CN106432246B

CN106432246B - Heteroaromatic compounds and their use in medicine

Info

Publication number: CN106432246B
Application number: CN201610639956.5A
Authority: CN
Inventors: 刘兵; 黄九忠; 张英俊; 郑常春; 薛亚萍; 邢伟; 许娟; 吴族平; 余天喜
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2015-08-05
Filing date: 2016-08-04
Publication date: 2020-07-07
Anticipated expiration: 2036-08-04
Also published as: CN106432246A

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 heteroaromatic compound. The invention also discloses the use of the compounds of the invention or pharmaceutical compositions thereof in the manufacture of a medicament for the treatment of autoimmune 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, which comprises a pharmaceutical composition of the compound. The invention also relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention in medicine.

Background

Protein kinases are composed of a series of structurally related enzymes, primarily responsible for the control of intracellular signal transduction processes. Generally, protein kinases mediate intracellular signals by affecting the transfer of phosphoryl groups from nucleoside triphosphates to protein receptors involved in signaling pathways. These phosphorylation events act as molecular switches that modulate or regulate the biological function of the target protein. Many diseases are associated with abnormal cellular responses triggered by the aforementioned protein kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, alzheimer's disease and hormone-related diseases.

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 genes (J.allergy Clin. Immunol., Leonard, et al,2000,105: 877-888).

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 effectiveOf (Blood,2004,103: 2009) 2018, it seems unlikely that JAK3 has 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 result in optimal efficacy-to-toxicity ratios. 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.

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, BTK, Cdk, CDK, CHK, C-Raf-1, Csk, EGFR, EphA, EphB, Erk, Fak, FGFR, Flt, Fms, Frk, Fyn, Gsk3.alpha., Gsk3.beta, HCK, Her/Erbb, IGF1, IKK.beta, Irak, Itk, JAK, Jnk, JKdr, Kit, LCK, MAP2K, MAP4K, MAPKK, Met, Mnk, MLK, p, FRA, PDGB, PDPK, Pim, Pibet, Pik, alpha. and PKC. 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 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:

X¹is-O-or-NH-;

each R^aAnd R^bIndependently hydrogen, deuterium, alkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, amino-substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl; or R^a、R^bTogether with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 12 atoms;

each R^cAnd R^dIndependently hydrogen, deuterium, alkyl-C (═ O) -, cyano-substituted alkyl-C (═ O) -, hydroxy-substituted alkyl-C (═ O) -, amino-substituted alkyl-C (═ O) -, haloalkyl-C (═ O) -, alkyl-CO) -, cycloalkyl-C (═ O) -, heterocyclyl-C (═ O) -, aryl-C (═ O) -or heteroaryl-C (═ O) -;

each R^a、R^b、R^cAnd R^dIndependently optionally substituted by one or more R¹Substitution;

each R¹Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl or halo C_1-3An alkoxy group.

In some of these embodiments, each R is^aAnd R^bIndependently of one another is hydrogen, deuterium, C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, amino substituted C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_6-10Aryl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl group, C_1-9Heteroaryl C_1-6Alkyl radical, C_2-10Heterocyclyl or C_2-10Heterocyclyl radical C_1-6An alkyl group; or R^a、R^bTogether with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 8 atoms;

each R^cAnd R^dIndependently of one another is hydrogen, deuterium, C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, cyano-substituted C_1-6alkyl-C (═ O) -, hydroxy-substituted C_1-6alkyl-C (═ O) -, amino-substituted C_1-6alkyl-C (═ O) -, halo-C_1-6alkyl-C (═ O) -, C_3-8cycloalkyl-C (═ O) -, C_2-10heterocyclyl-C (═ O) -, C_6-10aryl-C (═ O) -or C_1-9heteroaryl-C (═ O) -.

In some of these embodiments, each R is^aAnd R^bIndependently of one another is hydrogen, deuterium, C_1-6Alkyl, cyano-substituted C_1-3Alkyl, hydroxy substituted C_1-3Alkyl, amino substituted C_1-3Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-3An alkyl group; or R^a、R^bTogether with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 6 atoms;

each R^cAnd R^dIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4alkyl-C (═ O) -, cyano-substituted C_1-4alkyl-C (═ O) -, hydroxy-substituted C_1-4alkyl-C (═ O) -, amino-substituted C_1-4alkyl-C (═ O) -, halo-C_1-4alkyl-C (═ O) -, C_3-6cycloalkyl-C (═ O) -, C_2-6heterocyclyl-C (═ O) -, C_6-10aryl-C (═ O) -or C_1-5heteroaryl-C (═ O) -.

In another aspect, 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 a compound represented by formula (II):

wherein:

ring A is cycloalkyl, cycloalkenyl, C_2-4Heterocyclyl, piperidin-2-yl, piperidin-3-yl, homopiperazinyl, homomorpholinyl, C_6-10Heterocyclyl, aryl or heteroaryl;

ring B is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;

X²is-O-, -CR⁵R⁶-、-C(＝O)-、-(CR⁵R⁶)_m-CR⁷＝CR⁸-(CR⁵R⁶)_m-、-(CR⁵R⁶)_m-C≡C-(CR⁵R⁶)_m-、-N(R⁴)-、-N(R⁴)-(CR⁵R⁶)_n-、-N(R⁴)-C(＝O)-、-N(R⁴)-C(＝O)-N(R⁴)-、-C(＝O)-N(R⁴)-C(＝O)-、-S-、-S(＝O)-、-S(＝O)₂-、-S(＝O)₂-(CR⁵R⁶)_n-、-N(R⁴)-S(＝O)₂-or-N (R)⁴)-S(＝O)₂-N(R⁴)-；

Each R²Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, haloalkyl, cyano-substituted alkyl, hydroxyl-substituted alkyl, amino-substituted alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R⁹-S(＝O)₂-or R⁹-S(＝O)₂-N(R⁴)-；

Each R³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, halogen-substituted arylalkyl, cyano-substituted arylalkyl, heteroarylalkyl, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R¹⁰R¹¹N-or R¹⁰R¹¹N-S(＝O)₂-；

Each R⁴Independently hydrogen, alkyl, haloalkyl, alkoxyalkyl or alkylaminoalkyl;

each R⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy or alkylamino;

each R⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, alkyl or haloalkyl;

each R⁹Independently hydrogen, deuterium, alkyl, haloalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, amino-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

each R¹⁰And R¹¹Independently hydrogen, deuterium, alkyl, haloalkyl, cyano-substituted alkyl, hydroxySubstituted alkyl or amino substituted alkyl;

each m is independently 0,1, 2 or 3;

each n is independently 1 or 2;

each p and q is independently 0,1, 2,3,4, 5 or 6;

each R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹Ring A and ring B are independently optionally substituted with one or more R¹²Substitution;

each R¹²Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl or halo C_1-3An alkoxy group.

In some of these embodiments, ring A is C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, C_2-4Heterocyclyl, piperidin-2-yl, piperidin-3-yl, homopiperazinyl, homomorpholinyl, C_6-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

ring B is C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group.

In still other embodiments, ring a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidin-2-yl, piperidin-3-yl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, homopiperazinyl, homomorpholinyl, phenyl, indenyl, 2, 3-dihydroindenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl;

ring B is phenyl, indenyl, 2, 3-dihydroindenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

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 Y and Z is independently N or CR³；

Each X²、A、R²And R³Have 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:

In some of these embodiments, X is²is-O-, -CR⁵R⁶-、-C(＝O)-、-(CR⁵R⁶)_m-CR⁷＝CR⁸-(CR⁵R⁶)_m-、-(CR⁵R⁶)_m-C≡C-(CR⁵R⁶)_m-、-N(R⁴)-、-N(R⁴)-(CR⁵R⁶)_n-、-N(R⁴)-C(＝O)-、-N(R⁴)-C(＝O)-N(R⁴)-、-C(＝O)-N(R⁴)-C(＝O)-、-S-、-S(＝O)-、-S(＝O)₂-、-S(＝O)₂-(CR⁵R⁶)_n-、-N(R⁴)-S(＝O)₂-or-N (R)⁴)-S(＝O)₂-N(R⁴)-；

Each R⁴Independently of one another is hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl or C_1-6Alkylamino radical C_1-6An alkyl group;

each R⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6An alkylamino group;

each R⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-6Alkyl or halo C_1-6An alkyl group.

In still other embodiments, each R is⁴Independently of one another is hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Alkoxy radical C_1-4Alkyl or C_1-3Alkylamino radical C_1-3An alkyl group;

each R⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Alkoxy or C_1-4An alkylamino group;

each R⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-3Alkyl or halo C_1-3An alkyl group.

In still other embodiments, wherein each R is⁴Independently hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl, 1,1, 2-trifluoropropyl, 1,1, 2-trifluoroethyl, chloromethyl, chloroethyl, chloropropyl, 1,1, 1-trifluoroethyl, 1, 1-trifluoropropyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, N-methylaminomethyl, N-methylaminoethyl, N-methylaminopropyl, N-ethylaminomethyl, N-ethylaminoethyl, N-ethylaminopropyl, N-propylaminomethyl, N-propylaminoethyl, N-propylaminopropyl, N-dimethylaminomethyl, N-dimethylaminopropyl, N-dimethylaminomethyl, N-trifluoromethyl, N-propyl, N-trifluoromethyl, N-ethyl, N-propyl, N-isopropyl, N, N, N-dimethyl amineMethylethyl, N-dimethylaminopropyl, N-diethylaminomethyl, N-diethylaminoethyl, N-diethylaminopropyl, N-dipropylaminomethyl, N-dipropylaminoethyl or N, N-dipropylaminopropyl;

each R⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, methyl, ethyl, propyl, butyl, trifluoromethyl, 1,1, 2-trifluoropropyl, 1,1, 2-trifluoroethyl, chloromethyl, chloroethyl, chloropropyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoropropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N-dimethylamino, N-diethylamino, N-dipropylamino, N-dibutylamino;

each R⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, halomethyl, haloethyl or halopropyl.

In some of these embodiments, each R is²Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, amino substituted C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R⁹-S(＝O)₂-or R⁹-S(＝O)₂-N(R⁴)-；

Each R³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-10Aryl radical C_1-6Alkyl, halogen substituted C_6-10Aryl radical C_1-6Alkyl, cyano-substituted C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R¹⁰R¹¹N-or R¹⁰R¹¹N-S(＝O)₂-；

Each R⁹Independently of one another is hydrogen, deuterium, C_1-8Alkyl, halo C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, amino substituted C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

each R¹⁰And R¹¹Independently of one another is hydrogen, deuterium, C_1-6Alkyl, halo C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl or amino substituted C_1-6An alkyl group.

In still other embodiments, each R is²Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-4Alkyl, halo C_1-3Alkyl, cyano-substituted C_1-3Alkyl, hydroxy substituted C_1-4Alkyl, amino substituted C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy radical, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl radical, C_1-5Heteroaryl, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R⁹-S(＝O)₂-or R⁹-S(＝O)₂-N(R⁴)-；

Each R³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-4Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl radical, C_1-5Heteroaryl group, C_6-10Aryl radical C_1-3Alkyl, halogen substituted C_6-10Aryl radical C_1-3Alkyl, cyano-substituted C_6-10Aryl radical C_1-3Alkyl radical, C_1-5Heteroaryl C_1-3Alkyl radical, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R¹⁰R¹¹N-or R¹⁰R¹¹N-S(＝O)₂-；

Each R⁹Independently of one another is hydrogen, deuterium, C_1-6Alkyl, halo C_1-3Alkyl, cyano-substituted C_1-4Alkyl, hydroxy substituted C_1-3Alkyl, amino substituted C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group;

each R¹⁰And R¹¹Independently of one another is hydrogen, deuterium, C_1-3Alkyl, halo C_1-3Alkyl, cyano-substituted C_1-4Alkyl, hydroxy substituted C_1-3Alkyl or amino substituted C_1-3An alkyl group.

Still other embodiments are, methyl cyano, ethyl cyano, propyl cyano, butyl cyano, methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methylhydroxy, ethylhydroxy, propylhydroxy, aminomethyl, aminoethyl, aminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridinyl, oxetanyl, pyrrolinyl, pyrazolyl, imidazolinyl, tetrahydrofuranyl, thienyl, 1, 3-dioxolanyl, tetrahydropyranyl, thiopyranyl, piperidinyl, pyridinyl, morpholinyl, piperazinyl, homopiperidinyl, pyrrolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, oxiranyl phenyl, indenyl, 2, 3-dihydroindenyl, furanyl, imidazolyl, isoxazolyl, pyrrolyl;

each R¹⁰And R¹¹Independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, methyl, ethyl, butyl,Methyl cyano, ethyl cyano, propyl cyano, butyl cyano, methyl hydroxy, ethyl hydroxy, propyl hydroxy, aminomethyl, aminoethyl or aminopropyl.

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 a pharmaceutically acceptable excipient.

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 (I), formula (II), formula (IIa) or formula (IIb).

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I), formula (II), formula (IIa) or formula (IIb).

The foregoing has outlined only certain aspects of the present invention but is not limited in that these and other aspects will be more fully described in the following detailed description.

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 isomers), 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., High Performance Liquid Chromatography (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 designate the rotation of plane polarized light by the compound, where (-) or l denotes that the compound is left-handed and (+) or d denotes that the compound is right-handed. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity during the chemical reaction.

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. Racemic products can also be separated by chiral chromatography, e.g., HPLC using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^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. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, 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.

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 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.

In some of these embodiments, alkyl refers to C_1-3Alkyl consisting of 1-3C atoms, such embodiments 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)。

In some of these embodiments, alkyl refers to C_1-4Alkyl consisting of 1-4C atoms, such embodiments 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)。

In some of these embodiments, alkyl refers to C_1-5Alkyl consisting of 1-5C atoms, such embodiments 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)。

In some of these embodiments, alkyl refers to C_1-6Alkyl consisting of 1-6C atoms, such embodiments 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) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃)。

In some of these embodiments, alkyl refers to C_1-8Alkyl consisting of 1-8C atoms, such embodiments 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) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl.

The term "alkylene" denotes a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like. For alkylene groups, the manner in which the linker formula is written does not imply any orientation of the linker. For example, isopropylidene represents simultaneously-CH (CH)₃)CH₂-and-CH₂CH(CH₃)-。

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 be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In 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, an alkenyl groupContaining 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 —), 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 site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy)Radical, -OCH₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

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

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, trifluoromethyl, trifluoromethoxy, -CH₂Cl，-CH₂CF₃，-CH₂CH₂CF₃And the like.

The term "cyano-substituted alkyl" denotes an alkyl group substituted with one or more CN, examples of which include, but are not limited to, -CH₂CN，-CH₂CH₂CN，-CH(CN)CH₃，-CH₂CH₂CH₂CN，-CH(CN)CH₂CH₃，-CH₂CH(CN)CH₃，-C(CH₃)₂CN, and the like.

The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more OH, examples of which include, but are not limited to, -CH₂OH，-CH₂CH₂OH，-CH(OH)CH₃，-CH₂CH₂CH₂OH，-CH(OH)CH₂CH₃，-CH₂CH(OH)CH₃，-CH₂C(CH₃)₂OH and the like.

The term "carbocyclyl" or "carbocycle" denotes a mono-or polyvalent, saturated or partially unsaturated, mono-, bi-or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, benzocyclopentyl, benzocyclohexyl, and the like.

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 10 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.

In some of these embodiments, cycloalkyl refers to C_3-8Cycloalkyl consisting of 3 to 8C atoms, such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

In some of these embodiments, cycloalkyl refers to C_3-6Cycloalkyl consisting of 3 to 6C atoms, such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkenyl" denotes mono-, bi-or tricyclic ring systems containing 3 to 12 carbon atoms, mono-or polyvalent, non-aromatic, comprising at least one carbon-carbon double bond. In one embodiment, cycloalkenyl groups contain 3 to 12 carbon atoms; in another embodiment, cycloalkenyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkenyl groups contain 3 to 6 carbon atoms. The cycloalkenyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl, and the like.

The term "cycloalkylalkyl" denotes an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and the like.

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 may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl (tetrahydrofuran-2-yl or tetrahydrofuran-3-yl), dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, (1-oxo) -thiomorpholinyl, (1, 1-dioxo) -thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiofuranylHeterocycloheptyl, 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.

In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. 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. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.

In another embodiment, heterocyclyl is a 4-atom heterocyclylIt refers to a saturated or partially unsaturated monocyclic ring comprising 4 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group consisting of 4 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 5 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH₂Examples of the-group substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, heterocyclyl is a 6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -.The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiro-or fused-bicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 7 to 12 atoms may be carbon-based or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. Said heterocyclyl group of 7 to 12 atoms may be optionally substituted by one or more substituents as described herein.

In some of these embodiments, heterocyclyl refers to C_2-4Heterocyclyl, said heterocyclyl containing 2-4C atoms, such embodiments include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, or piperazinyl.

In some of these embodiments, heterocyclyl refers to C_6-10Heterocyclyl, said heterocyclyl comprising 6-10C atoms, such embodiments including but not limited to homopiperidinyl.

