WO2015039613A1 - 抑制btk和/或jak3激酶活性的化合物 - Google Patents

抑制btk和/或jak3激酶活性的化合物 Download PDF

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WO2015039613A1
WO2015039613A1 PCT/CN2014/086821 CN2014086821W WO2015039613A1 WO 2015039613 A1 WO2015039613 A1 WO 2015039613A1 CN 2014086821 W CN2014086821 W CN 2014086821W WO 2015039613 A1 WO2015039613 A1 WO 2015039613A1
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aliphatic
aliphatic hydrocarbon
amino
hydrocarbon group
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French (fr)
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刘金明
车美英
李功
李占梅
张烜
金孟燮
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Beijing Hanmi Pharmaceutical Co Ltd
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Beijing Hanmi Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compound which inhibits BTK (Bluton tyrosine kinase) and/or JAK3 (Janus tyrosine kinase 3) kinase activity, a pharmaceutical composition thereof, its use in pharmacy, use thereof to inhibit BTK and/or A method of JAK3 activity and a method of using the same for treating and/or preventing a BTK and/or JAK3 mediated disease or condition in a mammal, particularly a human.
  • BTK Bluton tyrosine kinase
  • JAK3 Japanese tyrosine kinase 3
  • Protein kinases are one of the largest families of human enzymes, and more than 500 have been identified in humans to date. They regulate complex signaling pathways by modulating the activity of specific proteins by transferring phosphate groups to proteins. Abnormal protein kinase activity is associated with many diseases such as cancer and autoimmune diseases. In view of the key role of protein kinases in signaling pathways and the correlation of kinase activity with various diseases, kinase inhibitors have become a hot trend in the development of small molecule chemical drugs.
  • BTK Boton tyrosine kinase
  • BCR B cell receptor
  • BTK inhibitors in the treatment of autoimmune diseases has been initially validated in preclinical animal models (Honigberg, LA et al, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107, 13075-13080) .
  • BTK also plays a role in signaling pathways in monocytes, macrophages, neutrophils and mast cells.
  • BTK inhibitors can inhibit cytokine release by Fc ⁇ R in monocytes and macrophages, including TNFa, IL-1 ⁇ and IL-6, and also inhibit granule degranulation mediated by Fc ⁇ R (Chang BY) Et al, Arthritis Research & Therapy, 2011, 13, R115).
  • BCR B cell receptor mediated signaling plays an important role in the survival of multiple lymphomas.
  • BTK can also be used as a therapeutic target for lymphoma.
  • Clinical trials have shown that BTK inhibitors have a significant effect in the treatment of chronic lymphocytic leukemia (CLL).
  • BTK inhibitors also have significant effects on other lymphomas such as diffuse large B-cell lymphomas and mantle cell lymphomas (Buggy, J. J et al, International Reviews of Immunology, 2012, 31, 119-132).
  • the Janus kinase family is an important tyrosine kinase that regulates cellular functions in the lymphoid hematopoietic system. It contains four known members, namely JAK1, JAK2, JAK3 and TYK2, of which JAK3 (Janus tyrosine kinase 3) is mainly expressed in lymphocytes and natural killer cells. JAK3 is linked to the common subunit ⁇ c chain of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors (Ghoreschi K et al, Immunological Reviews, 2009, 228, 273-87). These cytokines are mediated by JAK3 and play an important role in lymphocyte proliferation, differentiation and function.
  • JAK3 Kinases are a very attractive target for the treatment of immune-related disorders, such as autoimmune diseases such as rheumatoid arthritis or allograft rejection in organ transplant patients.
  • Selective JAK3 inhibitors have shown significant efficacy in clinical trials of rheumatoid arthritis.
  • BTK inhibitors and JAK3 inhibitors In addition to the separate application of BTK inhibitors and JAK3 inhibitors, inhibition of the BTK pathway and the JAK3 pathway may have synergistic effects in clinical applications.
  • Cetkovic-Cvrlje M et al. have shown that the combination of BTK inhibitors and JAK3 inhibitors can more effectively improve the survival rate of graft-versus-host disease (GVHD) animal models (Cetkovic-Cvrlje, M et al, British Journal of Haematology, 2004, 126, 821-827).
  • GVHD graft-versus-host disease
  • the epidermal growth factor receptor is a receptor for epidermal growth factor (EGF) cell proliferation and signaling, and is a transmembrane glycoprotein belonging to the tyrosine kinase family.
  • the wild-type epidermal growth factor receptor (EGFR WT ) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes, etc., and plays an important role in physiological processes such as cell growth, proliferation and distribution.
  • EGFR is highly expressed in many solid tumors and plays an important role in tumor cell proliferation, angiogenesis, metastasis and apoptosis.
  • anti-tumor drugs against EGFR There are many anti-tumor drugs against EGFR. However, due to the widespread distribution of EGFR WT in mammalian cells, inhibition of EGFR WT may have some toxic side effects.
  • the present invention provides a compound, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable salt thereof, which has the structural formula I (hereinafter sometimes referred to as Is a compound of formula I):
  • R is selected from a C 3-8 cycloalkyl group substituted by -NR 3 W; a 4-10 member saturated nitrogen heterocyclic group in which the nitrogen heterocyclic ring contains only one nitrogen atom, and the nitrogen atom is W a C 1-4 alkyl group substituted with a 4-10 membered saturated nitrogen heterocyclic group, wherein the nitrogen heterocyclic ring contains only one nitrogen atom, and the nitrogen atom is substituted by W;
  • W is selected from or
  • X is selected from S, O or NR 5 ;
  • Y is selected from N or CR 6 ;
  • Z is selected from a C 6-12 aryl group or a 5-12 membered heteroaryl group, which is optionally substituted with one or more R 7 ;
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, C 1- 8 aliphatic hydrocarbon group or C 1-8 halogenated aliphatic hydrocarbon group;
  • R 2 is selected from amino, C 1-8 aliphatic alkylamino or di (C 1-8 aliphatic) amino;
  • R 3 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 6 is selected from hydrogen, halogen, C 1-8 aliphatic hydrocarbon or C 1-8 halogenated aliphatic hydrocarbon;
  • Each R 7 is independently selected from the group consisting of halogen, nitro, cyano, heterocyclic, C 6-12 aryl, 5-12 membered heteroaryl, C 1-8 aliphatic, heterocyclyl C 1-8 Hydrocarbyl group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyloxy C 1-8 aliphatic hydrocarbon group, Amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon acylamino group C 1- 8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyl C 1-8 aliphatic hydrocarbon group, carboxyl C 1-8
  • a heterocyclic group denotes a saturated or partially unsaturated 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, each The heterocyclic group is optionally substituted independently with one or more substituents selected from the group consisting of halogen, heterocyclic group, 5-12 membered heteroaryl group, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon amino C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 Aliphatic, heterocyclic C 1-8 aliphatic, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di (C 1-8 aliphatic) amino, C 1-8 Aliphatic, C 1-8 aliphatic
  • the C 6-12 aryl group and the 5-12 membered heteroaryl group are independently optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-8 aliphatic hydrocarbon group, hydroxyl group, C 1-8 aliphatic hydrocarbon group , amino, C 1-8 aliphatic alkylamino or di (C 1-8 aliphatic) amino;
  • C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 at each occurrence. Cycloalkenyl.
  • the present invention provides a compound, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable salt thereof, which has the structural formula Ia (hereinafter sometimes referred to as Compound of formula Ia):
  • the invention provides a compound, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable salt thereof, which has the structural formula Ib (also sometimes referred to hereinafter)
  • structural formula Ib also sometimes referred to hereinafter
  • X, Y, Z, W, R 1 and R 2 are all as defined in formula I, and
  • l is selected from an integer from 0 to 4, wherein when l is 0, for
  • n is selected from an integer from 0 to 4; wherein when m is 0, for
  • n is selected from an integer from 0 to 3; wherein when n is 0, for
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the formula I according to the invention, in particular compounds of the formula Ia and Ib, or stereoisomers thereof, tautomers A construct, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention may further comprise one or more drugs selected from the group consisting of immunosuppressive agents, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, and TNF- ⁇ binding proteins. , interferons and interleukins.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, for use in the preparation of Use in drugs that inhibit BTK and/or JAK3 activity.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, for use in the preparation of Use in medicines for preventing or treating BTK and/or JAK3 mediated diseases.
  • compositions of the invention for the manufacture of a medicament for inhibiting BTK and/or JAK3 activity
  • the pharmaceutical composition comprises one or more compounds of the formula I according to the invention, in particular A compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition may further comprise one or more drugs selected from the group consisting of immunosuppressive agents, glucocorticoids, non-steroidal anti-inflammatory drugs, and Cox-2 specificity. Inhibitors, TNF- ⁇ binding proteins, interferons and interleukins.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, for use in inhibiting Activity of BTK and/or JAK3.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, for use in the prevention Or treatment of BTK and / or JAK3 mediated diseases.
  • Another aspect of the invention relates to a pharmaceutical combination
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • BTK BTK and/or JAK3.
  • Another aspect of the invention relates to a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof , preventing or treating BTK and/or JAK3 mediated diseases.
  • compositions of the invention in the manufacture of a medicament for the prevention or treatment of a BTK and/or JAK3 mediated disease, wherein the pharmaceutical composition comprises one or more of the invention A compound of formula I, especially a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may further comprise one or more drugs selected from the group consisting of immunosuppressive agents, glucocorticoids, non-steroidal anti-inflammatory drugs, and Cox-2 specificity. Inhibitors, TNF- ⁇ binding proteins, interferons and interleukins.
  • Another aspect of the invention relates to a method of inhibiting BTK and/or JAK3 activity in a biological system, the method comprising contacting said biological system with a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a construct, tautomer, solvate or pharmaceutically acceptable salt thereof, or a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer or tautomer thereof
  • a pharmaceutical composition of a solvate or a pharmaceutically acceptable salt thereof comprising contacting said biological system with a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a construct, tautomer, solvate or pharmaceutically acceptable salt thereof, or a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer or tautomer thereof.
  • Another aspect of the invention relates to a method of preventing or treating a BTK and/or JAK3 mediated disease comprising administering to a mammal, especially a human, in need thereof a therapeutically effective amount of a compound of the formula I according to the invention, in particular formula Ia And a compound of the formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or a compound of the formula I according to the invention, in particular a compound of the formula Ia and Ib, or a stereois A pharmaceutical composition of an isomer, a tautomer, a solvate or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof and Use of one or more active substances selected from the following for the preparation of a medicament for the treatment of BTK and/or JAK3 mediated diseases: immunosuppressive agents, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specificity Inhibitors, TNF- ⁇ binding proteins, interferons and interleukins.
  • active substances selected from the following for the preparation of a medicament for the treatment of BTK and/or JAK3 mediated diseases: immunosuppressive agents, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specificity Inhibitors, TNF- ⁇ binding proteins, interferons and interleukins.
  • the BTK and/or JAK3 mediated diseases are selected from autoimmune diseases, inflammatory diseases, xenogeneic immune conditions or diseases, thromboembolic diseases, and cancer.
  • a C 1-8 aliphatic hydrocarbon group means an aliphatic hydrocarbon group as defined below having a total of 1 to 8 carbon atoms
  • a C 1-8 alkyl group means an alkane as defined below having a total of 1 to 8 carbon atoms.
  • a C 3-8 cycloalkyl group means a cycloalkyl group as defined below having a total of 3 to 8 carbon atoms; and a C 6-12 aryl group means having a total of 6 to 12 carbon atoms as defined below Aryl.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • heterocyclyl aliphatic hydrocarbon group means that the heterocyclic group is bonded to the rest of the molecule through an aliphatic hydrocarbon group
  • aliphatic oxy group means that the aliphatic hydrocarbon group is bonded to the rest of the molecule through an oxy group, and the like.
  • Amino refers to a -NH 2 group.
  • Cyano refers to the -CN group.
  • Haldroxy means an -OH group.
  • Niro means a -NO 2 group.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, more preferably fluorine.
  • aliphatic group as a part of a separate group or other group means that it has only the carbon atom and the hydrogen atom and has a single bond to the remainder of the molecule, having the basic properties of the aliphatic compound. Saturated or unsaturated group.
  • the aliphatic hydrocarbon group includes a linear or branched alkyl group, an alkenyl group and an alkynyl group, and a cycloalkyl group and a cycloalkenyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group and the cycloalkenyl group are as defined below.
  • an aliphatic hydrocarbon group means an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and/or a cycloalkenyl group, and preferably an alkyl group and/or a cycloalkyl group.
  • the hydrogen on the aliphatic hydrocarbon group may be optionally substituted with any suitable group such as a halogen, a hydroxyl group, an amino group, a monosubstituted amino group, a disubstituted amino group, an alkoxy group, a heterocyclic group or the like.
  • alkyl as a separate group or part of another group means a straight consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds and attached to the rest of the molecule by a single bond. Chain or branched group.
  • the alkyl group may have, for example, 1 to 18, preferably 1 to 12, more preferably 1 to 8 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, hexyl, heptyl, 2-methyl
  • a hexyl group, a 3-methylhexyl group, an octyl group, a decyl group, a decyl group and the like are preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or a n-butyl group, and more preferably a methyl group and an ethyl group.
  • the hydrogen on the alkyl group may be optionally substituted with any suitable group such as a halogen, a hydroxyl group, an amino group, a monosubstituted amino group, a disubstituted amino group, an alkoxy group, a heterocyclic group or the like.
  • alkenyl as a part of a separate group or other group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having for example 2 to 18, preferably 2 to 10 a linear or branched hydrocarbon chain group which is more preferably 2 to 8 carbon atoms and which is bonded to the remainder of the molecule by a single bond, including but not limited to vinyl, propenyl, allyl, butan-1-
  • the alkenyl group, the but-2-enyl group, the pent-1-enyl group, the pent-2-enyl group, the pentane-1,4-dienyl group and the like are preferably a vinyl group or a propylene group.
  • the hydrogen on the alkenyl group may be optionally substituted with any suitable group such as a halogen, a hydroxyl group, an amino group, a monosubstituted amino group, a disubstituted amino group, an alkoxy group, a heterocyclic group or the like.
  • alkynyl as a part of a separate group or other group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having For example, 2 to 18, preferably 2 to 10, more preferably 2 to 8 carbon atoms and a straight or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond.
  • alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, pent-1-en-4-ynyl, and the like.
  • the hydrogen on the alkynyl group may be optionally substituted with any suitable group such as a halogen, a hydroxyl group, an amino group, a monosubstituted amino group, a disubstituted amino group, an alkoxy group, a heterocyclic group or the like.
  • cycloalkyl as a part of a separate group or other group means a stable saturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may Including a fused ring system or a bridged ring system having, for example, from 3 to 15, preferably from 3 to 12, more preferably from 3 to 8, even more preferably from 5 to 6 carbon atoms, and passing through any suitable carbon atom on the ring A single bond is attached to the rest of the molecule.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclic [2.2.1] Heptyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, and adamantyl, etc., preferably cyclobutyl, cyclo Pentyl, cyclohexyl.
  • the hydrogen on the cycloalkyl group may be optionally substituted with any suitable group such as a halogen, a hydroxyl group, an amino group, a monosubstituted amino group, a disubstituted amino group, an alkyl group, an alkoxy group, a heterocyclic group or the like.
  • cycloalkenyl as a part of a separate group or other group means a stable non-aromatic monocyclic or polycyclic group containing at least one double bond consisting only of carbon atoms and hydrogen atoms.
  • a cycloalkyl group which may include a fused ring system or a bridged ring system. It has, for example, from 3 to 15, preferably from 3 to 12, more preferably from 4 to 8 carbon atoms, and is attached to the remainder of the molecule via a single bond via any suitable carbon atom on the ring.
  • cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1H-fluorenyl, 2,3 - indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocycloheptene-6 -yl,6,7,8,9-tetrahydro-5-hydro-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, Bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, fluor
  • the hydrogen on the cycloalkenyl group may be optionally substituted with any suitable group such as a halogen, a hydroxyl group, an amino group, a monosubstituted amino group, a disubstituted amino group, an alkyl group, an alkoxy group, a heterocyclic group or the like.
  • haloaliphatic refers to an aliphatic hydrocarbon group substituted by one or more halogen atoms, wherein the aliphatic hydrocarbon group is as defined above.
  • examples thereof include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, chloromethyl, chloroethyl, dichloromethyl, 1,2- A chloroethyl group, a fluorovinyl group, a fluorocyclopentyl group, a fluorocyclohexyl group, a chlorocyclohexenyl group or the like is preferred.
  • hydroxyaliphatic refers to an aliphatic hydrocarbon group as defined above substituted with one or more hydroxy groups. Examples thereof include, but are not limited to, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxycyclopentyl, 4-hydroxycyclohexyl, 3,4-dihydroxycyclohexyl, etc., preferably 1-hydroxyethyl. .
  • aminoaliphatic refers to an aliphatic hydrocarbon group as defined above which is substituted by one or more amino groups.
  • aliphaticoxy as a separate group or part of another group refers to a radical of the formula -OR a where R a is an aliphatic hydrocarbon radical as defined above.
  • R a is an aliphatic hydrocarbon radical as defined above.
  • the aliphatic hydrocarbyl moiety in the aliphatic hydrocarbyloxy group can also be optionally substituted as described above for the aliphatic hydrocarbyl group.
  • aliphatic hydrocarbyloxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, vinyloxy, 1-propenyloxy,
  • a 1-propynyloxy group, a cyclopentyloxy group, a cyclohexyloxy group or the like is preferably a methoxy group or an ethoxy group, more preferably a methoxy group.
  • hydroxyaliphaticoxy refers to an aliphatic hydrocarbyloxy group as defined above wherein the aliphatic hydrocarbyl group is substituted by one or more hydroxyl groups. Examples thereof include, but are not limited to, 1-hydroxyethoxy, 1-hydroxypropoxy, 3-hydroxycyclopentanoxy, 3,4-dihydroxycyclohexyloxy and the like, preferably 1-hydroxyethoxy.
