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WO2015039612A1 - 抑制btk和/或jak3激酶活性的化合物 - Google Patents

抑制btk和/或jak3激酶活性的化合物 Download PDF

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Publication number
WO2015039612A1
WO2015039612A1 PCT/CN2014/086820 CN2014086820W WO2015039612A1 WO 2015039612 A1 WO2015039612 A1 WO 2015039612A1 CN 2014086820 W CN2014086820 W CN 2014086820W WO 2015039612 A1 WO2015039612 A1 WO 2015039612A1
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group
aliphatic
aliphatic hydrocarbon
amino
hydrocarbon group
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PCT/CN2014/086820
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English (en)
French (fr)
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WO2015039612A8 (zh
Inventor
刘金明
车美英
李功
李占梅
邱红娟
金孟燮
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北京韩美药品有限公司
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Priority to SG11201601980XA priority Critical patent/SG11201601980XA/en
Priority to NZ718728A priority patent/NZ718728A/en
Application filed by 北京韩美药品有限公司 filed Critical 北京韩美药品有限公司
Priority to BR112016005881A priority patent/BR112016005881A2/pt
Priority to EP14846251.8A priority patent/EP3048105A4/en
Priority to RU2016110755A priority patent/RU2650512C2/ru
Priority to MX2016003582A priority patent/MX368781B/es
Priority to JP2016543306A priority patent/JP6458039B2/ja
Priority to KR1020167009680A priority patent/KR101879422B1/ko
Priority to AU2014323777A priority patent/AU2014323777C1/en
Priority to US15/022,248 priority patent/US9840517B2/en
Priority to CA2924362A priority patent/CA2924362C/en
Publication of WO2015039612A1 publication Critical patent/WO2015039612A1/zh
Publication of WO2015039612A8 publication Critical patent/WO2015039612A8/zh
Priority to IL24461116A priority patent/IL244611B/en
Priority to PH12016500531A priority patent/PH12016500531B1/en
Priority to US15/799,315 priority patent/US10273242B2/en

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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, which promote lymphocyte proliferation, differentiation and function. Play an important role.
  • JAK3 kinase Loss of function of JAK3 kinase will result in immunodeficiency in humans and mice. Based on the important role of JAK3 kinase in the immune system, JAK3 kinase is a very attractive target for the treatment of immune-related disorders, such as autoimmune diseases such as rheumatoid arthritis or allogeneic transplantation in organ transplant patients. Objects are different. 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 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 2 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
  • V is selected from C or N;
  • X is selected from O, S or NR 4 ;
  • Y is selected from CH, O or S;
  • Z is selected from CH, O, S or NR 5 ;
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 is independently selected from the group consisting of halogen, nitro, cyano, heterocyclic, C 6-12 aryl, 5-12 membered heteroaryl, C 1-8 aliphatic, C 1-8 halogenated aliphatic a heterocyclic group C 1-8 aliphatic hydrocarbon group, a hydroxyl group C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon carbonyloxy C 1-8 aliphatic hydrocarbon group, Amino C 1-8 aliphatic hydrocarbon group, carboxyl 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 C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbon
  • 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, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, and C 1-8 aliphatic hydrocarbon based C 1-8 fat.
  • Hydrocarbyl 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 ,heterocyclyl, 5-12 membered heteroaryl, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, C 1-8 Hydrocarbylcarbonyl, heterocyclylcarbonyl, heterocyclyl C 1-8 aliphatic hydrocarbylcarbonyl, hydroxy C 1-8 aliphatic hydrocarbylcarbonyl, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbyl carbonyl, di(C 1-8 Aliphatic)amino C 1-8 aliphatic hydrocarbylcarbonyl, C 1-8 aliphatic hydro
  • 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 present invention provides a compound, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable salt thereof, which has the structural formula Ib (hereinafter sometimes referred to as Compound of formula Ib):
  • X, Y, Z, W and R 1 are all as defined in formula I;
  • l is selected from 0, 1, 2, 3 or 4, 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
  • the invention provides a compound, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable salt thereof, which has the structural formula Ic (also sometimes referred to hereinafter) Compound of formula Ic):
  • X, W, and R 1 are all as defined in Formula I;
  • l is selected from 0, 1, 2, 3 or 4; 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
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the present invention
  • a compound of formula I particularly a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof Use in the preparation of a medicament for inhibiting 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof Use in the preparation of a medicament for the prevention or treatment of 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, formula Ib and formula Ic, 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.
  • compositions of the invention in the manufacture of a medicament for the prevention or treatment of a BTK and/or JAK3 mediated disease
  • the pharmaceutical composition comprises one or more of the invention A compound of formula I, especially a compound of formula Ia, formula Ib and formula Ic, 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 compound of formula I according to the invention, in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, It is used to inhibit the 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof,
  • a compound of formula I according to the invention in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof,
  • BTK and / or JAK3 mediated diseases for the prevention 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • Another aspect of the invention relates to a compound of formula I comprising the invention, in particular of formula Ia, formula Ib and formula Ic
  • 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or a compound of formula I according to the invention, in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer thereof
  • a pharmaceutical composition of a tautomer, a solvate or a pharmaceutically acceptable salt thereof A pharmaceutical composition of a tautomer, a solvate or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a method of preventing or treating 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, in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or a compound of formula I according to the invention, in particular formula Ia, formula Ib And a pharmaceutical composition of a compound of formula Ic, or a stereoisomer, tautomer, solvate thereof, 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable thereof
  • a salt with one or more active substances selected from the group consisting of an immunosuppressant, a glucocorticoid, a non-steroidal anti-inflammatory drug, Cox- for the preparation of a medicament for the treatment of BTK and/or JAK3 mediated diseases 2 specific inhibitors, TNF- ⁇ binding protein, interferon and interleukin.
  • the BTK and/or JAK3 mediated diseases are selected from autoimmune diseases, inflammatory diseases, xenogeneic immune conditions or diseases, thromboembolic diseases, and cancer.
  • Figure 1 shows the inhibitory effect of Compound 132 on the BTK pathway in Ramos cells.
  • Figure 2 shows the mCIA score for compound 132.
  • Figure 3 shows the rAIA score for compound 132.
  • 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 fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • 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.
  • bases include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, hexyl, heptyl, 2-methyl Hexyl, 3-methylhexyl, octyl, decyl and decyl, etc., preferably methyl, ethyl, propyl, isopropyl, n-butyl, more preferably methyl, ethyl, propyl and isopropyl .
  • 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 can be optionally substituted with any suitable group, such as a halogen, a hydroxyl group, an amino group, an alkoxy group, a heterocyclic group, and 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 10, more preferably from 3 to 8 carbon atoms, and attached to the remainder of the molecule via a single bond via any suitable carbon atom on the ring .
  • 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 10, more preferably from 3 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
  • Hydrogen on the cycloalkenyl group The site is optionally substituted with any suitable group such as halogen, hydroxy, amino, monosubstituted amino, disubstituted amino, alkyl, alkoxy, heterocyclyl and 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.
  • 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 groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like, preferably dimethylamino.
  • 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, and examples thereof include, but are not limited to, a methoxyethoxy group, 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 1 to 3 stable 3- to 8-membered non-aromatic monocyclic groups selected from heteroatoms of nitrogen, oxygen and sulfur.
  • 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.
  • heterocyclic groups include, but are not limited to, nitrogen heterocycles Butyryl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, oxazinyl, dioxetane, tetra Hydroisoisolinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindole The group, octahydr
  • 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- 7-based Etc., phenyl is preferred.
  • 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 a stable comprising 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur 5- to 6-membered aromatic monocyclic group.
  • 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 specifically 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, octanoic acid, and Acid, citric acid, undecylenic 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, pyrogluta
  • “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-ethyl piperidine, 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.
  • terapéuticaally 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. , weight, physical condition, etc., but can be routinely disclosed by those skilled in the art based on their own knowledge and the present application The content is decided.
  • 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 2 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
  • V is selected from C or N;
  • X is selected from O, S or NR 4 ;
  • Y is selected from CH, O or S;
  • Z is selected from CH, O, S or NR 5 ;
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 is independently selected from the group consisting of halogen, nitro, cyano, heterocyclic, C 6-12 aryl, 5-12 membered heteroaryl, C 1-8 aliphatic, C 1-8 halogenated aliphatic a heterocyclic group C 1-8 aliphatic hydrocarbon group, a hydroxyl group C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon carbonyloxy C 1-8 aliphatic hydrocarbon group, Amino C 1-8 aliphatic hydrocarbon group, carboxyl 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 C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbon
  • 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, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, and C 1-8 aliphatic hydrocarbon based C 1-8 fat.
  • Hydrocarbyl 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 ,heterocyclyl, 5-12 membered heteroaryl, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, C 1-8 Hydrocarbylcarbonyl, heterocyclylcarbonyl, heterocyclyl C 1-8 aliphatic hydrocarbylcarbonyl, hydroxy C 1-8 aliphatic hydrocarbylcarbonyl, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbyl carbonyl, di(C 1-8 Aliphatic)amino C 1-8 aliphatic hydrocarbylcarbonyl, C 1-8 aliphatic hydro
  • 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.
  • R is selected from C 3-8 cycloalkyl substituted with -NR 2 W, wherein R 2 is selected from hydrogen or C 1-8 aliphatic;
  • R 3a , R 3b and R 3c 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 cyclohexyl substituted with -NR 2 W, wherein R 2 is selected from hydrogen or C 1-8 aliphatic;
  • R 3a , R 3b and R 3c 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 cyclohexyl substituted with -NR 2 W, wherein R 2 is selected from hydrogen or C 1-8 alkyl; Wherein R 3a , R 3b and R 3c are all hydrogen.
  • R is a 4-10 membered saturated azaheterocyclyl, wherein the azaheterocyclyl ring contains only one nitrogen atom and the nitrogen atom is replaced by W, wherein W is
  • R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is selected from C 1-8 alkyl, C 2 ⁇ 8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R is a 4-10 membered saturated azacyclic group wherein the nitrogen heterocyclyl ring contains only one nitrogen atom and the nitrogen atom is replaced by W, wherein W is Wherein R 3a , R 3b and R 3c are all hydrogen.
  • R is a 4-10 membered saturated azacyclic group wherein the nitrogen heterocyclic ring contains only one nitrogen atom and the nitrogen atom is replaced by W, wherein W is
  • R is C 1-4 alkyl substituted with a 4-10 membered saturated nitrogen heterocyclyl group, wherein the nitrogen heterocyclyl ring contains only one nitrogen atom and the nitrogen atom Replaced by W, where W is Wherein R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is selected from C 1-8 alkyl, C 2 ⁇ 8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R is C 1-4 alkyl substituted with a 4-10 membered saturated nitrogen heterocyclyl group, wherein the nitrogen heterocyclyl ring contains only one nitrogen atom and the nitrogen atom Replaced by W, where W is Wherein R 3a , R 3b and R 3c are all hydrogen.
  • R is C 1-4 alkyl substituted with a 4-10 membered saturated nitrogen heterocyclyl group, wherein the nitrogen heterocyclyl ring contains only one nitrogen atom and the nitrogen atom Replaced by W, where W is
  • X is O. In other embodiments of the compounds of Formula I, X is S. In still other embodiments of the compounds of Formula I, X is NR 4 and R 4 is selected from hydrogen or C 1-8 aliphatic hydrocarbon groups, 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 NR 4 and R 4 is selected from hydrogen or C 1-8 alkyl, more preferably selected from hydrogen or methyl.
  • V is C. In other embodiments of the compounds of Formula I, V is N.
  • Y is CH. In other embodiments of the compounds of Formula I, Y is O. In still other embodiments of the compounds of Formula I, Y is S.
  • Z is CH. In other embodiments of the compounds of Formula I, Z is O. In still other embodiments of the compounds of Formula I, Z is S. In other embodiments of the compounds of Formula I, Z is NR 5 and 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, R 5 is selected from hydrogen or C 1-8 alkyl, more preferably from hydrogen or methyl.
  • At least one of V, Y, and Z is heteroatoms.
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from Halogen, heterocyclic group, 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, C 1-8 aliphatic hydrocarbon group 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 Oxyl, heterocyclyloxy, heterocyclyl C 1-8 aliphatic hydrocarbyloxy, hydroxy C 1-8 aliphatic hydrocarbyloxy, 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 optionally substituted independently with one or more substituents selected from the group consisting of a hydroxyl group, a C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic alkyloxy group, an amino group, 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 4-8 at each occurrence. Cycloalkenyl.