The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein heterocyclyl and alkyl groups have the meaning as indicated in the present invention. Examples of such include, but are not limited to, thiomorpholin-4-ylmethyl, 1-oxo-thiomorpholin-4-ylmethyl, 1, 1-dioxo-thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, azetidin-1-ylethyl, azetidin-1-ylpropyl, pyrrolidin-2-ylmethyl, pyrrolidin-1-ylethyl, morpholin-4-ylmethyl, morpholin-4-ylpropyl, and the like.

The terms "fused bicyclic ring" and "fused bicyclic group" are used interchangeably herein and refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a bicyclic ring system. The term "bridged ring" means that any two rings share two atoms which may or may not be directly attached. For example, as depicted in formula a and formula B below, ring a and ring a 'share two directly connected C atoms, and ring B' share two non-directly connected C atoms. Each ring in the fused bicyclic ring is either a carbocyclic ring or a heterocyclic ring, and examples thereof include, but are not limited to, hexahydrofuro [3,2-b ] furan, 2,3,3a,4,7,7 a-hexahydro-1H-indene, 7-azabicyclo [2.2.1] heptane, fused bicyclo [3.3.0] octane, fused bicyclo [3.1.0] hexane, 1,2,3,4,4a,5,8,8 a-octahydronaphthalene, which are contained in the system of the fused bicyclic ring, and the fused bicyclic ring group may be substituted or unsubstituted.

A carbocyclyl group.

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, 2, 3-indanyl, naphthyl and anthryl. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "arylalkyl" or "aralkyl" means an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meaning described herein, examples of which include, but are not limited to, benzyl, phenethyl, p-toluylethyl, and the like.

In some of these embodiments, arylalkyl is substituted with halogen or cyano; examples include, but are not limited to, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-cyanobenzyl.

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 (e.g. 2-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), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), tetrahydroquinolyl (e.g., 1,2,3, 4-tetrahydroquinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), tetrahydroisoquinolyl (e.g., 1,2,3, 4-tetrahydroisoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.

In some of these embodiments, 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 set forth herein, examples of which include, but are not limited to, pyridin-2-ylmethyl, pyridin-2-ylethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.

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. It is composed ofIn some 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 "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_1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

The term "propyl" includes n-propyl, isopropyl; "butyl" includes n-butyl, isobutyl, sec-butyl, tert-butyl.

The term "propoxy" includes 1-propoxy, 2-propoxy; "butoxy" includes reference to 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, 2-methyl-2-propoxy.

The term "propylamino" includes 1-propylamino, 2-propylamino; "butylamino" includes 1-butylamino, 2-methyl-1-propylamino, 2-methyl-2-propylamino, 2-butylamino.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I), formula (II), formula (IIa) or formula (IIb). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) 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 these phosphate ester compoundsIs obtained by phosphorylation of hydroxyl on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward dB.Roche, ed., Bioreproducible Carriers in Drug designs, American pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and pharmaceutical Applications, Nature Review Drug Discovery,2008,7, 255-.

"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 J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates,camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumerate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodiate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, 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 (hepatic carcinoma), 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.

wherein:

X¹is-O-or-NH-;

each R^cAnd R^dIndependently hydrogen, deuterium, alkyl-C (═ O) -, cyano-substituted alkyl-C (═ O) -, hydroxy-substituted alkyl-C (═ O) -, amino-substituted alkyl-C (═ O) -, haloalkyl-C (═ O) -, cycloalkyl-C (═ O) -, heterocyclyl-C (═ O) -, aryl-C (═ O) -or heteroaryl-C (═ O) -;

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

In some of these embodiments, R is^a、R^bTogether with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 8 atoms.

In some of these embodiments, each R is^cAnd R^dIndependently of one another is hydrogen, deuterium, C_1-6Alkyl radical, C_1-6alkyl-C (═ O) -, cyano-substituted C_1-6alkyl-C (═ O) -, hydroxy-substituted C_1-6alkyl-C (═ O) -, amino-substituted C_1-6alkyl-C (═ O) -, halo-C_1-6alkyl-C (═ O) -, C_3-8cycloalkyl-C (═ O) -, C_2-10heterocyclyl-C (═ O) -, C_6-10aryl-C (═ O) -or C_1-9heteroaryl-C (═ O) -.

In some of these embodiments, each R is^aAnd R^bIndependently of one another is hydrogen, deuterium, C_1-6Alkyl, cyano-substituted C_1-3Alkyl, hydroxy substituted C_1-3Alkyl, amino substituted C_1-3Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-3An alkyl group.

In some of these embodiments, R is^a、R^bTogether with the N atom to which they are attached form a heterocyclic ring consisting of 3 to 6 atoms.

In some of these embodiments, each R is^cAnd R^dIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4alkyl-C (═ O) -, cyano-substituted C_1-4alkyl-C (═ O) -, hydroxy-substituted C_1-4alkyl-C (═ O) -, amino-substituted C_1-4alkyl-C (═ O) -, haloC_1-4alkyl-C (═ O) -, C_3-6cycloalkyl-C (═ O) -, C_2-6heterocyclyl-C (═ O) -, C_6-10aryl-C (═ O) -or C_1-5heteroaryl-C (═ O) -.

wherein:

ring B is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;

Each R²Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, haloalkyl, cyano-substituted alkyl, hydroxyl-substituted alkyl, amino-substituted alkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkylamino, cycloalkyl, heterocyclyl, arylHeteroaryl, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R⁹-S(＝O)₂-or R⁹-S(＝O)₂-N(R⁴)-；

each R¹⁰And R¹¹Independently hydrogen, deuterium, alkyl, haloalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl or amino-substituted alkyl;

each m is independently 0,1, 2 or 3;

each n is independently 1 or 2;

each p and q is independently 0,1, 2,3,4, 5 or 6;

each R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹Ring A and ring B are independently optionally substituted by oneA plurality of R¹²Substitution;

In some of these embodiments, ring A is C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, C_2-4Heterocyclyl, piperidin-2-yl, piperidin-3-yl, homopiperazinyl, homomorpholinyl, C_6-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group.

In some of these embodiments, ring B is C_3-8Cycloalkyl radical, C_3-8Cycloalkenyl radical, C_2-10Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group.

In still other embodiments, ring A is C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl radical, C_2-4Heterocyclyl, piperidin-2-yl, piperidin-3-yl, homopiperazinyl, homomorpholinyl, C_6-8Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In still other embodiments, ring B is C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl radical, C_2-8Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In still other embodiments, ring a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidin-2-yl, piperidin-3-yl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, homopiperazinyl, homomorpholinyl, phenyl, indenyl, 2, 3-dihydroindenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

In still other embodiments, ring B is phenyl, indenyl, 2, 3-dihydroindenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

wherein:

each Y and Z is independently N or CR³；

wherein:

Each of m, n and R⁴、R⁵、R⁶、R⁷And R⁸Have the meaning as described in the present invention.

In some of these embodiments, each R is⁴Independently of one another is hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl or C_1-6Alkylamino radical C_1-6An alkyl group.

In some of these embodiments, each R is⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6An alkylamino group.

In some of these embodiments, each R is⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-6Alkyl or halo C_1-6An alkyl group.

In still other embodiments, each R is⁴Independently of one another is hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Alkoxy radical C_1-4Alkyl or C_1-3Alkylamino radical C_1-3An alkyl group.

In still other embodiments, wherein each R is⁴Independently hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl, 1,1, 2-trifluoropropyl, 1,1, 2-trifluoroethyl, chloromethyl, chloroethyl, chloropropyl, 1,1, 1-trifluoroethyl, 1, 1-trifluoropropyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, N-methylaminomethyl, N-methylaminoethyl, N-methylaminopropyl, N-ethylaminomethyl, N-ethylaminoethyl, N-ethylaminopropyl, N-propylaminomethyl, N-propylaminoethyl, N-propylaminopropyl, N-dimethylaminomethyl, N-dimethylaminopropyl, N-dimethylaminomethyl, N-trifluoromethyl, N-propyl, N-trifluoromethyl, N-ethyl, N-propyl, N-isopropyl, N, N, N-dimethylaminoethyl, N-dimethylaminopropyl, N-diethylaminomethyl, N-diethylaminoethyl, N-diethylaminopropyl, N-dipropylaminoMethyl, N-dipropylaminoethyl or N, N-dipropylaminopropyl;

in still other embodiments, each R is⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Alkoxy or C_1-4An alkylamino group.

In still other embodiments, each R is⁵And R⁶Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, methyl, ethyl, propyl, butyl, trifluoromethyl, 1,1, 2-trifluoropropyl, 1,1, 2-trifluoroethyl, chloromethyl, chloroethyl, chloropropyl, 1,1, 1-trifluoroethyl, 1,1, 1-trifluoropropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N-dimethylamino, N-diethylamino, N-dipropylamino, N-dibutylamino;

in still other embodiments, each R is⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, C_1-3Alkyl or halo C_1-3An alkyl group.

In still other embodiments, each R is⁷And R⁸Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, halomethyl, haloethyl or halopropyl.

In still other embodiments, X is²is-O-, -CH₂-、-CHF-、-CF₂-、-CH(CF₃)-、-CH(NH(CH₃))-、-C(CH₃)(OH)-、-C(CH₃)₂-、-C(＝O)-、-CH＝CH-、-C≡C-、-NH-、-N(CH₃)-、-N(CH₂CH₂OCH₃)-、-NH-CH₂-、-S(＝O)-、-S(＝O)₂-、-S(＝O)₂-CH₂-、-NH-C(＝O)-、-NH-C(＝O)-NH-、-C(＝O)-NH-C(＝O)-、-NH-S(＝O)₂-or-NH-S (═ O)₂-NH-。

In some of these embodiments, each R is²Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanoHydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, amino substituted C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R⁹-S(＝O)₂-or R⁹-S(＝O)₂-N(R⁴)-；

Each R⁴And R⁹Have the meaning as described in the present invention.

In some of these embodiments, each R is³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-10Aryl radical C_1-6Alkyl, halogen substituted C_6-10Aryl radical C_1-6Alkyl, cyano-substituted C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R¹⁰R¹¹N-or R¹⁰R¹¹N-S(＝O)₂-；

Each R⁴、R⁹、R¹⁰And R¹¹Have the meaning as described in the present invention.

In some of these embodiments, each R is⁹Independently of one another is hydrogen, deuterium, C_1-8Alkyl, halo C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, amino substituted C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-10Aryl orC_1-9A heteroaryl group.

In some of these embodiments, each R is¹⁰And R¹¹Independently of one another is hydrogen, deuterium, C_1-6Alkyl, halo C_1-6Alkyl, cyano-substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl or amino substituted C_1-6An alkyl group.

Each R⁴And R⁹Have the meaning as described in the present invention.

In still other embodiments, each R is³Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, C_1-4Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-3Alkylamino radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl radical, C_1-5Heteroaryl group, C_6-10Aryl radical C_1-3Alkyl, halogen substituted C_6-10Aryl radical C_1-3Alkyl, cyano-substituted C_6-10Aryl radical C_1-3Alkyl radical, C_1-5Heteroaryl C_1-3Alkyl radical, R⁹-C(＝O)-N(R⁴)-、R⁹-N(R⁴)-C(＝O)-、R¹⁰R¹¹N-or R¹⁰R¹¹N-S(＝O)₂-；

In still other embodiments, each R is⁹Independently of one another is hydrogen, deuterium, C_1-6Alkyl, halo C_1-3Alkyl, cyano-substituted C_1-4Alkyl, hydroxy substituted C_1-3Alkyl, amino substituted C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

Still other embodiments are methyl cyano, ethyl cyano, propyl cyano, butyl cyano, methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, methylhydroxy, ethylhydroxy, propylhydroxy, aminomethyl, aminoethyl, aminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridinyl, oxetanyl, pyrrolinyl, pyrazolyl, imidazolinyl, tetrahydrofuranyl, thienyl, 1, 3-dioxolanyl, tetrahydropyranyl, thiopyranyl, piperidinyl, pyridinyl, morpholinyl, piperazinyl, homopiperidinyl, pyrrolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, oxiranyl phenyl, indenyl, 2, 3-dihydroindenyl, furanyl, imidazolyl, isoxazolyl, pyrrolyl.

In still other embodiments, each R is¹⁰And R¹¹Independently of one another is hydrogen, deuterium, C_1-3Alkyl, halo C_1-3Alkyl, cyano-substituted C_1-4Alkyl, hydroxy substituted C_1-3Alkyl or amino substituted C_1-3An alkyl group.

In still other embodiments, each R is¹⁰And R¹¹Independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, methylcyano, ethylcyano, propylcyano, butylcyano, methylhydroxy, ethylhydroxy, propylhydroxy, aminomethyl, aminoethyl, or aminopropyl.

In still other embodiments, R is²Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, methyl, ethyl, propyl, isopropyl, HO-CH₂-、HO-CH₂-CH₂-、HO-CH₂-CH₂-CH₂-、CN-CH₂-、CN-CH₂-CH₂-、CN-CH₂-CH₂-CH₂-, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, CH₃-C(＝O)-NH-、CN-CH₂-C(＝O)-NH-、CH₃CH₂-C(＝O)-NH-、CN-CH₂CH₂-C(＝O)-NH-、CH₃-S(＝O)₂-、CH₃CH₂-S(＝O)₂-、CH₃CH₂CH₂-S(＝O)₂-、CH₃CH₂CH₂CH₂-S(＝O)₂-、C(CH₃)₃-CH₂-S(＝O)₂-、CH₃-S(＝O)₂-NH-、CN-CH₂-S(＝O)₂-NH-、CH₃CH₂-S(＝O)₂-NH-or CN-CH₂CH₂-S(＝O)₂-NH-。

In still other embodiments, R is³Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, phenyl, benzyl, phenethyl, fluorobenzyl, chlorobenzyl, bromobenzyl, cyano-substituted benzyl, CH, or a salt thereof₃-C(＝O)-NH-、CN-CH₂-C(＝O)-NH-、CH₃CH₂-C(＝O)-NH-、CN-CH₂CH₂-C(＝O)-NH-、CH₃-NH-C(＝O)-、CN-CH₂-NH-C(＝O)-、CH₃CH₂-NH-C(＝O)-、CN-CH₂CH₂-NH-C(＝O)-、CN-CH₂-NH-、CN-CH₂CH₂-NH-、CN-CH₂CH₂CH₂-NH-、CH₃-NH-S(＝O)₂-、CN-CH₂-NH-S(＝O)₂-、CH₃CH₂-NH-S(＝O)₂-、CN-CH₂CH₂-NH-S(＝O)₂-、CH₃CH₂CH₂-NH-S(＝O)₂-or CN-CH₂CH₂CH₂-NH-S(＝O)₂-。

In another aspect, the present invention includes, but is in no way limited to, compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds having one of the following structures:

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 invention encompasses pharmaceutical compositions comprising a therapeutically effective amount required for the combination of a compound represented by formula (I), formula (II), formula (IIa) or formula (IIb) with at least one pharmaceutically acceptable excipient.

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), or formula (IIb).

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) or formula (IIb) or isolated enantiomers of the compounds of formula (I), formula (II), formula (IIa) or formula (IIb).

Pharmaceutically acceptable acid addition salts may be formed from the compounds of the present invention with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl, citrate, ethanedisulfonate, 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, dihydrogen, 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 from the compounds of the present invention 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 drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸Investigation of F-enriched Compounds on PET or SPECTIs particularly preferable. Isotopically enriched compounds of formula (I), formula (II), formula (IIa) or formula (IIb) can be prepared by conventional techniques known to those skilled in the art or by the procedures and preparations described in the examples and preparations of this invention using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I), formula (II), formula (IIa) or formula (IIb). 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. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

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

As described herein, the pharmaceutically acceptable pharmaceutical compositions of the present invention further comprise pharmaceutically acceptable adjuvants such as carriers, diluents, fillers, binders, flavoring agents or excipients, as used herein, including any solvent, diluent or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents:

in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & W ilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, Marcel Dekker, New York, taken together with The disclosure of The references herein, indicate that different adjuvants can be used In The preparation of pharmaceutically acceptable pharmaceutical compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable pharmaceutical composition, their use is contemplated by the present invention.

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 those 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.

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.

Substances which may be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, 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 cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

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), or formula (IIb) 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), or formula (IIb). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.

The 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).

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

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate.

Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

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

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including 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, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic 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, mercuric, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid suitable isotonicity 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 agents 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, cyclodextrin 35, sulfocyclodextrin 3632-sulfocyclodextrin 397, sulfobutyl-3632-sulfocyclodextrin, and sulfobutyl ether 3- β -3632-sulfocyclodextrin

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

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In 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 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.

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. 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 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 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 formoterol₂Adrenergic receptor agonists, such as compounds which provide effective bronchodilation for 12 hours or more, are preferred.