  • R a is an aliphatic hydrocarbon radical as defined above.
  • the aliphatic hydrocarbyl moiety in the aliphatic hydrocarbyl carbonyl group can also be optionally substituted as described above for the aliphatic hydrocarbyl group.
  • the aliphatic hydrocarbon group includes an alkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group and a cycloalkenylcarbonyl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group and the cycloalkenyl group are as defined above.
  • the aliphatic hydrocarbon group preferably means an alkylcarbonyl group and/or a cycloalkylcarbonyl group.
  • aliphatic hydrocarbon carbonyl groups include, but are not limited to, methylcarbonyl (also known as acetyl), ethylcarbonyl (also known as propionyl), isopropylcarbonyl, butylcarbonyl, vinylcarbonyl, propylenecarbonyl,
  • a cyclopentylcarbonyl group, a cyclohexylcarbonyl group or the like is preferably a methylcarbonyl group.
  • aliphatic amino as part of a separate group or other group refers to a radical of the formula -NHR a where R a is an aliphatic hydrocarbon radical as defined above.
  • the aliphatic hydrocarbon group amino group includes an alkylamino group, an alkenylamino group, an alkynylamino group, a cycloalkylamino group, and a cycloalkenylamino group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, and the cycloalkenyl group are as defined above.
  • the aliphatic amino group preferably means an alkylamino group and/or a cycloalkylamino group.
  • examples thereof include, but are not limited to, methylamino, ethylamino, isopropylamino, vinylamino, propenylamino, propynylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclohexenyl.
  • the amino group or the like is preferably a methylamino group, an ethylamino group or a cyclohexylamino group.
  • dialiphatic amino group preferably means a dialkylamino group.
  • dialkylamino group include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, methylethylamino group and the like, and a dimethylamino group is preferred.
  • the term "aliphatic oxyaliphaticoxy" as a part of a separate group or other group means that the aliphatic hydrocarbon group is substituted by an aliphatic hydrocarbyloxy group as defined above, as defined above Aliphatic oxy group.
  • the aliphatic hydrocarbyloxyalkyloxy group preferably means an alkoxyalkoxy group, an alkoxycycloalkoxy group and/or a cycloalkoxy alkoxy group, examples of which include, but are not limited to, methoxy Ethyl ethoxy, ethoxyethoxy, methoxycyclopentanoxy, methoxycyclohexaneoxy, cyclopentanoxymethoxy and the like.
  • aliphatic aminoaliphatic as a part of a separate group or other group refers to an aliphatic hydrocarbon group as defined above substituted with an aliphatic hydrocarbylamino group as defined above.
  • dialiphatic aminoaliphatic as a part of a separate group or other group refers to an aliphatic hydrocarbon group as defined above which is substituted by a dialiphatic amino group as defined above. Examples thereof include, but are not limited to, dimethylaminoethyl, diethylaminoethyl, (methyl)(ethyl)aminoethyl and the like, preferably dimethylaminoethyl.
  • dialiphatic aminoaliphatic amino as part of a separate group or other group refers to a lipid as defined above wherein the aliphatic hydrocarbon group is substituted with a dialiphatic amino group as defined above.
  • Hydrocarbylamino group examples thereof include, but are not limited to, dimethylaminoethylamino, diethylaminoethylamino, (methyl)(ethyl)aminoethylamino, and the like, preferably dimethylaminoethylamino.
  • heterocyclyl as a part of a separate group or other group means a stable 3 to 18 member consisting of 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur.
  • Non-aromatic cyclic group Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system.
  • the heterocyclic group is preferably a stable 3- to 12-membered non-aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably comprising a stable 3- to 8-membered non-aromatic monocyclic group of 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, more preferably stable containing 1 to 2 hetero atoms selected from nitrogen, oxygen and sulfur A 5- to 6-membered non-aromatic monocyclic group.
  • the nitrogen, carbon or sulfur atom in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl group or a heteroaryl group, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidine.
  • the heterocyclic group may be optionally substituted by any suitable substituent, the substitution Base groups include, but are not limited to, halogen, hydroxy, amino, alkyl, alkoxy, alkylcarbonyl, and the like.
  • azacyclohetero refers to a heterocyclic group as defined above containing at least one nitrogen atom in the ring.
  • heterocyclyloxy as a separate group or part of another group refers to a radical of the formula -OR h , wherein Rh is a heterocyclyl radical as defined above.
  • the heterocyclyl moiety in the heterocyclyloxy group can also be optionally substituted as described above for the heterocyclyl group.
  • R h is a heterocyclyl as hereinbefore defined base.
  • the heterocyclyl moiety in the heterocyclylcarbonyl group can also be optionally substituted as described above for the heterocyclyl.
  • heterocyclylamino as part of a separate group or other group refers to the formula R h -NH-, wherein R h is a heterocyclic group as defined above.
  • R h is a heterocyclic group as defined above.
  • the heterocyclyl moiety in the heterocyclylamino group can also be optionally substituted as described above for the heterocyclyl.
  • the heterocyclyl moiety in the heterocyclylaminoacyl group can also be optionally substituted as described above for the heterocyclyl group.
  • heterocyclyl aliphatic hydrocarbon group as a part of a separate group or other group refers to an aliphatic hydrocarbon group as defined above which is substituted by a heterocyclic group as defined above.
  • the heterocyclic moiety in the heterocyclic aliphatic hydrocarbon group may be optionally substituted as described above for the heterocyclic group, and the aliphatic hydrocarbon moiety in the heterocyclic aliphatic hydrocarbon group may be as described above for the aliphatic hydrocarbon group.
  • Optional replacement is optionally substituted as described above for the heterocyclic group.
  • heterocyclylaliphaticoxy refers to an aliphatic hydrocarbon group as defined above wherein the aliphatic hydrocarbon group is substituted by a heterocyclic group as defined above. Oxygen.
  • the heterocyclic moiety in the heterocyclylaliphaticoxy group may be optionally substituted as described above for the heterocyclic group, and the aliphatic hydrocarbyl moiety in the heterocyclic aliphatic hydrocarbyloxy group may be as described above for the aliphatic hydrocarbon group. It was replaced by any of them.
  • aryl as a part of a separate group or other group means a system having 6 to 18, preferably 6 to 12, carbon atoms and at least one aromatic ring.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system which can comprise a fused ring or a bridged ring system.
  • the aryl group is attached to the remainder of the molecule via a single bond via an aromatic ring atom.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-
  • a 7-group or the like is preferably a phenyl group.
  • heteroaryl as a part of a separate group or other group means having from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and 5 elements of at least one aromatic ring.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system, provided that the point of attachment is an aromatic ring atom .
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 a stable 5- to 8-membered aromatic monocyclic or bicyclic group to 3 heteroatoms selected from nitrogen, oxygen and sulfur, most preferably comprising 1 to 2 stable 5- to 6-membered aromatic monocyclic groups selected from hetero atoms of nitrogen, oxygen and sulfur.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl , triazinyl, pyrimidinyl, pyridazinyl, pyridazinyl, fluorenyl, isodecyl, oxazolyl, isoxazolyl, fluorenyl, quinolinyl, isoquinolinyl, diazonaphthyl , naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrinyl, phenanthryl, phenanthroline, acridinyl, phenazinyl, thiazolyl, isothiazolyl, benzothiazolyl
  • alkyl group optionally substituted with one or more halogens means that the alkyl group is unsubstituted or substituted with one or more halogens, and the description includes both substituted alkyl groups and unsubstituted alkyl groups.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compounds of formula I of the present invention contain olefinic double bonds, the compounds of formula I of the present invention are intended to comprise E- and Z-geometric isomers unless otherwise indicated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of formula I of the invention will also be embraced within the scope of the invention.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid capable of retaining the bioavailability of the free base without other side effects.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.;
  • the organic acid includes, but not limited to, formic acid, acetic acid, trifluoroacetic acid, propionic acid, caprylic acid, caproic acid, capric acid, eleven Carbenolic acid, glycolic acid, gluconic acid, lactic acid, oxalic acid, azelaic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, Stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, as
  • “Pharmaceutically acceptable base addition salt” refers to a salt that is capable of retaining the biological effectiveness of the free acid without other side effects. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexyl Amine, lysine, arginine, histidine, Caffeine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • the compound of the present invention may contain a plurality of cations or anions depending on the number of charged functional groups and the valence of the cation or anion.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. They either react in a solvent or precipitate out of the solvent or crystallize out.
  • the solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may also be an organic solvent. Solvates of the compounds of the invention are also within the scope of the invention.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present application may be a single preparation or a combination of a plurality of preparations.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • therapeutically effective amount refers to an amount of a compound of the invention sufficient to effectively treat a disease or condition in a mammal (e.g., a human) when the compound of the invention is administered to a mammal (e.g., a human).
  • the amount of a compound of the invention that constitutes a “therapeutically effective amount” depends on the particular compound employed, the particular condition being treated, the cause of the condition, the target of the drug, the severity of the disease, the mode of administration, and the age of the mammal to be treated. , body weight, physical condition, etc., but can be routinely determined by those skilled in the art based on their own knowledge and the content disclosed in the present application.
  • a compound, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable salt thereof having the formula I:
  • R is selected from a C 3-8 cycloalkyl group substituted by -NR 3 W; a 4-10 member saturated nitrogen heterocyclic group in which the nitrogen heterocyclic ring contains only one nitrogen atom, and the nitrogen atom is replaced by W Or a C 1-4 alkyl group substituted with a 4-10 membered saturated nitrogen heterocyclic group, wherein the nitrogen heterocyclic ring contains only one nitrogen atom, and the nitrogen atom is substituted by W;
  • W is selected from or
  • X is selected from S, O or NR 5 ;
  • Y is selected from N or CR 6 ;
  • Z is a C 6-12 aryl group or a 5-12 membered heteroaryl group, which is optionally substituted with one or more R 7 ;
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, C 1- 8 aliphatic hydrocarbon group or C 1-8 halogenated aliphatic hydrocarbon group;
  • R 2 is selected from amino, C 1-8 aliphatic alkylamino or di (C 1-8 aliphatic) amino;
  • R 3 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 6 is selected from hydrogen, halogen, C 1-8 aliphatic hydrocarbon or C 1-8 halogenated aliphatic hydrocarbon;
  • Each R 7 is independently selected from the group consisting of halogen, nitro, cyano, heterocyclic, C 6-12 aryl, 5-12 membered heteroaryl, C 1-8 aliphatic, heterocyclyl C 1-8 Hydrocarbyl group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyloxy C 1-8 aliphatic hydrocarbon group, Amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon acylamino group C 1- 8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyl C 1-8 aliphatic hydrocarbon group, carboxyl C 1-8
  • a heterocyclic group denotes a saturated or partially unsaturated 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, each The heterocyclic group is optionally substituted independently with one or more substituents selected from the group consisting of halogen, heterocyclic group, 5-12 membered heteroaryl group, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon amino C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 Aliphatic, heterocyclic C 1-8 aliphatic, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di (C 1-8 aliphatic) amino, C 1-8 Aliphatic, C 1-8 aliphatic
  • the C 6-12 aryl group and the 5-12 membered heteroaryl group are, independently, optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-8 aliphatic hydrocarbon group, hydroxyl group, C 1-8 aliphatic hydrocarbon group oxygen.
  • a base an amino group, a C 1-8 aliphatic alkylamino group or a di(C 1-8 aliphatic hydrocarbon) amino group;
  • C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 at each occurrence. Cycloalkenyl.
  • R is C 3-8 cycloalkyl substituted with -NR 3 W, wherein R 3 is selected from hydrogen or C 1-8 aliphatic, and W is selected from or Wherein R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1- at each occurrence. 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R is cyclohexane substituted with -NR 3 W, wherein R 3 is selected from hydrogen or C 1-8 aliphatic hydrocarbon, and W is selected from Wherein R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1- at each occurrence. 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R is cyclohexane substituted with -NR 3 W, wherein R 3 is selected from hydrogen or C 1-8 aliphatic hydrocarbon, and W is selected from Wherein R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1- at each occurrence. 8 alkyl and C 3-8 cycloalkyl, more preferably C 1-8 alkyl.
  • R is cyclohexane substituted with -NR 3 W, wherein R 3 is hydrogen, and W is selected from Wherein R 4a , R 4b and R 4c are all hydrogen.
  • R is cyclohexane substituted with -NR 3 W, wherein R 3 is selected from hydrogen or C 1-8 aliphatic hydrocarbon, and W is Wherein the C 1-8 aliphatic hydrocarbon group is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl, preferably selected from It is a C 1-8 alkyl group and a C 3-8 cycloalkyl group, more preferably a C 1-8 alkyl group.
  • R is cyclohexane substituted with -NR 3 W, wherein R 3 is selected from hydrogen, and W is
  • R is selected from a 4-10 membered saturated azaheterocyclyl, wherein said azaheterocyclyl ring contains only one nitrogen atom and the nitrogen atom is replaced by W; a 4-10 membered saturated azaheterocyclyl substituted C 1-4 alkyl group wherein the nitrogen heterocyclyl ring contains only one nitrogen atom, and the nitrogen atom is substituted by W, wherein each W is independently selected from to or
  • R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1- at each occurrence. 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R is selected from a 4-10 membered saturated azaheterocyclyl, wherein said azaheterocyclyl ring contains only one nitrogen atom and the nitrogen atom is replaced by W; a 4-10 membered saturated azaheterocyclyl substituted C 1-4 alkyl group wherein the nitrogen heterocyclyl ring contains only one nitrogen atom and the nitrogen atom is substituted by W, wherein each W is independently Wherein R 4a , R 4b and R 4c are all hydrogen.
  • R is selected from a 4-10 membered saturated azaheterocyclyl, wherein said azaheterocyclyl ring contains only one nitrogen atom and the nitrogen atom is replaced by W; a 4-10 membered saturated azaheterocyclyl substituted C 1-4 alkyl group wherein the nitrogen heterocyclyl ring contains only one nitrogen atom and the nitrogen atom is substituted by W, wherein each W is independently
  • X is S. In other embodiments of the compounds of Formula I, X is O.
  • X is NR 5 , wherein R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R 5 is selected from hydrogen or a C 1-8 alkyl.
  • R 5 is hydrogen.
  • Y is CR 6 , wherein R 6 is selected from hydrogen, halogen, C 1-8 aliphatic or C 1-8 halohydrocarbyl, wherein C 1-8 aliphatic is independently It is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • Y is CR 6 , wherein R 6 is selected from hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkyl.
  • Y is CR 6 , wherein R 6 is hydrogen.
  • Y is N.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di (C 1 a -8 aliphatic hydrocarbon group) amino group, a C 1-8 aliphatic hydrocarbon group or a C 1-8 halogenated aliphatic hydrocarbon group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl group, C 2-8 at each occurrence. Alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R 1 is selected from hydrogen, halogen, or C 1-8 alkyl.
  • R 1 is hydrogen
  • R 2 is selected from amino, C 1-8 aliphatic alkylamino or di(C 1-8 aliphatic alkyl)amino, wherein the C 1-8 aliphatic hydrocarbon group is independently present at each occurrence It is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R 2 is amino
  • Y is N, R 1 is hydrogen, and R 2 is amino.
  • Z is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo , hydroxy, heterocyclic, C 1-8 aliphatic hydrocarbon, hydroxy C 1-8 aliphatic hydrocarbon, amino C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic alkyl C 1-8 aliphatic hydrocarbon, C 1-8 halogen Aliphatic hydrocarbon group, C 1-8 aliphatic alkylamino C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon) amino C 1-8 aliphatic hydrocarbon group, heterocyclic group C 1-8 aliphatic hydrocarbon group, C 1-8 fat Hydrocarbyloxy, C 1-8 aliphatic hydrocarbylcarbonyl, heterocyclylamino, heterocyclylaminoacyl, heterocyclylaminosulfonyl, heterocyclylaminosulfin
  • a heterocyclic group denotes a saturated or partially unsaturated 3-12 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, each The heterocyclic group is optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic alkyloxy or C 1-8 aliphatic hydrocarbon carbonyl,
  • C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 at each occurrence. Cycloalkenyl.
  • Z is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo , heterocyclic group, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated fat Hydrocarbyl group, aminoacyl group, C 1-8 aliphatic amino group, di(C 1-8 aliphatic) amino group, aminosulfonyl group, C 1-8 aliphatic alkyl sulfonyl group, di(C 1-8 aliphatic alkyl) amino group Sulfonyl, aminosulfinyl, C 1-8 aliphatic alkyl sulfinyl, bis(C 1-8 aliphatic) aminosulfinyl
  • a heterocyclic group denotes a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, each The heterocyclic group is optionally substituted independently with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic alkyloxy or C 1-8 aliphatic hydrocarbon carbonyl,
  • C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 at each occurrence. Cycloalkenyl.
  • Z is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo , heterocyclic group, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxy C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group Aminoacyl, wherein heterocyclyl denotes a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, optionally independently of one or more independently Substituted with a substituent selected from a C 1-8 aliphatic hydrocarbon group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl
  • Z is phenyl or a 5-membered heteroaryl, which is optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo, heterocyclyl, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxy C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon amino group, wherein heterocyclic ring It represents a group containing one or two heteroatoms selected from N, O, S hetero atom saturated or partially unsaturated 5-6 membered heterocyclic group, optionally substituted with one or more substituents independently selected from C 1- independently 8 aliphatic hydrocarbon substituents, C 1-8 aliphatic hydrocarbon group wherein at each occurrence is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8
  • the compound of Formula I has the structural formula Ia:
  • X is S. In other embodiments, X is O. In other embodiments, X is selected from NR 5 , wherein R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl. In some embodiments, X is selected from NR 5 , wherein R 5 is selected from hydrogen or C 1-8 alkyl. In some embodiments, X is selected from NR 5 , wherein R 5 is selected from hydrogen or methyl, more preferably R 5 is hydrogen.
  • Y is selected from N.