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 6 ; each R 6 is independently selected from halo , heterocyclic group, 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, C 1-8 aliphatic hydrocarbon group 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, heterocyclic oxygen group, heterocyclic group C 1-8 aliphatic hydrocarbon group An oxy group, a heterocyclic group amino group, a C 1-8 aliphatic hydrocarbon group, a heterocyclic carbonyl group, a heterocyclic amino group, wherein the heterocyclic group,
  • R 1 is C 6-12 aryl, which is optionally substituted by one or more R 6 ; each R 6 is independently selected from halo, heterocyclyl, C 1- 8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbonoxy group, heterocyclic oxygen group, heterocyclic group C 1-8 aliphatic hydrocarbon group, hydroxyl group C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbyloxy group, C 1-8 aliphatic hydrocarbylamino group, di(C 1-8 aliphatic hydrocarbyl)amino group, heterocyclic amino group, amino C 1-8 aliphatic alkylamino group, C 1-8 aliphatic hydrocarbon amino C 1-8 aliphatic alkylamino group, di (C 1-8 aliphatic hydrocarbon) amino C 1-8 aliphatic alkylamino group,
  • 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 a hydroxyl group, a C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic alkyloxy group, an amino group, 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 4-8 at each occurrence. Cycloalkenyl.
  • R 1 is phenyl, which is optionally substituted with one or more R 6 ; each R 6 is independently selected from halo, heterocyclyl, C 1-8 aliphatic, C 1-8 aliphatic hydrocarbyloxy group, heterocyclic oxy group, heterocyclic group C 1-8 aliphatic hydrocarbyloxy group, hydroxy C 1-8 aliphatic hydrocarbyloxy group, C 1-8 aliphatic hydrocarbyloxy C 1-8 ester Hydrocarbyloxy, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, heterocyclylamino, C 1-8 aliphatic alkyl C 1-8 aliphatic alkyl, di (C 1-8) Hydrocarbyl)amino C 1-8 aliphatic alkylamino group, C 1-8 aliphatic hydrocarbylcarbonyl group, heterocyclic carbonyl group, C 1-8 aliphatic amino group, bis(C 1-8
  • a heterocyclic group denotes a saturated or partially unsaturated 3-8 membered impurity containing one or more, preferably one or two, heteroatoms selected from N, O, S.
  • a cyclic group preferably selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, each optionally substituted independently by one or more, preferably one or two, selected from Base substitution: hydroxyl group, C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group, 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 4-8 at each occurrence. Cycloalkenyl.
  • R 1 is phenyl, which is optionally substituted with one or more R 6 ; each R 6 is independently selected from halo, heterocyclyl, C 1-8 aliphatic, Heterocyclyl C 1-8 aliphatic hydrocarbyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclylaminoacyl, wherein heterocyclyl, as a separate group or part of another group, is meant to contain one or two a saturated or partially unsaturated 5-6 membered heterocyclic group selected from the group consisting of N, O, S heteroatoms, preferably selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, each optionally substituted independently
  • the ground is substituted with 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 cycloalkyl at each occurrence.
  • R 1 is 5-12 membered heteroaryl, which is optionally substituted by one or more R 6 , wherein each R 6 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, C 1-8 aliphatic hydrocarbon group 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, C 1-8 An aliphatic hydrocarbon carbonyl group, a heterocyclic carbonyl group, a heterocyclic oxy group, wherein:
  • 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 a hydroxyl group, a C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic alkyloxy group, an amino group, 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 4-8 at each occurrence. Cycloalkenyl.
  • R 1 is 5-10 membered heteroaryl optionally substituted by one or more R 6 , wherein each R 6 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, hydroxyl C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group 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, C 1-8 aliphatic hydrocarbon group Carbonyl group, wherein:
  • a heterocyclic group denotes a saturated or partially unsaturated 3-8 membered impurity containing one or more, preferably one or two, heteroatoms selected from N, O, S. a cyclic group, each heterocyclic group optionally being independently substituted by one or more, preferably one or two substituents selected from C 1-8 aliphatic hydrocarbon groups;
  • 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 compound of Formula I has the structural formula of Formula Ia:
  • each group has the following definition:
  • W is selected from
  • X is selected from S, O or NR 4 ;
  • Y is selected from CH, O or S;
  • Z is selected from CH, O, S or NR 5 ;
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 6 ;
  • R 2 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 is independently selected from the group consisting of halogen, nitro, cyano, heterocyclic, C 6-12 aryl, 5-12 membered heteroaryl, C 1-8 aliphatic, C 1-8 halogenated Hydrocarbyl group, heterocyclic group 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 carbonyloxy 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, 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, C 1-8 aliphatic hydrocarbon
  • 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, C 1-8 aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, and C 1-8 aliphatic hydrocarbon based C 1-8 fat.
  • Hydrocarbyl 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 ,heterocyclyl, 5-12 membered heteroaryl, hydroxy, C 1-8 aliphatic alkyloxy, amino, C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino, C 1-8 Hydrocarbylcarbonyl, heterocyclylcarbonyl, heterocyclyl C 1-8 aliphatic hydrocarbylcarbonyl, hydroxy C 1-8 aliphatic hydrocarbylcarbonyl, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbyl carbonyl, di(C 1-8 Aliphatic)amino C 1-8 aliphatic hydrocarbylcarbonyl, C 1-8 aliphatic hydro
  • 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.
  • W is Wherein R 3a , R 3b and R 3c 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 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R 3a , R 3b and R 3c are all hydrogen.
  • W is
  • X is S. In other embodiments of the compounds of Formula Ia, X is O. In still other embodiments of the compounds of Formula Ia, X is NR 4 , wherein R 4 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 NR 4 , wherein R 4 is selected from hydrogen or C 1-8 alkyl, more preferably from hydrogen or methyl, still more preferably hydrogen.
  • Y is CH. In other embodiments of the compounds of Formula Ia, Y is O. In still other embodiments of the compounds of Formula Ia, Y is S.
  • Z is CH. In other embodiments of the compounds of Formula Ia, Z is O. In still other embodiments of the compounds of Formula Ia, Z is S. In still other embodiments of the compounds of Formula Ia, Z is NR 5 , wherein R 5 is selected from hydrogen or C 1-8 aliphatic, 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. In still other embodiments, Z is NR 5 , wherein R 5 is preferably selected from hydrogen or C 1-8 alkyl, more preferably from hydrogen or methyl, still more preferably hydrogen.
  • At least one of Y and Z is a hetero atom.
  • Y is S and Z is CH.
  • Y is O and Z is CH.
  • Y is CH and Z is S. In other embodiments of the compounds of Formula Ia, Y is CH and Z is O.
  • Y is CH and Z is NR 5 , wherein R 5 is selected from hydrogen or C 1-8 aliphatic, wherein C 1-8 aliphatic is selected from C 1-8 alkane a group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 3-8 cycloalkyl group, and a C 4-8 cycloalkenyl group.
  • R 5 is selected from hydrogen or C 1-8 aliphatic, wherein C 1-8 aliphatic is selected from C 1-8 alkane a group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 3-8 cycloalkyl group, and a C 4-8 cycloalkenyl group.
  • Y is CH and Z is NR 5 , wherein R 5 is hydrogen.
  • R 1 is C 6-12 aryl or 5 to 12 membered heteroaryl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from halo , heterocyclic group, 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, C 1-8 aliphatic hydrocarbon group 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, C 1-8 aliphatic hydrocarbon oxygen , heterocyclyloxy, heterocyclyl C 1-8 aliphatic hydrocarbyloxy, hydroxy C 1-8 aliphatic hydrocarbyloxy, C 1-8 aliphatic
  • a heterocyclic group denotes a saturated or partially unsaturated 3-8 membered impurity containing one or more, preferably one or two, heteroatoms selected from O, N or S.
  • a cyclic group which is independently optionally substituted by one or more, optionally one or two substituents selected from C 1-8 aliphatic, hydroxy, C 1-8 aliphatic alkyl or C 1- 8 aliphatic hydrocarbyl 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.
  • R 1 is C 6-12 aryl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from halo, heterocyclyl, C 1- 8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbonoxy group, heterocyclic oxy group, heterocyclic group C 1-8 aliphatic hydrocarbon oxy group, hydroxy C 1-8 aliphatic hydrocarbon oxy group, C 1-8 aliphatic hydrocarbon oxy group C 1-8 aliphatic hydrocarbonoxy group, amino group, C 1-8 aliphatic hydrocarbon group amino group, di(C 1-8 aliphatic hydrocarbon group) amino group, heterocyclic amino group, amino C 1-8 aliphatic hydrocarbon group amino group, C 1-8 aliphatic hydrocarbon group amino group C 1-8 aliphatic alkylamino, di(C 1-8 aliphatic) amino C 1-8 aliphatic alkylamino, C 1-8 aliphatic hydrocarbylcarbony
  • R 1 is phenyl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from halo, heterocyclyl, C 1-8 aliphatic, C 1-8 aliphatic hydrocarbyloxy group, heterocyclic oxy group, heterocyclic group C 1-8 aliphatic hydrocarbyloxy group, hydroxy C 1-8 aliphatic hydrocarbyloxy group, C 1-8 aliphatic hydrocarbyloxy C 1-8 ester Hydrocarbyloxy, bis(C 1-8 aliphatic)amino, C 1-8 aliphatic alkylamino, heterocyclylamino, di(C 1-8 aliphatic) amino C 1-8 aliphatic alkylamino, C 1-8 An aliphatic hydrocarbon carbonyl group, a heterocyclic carbonyl group, a C 1-8 aliphatic alkyl acyl group or a heterocyclic amino acyl group, wherein the heterocycl
  • R 1 is phenyl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from halo, heterocyclyl, C 1-8 aliphatic, Heterocyclyloxy, heterocyclyl C 1-8 aliphatic hydrocarbyloxy, heterocyclylamino, heterocyclylcarbonyl or heterocyclylaminoacyl, wherein heterocyclyl, as part of a separate group or other group And 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 group consisting of piperidinyl, piperazinyl or morpholinyl, each The heterocyclic group is independently optionally substituted by one or two substituents selected from a C 1-8 aliphatic hydrocarbon group, and wherein the C 1-8 aliphatic hydrocarbon group is independently selected from a C 1-8 alkyl group at each occurrence C 3
  • R 1 is phenyl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from fluoro, chloro, methyl, methoxy, dimethyl Amino, methylaminoacyl, hydroxyethyloxy, methoxyethyloxy, dimethylaminoethylamino, heterocyclylethyloxy, heterocyclyl, cyclohexylamino, heterocyclylamino a heterocyclyloxy, heterocyclylcarbonyl or heterocyclylamino acyl group, wherein the heterocyclic group, as a separate group or part of another group, represents one or two heteroatoms selected from O, N or S a saturated or partially unsaturated 5-6 membered heterocyclic group of an atom, preferably selected from the group consisting of piperidinyl, piperazinyl, morpholinyl or tetrahydropyranyl, each independently optionally being
  • R 1 is phenyl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from fluoro, chloro, methyl, heterocyclyl, heterocycle a hexyloxy group, a heterocyclic amino group, a heterocyclic oxy group, a heterocyclic carbonyl group or a heterocyclic amino acyl group, wherein the heterocyclic group, as a separate group or part of another group, represents one or two a saturated or partially unsaturated 5-6 membered heterocyclic group selected from heteroatoms of O, N or S, preferably selected from piperidinyl, piperazinyl or morpholinyl, each heterocyclic group being independently It is optionally substituted by methyl or isopropyl.
  • R 1 is 5 to 12 membered heteroaryl, optionally substituted with one or more substituents R 6, wherein each R 6 is independently selected from heterocyclyl, C 1-8 Aliphatic, C 1-8 haloaliphatic, heterocyclyl C 1-8 aliphatic, hydroxy C 1-8 aliphatic, amino C 1-8 aliphatic, C 1-8 aliphatic alkyl C 1-8 a hydrocarbyl group, a di(C 1-8 aliphatic hydrocarbyl)amino C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbyloxy group or a C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, wherein the heterocyclic group, as an independent a group or part of another group, meaning a saturated or partially unsaturated 3-8 membered heterocyclic group containing one or two heteroatoms selected from O, N or S, independently optionally Or a plurality of C
  • R 1 is 5 to 10 membered heteroaryl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from heterocyclyl, C 1-8 Aliphatic, C 1-8 haloaliphatic, heterocyclyl C 1-8 aliphatic, hydroxy C 1-8 aliphatic, amino C 1-8 aliphatic, C 1-8 aliphatic alkyl C 1-8 a hydrocarbyl group, a di(C 1-8 aliphatic hydrocarbyl)amino C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbyloxy group or a C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, wherein the heterocyclic group, as an independent a group or part of another group, meaning a saturated or partially unsaturated 5-6 membered heterocyclic group containing one or two heteroatoms selected from O, N or S, preferably selected from morpholin
  • R 1 is 5-10 membered heteroaryl, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, isoxazolyl, pyridine Or imidazo[1,2-a]pyridinyl, which is optionally substituted by one or more R 6 , wherein each R 6 is independently selected from the group consisting of methyl, cyclobutyl, cyclopentyl, hydroxyethyl, A Oxyl, methoxyethyl, fluoroethyl, dimethylaminoethyl, 1-methyl-piperazin-4-yl or morpholin-4-ylethyl.
