drying, concentrating, separating and purifying by silica gel column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 40/1), yielding 0.32g of an orange viscous, yield: 65.6 percent.

MS-ESI:(ESI,pos.ion)m/z:597.2[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3-methyl-1- ((5-methylpyrimidin-2-yl) methyl) -1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) acrylamide

N- (3- ((7- (3-methyl-1- ((5-methylpyrimidin-2-yl) methyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) oxy) phenyl) acrylamide (0.30g,0.50mmol) was dissolved in dichloromethane (10mL) and TFA (5mL) was added and the reaction stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, THF (10mL) and TEA (5mL) were added, and the mixture was again concentrated in a chamberStirring at room temperature for 12h, concentrating the reaction solution under reduced pressure, removing solvent, adding saturated sodium bicarbonate water solution (30mL), extracting with dichloromethane (30mL × 3), washing with saturated sodium chloride water (30mL), drying with anhydrous sodium sulfate, and separating and purifying the concentrated crude product by silica gel column chromatography (eluent: CH₂Cl₂MeOH (v/v) ═ 10/1), yielding 0.04g of a light yellow solid, yield: 17.6 percent.

MS-ESI:(ESI,pos.ion)m/z:467.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):(ppm)12.17(s,1H),10.21(s,1H),8.57(s,2H),8.15(s,1H),8.12(s,1H),7.92(d,J＝2.7Hz,1H),7.60(s,1H),7.40(d,J＝8.1Hz,1H),7.33(t,J＝8.1Hz,1H),6.88(dd,J₁＝8.0Hz,J₂＝1.6Hz,1H),6.36(dd,J₁＝16.9Hz,J₂＝10.2Hz,1H),6.19(dd,J₁＝17.0Hz,J₂＝1.6Hz,1H),5.71(dd,J₁＝10.2Hz,J₂＝1.6Hz,1H),5.35(s,2H),2.25(d,J＝10.3Hz,6H)。

By analogy with the synthetic methods of the examples of the present invention, and the synthetic methods described in the present invention, with appropriate alternative starting materials, the compounds shown in table 1 were prepared:

table 1 name and characterization data for the compounds

Biological activity

Biological example 1JAK1/2/3 in vitro Activity test method

1. Compounds were tested for JAK1/2/3 enzyme inhibition using Caliper Mobility Shift Assay.

2. Preparing a 1-time kinase reaction solution: JAK 1: 25mM HEPES, pH 7.5; 0.001% Brij-35; 0.01% Triton; 0.5mM EGTA; 10mM MgCl₂；JAK2/3：50mM HEPES,pH 7.5；0.0015％Brij-35；10mMMgCl₂；2mM DTT。

3. Preparing a reaction termination solution: 100mM HEPES, pH 7.5; 0.0015% Brij-35; 0.2% CoatingReagent #3(Caliper, cat # 760050); 50mM EDTA.

4. Enzyme formulation (JAK 1/2/3): enzyme solutions were prepared using 1-fold kinase reaction solutions at final concentrations of JAK1(30nM), JAK2(2nM), and JAK3(4 nM).

5. Preparing a substrate: a substrate solution was prepared using 1-fold of the kinase reaction solution, and the final concentration of the substrate was shown in Table 2.

TABLE 2 Final substrate formulation concentrations

According to the optimization result of the experimental method, a 384-well plate (Corning, Cat.No.3573, Lot.No.12608008) is adopted for the experiment to detect, the JAK1/2/3 enzyme concentration is prepared into JAK1(75nM), JAK2(5nM), JAK 3(10nM), the reaction final concentration is JAK1(30nM), JAK2(2nM) and JAK3(4 nM); the concentration of a substrate Peptide FAM-P22 is prepared to be 7.5 mu M, and the final reaction concentration is 3 mu M; the ATP preparation concentrations were JAK1 (225. mu.M), JAK2 (50. mu.M), JAK3 (15.5. mu.M), and the final reaction concentrations were JAK1 (90. mu.M), JAK2 (20. mu.M), JAK3 (6.2. mu.M); the concentration of Peptide D (sequence 5-FAM-C6-KKHTDDGYMPMSPGVA-NH2) is prepared to be 7.5 mu M, and the final reaction concentration is 3 mu M; both the enzyme and the substrate were prepared using 1-fold kinase reaction solution. The reaction system is shown in Table 3.