  • Y is CR 6 , wherein R 6 is selected from hydrogen, halogen, C 1-8 aliphatic or C 1-8 halohydrocarbyl, wherein each occurrence of a C 1-8 aliphatic hydrocarbon group It is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • Y is CR 6 , wherein R 6 is selected from hydrogen, halogen, C 1-8 alkyl, or C 1-8 haloalkyl.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, C 1-8 alkoxy, amino, C 1-8 alkylamino, di ( a C 1-8 alkyl)amino group, a C 1-8 alkyl group or a C 1-8 haloalkyl group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from a C 1-8 alkyl group, a C 2-8 alkenyl group, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R 1 is selected from hydrogen or halogen.
  • R 1 is hydrogen.
  • R 2 is selected from amino, C 1-8 alkylamino or di(C 1-8 alkyl)amino. In some embodiments of the compounds of Formula Ia of the invention, R 2 is amino.
  • Y is N, R 1 is hydrogen, R 2 is an amino group.
  • Z is C 6-12 aryl or 5 to 12 membered heteroaryl, which is optionally substituted by one or more R 7 , wherein each R 7 is independently selected From halogen, hydroxy, heterocyclic, C 1-8 aliphatic, hydroxy C 1-8 aliphatic, amino C 1-8 aliphatic, C 1-8 aliphatic oxy C 1-8 aliphatic, C 1- 8 haloaliphatic, C 1-8 aliphatic alkyl C 1-8 aliphatic, di (C 1-8 aliphatic) amino C 1-8 aliphatic, heterocyclic C 1-8 aliphatic, C 1- 8 aliphatic hydrocarbyloxy, heterocyclylamino, heterocyclylamino, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylsulfonyl, heterocyclylsulfinyl, amino, C 1-8 aliphatic alkylamino , (C 1-8 aliphatic alkylamino , (C 1-8
  • An 8-membered heterocyclic group each optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-8 aliphatic, C 1-8 aliphatic alkyl or C 1-8 aliphatic hydrocarbylcarbonyl group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 naphthane at each occurrence And C 4-8 cycloalkenyl.
  • Z is C 6-12 aryl or 5 to 12 membered heteroaryl optionally substituted by one or more R 7 wherein each R 7 is independently selected From halogen, heterocyclic group, C 1-8 aliphatic hydrocarbon group, hydroxyl C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic alkyloxy C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, C 1-8 Aliphatic amino group C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic alkylamino group, wherein heterocyclic group, as independent group or other group a portion, representing a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or two heteroatoms selected from N, O and S, each heterocyclic group optionally being independently selected by one or more Substituted from the following
  • Z is C 6-12 aryl optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo, hydroxy, heterocyclyl , C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, heterocyclic group oxy group, heterocyclic group Base C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, heterocyclylamino, amino C 1-8 aliphatic alkylamino, C 1-8 Hydrocarbylamino C 1-8 aliphatic hydrocarbylamino, di(C 1-8 aliphatic hydrocarbyl)amino C 1-8 aliphatic hydrocarbylamino, heterocyclylcarbonyl, heterocyclylamino
  • Z is phenyl optionally substituted by one or more R 7 wherein each R 7 is independently selected from halo, heterocyclyl, C 1-8 Hydrocarbyl group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbyloxy group, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbyloxy group, heterocyclic oxy group, heterocyclic C 1-8 ester Hydrocarbyloxy, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, heterocyclylamino, di(C 1-8 aliphatic) amino C 1-8 aliphatic alkyl, heterocyclylcarbonyl a heterocyclic aminoacyl group, a C 1-8 aliphatic alkylamino group, a di(C 1-8 aliphatic alkyl)amino acyl group, wherein the heterocyclic group, as a separate
  • Z is phenyl optionally substituted by one or more R 7 , each R 7 being independently selected from halo, hydroxy, heterocyclyl, C 1-8 Alkyl, C 3-8 cycloalkyl, heterocyclyl C 1-8 alkyl, hydroxy C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyloxy, C 1-8 alkane Alkoxy C 1-8 alkyloxy, heterocyclyloxy, heterocyclyl C 1-8 alkyloxy, C 1-8 alkylamino, di(C 1-8 alkyl)amino, hetero Cycloamino, di(C 1-8 alkyl)amino C 1-8 alkylamino, heterocyclylcarbonyl, heterocyclylamino, C 1-8 alkylamino or C 3-8 cycloalkylamino
  • a heterocyclic group as a separate group or part of another group, represents a saturated or partially
  • Z is phenyl optionally substituted by one or more R 7 , each R 7 being independently selected from heterocyclyl or C 1-8 aliphatic alkylamino
  • R 7 being independently selected from heterocyclyl or C 1-8 aliphatic alkylamino
  • An acyl group wherein heterocyclyl denotes a saturated or partially unsaturated 5-6 membered heterocyclic group containing one or two heteroatoms selected from O, N and S, independently independently selected from one or two Substituent substitution of a C 1-8 aliphatic hydrocarbon group.
  • Z is phenyl optionally substituted by one or more R 7 , each R 7 being independently selected from 1-methyl-piperazin-4-yl or Methylaminoacyl.
  • Z is a 5-12 membered heteroaryl optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo, heterocyclyl , C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, heterocyclic group C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, amino group C 1-8 Aliphatic, C 1-8 aliphatic alkyl C 1-8 aliphatic, di (C 1-8 aliphatic) amino C 1-8 aliphatic, C 1-8 aliphatic alkyloxy, C 1-8 aliphatic alkyloxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbonoxy C 1-8 aliphatic hydrocarbonoxy group, heterocyclic oxygen group, heterocyclic group C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated alipha
  • Z is a 5-12 membered heteroaryl optionally substituted by one or more R 7 , wherein each R 7 is independently selected from halo, heterocyclyl , C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, heterocyclic group C 1-8 aliphatic hydrocarbon group, hydroxyl C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group or C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, wherein A cyclic group, as part of a separate group or other group, represents a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or two heteroatoms selected from O,
  • Z is a 5-10 membered heteroaryl optionally substituted with one or more R 7 wherein each R 7 is independently selected from heterocyclyl, C 1 -8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, heterocyclic group C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group amino group C 1- 8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon) amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group or C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, wherein heterocyclic group, As a separate group or part of another group, a saturated or partially unsaturated 5-6 membered heterocyclic group containing one or two heteroatoms selected from O, N or S, preferably selected from the
  • Z is selected from a 5-10 membered heteroaryl group, preferably selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, isoxazole a pyridyl or pyridyl[1,2-a]pyridinyl group optionally substituted by one or more R 7 wherein each R 7 is independently selected from C 3-8 cycloalkyl, heterocyclyl, C 1-8 alkyl, heterocyclic C 1-8 alkyl, hydroxy C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyloxy C 1-8 alkyl, amino C 1- 8- alkyl, C 1-8 alkylamino C 1-8 alkyl, di(C 1-8 alkyl)amino C 1-8 alkyl, C 1-8 alkyloxy, wherein heterocyclic group, as a separate
  • Z is selected from a 5-membered heteroaryl group, preferably selected from pyrazolyl or isoxazolyl, optionally substituted by one or more R 7 , wherein each R 7 independently selected from C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxy C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, wherein C 1-8 fat
  • the hydrocarbyl group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl at each occurrence, preferably independently It is selected from a C 1-8 alkyl group and a C 3-8 cycloalkyl group.
  • Z is selected from a 5-10 membered heteroaryl group, preferably selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, isoxazole a pyridyl or pyridyl [1,2-a]pyridinyl group optionally substituted by one or more R 7 wherein each R 7 is independently selected from the group consisting of methyl, cyclobutyl, cyclopentyl, hydroxy Base, methoxy, methoxyethyl, fluoroethyl, dimethylaminoethyl, 1-methyl-piperazin-4-yl or morpholin-4-ylethyl.
  • Z is selected from a 5-6 membered heteroaryl group, preferably selected from pyrazolyl, isothiazolyl or pyridyl, optionally substituted by one or more R 7 , Wherein each R 7 is independently selected from the group consisting of methyl, hydroxyethyl, methoxy, methoxyethyl, fluoroethyl.
  • Z is selected from the group consisting of:
  • each group has the following definition:
  • W is selected from or
  • X is NR 5 ;
  • Y is N
  • Z is selected from phenyl or five-membered heterocyclic groups, which are optionally substituted by one or more R 7 ;
  • R 1 is hydrogen
  • R 2 is an amino group
  • R 3 is hydrogen
  • R 4a , R 4b and R 4c are all hydrogen
  • R 5 is hydrogen
  • Each R 7 is independently selected from the group consisting of halogen, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxy C 1-8 aliphatic hydrocarbon group, halogenated C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic alkylamino or heterocyclic group, wherein the heterocyclic group means a saturated or partially unsaturated 5-6 membered heterocyclic group containing one or two hetero atoms selected from O, N or S, Independently optionally substituted by one or two substituents selected from C 1-8 aliphatic hydrocarbon groups, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl and C 3-8 at each occurrence Cycloalkyl.
  • the compound is selected from the group consisting of:
  • the compound of Formula I has the structural formula Ib:
  • X, Y, Z, W, R 1 and R 2 are all as defined in formula I;
  • l is selected from an integer from 0 to 4, wherein when l is 0, for
  • n is selected from an integer from 0 to 4; wherein when m is 0, for
  • n is selected from an integer from 0 to 3; wherein when n is 0, for
  • each group has the following definition:
  • W is selected from or
  • X is selected from S, O or NR 5 ;
  • Y is selected from N or CR 6 ;
  • Z is a 5-12 membered heteroaryl group which is optionally substituted with one or more R 7 ;
  • l is selected from 0, 1 or 2, wherein when l is 0, for
  • n is selected from 0, 1, 2, 3 or 4; wherein when m is 0, for
  • n is selected from 0, 1, 2 or 3; wherein when n is 0, for
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, C 1- 8 aliphatic hydrocarbon group or C 1-8 halogenated aliphatic hydrocarbon group;
  • R 2 is selected from amino, C 1-8 aliphatic alkylamino or di (C 1-8 aliphatic) amino;
  • R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 6 is selected from hydrogen, halogen, C 1-8 aliphatic hydrocarbon or C 1-8 halogenated aliphatic hydrocarbon;
  • Each R 7 is independently selected from the group consisting of halogen, nitro, cyano, C 1-8 aliphatic, C 1-8 haloaliphatic, hydroxy C 1-8 aliphatic, C 1-8 aliphatic alkyl C 1 -8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, heterocyclic group C 1- 8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyl C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon oxycarbonyl C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyloxy C 1-8 aliphatic hydrocarbon group, Aminoacyl C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic alkyl acyl C 1-8 aliphatic
  • a heterocyclic group denotes a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, each The heterocyclic group is independently optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic alkyloxy or C 1-8 aliphatic hydrocarbon carbonyl;
  • the C 6-12 aryl group and the 5-12 membered heteroaryl group are independently optionally substituted by one or more substituents selected from halogen or a C 1-8 aliphatic hydrocarbon group;
  • C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4- at each occurrence. 8 cycloalkenyl.
  • W is selected from Wherein R 4a , R 4b and R 4c are independently selected from hydrogen, halogen or di(C 1-8 alkyl)aminomethyl. In other embodiments, W is selected from Wherein R 4a , R 4b and R 4c are all hydrogen.
  • W is selected from
  • X is selected from NR 5 , wherein R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1- 8- alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • X is selected from NR 5 , wherein R 5 is selected from hydrogen or C 1-8 alkyl.
  • X is selected from NR 5 , wherein R 5 is selected from hydrogen or methyl.
  • X is selected from NR 5 , wherein R 5 is selected from hydrogen.
  • Y is selected from N.
  • Y is selected from CR 6 wherein R 6 is selected from hydrogen, halogen, C 1-8 aliphatic or C 1-8 halohydrocarbyl, wherein C 1-8 aliphatic is independently selected From C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • Y is selected from CR 6 wherein R 6 is selected from hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkyl.
  • R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, C 1-8 alkoxy, amino, C 1-8 alkylamino, di ( C 1-8 alkyl)amino, C 1-8 alkyl or C 1-8 haloalkyl. In some embodiments, R 1 is selected from hydrogen or halogen. In some embodiments, R 1 is selected from hydrogen.
  • R 2 is selected from amino, C 1-8 alkylamino or di(C 1-8 alkyl)amino. In some embodiments, R 2 is selected from the group consisting of amino groups.
  • compounds of Formula Ib are N, R 1 is hydrogen, R 2 is an amino group.
  • Y is CR 6 , R 1 is hydrogen, and R 2 is amino, wherein R 6 is selected from hydrogen, halogen, C 1-8 aliphatic or C 1-8 An aliphatic hydrocarbon group wherein the C 1-8 aliphatic hydrocarbon group is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 ring Alkenyl.
  • Y is CR 6 , R 1 is hydrogen, and R 2 is amino, wherein R 6 is selected from hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkane. base.
  • Z is selected from a 5-10 membered heteroaryl group, which is optionally substituted with one or more R 7 ; each R 7 is independently selected from halo, heterocycle Base, C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, heterocyclic group C 1-8 aliphatic hydrocarbon group, hydroxyl C 1-8 aliphatic hydrocarbon group, hydroxyl group C 1-8 aliphatic hydrocarbon group, amino group C 1- 8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, di (C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group Carbonyl, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarby
  • a heterocyclic group denotes a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, preferably selected From piperidinyl, piperazinyl, morpholinyl or tetrahydropyranyl, each heterocyclic group is independently optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-8 a hydrocarbyl group, a C 1-8 aliphatic hydrocarbyloxy group or a C 1-8 aliphatic hydrocarbyl carbonyl group,
  • C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 at each occurrence. Cycloalkenyl.
  • Z is selected from 5-6 membered heteroaryl, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl, isomeric Thiazolyl or pyridyl, and Z is optionally substituted by one or more R 7 ; each R 7 is independently selected from halo, C 1-8 aliphatic, hydroxy C 1-8 aliphatic, C 1-8 Hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon amino C 1-8 aliphatic hydrocarbon group, di(C 1-8 aliphatic hydrocarbon) amino C 1-8 aliphatic hydrocarbon group, hetero a cyclic C 1-8 aliphatic hydrocarbon group, a heterocyclic group or a C 1-8 aliphatic hydrocarbon group, wherein the heterocyclic group, as a separate group
  • a saturated or partially unsaturated 5-6 membered heterocyclic group of a hetero atom of S preferably selected from the group consisting of piperidinyl, piperazinyl, morpholinyl or tetrahydropyranyl, each optionally being independently
  • the ground is substituted with one or more C 1-8 aliphatic hydrocarbon groups, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from C 1-8 alkyl and C 3-8 cycloalkyl at each occurrence.
  • Z is selected from a 5-membered heteroaryl group, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl.
  • each R 7 is independently selected from the group consisting of methyl, ethyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, hydroxyethyl, A Oxymethyl, methoxyethyl, methoxypropyl, dimethylaminoethyl, morpholin-4-ylethyl, tetrahydropyranyl or methylcarbonyl.
  • Z is selected from the group consisting of:
  • l is selected from 0, 1 or 2.
  • m is selected from 0, 1, 2, or 3.
  • n is selected from 0, 1 or 2.
  • m and n are not 0 at the same time.
  • each group has the following definition:
  • W is selected from or
  • X is selected from NR 5 ;
  • Y is selected from N;
  • Z is selected from a 5-membered heterocyclic group, which is optionally substituted with one or more R 7 ;
  • R 1 is hydrogen
  • R 2 is an amino group
  • R 3 is hydrogen
  • R 4a , R 4b and R 4c are all hydrogen
  • R 5 is selected from hydrogen
  • R 7 is a C 1-8 aliphatic hydrocarbon group, wherein the C 1-8 aliphatic hydrocarbon group is independently selected from a C 1-8 alkyl group and a C 3-8 cycloalkyl group;
  • l is selected from 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1, or 2.
  • the compound of Formula Ib is independently selected from:
  • the compounds of formula I according to the invention may contain one or more chiral carbon atoms, each asymmetric carbon atom may be in the R or S configuration, two The configurations are all within the scope of the invention.
  • the compounds may exist as enantiomers, diastereomers or mixtures thereof.
  • the above compounds may be selected from the racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by chiral chromatography or fractional crystallization.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the formula I according to the invention, in particular a compound of the formula Ia and Ib, or a stereoisomer, tautomer, solvate thereof or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.
  • compositions of the present invention can be prepared by methods well known in the pharmaceutical art.
  • a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of the formula I according to the invention, in particular a compound of the formula Ia and formula Ib, or a pharmaceutically acceptable salt or prodrug thereof, with sterile distilled water, Thereby a solution is formed.
  • Surfactants may be added to promote the formation of a homogeneous solution or suspension.
  • Actual methods of preparing pharmaceutical compositions are known to those skilled in the art, for example see The Science and Practice of Pharmacy (Pharmaceutical Science and Practice), 20 th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compounds of the formula I according to the invention in particular the compounds of the formulae Ia and Ib, which may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions; Wait.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers. The particular mode of administration and dosage form will depend on the physicochemical properties of the compound itself, as well as the severity of the condition to be treated.
  • the compounds of formula I according to the invention in particular the compounds of formula Ia or formula Ib, or the pharmaceutical compositions of the invention may also be used in combination or in combination with one or more other drugs.
  • Drugs which may be combined with a compound of formula I of the invention, particularly a compound of formula Ia or formula Ib, or a pharmaceutical composition of the invention include, but are not limited to:
  • immunosuppressive agents such as methotrexate and cyclophosphamide
  • glucocorticoids such as dexamethasone and betamethasone
  • Non-steroidal anti-inflammatory drugs such as salicylates and aryl alkanoic acids
  • Cox-2 specific inhibitors such as rofecoxib and celecoxib
  • TNF- ⁇ binding proteins such as infliximab and adalimumab
  • Drugs such as interferon (such as interferon- ⁇ , interferon ⁇ ) and interleukin (such as interleukin-2).