  • R 1 is a 5-membered heteroaryl, preferably selected from pyrazolyl, thienyl, thiazolyl, isothiazolyl or isoxazolyl, optionally substituted by one or more R a 6- substituted group wherein each R 6 is independently selected from the group consisting of C 1-8 aliphatic hydrocarbon groups, C 1-8 halogenated aliphatic hydrocarbon groups, heterocyclic C 1-8 aliphatic hydrocarbon groups, hydroxy C 1-8 aliphatic hydrocarbon groups, C 1-8 An aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, a di(C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group or a C 1-8 aliphatic hydrocarbon group C 1-8 aliphatic hydrocarbon group, wherein the heterocyclic group is independently a moiety of a group or other group denotes a saturated or partially unsaturated 5-6 membered heterocyclic
  • R 1 is a 5-membered heteroaryl, preferably selected from pyrazolyl, thienyl, thiazolyl, isothiazolyl or isoxazolyl, optionally substituted by one or more R a 6- substituted group wherein each R 6 is independently selected from the group consisting of methyl, cyclobutyl, cyclopentyl, hydroxyethyl, methoxyethyl, fluoroethyl, dimethylaminoethyl or morpholin-4- Base ethyl.
  • R 1 is selected from:
  • R 2 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 2 is selected from hydrogen or C 1-8 alkyl.
  • R 2 is selected from hydrogen or methyl.
  • R 2 is hydrogen.
  • each group has the following definition:
  • W is selected from
  • X is selected from O, S or NR 4 ;
  • Y is selected from CH, O or S;
  • Z is selected from CH, O, S or NR 5 ;
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 6 ;
  • R 2 is hydrogen
  • R 3a , R 3b and R 3c are all hydrogen
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 5 is hydrogen
  • Each R 6 is independently selected from the group consisting of halogen, heterocyclic group, 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, 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, C 1-8 aliphatic alkyloxy, heterocyclyloxy, heterocyclyl C 1-8 aliphatic hydrocarbyloxy, hydroxy C 1-8 aliphatic hydrocarbyloxy, C 1-8 aliphatic hydrocarbyloxy C 1 -8 aliphatic hydrocarbyloxy group, C 1-8 aliphatic hydrocarbylamino group, di(C 1-8 aliphatic hydro
  • 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 a hydroxyl group, a C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon group 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 4-8 at each occurrence. Cycloalkenyl.
  • each group has the following definition:
  • W is selected from
  • X is NR 4 ;
  • Y is CH
  • Z is O or S
  • R 1 is C 6-12 aryl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 6 ;
  • R 2 is hydrogen
  • R 3a , R 3b and R 3c are all hydrogen
  • R 4 is hydrogen
  • Each R 6 is independently selected from the group consisting of halogen, heterocyclic group, 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, 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
  • 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 C 1-8 aliphatic hydrocarbon groups;
  • 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 compound of Formula Ia is selected from the group consisting of:
  • the compound of Formula I has the structural formula Ib:
  • X, Y, Z, W, R 1 are all as defined in formula I;
  • l is selected from 0, 1, 2, 3 or 4, 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
  • each group has the following definition:
  • W is selected from
  • X is selected from O, S or NR 4 ;
  • Y is selected from CH, O or S;
  • Z is selected from CH, O, S or NR 5 ;
  • l is selected from 0, 1, 2, 3 or 4, 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 a 5-6 membered heteroaryl group, which is optionally substituted with one or more R 6 ;
  • R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 is independently selected from the group consisting of halogen, nitro, cyano, C 1-8 aliphatic hydrocarbon, C 1-8 halogenated aliphatic hydrocarbon, hydroxy C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic alkyloxy 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
  • each heterocyclic group optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-8 aliphatic, C 1-8 An aliphatic hydrocarbon group or a C 1-8 aliphatic hydrocarbon group; a C 6-12 aryl group and a 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 4-8 at each occurrence. Cycloalkenyl.
  • W is Wherein R 3a , R 3b and R 3c 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 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • R 3a , R 3b and R 3c are all hydrogen.
  • W is
  • X is O.
  • X is NR 4 , wherein R 4 is selected from hydrogen or C 1-8 aliphatic, 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.
  • X is NR 4 , wherein R 4 is selected from hydrogen or C 1-8 alkyl.
  • X is NR 4 , wherein R 4 is selected from hydrogen or methyl.
  • Y is CH. In other embodiments of the compounds of Formula Ib, Y is S. In other embodiments of the compounds of Formula Ib, Y is O.
  • Z is CH. In other embodiments of the compounds of Formula Ib, Z is S. In still other embodiments of the compounds of Formula Ib, Z is O. In still other embodiments of the compounds of Formula Ib, Z 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. In some embodiments, Z is NR 5 , wherein R 5 is selected from hydrogen or C 1-8 alkyl. In some embodiments, Z is NR 5 , wherein R 5 is selected from hydrogen or methyl.
  • At least one of Y and Z is a hetero atom.
  • Y is S and Z is CH. In other embodiments, Y is O and Z is CH.
  • Y is CH and Z is S. In other embodiments, Y is CH and Z is O. In still other embodiments, Y is CH and Z 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. In still other embodiments, Y is CH and Z is NR 5 , wherein R 5 is selected from hydrogen or C 1-8 alkyl, preferably selected from hydrogen or methyl.
  • R 1 is a 5-6 membered heterocyclyl optionally substituted with one or more R 6 , wherein each R 6 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, C 1-8 aliphatic hydrocarbon 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 fat a hydrocarbylcarbonyl group, a heterocyclic carbonyl group, a heterocyclic oxy group, wherein:
  • 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 a hydroxyl group, a C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic alkyloxy group, an amino group, 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 4-8 at each occurrence. Cycloalkenyl.
  • R 1 is a 5-membered heterocyclyl, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl, and R 1 optionally substituted by one or two R 6 ; wherein each R 6 is independently selected from halo, C 1-8 aliphatic, hydroxy C 1-8 aliphatic, C 1-8 aliphatic alkyl, 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) amino C 1-8 aliphatic hydrocarbon group a heterocyclic group C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon group or a heterocyclic group, wherein the heterocyclic group
  • R 1 is a 5-membered heterocyclyl, preferably selected from pyrazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl, and R 1 is optionally Two R 6 substituted; wherein each R 6 is independently selected from a C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon amino C 1-8 aliphatic hydrocarbon group , a di(C 1-8 aliphatic hydrocarbon) amino C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon carbonyl group, a heterocyclic group or a heterocyclic group C 1-8 aliphatic hydrocarbon group, wherein: a heterocyclic group, as an independent group a portion of a group or other group, meaning a saturated or partially unsaturated 5-6 membered heterocyclic group
  • R 1 is a 5-membered heterocyclyl, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl, and R 1 optionally substituted by one or two R 6 ; wherein each R 6 is independently selected from the group consisting of methyl, ethyl, isopropyl, n-butyl, hydroxyethyl, methoxymethyl, methoxyethyl , methoxypropyl, cyclobutyl, cyclopentyl, dimethylaminoethyl, morpholin-4-ylethyl, tetrahydropyran-4-yl or methylcarbonyl.
  • R 1 is a 5-membered heterocyclyl, preferably selected from pyrazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl, and R 1 is optionally Substituted by two R 6 ; wherein each R 6 is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclobutane, cyclopentane, methoxymethyl, methoxyethyl, methoxypropyl , dimethylaminoethyl, morpholin-4-ylethyl, tetrahydropyran-4-yl or methylcarbonyl.
  • R 1 is selected from:
  • 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 meaning:
  • W is selected from
  • X is selected from O, S or NR 4 ;
  • Y is selected from CH, O or S;
  • Z is selected from CH, O, S or NR 5 ;
  • l is selected from 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • R 1 is a 5-6 membered heteroaryl group, which is optionally substituted with one or more R 6 ;
  • R 3a , R 3b and R 3c are all hydrogen
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • R 5 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 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, amino C 1-8 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 aliphatic hydrocarbon group or heterocyclic group ,among them:
  • 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 with one or more substituents selected from 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 4-8 at each occurrence. Cycloalkenyl.
  • each group has the following meaning:
  • W is selected from
  • X is selected from O or NR 4 ;
  • Y is selected from CH or S
  • Z is selected from CH, O or S
  • l is selected from 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • R 1 is a 5-membered heteroaryl optionally substituted with one or more R 6 ;
  • R 3a , R 3b and R 3c are all hydrogen
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 is independently selected from the group consisting of halogen, C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbyloxy C 1-8 aliphatic hydrocarbon group, amino C 1-8 aliphatic hydrocarbon group, and C 1-8 aliphatic hydrocarbon amino 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 group or heterocyclic group, wherein:
  • a heterocyclic group denotes a saturated or partially unsaturated 5-6 membered heterocyclic group containing one or more heteroatoms selected from N, O, S, each The heterocyclic group is optionally substituted with one or more substituents selected from a C 1-8 aliphatic hydrocarbon group;
  • C 1-8 aliphatic hydrocarbon group is independently selected from the group consisting of a C 1-8 alkyl group and a C 3-8 cycloalkyl group at each occurrence.
  • the compound of Formula Ib is selected from the group consisting of:
  • the compound of Formula I has the structural formula Ic:
  • X, W, and R 1 are all as defined in Formula I;
  • l is selected from 0, 1, 2, 3 or 4; 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
  • each group has the following definition:
  • W is selected from
  • X is selected from O, S or NR 4 ;
  • l is selected from 0, 1, 2, 3 or 4; 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 a 5-6 membered heteroaryl group, which is optionally substituted with one or more R 6 ;
  • R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl;
  • R 4 is selected from hydrogen or a C 1-8 aliphatic hydrocarbon group
  • Each R 6 is independently selected from the group consisting of halogen, nitro, cyano, C 1-8 aliphatic hydrocarbon, C 1-8 halogenated aliphatic hydrocarbon, hydroxy C 1-8 aliphatic hydrocarbon, C 1-8 aliphatic alkyloxy 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 acy
  • 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 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 4-8 at each occurrence. Cycloalkenyl.
  • W is selected from Wherein R 3a , R 3b and R 3c are independently selected from hydrogen, halogen or di(C 1-8 aliphatic alkyl)aminomethyl, wherein the C 1-8 aliphatic hydrocarbon group is selected from C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl.
  • W is selected from Wherein R 3a , R 3b and R 3c are all hydrogen.
  • W is selected from
  • X is O. In other embodiments of the compounds of Formula Ic, X is S. In still other embodiments of the compounds of Formula Ic, X is NR 4 , wherein R 4 is selected from hydrogen or C 1-8 aliphatic, 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. In still other embodiments, X is NR 4 , wherein R 4 is selected from hydrogen or C 1-8 alkyl. In still other embodiments, X is NR 4 , wherein R 4 is selected from hydrogen or methyl. In still other embodiments, X is NR 4 , wherein R 4 is hydrogen.
  • R 1 is 5-6 membered heteroaryl, preferably selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl a group optionally substituted by one or more R 6 , wherein each R 6 is independently selected from the group consisting of halogen, nitro, cyano, C 1-8 aliphatic, C 1-8 haloaliphatic, hydroxy C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon group 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, bis (C 1-8 fat) Hydrocarbyl)amino C 1-8 aliphatic hydrocarbon group, heterocyclic group C 1-8 aliphatic hydrocarbon group, C 1-8 aliphatic hydrocarbon carbonyl
  • 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 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 4-8 at each occurrence. Cycloalkenyl.