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

Examples include methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), 6, 9-difluoro-11-1-hydroxy-16 0-methyl-17 2- [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17-thiocarboxylic acid S-fluoromethyl ester, 6, 9-difluoro-11-hydroxy-16-methyl-17- [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17-thiocarboxylic acid S-fluoromethyl ester, 6, 9-difluoro-17- [ (2-furancarbonyl) oxy ] -11-hydroxy-16-8-methyl-3-oxo-androsta-1, 4-diene-17-thiocarboxylic acid S-fluoromethyl ester (furoic acid fluocinolone), 6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-androsta-1, 4-diene-17-thiocarboxylic acid S-fluoromethyl ester (furoyloxypropionic acid S-17-6-2-oxo-2-oxo-androsta-1, 4-diene-17-6-2-carbonyl-oxo-6-2-oxo-2-oxo-6-1, 4-diene-2-diene-6-2-difluoro-oxo-2-6-methyloxa-6-methyloxa-oxa-6-methyloxa-6-methyloxandrographocinolic acid S-6-methyloxa-6-difluoro-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-6-methyloxa-.

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 invention provides a combination comprising a compound disclosed herein and non-steroidal anti-inflammatory drugs (NSAID's) examples of NSAID's include cromolyn sodium, nedocromil sodium (nedocromil sodium), Phosphodiesterase (PDE) inhibitors (such as theophylline, PDE4 inhibitors, or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (such as montelukast), iNOS inhibitors, trypsin and elastase inhibitors, β -2 integrin antagonists, and adenosine receptor agonists or antagonists (such as adenosine 2a receptor agonists), cytokine antagonists (such as chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors.

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, M₁/M₃Or M₂/M₃Dual receptor antagonists or M₁/M₂/M₃Compounds which are pan-antagonists of the receptor. Exemplary compounds for inhalation administration include ipratropium (e.g., as bromide, CAS 22254-24-6, to

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

Sold under trade name); also of interest are revatoxate (e.g., as the hydrobromide salt, CAS 262586-79-8) and LAS-34273 as disclosed in WO 01/04118. Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromide CAS133099-07-7, to

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

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

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

Sold under the trade name of TrisLoronium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or its succinate CAS242478-38-2, Compound YM-905, to

Sold under the trade name).

In another aspect, the invention provides a combination comprising a compound disclosed herein and an antagonist of H1. Examples of H1 antagonists include, but are not limited to, amxanthene (amelexanox), sisimizole (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (bropheriramine), cetirizine (cetirizine), levocetirizine (levocetirizine), efletirizine (efletirizine), chlorpheniramine (chlorpheniramine), clemastine (clintine), cyclizine (cyclizine), caristine (carebastine), cyproheptadine (procetyline), carbinoxamine (carbinoxamine), descarboethoxy loratadine (descarboethoxyloratoridine), doxylamine (doxylamine), dimethylhexidipine (mepiquin), clemastine (fenadine (e), clemastine (fenadine), clemastine (e (fenadine), fenadine (fenadine), clemastine (doxylamine), clemastine (fenadine), clemastine (meplate (meperidine), clemastine (e), clemastine (e), clemastine (, Minoxidine (meclizine), norastemizole (norastemizole), olopatadine (olopatadine), piperazines (picumast), pyrilamine (pyrilamine), promethazine (promethazine), terfenadine (terfenadine), tripelennamine (tripelenamine), temastine (temelastine), isobutylazine (trimeprazine), and triprolidine (triprolidine), with cetirizine (cetirizine), levocetirizine (levocetirizine), efletirizine (efletirizine), and fexofenadine (fexofenadine) being preferred. In 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 combination of a compound disclosed herein and β 2-adrenoreceptor 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 that induce a cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antineoplastic antimetabolite; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; 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 (aminoglutethimide), lotemide (rogethimide), pirglutethimide (pyriglutethimide), trostane (trilostane), testolactone (testolactone), ketoconazole (ketoconazole), fluconazole (vorozole), fadrozole (fadrozole), anastrozole (anastrozole) and letrozole (letrozole). Exemestane can be marketed, e.g. under the trademark Emametan

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

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

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

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

Or

Form (1) ofAnd (4) administration. 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 (raloxifene hydrochloride). 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 inDisclosed in US4,100,274 and commercially available, e.g. under the trade mark

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

Daunorubicin (daunorubicin); epirubicin (epirubicin); idarubicin (idarubicin); 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 VM

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 inhibitors. Including, but not limited to, taxanes such as paclitaxel (paclitaxel) and docetaxel (docetaxel); vinca alkaloids, such as vinblastine (vinblastine), especially vinblastine sulfate, vincristine, especially vinblastine sulfate and vinorelbine (vinorelbine); discodermolides; colchicine; and epothilones and derivatives thereof, 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). The vinblastine sulfate can be selected fromCommercially available, e.g. under the trade mark VINBALLASTIN

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; card with a detachable coverCapecitabine (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 AG 213, 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), WO 96/33980 (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.

Compounds which induce a cell differentiation process are retinoic acid, α -, gamma-or delta-tocopherol, α -, gamma-or delta-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 availableSuch as the trade name

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

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

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

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

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

Is administered in the form of (1).

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

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

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

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

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

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

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

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

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

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

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

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

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

PR064553(anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments (so long as they have the desired biological activity). For the treatment of Acute Myeloid Leukemia (AML), the disclosed compounds can be used in combination with standard leukemia therapies, especially in combination with therapies for the treatment of AML. In particular, the compounds 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.

Such agents include, but are not limited to chloroquine sulfate, atovaquone-proguanil, artemether-lumefantrine, quinine sulfate, artesunate, quinine, doxycycline, clindamycin (clindamycin), meglumine antimony (meglumine antimonitate), sodium stibogluconate (sodium stibogluconate), miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycin), eflornithine (eflornithine), nifurtimox (furtioxime), suramin (salamin), melarsol (methadol), medoxomil), sulfadimidine (sulfadiazine), sulfadiazine β), sulfadimidine (sulfadiazine), sulfadimidine (sulfadoxazone), sulfadoxylamine (sulfadoxazone), sulfadimidine (sulfadoxylamine, sulfadoxylamine (sulfadoxylamine).

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 together with them in pharmaceutical compositions.

For an individual of about 50-70kg, the disclosed pharmaceutical compositions and combinations may be in unit dosage form containing from about 1-1000mg, or from about 1-500mg, or from about 1-250mg, or from about 1-150mg, or from about 0.5-100mg, or from about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend 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 methods described herein, wherein the substituents are as defined for formula (I), formula (II), formula (IIa) or formula (IIb), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

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

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. 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 Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

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

CD₃OD deuterated methanol

EtOH, ethanol

HCOOH formic acid

CH₃CN, MeCN acetonitrile

(Boc)₂Di-tert-butyl O dicarbonate

DCM,CH₂Cl₂Methylene dichloride

CHCl₃Chloroform, chloroform

CDCl₃Deuterated chloroform

CDI N, N' -carbonyldiimidazole

DCC dicyclohexylcarbodiimide

DMSO dimethyl sulfoxide

DIEA, DIPEA N, N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

Et₃N,TEA,NEt₃Triethylamine

EtOAc ethyl acetate

PE Petroleum Ether

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

HOBT 1-hydroxybenzotriazole

HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

LiOH lithium hydroxide

NaH sodium hydride

NaOH sodium hydroxide

NaHCO₃Sodium bicarbonate

Na₂SO₄Sodium sulfate

KOH potassium hydroxide

K₂CO₃Potassium carbonate

HCl hydrogen chloride

H₂SO₄Sulfuric acid

TFA trifluoroacetic acid

THF tetrahydrofuran

Pd/C palladium on carbon

Pd(OH)₂Palladium hydroxide

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

SEMCl 2- (trimethylsilyl) ethoxymethyl chloride

TsCl tosyl chloride

X-Phos 2-dicyclohexylphos-2, 4, 6-triisopropylbiphenyl

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

g

mg of

mol mole of

mmol millimole

h hours

min for

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

Peptide 22 labeled with Peptide FAM-P22 fluorescein

ATP adenosine triphosphate

96-well plate

384-well plate

Staurosporine Staurosporine

Coating Reagent #3 #3 Coating agent

The following synthetic methods describe the procedures for preparing the compounds of the present invention. Wherein R is^xIs alkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, amino-substituted alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; x¹，X²，R^a，R^b，R²，R³Ring a and ring B have the meaning as described in the present invention.

Synthesis method 1

Compounds 1-13 can be prepared by synthetic method one. Reacting compound 1-1 with a brominating agent (such as Br) at-20 deg.C to 40 deg.C₂NBS, etc.) to obtain a compound 1-2; the compound 1-2 reacts with trimethylsilylacetylene in a polar solvent (such as dimethyl sulfoxide, N, N-dimethyl amide, 1, 4-dioxane, and the like) under the condition of transition metal catalysis at the temperature of 25-80 ℃ to obtain a compound 1-3; the compound 1-3 is reacted with alkali (such as sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc.) or fluoride (such as tetrabutylammonium fluoride) to obtain compound 1-4; reacting the compound 1-4 with formaldehyde to generate a dihydroxymethyl compound 1-5; oxidizing the compound 1-5 under an acidic condition to obtain a compound 1-6; compounds 1-6 are reacted with HNR by condensing reagents (e.g., EDCI, DCC, HATU, etc.)^aR^bReacting to obtain a compound 1-7; reacting compound 1-7 with SEMCl under the action of alkali (such as sodium hydride, potassium tert-butoxide, etc.) to obtain compound 1-8; reacting the compounds 1-8 with the compounds 1-9 under the action of alkali (such as inorganic alkali such as potassium carbonate, cesium carbonate, potassium phosphate and the like) at the temperature of 25-160 ℃ and under the catalysis of metal (such as copper (0), copper (I), copper (II), palladium (0), Ni (0) and the like) to obtain compounds 1-10; reacting the compounds 1-10 under acidic conditions (such as trifluoroacetic acid, hydrogen chloride and the like), concentrating the solvent, and reacting under alkaline conditions (such as ethylenediamine, triethylamine, sodium hydroxide, sodium bicarbonate and the like) to obtain compounds 1-11; carrying out catalytic hydrogenation on the compounds 1-11 to obtain compounds 1-12; the compounds 1-12 react with acyl chloride under the action of alkali to obtain target compounds 1-13.

Synthesis method II

Compounds 1-13 can be prepared by synthesis method two. Carrying out catalytic hydrogenation on the compound 1-10 to obtain a compound 1-11-1; reacting the compound 1-11-1 with acyl chloride under the action of alkali to obtain a compound 1-12-1; after the compound 1-12-1 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 1-13.

Synthesis method III

The compounds 2-9 can be prepared by a third synthesis method. Reacting the compound 2-6 with the compound 2-7 to obtain a compound 2-8; after the compound 2-8 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 2-9.

Intermediates 2-6 have two synthetic routes, one route: reacting compound 1-4 with SEMCl under the action of alkali (such as sodium hydride, potassium tert-butoxide, etc.) to obtain compound 2-1; reacting the compound 2-1 with a bromination reagent in a polar solvent (such as DMSO, DMF, acetone, and the like) to obtain a compound 2-2; reacting the compound 2-2 with the compound 2-3 to obtain a compound 2-4; carrying out catalytic hydrogenation on the compound 2-4 to obtain a compound 2-5; reacting the compound 2-5 with acyl chloride under the action of alkali to obtain a compound 2-6; and (2) a second way: reacting 3-aminophenol with acyl chloride to obtain a compound 2-1-1; the compound 2-1-1 reacts with the compound 2-2 to obtain a compound 2-6.

Synthesis method IV

The compounds 3-5 can be prepared by the fourth synthesis method. Reacting compound 2-1 with iodinating agent in polar solvent (such as DMSO, DMF, acetone, etc.) to obtain compound 3-1; the compound 2-1 can also react with a brominating reagent in a polar solvent (such as DMSO, DMF, acetone, and the like) to obtain a corresponding compound; reacting the compound 3-1 with the compound 2-7 to obtain a compound 3-2; reacting the compound 3-2 with the compound 3-3 to obtain a compound 3-4; after the compound 3-4 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 3-5.

Example 1

2- (3- (2-cyanoacetamido) phenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of compound 3, 5-dibromopyrazine-2-amine

Dissolving 2-aminopyrazine (8.00g,84.12mmol) in dimethyl sulfoxide (160mL) at room temperature, adding water (4mL), slowly adding N-bromosuccinimide (31.50g,177.00mmol) to the reaction solution in batches within 30min under ice bath, stirring at room temperature overnight after the addition is finished, adding water (500mL) for quenching, extracting with ethyl acetate (500mL × 3), and extracting with anhydrous Na₂SO₄Drying, removal of the solvent and column chromatography of the residue (eluent: PE/EtOAc (v/v) ═ 6/1) gave 16.40g of a light yellow solid, yield: 76.6 percent.

MS(ESI,pos.ion)m/z:253.90[M+1]⁺。

Step 2: synthesis of compound 5-bromo-3- ((trimethylsilyl) ethynyl) pyrazine-2-amine

A mixture of 3, 5-dibromopyrazin-2-amine (16.30g,64.50mmol), cuprous iodide (2.45g,12.90mmol), palladium tetratriphenylphosphine (3.70g,3.20mmol) and N, N-dimethylformamide (80mL) was placed in a single vial under ice-bath in a N-flask₂Adding triethylamine under protection(44.8mL,321mmol), trimethylsilylacetylene (8.7mL,61.3mmol) was slowly added dropwise over 10min, and after the addition was complete, the mixture was stirred at room temperature for 1 h. Filtration, washing of the filter cake with dichloromethane (100mL), concentration of the filtrate and column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 20/1) gave 14.70g of a white solid, yield: 84.4 percent.

MS(ESI,pos.ion)m/z:271.02[M+1]⁺。

And step 3: synthesis of compound 2-bromo-5H-pyrrolo [2,3-b ] pyrazine

Potassium tert-butoxide (3.70g,33.0mmol) was dissolved in THF (80mL) under N₂Under protection, a THF (84mL) solution of 5-bromo-3- ((trimethylsilyl) ethynyl) pyrazine-2-amino (9.00g,33.0mmol) is slowly dropped within 30min, after dropping, the solution is stirred at room temperature for 30min, reflux reaction is carried out for 1h, cooling to room temperature, filtration is carried out, a filter cake is washed by ethyl acetate (200mL), saturated saline (50mL × 2) is used for washing, after water phases are combined, extraction is carried out by ethyl acetate (60mL × 2), organic phases are combined, and anhydrous Na is used for extracting₂SO₄Drying, removal of solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 3/1) afforded 5.0g of a yellow solid, yield: 76.0 percent.

MS(ESI,pos.ion)m/z:198.00[M+1]⁺。

And 4, step 4: synthesis of compound (2-bromo-5H-pyrrolo [2,3-b ] pyrazine-5, 7-diyl) dimethanol

The compound 2-bromo-5H-pyrrolo [2,3-b ] pyrazine (3.00g,15.0mmol) was dissolved in 1, 4-dioxane (60mL), sodium hydroxide solution (2.0M,15.0mL) and formaldehyde solution (37%, 11.4mL) were added in this order, and the mixture was stirred at room temperature overnight, the reaction was concentrated to give a brown oil, which was adjusted to pH 7 with HCl (1.0M) to precipitate a pale yellow solid, filtered, the filtrate was extracted with EtOAc/MeOH ((v/v) ═ 5/1,20mL × 2), the organic phase was concentrated, and the filter cake was combined and evaporated to dryness to give 4.0g of a yellow solid with a yield of 99.0%.

MS(ESI,pos.ion)m/z:258.00[M+1]⁺。

And 5: synthesis of compound 2-bromo-5H-pyrrolo [2,3-b ] pyrazine-7-carboxylic acid

The compound (2-bromo-5H-pyrrolo [2,3-b ] pyrazine-5, 7-diyl) dimethanol (4.00g,15mmol) was dissolved in acetone (1500mL), and Jones' reagent (2.6M,22mL) was slowly added with stirring, and reacted overnight in an oil bath at 44 ℃. Celite filtration and concentration of the organic phase afforded 4.70g of a brown solid, yield: 130.0% (containing inorganic salts).

MS(ESI,pos.ion)m/z:242.0[M+1]⁺。

Step 6: synthesis of compound 2-bromo-N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Under water bath, 2-bromo-5H-pyrrolo [2,3-b ] is added]1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.21g,11.50mmol), 1-hydroxybenzotriazole (1.56g,11.5mmol) and 2-isopropylamine (1.97mL,23.10mmol) were added sequentially to a solution of pyrazine-7-carboxylic acid (1.40g,5.80mmol) in N, N-dimethylformamide (8mL), stirred at room temperature overnight, saturated saline (50mL) was added, dichloromethane (30mL × 3) was extracted, and anhydrous Na was added₂SO₄Drying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)₂Cl₂MeOH (v/v) ═ 50/1), yielding 450mg of a brown solid, yield: 27.0 percent.

MS(ESI,pos.ion)m/z:283.0[M+1]⁺。

And 7: synthesis of compound 2-bromo-N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

2-bromo-N-isopropyl-5H-pyrrolo [2,3-b ]]Pyrazine-7-carboxamide (1.00g,3.50mmol) was mixed with sodium hydride (60%, 212mg,5.30mmol) in N₂Under protection, N-dimethylformamide (35mL) was added to the mixture in a water bath, the mixture was stirred at room temperature for 1 hour, 2- (trimethylsilyl) ethoxymethyl chloride (950. mu.L, 5.28mmol) was slowly added dropwise thereto, the mixture was stirred at room temperature overnight, saturated brine (20mL) and dichloromethane (25mL × 3) were added, and the mixture was extracted with anhydrous Na₂SO₄Drying, removal of the solvent and column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 5/1) gave 1.05g of a pale yellow solid, yield: 70.0 percent.