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, for use in inhibiting Activity of BTK and/or JAK3.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, for use in the prevention And/or treatment of BTK and/or JAK3 mediated diseases.
  • Another aspect of the invention relates to a pharmaceutical combination
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • BTK BTK and/or JAK3.
  • Another aspect of the invention relates to a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical combination comprising a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • BTK and/or JAK3 mediated diseases for the prevention and/or treatment of BTK and/or JAK3 mediated diseases.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof or in accordance with the invention
  • a pharmaceutical composition of a compound of formula I, particularly a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, is prepared for inhibiting BTK and/or Use in JAK3 active drugs.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or A pharmaceutical composition of the invention, in particular a compound of the formula Ia and a compound of the formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, for the preparation of a therapeutic and/or Use in drugs that prevent BTK and/or JAK3 mediated diseases.
  • Another aspect of the invention relates to a compound of formula I according to the invention, in particular a compound of formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or A pharmaceutical composition of the invention, in particular a compound of the formula Ia and a compound of the formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, for the preparation of a therapeutic and/or Use in drugs that prevent BTK and/or JAK3 mediated diseases.
  • Another aspect of the invention relates to a method of inhibiting BTK and/or JAK3 activity in a biological system, the method comprising contacting the biological system with a compound of formula I of the invention, in particular a compound of formula Ia and formula Ib, or a A construct, tautomer, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above compound.
  • the biological system is an enzyme, a cell, a mammal.
  • mammals include, but are not limited to, humans; non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and Cats; laboratory animals, including rodents such as rats, mice, and guinea pigs.
  • non-human primates eg, chimpanzees and other mites and monkeys
  • livestock such as cattle, horses, sheep, goats, pigs
  • domestic animals such as rabbits, dogs, and Cats
  • laboratory animals including rodents such as rats, mice, and guinea pigs.
  • Another aspect of the invention relates to a method of inhibiting BTK and/or JAK3 in a mammal, especially a human, comprising administering to a mammal, especially a human, in need thereof a therapeutically effective amount of a compound of formula I according to the invention , in particular a compound of the formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or a package thereof
  • a pharmaceutical composition comprising the above compound.
  • Another aspect of the invention relates to a method of treating and/or preventing a BTK and/or JAK3 mediated disease, the method comprising administering to a mammal, especially a human, in need thereof, a therapeutically effective amount of a compound of the formula I according to the invention
  • a compound of the formula Ia and formula Ib, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the above compound.
  • the mentioned BTK and/or JAK3 mediated diseases are selected from autoimmune diseases, inflammatory diseases, xenogeneic immune conditions or diseases, thromboembolic diseases and cancers.
  • the autoimmune diseases and inflammatory diseases are selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.
  • the cancer is selected from the group consisting of B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, Set of cell lymphoma, small lymphocytic lymphoma, and the like.
  • compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • a "therapeutically effective amount" of a compound of the invention is determined by the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the dose for parenteral administration may be 1-200 mg/kg
  • the dose for oral administration may be 1-1000 mg/kg.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group "PG".
  • PG protecting group
  • Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • protecting groups are detailed in Greene, TW and PGMWuts, Protective Groups in Organi Synthesis (Protective Groups in Organic Synthesis), (1999), 4 th Ed., Wiley medium.
  • the protecting group can also be a polymeric resin.
  • Reaction route I includes the following steps:
  • Step 1 The compound of formula 3a or 3b is prepared by subjecting a compound of formula 1 to a substitution reaction with a compound of formula 2a or 2b, respectively.
  • the base used in the reaction may be selected from an organic base such as triethylamine, N,N-diisopropylethylamine or pyridine, and the base used in the reaction may also be used. It is selected from inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydroxide.
  • the reaction can also be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid and the like.
  • the reaction temperature is -80 ° C to 120 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene, methanol, ethanol, isopropanol, butanol and the like.
  • Step 2 Removal of the protecting group PG of the compound of formula 3a or 3b produces a compound of formula 4a or 4b.
  • the protecting group PG in the compound of the formula 3a or 3b may be a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group or the like.
  • the deprotection conditions for the reaction can be carried out under acid catalysis, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid and the like.
  • the reaction may also be catalytically hydrogenated under acidic or neutral conditions using a palladium catalyst.
  • the palladium catalyst of the present invention may be selected from palladium carbon and palladium hydroxide, and the acid of the reaction may be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, and hydrogen chloride. , 4-dioxane solution, sulfuric acid, and the like.
  • the reaction temperature is -80 ° C to 120 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene, methanol, ethanol, and the like.
  • Step 3 The compound of formula 4a or 4b is subjected to a condensation reaction to give a compound of formula 5a or 5b.
  • the condensation reagent may be selected from the group consisting of carbonyl diimidazole (CDI), O-benzotriazole-N, N, N', N'-tetramethyl urea tetrafluoroboric acid (TBTU), dicyclohexyl carbon Diimine (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and the like.
  • the base used in the reaction may be selected from the group consisting of triethylamine, N,N-diisopropylethylamine, pyridine and the like.
  • the reaction temperature is from 0 ° C to 80 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene and the like.
  • Step 4 The compound of formula 5a or 5b is subjected to a substitution reaction to give the corresponding compound of formula Ia or Ib.
  • the reaction can be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid. Wait.
  • the reaction can also be carried out in the presence of a base, and the base used in the reaction can be selected from strong bases such as sodium hydroxide, sodium t-butoxide, and sodium hydride.
  • This reaction can also be carried out in the presence of a palladium catalyst.
  • the palladium catalyst which can be used in the present invention is selected from the group consisting of bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) , tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) and palladium chloride (PdCl 2 ).
  • the base usable under this condition is preferably an inorganic base such as sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate or the like.
  • the reaction temperature is from 80 ° C to 160 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, toluene, ethanol, isopropanol, butanol, 2-butanol, water, and mixtures thereof.
  • Step 1 The compound of formula 3a or 3b is prepared by subjecting a compound of formula 1 to a substitution reaction with a compound of formula 2a or 2b, respectively.
  • the base used in the reaction may be selected from an organic base such as triethylamine, N,N-diisopropylethylamine or pyridine, and the base used in the reaction may also be used. It is selected from inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydroxide.
  • the reaction can also be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid and the like.
  • the reaction temperature is -80 ° C to 120 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene, methanol, ethanol, isopropanol, butanol and the like.
  • Step 5 Substituting a compound of formula 3a or 3b to give a compound of formula 6a or 6b.
  • the reaction can be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid. Wait.
  • the reaction can also be carried out in the presence of a base, and the base used in the reaction can be selected from strong bases such as sodium hydroxide, sodium t-butoxide, and sodium hydride.
  • the reaction can also be carried out in the presence of a palladium catalyst, and the palladium catalyst which can be used in the present invention is selected from the group consisting of bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ), tris(dibenzylidene).
  • a palladium catalyst which can be used in the present invention is selected from the group consisting of bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ), tris(dibenzylidene).
  • the base usable under this condition is preferably an inorganic base such as sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate or the like.
  • the reaction temperature is from 80 ° C to 160 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, toluene, ethanol, isopropanol, butanol, 2-butanol, water, and mixtures thereof.
  • Step 6 Removal of the protecting group PG of the compound of formula 6a or 6b produces a compound of formula 7a or 7b.
  • the protecting group in the compound of the formula 6a or 6b may be a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group or the like.
  • the deprotection conditions for the reaction can be carried out under acid catalysis, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid and the like.
  • the reaction can also be catalytically hydrogenated using a palladium catalyst under acidic or neutral conditions.
  • the palladium catalyst of the present invention is selected from the group consisting of palladium carbon and palladium hydroxide
  • the acid of the reaction can be selected from the group consisting of 1,4-dioxane of hydrochloric acid and hydrogen chloride. Hexacyclic solution, sulfuric acid, and the like.
  • the reaction temperature is -80 ° C to 120 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene, methanol, ethanol, and the like.
  • Step 7 The compound of formula 7a or 7b is subjected to a condensation reaction to give the corresponding compound of formula Ia or Ib.
  • the condensation reagent may be selected from the group consisting of carbonyl diimidazole (CDI), O-benzotriazole-N, N, N', N'-tetramethyl urea tetrafluoroboric acid (TBTU), dicyclohexyl carbon Diimine (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and the like.
  • the base used in the reaction may be selected from the group consisting of triethylamine, N,N-diisopropylethylamine, pyridine and the like.
  • the reaction temperature is from 0 ° C to 80 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene and the like.
  • Step 8 A compound of formula 4a is prepared by subjecting a compound of formula 1 to a substitution reaction with a compound of formula 8a.
  • the base used in the reaction may be selected from an organic base such as triethylamine, N,N-diisopropylethylamine or pyridine, and the base used in the reaction may also be used. It is selected from inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydroxide.
  • the reaction can also be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid and the like.
  • the reaction temperature is -80 ° C to 120 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene, methanol, ethanol, isopropanol, butanol and the like.
  • Step 3 The compound of formula 4a is subjected to a condensation reaction to give a compound of formula 5a.
  • the condensation reagent may be selected from the group consisting of carbonyl diimidazole (CDI), O-benzotriazole-N, N, N', N'-tetramethyl urea tetrafluoroboric acid (TBTU), dicyclohexyl carbon Diimine (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and the like.
  • the base used in the reaction may be selected from the group consisting of triethylamine, N,N-diisopropylethylamine, pyridine and the like.
  • the reaction temperature is from 0 ° C to 80 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, dichloromethane, toluene and the like.
  • Step 4 The compound of formula 5a is subjected to a substitution reaction to give the corresponding compound of formula Ia.
  • the reaction can be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, hydrogen chloride in 1,4-dioxane solution, acetic acid, sulfuric acid. Wait.
  • the reaction can also be carried out in the presence of a base, and the base used in the reaction can be selected from strong bases such as sodium hydroxide, sodium t-butoxide, and sodium hydride.
  • This reaction can also be carried out in the presence of a palladium catalyst.
  • the palladium catalyst which can be used in the present invention is selected from the group consisting of bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) Tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate (Pd(OAc) 2 ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) and palladium chloride (PdCl 2 ).
  • the base usable under this condition is preferably an inorganic base such as sodium carbonate, potassium carbonate, potassium phosphate, cesium carbonate or the like.
  • the reaction temperature is from 80 ° C to 160 ° C.
  • the solvent used in the reaction may be selected from the group consisting of 1,4-dioxane, toluene, ethanol, isopropanol, butanol, 2-butanol, water, and mixtures thereof.
  • the unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
  • the identification of the final product was performed by nuclear magnetic resonance (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).
  • Step 1 Preparation of (cis-4-((5-aminoacyl-2-chloropyrimidin-4-yl)amino)cyclohexyl)aminocarboxylic acid tert-butyl ester
  • step 1 The product obtained in the step 1 (100 mg, 0.27 mmol) was dissolved in methanol (2 mL), and 4N hydrogen chloride in 1,4-dioxane solution (4 mL, 1 mmol) was added, and the reaction mixture was reacted at room temperature for 2 hours. After the reaction mixture was concentrated, the residue was evaporated, mjjjjjjjj Acryloyl chloride (36.8 ⁇ L, 0.41 mmol) was added dropwise to the above solution at 0 °C. The reaction solution was allowed to react at room temperature overnight. The reaction mixture was washed with EtOAc EtOAc. Yield: 80.3%.
  • Step 3 Preparation of 4-((cis-4-acryloylaminocyclohexyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide
  • Step 1 (cis-4-((5-Aminoacyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)aminocarboxylic acid Preparation of tert-butyl ester
  • Step 2 Preparation of 4-((cis-4-aminocyclohexyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide
  • Step 3 Preparation of 4-((cis-4-propynylaminocyclohexyl)amino)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide
  • Step 1 Preparation of (R)-3-((5-Aminoacyl-2-chloropyrimidin-4-yl)amino)pyrrolidinyl-1-carboxylic acid tert-butyl ester
  • step 1 The product obtained in the step 1 (100 mg, 0.29 mmol) was dissolved in methanol (2mL), 4N hydrogen chloride in 1,4-dioxane solution (4 mL, 1 mmol), and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced vacuo. m. m. Acryloyl chloride (30.7 ⁇ L, 0.32 mmol) was added dropwise to the above solution at 0 ° C, and allowed to react at room temperature overnight. The reaction mixture was washed with EtOAc EtOAc. Yield: 96.1%.
  • Step 3 Preparation of (R)-4-((1-acryloylpyrrolidin-3-yl)amino)-2-((3-methylisothiazol-5-yl)amino)pyrimidine-5-carboxamide
  • Step 1 (R)-3-((5-Aminoacyl-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)amino)pyrrolidinyl-1-carboxylic acid Preparation of butyl ester
  • Step 3 (R)-4-((1-propynylacylpyrrolidin-3-yl)amino)-2-((3-methylisothiazol-5-yl)amino)pyrimidine-5-carboxamide preparation
  • Test Example 1 BTK kinase activity inhibition experiment
  • BTK kinase purchased from Invitrogen, Cat. No. PV3363
  • reaction buffer 40 mM Tris-HCl, pH 7.5; 20 mM MgCl 2 , 0.1 mg/ml BSA; 1 mM DTT; 2 mM MnCl 2
  • concentration was 1.1 ng/ ⁇ L
  • the compounds of the invention were diluted with deionized water to a final concentration (4 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 20 nM, 4 nM, 0.8 nM, respectively) 4 times (ie, 40 ⁇ M, 4 ⁇ M, 0.4 ⁇ M, 80 nM, 16 nM, 3.2 nM). ), and added to the 96-well plate experimental well at 2.5 ⁇ L/well. After incubation at 25 ° C for 10 minutes, ATP (50 ⁇ M) (purchased from Promega, Cat. No. V9102) and 0.2 ⁇ g/ ⁇ L of the enzyme reaction substrate Poly E4Y1 (purchased from Sigma, Cat. No.
  • Table III shows the inhibitory activity of the compounds of the present invention is selected in the analysis of BTK activity, wherein activity designated as IC "+++” to provide compound 50 nM; activity designated as IC "++” 50 to provide compound 50 ⁇ IC 50 ⁇ 100 nM; compounds designated as "+” by activity provide an IC 50 of 100 ⁇ IC 50 ⁇ 1000 nM.
  • Test Example 2 JAK3 and EGFR WT kinase activity inhibition experiments
  • JAK3 kinase purchased from SignalChem, Cat. No. J03-11G
  • EGFR WT kinase purchased from Promega, Cat. No. V3831
  • reaction buffer EGFR WT : 40 mM Tris-HCl, pH 7.5, 20 mM MgCl 2 , 0.1 mg/ MLB BSA, 1 mM DTT, 2 mM MnCl 2
  • JAK 3 40 mM Tris-HCl, pH 7.5, 20 mM MgCl 2 , 0.1 mg/ml BSA, 1 mM DTT
  • diluted to a final concentration of 2 times JAK3 final concentration 0.5 ng/ ⁇ L, EGFR
  • the final concentration of WT was 0.65 ng/ ⁇ L
  • the compounds of the invention were diluted with deionized water to a final concentration (4 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 20 nM, 4 nM, 0.8 nM, respectively) 4 times (ie, 40 ⁇ M, 4 ⁇ M, 0.4 ⁇ M, 80 nM, 16 nM, 3.2 nM). ), and added to the 96-well plate experimental well at 2.5 ⁇ L/well. After incubation at 25 ° C for 10 minutes, 10 ⁇ M ATP (purchased from Promega, Cat. No. V9102) and 0.2 ⁇ g/ ⁇ L enzyme reaction substrate Poly E4Y1 (purchased from Sigma, Cat. No. P0275-25MG) were added at 2.5 ⁇ L/well.
  • reaction was carried out at ° C for 60 minutes. After completion of the reaction, each well was added 10 ⁇ L ADP-Glo reagent (ADP-Glo TM kinase assay kit purchased from Promega, NO: V9102), reacted at 25 °C 40 min, each well was added 20 ⁇ L ADP-Glo Kinase Assay The reaction was carried out at 25 ° C for 30 minutes, and the kinase activity was measured by the luminescence method according to the ADP-Glo kinase assay kit, and the IC 50 of the test compound was calculated.
  • ADP-Glo reagent ADP-Glo TM kinase assay kit purchased from Promega, NO: V9102
  • the ratio of activity of EGFR WT and JAK3 is the ratio of the IC 50 value of EGFR WT of the compound of the present invention to the IC 50 value of JAK3, expressed in a fold relationship.
  • the results are shown in Table 4.
  • Table 4 shows the activity assay of JAK3 inhibitory activity of selected compounds of the present invention, and the selective inhibition assay for selected compounds of the present invention EGFR WT in the active EGFR WT.
  • EGFR WT and JAK3 activity ratios are designated as "A" compounds that provide EGFR WT /JAK3 greater than 100-fold; EGFR WT and JAK3 activity ratios designated as “B” compounds provide EGFR WT /JAK3 at 50-fold and 100-fold EGFR WT /JAK3 is less than 50-fold in the ratio of EGFR WT and JAK3 activity ratios designated as "C", the higher the ratio, the higher the selectivity and the lower the toxic side effects.