  • R 1 is a 5-membered heteroaryl, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl or isothiazolyl, which is optionally Substituted by one or more R 6 wherein each R 6 is independently selected from halo, C 1-8 aliphatic, hydroxy C 1-8 aliphatic, C 1-8 aliphatic alkyl C 1-8 aliphatic , a (C 1-8 aliphatic hydrocarbon group) amino C 1-8 aliphatic hydrocarbon group, a heterocyclic group C 1-8 aliphatic hydrocarbon group, a C 1-8 aliphatic hydrocarbon group or a heterocyclic group, wherein: a heterocyclic group, as an independent group a portion of a group or other group, meaning a saturated or partially unsaturated 5-6 membered heterocyclic group containing one or two heteroatoms selected from N, O
  • a morpholino group or a tetrahydropyranyl group each heterocyclic group optionally substituted by one or more substituents selected from a C 1-8 aliphatic hydrocarbon group; wherein the C 1-8 aliphatic hydrocarbon group is independently present at each occurrence It is selected from a C 1-8 alkyl group and a C 3-8 cycloalkyl group.
  • R 1 is a 5-membered heteroaryl, preferably selected from pyrazolyl or isothiazolyl, optionally substituted by one or more R 6 , wherein each R 6 is independently selected From halogen or C 1-8 aliphatic hydrocarbon groups.
  • R 1 is a 5-membered heteroaryl, preferably selected from pyrrolyl, pyrazolyl, imidazolyl, thienyl, isoxazolyl, thiazolyl and isothiazolyl, which is optionally Substituted by one or more R 6 wherein each R 6 is independently selected from the group consisting of methyl, ethyl, isopropyl, n-butyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy Alkyl, dimethylaminoethyl, morpholin-4-ylethyl, tetrahydropyran-4-yl, cyclobutyl, cyclopentyl, methylcarbonyl, more preferably selected from methyl.
  • R 1 is selected from:
  • l is selected from 0, 1 or 2, more preferably selected from 0 or 1.
  • m is selected from 0, 1, 2 or 3, preferably selected from 1, 2 or 3.
  • n is selected from 0, 1 or 2, more preferably selected from 0.
  • m and n are not 0 at the same time.
  • each group has the following definition:
  • W is selected from
  • X is NR 4 ;
  • l is selected from 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • R 1 is a 5-6 membered heteroaryl group, which is optionally substituted with one or more R 6 ;
  • R 3a , R 3b and R 3c are all hydrogen
  • R 4 is hydrogen
  • Each R 6 is independently selected from the group consisting of halogen, heterocyclic group, C 1-8 aliphatic hydrocarbon group, C 1-8 halogenated aliphatic hydrocarbon group, hydroxy C 1-8 aliphatic hydrocarbon group, and C 1-8 aliphatic hydrocarbon oxy group 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 An aliphatic hydrocarbon group or a C 1-8 aliphatic hydrocarbon carbonyl group, wherein: a heterocyclic group, as a separate group or part of another group, represents a saturated or partially unsaturated hetero atom containing one or two selected from N, O, S a saturated 3-8 membered heterocyclic group, each heterocyclic group optionally substituted by one or more substituents selected from halogen or
  • 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.
  • each group has the following definition:
  • W is selected from
  • X is NR 4 ;
  • l is selected from 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • R 1 is a 5-membered heteroaryl optionally substituted with one or more R 6 ;
  • R 3a , R 3b and R 3c are all hydrogen
  • R 4 is hydrogen
  • Each R 6 is independently selected from a C 1-8 aliphatic hydrocarbon group
  • 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.
  • the compound of Formula Ic is selected from the group consisting of:
  • the compounds of formula I according to the invention may contain one or more chiral carbon atoms, each asymmetric carbon atom may be R or S Type, both configurations are 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, Ib and Ic, or a stereoisomer, tautomer thereof, a solvate 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 may be combined with a compound of formula I, in particular a compound of formula Ia, formula Ib and formula Ic, or a pharmaceutically acceptable salt or prodrug thereof, in sterilized distilled water. It is prepared to form a solution.
  • 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, Ib and Ic, which may be in the form of solids, may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or water-in-water Oil emulsions, etc.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used 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 compound of the formula I according to the invention in particular the compound of the formula Ia, the formula Ib and the formula Ic, or the pharmaceutical composition comprising the compound of the formula I according to the invention, in particular the compound of the formula Ia, the formula Ib and the formula Ic, may also be associated with one or more Other drugs are used in combination or in combination.
  • 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, It is used to inhibit the 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof,
  • a compound of formula I according to the invention in particular a compound of formula Ia, formula Ib and formula Ic, 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical composition for the prevention and/or treatment of BTK and/or JAK3 mediated diseases in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof
  • a pharmaceutical composition for the prevention and/or treatment of BTK and/or JAK3 mediated diseases in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof or A pharmaceutical composition comprising a compound of formula I according to the invention, in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, for preparation Use in a medicament for inhibiting 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, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, Or a pharmaceutical composition comprising a compound of formula I according to the invention, in particular a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof, Use in the preparation of a medicament for the treatment and/or prevention 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 combination of formula Ia, formula Ib and formula Ic Or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, or a compound of formula I according to the invention, in particular a compound of formula Ia, formula Ib and formula Ic, or a Use of a pharmaceutical composition of an isomer, a tautomer, a solvate or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of 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, formula Ib and formula Ic, or A stereoisomer, 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 And especially a compound of formula Ia, formula Ib and formula Ic, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof or 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 And especially a compound of formula Ia, formula Ib and formula Ic, 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, Formula 3b or Formula 3c is substituted with a compound of Formula 2a, Formula 2b or Formula 2c, respectively, to prepare a compound of Formula 3a, Formula 3b or Formula 3c.
  • 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, formula 3b or formula 3c produces a compound of formula 4a, formula 4b or formula 4c.
  • the protecting group PG in the compound of Formula 3a, Formula 3b or Formula 3c may be t-butoxycarbonyl, benzyloxycarbonyl, benzyl 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 acidic Or under neutral conditions, using a palladium catalyst for catalytic hydrogenation
  • the palladium catalyst of the present invention may be selected from palladium carbon and palladium hydroxide
  • the acid of the reaction may be selected from hydrochloric acid, trifluoroacetic acid, hydrogen chloride, 1,4-dioxane. Ring solution, sulfuric acid, etc.
  • 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, ethanol, and the like.
  • Step 3 The compound of Formula 4a, Formula 4b or Formula 4c is subjected to a condensation reaction to give a compound of Formula 5a, Formula 5b or Formula 5c.
  • 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, sodium hydride, 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 Substituting a compound of formula 5a, formula 5b or formula 5c to give the corresponding compound of formula Ia, formula Ib or formula Ic.
  • the reaction may be carried out in the presence of an acid or under neutral conditions, and the acid used in the reaction may 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 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, cesium carbonate, 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, Formula 3b or Formula 3c is substituted with a compound of Formula 2a, Formula 2b or Formula 2c, respectively, to prepare a compound of Formula 3a, Formula 3b or Formula 3c.
  • 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, Formula 3b or Formula 3c to give a compound of Formula 6a, Formula 6b or Formula 6c.
  • 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 a strong base such as sodium hydroxide, sodium t-butoxide or 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, formula 6b or formula 6c.
  • the compound of formula 7a, formula 7b or formula 7c is prepared.
  • the protecting group PG in the compound of Formula 6a, Formula 6b or Formula 6c may be t-butoxycarbonyl, benzyloxycarbonyl, benzyl 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, formula 7b or formula 7c is subjected to a condensation reaction to give the corresponding compound of formula Ia, formula Ib or formula Ic.
  • 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 1a to 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-((2-chlorothiophene[3,2-d]pyrimidin-4-yl)amino)cyclohexylaminocarboxylic acid tert-butyl ester
  • Step 2 Preparation of cis-N 1 -(2-chlorothiophene[3,2-d]pyrimidin-4-yl)cyclohexyl-1,4-diamine
  • Step 4 N-(cis-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)amino)) Preparation of hexyl) acrylamide
  • Step 1 Preparation of cis-N 1 -(2-chlorofuran[3,2-d]pyrimidin-4-yl)cyclohexyl-1,4-diamine
  • 2,4-Dichlorofuran [3,2-d]pyrimidine (188 mg, 1 mmol) was dissolved in dichloromethane (5 mL) and added dropwise to cis-1,4-cyclohexanediamine (456 mg, 4.0 mmol) In a solution of dichloromethane (10 mL). The reaction was stirred at room temperature overnight then concentrated. The residue was taken into water (20 mL)EtOAc. The organic layer was dried over anhydrous sodium sulfate EtOAc. Yield: 52.6%.
  • Step 3 N-(cis-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)furan[3,2-d]pyrimidin-4-yl)amino)) Preparation of hexyl) acrylamide
  • Step 1 Preparation of cis-N 1 -(2-chloro-5H-pyrrole[3,2-d]pyrimidin-4-yl)cyclohexyl-1,4-diamine
  • 2,4-Dichloropyrrole [3,2-d]pyrimidine (187 mg, 1 mmol) was dissolved in dichloromethane (5 mL) and added dropwise to cis-1,4-cyclohexanediamine (456 mg, 4.0 mmol) In a solution of dichloromethane (10 mL). The reaction was stirred at room temperature overnight then concentrated. The residue was taken up in water (20 mL)EtOAc. The organic layer was dried over anhydrous sodium sulfate. Yield: 56.6%.
  • Step 1 Preparation of (cis-4-((2-chlorothiophene[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)aminocarboxylic acid tert-butyl ester
  • the product obtained in the step 1 (50 mg, 0.13 mmol) was dissolved in methanol (2mL), 4N hydrogen chloride in 1,4-dioxane solution (4 mL, 1 mmol), and the reaction mixture was reacted at room temperature for 2 hours. After the reaction mixture was concentrated, the viscous liquid was dissolved in dichloromethane (5mL), and triethylamine (54 ⁇ L, 0.39 mmol) was added. Acryloyl chloride (14 ⁇ L, 0.14 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: 91.5%.
  • Step 3 N-(cis-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)thiophene[2,3-d]pyrimidin-4-yl)amino)) Preparation of hexyl) acrylamide
  • Step 1 (cis-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)amino)cyclohexyl) Preparation of tert-butyl aminocarboxylate
  • Step 2 N 4 -(cis-4-aminocyclohexyl)-N 2 -(1-methyl-1H-pyrazol-4-yl)thiophene [3,2-d]pyrimidine-2,4-di Preparation of amine
  • Step 3 N-(cis-4-((2-((1-methyl-1H-pyrazol-4-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)amino)) Preparation of hexyl)propyne amide
  • Step 1 Preparation of 3-(((2-chlorothiophene[3,2-d]pyrimidin-4-yl)amino)methyl)azetidine-1-carboxylic acid tert-butyl ester
  • Step 4 1-(3-(((2-(1-methyl-1H-pyrazol-4-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)amino)methyl) Preparation of azetidin-1-yl)-2-ene-1-propanone
  • Step 1 Preparation of tert-butyl 3-(((2-chlorofuran[3,2-d]pyrimidin-4-yl)amino)methyl)azetidin-1-carboxylate
  • step 2 The product from step 2 (0.84 mmol) was dissolved in dichloromethane (10 mL). A solution of acryloyl chloride (83.1 mg, 0.92 mmol) dissolved in dichloromethane (5 mL) was added dropwise to the above solution under ice bath. The reaction solution was allowed to react at room temperature overnight. The reaction mixture was washed with EtOAc EtOAc. Yield: 72.0%. MS (ESI, m / z) : [M + H] +: 293.0.
  • Step 4 1-(3-(((2-(1-methyl-1H-pyrazol-4-yl)amino)furan[3,2-d]pyrimidin-4-yl)amino)methyl) Preparation of azetidin-1-yl)-2-ene-1-propanone
  • Step 3 1-(3-(((2-(1-methyl-1H-pyrazol-4-yl)amino)-5H-pyrrole[3,2-d]pyrimidin-4-yl)amino) Preparation of methyl)azetidin-1-yl)-2-ene-1-propanone
  • Step 3 1-(3-(((5-methyl-1H-pyrazol-4-yl)amino)-5H-pyrrole[3,2-d]pyrimidine-4 -base) Preparation of amino)methyl)azetidin-1-yl)-2-ene-1-propanone
  • Step 1 Preparation of 3-(((2-chlorothiophene[2,3-d]pyrimidin-4-yl)amino)methyl)azetidine-1-carboxylic acid tert-butyl ester
  • step 1 The product obtained in the step 1 (425 mg, 1.20 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was stirred at room temperature, and stirred for 3 hr. Re-dissolved in dichloromethane (30 mL), and added N,N-diisopropylethylamine (417 ⁇ L, 2.40 mmol) under stirring at room temperature, and slowly add acryloyl chloride (140 ⁇ L, 1.73 mmol) in dichloromethane under ice bath. 20 mL) solution. After 5 hours, water (50 mL) was added. This was separated by silica gel column chromatography (EtOAc:EtOAc:EtOAc Yield: 81.1%. MS (ESI, m/z): [M+H] + : 309.1.