TABLE 3 treatment of JAK1/2/3 enzyme IC with the compounds of the invention₅₀Detection system

The test was carried out using a 384-well plate, and a test sample well, a positive control well, and a negative control well were set in the experiment, each sample was tested for the inhibitory effect of a compound at 8 concentrations on JAK1/2/3 enzyme using duplicate wells, the enzyme and substrate reaction wells were used as positive controls, and the enzyme-free wells (kinase reaction solution) were used as negative controls. Adding corresponding samples, buffer solution and enzyme into each well in sequence according to the sequence shown in Table 3, incubating in a constant temperature oven at 25 deg.C (RT) for 10min, adding prepared Peptide solution into each well, incubating at 28 deg.C for 60min, and adding reaction productAfter stopping, detection is carried out by using a Caliper EZ Reader at the excitation wavelength of FP485 nM/525 nM, and the read data is the conversion rate. The inhibition of JAK1/2/3 enzyme was plotted at different concentrations of compound using Graph Pad Prism 5 software to calculate IC₅₀The results are shown in Table 4.

TABLE 4 inhibition data of JAK1/2/3 enzyme by the compound of example 1 of the present invention

The data in Table 4 show that the compound of the invention in example 1 has a strong inhibition effect on JAK3 kinase, and shows good selectivity on JAK 3. Example 1 is representative of the compounds of the invention, other compounds of the invention also have good selectivity for JAK 3.

Biological example 2BTK and EGFR^T790MIn vitro activity test method

1.1 Xkinase buffer and termination experiment buffer preparation

(1)1 Xkinase buffer (50mM HEPES, pH 7.5, 0.01% Brij-35,10mM MgCl)₂2mM DTT); (2) termination experiment buffer (100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3,50mM EDTA).

2. Compound preparation for testing kinases: serial dilution of compounds

(1) Compounds were diluted 50-fold with 100% DMSO, and 100 μ Ι _ of compound solution at this concentration was transferred to one well of a 96-well plate; if compounds were tested starting at 10000nM, a 500. mu.M DMSO solution of the compound was prepared at this step; (2) serial dilutions of compounds were performed 4-fold for 10 concentration gradients; (3) add 100 μ L of 100% DMSO solution to both wells as no compound control and no enzyme control, label the plate as a source plate; (4) preparing a middle plate: mu.L of each concentration of compound was transferred from the source plate to the intermediate plate, and 90. mu.L of 1 Xkinase buffer was added and mixed by shaking for 10 min.

3. Preparing the test plate

Transferring 5 μ L of compound solution from a corresponding well in the middle plate of a 96-well plate to a corresponding 384-well plate; for example, a1 in a 96-well plate was transferred to a1 and a2 in a 384-well plate, a2 in a 96-well plate was transferred to A3 and a4 in a 384-well plate, and so on.

4. Kinase reaction

(1) Preparation of 2.5 × enzyme solution: adding enzyme into 1 Xkinase buffer solution; (2) preparation of 2.5 × peptide solution: adding fluorescein labeled peptide and ATP into 1 Xkinase buffer solution; (3) the 384-well assay plate already contains 5. mu.L of a 10% DMSO compound solution; (4) add 10. mu.L of 2.5 Xenzyme solution to 384-well assay plates containing 5. mu.L of compound solution with 10% DMSO content; (5) incubating at room temperature for 10 min; (6) add 10. mu.L of 2.5 XPeptide solution to 384 well assay plates; (7) kinase reaction and termination: after incubation at 28 ℃ for 1 hour, the reaction was stopped by adding 25. mu.L of stop buffer. 5. Data measurement

Data is read and collected.