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Abstract

一种可以抑制BTK和/或JAK3激酶活性的化合物、药物组合物以及制备药物的用途，所述化合物具有结构式I，其中各取代基的定义如说明书所述。

Description

抑制BTK和/或JAK3激酶活性的化合物 技术领域
本发明涉及抑制BTK(布鲁顿酪氨酸激酶)和/或JAK3(Janus酪氨酸激酶3)激酶活性的化合物、其药物组合物、其在制药中的用途、使用其抑制BTK和/或JAK3活性的方法以及使用其治疗和/或预防哺乳动物(尤其是人)中BTK和/或JAK3介导的疾病或病症的方法。
背景技术
蛋白质激酶是组成人类酶的最大家族之一，迄今为止在人体中已鉴定出超过500种。他们通过向蛋白质转移磷酸基团来调节特定蛋白质的活性，从而调节复杂的信号传导通路。异常的蛋白质激酶活性与癌症，自身免疫性疾病等多种疾病相关。鉴于蛋白质激酶在信号传导通路中的关键作用以及激酶活性与多种疾病的相关性，激酶抑制剂已经成为了小分子化学药物研发的热门方向。
BTK(布鲁顿酪氨酸激酶)是属于TEC家族的非受体酪氨酸激酶，是B细胞受体(BCR)信号传导过程中的重要介质。BTK是早期B细胞发育以及成熟B细胞活化，信号转导和存活的重要调节剂，因此BTK抑制剂可以用于治疗B细胞异常活化相关的疾病，例如自身免疫性疾病，包括类风湿性关节炎和系统性红斑狼疮等。BTK抑制剂治疗自身免疫性疾病的效果在临床前动物模型上得到了初步的验证(Honigberg,L.A et al,Proceedings of the National Academy of Sciences of the United States of America,2010,107,13075-13080)。除了B细胞以外，实验证据表明BTK在单核细胞，巨噬细胞，中性粒细胞和肥大细胞的信号通路中也有作用。BTK抑制剂可以抑制单核细胞以及巨噬细胞由FcγR介导的细胞因子释放，这些细胞因子包括TNFa，IL-1β和IL-6，也可以抑制由FcεR介导的肥大细胞脱颗粒(Chang B.Y et al,Arthritis Research&Therapy,2011,13,R115)。
B细胞受体(BCR)介导的信号通路对多种淋巴瘤的存活起重要作用。作为BCR通路中的关键激酶，BTK也可以作为淋巴瘤的治疗靶点。临床实验表明，BTK抑制剂治疗慢性淋巴细胞性白血病(CLL)有显著的疗效。BTK抑制剂对其它淋巴瘤例如弥散性大B细胞淋巴瘤和套细胞淋巴瘤等也有明显的效果(Buggy,J.J et al,International Reviews of Immunology,2012,31,119-132)。
Janus激酶家族是调节淋巴造血系统中细胞功能的重要酪氨酸激酶。其包含4个已知成员，分别是JAK1、JAK2、JAK3和TYK2，其中JAK3(Janus酪氨酸激酶3)主要在淋巴细胞和自然杀伤性细胞中表达。JAK3与IL-2，IL-4，IL-7，IL-9，IL-15和IL-21受体的共同亚单位γc链连接(Ghoreschi K et al,Immunological Reviews,2009,228,273-87)。这些细胞因子通过JAK3的介导，对淋巴细胞的增殖、分化及其功能起重要的作用。JAK3激酶的功能缺失将导致人类和小鼠的免疫缺陷。基于JAK3激酶在免疫系统中的重要作用，JAK3 激酶是一个非常有吸引力的靶点用于治疗免疫相关的病症，例如类风湿性关节炎等自身免疫性疾病或者器官移植病人的同种异体移植物排异。选择性的JAK3抑制剂在类风湿性关节炎的临床实验中表现出了显著的疗效。
除了BTK抑制剂和JAK3抑制剂各自单独的应用，同时抑制BTK通路和JAK3通路有可能在临床应用上表现出协同的疗效。例如，Cetkovic-Cvrlje M等通过实验表明，联合应用BTK抑制剂和JAK3抑制剂可以更有效地提高移植物抗宿主病(GVHD)动物模型的存活率(Cetkovic-Cvrlje,M et al,British Journal of Haematology,2004,126,821-827)。
表皮生长因子受体(EGFR)是表皮生长因子(EGF)细胞增殖和信号传导的受体，是一种属于酪氨酸激酶家族的跨膜糖蛋白。野生型的表皮生长因子受体(EGFRWT)广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面，对细胞的生长、增殖和分发等生理过程发挥重要的作用。EGFR在许多实体肿瘤中高表达，在肿瘤细胞的增殖、血管生成、转移和凋亡过程中起到重要作用。目前存在许多针对EGFR的抗肿瘤药物。但由于EGFRWT在哺乳动物细胞中广泛分布，对EGFRWT的抑制可能具有一定的毒副作用。
因此，有必要开发具有良好的活性、可以口服、并在体内表现出有利于治疗应用的药代动力学性质、对EGFRWT没有强抑制作用、潜在毒副作用低的针对BTK和/或JAK3通路的新型化合物。
发明内容
根据本发明的一个方面，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式I(在下文中有时也被称为式I化合物)：
Figure PCTCN2014086821-appb-000001
其中：
R选自于被-NR3W取代的C3-8环烷基；4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；
W选自于
Figure PCTCN2014086821-appb-000002
或
Figure PCTCN2014086821-appb-000003
X选自于S、O或NR5；
Y选自于N或CR6；
Z选自于C6-12芳基或5-12元杂芳基，其任选地被一个或多个R7取代；
R1选自于氢、卤素、硝基、氰基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基或C1-8卤代脂烃基；
R2选自于氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
R3选自于氢或C1-8脂烃基；
R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R5选自于氢或C1-8脂烃基；
R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基；
每个R7独立地选自卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、羧基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、 杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基氨基亚磺酰基、杂环基氨基亚磺酰基、二(C1-8脂烃基)膦酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、杂环基、5-12元杂芳基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在一些实施方式中，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式Ia(在下文中有时也被称为式Ia化合物)：
Figure PCTCN2014086821-appb-000004
其中，X、Y、Z、W、R1、R2和R3均如式I中所定义。
在另一些实施方式中，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式Ib(在下文中有时也被称为式Ib化合物)：
Figure PCTCN2014086821-appb-000005
其中：
X、Y、Z、W、R1和R2均如式I中所定义，且
l选自于0至4的整数，其中当l是0时，
Figure PCTCN2014086821-appb-000006
为
Figure PCTCN2014086821-appb-000007
m选自于0至4的整数；其中当m是0时，
Figure PCTCN2014086821-appb-000008
为
Figure PCTCN2014086821-appb-000009
n选自于0至3的整数；其中当n是0时，
Figure PCTCN2014086821-appb-000010
为
Figure PCTCN2014086821-appb-000011
本发明的另一方面涉及一种药物组合物，所述药物组合物包含一种或多种本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明所述的药物组合物还可以包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备用于抑制BTK和/或JAK3活性的药物中的用途。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备用于预防或治疗BTK和/或JAK3介导的疾病的药物中的用途。
本发明的另一方面涉及本发明的药物组合物在制备抑制BTK和/或JAK3活性的药物中的用途，其中所述药物组合物包含一种或多种本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。在一些实施方式中，除前述化合物外，所述药物组合物还可以包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于预防或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，预防或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及本发明的药物组合物在制备用于预防或治疗BTK和/或JAK3介导的疾病的药物中的用途，其中所述药物组合物包含一种或多种本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐中，以及药学上可接受的辅料。在一些实施方式中，除前述化合物外，所述药物组合物还可以包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
本发明的另一方面涉及在生物体系中抑制BTK和/或JAK3活性的方法，该方法包含使所述生物体系接触本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物。
本发明的另一方面涉及预防或治疗BTK和/或JAK3介导的疾病的方法，包含对有需要的哺乳动物(尤其是人)给予治疗有效量的本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物。
本发明的另一方面涉及本发明所述的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐与一种或多种选自以下的活性物质在制备用于治疗BTK和/或JAK3介导的疾病的药物中的应用：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
在本申请中，BTK和/或JAK3介导的疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病和癌症。
具体实施方式
除非另有定义，否则本文所用的科技术语具有与权利要求主题所属领域技术人员通常所理解的涵义相同的涵义。
应理解，上述简述和下文的详述为示例性且仅用于举例说明，而不对本发明主题作任何限制。
本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-8脂烃基是指具有总共1至8个碳原子的如下文所定义的脂烃基；C1-8烷基是指具有总共1至8个碳原子的如下文所定义的烷基；C3-8环烷基是指具有总共3至8个碳原子的如下文所定义的环烷基；C6-12芳基是指具有总共6至12个碳原子的如下文所定义的芳基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除非本说明书中另外特别指明，本发明所述的所有组合基团(即是指由两个或两个以上的基团组合起来的基团)是以最后描述的基团作为连接位点与分子其余部分连接。举例来说，基团“杂环基脂烃基”是指杂环基通过脂烃基与分子其余部分连接；基团“脂烃基氧基”是指脂烃基通过氧基与分子其余部分连接等等。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义：
“氨基”是指-NH2基团。
“氰基”是指-CN基团。
“羟基”是指-OH基团。
“硝基”是指-NO2基团。
“氧代”是指＝O取代基。
“羰基”或“酰基”是指-C(＝O)-基团。
“巯基”是指-S基团。
“磺酰基”是指-S(＝O)2-基团。
“亚磺酰基”是指-S(＝O)-基团。
“膦酰基”是指-P(＝O)(OH)2基团。
“氨基酰基”是指-C(＝O)-NH2基团。
“氨基磺酰基”是指-S(＝O)2-NH2基团。
“氨基亚磺酰基”是指-S(＝O)-NH2基团。
在本申请中，术语“卤素”是指氟、氯、溴或碘，优选氟或氯，更优选氟。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基”是指具有脂肪族化合物基本属性的仅由碳原子和氢原子组成且通过单键与分子的其余部分连接的饱和或不饱和的基团。脂烃基包括直链或支链的烷基、烯基和炔基以及环烷基和环烯基，其中烷基、烯基、炔基、环烷基和环烯基均如下文所定义。在本申请中，脂烃基是指烷基、烯基、炔基、环烷基和/或环烯基，优选是指烷基和/或环烷基。脂烃基上的氢均可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键且通过单键与分子的其余部分连接的直链或支链的基团。烷基可以具有例如1至18个、优选1至12个、更优选1至8个碳原子。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等，优选甲基、乙基、丙基、异丙基、正丁基，更优选甲基和乙基。烷基上的氢均可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至18个、优选2至10个、更优选2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，包括但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-2-烯基、戊-1,4-二烯基等，优选乙烯基、丙烯基。烯基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至18个、优选为2至10个、更优选2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。炔基的实例包括但不限于乙炔基、丙-1-炔基、戊-1-烯-4-炔基等。炔基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的饱和的非芳香族单环或多环烃基，其可包括稠合环体系或桥环体系，具有例如3至15个、优选3至12个、更优选3至8个、甚至更优选5-6个碳原子，且经由环上任何适宜的碳原子通过单键与分子的其余部分连接。环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、和金刚烷基等，优选环丁基、环戊基、环己基。环烷基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“环烯基”意指仅由碳原子和氢原子组成的、含有至少一个双键的稳定的非芳香族单环或多环烃基，其可包括稠合环体系或桥环体系。其具有例如3至15个、优选3至12个、更优选4至8个碳原子，且经由环上任何适宜的碳原子通过单键与分子的其余部分连接。环烯基的实例包括但不限于环丁烯基、环戊烯基、环己烯基、1,3-环己二烯、1,4-环己二烯、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5-氢-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、八氢-4,7-亚甲基-1-氢-茚基和八氢-2,5-亚甲基 -并环戊二烯基等。环烯基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷基、烷氧基、杂环基等等。
在本申请中，术语“卤代脂烃基”是指被一个或多个卤素原子取代的脂烃基，其中脂烃基如上文所定义。其实例包括但不限于氟甲基、二氟甲基、三氟甲基、氟乙基、1,1-二氟乙基、氯甲基、氯乙基、二氯甲基、1,2-二氯乙基、氟代乙烯基、氟代环戊基、氟代环己基、氯代环己烯基等，优选氟乙基。
在本申请中，术语“羟基脂烃基”是指被一个或多个羟基取代的如上文所定义的脂烃基。其实例包括但不限于1-羟基乙基、1,2-二羟基乙基、3-羟基环戊基、4-羟基环己基，3,4-二羟基环己基等，优选1-羟基乙基。
在本申请中，术语“氨基脂烃基”是指被一个或多个氨基取代的如上文所定义的脂烃基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氧基”是指式-ORa基团，其中Ra为如上文所定义的脂烃基。脂烃基氧基中的脂烃基部分也可如上文对脂烃基所述的那样被任选取代。脂烃基氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、乙烯基氧基、1-丙烯基氧基、1-丙炔基氧基、环戊基氧基、环己基氧基等，优选甲氧基、乙氧基，更优选甲氧基。
在本申请中，术语“羟基脂烃基氧基”是指其中脂烃基被一个或多个羟基取代的如上文所定义的脂烃基氧基。其实例包括但不限于1-羟基乙氧基、1-羟基丙氧基、3-羟基环戊烷氧基、3,4-二羟基环己烷氧基等，优选1-羟基乙氧基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基羰基”是指式-C(＝O)-Ra基团，其中Ra为如上文所定义的脂烃基。脂烃基羰基中的脂烃基部分也可如上文对脂烃基所述的那样被任选取代。脂烃基羰基包括烷基羰基、烯基羰基、炔基羰基、环烷基羰基和环烯基羰基，其中烷基、烯基、炔基、环烷基和环烯基均如上面所定义的。在本申请中，脂烃基羰基优选是指烷基羰基和/或环烷基羰基。脂烃基羰基的实例包括但不限于甲基羰基(也被称为乙酰基)、乙基羰基(也被称为丙酰基)、异丙基羰基、丁基羰基、乙烯基羰基、丙烯基羰基、环戊基羰基、环己基羰基等，优选甲基羰基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氨基”是指式-NHRa基团，其中Ra为如上文所定义的脂烃基。脂烃基氨基包括烷基氨基、烯基氨基、炔基氨基、环烷基氨基和环烯基氨基，其中烷基、烯基、炔基、环烷基和环烯基均如上面所定义的。在本申请中，脂烃基氨基优选是指烷基氨基和/或环烷基氨基。其实例包括但不限于甲基氨基、乙基氨基、异丙基氨基、乙烯基氨基、丙烯基氨基、丙炔基氨基、环丁基氨基、环戊基氨基、环己基氨基、环己烯基氨基等，优选甲基氨基、乙基氨基、环己基氨基。
在本申请中，作为独立的基团或其它基团的一部分，术语“二脂烃基氨基”是指氨基上的两个氢分别被脂烃基取代的氨基基团，可用式-NRaRb表示，其中Ra和Rb分别独立地为如上文所定义的脂烃基。在本申请中，二脂烃基氨基优选是指二烷基氨基。二烷基氨基的 实例包括但不限于二甲基氨基、二乙基氨基、二丙基氨基、甲基乙基氨基等，优选二甲基氨基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氧基脂烃基氧基”是指其中的脂烃基被如上文所定义的脂烃基氧基取代的如上文所定义的脂烃基氧基。在本申请中，脂烃基氧基脂烃基氧基优选是指烷氧基烷氧基、烷氧基环烷氧基和/或环烷氧基烷氧基，其实例包括但不限于如甲氧基乙氧基、乙氧基乙氧基、甲氧基环戊烷氧基、甲氧基环己烷氧基、环戊烷氧基甲氧基等。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氨基脂烃基”是指被如上文所定义的脂烃基氨基取代的如上文所定义的脂烃基。
在本申请中，作为独立的基团或其它基团的一部分，术语“二脂烃基氨基脂烃基”是指被如上文所定义的二脂烃基氨基取代的如上文所定义的脂烃基。其实例包括但不限于二甲基氨基乙基、二乙基氨基乙基、(甲基)(乙基)氨基乙基等，优选二甲基氨基乙基。
在本申请中，作为独立的基团或其它基团的一部分，术语“二脂烃基氨基脂烃基氨基”是指其中脂烃基被如上文所定义的二脂烃基氨基取代的如上文所定义的脂烃基氨基。其实例包括但不限于二甲基氨基乙基氨基、二乙基氨基乙基氨基、(甲基)(乙基)氨基乙基氨基等，优选二甲基氨基乙基氨基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氨基酰基”是指其中氨基上的一个氢被如上文所定义的脂烃基替代的氨基酰基，其可以表示为式-C(＝O)-NH-Ra，其中Ra为如上文所定义的脂烃基。其实例包括但不限于-C(＝O)-NH-CH3、-C(＝O)-NH-C2H5、环己基氨基酰基等，优选-C(＝O)-NH-CH3。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基”意指由含有1至6个选自氮、氧和硫的杂原子组成的稳定的3元至18元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系或桥环体系。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的3元至12元非芳香性单环或双环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的3元至8元非芳香性单环基团，更优选为包含1至2个选自氮、氧和硫的杂原子的稳定的5元至6元非芳香性单环基团。杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。杂环基的实例包括但不限于：氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、吗啉基、硫代吗啉基、哌嗪基、哌啶基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等，优选哌嗪基、哌啶基、四氢吡喃基、吗啉基，更优选哌嗪基。杂环基可任选地被任意适当的取代基取代，该取代 基包括但不限于卤素、羟基、氨基、烷基、烷氧基、烷基羰基等等。
在本申请中，“氮杂环基”是指环上含有至少一个氮原子的如上文所定义的杂环基。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基氧基”是指式-ORh基团，其中Rh为如上文所定义的杂环基。杂环基氧基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基羰基”是指式-C(＝O)-Rh基团，其中Rh为如上文所定义的杂环基。杂环基羰基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基氨基”是指式Rh-NH-，其中Rh为如上文所定义的杂环基。杂环基氨基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基氨基酰基”是指其中氨基上的一个氢被如上文所定义的杂环基替代的氨基酰基，其可以表示为式-C(＝O)-NH-Rh，其中Rh为如上文所定义的杂环基。杂环基氨基酰基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基脂烃基”是指被如上文所定义的杂环基取代的如上文所定义的脂烃基。杂环基脂烃基中的杂环基部分可如上文关于杂环基所述的那样被任选取代，并且杂环基脂烃基中的脂烃基部分可如上文关于脂烃基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基脂烃基氧基”是指其中脂烃基被如上文所定义的杂环基取代的如上文所定义的脂烃基氧基。杂环基脂烃基氧基中的杂环基部分可如上文关于杂环基所述的那样被任选取代，并且杂环基脂烃基氧基中的脂烃基部分可如上文关于脂烃基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“芳基”意指具有6至18个、优选为6至12个碳原子及至少一个芳香环的体系。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，其可以包含稠合环或桥环体系。芳基经由芳香族环原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等，优选苯基。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂芳基”意指环内具有1至4个选自氮、氧及硫的杂原子，以及至少一个芳香环的5元至16元环体系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，其可包括稠合环体系或桥环体系，条件是连接点为芳香族环原子。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性单环或双环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至8元芳香性单环或双环基团，最优选包含 1至2个选自氮、氧和硫的杂原子的稳定的5元至6元芳香性单环基团。杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、咪唑基、苯并咪唑基、吡唑基、苯并吡唑基、三唑基、四唑基、吡啶基、吡嗪基、三嗪基、嘧啶基、哒嗪基、吲嗪基、吲哚基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、噻唑基、异噻唑基、苯并噻唑基、苯并噻吩基、噁唑基、异噁唑基、噁二唑基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、咪唑[1,2-a]吡啶基等，优选吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基、异噻唑基、吡啶基、咪唑[1,2-a]吡啶基，更优选吡唑基、异噁唑基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被一个或多个卤素取代的烷基”表示烷基未被取代或被一个或多个卤素取代，且该描述同时包括被取代的烷基与未被取代的烷基。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