  • Step 3 1-(3-(((2-(1-methyl-1H-pyrazol-4-yl)amino)thiophene[2,3-d]pyrimidin-4-yl)amino)methyl) Preparation of azetidin-1-yl)-2-ene-1-propanone
  • Step 1 Preparation of (R)-3-((2-chlorothiophene[3,2-d]pyrimidin-4-yl)amino)pyrrolidin-1-ylcarboxylic acid tert-butyl ester
  • Step 3 Preparation of (R)-1-(3-((2-chlorothiophene[3,2-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2-ene-1-propanone
  • Step 4 (R)-1-(3-((2-Chlorothiophene[3,2-d]pyrimidin-4-yl)methyl)amino)pyrrolidin-1-yl)-2-ene-1- Preparation of acetone
  • Methyl iodide (24 [mu]L, 0.39 mmol) was added to a solution of EtOAc (EtOAc, m. Stir at room temperature for 3 hours. The reaction mixture was concentrated and evaporated to silicagel elut elut elut elut elut Yield: 76.5%.
  • Step 5 (R)-1-(3-(methyl(2-((1-methyl-1H-pyrazol-4-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)) Preparation of amino)pyrrolidin-1-yl)-2-ene-1-propanone
  • Step 3 1-(3-(((2-(1-isopropyl-1H-pyrazol-4-yl-amino)thiophene[3,2-d]pyrimidin-4-yl)amino)methyl) ) Preparation of azetidin-1-yl)-2-ene-1-propanone
  • Step 1 (R)-3-((2-((3-Methylisothiazol-5-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)amino)pyrrolidin-1-carboxylate Preparation of t-butyl acid ester
  • step 1 The product obtained in the above step 1 (35 g, 0.081 mol) was dissolved in dichloromethane (1.5 L), and methanol (1 L) was added to dissolve. A 4N solution of hydrogen chloride in 1,4-dioxane (200 mL, 0.8 mol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and taken directly to the next. MS (ESI, m/z): [M+H] + : 333.1.
  • Step 3 (R)-1-(3-((2-(3-methylisothiazol-5-yl)amino)thiophene[3,2-d]pyrimidin-4-yl)amino)pyrrolidine- Preparation of 1-yl)-2-en-1-propanone
  • step 2 The product obtained in the step 2 (26.9 g, 0.081 mol) was dissolved in dichloromethane (500 mL), triethylamine (16.36 g, 0.162 mol) was added in an ice bath, and acryloyl chloride (7.33 g, 0.081) was added dropwise in an ice bath. A solution of mol in dichloromethane (50 mL) was allowed to react at room temperature overnight. The reaction mixture was concentrated under reduced vacuolulululululululululululululu Yield: 47.9%.
  • Step 1 Preparation of (R)-3-((2-chloropyrrole[2,1-f][1,2,4]triazin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 (R)-1-(3-((2-Chloropyrrol[2,1-f][1,2,4]triazin-4-yl)amino)piperidin-1-yl)-2 -Alken-1-propanone preparation
  • Step 3 (R)-1-(3-((2-(3-methylisothiazol-5-yl)amino)pyrrole[2,1-f][1,2,4]triazine-4 Of -amino)piperidin-1-yl)-2-ene-1-propanone
  • Step 1 (R)-3-((2-((3-methylisothiazol-5-yl)amino)pyrrole [2,1-f][1,2,4]triazin-4-yl) Preparation of amino)piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 (R)-N 2 -(3-Methylisothiazol-5-yl)-N 4 -(piperidin-3-yl)pyrrole [2,1-f][1,2,4] Preparation of azine-2,4-diamine
  • Step 3 (R)-1-(3-((2-(3-methylisothiazol-5-yl)amino)pyrrole[2,1-f][1,2,4]triazine-4 Of -amino)piperidin-1-yl)-2-yn-1-one
  • 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 IX show 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 kinase activity inhibition assay
  • JAK3 kinase purchased from SignalChem, Cat. No. J03-11G was diluted to a final concentration of 2 times with a reaction buffer (40 mM Tris-HCl, pH 7.5; 20 mM MgCl 2 ; 0.1 mg/ml BSA; 1 mM DTT) (final concentration was 0.5 ng/ ⁇ L) was added to the 96-well plate at 5 ⁇ L/well.
  • a reaction buffer 40 mM Tris-HCl, pH 7.5; 20 mM MgCl 2 ; 0.1 mg/ml BSA; 1 mM DTT
  • 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 was purchased from Promega, NO: V9102), reacted at 25 °C 40 min, each well was added 20 ⁇ L ADP-Glo Kinase Assay and 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 compound of the present invention was calculated. The results are shown in Table 10.
  • Table 10 shows the activity of the selected compounds of the present invention in the activity inhibition assay of JAK3, wherein the compound designated as "+++” has an IC 50 ⁇ 10 nM; the compound designated as “++” has an IC 50 of 10 ⁇ IC 50 ⁇ 100 nM; compounds designated as "+” by activity provide an IC 50 of 100 ⁇ IC 50 ⁇ 1000 nM.
  • Test Example 3 IL-2 induced CTLL-2 cell proliferation assay
  • the compounds of the invention were diluted 3-fold with RPMI-1640 complete medium (purchased from Gibco, Cat. No. 22440) to a final concentration (1 ⁇ M, 0.2 ⁇ M, 40 nM, 8 nM, 1.6 nM and 0.32 nM, respectively) (ie, 3 ⁇ M, 0.6 ⁇ M, 120 nM, 24 nM, 4.8 nM and 0.96 nM), 50 ⁇ L of compound/well was added to the 96-well plate test well and set to contain IL-2 (abbreviated as IL-2 + ) (IL-2 was purchased from R&D, article number: 402-ML-020/CF) and control wells without IL-2 (abbreviated as IL-2-) (plus 50 ⁇ L of medium).
  • IL-2 + IL-2 was purchased from R&D, article number: 402-ML-020/CF
  • IL-2- control wells without IL-2 (abbreviated as IL-2-) (plus 50 ⁇ L
  • Logarithmic growth phase CTLL-2 cells (purchased from ATCC, item number: TIB-214) were washed with PBS buffer (pH 7.2) and resuspended in RPMI-1640 complete medium without IL-2 at 50000 cells/ 50 ⁇ L/well was seeded in the experimental wells and control wells of the 96-well plates, and the experimental plates were pre-incubated for 1 hour at 37 ° C, 5% CO 2 . Thereafter, RPMI-1640 complete medium (50 ⁇ L/well) containing IL-2 was added to the experimental wells and IL-2 + control wells, and RPMI-1640 without IL-2 was completely cultured in IL-2-control wells.
  • Table 12 shows the activity of the selected compounds of the present invention in the CTLL-2 cell proliferation assay, wherein the compound designated as "+++” has an IC 50 ⁇ 100 nM; the activity is designated as "++". 50 is 100 ⁇ IC 50 ⁇ 1000 nM.
  • Test Example 4 Ramos cell p-BTK and p-PCL- ⁇ 2 inhibition experiments (Western blot)
  • Ramos cells cultured for 1 hour after starvation were treated with the compound of the present invention for 1 hour, and then washed with PBS buffer (pH 7.2).
  • the cells were resuspended in 100 ⁇ L of serum-free medium containing 1 ⁇ M of anti-human IgM F(ab') 2 (purchased from SBA, Cat. No. 2022-01), and incubated on ice for 10 minutes.
  • IgM was washed away with PBS buffer (pH 7.2) and resuspended in 100 ⁇ L of protein lysate (purchased from Sigma, Cat. No. C2978). Protein samples were prepared and quantified.
  • a 100 ⁇ g protein sample was taken and subjected to polyacrylamide gel electrophoresis at a voltage of 200V. After the end of the electrophoresis, the protein was transferred to a PVDF membrane and blocked with 3% BSA for 2 hours at room temperature.
  • the corresponding antibodies anti-p-BTK (pY223) (purchased from CST, Cat. No.
  • anti-BTK purchased from Abcam, article number: ab118156
  • anti-p-PLC ⁇ 2 pY1217)
  • anti-PLC ⁇ 2 purchased from CST, item number: 3872S
  • anti- ⁇ -actin purchased from CWBIO, item number: CW0096A
  • CWBIO item number: CW0096A
  • horseradish peroxidase-labeled IgG secondary antibody purchased from CWBIO, item number: CW0103A
  • ECL substrate purchased from GE, item number: RPN2109
  • the compound 132 of the present invention was tested as described above, and the results showed that the compound 132 significantly inhibited the expression of p-BTK and p-PLC ⁇ 2 in Ramos cells in a dose-dependent manner.
  • Test Example 5 Type 2 collagen induced DBA/1J mouse arthritis model (CIA)
  • the CIA model is an animal model widely used to study the treatment of human rheumatoid arthritis.
  • the experimental animals used in this experiment were DBA/1J mice (male, 6-8 weeks old, purchased from Shanghai Slack Laboratory Animal Co., Ltd.) and were housed in the IVC system.
  • a bovine type II collagen solution (CII) (purchased from Chondrex, Cat. No. 20022) and an equal volume of complete Freund's adjuvant (CFA) (purchased from Sigma-Aldrich, article number: F5881) Emulsification was carried out using an electronic homogenizer to prepare an emulsion, and then 70 ⁇ L of the prepared emulsion was intradermally injected and injected into the tail of the mouse to perform primary immunization. After three weeks of initial immunization, boost the immunization once.
  • CII bovine type II collagen solution
  • CFA complete Freund's adjuvant
  • IFA incomplete Freund's adjuvant
  • mice The severity of arthritis in mice was divided into 0 to 4 points according to the following criteria (0 points: no edema or swelling; 1 point: mild edema and redness, limited to ankle or tibia; 2 points: mild edema and hair Red, from ankle to humerus; 3 points: moderate edema and redness, from ankle to humerus; 4 points: severe edema and redness, from ankle to the entire foot, toes, or ankle or wrist stiffness)
  • the limbs of each mouse were scored and summed, with a maximum score of 16 points (4 ⁇ 4).
  • arthritis score they were divided into three groups, one group of model control group and two groups of drug groups, each group of 5 to 7 mice.
  • the average score of arthritis severity score of each group of mice at the beginning of treatment was The value is about 1-2 points.
  • Two doses of 3 mg/kg and 10 mg/kg were designed, administered orally, once a day for 14 days.
  • the normal control group was set, and the test results were compared with the results of the normal control group and the model control group to determine the therapeutic effect of the test compound on the arthritis of the model.
  • the compound 132 of the present invention has a good arthritis therapeutic effect in the CIA model at a prescribed dose, and is dose-dependent.
  • the toes were scored separately with a maximum score of 16.
  • the toe volume of the rat was measured by the toe volumetric drainage method, and the volume (mL) below the ankle joint was measured (PV-200 toe volume measuring instrument, Chengdu Taimeng Technology Co., Ltd.).
  • the rat toe volume was measured from the 10th day of immunization, that is, the first day of administration, and was measured every two days.
  • the volume of the limbs measured per rat was added and divided by 4 to obtain an average value.
  • Two doses of 30 mg/kg and 100 mg/kg were designed separately, orally, once a day for 7 days.
  • the normal control group and the model control group were set, and the test results were compared with the results of the normal control group and the model control group to determine the therapeutic effect of the test compound on the arthritis of the model.
  • the compound 132 of the present invention has a good arthritis therapeutic effect in the AIA model at the set administration dose.