6. Fitting of curves

(1) Copying and converting the measured data;

(2) conversion to inhibition rate:

suppression ratio ═ (max-sample value)/(max-min) × 100;

wherein "maximum" is DMSO control; "minimum" is the value of the kinase-free control well.

(3) Inputting the data into corresponding analysis software Xlfit to obtain IC₅₀The values, experimental results are shown in tables 5 and 6.

TABLE 5 inhibition data of BTK enzyme by some of the compounds of the examples of the invention

Examples	BTK IC50(nM)	Examples	BTK IC50(nM)	Examples	BTK IC50(nM)
						Example 1	37.54	Example 11	52.29	Example 16	36.41
Example 2	14.63	Example 12	5.77	Example 17	14.77
						Example 3	13.63	Example 13	13.80	Example 18	60.23
Example 4	11.53	Example 14	2.78	Example 19	10.97
						Example 9	42.35	Examples15	20.78	Example 22	14.37

The data in Table 5 show that the compounds of some examples of the present invention have strong inhibitory effect on BTK. The compounds of the examples in table 5 are representative of the compounds of the present invention, and other compounds of the present invention also have strong inhibitory effects on BTK.

Table 6 EGFR treatment with the compound of example 1 of the present invention^T790MSuppression data of

Examples	EGFRT790M IC50(nM)
		Example 1	10

Table 6 shows that example 1 of the present invention is directed to EGFR^T790MThe kinase has stronger inhibiting effect. Example 1 is representative of a compound of the invention, other compounds of the invention being on EGFR^T790MThe kinase also has strong inhibiting effect.

Biological example 3 test compound rat in vivo PK studies

Male SD rats were given 5mg/kg of test compound by oral gavage or 1mg/kg of test compound by hind limb intravenous injection. Collecting blood from tail vein at time points (0.083, 0.25, 0.5, 1, 2, 5, 7 and 24h) after administration, wherein the blood collection amount is 200-400 μ L/time point, and collecting blood from K-adding chamber₂EDTA in an anticoagulation tube. The samples were centrifuged at 12000rpm for 2min at 4 ℃ within 60min, plasma was separated and stored at-80 ℃ to be assayed. Plasma sample channelAfter liquid-liquid extraction, quantitative analysis was performed in a triple quadrupole tandem mass spectrometer in a multiple reactive ion monitoring (MRM) mode. Pharmacokinetic parameters were calculated using winnonlin6.3 software, a non-compartmental model method.

Table 7 PK parameters in rats for the compound of example 2 of the invention

And (4) conclusion: as shown in Table 7, the compound of example 2 of the present invention has a slow clearance rate in rats, a long half-life period in intravenous injection and oral administration, and a high bioavailability.

Claims (5)

1. A compound which is a compound represented by formula (V) or a stereoisomer or a pharmaceutically acceptable salt of the compound represented by formula (V):

wherein:

L¹is-O-or-S-;

R²is hydrogen or deuterium;

each R³And R⁴Independently hydrogen or deuterium;

each R^5xAnd R^5yIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-4Alkyl or halo C_1-4An alkyl group;

R^5ais pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, thiazolylmethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl or pyrazolylethyl; r^5aIndependently optionally substituted by one or more R¹⁴Substituted;

each R¹⁴Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C_1-4Alkyl or halo C_1-4An alkyl group.

2. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer or pharmaceutically acceptable salt of a compound having one of the following structures:

3. A pharmaceutical composition comprising a compound of any one of claims 1-2, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or vehicle.

4. Use of a compound according to any one of claims 1-2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for preventing, treating or ameliorating an autoimmune disease or a proliferative disease in a patient;

wherein the autoimmune disease is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia or lymphoma;

the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

5. Use of a compound according to any one of claims 1 to 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for inhibiting or modulating protein kinase activity; wherein the protein kinase is JAK1, JAK2, JAK3, BTK or EGFR.