MS(ESI,pos.ion)m/z:415.2[M+1]⁺。

And 8: synthesis of compound N-isopropyl-2- (3-nitrophenoxy) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

N, N-dimethylglycine (100mg,0.97mmol), cesium carbonate (473mg,1.45mmol), cuprous iodide (185mg,0.97mmol) and 3-nitrophenol (162mg,1.16mmol) were sequentially charged to 2-bromo-N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ]]Pyrazine-7-carboxamide (400mg,0.96mmol) in 1, 4-dioxane (15mL) was substituted for N₂Reflux reaction at 115 ℃ for 4.5h, filtration, concentration of the filtrate, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 4/1) gave 340mg of a pale yellow solid, yield: 74.51 percent.

MS(ESI,pos.ion)m/z:472.2[M+1]⁺。

And step 9: synthesis of compound N-isopropyl-2- (3-nitrophenoxy) -5H-pyrrolo [2,3-b ] pyrazine-7-formamide

The compound N-isopropyl-2- (3-nitrophenoxy) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] is reacted at room temperature]Pyrazine-7-carboxamide (340mg,0.72mmol) was dissolved in dichloromethane (8mL), trifluoroacetic acid (2mL) was added, stirred at room temperature for 3h, concentrated, dissolved in THF (10mL), pH adjusted to basic, stirred at room temperature for 2h, diluted with water (15mL), extracted with dichloromethane (25mL × 3), extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 2/1) afforded 240mg of a light yellow solid, yield: 97.54 percent.

MS(ESI,pos.ion)m/z:342.1[M+1]⁺。

Step 10: synthesis of compound 2- (3-aminophenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound N-isopropyl-2- (3-nitrophenoxy) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (250mg,0.73mmol) was dissolved in methanol (14mL), Pd/C (77.7mg,0.073mmol) was added in H₂After stirring at room temperature for 30 minutes under an atmosphere, filtration was carried out to give a pale yellow filtrate, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 240mg of a pale yellow oil, yield: 96 percent. MS (ESI, pos.ion) M/z 312.1[ M + 1]]⁺。

Step 11: synthesis of compound 2- (3- (2-cyanoacetamido) phenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- (3-aminophenoxy) -N-isopropyl-5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (60mg,0.19mmol) was dissolved in anhydrous dichloromethane (15mL), triethylamine (80.25. mu.L, 0.58mmol) was added, freshly prepared cyanoacetyl chloride (0.38mmol) was added in an ice bath, stirring was continued while cooling and allowed to warm to room temperature naturally, after stirring for 6 hours, diluted with water (10mL), extracted with dichloromethane (15mL × 3), and extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 2/1), and isolation on preparative plates afforded 3mg of a light yellow solid, yield: 4.1 percent.

MS(ESI,pos.ion)m/z:379.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.72(s,1H),10.52(s,1H),8.31(s,1H),8.25(s,1H),7.58(m,1H),7.46(t,J＝7.8Hz,1H),7.39(m,2H),7.0(m,1H),3.92(m,1H),3.90(s,2H),0.91(d,J＝6.6Hz,6H)。

Example 2

N-isopropyl-2- ((3-propionamidophenyl) amino) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of compound N-isopropyl-2- ((3-nitrophenyl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

N₂1, 4-Dioxahexacyclic compound (8mL) was added to 2-bromo-N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] under protection]Pyrazine-7-carboxamide (0.25g,0.60mmol), Xantphos (0.018g,0.03mmol), Palladium acetate (70mg,0.03mmol), Cesium carbonate (0.21g,0.64mmol) and 3-nitroaniline (0.1g,0.72mmol) in a mixture at 110 ℃ for 4H reflux reaction, filtration, dilution with dichloromethane (20mL), and filtrate with H₂Washing with O (30mL), back-extracting the aqueous phase with dichloromethane (30mL × 3), combining the organic layers, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (leaching)Washing agent: PE/EtOAc (v/v) ═ 2/1), yielding 190mg of a yellow solid, yield: 87.85 percent.

MS(ESI,pos.ion)m/z:471.2[M+1]⁺。

Step 2: synthesis of compound 2- ((3-aminophenyl) amino) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound N-isopropyl-2- ((3-nitrophenyl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (0.43g,0.91mmol) was dissolved in methanol (30mL), Pd/C (200mg) was added, and the mixture was washed with water and brine₂The mixture was stirred at room temperature for 40 minutes under an atmosphere. Filtering to obtain light yellow filtrate, removing solvent, and performing column chromatography to the concentrated solution (eluent: CH)₂Cl₂/CH₃OH (v/v) ═ 60/1), yielding 350mg of a yellow solid, yield: 86.94 percent.

MS(ESI,pos.ion)m/z:441.2[M+1]⁺。

And step 3: synthesis of compound 2- ((3-propionamidophenyl) amino) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- ((3-aminophenyl) amino) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (0.15g,0.34mmol) was dissolved in anhydrous dichloromethane (30mL), triethylamine (0.3mL,2mmol) was added, propionyl chloride (0.15mL,1.7mmol) was added under ice bath, stirring was continued under ice bath, and it was allowed to warm to room temperature naturally and stirred for 2 hours, diluted with water (35mL), extracted with dichloromethane (35mL × 3), and extracted with anhydrous Na₂SO₄Drying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)₂Cl₂/CH₃OH (v/v) ═ 60/1), yielding 140mg of a yellow solid, yield: 82.79 percent.

MS(ESI,pos.ion)m/z:497.3[M+1]⁺。

And 4, step 4: synthesis of compound N-isopropyl-2- ((3-propionamidophenyl) amino) -5H-pyrrolo [2,3-b ] pyrazine-7-formamide

The compound 2- ((3-propionamidophenyl) amino) -N-isopropyl-5- ((2- (trimethyl) amino) is reacted at room temperatureSilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (0.14g,0.28mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (2.2mL,28mmol) was added, the mixture was stirred at room temperature for 6h, concentrated under reduced pressure, and the residue was dissolved in THF (15mL) and washed with saturated NaHCO₃The solution was made basic and allowed to react overnight at room temperature, diluted with water (30mL), extracted with dichloromethane (30mL × 3), and the organic layer was washed with anhydrous Na₂SO₄Drying, concentrating under reduced pressure, and separating the concentrated solution by column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 10/1), yielding 85mg of a yellow solid.

MS(ESI,pos.ion)m/z:367.3[M+1]⁺；

¹H NMR(600MHz,CD₃OD):δ(ppm)8.01(s,1H),7.96(s,1H),7.80(s,1H),7.54(d,J＝8.0Hz,1H),7.28(t,J＝8.1Hz,1H),7.14(d,J＝7.5Hz,1H),4.27-4.20(m,1H),2.41(q,J＝7.6Hz,2H),1.27(d,J＝6.6Hz,6H),1.23(t,J＝7.6Hz,3H)。

Example 3

2- (3-Acylaminophenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of compound 2- (3-aminophenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound N-isopropyl-2- (3-nitrophenoxy) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (1.7g,3.6mmol) was dissolved in methanol (50mL), Pd/C (1.0g) was added, and the mixture was washed with water and brine₂The mixture was stirred at room temperature for 70 minutes under an atmosphere. Filtering to obtain light yellow filtrate, removing solvent, and performing column chromatography to the concentrated solution (eluent: CH)₂Cl₂MeOH (v/v) ═ 80/1), yielding 1.5g of a light yellow solid, yield: 94 percent.

MS(ESI,pos.ion)m/z:442.3[M+1]⁺。

Step 2: synthesis of compound 2- (3-acetamidophenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- (3-aminophenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (130mg,0.29mmol) was dissolved in anhydrous dichloromethane (15mL), triethylamine (122. mu.L, 0.88mmol) was added, acetyl chloride (4.7. mu.L, 0.44mmol) was added in an ice bath, stirring was continued in an ice bath, and it was allowed to warm to room temperature naturally and stirred for 6 hours, diluted with water (10mL), extracted with dichloromethane (15mL × 3), and extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 2/1) afforded 100mg of a light yellow oil, yield: 70.9 percent.

MS(ESI,pos.ion)m/z:484.2[M+1]⁺。

And step 3: synthesis of compound 2- (3-acetaminophenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- (3-acetamidophenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine-7-carboxamide (100mg,0.20mmol) was dissolved in anhydrous dichloromethane (5mL), trifluoroacetic acid (2mL) was added, and stirring was carried out at room temperature for 5 h; concentrating, dissolving in tetrahydrofuran (10mL), adjusting pH to>7, stir at room temperature for 3h, dilute with water (10mL), extract with dichloromethane (15mL × 3), dry Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 2/1) afforded 70mg of a grey solid, yield: 95.8 percent.

MS(ESI,pos.ion)m/z:354.0[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.70(s,1H),10.11(s,1H),8.29(s,1H),8.25(s,1H),7.65(s,1H),7.39(m,3H),6.95(m,1H),3.92(m,1H),2.03(s,3H),0.91(d,J＝6.6Hz,6H)。

Example 4

N-cyclobutyl-2- ((3-propionamidophenyl) amino) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of Compound N- (3-nitrophenyl) propionamide

3-nitroaniline (1.2g,8.7mmol) was dissolved in anhydrous dichloromethane (50mL), triethylamine (6mL,43.0mmol) was added, propionyl chloride (1.5mL,17mmol) was added under ice bath, stirring was continued under ice bath, which was allowed to warm to room temperature naturally and stirred for 2 hours, diluted with water (150mL), extracted with dichloromethane (150mL × 3), and extracted with anhydrous Na₂SO₄Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 3/1) afforded 1.6g of a beige solid, yield: 95 percent.

MS(ESI,pos.ion)m/z:195.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)10.34(s,1H),8.63(s,1H),7.88(dd,J＝14.9,7.9Hz,2H),7.58(t,J＝7.8Hz,1H),2.37(d,J＝7.3Hz,2H),1.10(t,J＝7.1Hz,3H)。

Step 2: synthesis of Compound N- (3-aminophenyl) propionamide

The compound N- (3-nitrophenyl) propionamide (1.6g,8.2mmol) was dissolved in methanol (30mL), Pd/C (10%, 800mg) was added, and the mixture was stirred in H₂Stirred at room temperature for 2h under an atmosphere. Filtering to obtain light yellow filtrate, removing solvent, and performing column chromatography to the concentrated solution (eluent: CH)₂Cl₂/CH₃OH (v/v) ═ 60/1), yielding 1.3g of a yellow solid, yield: 96 percent.

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.51(s,1H),6.90(dd,J＝15.9,7.9Hz,2H),6.68(d,J＝7.6Hz,1H),6.23(d,J＝7.6Hz,1H),5.00(s,2H),2.27(q,J＝7.4Hz,2H),1.06(t,J＝7.5Hz,3H)。

And step 3: synthesis of compound 2-bromo-N-cyclobutyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Under ice bath, (COCl)₂(7.5mL) and DMF (0.4mL) were added slowly dropwise to 2-bromo-5H-pyrrolo [2,3-b ]]Pyrazine-7-carboxylic acid (60%, 4.00g,8.26mmol) was reacted in dichloromethane (150mL) at room temperature for 2 h. Concentrated under reduced pressure, the residue was dissolved in methylene chloride (120mL), and a mixture of cyclobutyl amine (2.2mL,26mmol) and triethylamine (2.4mL) was added to the solution to react overnight. Quench the reaction with water (150mL), dichloromethaneAlkane (150mL × 3) extraction and organic layer over anhydrous Na₂SO₄Drying, concentrating under reduced pressure, and performing column chromatography (eluent: Cl)₂CH₂MeOH (v/v) ═ 30/1), yielding 1.20g of a tan solid, yield: 49.0 percent.

MS(ESI,pos.ion)m/z:295.1[M+1]⁺。

And 4, step 4: synthesis of the compound 2-bromo-N-cyclobutyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

2-bromo-N-cyclobutyl-5H-pyrrolo [2,3-b ]]Pyrazine-7-carboxamide (1.10g,3.70mmol) was mixed with sodium hydride (60%, 0.24g,6.00mmol) in N₂Under protection, N-dimethylformamide (30mL) was added under ice-bath, and after stirring at room temperature for 1.5h, 2- (trimethylsilyl) ethoxymethyl chloride (1.1mL,6.20mmol) was slowly added dropwise under ice-bath, and after stirring at room temperature overnight, saturated brine (150mL), dichloromethane (150mL × 3) were added, extraction was performed, and anhydrous Na was added₂SO₄Drying, removal of solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 3/1) afforded 1.27g of an off-white solid, yield: 80.0 percent.

MS(ESI,pos.ion)m/z:425.1[M+1]⁺。

And 5: synthesis of compound N-cyclobutyl-2- ((3-propionamidophenyl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

N₂Under protection, 1, 4-dioxane (10mL) was added to 2-bromo-N-cyclobutyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ]]Pyrazine-7-carboxamide (0.2g,0.47mmol), Xantphos (14mg,0.02mmol), palladium acetate (6mg,0.026mmol), cesium carbonate (0.17g,0.52mmol) and N- (3-aminophenyl) propionamide (0.095g,0.578mmol) at 110 deg.C for 4H, filtering, reacting the filtrate with H₂Washing with O (30mL), back-extracting the aqueous phase with dichloromethane (30mL × 3), combining the organic layers, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating the concentrated solution by column chromatography (eluent: CH)₂Cl₂/CH₃OH (v/v) ═ 50/1), yielding 200mg of a yellow solid, yield: 83.62 percent.

MS(ESI,pos.ion)m/z:509.3[M+1]⁺。

Step 6: synthesis of compound N-cyclobutyl-2- ((3-propionamidophenyl) amino) -5H-pyrrolo [2,3-b ] pyrazine-7-formamide

The compound N-cyclobutyl-2- ((3-propionamidophenyl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] at room temperature]Pyrazine-7-carboxamide (0.22g,0.43mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (8mL) was added, stirring at room temperature for 4h, then concentrated under reduced pressure, the residue was taken up in THF (10mL), and saturated NaHCO was used₃The solution was made basic and allowed to react overnight at room temperature, diluted with water (30mL), extracted with dichloromethane (30mL × 3), and the organic layer was washed with anhydrous Na₂SO₄Drying, concentrating under reduced pressure, and separating the concentrated solution by column chromatography (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 150mg of a yellow solid.

MS(ESI,pos.ion)m/z:379.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.34(s,1H),9.87(s,1H),9.48(s,1H),8.28(d,J＝8.0Hz,1H),8.02(d,J＝5.1Hz,2H),7.88(s,1H),7.58(d,J＝7.8Hz,1H),7.25(t,J＝8.0Hz,1H),7.13(d,J＝7.8Hz,1H),4.47(d,J＝8.1Hz,1H),2.32(dt,J＝13.1,5.3Hz,4H),1.95-1.86(m,2H),1.74-1.65(m,2H),1.09(t,J＝7.5Hz,3H)。

Example 5

2- (3- (cyclopropylcarboxamido) phenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of compound 2- (3- (cyclopropylcarboxamido) phenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- (3-aminophenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide (0.12g,0.27mmol) was dissolved in anhydrous dichloromethane (30mL), triethylamine (0.2mL,1.00mmol) was added, cyclopropylcarbonyl chloride (0.05mL,0.60mmol) was added under ice bath, the mixture was naturally warmed to room temperature and stirred for 5 hours, the reaction was quenched by addition of saturated saline (35mL), dichloromethane (35mL × 3) was extracted, dried over anhydrous sodium sulfate was removed, and the concentrate was subjected to column chromatography (eluent: dichloromethane/methanol (v/v) ═ 65/1) to give 120mg of a pale yellow oil with a yield of 86.64%.

MS(ESI,pos.ion)m/z:510.4[M+1]⁺。

Step 2: synthesis of compound 2- (3- (cyclopropylcarboxamido) phenoxy) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- (3- (cyclopropylcarboxamido) phenoxy) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide (0.12g,0.24mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (5mL) was added, the reaction was stirred at room temperature overnight, concentrated under reduced pressure, the residue was dissolved in THF (6mL), made basic with a saturated sodium bicarbonate solution (pH 8-9), stirred at room temperature overnight, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: dichloromethane/methanol (v/v) ═ 12.5/1) to give a pale yellow solid, which was subjected to preparative thin layer chromatography to give 79mg of a white solid with a yield of 72.77%.

MS(ESI,pos.ion)m/z:380.0[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.70(s,1H),10.36(s,1H),8.29(s,1H),8.24(s,1H),7.68(s,1H),7.43-7.39(m,3H),6.95(dt,J＝6.9,2.1Hz,1H),3.95-3.92(m,1H),0.92(d,J＝6.6Hz,6H),0.88-0.83(m,1H),0.81-0.74(m,4H)。

Example 6

2- ((1- (2-cyanoacetyl) piperidin-3-yl) amino) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

Step 1: synthesis of compound 2- (3- (1-tert-butoxycarbonyl) piperidinylamino) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2-bromo-N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide (20mg,0.048mmol), 3-aminopiperidine-1-tert-butoxycarbonyl (14.5mg,0.07mmol), X-Phos (2.3mg,0.0047mmol), cesium carbonate (47mg,0.14mmol) and palladium acetate (1.1mg,0.005mmol) were mixed, 1, 4-dioxane (5mL) was added, nitrogen was exchanged, after refluxing at 115 ℃ for 5 hours, cooled to room temperature, directly filtered, concentrated, and the concentrate was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 14mg of a brown solid, yield: 54.31 percent.