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Abstract

本发明涉及抑制BTK（布鲁顿酪氨酸激酶）和/或JAK3（Janus酪氨酸激酶3）激酶活性的化合物、其药物组合物、其在制药中的用途、使用其抑制BTK和/或JAK3活性的方法以及使用其治疗和/或预防哺乳动物（尤其是人）中BTK和/或JAK3介导的疾病或病症的方法。所述化合物具有结构式（I）。

Description

抑制BTK和/或JAK3激酶活性的化合物 技术领域
本发明涉及抑制BTK(布鲁顿酪氨酸激酶)和/或JAK3(Janus酪氨酸激酶3)激酶活性的化合物、其药物组合物、其在制药中的用途、使用其抑制BTK和/或JAK3活性的方法以及使用其治疗和/或预防哺乳动物(尤其是人)中BTK和/或JAK3介导的疾病或病症的方法。
背景技术
蛋白质激酶是组成人类酶的最大家族之一，迄今为止在人体中已鉴定出超过500种。他们通过向蛋白质转移磷酸基团来调节特定蛋白质的活性，从而调节复杂的信号传导通路。异常的蛋白质激酶活性与癌症，自身免疫性疾病等多种疾病相关。鉴于蛋白质激酶在信号传导通路中的关键作用以及激酶活性与多种疾病的相关性，激酶抑制剂已经成为了小分子化学药物研发的热门方向。
BTK(布鲁顿酪氨酸激酶)是属于TEC家族的非受体酪氨酸激酶，是B细胞受体(BCR)信号传导过程中的重要介质。BTK是早期B细胞发育以及成熟B细胞活化，信号转导和存活的重要调节剂，因此BTK抑制剂可以用于治疗B细胞异常活化相关的疾病，例如自身免疫性疾病，包括类风湿性关节炎和系统性红斑狼疮等。BTK抑制剂治疗自身免疫性疾病的效果在临床前动物模型上得到了初步的验证(Honigberg,L.A et al,Proceedings of the National Academy of Sciences of the United States of America,2010,107,13075-13080)。除了B细胞以外，实验证据表明BTK在单核细胞、巨噬细胞、中性粒细胞和肥大细胞的信号通路中也有作用。BTK抑制剂可以抑制单核细胞以及巨噬细胞由FcγR介导的细胞因子释放，这些细胞因子包括TNFa，IL-1β和IL-6，也可以抑制由FcεR介导的肥大细胞脱颗粒(Chang B.Y et al,Arthritis Research&Therapy,2011,13,R115)。
B细胞受体(BCR)介导的信号通路对多种淋巴瘤的存活起重要作用。作为BCR通路中的关键激酶，BTK也可以作为淋巴瘤的治疗靶点。临床实验表明，BTK抑制剂治疗慢性淋巴细胞性白血病(CLL)有显著的疗效。BTK抑制剂对其它淋巴瘤例如弥散性大B细胞淋巴瘤和套细胞淋巴瘤等也有明显的效果(Buggy,J.J et al,International Reviews of Immunology,2012,31,119-132)。
Janus激酶家族是调节淋巴造血系统中细胞功能的重要酪氨酸激酶。其包含4个已知成员，分别是JAK1、JAK2、JAK3和TYK2，其中JAK3(Janus酪氨酸激酶3)主要在淋巴细胞和自然杀伤性细胞中表达。JAK3与IL-2，IL-4，IL-7，IL-9，IL-15和IL-21受体的共同亚单位γc链连接(Ghoreschi K et al,Immunological Reviews,2009,228,273-87)。这些细胞因子通过JAK3的介导，对淋巴细胞的增殖、分化及其功能 起重要的作用。JAK3激酶的功能缺失将导致人类和小鼠的免疫缺陷。基于JAK3激酶在免疫系统中的重要作用，JAK3激酶是一个非常有吸引力的靶点用于治疗免疫相关的病症，例如类风湿性关节炎等自身免疫性疾病或者器官移植病人的同种异体移植物排异。选择性的JAK3抑制剂在类风湿性关节炎的临床实验中表现出了显著的疗效。
除了BTK抑制剂和JAK3抑制剂各自单独的应用，同时抑制BTK通路和JAK3通路有可能在临床应用上表现出协同的疗效。例如，Cetkovic-Cvrlje M等通过实验表明，联合应用BTK抑制剂和JAK3抑制剂可以更有效地提高移植物抗宿主病(GVHD)动物模型的存活率(Cetkovic-Cvrlje,M et al,British Journal of Haematology,2004,126,821-827)。
因而有必要开发具有良好的活性、可以口服、并在体内表现出有利于治疗应用的药代动力学性质、同时具有足够低的毒副作用的针对BTK和/或JAK3通路的新型化合物。
发明内容
根据本发明的一个方面，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式I(在下文中有时也被称为式I化合物)：
Figure PCTCN2014086820-appb-000001
其中：
R选自被-NR2W取代的C3-8环烷基；4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；
W选自
Figure PCTCN2014086820-appb-000002
V选自C或N；
X选自于O、S或NR4；
Y选自于CH、O或S；
Z选自CH、O、S或NR5；
R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；
R2选自于氢或C1-8脂烃基；
R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R4选自于氢或C1-8脂烃基；
R5选自于氢或C1-8脂烃基；
每个R6独立地选自卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、羧基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基 磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基或二(C1-8脂烃基)膦酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、杂环基、5-12元杂芳基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在一些实施方式中，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式Ia(在下文中有时也被称为式Ia化合物)：
Figure PCTCN2014086820-appb-000003
其中，X、Y、Z、W、R1和R2均如式I中所定义。
在一些实施方式中，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式Ib(在下文中有时也被称为式Ib化合物)：
Figure PCTCN2014086820-appb-000004
其中：
X、Y、Z、W和R1均如式I中所定义；
l选自0、1、2、3或4，其中当l是0时，
Figure PCTCN2014086820-appb-000005
为
Figure PCTCN2014086820-appb-000006
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086820-appb-000007
为
Figure PCTCN2014086820-appb-000008
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086820-appb-000009
为
Figure PCTCN2014086820-appb-000010
在一些实施方式中，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式Ic(在下文中有时也被称为式Ic化合物)：
Figure PCTCN2014086820-appb-000011
其中：
X、W、R1均如式I中所定义；
l选自于0、1、2、3或4；其中当l是0时，
Figure PCTCN2014086820-appb-000012
为
Figure PCTCN2014086820-appb-000013
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086820-appb-000014
为
Figure PCTCN2014086820-appb-000015
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086820-appb-000016
为
Figure PCTCN2014086820-appb-000017
本发明的另一方面涉及一种药物组合物，所述药物组合物包含一种或多种本发 明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明所述的药物组合物还可以包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备用于抑制BTK和/或JAK3活性的药物中的用途。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备用于预防或治疗BTK和/或JAK3介导的疾病的药物中的用途。
本发明的另一方面涉及本发明的药物组合物在制备抑制BTK和/或JAK3活性的药物中的用途，其中所述药物组合物包含一种或多种本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。在一些实施方式中，除前述化合物外，所述药物组合物还可以包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
本发明的另一方面涉及本发明的药物组合物在制备用于预防或治疗BTK和/或JAK3介导的疾病的药物中的用途，其中所述药物组合物包含一种或多种本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。在一些实施方式中，除前述化合物外，所述药物组合物还可以包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于预防或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia、式Ib和式Ic 化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于预防或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及在生物体系中抑制BTK和/或JAK3活性的方法，该方法包含使所述生物体系接触本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物。
本发明的另一方面涉及预防或治疗BTK和/或JAK3介导的疾病的方法，该方法包含对有需要的哺乳动物(尤其是人)给予治疗有效量的本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物。
本发明的另一方面涉及本发明所述的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐与一种或多种选自以下的活性物质在制备用于治疗BTK和/或JAK3介导的疾病的药物中的应用：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
在本申请中，BTK和/或JAK3介导的疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病和癌症。
附图说明
图1化合物132在Ramos细胞中对BTK通路的抑制效果。
图2化合物132的mCIA评分。
图3化合物132的rAIA评分。
具体实施方式
除非另有定义，否则本文所用的科技术语具有与权利要求主题所属领域技术人员通常所理解的涵义相同的涵义。
应理解，上述简述和下文的详述为示例性且仅用于举例说明，而不对本发明主题作任何限制。
本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-8脂烃基是指具有总共1至8个碳原子的如下文所定义的脂烃基； C1-8烷基是指具有总共1至8个碳原子的如下文所定义的烷基；C3-8环烷基是指具有总共3至8个碳原子的如下文所定义的环烷基；C6-12芳基是指具有总共6至12个碳原子的如下文所定义的芳基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除非本说明书中另外特别指明，本发明所述的所有组合基团(即是指由两个或两个以上的基团组合起来的基团)是以最后描述的基团作为连接位点与分子其余部分连接。举例来说，基团“杂环基脂烃基”是指杂环基通过脂烃基与分子其余部分连接；基团“脂烃基氧基”是指脂烃基通过氧基与分子其余部分连接等等。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义：
“氨基”是指-NH2基团。
“氰基”是指-CN基团。
“羟基”是指-OH基团。
“硝基”是指-NO2基团。
“氧代”是指＝O取代基。
“羰基”或“酰基”是指-C(＝O)-基团。
“巯基”是指-S基团。
“磺酰基”是指-S(＝O)2-基团。
“亚磺酰基”是指-S(＝O)-基团。
“膦酰基”是指-P(＝O)(OH)2基团。
“氨基酰基”是指-C(＝O)-NH2基团。
“氨基磺酰基”是指-S(＝O)2-NH2基团。
“氨基亚磺酰基”是指-S(＝O)-NH2基团。
在本申请中，术语“卤素”是指氟、氯、溴或碘，优选氟或氯。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基”是指具有脂肪族化合物基本属性的仅由碳原子和氢原子组成且通过单键与分子的其余部分连接的饱和或不饱和的基团。脂烃基包括直链或支链的烷基、烯基和炔基以及环烷基和环烯基，其中烷基、烯基、炔基、环烷基和环烯基均如下文所定义。在本申请中，脂烃基是指烷基、烯基、炔基、环烷基和/或环烯基，优选是指烷基和/或环烷基。脂烃基上的氢均可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键且通过单键与分子的其余部分连接的直链或支链的基团。烷基可以具有例如1至18个、优选1至12个、更优选1至8个碳原子。烷 基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等，优选甲基、乙基、丙基、异丙基、正丁基，更优选甲基、乙基、丙基和异丙基。烷基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至18个、优选2至10个、更优选2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，包括但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-2-烯基、戊-1,4-二烯基等，优选乙烯基、丙烯基。烯基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至18个、优选为2至10个、更优选2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。炔基的实例包括但不限于乙炔基、丙-1-炔基、戊-1-烯-4-炔基等。炔基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的饱和的非芳香族单环或多环烃基，其可包括稠合环体系或桥环体系，具有例如3至15个、优选3至10个、更优选3至8个碳原子，且经由环上任何适宜的碳原子通过单键与分子的其余部分连接。环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、和金刚烷基等，优选环丁基、环戊基、环己基。环烷基上的氢可任选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷基、烷氧基、杂环基等等。
在本申请中，作为独立的基团或其它基团的一部分，术语“环烯基”意指仅由碳原子和氢原子组成的、含有至少一个双键的稳定的非芳香族单环或多环烃基，其可包括稠合环体系或桥环体系。其具有例如3至15个、优选3至10个、更优选3至8个碳原子，且经由环上任何适宜的碳原子通过单键与分子的其余部分连接。环烯基的实例包括但不限于环丁烯基、环戊烯基、环己烯基、1,3-环己二烯、1,4-环己二烯、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5-氢-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、八氢-4,7-亚甲基-1-氢-茚基和八氢-2,5-亚甲基-并环戊二烯基等。环烯基上的氢可任 选地被适宜的任何基团取代，例如卤素、羟基、氨基、单取代氨基、二取代氨基、烷基、烷氧基、杂环基等等。
在本申请中，术语“卤代脂烃基”是指被一个或多个卤素原子取代的脂烃基，其中脂烃基如上文所定义。其实例包括但不限于氟甲基、二氟甲基、三氟甲基、氟乙基、1,1-二氟乙基、氯甲基、氯乙基、二氯甲基、1,2-二氯乙基、氟代乙烯基、氟代环戊基、氟代环己基、氯代环己烯基等，优选氟乙基。
在本申请中，术语“羟基脂烃基”是指被一个或多个羟基取代的如上文所定义的脂烃基。其实例包括但不限于1-羟基乙基、1,2-二羟基乙基、3-羟基环戊基、4-羟基环己基，3,4-二羟基环己基等，优选1-羟基乙基。
在本申请中，术语“氨基脂烃基”是指被一个或多个氨基取代的如上文所定义的脂烃基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氧基”是指式-ORa基团，其中Ra为如上文所定义的脂烃基。脂烃基氧基中的脂烃基部分也可如上文对脂烃基所述的那样被任选取代。脂烃基氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、乙烯基氧基、1-丙烯基氧基、1-丙炔基氧基、环戊基氧基、环己基氧基等，优选甲氧基、乙氧基。