由于本发明的式I化合物含有烯双键，因此，除非另有说明，否则本发明的式I化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的式I化合物的所有互变异构形式也将包含在本发明的范围内。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的、与无机酸或有机酸所形成的盐。所述无机酸包括但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等；所述有机酸包括但不限于甲酸、乙酸、三氟乙酸、丙酸、辛酸、己酸、癸酸、十一碳烯酸、乙醇酸、葡糖酸、乳酸、草酸、癸二酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、硬脂酸、油酸、肉桂酸、月桂酸、苹果酸、谷氨酸、焦谷氨酸、天冬氨酸、苯甲酸、甲磺酸、对甲苯磺酸、海藻酸、抗环血酸、水杨酸、4-氨基水杨酸、萘二磺酸等。这些盐可通过本领域已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的盐。这些盐是通过将无机碱或有机碱添加至游离酸而制备的。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐和镁盐。衍生自有机碱的盐包括但不限于以下碱的盐：伯胺、仲胺及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、 咖啡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。
根据带电荷官能团的数目和阳离子或阴离子的化合价，本发明化合物可以含有多个阳离子或阴离子。
通常，结晶化作用会产生本发明化合物的溶剂化物。在本申请中，“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。溶剂可以是水，该情况下的溶剂化物是水合物。或者，溶剂也可以是有机溶剂。本发明化合物的溶剂化物也属于本发明范围之内。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物递送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的辅料。本申请的药物组合物可以是单个制剂，也可以是多个制剂的组合。
在本申请中，“药学上可接受的辅料”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，“治疗有效量”是指本发明化合物的量，当本发明化合物被给予哺乳动物(例如人)时，该量足以有效地治疗哺乳动物(例如人)的疾病或病症。构成“治疗有效量”的本发明化合物的量取决于所用的具体化合物、要治疗的具体病症、病症的起因、药物的靶点、疾病的严重程度、给药方式以及待治疗的哺乳动物的年龄、体重、身体状况等，但可常规地由本领域技术人员根据其自身的知识及本申请公开的内容而决定。
根据本发明的一个方面，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式I：
Figure PCTCN2014086821-appb-000012
其中：
R选自被-NR3W取代的C3-8环烷基；4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；
W选自于
Figure PCTCN2014086821-appb-000013
或
Figure PCTCN2014086821-appb-000014
X选自于S、O或NR5；
Y选自于N或CR6；
Z为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R7取代；
R1选自于氢、卤素、硝基、氰基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基或C1-8卤代脂烃基；
R2选自于氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
R3选自于氢或C1-8脂烃基；
R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R5选自于氢或C1-8脂烃基；
R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基；
每个R7独立地选自卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、羧基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基 C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基氨基亚磺酰基、杂环基氨基亚磺酰基、二(C1-8脂烃基)膦酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、杂环基、5-12元杂芳基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
C6-12芳基和5-12元杂芳基独立地任选地被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R为被-NR3W取代的C3-8环烷基，其中R3选自于氢或C1-8脂烃基，且W选自于
Figure PCTCN2014086821-appb-000015
或
Figure PCTCN2014086821-appb-000016
其中R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在式I化合物的一些实施方式中，R为被-NR3W取代的环己烷，其中R3选自于氢或C1-8脂烃基，且W选自于
Figure PCTCN2014086821-appb-000017
其中R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R为被-NR3W取代的环己烷，其中R3选自于氢或C1-8脂烃基，且W选自于
Figure PCTCN2014086821-appb-000018
其中R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基，更优 选为C1-8烷基。
在式I化合物的一些实施方式中，R为被-NR3W取代的环己烷，其中R3为氢，且W选自于
Figure PCTCN2014086821-appb-000019
其中R4a、R4b和R4c均为氢。
在式I化合物的一些实施方式中，R为被-NR3W取代的环己烷，其中R3选自于氢或C1-8脂烃基，且W为
Figure PCTCN2014086821-appb-000020
其中C1-8脂烃基选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基，优选选自于C1-8烷基和C3-8环烷基，更优选为C1-8烷基。
在式I化合物的一些实施方式中，R为被-NR3W取代的环己烷，其中R3选自于氢，且W为
Figure PCTCN2014086821-appb-000021
在式I化合物的一些实施方式中，R选自于4-10元饱和的氮杂环基，其中所述氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中所述氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中每个W独立地选自于
Figure PCTCN2014086821-appb-000022
或
Figure PCTCN2014086821-appb-000023
其中R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R选自于4-10元饱和的氮杂环基，其中所述氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中所述氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中每个W独立地为
Figure PCTCN2014086821-appb-000024
其中R4a、R4b和R4c均为氢。
在式I化合物的一些实施方式中，R选自于4-10元饱和的氮杂环基，其中所述氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中所述氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中每个W独立地为
Figure PCTCN2014086821-appb-000025
在式I化合物的一些实施方式中，X为S。在式I化合物的另一些实施方式中，X为 O。
在式I化合物的一些实施方式中，X为NR5，其中R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，X为NR5，其中R5选自于氢或C1-8烷基。在一些实施方式中，X为NR5，其中R5为氢。
在式I化合物的一些实施方式中，Y为CR6，其中R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在式I化合物的一些实施方式中，Y为CR6，其中R6选自于氢、卤素、C1-8烷基或C1-8卤代烷基。在式I化合物的一些实施方式中，Y为CR6，其中R6为氢。
在式I化合物的一些实施方式中，Y为N。
在式I化合物的一些实施方式中，R1选自于氢、卤素、硝基、氰基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基或C1-8卤代脂烃基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R1选自于氢、卤素或C1-8烷基。
在式I化合物的一些实施方式中，R1为氢。
在式I化合物的一些实施方式中，R2选自于氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R2为氨基。
在式I化合物的一些实施方式中，Y为N，R1为氢，R2为氨基。
在式I化合物的一些实施方式中，Z为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R7取代，其中每个R7独立地选自卤素、羟基、杂环基、C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基羰基、杂环基氨基、杂环基氨基酰基、杂环基氨基磺酰基、杂环基氨基亚磺酰基、杂环基氧基、杂环基羰基、杂环基磺酰基、杂环基亚磺酰基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、杂环基C1-8脂烃基氧基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，Z为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基、杂环基氧基、杂环基氨基、杂环基氨基酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，Z为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氨基酰基，其中杂环基表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，其任选独立地被一个或多个独立地选自C1-8脂烃基的取代基取代，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，Z为苯基或5元杂芳基，其任选地被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氨基酰基，其中杂环基表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，其任选独立地被一个或多个独立地选自C1-8脂烃基的取代基取代，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，式I化合物具有结构式Ia：
Figure PCTCN2014086821-appb-000026
其中，X、Y、Z、W、R1、R2和R3均如式I中所定义。
在本发明的式Ia化合物的一些实施方式中，X为S。在另一些实施方式中，X为O。在另一些实施方式中，X选自于NR5，其中R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独 立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，X选自于NR5，其中R5选自于氢或C1-8烷基。在一些实施方式中，X选自于NR5，其中R5选自于氢或甲基，更优选R5为氢。
在本发明的式Ia化合物的一些实施方式中，Y选自于N。在另一些实施方式中，Y为CR6，其中R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基，其中C1-8脂烃基在每次出现时独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，Y为CR6，其中R6选自于氢、卤素、C1-8烷基或C1-8卤代烷基。
在本发明的式Ia化合物的一些实施方式中，R1选自于氢、卤素、硝基、氰基、羟基、C1-8烷氧基、氨基、C1-8烷基氨基、二(C1-8烷基)氨基、C1-8烷基或C1-8卤代烷基，其中C1-8脂烃基独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，R1选自于氢或卤素。在一些实施方式中，R1为氢。
在本发明的式Ia化合物的一些实施方式中，R2选自于氨基、C1-8烷基氨基或二(C1-8烷基)氨基。在本发明的式Ia化合物的一些实施方式中，R2为氨基。
在本发明的式Ia化合物的一些实施方式中，Y为N，R1为氢，R2为氨基。
在本发明的式Ia化合物的一些实施方式中，Z为C6-12芳基或5至12元杂芳基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、羟基、杂环基、C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基氧基、杂环基氨基、杂环基氨基酰基、杂环基氧基、杂环基羰基、杂环基磺酰基、杂环基亚磺酰基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、氨基酰基、C1-8脂烃基羰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氨基磺酰基、C1-8脂烃基氨基亚磺酰基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、杂环基C1-8脂烃基氧基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O和S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ia化合物的一些优选方式中，Z为C6-12芳基或5至12元杂芳基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O和S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ia化合物的一些实施方式中，Z为C6-12芳基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、羟基、杂环基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、杂环基羰基、杂环基氨基酰基、杂环基氨基磺酰基、杂环基氨基亚磺酰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氨基磺酰基、C1-8脂烃基氨基亚磺酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N和S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ia化合物的一些实施方式中，Z为苯基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、杂环基羰基、杂环基氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N和S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或多个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ia化合物的一些实施方式中，Z为苯基，其任选被一个或多个R7取代，每个R7独立地选自卤素、羟基、杂环基、C1-8烷基、C3-8环烷基、杂环基C1-8烷基、羟基C1-8烷基、C1-8卤代烷基、C1-8烷基氧基、C1-8烷基氧基C1-8烷基氧基、杂环基氧基、杂环基C1-8烷基氧基、C1-8烷基氨基、二(C1-8烷基)氨基、杂环基氨基、二(C1-8烷基)氨基C1-8烷基氨基、杂环基羰基、杂环基氨基酰基、C1-8烷基氨基酰基或C3-8环烷基氨基，其中杂环基，作为独立的基团或它他基团的一部分，表示含一个或两个选自O、N和S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选四氢吡喃基、哌啶基、吗啉基或哌嗪基，每个杂环基独立地任选被一个或两个选自以下的取代基取代：羟基、C1-8烷基、C1-8烷基氧基、C1-8烷基羰基。
在本发明的式Ia化合物的一些实施方式中，Z为苯基，其任选被一个或多个R7取代，每个R7独立地选自于杂环基或C1-8脂烃基氨基酰基，其中杂环基表示含一个或两个选自O、N和S的杂原子的饱和或部分不饱和的5-6元杂环基团，其独立地任选被一个或两个选自C1-8脂烃基的取代基取代。
在本发明的式Ia化合物的一些实施方式中，Z为苯基，其任选被一个或多个R7取代，每个R7独立地选自于1-甲基-哌嗪-4基或甲基氨基酰基。
在本发明的式Ia化合物的另一些实施方式中，Z为5-12元杂芳基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、羟基C1-8脂烃基氧基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基氨基酰基、杂环基氨基磺酰基、杂环基氨基亚磺酰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氨基磺酰基、C1-8脂烃基氨基亚磺酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或多个选自O、N或S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基独立地任选被一个或多个选自如下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，以及其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ia化合物的另一些实施方式中，Z为5-12元杂芳基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基氧基C1-8脂烃基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或多个选自如下的取代基取代：C1-8脂烃基或C1-8脂烃基氧基，以及其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ia化合物的一些实施方式中，Z为5-10元杂芳基，其任选被一个或多个R7取代，其中每个R7独立地选自杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基氧基C1-8脂烃基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、四氢吡喃基、吗啉基或哌嗪基，每个杂环基独立地任选被一个或多个C1-8脂烃基取代，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在本发明的式Ia化合物的一些实施方式中，Z选自5-10元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、异噻唑基、异噁唑基、吡啶基或咪唑[1,2-a]吡啶基，其任选被一个或多个R7取代，其中每个R7独立地选自C3-8环烷基、杂环基、C1-8烷基、杂环基C1-8烷基、羟基C1-8烷基、C1-8卤代烷基、C1-8烷基氧基C1-8烷基、氨基C1-8烷基、C1-8烷基氨基C1-8烷基、二(C1-8烷基)氨基C1-8烷基、C1-8烷基氧基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分 不饱和的5-6元杂环基团，优选选自吗啉基或哌嗪基，每个杂环基独立地任选被一个或多个C1-8烷基取代。
在本发明的式Ia化合物的一些实施方式中，Z选自5元杂芳基，优选选自吡唑基或异噁唑基，其任选被一个或多个R7取代，其中每个R7独立地选自C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8卤代脂烃基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基，优选独立地选自C1-8烷基和C3-8环烷基。
在本发明的式Ia化合物的一些实施方式中，Z选自5-10元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、异噻唑基、异噁唑基、吡啶基或咪唑[1,2-a]吡啶基，其任选被一个或多个R7取代，其中每个R7独立地选自甲基、环丁基、环戊基、羟基乙基、甲氧基、甲氧基乙基、氟代乙基、二甲基氨基乙基、1-甲基-哌嗪-4-基或吗啉-4-基乙基。
在本发明的式Ia化合物的一些实施方式中，Z选自5-6元杂芳基，优选选自吡唑基、异噻唑基或吡啶基，其任选被一个或多个R7取代，其中每个R7独立地选自甲基、羟基乙基、甲氧基、甲氧基乙基、氟代乙基。
在本发明的式Ia化合物的一些实施方式中，Z选自于：
Figure PCTCN2014086821-appb-000027
Figure PCTCN2014086821-appb-000028
在本发明的式Ia化合物的一些实施方式中，各基团具有如下定义：
W选自于
Figure PCTCN2014086821-appb-000029
或
Figure PCTCN2014086821-appb-000030
X为NR5；
Y为N；
Z选自于苯基或五元杂环基，其任选被一个或多个R7取代；
R1为氢；
R2为氨基；
R3为氢；
R4a、R4b和R4c均为氢；
R5为氢；
每个R7独立地选自于卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、卤代C1-8脂烃基、C1-8脂烃基氨基酰基或杂环基，其中杂环基表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，其独立地任选被一个或两个选自C1-8脂烃基的取代基取代，其中C1-8脂烃基在每次出现时独立地选自于C1-8烷基和C3-8环烷基。
在本发明的式Ia化合物的一些实施方式中，所述化合物选自于：
Figure PCTCN2014086821-appb-000031
在式I化合物的一些实施方式中，式I化合物具有结构式Ib：
Figure PCTCN2014086821-appb-000032
其中：
X、Y、Z、W、R1和R2均如式I中所定义；
l选自于0至4的整数，其中当l是0时，
Figure PCTCN2014086821-appb-000033
为
Figure PCTCN2014086821-appb-000034
m选自于0至4的整数；其中当m是0时，
Figure PCTCN2014086821-appb-000035
为
Figure PCTCN2014086821-appb-000036
n选自于0至3的整数；其中当n是0时，
Figure PCTCN2014086821-appb-000037
为
Figure PCTCN2014086821-appb-000038
在式Ib化合物的一些实施方式中，各基团具有如下定义：
W选自于
Figure PCTCN2014086821-appb-000039
或
Figure PCTCN2014086821-appb-000040
X选自于S、O或NR5；
Y选自于N或CR6；
Z为5-12元杂芳基，其任选地被一个或多个R7取代；
l选自于0、1或2，其中当l是0时，
Figure PCTCN2014086821-appb-000041
为
Figure PCTCN2014086821-appb-000042
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086821-appb-000043
为
Figure PCTCN2014086821-appb-000044
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086821-appb-000045
为
Figure PCTCN2014086821-appb-000046
R1选自于氢、卤素、硝基、氰基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基或C1-8卤代脂烃基；
R2选自于氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R5选自于氢或C1-8脂烃基；
R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基；