MS (ESI, pos. ion) m/z: no response.

Step 2: synthesis of compound N-isopropyl-2- (piperidin-3-ylamino) -5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

The compound 2- (3- (1-tert-butoxycarbonyl) piperidinamino) -N-isopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxamide (20mg,0.037mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (0.5mL) was added at room temperature, stirring was continued for 4 hours at this temperature, and direct concentration gave a yellow oil, which was dissolved by addition of tetrahydrofuran (5mL), adjusted to pH by addition of triethylamine>7, stirring for 2 hours at room temperature, directly concentrating, and performing column chromatography on the concentrated solution (eluent: CH)₂Cl₂MeOH (v/v) ═ 5/1), yielding 10mg of yellow oil, yield: 88.10 percent.

MS(ESI,pos.ion)m/z:303.2[M+1]⁺。

And step 3: synthesis of compound 2- ((1- (2-cyanoacetyl) piperidin-3-yl) amino) -N-isopropyl-5H-pyrrolo [2,3-b ] pyrazine-7-carboxamide

To the compound N-isopropyl-2- (piperidin-3-ylamino) -5H-pyrrolo [2,3-b]1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (316.2mg,1.65mmol), 1-hydroxybenzotriazole (223.5mg,1.65mmol), diisopropylethylamine (230. mu.L) and 2-cyanoacetic acid (70.4mg,0.83mmol) were added sequentially to a solution of pyrazine-7-carboxamide (100mg,0.33mmol) in N, N-dimethylformamide (6mL), stirred at room temperature for 24 hours, quenched with water (15mL), extracted with dichloromethane (15mL × 3), and extracted with anhydrous sodium sulfateDrying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)₂Cl₂MeOH (v/v) ═ 20/1), yielding 20mg of a grey solid, yield: 16.37 percent.

MS(ESI,pos.ion)m/z:370.30[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.10(s,1H),8.10(dt,J＝19.8,9.9Hz,1H),7.89(d,J＝6.1Hz,1H),7.74(m,1H),7.06(dd,J＝37.2,7.2Hz,1H),4.07(m,4H),3.79(m,1H),3.59(m,1H),3.15(dd,J＝22.5,7.7Hz,2H),1.78(m,4H),1.21(td,J＝11.7,5.7Hz,6H)。

Example 7

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

Step 1: synthesis of Compound N- (3-hydroxyphenyl) propionamide

Propionyl chloride (4.20mL,48.00mmol) was slowly added dropwise to a solution of 3-aminophenol (5.00g,45.82mmol) and triethylamine (12.80mL,91.80mmol) in dichloromethane (100mL) under ice-bath, and after completion of the dropwise addition, the reaction was stirred at room temperature overnight, the reaction was quenched with water (150mL), dichloromethane (150mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 1.82g of a pale yellow solid, yield: 24.0%.

MS(ESI,pos.ion)m/z:166.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)9.69(s,1H),9.31(s,1H),7.21(s,1H),7.04(t,J＝10.6Hz,1H),6.94(d,J＝8.0Hz,1H),6.41(dd,J＝7.9,1.6Hz,1H),2.28(q,J＝7.5Hz,2H),1.07(t,J＝7.5Hz,3H)。

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

Under nitrogen protection, 1, 4-dioxane (45mL) was added to a mixture of 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (3.50g,8.60mmol), N- (3-hydroxyphenyl) propionamide (1.80g,11.00mmol), cesium carbonate (4.20g,13.00mmol), cuprous iodide (1.80g,9.50mmol), and N, N-dimethylglycine (1.00g,9.50mmol), the reaction was refluxed at 115 ℃ for 4 hours, the reaction was cooled to room temperature, celite was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 3.50g of a pale yellow solid, yield: 83.0 percent.

MS(ESI,pos.ion)m/z:491.1[M+1]⁺。

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

1, 4-dioxane (14mL) and water (3.5mL) were added to the compound N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) under nitrogen]Pyrazin-2-yl) oxy) phenyl) propionamide (490mg,1.00mmol), 1- (2-methoxyethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (500mg,1.98mmol), potassium carbonate (210mg,1.50mmol) and 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (Pd (dppf) Cl₂) (37mg,0.05mmol) in the mixture, the reaction mixture was refluxed at 110 ℃ overnight, the reaction mixture was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and column chromatography was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/2), yielding 350mg of a brown oil, yield: 65.4 percent.

MS(ESI,pos.ion)m/z:536.9[M+1]⁺。

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

The compound N- (3- ((7- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) propionamide (350mg,0.65mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with a sodium hydroxide solution (2M) (pH 8-9), stirred at 45 ℃ for 1.5H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate) to obtain 180mg of a beige solid with a yield: 67.9%.

MS(ESI,pos.ion)m/z:407.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.08(s,1H),9.95(s,1H),8.12(s,1H),8.09(s,1H),8.03(s,1H),7.85(s,1H),7.53(s,1H),7.39(d,J＝7.9Hz,1H),7.34(t,J＝8.1Hz,1H),6.87(d,J＝7.6Hz,1H),4.23(t,J＝5.1Hz,2H),3.66(t,J＝5.2Hz,2H),3.20(s,3H),2.30(q,J＝7.4Hz,2H),1.06(t,J＝7.5Hz,3H)。

Example 8

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

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

1, 4-Dioxahexacyclic (14mL) and water (3.5mL) were added to N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) under nitrogen]Pyrazin-2-yl) oxy) phenyl) propionamide (490mg,1.00mmol), 1-methyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (320mg,1.54mmol), potassium carbonate (210mg,1.52mmol) and 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (Pd (dppf) Cl₂) (37mg,0.05mmol) in the mixture, reflux-reacting at 115 ℃ overnight, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and subjecting the concentrate to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/4), giving 320mg of a brown solid, yield: 72.4 percent.

MS(ESI,pos.ion)m/z:493.3[M+1]⁺。

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

The compound N- (3- ((7- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) propionamide (310mg,0.57mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with ethylenediamine (pH 9), stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated off, and the residue was subjected to column chromatography (eluent: ethyl acetate) to obtain 150mg of a beige solid in a yield of 73.1%.

MS(ESI,pos.ion)m/z:363.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.09(s,1H),9.94(s,1H),8.11(s,1H),8.09(s,1H),8.02(s,1H),7.82(s,1H),7.54(s,1H),7.35(dt,J＝16.0,8.1Hz,2H),6.86(d,J＝7.8Hz,1H),3.82(s,3H),2.30(q,J＝7.5Hz,2H),1.06(t,J＝7.5Hz,3H)。

Example 9

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

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

Acetonitrile (20mL) and water (6mL) were added to a mixture of 2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (270mg,0.59mmol), 1-methylpyrazole borate (140mg,0.67mmol), sodium carbonate (160mg,1.90mmol) and bis (triphenylphosphine) palladium dichloride (20mg,0.028mmol) under nitrogen, reacted at 60 ℃ for 5.5H, the reaction was cooled to room temperature, silica gel was added to concentrate and stir the sample, column chromatography was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 199mg of a pale yellow solid, yield: 81.9 percent.

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

Adding 1, 4-dioxane (10mL) into a mixture of 2-bromo-7- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (130mg,0.32mmol), N- (3-aminophenyl) propionamide (57mg,0.35mmol), cesium carbonate (210mg,0.64mmol), palladium acetate (5mg,0.02mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17mg,0.03mmol) under the protection of nitrogen, refluxing at 110 ℃ for 6H, cooling the reaction solution to room temperature, filtering with diatomaceous earth, concentrating the filtrate under reduced pressure, and performing column chromatography on the concentrated solution (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1), 122mg of a pale yellow solid are obtained, yield: 80.0 percent.

MS(ESI,pos.ion)m/z:491.9[M+1]⁺。

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

The compound N- (3- ((7- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) propionamide (122mg,0.25mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2h, silica gel was added to the reaction solution, and the mixture was directly spin-dried and sample-stirred and subjected to column chromatography (eluent: dichloromethane/methanol (v/v) ═ 20/1) to give 58mg of a pale yellow solid, yield: and (4) 64.7%.

MS(ESI,pos.ion)m/z:362.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.62(s,1H),9.81(s,1H),9.18(s,1H),8.24(s,1H),8.16(s,1H),7.95(s,1H),7.93(s,1H),7.83(s,1H),7.52(d,J＝8.1Hz,1H),7.23(t,J＝8.0Hz,1H),7.01(d,J＝8.1Hz,1H),3.89(s,3H),2.35(dd,J＝14.9,7.4Hz,2H),1.11(t,J＝7.4Hz,2H)。

Example 10

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

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

1, 4-Dioxahexacyclic (14mL) and water (3.5mL) were added to N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) under nitrogen]Pyrazin-2-yl) oxy) phenyl) propionamide (490mg,1.00mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (4-fluorobenzyl) -1H-pyrazole (500mg,1.65mmol), potassium carbonate (210mg,1.52mmol) and 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (Pd (dppf) Cl₂) (37mg,0.05mmol) in the mixture, reflux-reacting at 115 ℃ overnight, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and separating by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/8), yielding 350mg of a yellow solid, yield: and (5) 59.8%.

MS(ESI,pos.ion)m/z:587.3[M+1]⁺。

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

The compound N- (3- ((7- (1- (4-fluorobenzyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) was reacted at room temperature]Pyrazin-2-yl) oxy) phenyl) propionamide (350mg,0.48mmol) was dissolved in dichloromethane (6mL), trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7h, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), which was made basic with ethylenediamine (1.5mL) (pH 9), the reaction was stirred at room temperature overnight, water (30mL) was added for dilution, dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate) to give 150mg of a pale yellow solid, yield: 68.8%. MS (ESI, pos.ion) M/z 456.8[ M +1 ] M/z]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.10(s,1H),9.95(s,1H),8.21-8.04(m,3H),7.89(s,1H),7.53(s,1H),7.34(dd,J＝35.6,28.0Hz,4H),7.16(d,J＝7.7Hz,2H),6.86(d,J＝6.5Hz,1H),5.30(s,2H),2.29(d,J＝6.8Hz,2H),1.05(s,3H)。

Example 11

4- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl) methyl) benzonitrile

Step 1: synthesis of Compound 4- ((4-iodo-1H-pyrazol-1-yl) methyl) benzonitrile

Cesium carbonate (2.36g,10.31mmol), potassium iodide (450mg,2.58mmol), 4- (bromomethyl) benzonitrile (1.50g,7.73mmol) and 4-iodopyrazole (3.35g,22.78mmol) were mixed, N-dimethylformamide (20mL) was added thereto, reacted at room temperature for 8h, diluted with water (50mL), the reaction solution was extracted with ethyl acetate (50mL × 3), the organic phase was concentrated, and column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 10/1) was performed to obtain 1.01g of a white solid, yield: 62.8%.

MS(ESI,pos.ion)m/z:309.8[M+1]⁺。

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

Under the protection of nitrogen, potassium acetate (960mg,9.78mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (115mg,0.16mmol), 4- ((4-iodo-1H-pyrazol-1-yl) methyl) benzonitrile (1.01g,3.24mmol) and pinacol diboron (980mg,3.88mmol) were mixed, N-dimethylformamide (15.00mL) was then added, the reaction was carried out at 85 ℃ for 24 hours, the reaction solution was cooled to room temperature, celite was filtered, the filtrate was diluted with water (50mL), extracted with ethyl acetate (50mL × 3), the organic phase was concentrated, and separation was carried out by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 4/1) to obtain 900mg of a yellow oily substance with a yield of 90.2%.

MS(ESI,pos.ion)m/z:310.2[M+1]⁺。

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

Under the protection of nitrogen, adding 2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine (300mg,0.66mmol), 4- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) benzonitrile (270mg,0.70mmol), sodium carbonate (210mg,1.98mmol) and Pd (PPh)₃)₂Cl₂(25mg,0.03mmol) of the mixture was added CH in sequence₃CN (6mL) and H₂O (2mL), reacted at 65 ℃ for 16.5h, diluted with water (30mL), the reaction solution was extracted with ethyl acetate (30mL × 3), the organic phase was concentrated, and separated by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 240mg of a white solid with a yield of 71.31%.

MS(ESI,pos.ion)m/z:510.5[M+1]⁺。

And 4, step 4: synthesis of compound 4- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl) methyl) benzonitrile

Under nitrogen protection, 1, 4-dioxane (8mL) was added to a mixture of 4- ((4- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl) methyl) benzonitrile (180mg,0.35mmol), 1-methyl-1H-pyrazol-4-amine (50mg,0.51mmol), cesium carbonate (200mg,0.61mmol), palladium acetate (6mg,0.03mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) (12mg,0.06mmol), the reaction was refluxed overnight at 110 ℃, the reaction was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, column chromatography (eluent: ethyl acetate) gave 160mg of a yellow oil, yield: 68.9 percent.

MS(ESI,pos.ion)m/z:526.3[M+1]⁺。

And 5: synthesis of compound 4- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl) methyl) benzonitrile

Compound 4- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -1H-pyrazol-1-yl) methyl) benzonitrile (150mg,0.28mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made alkaline with ethylenediamine (1mL) (pH ═ 9), the reaction was stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate/methanol (v/v) ═ 20/1) to give 90mg of a yellow solid with a yield of 79.8%.

MS(ESI,pos.ion)m/z:396.0[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.57(d,J＝2.1Hz,1H),9.03(s,1H),8.31(s,1H),8.03(s,2H),7.90-7.75(m,4H),7.54(s,1H),7.42(d,J＝8.2Hz,2H),5.56(s,2H),3.77(s,3H)。

Example 12

7- (1- (4-fluorobenzyl) -1H-pyrazol-4-yl) -N- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-amine

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

Adding 1, 4-dioxane (6mL) into a mixture of 2-bromo-7- (1- (4-fluorobenzyl) -1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (160mg,0.32mmol), 1-methyl-1H-pyrazol-4-amine (60mg,0.62mmol), cesium carbonate (170mg,0.52mmol), palladium acetate (4mg,0.02mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) (10mg,0.02mmol) under nitrogen protection, refluxing at 110 ℃ for reaction overnight, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, performing column chromatography (eluent: ethyl acetate), 150mg of yellow oil are obtained, yield: 72.6 percent.

MS(ESI,pos.ion)m/z:519.3[M+1]⁺。

Step 2: synthesis of compound 7- (1- (4-fluorobenzyl) -1H-pyrazol-4-yl) -N- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2,3-b ] pyrazin-2-amine

The compound 7- (1- (4-fluorobenzyl) -1H-pyrazol 4-yl) -N- (1-methyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-amine (150mg,0.23mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with ethylenediamine (1mL) (pH 9) and stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by column chromatography, and the residue was separated (eluent: ethyl acetate/methanol (v/v) ═ 9/1) to obtain 60mg of a yellow solid with a yield of 66.8%.

MS(ESI,pos.ion)m/z:389.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.56(s,1H),9.02(s,1H),8.27(s,1H),8.04(s,1H),8.00(d,J＝2.0Hz,1H),7.81(d,J＝2.4Hz,1H),7.77(d,J＝2.7Hz,1H),7.55(d,J＝2.4Hz,1H),7.36(dd,J＝8.6,5.6Hz,2H),7.20(t,J＝8.9Hz,2H),5.42(s,2H),3.81(s,3H)。

Example 13

N- (3- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) propanamide

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

1, 4-dioxane (12mL) and water (3mL) were added to N- (3- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) under nitrogen]Pyrazin-2-yl) oxy) phenyl) propionamide (400mg,0.81mmol), 3- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl) phenyl) amino) propionitrile (350mg,1.29mmol), potassium carbonate (170 mg)1.23mmol) and 1,1' -bis-diphenylphosphino ferrocene dichloropalladium (Pd (dppf) Cl₂) (30mg,0.04mmol) in the mixture, reflux-reacting at 110 ℃ overnight, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and separating by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/9), giving 380mg of a yellow solid, yield: 75.5 percent.

MS(ESI,pos.ion)m/z:556.8[M+1]⁺。

Step 2: synthesis of the compound N- (3- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) propionamide

The compound N- (3- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) phenyl) propionamide (350mg,0.50mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (3mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with ethylenediamine (2mL) (pH 9), stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated off, and the residue was subjected to column chromatography (eluent: ethyl acetate) to give 135mg of a pale yellow solid with a yield of 62.9%.