在本申请中，术语“羟基脂烃基氧基”是指其中脂烃基被一个或多个羟基取代的如上文所定义的脂烃基氧基。其实例包括但不限于1-羟基乙氧基、1-羟基丙氧基、3-羟基环戊烷氧基、3,4-二羟基环己烷氧基等，优选1-羟基乙氧基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基羰基”是指式-C(＝O)-Ra基团，其中Ra为如上文所定义的脂烃基。脂烃基羰基中的脂烃基部分也可如上文对脂烃基所述的那样被任选取代。脂烃基羰基包括烷基羰基、烯基羰基、炔基羰基、环烷基羰基和环烯基羰基，其中烷基、烯基、炔基、环烷基和环烯基均如上面所定义的。在本申请中，脂烃基羰基优选是指烷基羰基和/或环烷基羰基。脂烃基羰基的实例包括但不限于甲基羰基(也被称为乙酰基)、乙基羰基(也被称为丙酰基)、异丙基羰基、丁基羰基、乙烯基羰基、丙烯基羰基、环戊基羰基、环己基羰基等，优选甲基羰基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氨基”是指式-NHRa基团，其中Ra为如上文所定义的脂烃基。脂烃基氨基包括烷基氨基、烯基氨基、炔基氨基、环烷基氨基和环烯基氨基，其中烷基、烯基、炔基、环烷基和环烯基均如上面所定义的。在本申请中，脂烃基氨基优选是指烷基氨基和/或环烷基氨基。其实例包括但不限于甲基氨基、乙基氨基、异丙基氨基、乙烯基氨基、丙烯基氨基、丙炔基氨基、环丁基氨基、环戊基氨基、环己基氨基、环己烯基氨基等，优选甲基氨基、乙基氨基、环己基氨基。
在本申请中，作为独立的基团或其它基团的一部分，术语“二脂烃基氨基”是指氨基上的两个氢分别被脂烃基取代的氨基基团，可用式-NRaRb表示，其中Ra和Rb分别独立地为如上文所定义的脂烃基。在本申请中，二脂烃基氨基优选是指二烷基氨基。二烷基氨基的实例包括但不限于二甲基氨基、二乙基氨基、二丙基氨基、甲基乙基氨基等，优选二甲基氨基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氧基脂烃基氧基”是指其中的脂烃基被如上文所定义的脂烃基氧基取代的如上文所定义的脂烃基氧基。脂烃基氧基脂烃基氧基优选是指烷氧基烷氧基、烷氧基环烷氧基和/或环烷氧基烷氧基，其实例包括但不限于如甲氧基乙氧基、乙氧基乙氧基、甲氧基环戊烷氧基、甲氧基环己烷氧基、环戊烷氧基甲氧基等。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氨基脂烃基”是指被如上文所定义的脂烃基氨基取代的如上文所定义的脂烃基。
在本申请中，作为独立的基团或其它基团的一部分，术语“二脂烃基氨基脂烃基”是指被如上文所定义的二脂烃基氨基取代的如上文所定义的脂烃基。其实例包括但不限于二甲基氨基乙基、二乙基氨基乙基、(甲基)(乙基)氨基乙基等，优选二甲基氨基乙基。
在本申请中，作为独立的基团或其它基团的一部分，术语“二脂烃基氨基脂烃基氨基”是指其中脂烃基被如上文所定义的二脂烃基氨基取代的如上文所定义的脂烃基氨基。其实例包括但不限于二甲基氨基乙基氨基、二乙基氨基乙基氨基、(甲基)(乙基)氨基乙基氨基等，优选二甲基氨基乙基氨基。
在本申请中，作为独立的基团或其它基团的一部分，术语“脂烃基氨基酰基”是指其中氨基上的一个氢被如上文所定义的脂烃基替代的氨基酰基，其可以表示为式-C(＝O)-NH-Ra，其中Ra为如上文所定义的脂烃基。其实例包括但不限于-C(＝O)-NH-CH3、-C(＝O)-NH-C2H5、环己基氨基酰基等，优选-C(＝O)-NH-CH3。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基”意指由含有1至6个选自氮、氧和硫的杂原子组成的稳定的3元至18元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系或桥环体系。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的3元至12元非芳香性单环或双环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的3元至8元非芳香性单环基团。杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。杂环基的实例包括但不限于：氮杂环 丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、吗啉基、硫代吗啉基、哌嗪基、哌啶基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等，优选哌嗪基、哌啶基、四氢吡喃基、吗啉基。杂环基可任选地被任意适当的取代基取代，该取代基包括但不限于卤素、羟基、氨基、烷基、烷氧基、烷基羰基等等。
在本申请中，“氮杂环基”是指环上含有至少一个氮原子的如上文所定义的杂环基。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基氧基”是指式-ORh基团，其中Rh为如上文所定义的杂环基。杂环基氧基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基羰基”是指式-C(＝O)-Rh基团，其中Rh为如上文所定义的杂环基。杂环基羰基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基氨基”是指式Rh-NH-，其中Rh为如上文所定义的杂环基。杂环基氨基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基氨基酰基”是指其中氨基上的一个氢被如上文所定义的杂环基替代的氨基酰基，其可以表示为式-C(＝O)-NH-Rh，其中Rh为如上文所定义的杂环基。杂环基氨基酰基中的杂环基部分也可如上文关于杂环基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基脂烃基”是指被如上文所定义的杂环基取代的如上文所定义的脂烃基。杂环基脂烃基中的杂环基部分可如上文关于杂环基所述的那样被任选取代，并且杂环基脂烃基中的脂烃基部分可如上文关于脂烃基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂环基脂烃基氧基”是指其中脂烃基被如上文所定义的杂环基取代的如上文所定义的脂烃基氧基。杂环基脂烃基氧基中的杂环基部分可如上文关于杂环基所述的那样被任选取代，并且杂环基脂烃基氧基中的脂烃基部分可如上文关于脂烃基所述的那样被任选取代。
在本申请中，作为独立的基团或其它基团的一部分，术语“芳基”意指具有6至18个、优选为6至12个碳原子及至少一个芳香环的体系。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，其可以包含稠合环或桥环体系。芳基经由芳香族环原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基 等，优选苯基。
在本申请中，作为独立的基团或其它基团的一部分，术语“杂芳基”意指环内具有1至4个选自氮、氧及硫的杂原子，以及至少一个芳香环的5元至16元环体系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，其可包括稠合环体系或桥环体系，条件是连接点为芳香族环原子。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性单环或双环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至8元芳香性单环或双环基团，最优选包含1至2个选自氮、氧和硫的杂原子的稳定的5元至6元芳香性单环基团。杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、咪唑基、苯并咪唑基、吡唑基、苯并吡唑基、三唑基、四唑基、吡啶基、吡嗪基、三嗪基、嘧啶基、哒嗪基、吲嗪基、吲哚基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、噻唑基、异噻唑基、苯并噻唑基、苯并噻吩基、噁唑基、异噁唑基、噁二唑基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、咪唑[1,2-a]吡啶基等，优选吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基、异噻唑基、吡啶基、咪唑[1,2-a]吡啶基，更优选吡唑基、噻吩基、异噁唑基、噻唑基、异噻唑基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被一个或多个卤素取代的烷基”表示烷基未被取代或被一个或多个卤素取代，且该描述同时包括被取代的烷基与未被取代的烷基。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
由于本发明的式I化合物含有烯双键，因此，除非另外特别指明，否则本发明的式I化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的式I化合物的所有互变异构形式也将包含在本发明的范围内。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的、与无机酸或有机酸所形成的盐。所述无机酸包括但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等；所述有机酸包括但不限于甲酸、乙酸、三氟乙酸、丙酸、辛酸、己 酸、癸酸、十一碳烯酸、乙醇酸、葡糖酸、乳酸、草酸、癸二酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、硬脂酸、油酸、肉桂酸、月桂酸、苹果酸、谷氨酸、焦谷氨酸、天冬氨酸、苯甲酸、甲磺酸、对甲苯磺酸、海藻酸、抗环血酸、水杨酸、4-氨基水杨酸、萘二磺酸等。这些盐可通过本领域已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的盐。这些盐是通过将无机碱或有机碱添加至游离酸而制备的。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐和镁盐。衍生自有机碱的盐包括但不限于以下碱的盐：伯胺、仲胺及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。
根据带电荷官能团的数目和阳离子或阴离子的化合价，本发明化合物可以含有多个阳离子或阴离子。
通常，结晶化作用会产生本发明化合物的溶剂化物。在本申请中，“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。溶剂可以是水，该情况下的溶剂化物是水合物。或者，溶剂也可以是有机溶剂。本发明化合物的溶剂化物也属于本发明范围之内。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物递送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的辅料。本申请的药物组合物可以是单个制剂，也可以是多个制剂的组合。
在本申请中，“药学上可接受的辅料”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，“治疗有效量”是指本发明化合物的量，当本发明化合物被给予哺乳动物(例如人)时，该量足以有效地治疗哺乳动物(例如人)的疾病或病症。构成“治疗有效量”的本发明化合物的量取决于所用的具体化合物、要治疗的具体病症、病症的起因、药物的靶点、疾病的严重程度、给药方式以及待治疗的哺乳动物的年龄、体重、身体状况等，但可常规地由本领域技术人员根据其自身的知识及本申请公开 的内容而决定。
根据本发明的一个方面，本发明提供了一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式I：
Figure PCTCN2014086820-appb-000018
其中：
R选自被-NR2W取代的C3-8环烷基；4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；
W选自
Figure PCTCN2014086820-appb-000019
V选自C或N；
X选自于O、S或NR4；
Y选自于CH、O或S；
Z选自CH、O、S或NR5；
R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；
R2选自于氢或C1-8脂烃基；
R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R4选自于氢或C1-8脂烃基；
R5选自于氢或C1-8脂烃基；
每个R6独立地选自卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、羧基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧 基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基或二(C1-8脂烃基)膦酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、杂环基、5-12元杂芳基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R选自被-NR2W取代的C3-8环烷基，其中R2选自于氢或C1-8脂烃基；W选自
Figure PCTCN2014086820-appb-000020
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R选自被-NR2W取代的环己基，其中R2选自于氢或C1-8脂烃基；W选自
Figure PCTCN2014086820-appb-000021
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R选自被-NR2W取代的环己基，其中R2选自于氢或C1-8烷基；W选自
Figure PCTCN2014086820-appb-000022
其中R3a、R3b和R3c均为氢。
在式I化合物的一些实施方式中，R为4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中W为
Figure PCTCN2014086820-appb-000023
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在一些实施方式中，R为4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中W为
Figure PCTCN2014086820-appb-000024
其中R3a、R3b和R3c均为氢。
在式I化合物的一些实施方式中，R为4-10元饱和的氮杂环基，其中该氮杂环 基环上仅含一个氮原子，且该氮原子被W取代，其中W为
Figure PCTCN2014086820-appb-000025
在式I化合物的一些实施方式中，R为被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中W为
Figure PCTCN2014086820-appb-000026
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中C1-8脂烃基选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R为被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中W为
Figure PCTCN2014086820-appb-000027
其中R3a、R3b和R3c均为氢。
在式I化合物的一些实施方式中，R为被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代，其中W为
Figure PCTCN2014086820-appb-000028
在式I化合物的一些实施方式中，X为O。在式I化合物的另一些实施方式中，X为S。在式I化合物的又一些实施方式中，X为NR4，R4选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，X为NR4，R4选自于氢或C1-8烷基，更优选选自于氢或甲基。
在式I化合物的一些实施方式中，V为C。在式I化合物的另一些实施方式中，V为N。
在式I化合物的一些实施方式中，Y为CH。在式I化合物的另一些实施方式中，Y为O。在式I化合物的又一些实施方式中，Y为S。
在式I化合物的一些实施方式中，Z为CH。在式I化合物的另一些实施方式中，Z为O。在式I化合物的又一些实施方式中，Z为S。在式I化合物的另一些实施方式中，Z为NR5，R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，R5选自于氢或C1-8烷基，更优选选自于氢或甲基。
在式I化合物的一些实施方式中，V、Y和Z中的至少一个杂原子。
在式I化合物的一些实施方式中，R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、 氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基、氨基、C1-8脂烃基羰基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基氧基、杂环基C1-8脂烃基氧基、杂环基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基氨基酰基，其中：杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自C1-8脂烃基的取代基取代。
在式I化合物的一些实施方式中，R1为C6-12芳基，其任选地被一个或多个R6取代；每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基、氨基、 C1-8脂烃基羰基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R1为苯基，其任选地被一个或多个R6取代；每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基氨基酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个、优选一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，优选选自哌啶基、哌嗪基、吗啉基、四氢吡喃基，每个杂环基任选独立地被一个或多个、优选一个或两个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基羰基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R1为苯基，其任选地被一个或多个R6取代；每个R6独立地选自卤素、杂环基、C1-8脂烃基、杂环基C1-8脂烃基氧基、杂环基氨基、杂环基羰基、杂环基氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、哌嗪基、吗啉基，每个杂环基任选独立地被一个或两个选自C1-8脂烃基的取代基取代，其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在式I化合物的一些实施方式中，R1为5-12元杂芳基，其任选地被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基羰基、杂环基羰基、杂环基氧基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基、氨基、C1-8脂烃基羰基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，R1为5-10元杂芳基，其任选地被一个或多个R6取代，其中每个R6独立地选自杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基羰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个、优选一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个、优选一个或两个选自C1-8脂烃基的取代基取代；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式I化合物的一些实施方式中，式I化合物具有式Ia结构式：
