WO2015039613A1 - Composé inhibant les activités kinase de btk et/ou jak3 - Google Patents

Composé inhibant les activités kinase de btk et/ou jak3 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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group
aliphatic
aliphatic hydrocarbon
amino
hydrocarbon group
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Chinese (zh)
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刘金明
车美英
李功
李占梅
张烜
金孟燮
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北京韩美药品有限公司
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Publication of WO2015039613A1 publication Critical patent/WO2015039613A1/fr

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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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • 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

L'invention concerne un composé pouvant inhiber les activités kinase de BTK et/ou JAK3, une composition pharmaceutique, ainsi que des applications dans la préparation d'un médicament. Le composé est tel que représenté par la formule structurale I, dans laquelle les définitions des substituants ont la signification indiquée dans la description.
PCT/CN2014/086821 2013-09-18 2014-09-18 Composé inhibant les activités kinase de btk et/ou jak3 WO2015039613A1 (fr)

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