MS(ESI,pos.ion)m/z:426.9[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.28(s,1H),9.94(s,1H),8.30(s,1H),8.16(s,1H),7.47(s,1H),7.41(d,J＝8.0Hz,1H),7.34(t,J＝8.1Hz,1H),7.31(s,1H),7.21(d,J＝7.5Hz,1H),7.06(t,J＝7.8Hz,1H),6.87(d,J＝7.9Hz,1H),6.47(d,J＝7.8Hz,1H),5.76(t,J＝5.9Hz,1H),3.14(dd,J＝12.2,6.1Hz,2H),2.62(t,J＝6.2Hz,2H),2.30(q,J＝7.5Hz,2H),1.05(t,J＝7.5Hz,3H)。

Example 14

N- (6- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) -2, 3-dihydro-1H-inden-1-yl) acetamide

Step 1: synthesis of the compound N- (6- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) -2, 3-dihydro-1H-inden-1-yl) acetamide

Under the protection of nitrogen, the compound 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine (300mg,0.74mmol), N- (6-hydroxy-2, 3-dihydro-1H-inden-1-yl) acetamide (165mg,0.88mmol), cuprous iodide (170mg,0.74mmol), dimethylglycine (230mg,0.23mmol) and cesium carbonate (620mg,1.84mmol) were mixed, DMSO (15mL) was added, the temperature was raised to 120 ℃ for reaction for 18H, the reaction mixture was cooled to room temperature, diluted with water (50mL), extracted with ethyl acetate (50mL × 3), and dried over Na₂SO₄Drying, removal of the solvent and column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 138mg of a pale yellow solid, yield: 36.6 percent.

MS(ESI,pos.ion)m/z:516.7[M+1]⁺。

Step 2: synthesis of the compound N- (6- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) -2, 3-dihydro-1H-inden-1-yl) acetamide

1, 4-Dioxahexacyclic (10mL) and water (2mL) were added to N- (6- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] under nitrogen]Pyrazin-2-yl) oxy) -2, 3-dihydro-1H-inden-1-yl) acetamide (138mg,0.27mmol), 3- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile (134mg,0.48mmol), potassium carbonate (98mg,0.67mmol) and Pd (dppf) Cl₂(13mg,0.02mmol) of the mixture at 110 ℃ for 16h under reflux, cooling the reaction solution to room temperature, filtering through celite, concentrating the filtrate under reduced pressure, and separating by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/2) to give 86mg of an off-white solid, yield: and (5) 55.3%. MS (ESI, pos. ion) M/z 582.8[ M +1 ]]⁺。

And step 3: synthesis of the compound N- (6- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) -2, 3-dihydro-1H-inden-1-yl) acetamide

The compound N- (6- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) oxy) -2, 3-dihydro-1H-inden-1-yl) acetamide (86mg,0.15mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, and the mixture was directly spin-dried and sample-stirred, and column chromatography was performed (eluent: dichloromethane/methanol (v/v) ═ 20/1) to give 41mg of a pale yellow solid, yield: 61.4 percent.

MS(ESI,pos.ion)m/z:453.3[M+1]⁺；

¹H NMR(600MHz,MeOH-d₄):δ(ppm)12.24(s,1H),8.26-8.24(m,2H),8.11(s,1H),7.29(d,J＝8.4Hz,1H),7.25(s,1H),7.19(d,J＝7.8Hz,2H),7.09-7.07(m,1H),7.03(s,1H),6.47(dd,J＝7.8,1.8Hz,1H),5.83(t,J＝6.6Hz,1H),5.28(dd,J＝18.2,1.8Hz,1H),3.23(dd,J＝12.6,6.6Hz,1H),2.96-2.89(m,1H),2.84-2.78(m,1H),2.62(t,J＝6.6Hz,2H),2.45-2.40(m,1H),1.86-1.80(m,1H),1.82(s,3H)。

Example 15

3- ((3- (2-phenoxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

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

Under nitrogen protection, compound 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (290mg,0.71mmol), phenol (150mg,1.42mmol), cuprous iodide (200mg,1.07mmol), dimethylglycine (120mg,1.07mmol) and cesium carbonate (560mg,1.78mmol) were mixed, dioxane (15mL) was added, temperature was raised to 120 ℃ for reaction for 18H, the reaction solution was cooled to room temperature, silica gel was added, and column chromatography separation was performed directly spin-dried with stirring (eluent: petroleum ether/ethyl acetate (v/v) ═ 10/1) to give 279mg of a pale yellow solid, yield: 93.1 percent.

MS(ESI,pos.ion)m/z:420.1,422.1[M+1]⁺。

Step 2: synthesis of the compound 3- ((3- (2-phenoxy-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

1, 4-Dioxahexacyclic (10mL) and water (2mL) were added to 7-bromo-2-phenoxy-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] under nitrogen]Pyrazine (162mg,0.39mmol), 3- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile (150mg,0.55mmol), potassium carbonate (120mg,0.86mmol) and Pd (dppf) Cl₂(13mg,0.02mmol) of the mixture was reacted at 110 ℃ under reflux for 14 hours, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 3/1) to give 110mg of a yellow oil, yield: 58.8 percent.

MS(ESI,pos.ion)m/z:486.3[M+1]⁺。

And step 3: synthesis of compound 3- ((3- (2-phenoxy-5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

The compound 3- ((3- (2-phenoxy-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (110mg,0.23mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was carried out at room temperature for 2h, silica gel was added to the reaction solution, and column chromatography was carried out directly with spin-drying and sample-stirring (eluent: dichloromethane/methanol (v/v) ═ 40/1) to give 50mg of a yellow oil, which was then purified with a preparative thin layer to give 35mg of a pale yellow solid, yield: 43.5 percent.

MS(ESI,pos.ion)m/z:356.2[M+1]⁺；

¹H NMR(400MHz,MeOD-d₄):δ(ppm)12.25(s,1H),8.27(s,1H),8.16(s,1H),7.45(t,J＝7.9Hz,2H),7.27-7.17(m,5H),7.04(t,J＝7.8Hz,1H),6.45(dd,J＝8.0,1.5Hz,1H),5.73(t,J＝5.8Hz,1H),3.11(q,J＝6.2Hz,2H),2.60(t,J＝6.3Hz,2H)。

Example 16

3- ((3- (2- ((4-morpholinylphenyl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of compound 3- ((3-bromophenyl) amino) propionitrile

To a solution of m-bromoiodobenzene (4.0g,14.1mmol) in dimethylsulfoxide (40mL), 3-aminopropionitrile (1.5mL,20mmol), cuprous iodide (2.8g,15mmol), cesium carbonate (7.0g,21.5mmol) and N, N-dimethylglycine (1.5g,14mmol) were added in this order, reacted at 70 ℃ for 5 hours, quenched with water (40mL), extracted with dichloromethane (40mL × 3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: PE/v) 2/1) to give 3.0g of a pale yellow oil with a yield of 94%.

MS(ESI,pos.ion)m/z:225.0,227.0[M+1]⁺。

Step 2: synthesis of compound 3- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile

To a solution of 3- ((3-bromophenyl) amino) propionitrile (3.0g,13mmol) in dimethyl sulfoxide (36mL) were added in succession pinacol ester of diboronic acid (5.1g,20mmol), potassium acetate (3.3g,34mmol) and Pd (dppf) Cl₂(950mg,1.28mmol)，N₂The reaction was refluxed at 100 ℃ for 8 hours, quenched with water (40mL), extracted with dichloromethane (40mL × 3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 1.6g yellow oil, yield: 44%.

MS(ESI,pos.ion)m/z:273.0[M+1]⁺。

And step 3: synthesis of the compound 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Under the protection of nitrogen, adding 2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine (603mg,1.33mmol), 3- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile (432mg,1.59mmol), sodium carbonate (335mg,3.98mmol) and Pd (PPh)₃)₂Cl₂(47mg,0.06mmol)To the mixture of (A) and (B) in sequence₃CN (24mL) and H₂O (7mL), reacted at 60 ℃ for 7h, then directly stirred with silica gel and separated by column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 4/1) to give 454mg of a white solid, yield: 85.5 percent.

MS(ESI,pos.ion)m/z:510.5[M+1]⁺。

And 4, step 4: synthesis of the compound 3- ((3- (2- ((4-morpholinylphenyl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

1, 4-dioxane (12mL) was added to a mixture of 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (200mg,0.42mmol), 4-morpholinanilide (91mg,0.51mmol), cesium carbonate (280mg,0.85mmol), palladium acetate (6mg,0.02mmol) and Xantphos (25mg,0.04mmol) under nitrogen, the reaction was refluxed at 110 ℃ for 5H, the reaction was cooled to room temperature, celite was filtered, the filtrate was concentrated under reduced pressure, and separation was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 229mg of a yellow oil, yield: 91.2 percent.

MS(ESI,pos.ion)m/z:569.9[M+1]⁺。

And 5: synthesis of compound 3- ((3- (2- ((4-morpholinophenyl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

The compound 3- ((3- (2- ((4-morpholinylphenyl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (220mg,0.39mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, and column chromatography was performed directly with spin-drying and sample-stirring (eluent: dichloromethane/methanol (v/v) ═ 5/1) to obtain 155mg of a pale yellow solid, yield: 64.8 percent.

MS(ESI,pos.ion)m/z:440.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.77(s,1H),8.99(s,1H),7.97(s,1H),7.90(s,1H),7.73(d,J＝8.9Hz,2H),7.43(d,J＝7.6Hz,1H),7.38(s,1H),7.16(t,J＝7.8Hz,1H),6.94(d,J＝8.9Hz,2H),6.51(d,J＝8.0Hz,1H),5.75(t,J＝6.0Hz,1H),3.82-3.68(m,4H),3.43-3.39(t,J＝6.6Hz,2H),3.09-3.01(m,4H),2.74(t,J＝6.4Hz,2H)。

Example 17

3- ((3- (2- (phenylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of the compound 3- ((3- (2- (phenylamino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Under nitrogen protection, 1, 4-dioxane (10mL) was added to a mixture of 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (350mg,0.67mmol), aniline (100mg,1.00mmol), cesium carbonate (370mg,1.14mmol), palladium acetate (9mg,0.04mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xanthhos) (22mg,0.04mmol), the reaction was refluxed at 110 ℃ overnight, the reaction was cooled to room temperature, celite was filtered, the filtrate was concentrated under reduced pressure, column chromatography was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/2) to give 287mg of a yellow solid, yield: 75.5 percent.

MS(ESI,pos.ion)m/z:484.9[M+1]⁺。

Step 2: synthesis of compound 3- ((3- (2- (phenylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Compound 3- ((3- (2- (phenylamino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) at room temperature]Pyrazin-7-yl) phenyl) amino) propionitrile (270mg,0.45mmol) was dissolved in dichloromethane (6mL), trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7h, the reaction mixture was concentrated under reduced pressure, tetrahydrofuran (6mL) was dissolved in the residue, the reaction was adjusted to basic (pH 9) with ethylenediamine (2mL), the reaction was stirred at room temperature for 1h, water (30mL) was added for dilution, dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatographyChromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/9) gave 125mg of a pale yellow solid, yield: 79.1 percent. MS (ESI, pos. ion) M/z 354.9[ M +1 ]]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.85(s,1H),9.23(s,1H),8.03(d,J＝2.8Hz,1H),7.97(s,1H),7.85(d,J＝7.7Hz,2H),7.44(d,J＝7.6Hz,1H),7.39(s,1H),7.32(t,J＝7.8Hz,2H),7.16(t,J＝7.8Hz,1H),6.90(t,J＝7.3Hz,1H),6.52(d,J＝8.0Hz,1H),5.77(t,J＝6.1Hz,1H),3.42(dd,J＝12.7,6.4Hz,2H),2.74(t,J＝6.5Hz,2H)。

Example 18

3- ((3- (2- ((1-methyl-1H-pyrazol 4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of compound 3- ((3- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Adding 1, 4-dioxane (8mL) into a mixture of 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (250mg,0.45mmol), 1-methyl-1H-pyrazol-4-amine (60mg,0.62mmol), cesium carbonate (240mg,0.74mmol), palladium acetate (6mg,0.026mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) (14mg,0.024mmol) under nitrogen protection, refluxing at 110 ℃ for 7 hours, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, separating by column chromatography (eluent: ethyl acetate), 200mg of a pale yellow oil are obtained, yield: 77.3 percent.

MS(ESI,pos.ion)m/z:489.3[M+1]⁺。

Step 2: synthesis of compound 3- ((3- (2- ((1-methyl-1H-pyrazol 4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

The compound 3- ((3- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (180mg,0.31mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with ethylenediamine (1mL) to pH 9, stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate/methanol (v/v) ═ 1/50) to obtain 85mg of a yellow solid with a yield of 75.7%.

MS(ESI,pos.ion)m/z:359.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.72(s,1H),9.06(s,1H),8.14(s,1H),7.92(d,J＝2.4Hz,1H),7.83(s,1H),7.55(s,1H),7.40(d,J＝7.6Hz,1H),7.37(s,1H),7.19(t,J＝7.8Hz,1H),6.52(d,J＝7.9Hz,1H),5.87(t,J＝6.1Hz,1H),3.85(s,3H),3.41(d,J＝6.3Hz,2H),2.76(t,J＝6.5Hz,2H)。

Example 19

3- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of compound 3- ((4-bromophenyl) amino) propionitrile

To a solution of p-bromoiodobenzene (1.0g,3.53mmol) in dimethylsulfoxide (16mL) was added 3-aminopropionitrile (400. mu.L, 5.32mmol), cesium carbonate (1.7g,5.2mmol), N, N-dimethylglycine (400mg,3.80mmol) and cuprous iodide (675mg,3.54mmol) in this order, reacted at 70 ℃ for 7.5 hours under nitrogen, quenched with water (30mL), extracted with dichloromethane (30mL × 3), dried over anhydrous sodium sulfate, the solvent removed, and the concentrate was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 300mg of a pale yellow solid with a yield: 37.7%. MS (ESI, pos.ion) M/z:225.0,227.0[ M +1 ] (. M + 3/1)]⁺。

Step 2: synthesis of compound 3- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile

To 3- ((4-bromophenyl) aminoTo a solution of 1, 4-dioxane (8mL) of yl) propionitrile (300mg,1.33mmol) were added pinacol diboron (410mg,1.61mmol), potassium acetate (330mg,3.36mmol) and Pd (dppf) Cl in that order₂(100mg,0.14mmol) under nitrogen at 110 ℃ for 24h under reflux, filtered, the filtrate concentrated and the concentrate subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 290mg of a pale yellow oil, yield: 79.93 percent.

MS(ESI,pos.ion)m/z:273.30[M+1]⁺。

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

Under the protection of nitrogen, adding 2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine (650mg,1.43mmol), 3- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) propionitrile (480mg,1.41mmol), sodium carbonate (460mg,4.34mmol) and Pd (PPh)₃)₂Cl₂(50mg,0.07mmol) of the mixture was added CH in sequence₃CN (15mL) and H₂O (5mL), 60 ℃ overnight. Silica gel was added directly to mix the sample and column chromatography was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 5/1) to give 500mg of a white solid, yield: 73.96 percent.

MS(ESI,pos.ion)m/z:472.20,474.20[M+1]⁺。

And 4, step 4: synthesis of compound 1-methyl-1H-pyrazol-4-amine

Pd/C (10%, 500mg) was added to a mixture of 1-methyl-4-nitro-1H-pyrazole (1.90g,14.9mmol) and methanol (25mL), and reacted under hydrogen at room temperature overnight. Celite filtration, washing of the filter cake with dichloromethane, concentration of the filtrate under reduced pressure and column chromatography (eluent: ethyl acetate/methanol (v/v) ═ 18/1) gave 1.35g of a black solid, yield: 83.7 percent.

MS(ESI,pos.ion)m/z:98.1[M+1]⁺。

And 5: synthesis of compound 3- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Adding 1, 4-dioxane (8mL) into a mixture of 3- ((4- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (235mg,0.42mmol), 1-methyl-1H-pyrazol-4-amine (60mg,0.62mmol), cesium carbonate (240mg,0.74mmol), palladium acetate (6mg,0.03mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) (14mg,0.03mmol) under nitrogen protection, refluxing at 110 ℃ overnight, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, separating (eluent: ethyl acetate), 150mg of yellow oil are obtained, yield: 72.6 percent.

MS(ESI,pos.ion)m/z:488.9[M+1]⁺。

Step 6: synthesis of compound 3- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

The compound 3- ((4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (150mg,0.25mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with ethylenediamine (1mL) to pH 9, stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate/methanol (v/v) ═ 20/1) to obtain 55mg of a yellow solid with a yield of 62.5%.

MS(ESI,pos.ion)m/z:359.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.56(d,J＝1.9Hz,1H),9.04(s,1H),8.08(s,1H),7.92(d,J＝8.5Hz,2H),7.81(s,2H),7.59(s,1H),6.74(d,J＝8.6Hz,2H),5.87(t,J＝6.2Hz,1H),3.87(s,3H),3.40(q,J＝6.4Hz,2H),2.76(t,J＝6.5Hz,2H)。

Example 20

3- ((3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of the compound 3- ((3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Adding 1, 4-dioxane (6mL) into a mixture of 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (250mg,0.53mmol), 5-methyl-1H-pyrazol-3-amine (70mg,0.72mmol), cesium carbonate (250mg,0.77mmol), palladium acetate (9mg,0.04mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos) (22mg,0.04mmol) under nitrogen protection, refluxing at 110 ℃ overnight, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and isolating (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/2), 80mg of a pale yellow solid are obtained, yield: 26.3 percent.