每个R7独立地选自卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基氨基亚磺酰基、杂环基氨基亚磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自卤素或C1-8脂烃基的取代基取代；
其中，C1-8脂烃基在每次出现时独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ib化合物的一些实施方式中，W选自于其中，R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8烷基)氨基甲基。在另一些实施方式中，W选自于
Figure PCTCN2014086821-appb-000048
其中，R4a、R4b和R4c均为氢。
在本发明的式Ib化合物的另一些实施方式中，W选自于
Figure PCTCN2014086821-appb-000049
在本发明的式Ib化合物的一些实施方式中，X选自于NR5，其中R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，X选自于NR5，其中R5选自于氢或C1-8烷基。在一些实施方式中，X选自于NR5，其中R5选自于氢或甲基。在又一些实施方式中，X选自于NR5，其中R5选自于氢。
在本发明的式Ib化合物的一些实施方式中，Y选自于N。在另一些实施方式中，Y选自于CR6，其中R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基，其中C1-8脂烃基独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在另一些实施方式中，Y选自于CR6，其中R6选自于氢、卤素、C1-8烷基或C1-8卤代烷基。
在本发明的式Ib化合物的一些实施方式中，R1选自于氢、卤素、硝基、氰基、羟基、C1-8烷氧基、氨基、C1-8烷基氨基、二(C1-8烷基)氨基、C1-8烷基或C1-8卤代烷基。在一些实施方式中，R1选自于氢或卤素。在一些实施方式中，R1选自于氢。
在本发明的式Ib化合物的一些实施方式中，R2选自于氨基、C1-8烷基氨基或二(C1-8烷基)氨基。在一些实施方式中，R2选自于氨基。
在本发明的式Ib化合物的一些实施方式中，Y为N，R1为氢，R2为氨基。
在本发明的式Ib化合物的一些实施方式中，Y为CR6，R1为氢，R2为氨基，其中R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基，其中C1-8脂烃基独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ib化合物的一些实施方式中，Y为CR6，R1为氢，R2为氨基，其中R6选自于氢、卤素、C1-8烷基或C1-8卤代烷基。
在本发明的式Ib化合物的一些实施方式中，Z选自于5-10元杂芳基，其任选地被一个或多个R7取代；每个R7独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、羟基C1-8脂烃基氧基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、杂环基羰基、杂环基氨基酰基、杂环基氨基磺酰基、杂环基氨基亚磺酰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氨基磺酰基、C1-8脂烃基氨基亚磺酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，优选选自哌啶基、哌嗪基、吗啉基或四氢吡喃基，每个杂环基独立地任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基，
其中C1-8脂烃基在每次出现时独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在本发明的式Ib化合物的一些实施方式中，Z选自于5-6元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基、异噻唑基或吡啶基，并且Z任选地被一个或多个R7取代；每个R7独立地选自卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、杂环基或C1-8脂烃基羰基，其中，杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、哌嗪基、吗啉基或四氢吡喃基，每个杂环基任选独立地被一个或多个C1-8脂烃基取代，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在本发明的式Ib化合物的一些实施方式中，Z选自于5元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且Z任选地被一个或两个R7取代；每个R7独立地选自甲基、乙基、异丙基、正丁基、环丁基、环戊基、羟基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、二甲基氨基乙基、吗啉-4-基乙基、四氢吡喃基或甲基羰基。
在本发明的式Ib化合物的一些实施方式中，Z选自于：
Figure PCTCN2014086821-appb-000050
在式Ib化合物的一些实施方式中，l选自于0、1或2。
在式Ib化合物的一些实施方式中，m选自于0、1、2或3。
在式Ib化合物的一些实施方式中，n选自于0、1或2。
在式Ib化合物的一些实施方式中，m和n不同时为0。
在式Ib化合物的一些实施方式中，各基团具有如下定义：
W选自于
Figure PCTCN2014086821-appb-000051
或
Figure PCTCN2014086821-appb-000052
X选自于NR5；
Y选自于N；
Z选自于5元杂环基，其任选被一个或多个R7取代；
R1为氢；
R2为氨基；
R3为氢；
R4a、R4b和R4c均为氢；
R5选自于氢；
R7为C1-8脂烃基，其中C1-8脂烃基独立地选自于C1-8烷基和C3-8环烷基；
l选自于0、1或2；
m选自于0、1、2或3；
n选自于0、1或2。
在式Ib化合物的一些实施方式中，该式Ib化合物独立地选自于：
Figure PCTCN2014086821-appb-000053
本发明的式I化合物，特别是式Ia和式Ib化合物，或其药学上可接受的盐可能含一个或多个手性碳原子，每个不对称碳原子可以是R或S构型，两种构型都在本发明范围之内。因此，化合物可以作为对映异构体、非对映异构体或它们的混合物存在。上述化合物可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术拆分，例如通过手性色谱法或者分段结晶法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法解析外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL  ORGANIC CHEMISTRY 5.sup.TH Ed.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
本发明的另一方面涉及药物组合物，其包含一种或多种本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明的药物组合物可以被配制为固态、半固态、液态或气态制剂，如片剂、胶囊、粉剂、颗粒剂、膏剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶。
本发明的药物组合物可以通过制药领域中公知的方法制备。例如，旨在注射给药的药物组合物可以通过将本发明的式I化合物，特别是式Ia和式Ib化合物，或其药学上可接受的盐或前药与灭菌的蒸馏水组合来制备，从而形成溶液剂。可添加表面活性剂以促进形成均匀溶液或混悬液。制备药物组合物的实际方法为本领域技术人员所已知，例如可参见The Science and Practice of Pharmacy(制药科学与实践)，20thEdition(Philadelphia College of Pharmacy and Science,2000)。
本发明的药物组合物的给药途径包括但不限于口服、局部、经皮、肌肉、静脉、吸入、肠胃外、舌下、直肠、阴道及鼻内。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的式I化合物，特别是式Ia和式Ib化合物，可以是固体粉末或颗粒；水性或非水性液体中的溶液或混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其它辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括但不限于水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或混悬液。具体的给药方式和剂型取决于化合物本身的理化性质以及待治疗疾病的严重程度等。本领域技术人员能够根据上述因素并结合其自身具有的知识来确定具体的给药途径。例如可参见：李俊，《临床药理学》，人民卫生出版社，2008.06；丁玉峰，论临床剂型因素与合理用药，医药导报，26(5)，2007；Howard C.Ansel,Loyd V.Allen,Jr.,Nicholas G.Popovich著，江志强主译，《药物剂型与给药体系》，中国医药科技出版社，2003.05。
本发明的式I化合物，特别是式Ia或式Ib化合物，或者本发明的药物组合物还可以与一种或多种其它药物联合或组合使用。可以与本发明的式I化合物，特别是式Ia或式Ib化合物，或者本发明的药物组合物联用的药物包括但不限于：
1)免疫抑制剂如甲氨蝶呤和环磷酰胺等药物；
2)糖皮质激素如地塞米松和倍他米松等药物；
3)非甾体抗炎药如水杨酸盐和芳基链烷酸等药物；
4)Cox-2特异性抑制剂如罗非昔布和塞来昔布等药物；
5)TNF-α结合蛋白如英利昔单抗和阿达木单抗等药物；
6)干扰素(例如干扰素-β、干扰素γ)和白细胞介素(例如白细胞介素-2)等药物。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于预防和/或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于预防和/或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐或者包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物在制备用于抑制BTK和/或JAK3活性的药物中的用途。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物在制备用于治疗和/或预防BTK和/或JAK3介导的疾病的药物中的用途。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物在制备用于治疗和/或预防BTK和/或JAK3介导的疾病的药物中的用途。
本发明的另一方面涉及在生物体系中抑制BTK和/或JAK3活性的方法，该方法包括使所述生物体系接触本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含上述化合物的药物组合物。在一些实施方式中，所述生物体系是酶、细胞、哺乳动物。哺乳动物的实例包括但不限于：人；非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。
本发明的另一方面涉及抑制哺乳动物(尤其是人)的BTK和/或JAK3的方法，所述方法包括对有需要的哺乳动物(尤其是人)给予治疗有效量的本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上接受的盐，或者包 含上述化合物的药物组合物。
本发明的另一方面涉及治疗和/或预防BTK和/或JAK3介导的疾病的方法，所述方法包括对有需要的哺乳动物(尤其是人)给予治疗有效量的本发明的式I化合物，特别是式Ia和式Ib化合物，或其立体异构体、互变异构体、溶剂化物或其药学上接受的盐或者包含上述化合物的药物组合物。
在本申请中，所提及的BTK和/或JAK3介导的疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病和癌症。所述自身免疫性疾病和炎性疾病选自类风湿性关节炎、骨关节炎、青少年关节炎、慢性阻塞性肺疾病、多重硬化、系统性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎和肠道易激综合症等。所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤等。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。本发明化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。通常，经胃肠外给药的剂量可以是1-200mg/kg，口服给药的剂量可以是1-1000mg/kg。
本文中所提供的有效剂量的范围并非意图限制本发明的范围，而是代表优选的剂量范围。但是，最优选的剂量可针对个别个体而进行调整，这是本领域技术人员所了解且可决定的(例如参阅Berkow等人编著，Merck手册，第16版，Merck公司，Rahway,N.J.,1992)。
本发明化合物的制备
以下反应方案以式Ia和式Ib化合物为例示例性地说明本发明的式I化合物的制备方法。
本领域技术人员应当理解，在以下描述中，只有当取代基的组合可以得到稳定的化合物时，这类取代基的组合才是允许的。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基“PG”保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。
保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis(有机合成中的保护基),(1999),4thEd.,Wiley中。保护基还可为聚合物树脂。
本发明的式Ia和式Ib化合物可按照下列反应路线I所示的方法进行制备：
反应路线I
Figure PCTCN2014086821-appb-000054
其中，各式中的基团X、Y、Z、W、R1、R2和R3均如上文对式Ia中所定义的；或者
Figure PCTCN2014086821-appb-000055
其中，各式中的基团X、Y、Z、W、R1、R2、l、m和n均如上文对式Ib所定义的。
反应路线I中包括如下步骤：
步骤1：使式1化合物分别与式2a或2b化合物发生取代反应制备式3a或3b化合物。
在该步骤中，优选在碱的存在下进行，用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等有机碱，用于该反应的碱也可以选自碳酸钠、碳酸钾、氢氧化钠等无机碱。该反应也可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇、异丙醇、丁醇等。
步骤2：脱除式3a或3b化合物的保护基PG制备式4a或4b化合物。
式3a或3b化合物中的保护基PG可以是叔丁氧羰基、苄氧羰基、苄基等。用于该反应的脱保护条件可以在酸催化下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在酸性或者中性条件下，使用钯催化剂进行催化氢化，本发明的钯催化剂可以选自钯碳和氢氧化钯，该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇等。
步骤3：使式4a或4b化合物发生缩合反应得到式5a或5b化合物。
在该步骤中，缩合试剂可以选自羰基二咪唑(CDI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)等。用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等。反应温度为0℃至80℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯等。
步骤4：使式5a或5b化合物发生取代反应得到相应的式Ia或Ib化合物。
在该步骤中，反应可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在碱的存在下进行，用于该反应的碱可以选自氢氧化钠、叔丁醇钠、氢化钠等强碱。该反应也可以在钯催化剂的存在下进行。可以用于本发明的钯催化剂选自二(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯(Pd(OAc)2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)。该条件下可用的碱优选为无机碱，例如碳酸钠、碳酸钾、磷酸钾、碳酸铯等。反应温度为80℃至160℃。用于该反应的溶剂可以选自1,4-二氧六环、甲苯、乙醇、异丙醇、丁醇、2-丁醇、水及其混合物。
本发明的式Ia和Ib化合物也可按照下列反应路线II所示的方法进行制备：
反应路线II
Figure PCTCN2014086821-appb-000056
其中，各式中的基团X、Y、Z、W、R1、R2和R3均如上文对式Ia所定义的；或者
Figure PCTCN2014086821-appb-000057
其中，各式中的基团X、Y、Z、W、R1、R2、l、m和n均如上文对式Ib所定义的。
反应路线II中包括如下步骤：
步骤1：使式1化合物分别与式2a或2b化合物发生取代反应制备式3a或3b化合物。
在该步骤中，优选在碱的存在下进行，用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等有机碱，用于该反应的碱也可以选自碳酸钠、碳酸钾、氢氧化钠等无机碱。该反应也可以在酸的存在或者中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇、异丙醇、丁醇等。
步骤5：使式3a或3b化合物发生取代反应得到式6a或6b化合物。
在该步骤中，反应可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在碱的存在下进行，用于该反应的碱可以选自氢氧化钠、叔丁醇钠、氢化钠等强碱。该反应也可以在钯催化剂的存在下进行，可以用于本发明的钯催化剂选自二(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯(Pd(OAc)2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)。该条件下可用的碱优选为无机碱，例如碳酸钠、碳酸钾、磷酸钾、碳酸铯等。反应温度为80℃至160℃。用于该反应的溶剂可以选自1,4-二氧六环、甲苯、乙醇、异丙醇、丁醇、2-丁醇、水及其混合物。
步骤6：脱除式6a或6b化合物的保护基PG制备式7a或7b化合物。
式6a或6b化合物中的保护基可以是叔丁氧羰基、苄氧羰基、苄基等。用于该反应的脱保护条件可以在酸催化下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在酸性或者中性条件下，使用钯催化剂进行催化氢化，本发明的钯催化剂选自钯碳和氢氧化钯，该反应的酸可以选自盐酸、氯化氢的1,4-二氧六环溶液、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇等。
步骤7：使式7a或7b化合物发生缩合反应得到相应的式Ia或Ib化合物。
在该步骤中，缩合试剂可以选自羰基二咪唑(CDI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)等。用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等。反应温度为0℃至80℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯等。
本发明的式Ia化合物还可按照下列反应路线III所示的方法进行制备：
反应路线III
Figure PCTCN2014086821-appb-000058
其中，各式中的基团X、Y、Z、W、R1、R2和R3均如上文对式Ia所定义的。
步骤8：使式1化合物与式8a化合物发生取代反应制备式4a化合物。
在该步骤中，优选在碱的存在下进行，用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等有机碱，用于该反应的碱也可以选自碳酸钠、碳酸钾、氢氧化钠等无机碱。该反应也可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇、异丙醇、丁醇等。
步骤3：使式4a化合物发生缩合反应得到式5a化合物。
在该步骤中，缩合试剂可以选自羰基二咪唑(CDI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)等。用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等。反应温度为0℃至80℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯等。
步骤4：使式5a化合物发生取代反应得到相应的式Ia化合物。
在该步骤中，反应可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在碱的存在下进行，用于该反应的碱可以选自氢氧化钠、叔丁醇钠、氢化钠等强碱。该反应也可以在钯催化剂的存在下进行。可以用于本发明的钯催化剂选自二(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯(Pd(OAc)2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)。该条件下可用的碱优选为无机碱，例如碳酸钠、碳酸钾、磷酸钾、碳酸铯等。反应温度为80℃至160℃。用于该反应的溶剂可以选自1,4-二氧六环、甲苯、乙醇、异丙醇、丁醇、2-丁醇、水及其混合物。
本领域技术人员可以理解，上述反应路线和制备方法仅用于简明和清楚说明的目的，并不是限制性的，通过选择合理的反应原料(其可以是商购获得到的或者采用本领域公知 的方法制备得到的)，采用上述类似的方法也可以得到本发明的式I化合物。
实施例
下文所描述的实验、合成方法以及所涉及的中间体是对本发明的阐明，并不限制本发明的范围。
本发明中实验所使用的起始原料或购买自试剂供应商或经由本领域公知的方法由已知原料制备。除非另有说明，本文的实施例应用下述条件：
温度的单位是摄氏度(℃)；室温的定义是18-25℃；
有机溶剂使用无水硫酸镁或无水硫酸钠干燥；使用旋转蒸发仪在减压升温条件下旋干(例如：15mmHg，30℃)；
柱层析分离时使用200-300目硅胶作为载体，TLC表示薄层色谱法；
通常情况下，反应的进度通过TLC或LC-MS监测；
最终产品的鉴定由核磁共振(Bruker AVANCE 300，300MHz)和LC-MS(Bruker esquine6000，Agilent 1200series)完成。
实施例1
4-((顺式-4-丙烯酰基氨基环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000059
步骤1：(顺式-4-((5-氨基酰基-2-氯嘧啶-4-基)氨基)环己基)氨基羧酸叔丁酯的制备
Figure PCTCN2014086821-appb-000060
将2,4-二氯嘧啶-5-甲酰胺(191mg,1mmol)和顺式-4-氨基环己基氨基羧酸叔丁酯(235mg,1.1mmol)溶于二氯甲烷(5mL)中，加入N,N-二异丙基乙胺(521μL,3mmol)。反应液室温搅拌过夜，之后浓缩。残余物加入水(20mL)，用乙酸乙酯(20mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，柱层析分离(洗脱液：二氯甲烷：甲醇＝10:1)，得到150mg淡黄色固体。收率：40.6％。MS(ESI,m/z):[M+H]+:370.1；1H-NMR(300MHz,DMSO-d6):8.58(s,1H),8.21(s,1H),7.66(s,1H),4.03(s,1H),3.45(s,1H),1.75-1.1.43(m,8H),1.35(s,9H)。
步骤2：4-((顺式-4-丙烯酰基氨基环己基)氨基)-2-氯嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000061
将步骤1所得产物(100mg,0.27mmol)溶于甲醇(2mL)中，加入4N的氯化氢的1,4-二氧六环溶液(4mL,1mmol)，反应液在室温下反应2小时。反应液浓缩后，将剩余的粘稠液体溶于二氯甲烷(5mL)中，加入三乙胺(112μL,0.81mmol)。在0℃下将丙烯酰氯(36.8μL,0.41mmol)滴加在上述溶液中。反应液在室温下反应过夜。反应液经水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，柱层析分离(洗脱液：二氯甲烷/甲醇＝8:1)，得到70mg白色固体。收率：80.3％。MS(ESI,m/z):[M+H]+:324.1；1H-NMR(300MHz,CD3OD):8.54(s,1H),6.39-6.18(m,2H),5.71-5.67(dd,1H,J＝3.0Hz,J＝9.0Hz),4.33-4.31(s,1H),4.00-3.93(s,1H),1.89-1.60(m,8H)。
步骤3：4-((顺式-4-丙烯酰基氨基环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
将步骤2所得产物(20mg,0.062mmol)和1-甲基-1H-吡唑-4-胺(6.6mg,0.068mmol)溶于异丙醇(2mL)中，加入三氟乙酸(250mg,2.2mmol)。反应液在微波辐射90℃下反应1小时。反应液冷却至室温，减压浓缩，柱层析分离(洗脱液：二氯甲烷/甲醇＝6:1)得到10mg白色固体。收率：42.0％。MS(ESI,m/z):[M+H]+:385.2；1H-NMR(300MHz,CDCl3)δ:7.51(s,1H),6.94(s,1H),6.72(s,1H),5.46-5.30(m,2H),4.77-4.73(dd,1H,J＝2.7Hz,J＝9.3Hz),3.37(s,1H),3.03(s,1H),3.02(s,3H),0.98-0.72(m,8H)。