MS(ESI,pos.ion)m/z:488.9[M+1]⁺。

Step 2: synthesis of compound 3- ((3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

The compound 3- ((3- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (70mg,0.11mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 7H, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made basic with ethylenediamine (1mL) to pH 9, stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate) to give 20mg of a yellow solid, yield: 48.7%.

MS(ESI,pos.ion)m/z:359.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.80(s,1H),11.75(s,1H),9.29(s,1H),8.16(s,1H),7.98(d,J＝2.9Hz,1H),7.45(d,J＝7.5Hz,1H),7.35(s,1H),7.15(t,J＝7.8Hz,1H),6.56-6.45(m,2H),5.78(t,J＝6.1Hz,1H),3.42(dd,J＝12.7,6.4Hz,2H),2.76(t,J＝6.5Hz,2H),2.25(s,3H)。

Example 21

3- ((3- (2- (benzylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of the compound 3- ((3- (2- (benzylamino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Dioxane (10mL) was added to a mixture of benzylamine (52mg,0.49mmol), 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (180mg,0.38mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (23mg,0.04mmol), palladium acetate (4mg,0.02mmol) and cesium carbonate (225mg,0.69mmol) under nitrogen, reacted at 100 ℃ for 6H, silica gel was added to the reaction solution, and the reaction solution was directly spin-dried and stirred to give 80mg of pale yellow oil, yield: 42.1 percent.

MS(ESI,pos.ion)m/z:499.2[M+1]⁺。

Step 2: synthesis of Compound 3- ((3- (2- (benzylamino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

The compound 3- ((3- (2- (benzylamino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (80mg,0.16mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, and the mixture was directly spin-dried and sample-stirred and subjected to column chromatography (eluent: dichloromethane/methanol (v/v) ═ 60/1) to give 37mg of a pale yellow solid, yield: 62.6 percent.

MS(ESI,pos.ion)m/z:368.9[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.58(d,J＝2.7Hz,1H),7.90(d,J＝3.0Hz,1H),7.73(s,1H),7.48(d,J＝1.8Hz,1H),7.44(s,1H),7.43(s,1H),7.37-7.30(m,3H),7.22(t,J＝7.3Hz,1H),7.15(t,J＝5.8Hz,1H),7.07(t,J＝7.8Hz,1H),6.44(dd,J＝8.0,1.6Hz,1H),5.72(t,J＝6.2Hz,1H),4.60(d,J＝5.9Hz,2H),3.36-3.26(m,2H),2.69(t,J＝6.5Hz,2H)。

Example 22

3- ((3- (2- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of compound 3- ((3- (2- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

DMF (17mL) was added to 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b) under nitrogen]Pyrazin-7-yl) phenyl) amino) propionitrile (218mg,0.46mmol), 4-ethynyl-1-methyl-1H-pyrazole (73mg,0.69mmol), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (202mg,1.31mmol), bis (triphenylphosphine) palladium dichloride (16mg,0.02mmol) and cuprous iodide (24mg,0.13mmol) were mixed, heated to 80 ℃ for reaction for 6h, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50mL × 3), and extracted with anhydrous Na₂SO₄Drying, removal of the solvent and column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1) gave 260mg of a pale yellow solid, yield: 92.2 percent.

MS(ESI,pos.ion)m/z:497.9[M+1]⁺。

Step 2: synthesis of compound 3- ((3- (2- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Compound 3- ((3- (2- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (257mg,0.52mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, the mixture was spin-dried and sample-stirred, and column chromatography was performed (eluent: dichloromethane/methanol (v/v) ═ 30/1) to give 125mg of a pale yellow solid, yield: 65.9 percent.

MS(ESI,pos.ion)m/z:367.9[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.40(s,1H),8.45(s,1H),8.39(s,1H),8.18(s,1H),7.80(s,1H),7.44(d,J＝7.6Hz,1H),7.40(s,1H),7.18(t,J＝7.8Hz,1H),6.54(d,J＝8.0Hz,1H),5.97(t,J＝6.0Hz,1H),3.90(s,3H),3.42(dd,J＝12.8,6.4Hz,2H),2.79(t,J＝6.6Hz,2H)。

Example 23

N- (2- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) methanesulfonamide

Step 1: synthesis of compound N- (2-aminophenyl) methanesulfonamide

O-phenylenediamine (228mg,2.10mmol), triethylamine (0.49mL,3.49mmol) and DMAP (43mg,0.35mmol) were mixed at room temperature, DCM (10.00mL) and methanesulfonyl chloride (200mg,1.75mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours, extracted with ethyl acetate (100mL × 3), and extracted with anhydrous Na₂SO₄Drying, removal of solvent and column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) gave 175mg of a grey solid, yield: 53.2 percent.

MS(ESI,pos.ion)m/z:187.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)8.68(s,1H),7.05(d,J＝7.8Hz,1H),7.02-6.93(m,1H),6.77-6.70(m,1H),6.60-6.48(m,1H),5.09(s,2H),2.90(s,3H)。

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

Adding 1, 4-dioxane (10mL) into a mixture of N- (2-aminophenyl) methanesulfonamide (74mg,0.40mmol), 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (150mg,0.32mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (18mg,0.03mmol), palladium acetate (4mg,0.02mmol) and cesium carbonate (210mg,0.65mmol) under nitrogen protection, refluxing at 110 ℃ for 6H, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and performing column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1), 100mg of a yellow solid are obtained, yield: 54.5 percent.

MS(ESI,pos.ion)m/z:578.3[M+1]⁺。

And step 3: synthesis of the compound N- (2- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) methanesulfonamide

The compound N- (2- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) methanesulfonamide (100mg,0.17mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was carried out at room temperature for 2h, silica gel was added to the reaction solution, spin-dried, and sample-stirred, and column chromatography was carried out (eluent: dichloromethane/methanol (v/v) ═ 30/1) to give 35mg of a brown oil, which was then purified with a preparative thin layer to give 10mg of a yellow solid, yield: 12.9 percent.

MS(ESI,pos.ion)m/z:448.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.92(s,1H),8.98(s,1H),8.43(s,1H),8.20(d,J＝8.2Hz,1H),8.07(d,J＝2.6Hz,1H),8.07(s,1H),7.39-7.33(m,3H),7.32-7.27(m,1H),7.11(t,J＝7.8Hz,1H),7.07-7.02(m,1H),6.50(dd,J＝8.0,1.6Hz,1H),5.76(t,J＝6.1Hz,1H),2.94(s,2H),2.68(t,J＝6.4Hz,2H),0.86(t,J＝7.0Hz,2H)。

Example 24

N- (3- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) methanesulfonamide

Step 1: synthesis of compound N- (3-aminophenyl) -N- (methylsulfonyl) methanesulfonamide

At room temperature, m-nitroaniline (200mg,1.45mmol), triethylamine (0.42mL,3.06mmol) and DMAP (38mg,0.29mmol) were mixed, DCM (10.00mL) and methylsulfonyl chloride (260mg,2.26mmol) were added in that order, and the mixture was stirred at room temperature for 12h, diluted with water (30mL), extracted with ethyl acetate (30mL × 3), and purified with anhydrous Na₂SO₄Drying and removal of the solvent gave 200mg of a pale yellow solid, iron powder (150mg,2.68mmol), ammonium chloride (225mg,4.25mmol), water (2.00mL) and ethanol (10.00mL) were added, the temperature was raised to 90 ℃ and stirred for 4h, the reaction solution was cooled to room temperature, silica gel was added, spin-dried and sample-stirred, and column chromatography was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1) to give 86mg of a white solid, yield: 22.4 percent.

MS(ESI,pos.ion)m/z:264.9[M+1]⁺。

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

Adding 1, 4-dioxane (10mL) into a mixture of N- (3-aminophenyl) -N- (methylsulfonyl) methanesulfonamide (86mg,0.38mmol), 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (180mg,0.38mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (23mg,0.04mmol), palladium acetate (5mg,0.02mmol) and cesium carbonate (250mg,0.77mmol) under nitrogen protection, refluxing at 110 ℃ for 6H, cooling the reaction solution to room temperature, filtering with celite, concentrating the filtrate under reduced pressure, and separating (eluent: petroleum ether/ethyl acetate (v/v) ═ 1/1), 200mg of a yellow solid are obtained, yield: 65.9 percent.

MS(ESI,pos.ion)m/z:577.8[M+1]⁺。

And step 3: synthesis of the compound N- (3- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) methanesulfonamide

The compound N- (3- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) phenyl) methanesulfonamide (200mg,0.35mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, the mixture was spin-dried and sample-stirred, and column chromatography was performed (eluent: dichloromethane/methanol (v/v) ═ 20/1) to give 61mg of a pale yellow solid, yield: 39.4 percent.

MS(ESI,pos.ion)m/z:447.8[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.87(s,1H),9.63(s,1H),9.32(s,1H),8.04(d,J＝2.8Hz,1H),7.98(s,1H),7.95(d,J＝8.1Hz,1H),7.45(d,J＝7.5Hz,1H),7.39(s,1H),7.35(s,1H),7.27(t,J＝8.1Hz,1H),7.17(t,J＝7.8Hz,1H),6.76(d,J＝7.3Hz,1H),6.52(dd,J＝7.9,1.1Hz,1H),5.76(t,J＝6.1Hz,1H),3.41(dd,J＝12.7,6.4Hz,2H),2.98(s,3H),2.74(t,J＝6.5Hz,2H)。

Example 25

4- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) benzonitrile

Step 1: synthesis of the compound 4- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) benzonitrile

Under nitrogen protection, 1, 4-dioxane (10mL) was added to a mixture of p-aminobenzonitrile (53mg,0.43mmol), 3- ((3- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (160mg,0.34mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (23mg,0.04mmol), palladium acetate (4mg,0.02mmol) and cesium carbonate (210mg,0.65mmol), the reaction was refluxed at 110 ℃ for 6H, the reaction solution was cooled to room temperature, celite was filtered, the filtrate was concentrated under reduced pressure, column chromatography was performed (eluent: petroleum ether/ethyl acetate (v/v) ═ 2/1) to give 153mg of a pale yellow oil, yield: 88.6 percent.

MS(ESI,pos.ion)m/z:510.2[M+1]⁺。

Step 2: synthesis of compound 4- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) benzonitrile

The compound 4- ((7- (3- ((2-cyanoethyl) amino) phenyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) benzonitrile (153mg,0.30mmol) was dissolved in dichloromethane (6mL) at room temperature, trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, and the mixture was directly spin-dried and sample-stirred and subjected to column chromatography (eluent: dichloromethane/methanol (v/v) ═ 40/1) to give 90mg of a pale yellow solid, yield: 81.7 percent.

MS(ESI,pos.ion)m/z:380.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.04(d,J＝2.6Hz,1H),9.88(s,1H),8.13(d,J＝2.9Hz,1H),8.05(s,1H),7.99(d,J＝8.8Hz,2H),7.73(d,J＝8.9Hz,2H),7.41(d,J＝7.8Hz,1H),7.35(d,J＝1.7Hz,1H),7.21(t,J＝7.8Hz,1H),6.54(dd,J＝8.0,1.7Hz,1H),5.85(t,J＝6.1Hz,1H),3.43(q,J＝6.4Hz,2H),2.76(t,J＝6.5Hz,2H)。

Example 26

4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenol

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

Acetonitrile (12mL) and water (3mL) were added to a mixture of 2-bromo-7-iodo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (330mg,0.73mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (242mg,1.09mmol), sodium carbonate (193mg,1.83mmol), and bis triphenylphosphine palladium dichloride (26mg,0.04mmol) under nitrogen, after 12 hours of reaction at 60 ℃, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (eluent: petroleum ether/ethyl acetate (v/v) ═ 5/1) to give 265mg of a yellow oil, yield: 86.8 percent.

MS(ESI,pos.ion)m/z:419.8[M+1]⁺。

Step 2: synthesis of the compound 4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenol

Under nitrogen protection, 1, 4-dioxane (12mL) was added to a mixture of 4- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenol (265mg,0.63mmol), 1-methyl-1H-pyrazol-4-amine (160mg,1.58mmol), cesium carbonate (615mg,1.89mmol), palladium acetate (8mg,0.03mmol) and Xantphos (36mg,0.06mmol), the reaction was refluxed at 110 ℃ for 5H, the reaction was cooled to room temperature, celite was filtered, the filtrate was concentrated under reduced pressure, and column chromatography was performed (eluent: ethyl acetate) to give 111mg of a dark yellow solid, yield: 40.3 percent.

MS(ESI,pos.ion)m/z:437.2[M+1]⁺。

And step 3: synthesis of compound 4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenol

The compound 4- (2- ((1-methyl-1H-pyrazol-4-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] at room temperature]Pyrazin-7-yl) phenol (121mg,0.28mmol) was dissolved in dichloromethane (6mL), trifluoroacetic acid (6mL) was added, and the reaction was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, dichloromethane (6mL) and ethylenediamine (1mL) were added, stirring was performed at room temperature for 2 hours, silica gel was added to the reaction solution, the mixture was spin-dried and sample-stirred, and column chromatography was performed (eluent: dichloromethane/methanol (v/v) ═ 10/1) to give 55mg of a pale yellow solid, yield: 64.8 percent. MS (ESI, pos.ion) M/z 307.2[ M +1 ]]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)11.62(s,1H),9.30(s,1H),9.06(s,1H),8.07(s,1H),7.96(d,J＝8.0Hz,1H),7.85(s,1H),7.82(s,1H),7.57(s,1H),6.86(d,J＝8.0Hz,2H),3.85(s,2H)。

Example 27

3- ((4- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of compound 3- ((4- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Compound 3- ((4- (2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) phenyl) amino) propionitrile (220mg,0.46mmol), 3-amino-5-methyl-1H-pyrazole (100mg,1.03mmol), caesium carbonate (360mg,1.10mmol), Xantphos (25mg,0.04mmol) and palladium acetate (10mg,0.04mmol) were mixed, N₂Adding 1, 4-dioxane (8mL) under protection, heating to 110 deg.C, stirring, reacting for 8 hr, cooling the reaction solution to room temperature, filtering with diatomaceous earth, concentrating the filtrate under reduced pressure, and performing column chromatography (eluent: ethyl acetate) to obtain 80mg yellow oil, yield: 35.15 percent.

MS(ESI,pos.ion)m/z:489.30[M+1]⁺。

Step 2: synthesis of compound 3- ((4- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Compound 3- ((4- (2- ((5-methyl-1H-pyrazol-3-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile (80mg,0.16mmol) was dissolved in dichloromethane (6mL,93.3mmol), trifluoroacetic acid (2mL,25.8mmol) was added, the reaction was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (6mL), made alkaline (pH 9) with ethylenediamine (1mL), the reaction was stirred at room temperature for 1H, diluted with water (30mL), dichloromethane (30mL × 3) was extracted, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by concentration, and the residue was subjected to column chromatography (eluent: ethyl acetate/methanol (v/v) ═ 20/1) to give 23mg of a yellow solid with a yield of 39.2%.

MS(ESI,pos.ion)m/z:359.00[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆+D₂O):δ(ppm)8.77(s,1H),8.13(s,1H),7.73(d,J＝8.6Hz,2H),6.72(d,J＝8.7Hz,2H),5.35(s,1H),3.38(t,J＝6.5Hz,2H),2.74(t,J＝6.5Hz,2H),2.13(s,3H)。

Example 28

3- ((3- (2- (methyl (3-methyl-1H-pyrazol-5-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

Step 1: synthesis of Compound 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester

To a solution of compound 3-methyl-1H-pyrazol-5-amine (1.73g,17.8mmol) in THF (35mL) under ice-bath was added NaH (60%, 930mg,23.25mmol), stirred at room temperature for 0.5H, and added (BOC)₂O (4.51mL,19.6mmol), stirred at room temperature for 5 hours, diluted with water (30mL), extracted with dichloromethane (30mL × 3), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 510mg of a pale yellow solid in 14.5% yield.

MS(ESI,pos.ion)m/z:142.2[M-55]⁺。

Step 2: synthesis of compound tert-butyl 5- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) -3-methyl-1H-pyrazole-1-carboxylate

To a mixture of the compound 2, 7-dibromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (50mg,0.12mmol), 5-amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (28mg,0.13mmol), Xantphos (15mg,0.02mmol), cesium carbonate (60mg,0.18mmol) and palladium acetate (3mg,0.01mmol) was added 1, 4-dioxane (5mL), nitrogen protected, refluxed at 110 ℃ for 5.5H, diluted with water (15mL), dichloromethane (20mL × 3) extracted, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 40mg of a yellow solid with a yield of 62.22%.

MS(ESI,pos.ion)m/z:524.8[M+1]⁺。

And step 3: synthesis of compound tert-butyl 5- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) (methyl) amino) -3-methyl-1H-pyrazole-1-carboxylate

To a solution of compound 5- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) amino) -3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (150mg,0.28mmol) in THF (8mL) under ice-bath was added NaH (60%, 20mg,0.50mmol), stirred at room temperature for 0.5H, iodomethane (25 μ L,0.40mmol) was added, stirring at room temperature was continued overnight, quenched with water (30mL), extracted with dichloromethane (30mL × 3), dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography (eluent: PE/v) ═ 3/1) to give 130mg of a yellow oil, yield: EtOAc 84.41%.

MS(ESI,pos.ion)m/z:539.30[M+1]⁺。

And 4, step 4: synthesis of compound 3- ((3- (2- (methyl (3-methyl-1H-pyrazol-5-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrazolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

To the compound 5- ((7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) (methyl) amino) -3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (130mg,0.24mmol) in 1, 4-dioxane (6mL) was added 3- (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) anilino) propionitrile (90mg,0.33mmol), potassium carbonate (50mg,0.36mmol), Pd (dppf) Cl₂(20mg,0.03mmol) and water (1.5mL) under nitrogen at 110 deg.C for 6h under reflux, diluted with water (40mL), extracted with dichloromethane (55mL × 3), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 75mg of an off-white solid in 61.69% yield.

MS(ESI,pos.ion)m/z:503.40[M+1]⁺。

And 5: synthesis of compound 3- ((3- (2- (methyl (3-methyl-1H-pyrazol-5-yl) amino) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) phenyl) amino) propionitrile

To the compound 3- ((3- (2- (methyl (3-methyl-1H-pyrazol-5-yl) amino) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrazolo [2, 3-b)]Pyrazin-7-yl) phenyl) amino) propionitrile (75mg,0.15mmol) of CH₂Cl₂To the solution (6mL) was added TFA (2mL), stirred overnight at room temperature, the solvent was concentrated, dissolved in tetrahydrofuran (6mL), neutralized with ethylenediamine to pH>7, stirred at room temperature for 3 hours, diluted with water (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (eluent: EtOAc) to give 31mg of a yellow solid in 55.80% yield.

MS(ESI,pos.ion)m/z:373.00[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.12(s,1H),11.83(s,1H),8.22(d,J＝28.3Hz,1H),8.08(d,J＝2.4Hz,1H),7.58(d,J＝28.3Hz,1H),7.39(d,J＝7.6Hz,1H),7.11(m,1H),6.49(d,J＝7.9Hz,1H),6.03(d,J＝14.3Hz,1H),5.87(t,J＝6.1Hz,1H),3.50(d,J＝14.8Hz,3H),3.43(dd,J＝12.8,6.4Hz,2H),2.76(dd,J＝17.9,11.3Hz,2H),2.23(d,J＝26.3Hz,3H)。

Example 29

N- (2-cyanoethyl) -3- (2- (cyclopropylcarbonyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

Step 1: synthesis of compound 5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine-2-carbonitrile

To a solution of 2-bromo-5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine (2.0g,5.7mmol) in DMF (20mL) were added zinc cyanide (1.0g,8.5mmol) and tetrakis (triphenylphosphine) palladium (2.0g,1.7mmol) in that order, displaced with nitrogen, reacted at 100 ℃ for 6 hours, filtered through celite, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give 1.7g of a pale yellow solid, yield: 100 percent.

MS(ESI,pos.ion)m/z:299.2[M+1]⁺。

Step 2: synthesis of cyclopropyl (5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazin-2-yl) methanone compound

To a solution of the compound 5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazine-2-carbonitrile (1.7g,5.7mmol) in anhydrous THF (30mL) at-20 ℃ was added cyclopropylmagnesium bromide (7.5mL,7.5mmol), allowed to warm to room temperature, followed by stirring for 12 hours, addition of a saturated ammonium chloride solution (30mL) for dilution, extraction with dichloromethane (30mL × 3), drying over anhydrous sodium sulfate, concentration, and column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give 1.7g of a pale yellow oil with a yield of 87.2%.

MS(ESI,pos.ion)m/z:342.3[M+1]⁺。

And step 3: synthesis of compound cyclopropyl (5H-pyrrolo [2,3-b ] pyrazin-2-yl) methanone

To a solution of cyclopropyl (5-p-toluenesulfonyl-5H-pyrrolo [2,3-b ] pyrazin-2-yl) methanone (2.2g,5.2mmol) in methanol (30mL) at room temperature was added potassium hydroxide (870mg,15.51mmol), reacted at 50 ℃ for 1 hour, directly added silica gel and stirred, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 840mg of a brown solid, yield: 87 percent.

MS(ESI,pos.ion)m/z:188.3[M+1]⁺。

And 4, step 4: synthesis of compound (7-bromo-5H-pyrrolo [2,3-b ] pyrazin-2-yl) (cyclopropyl) methanone

To a solution of cyclopropyl (5H-pyrrolo [2,3-b ] pyrazin-2-yl) methanone (400mg,2.14mmol) in acetone (10mL) was added N-bromosuccinimide (570mg,3.20mmol), stirred at room temperature for 1 hour, the solvent was concentrated, diluted with water (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 600mg of a brown solid with a yield of 100%.

MS(ESI,pos.ion)m/z:266.2,268.1[M+1]⁺。

And 5: synthesis of compound (7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) (cyclopropyl) methanone

To a solution of compound (7-bromo-5H-pyrrolo [2,3-b ] pyrazin-2-yl) (cyclopropyl) methanone (600mg,2.25mmol) in THF (12mL) under ice bath was added sodium hydride (60% in oil,140mg,3.50mmol), and after stirring at this temperature for 1 hour, SEMCl (600 μ L,3.39mmol) was added, allowed to spontaneously rise to room temperature for 12 hours, and then saturated ammonium chloride solution (30mL) was added for dilution, dichloromethane (30mL × 3) was extracted, dried over anhydrous sodium sulfate, concentrated, and column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) gave 420mg of a yellow oil with a yield of 47%.

MS(ESI,pos.ion)m/z:396.2,398.3[M+1]⁺。

Step 6: synthesis of the compound N- (2-cyanoethyl) -3- (2- (cyclopropylcarbonyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

To the compound (7-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b)]To a solution of pyrazin-2-yl) (cyclopropyl) methanone (420mg,1.06mmol) in 1, 4-dioxane (8mL) was added potassium carbonate (220mg,1.59mmol), N- (2-cyanoethyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaboropan-2-yl) benzenesulfonamide (520mg,1.55mmol), Pd (dppf) Cl₂(80mg,0.11mmol) and water (2mL), replaced with nitrogen, reacted at 110 ℃ under reflux for 5 hours, diluted with water (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 70mg of a pale yellow oil, yield: 12.57%.

MS(ESI,pos.ion)m/z:526.2[M+1]⁺。

And 7: synthesis of compound N- (2-cyanoethyl) -3- (2- (cyclopropylcarbonyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

To a solution of the compound N- (2-cyanoethyl) -3- (2- (cyclopropylcarbonyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide (70mg,0.13mmol) in dichloromethane (6mL) was added trifluoroacetic acid (2mL), stirred at room temperature for 12 hours, concentrated directly, dissolved by addition of THF (6mL), ethylenediamine adjusted to pH >7, stirred at room temperature for 2 hours, diluted with water (20mL), dichloromethane (20mL × 3) extracted, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 23mg of a red-brown solid in 43.68% yield.

MS(ESI,pos.ion)m/z:396.30[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.92(s,1H),9.00(s,1H),8.94(s,1H),8.78(s,1H),8.48(m,1H),8.06(t,J＝5.9Hz,1H),7.72(m,2H),3.07(m,2H),2.65(m,2H),1.17(m,5H)。

Example 30

N- (2-cyanoethyl) -3- (2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

Step 1: synthesis of compound cyclopropyl (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) methanone

To a solution of the compound 5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine-2-carbonitrile (1.6g,5.8mmol) in THF (20mL) at-20 ℃ was added cyclopropyl magnesium bromide (1.0M,10mL,10mmol), allowed to spontaneously warm to room temperature, followed by further reaction for 12 hours, dilution with saturated ammonium chloride solution (30mL), extraction with dichloromethane (30mL × 3), drying over anhydrous sodium sulfate, concentration, column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give 1.4g of a pale yellow solid in 76% yield.

MS(ESI,pos.ion)m/z:318.1[M+1]⁺。

Step 2: synthesis of compound 1-cyclopropyl-1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) -2,2, 2-trifluoroethanol

To a solution of cyclopropyl (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) methanone (270mg,0.85mmol) in THF (10mL) was added trifluoromethyl trimethylsilyl (250 μ L,1.70mmol) and a THF solution of tetrabutylammonium fluoride (1.0M,1.3mL,1.3mmol) under ice-bath, stirred at room temperature for 11 hours, diluted with a saturated ammonium chloride solution (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give 220mg of a pale yellow oil in 66.76% yield.

MS(ESI,pos.ion)m/z:388.20[M+1]⁺。

And step 3: synthesis of compound 1-cyclopropyl-1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) -2,2, 2-trifluoroethanol

To the compound 1-cyclopropyl-1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]pyrazin-2-yl) -2,2, 2-trifluoroethanol (900mg,2.32mmol) in CH₂Cl₂Trifluoroacetic acid (3.5mL,47mmol) was added to the solution (10mL), stirred at room temperature for 2.5 hours, the solvent was concentrated, dissolved in THF (6mL), and ethylenediamine was added to adjust the pH>7, stirred at room temperature for 2 hours, diluted with saturated ammonium chloride solution (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 450mg of a pale yellow oil, yield: 75.33%.

MS(ESI,pos.ion)m/z:258.1[M+1]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)9.20(s,1H),8.67(s,1H),7.77-7.70(m,1H),6.79(dd,J＝3.6,1.9Hz,1H),5.80(s,1H),1.72-1.62(m,1H),1.05(td,J＝10.2,5.0Hz,1H),0.75-0.63(m,1H),0.38-0.24(m,2H)。

And 4, step 4: synthesis of compound 2- (1-chloro-1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazine

To a solution of the compound 1-cyclopropyl-1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) -2,2, 2-trifluoroethanol (450mg,1.75mmol) in dichloromethane (10mL) was added triethylamine (0.5mL,4mmol) and thionyl chloride (450 μ L,6.20mmol) under water bath, stirred at room temperature for 4 hours, diluted with saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 300mg of a white solid in 62.21% yield.

MS(ESI,pos.ion)m/z:276.2[M+1]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)8.95(s,1H),8.84(s,1H),7.71-7.68(m,1H),6.84(dd,J＝3.7,1.9Hz,1H),2.34-2.25(m,1H),1.07-0.98(m,1H),0.88-0.78(m,1H),0.77-0.67(m,1H),0.61(td,J＝10.8,5.3Hz,1H)。

And 5: synthesis of compound 2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazine

To the compound 2- (1-chloro-1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b]Pyrazine (300mg,1.09mmol) in MeOH (6mL) with Pd (OH) added₂(20%, 30mg) was reacted under a hydrogen atmosphere for 1 hour, and passed through celiteFiltration, concentration and column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) gave 130mg of a light yellow solid, yield: 49.5 percent.

MS(ESI,pos.ion)m/z:242.3[M+1]⁺；

¹H NMR(400MHz,CDCl₃):δ(ppm)8.92(s,1H),8.33(s,1H),7.70-7.62(m,1H),6.79(dd,J＝3.7,1.9Hz,1H),2.89(dq,J＝18.1,9.0Hz,1H),1.66-1.59(m,1H),0.93-0.82(m,1H),0.69-0.52(m,2H),0.25-0.17(m,1H)。

Step 6: synthesis of compound 7-bromo-2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazine

To a solution of the compound 2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazine (130mg,0.54mmol) in acetone (8mL) was added N-bromosuccinimide (148mg,0.83mmol) at room temperature, stirred at room temperature for 1 hour, diluted with water (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, and concentrated to give 190mg of crude product as a pale yellow solid in 99% yield.

MS(ESI,pos.ion)m/z:320.2,322.2[M+1]⁺。

And 7: synthesis of compound 7-bromo-2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine

To a solution of the compound 7-bromo-2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazine (200mg,0.62mmol) in THF (8mL) under ice-water bath was added sodium hydride (60% in oil,40mg,1.0mmol), stirred at room temperature for 1 hour, added SEMCl (170 μ L,0.961mmol), stirred at room temperature for 12 hours, diluted with a saturated ammonium chloride solution (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give 150mg of a pale yellow oil with a yield: 53.3%.

MS(ESI,pos.ion)m/z:450.3,452.3[M+1]⁺。

And 8: synthesis of the compound N- (2-cyanoethyl) -3- (2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

To the compound 7-bromo at room temperature-2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine (150mg,0.33mmol) in 1, 4-Ring dioxide (6mL) was added N- (2-cyanoethyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide (170mg,0.51mmol), potassium carbonate (70mg,0.51mmol), Pd (dppf) Cl₂(30mg,0.04mmol) and water (1.5mL), nitrogen displacement, reaction at 110 ℃ for 6 hours, dilution with water (20mL), extraction with dichloromethane (20mL × 3), drying over anhydrous sodium sulfate, concentration, column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 130mg of a pale yellow oil, yield: 67.34%. MS (ESI, pos.ion) M/z:580.50[ M +1 ]/(2/1)]⁺。

And step 9: synthesis of compound N- (2-cyanoethyl) -3- (2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide

Trifluoroacetic acid (2mL) was added to a solution of the compound N- (2-cyanoethyl) -3- (2- (1-cyclopropyl-2, 2, 2-trifluoroethyl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) benzenesulfonamide (130mg,0.22mmol) in dichloromethane (6mL) at room temperature, stirred at room temperature for 12 hours, directly concentrated, dissolved with THF (6mL), ethylenediamine adjusted to pH >7, stirred at room temperature for 2 hours, diluted with water (20mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated, and isolated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 52mg of a white solid with a yield of 51.6%.

MS(ESI,pos.ion)m/z:450.40[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆+D₂O):δ(ppm)8.81(s,1H),8.54(s,1H),8.43-8.39(m,1H),8.37(s,1H),7.68-7.63(m,2H),3.38-3.29(m,1H),3.05(t,J＝6.4Hz,2H),2.63(t,J＝6.4Hz,2H),1.66-1.56(m,1H),0.80-0.72(m,1H),0.61(td,J＝9.6,4.8Hz,1H),0.50-0.41(m,1H),0.22(td,J＝9.8,4.8Hz,1H)。

By a similar synthetic method to the examples of the invention, the compounds shown in table 1 were prepared:

table 1 Structure and MS data for Compounds

Biological activity

Biological example 1 JAK1/2/3 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；10mM MgCl₂；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 JAK 3(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 for detection, 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 JAK 3(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 Compound vs JAK1/2/3 enzyme IC₅₀Detection 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, and each sample was tested for the inhibitory effect of the compound on JAK1/2/3 enzyme at 8 concentrations in duplicate wells, with the enzyme and substrate reaction well as the positive control, and the enzyme-free well (kinase reaction solution) as the negative control. After adding corresponding samples, buffer solution and enzyme into each hole in sequence according to the table 3, incubating in a constant temperature box at 25 ℃ (RT) for 10min, adding prepared Peptide solution into each hole, incubating at the constant temperature of 28 ℃ for 60min, adding reaction termination solution, detecting by using a Caliper EZ Reader at the excitation wavelength of FP485 nM/525 nM, and reading data as 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.

Enzyme (JAK1/2/3) inhibition data for the compounds of Table 4

The data in Table 4 show that the compound has stronger inhibition effect on JAK1, JAK2 and JAK3 kinases. The examples in table 4 are typical of the compounds of the present invention, and other compounds of the present invention also have strong inhibitory effects on JAK1, JAK2 and JAK3 kinases.

It will be evident to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.

Claims

1. A compound, which is a compound represented by formula (II) or a pharmaceutically acceptable salt of a compound represented by formula (II):

wherein:

ring a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl or pyrazolyl;

ring B is phenyl;

X²is-C (═ O) -or-N (R)⁴)-；

Each R²Independently of one another hydrogen, cyano, C_1-4Alkyl, hydroxy substituted C_1-4Alkyl or morpholinyl;

each R³Independently is R¹⁰R¹¹N-or R¹⁰R¹¹N-S(＝O)₂-；

Each R⁴Independently is hydrogen or C_1-4An alkyl group;

each R¹⁰Independently hydrogen or deuterium;

each R¹¹Independently cyanoethyl;

each p and q is independently 1.

2. The compound of claim 1, wherein each R⁴Independently hydrogen, methyl, ethyl, propyl or butyl.

3. The compound of claim 1, each R²Is hydrogen, cyano, methyl, ethyl, propyl, HO-CH₂-、HO-CH₂-CH₂-、HO-CH₂-CH₂-CH₂-or morpholinyl;

each R³Is CN-CH₂CH₂-NH-or CN-CH₂CH₂-NH-S(＝O)₂-。

4. A compound which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:

5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5, further comprising an additional therapeutic agent selected from the group consisting of antiproliferatives, anti-inflammatories, immunomodulators, neurotrophic factors, agents for treating cardiovascular disease, and agents for treating diabetes.

7. Use of a compound of any one of claims 1-4 or a pharmaceutical composition of any one of claims 5-6 in the manufacture of a medicament for preventing, treating, or ameliorating an autoimmune disease or a proliferative disease in a patient;

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

wherein the proliferative disease is 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.

8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 6 for the preparation of a medicament for inhibiting or modulating protein kinase activity; wherein the protein kinase is JAK1, JAK2 or JAK 3.