下列化合物(表一)利用类似起始原料通过类似于实施例1的合成方法制备。
表一
Figure PCTCN2014086821-appb-000062
Figure PCTCN2014086821-appb-000063
实施例8
4-((顺式-4-丙炔酰基氨基环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000064
步骤1：(顺式-4-((5-氨基酰基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)氨基)环己基)氨基羧酸叔丁酯的制备
Figure PCTCN2014086821-appb-000065
将实施例1中步骤1所得产物(370mg,1mmol)和1-甲基-1H-吡唑-4-胺(107mg,1.1mmol)溶于1,4-二氧六环(5mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝30:1)得到362mg黄色固体。收率：80.4％。MS(ESI,m/z):[M+H]+:431.2。
步骤2：4-((顺式-4-氨基环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000066
将上述步骤1所得产物(86mg,0.2mmol)溶于二氯甲烷(10mL)，加入4N的氯化氢的1,4-二氧六环溶液(0.5mL,2mmol)，室温下反应2小时。反应液减压浓缩，直接投入下一步。MS(ESI,m/z):[M+H]+:331.2。
步骤3：4-((顺式-4-丙炔酰基氨基环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备
将步骤2所得产物(33mg,0.1mmol)和丙炔酸(8.4mg，0.12mmol)溶于四氢呋喃(10mL)中，然后加入N,N-二异丙基乙胺(53μL)。混合液在室温下搅拌30分钟，然后再加入TBTU(4mg)，混合液在室温下搅拌过夜。浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到7.3mg淡黄色固体。收率:19.1％。MS(ESI,m/z):[M+H]+:383.2。
实施例9
(R)-4-((1-丙烯酰基吡咯烷-3-基)氨基)-2-((3-甲基异噻唑-5-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000067
步骤1：(R)-3-((5-氨基酰基-2-氯嘧啶-4-基)氨基)吡咯烷基-1-羧酸叔丁酯的制备
Figure PCTCN2014086821-appb-000068
将2,4-二氯嘧啶-5-甲酰胺(191mg,1mmol)和(R)-N-叔丁氧基羰基-3-氨基吡咯烷盐酸盐(205mg,1.1mmol)溶于二氯甲烷(5mL)中，加入三乙胺(416μL,3mmol)。反应液室温搅拌过夜，之后浓缩。残余物加入水，用乙酸乙酯萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝1:1)，得到120mg淡黄色固体。收率：35.2％。MS(ESI,m/z):[M+H]+:342.1；1H-NMR(300MHz,CDCl3):8.47(s,1H),7.40(s,1H),6.49(s,1H),4.62-4.60(m,1H),3.68-3.62(m,1H),3.39-3.35(m,2H),3.21-3.16(m,1H),2.17-2.16(m,1H),1.88-1.85(m,1H),1.35(s,9H)。
步骤2：(R)-4-((1-丙烯酰基吡咯烷-3-基)氨基)-2-氯嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000069
将步骤1所得产物(100mg,0.29mmol)溶于甲醇(2mL)中，加入4N的氯化氢的1,4-二氧六环溶液(4mL,1mmol)，反应液在室温下反应2小时。将反应液减压浓缩，所得粘稠液体溶于二氯甲烷(5mL)中，加入三乙胺(121μL,0.87mmol)。在0℃下将丙烯酰氯(30.7μL,0.32mmol)滴加在上述溶液中，室温下反应过夜。反应液经水洗，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝8:1)，得到90mg白色固体。收率：96.1％。MS(ESI,m/z):[M+H]+:324.1；1H-NMR(300MHz,DMSO-d6):8.65(s,1H),8.23(s,1H),7.39(s,1H),6.21-6.04(m,2H),5.87-5.83(m,1H),4.62-4.60(m,1H),3.68-3.62(m,1H),3.39-3.35(m,2H),3.21-3.16(m,1H),2.17-2.16(m,1H),1.88-1.85(m,1H)。
步骤3：(R)-4-((1-丙烯酰基吡咯烷-3-基)氨基)-2-((3-甲基异噻唑-5-基)氨基)嘧啶-5-甲酰胺的制备
将步骤2所得产物(20mg,0.062mmol)、3-甲基异噻唑-5-胺盐酸盐(11mg,0.074mmol)、碳酸铯(60.6mg,0.186mmol)、(±)-2,2'-双-(二苯膦基)-1,1'-联萘(7.5mg,0.0124mmol)和三(二亚苄基丙酮)二钯(5.7mg,0.0062mmol)溶于1,4-二氧六环/水＝20/1(10mL)中。反应液在氮气保护下回流过夜。反应液冷却至室温，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到10mg淡黄色固体。收率：45.3％。MS(ESI,m/z):[M+H]+:357.2；1H-NMR(300MHz,CDCl3)δ:7.48(s,1H),6.53-6.31(m,2H),5.79-5.73(m,1H),4.81-4.71(m,1H),4.09(s,3H),4.06-3.92(m,1H),3.82-3.59(m,3H),2.43-2.32(m,1H),2.18-2.08(m,3H)。
下列化合物(表二)利用类似起始原料通过类似于实施例9的合成方法制备：
表二
Figure PCTCN2014086821-appb-000070
实施例12
(R)-4-((1-丙炔酰基吡咯烷-3-基)氨基)-2-((3-甲基异噻唑-5-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000071
步骤1：(R)-3-((5-氨基酰基-2-((3-甲基异噻唑-5-基)氨基)嘧啶-4-基)氨基)吡咯烷基-1-羧酸叔丁酯的制备
Figure PCTCN2014086821-appb-000072
将实施例9中步骤1所得产物(342mg,1mmol)、3-甲基异噻唑-5-胺盐酸盐(166mg,1.1mmol)溶于1,4-二氧六环/水中(21mL,20:1)，加入三(二亚苄基丙酮)二钯(46mg,0.05mmol)、(±)-2,2'-双-(二苯膦基)-1,1'-联萘(63mg,0.1mmol)和碳酸铯(650mg,2mmol)，氮气保护，在100℃下回流过夜。反应液冷却至室温，经硅藻土过滤，滤液减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷：甲醇＝30:1)，得到315mg淡黄色固体。收率：75.2％。MS(ESI,m/z):[M+H]+:420.3。
步骤2：(R)-2-((3-甲基异噻唑-5-基)氨基)-4-(吡咯烷-3-基氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2014086821-appb-000073
将上述步骤1所得产物(84mg,0.2mmol)溶于二氯甲烷(10mL)，加入4N的氯化氢的1,4-二氧六环溶液(0.5mL,2mmol)，室温下反应2小时。反应液减压浓缩，直接投入下一步。MS(ESI,m/z):[M+H]+:320.2。
步骤3：(R)-4-((1-丙炔酰基吡咯烷-3-基)氨基)-2-((3-甲基异噻唑-5-基)氨基)嘧啶-5-甲酰胺的制备
将步骤2所得产物(32mg,0.1mmol)和丙炔酸(8.4mg，0.12mmol)溶于四氢呋喃(10mL)中，然后加入N,N-二异丙基乙胺(53μL)。混合液在室温下搅拌30分钟，然后再加入TBTU(4mg)，混合液在室温下搅拌过夜。浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到6.8mg淡黄色固体。收率:18.3％。MS(ESI,m/z):[M+H]+:372.2。
生物活性评价
测试实施例1：BTK激酶活性抑制实验
将BTK激酶(购自Invitrogen，货号：PV3363)用反应缓冲液(40mM Tris-HCl，pH 7.5；20mM MgCl2,0.1mg/ml BSA；1mM DTT；2mM MnCl2)稀释到2倍终浓度(终浓度为1.1ng/μL)并以5μL/孔加入96孔板。将本发明的化合物用去离子水梯度稀释为终浓度(分别为10μM,1μM,0.1μM,20nM,4nM,0.8nM)的4倍(即，40μM,4μM,0.4μM,80nM,16nM,3.2nM)，并以2.5μL/孔加入96孔板实验孔。于25℃孵育10分钟后，以2.5μL/孔加入ATP(50μM)(购自Promega，货号：V9102)和0.2μg/μL酶反应底物Poly E4Y1(购自Sigma，货号：P0275-25MG)，于25℃反应120分钟。反应结束后，每孔加入10μL ADP-Glo试剂(ADP-GloTM激酶检测试剂盒，购自Promega，货号：V9102)，于25℃反应40分钟后，每孔再加入20μL ADP-Glo激酶检测试剂并于25℃反应30分钟，按照ADP-Glo激酶检测试剂盒说明书采用发光法进行激酶活性检测，并计算本发明化合物的IC50，结果见表三。
表三BTK的活性抑制分析结果
化合物 BTK
1 +++
2 +++
3 +++
4 +++
5 +
6 +++
7 +++
9 +++
10 +++
11 +++
表三显示在BTK的活性抑制分析中所选本发明化合物的活性，其中活性指定为“+++”的化合物提供的IC50≤50nM；活性指定为“++”的化合物提供的IC50为50<IC50≤100nM；活性指定为“+”的化合物提供的IC50为100<IC50<1000nM。
测试实施例2：JAK3和EGFRWT激酶活性抑制实验
将JAK3激酶(购自SignalChem，货号：J03-11G)和EGFRWT激酶(购自Promega，货号：V3831)用反应缓冲液(EGFRWT：40mM Tris-HCl，pH 7.5，20mM MgCl2，0.1mg/ml BSA，1mM DTT，2mM MnCl2；JAK3：40mM Tris-HCl，pH 7.5，20mM MgCl2，0.1mg/ml BSA，1mM DTT)稀释到2倍终浓度(JAK3终浓度为0.5ng/μL，EGFRWT终浓度为0.65ng/μL)，并以5μL/孔加入96孔板。将本发明的化合物用去离子水梯度稀释为终浓度(分别为10μM,1μM,0.1μM,20nM,4nM,0.8nM)的4倍(即，40μM,4μM,0.4μM,80nM,16nM,3.2nM)，并以2.5μL/孔加入96孔板实验孔。于25℃孵育10分钟后，以2.5μL/孔加入10μM ATP(购自Promega，货号：V9102)和0.2μg/μL酶反应底物Poly E4Y1(购自Sigma，货号：P0275-25MG)，于25℃反应60分钟。反应结束后，每孔加入10μL ADP-Glo试剂(ADP-GloTM激酶检测试剂盒，购自Promega，货号：V9102)，于25℃反应40分钟后，每孔再加入20μL ADP-Glo激酶检测试剂并于25℃反应30分钟，按照ADP-Glo激酶检测试剂盒说明书采用发光法进行激酶活性检测，并计算待测化合物的IC50。其中，EGFRWT和JAK3的活性比例(EGFRWT/JAK3)为本发明化合物的EGFRWT的IC50值和JAK3的IC50值的比值，以倍数关系表示。结果见表四。
表四JAK3的活性抑制以及对EGFRWT的选择性分析结果
化合物 JAK3 EGFRWT/JAK3
9 +++ B
10 +++ A
11 ++ C
表四显示在JAK3的活性抑制分析中所选本发明化合物的活性，以及在EGFRWT的活性抑制分析中所选本发明化合物对EGFRWT的选择性。其中JAK3的活性指定为“+++”的化合物提供的IC50≤10nM；JAK3的活性指定为“++”的化合物提供的IC50为10<IC50≤100nM。EGFRWT和JAK3的活性比例指定为“A”的化合物提供的EGFRWT/JAK3大于100倍；EGFRWT和JAK3的活性比例指定为“B”的化合物提供的EGFRWT/JAK3在50倍和100倍之间(包括50倍和100倍)；EGFRWT和JAK3的活性比例指定为“C”的化合物提供的EGFRWT/JAK3小于50倍，其中比例越大，选择性越高，毒副作用越低。
结果表明，化合物9-11具有良好的抑制JAK3激酶的活性。并且由于对EGFRWT的抑制可能导致潜在的毒副作用，因而对化合物9-11测定了其对EGFRWT激酶的抑制选择性，选择性越高，毒副作用越低。上述结果表明化合物9和10具有较低的毒副作用，从而具有较好的安全性。

Claims (25)

  1. 一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式I：
    Figure PCTCN2014086821-appb-100001
    其中：
    R选自被-NR3W取代的C3-8环烷基；4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；
    W选自于
    Figure PCTCN2014086821-appb-100002
    或
    Figure PCTCN2014086821-appb-100003
    X选自于S、O或NR5；
    Y选自于N或CR6；
    Z为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R7取代；
    R1选自于氢、卤素、硝基、氰基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基或C1-8卤代脂烃基；
    R2选自于氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
    R3选自于氢或C1-8脂烃基；
    R4a、R4b和R4c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
    R5选自于氢或C1-8脂烃基；
    R6选自于氢、卤素、C1-8脂烃基或C1-8卤代脂烃基；
    每个R7独立地选自卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、羧基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧 基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基氨基亚磺酰基、杂环基氨基亚磺酰基、二(C1-8脂烃基)膦酰基，其中：
    杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、羟基、杂环基、5-12元杂芳基、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
    C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
    其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中Y为N，R1为氢，R2为氨基。
  3. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中该化合物具有结构式Ia：
    Figure PCTCN2014086821-appb-100004
    其中，X、Y、Z、W、R1、R2和R3均如权利要求1或2中所定义。
  4. 根据权利要求3所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中Z选自于C6-12芳基或5至12元杂芳基，其任选被一个或多个R7取代，其中每个R7独立地选自卤素、羟基、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、C1-8脂烃基氨基酰基、杂环基氨基酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基磺酰基或杂环基氨基亚磺酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或两个选自如下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基或C1-8脂烃基羰基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  5. 根据权利要求3所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中Z选自于：
    Figure PCTCN2014086821-appb-100005
    Figure PCTCN2014086821-appb-100006
  6. 根据权利要求3所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    W选自于
    Figure PCTCN2014086821-appb-100007
    或
    Figure PCTCN2014086821-appb-100008
    X为NR5；
    Y为N；
    Z选自于苯基或五元杂环基，其任选被一个或多个R7取代，
    R1为氢；
    R2为氨基；
    R3为氢；
    R4a、R4b和R4c均为氢；
    R5为氢；
    每个R7独立地选自卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、卤代C1-8脂烃基、C1-8脂烃基氨基酰基、杂环基，其中杂环基表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，其独立地任选被一个或两个选自C1-8脂烃基的取代基取代，其中C1-8脂烃基在每次出现时独立地选自于C1-8烷基和C3-8环烷基。
  7. 根据权利要求3至6中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中，所述化合物选自于：
    Figure PCTCN2014086821-appb-100009
  8. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中该化合物具有结构式Ib：
    Figure PCTCN2014086821-appb-100010
    其中：
    X、Y、Z、W、R1和R2均如权利要求1或2中所定义；
    l选自于0至4的整数，其中当l是0时，
    Figure PCTCN2014086821-appb-100011
    为
    Figure PCTCN2014086821-appb-100012
    m选自于0至4的整数；其中当m是0时，
    Figure PCTCN2014086821-appb-100013
    为
    Figure PCTCN2014086821-appb-100014
    n选自于0至3的整数；其中当n是0时，
    Figure PCTCN2014086821-appb-100015
    为
    Figure PCTCN2014086821-appb-100016
  9. 根据权利要求8所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    Z为5-6元杂芳基，其任选地被一个或多个R7取代；
    每个R7独立地选自卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基氨基亚磺酰基、杂环基氨基亚磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中：
    杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基或C1-8脂烃基羰基；
    C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自卤素或C1-8脂烃基的取代基取代；
    其中，C1-8脂烃基在每次出现时独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  10. 根据权利要求8所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中Z选自于5-6元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且Z任选地被一个或两个R7取代；每个R7独立地选自C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、杂环基或C1-8脂烃基羰基，其中，杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自于哌啶基、哌嗪基、吗啉基或四氢吡喃基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
  11. 根据权利要求8所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中Z选自于：
    Figure PCTCN2014086821-appb-100017
  12. 根据权利要求8所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    W选自于
    Figure PCTCN2014086821-appb-100018
    或
    Figure PCTCN2014086821-appb-100019
    X为NR5；
    Y为N；
    Z为5元杂芳基，其任选地被一个或多个R7取代；；
    R1为氢；
    R2为氨基；
    R3为氢；
    R4a、R4b和R4c均为氢；
    R5为氢；
    每个R7独立地选自于C1-8脂烃基；
    l选自于0、1或2；
    m选自于0、1、2或3；
    n选自于0、1或2。
  13. 根据权利要求8至12中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中所述化合物选自于：
    Figure PCTCN2014086821-appb-100020
  14. 一种药物组合物，包含如权利要求1-13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐以及药学上可接受的辅料。
  15. 根据权利要求14所述的药物组合物，还包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
  16. 如权利要求1-13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备抑制BTK和/或JAK3活性的药物中的用途。
  17. 如权利要求1-13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备用于预防或治疗由BTK和/或JAK3介导的疾病的药物中的用途。
  18. 根据权利要求17所述的用途，其中所述疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病和癌症。
  19. 根据权利要求17所述的用途，其中所述疾病选自类风湿性关节炎、骨关节炎、青少年关节炎、慢性阻塞性肺疾病、多重硬化、系统性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎和肠道易激综合症。
  20. 根据权利要求19所述的用途，其中所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤。
  21. 一种在生物体系中抑制BTK和/或JAK3活性的方法，包含使生物体系接触权利要求1-13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐或权利要求14或15所述的药物组合物。
  22. 根据权利要求21所述的方法，其中所述生物体系是酶、细胞或哺乳动物。
  23. 一种预防或治疗BTK和/或JAK3介导的疾病的方法，包含给予有需要的受试者治疗有效剂量的权利要求1-13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐或权利要求14或15所述的药物组合物。
  24. 根据权利要求23所述的方法，其中所述疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病或癌症。
  25. 权利要求1-13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物 或其药学上可接受的盐与一种或多种选自以下的活性物质在制备用于治疗BTK和/或JAK3介导的疾病的药物中的应用：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
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