Figure PCTCN2014086820-appb-000029
其中，X、Y、Z、W、R1和R2均如式I中所定义。
在式Ia化合物的一些实施方式中，各基团具有如下定义：
W选自
Figure PCTCN2014086820-appb-000030
X选自于S、O或NR4；
Y选自于CH、O或S；
Z选自于CH、O、S或NR5；
R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；
R2选自于氢或C1-8脂烃基；
R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R4选自于氢或C1-8脂烃基；
R5选自于氢或C1-8脂烃基；
每个R6独立地选自于卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、 C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基或二(C1-8脂烃基)膦酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、杂环基、5-12元杂芳基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基 羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ia化合物的一些实施方式中，W为
Figure PCTCN2014086820-appb-000031
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中，C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，W为
Figure PCTCN2014086820-appb-000032
其中R3a、R3b和R3c均为氢。
在式Ia化合物的一些实施方式中，W为
Figure PCTCN2014086820-appb-000033
在式Ia化合物的一些实施方式中，X为S。在式Ia化合物的另一些实施方式中，X为O。在式Ia化合物的又一些实施方式中，X为NR4，其中R4选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，X为NR4，其中R4选自于氢或C1-8烷基，更优选选自于氢或甲基，还更优选为氢。
在式Ia化合物的一些实施方式中，Y为CH。在式Ia化合物的另一些实施方式中，Y为O。在式Ia化合物的又一些实施方式中，Y为S。
在式Ia化合物的一实施方式中，Z为CH。在式Ia化合物的另一些实施方式中，Z为O。在式Ia化合物的又一些实施方式中，Z为S。在式Ia化合物的又一些实施方式中，Z为NR5，其中R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在又一些实施方式中，Z为NR5，其中R5优选选自于氢或C1-8烷基，更优选选自于氢或甲基，还更优选为氢。
在式Ia化合物的一些实施方式中，Y和Z中至少有一个为杂原子。
在式Ia化合物的一些实施方式中，Y为S，Z为CH。
在式Ia化合物的一些实施方式中，Y为O，Z为CH。
在式Ia化合物的一些实施方式中，Y为CH，Z为S。在式Ia化合物的另一些实施方式中，Y为CH，Z为O。
在式Ia化合物的一些实施方式中，Y为CH，Z为NR5，其中R5选自于氢或C1-8脂烃基时，其中C1-8脂烃基选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，Y为CH，Z为NR5，其中R5为氢。
在式Ia化合物的一些实施方式中，R1为C6-12芳基或5至12元杂芳基，其任选被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、杂环基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基或杂环基氨基亚磺酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含一个或多个、优选一个或两个选自O、N或S的杂原子的饱和或部分不饱和的3-8元杂环基团，其独立地任选被一个或多个、任选一个或两个选自如下的取代基取代：C1-8脂烃基、羟基、C1-8脂烃基氧基或C1-8脂烃基羰基，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ia化合物的一些实施方式中，R1为C6-12芳基，其任选被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、氨基酰基、C1-8脂烃基氨基酰基二(C1-8脂烃基)氨基酰基、杂环基氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基或杂环基氨基亚磺酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的3-8元杂环基团，其独立地任选被一个或两个选自如下的取代基取代：C1-8脂烃基、羟基、C1-8 脂烃基氧基或C1-8脂烃基羰基，以及其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ia化合物的一些实施方式中，R1为苯基，其任选被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、二(C1-8脂烃基)氨基、C1-8脂烃基氨基、杂环基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、C1-8脂烃基氨基酰基或杂环基氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、哌嗪基、吗啉基或四氢吡喃基，每个杂环基独立地任选被一个或多个选自如下的取代基取代：C1-8脂烃基、羟基、C1-8脂烃基氧基或C1-8脂烃基羰基，以及其中C1-8脂烃基在每次出现时独立地选自于C1-8烷基和C3-8环烷基。
在式Ia化合物的一些实施方式中，R1为苯基，其任选被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、杂环基氧基、杂环基C1-8脂烃基氧基、杂环基氨基、杂环基羰基或杂环基氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、哌嗪基或吗啉基，每个杂环基独立地任选被一个或两个选自C1-8脂烃基的取代基取代，以及其中C1-8脂烃基在每次出现时独立地选自于C1-8烷基和C3-8环烷基。
在式Ia化合物的一些实施方式中，R1为苯基，其任选被一个或多个R6取代，其中每个R6独立地选自氟、氯、甲基、甲氧基、二甲基氨基、甲基氨基酰基、羟基乙基氧基、甲氧基乙基氧基、二甲基氨基乙基氨基、杂环基乙基氧基、杂环基、环己基氨基、杂环基氨基、杂环基氧基、杂环基羰基或杂环基氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、哌嗪基、吗啉基或四氢吡喃基，每个杂环基独立地任选被一个或多个选自如下的取代基取代：甲基、甲基羰基、羟基、甲氧基或异丙基。
在式Ia化合物的一些实施方式中，R1为苯基，其任选被一个或多个R6取代，其中每个R6独立地选自氟、氯、甲基、杂环基、杂环基乙基氧基、杂环基氨基、杂环基氧基、杂环基羰基或杂环基氨基酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自哌啶基、哌嗪基或吗啉基，每个杂环基独立地任选被甲基或异丙基取代。
在式Ia化合物的一些实施方式中，R1为5至12元杂芳基，其任选被一个或多 个R6取代，其中每个R6独立地选自杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基氧基C1-8脂烃基，其中杂环基，作为独立的基团或其它基团的一部分时，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的3-8元杂环基团，其独立地任选被一个或多个C1-8脂烃基取代，以及其中C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ia化合物的一些实施方式中，R1为5至10元杂芳基，其任选被一个或多个R6取代，其中每个R6独立地选自杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基氧基C1-8脂烃基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自吗啉基、哌啶基、哌嗪基或四氢吡喃基，每个杂环基独立地任选被一个或多个C1-8脂烃基取代，以及其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在式Ia化合物的一些实施方式中，R1为5-10元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、异噻唑基、异噁唑基、吡啶基或咪唑[1,2-a]吡啶基，其任选被一个或多个R6取代，其中每个R6独立地选自甲基、环丁基、环戊基、羟基乙基、甲氧基、甲氧基乙基、氟代乙基、二甲基氨基乙基、1-甲基-哌嗪-4-基或吗啉-4-基乙基。
在式Ia化合物的一些实施方式中，R1为5元杂芳基，优选选自吡唑基、噻吩基、噻唑基、异噻唑基或异噁唑基，其任选被一个或多个R6取代，其中每个R6独立地选自C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基或C1-8脂烃基氧基C1-8脂烃基，其中杂环基，作为独立的基团或其它基团的一部分，表示含一个或两个选自O、N或S的杂原子的饱和或部分不饱和的5-6元杂环基团，每个杂环基独立地任选被一个或多个C1-8脂烃基取代，以及其中C1-8脂烃基独立地选自C1-8烷基和C3-8环烷基。
在式Ia化合物的一些实施方式中，R1为5元杂芳基，优选选自吡唑基、噻吩基、噻唑基、异噻唑基或异噁唑基，其任选被一个或多个R6取代，其中每个R6独立地选自甲基、环丁基、环戊基、羟基乙基、甲氧基乙基、氟代乙基、二甲基氨基乙基或吗啉-4-基乙基。
在式Ia化合物的一些实施方式中，R1选自于：
Figure PCTCN2014086820-appb-000034
在式Ia化合物的一些实施方式中，R2选自氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，R2选自氢或C1-8烷基。在一些实施方式中，R2选自氢或甲基。在一些实施方式中，R2为氢。
在式Ia化合物的一些实施方式中，各基团具有以下定义：
W选自于
Figure PCTCN2014086820-appb-000035
X选自于O、S或NR4；
Y选自于CH、O或S；
Z选自于CH、O、S或NR5；
R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；
R2为氢；
R3a、R3b和R3c均为氢；
R4选自于氢或C1-8脂烃基；
R5为氢；
每个R6独立地选自于卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基氨基酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基或杂环基氨基亚磺酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ia化合物的一些实施方式中，各基团具有以下定义：
W选自于
Figure PCTCN2014086820-appb-000036
X为NR4；
Y为CH；
Z为O或S；
R1为C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；
R2为氢；
R3a、R3b和R3c均为氢；
R4为氢；
每个R6独立地选自于卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基氧基、杂环基C1-8脂烃基氧基、杂环基氨基、杂环基羰基或杂环基氨基酰基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自C1-8脂烃基的取代基取代；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ia化合物的一些实施方式中，式Ia化合物选自于：
Figure PCTCN2014086820-appb-000037
Figure PCTCN2014086820-appb-000038
Figure PCTCN2014086820-appb-000039
在式I化合物的一些实施方式中，式I化合物具有结构式Ib：
Figure PCTCN2014086820-appb-000040
其中：
X、Y、Z、W、R1均如式I中所定义；
l选自0、1、2、3或4，其中当l是0时，
Figure PCTCN2014086820-appb-000041
为
Figure PCTCN2014086820-appb-000042
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086820-appb-000043
为
Figure PCTCN2014086820-appb-000044
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086820-appb-000045
为
Figure PCTCN2014086820-appb-000046
在式Ib化合物的一些实施方式中，各基团具有如下定义：
W选自于
Figure PCTCN2014086820-appb-000047
X选自于O、S或NR4；
Y选自于CH、O或S；
Z选自于CH、O、S或NR5；
l选自0、1、2、3或4，其中当l是0时，
Figure PCTCN2014086820-appb-000048
为
Figure PCTCN2014086820-appb-000049
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086820-appb-000050
为
Figure PCTCN2014086820-appb-000051
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086820-appb-000052
为
Figure PCTCN2014086820-appb-000053
R1为5-6元杂芳基，其任选地被一个或多个R6取代；
R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R4选自于氢或C1-8脂烃基；
R5选自氢或C1-8脂烃基；
每个R6独立地选自卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8烷基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自卤素或C1-8脂烃基的取代基取代，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ib化合物的一些实施方式中，W为
Figure PCTCN2014086820-appb-000054
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中，C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，W为
Figure PCTCN2014086820-appb-000055
其中R3a、R3b和R3c均为氢。
在式Ib化合物的一些实施方式中，W为
Figure PCTCN2014086820-appb-000056
在式Ib化合物的一些实施方式中，X为O。
在式Ib化合物的一些实施方式中，X为NR4，其中R4选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，X为NR4，其中R4选自于氢或C1-8烷基。在一些实施方式中，X为NR4，其中R4选自于氢或甲基。
在式Ib化合物的一些实施方式中，Y为CH。在式Ib化合物的另一些实施方式中，Y为S。在式Ib化合物的另一些实施方式中，Y为O。
在式Ib化合物的一些实施方式中，Z为CH。在式Ib化合物的另一些实施方式中，Z为S。在式Ib化合物的又一些实施方式中，Z为O。在式Ib化合物的又一些实施方式中，Z为NR5，其中，R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在一些实施方式中，Z为NR5，其中R5选自于氢或C1-8烷基。在一些实施方式中，Z为NR5，其中，R5选自于氢或甲基。
在式Ib化合物的一些实施方式中，Y和Z中至少一个为杂原子。
在式Ib化合物的一些实施方式中，Y为S，Z为CH。在另一些实施方式中，Y为O，Z为CH。
在式Ib化合物的一些实施方式中，Y为CH，Z为S。在另一些实施方式中，Y为CH，Z为O。在又一些实施方式中，Y为CH，Z为NR5，其中，R5选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在又一些实施方式中，Y为CH，Z为NR5，其中，R5选自于氢或C1-8烷基，优选选自于氢或甲基。
在式Ib化合物的一些实施方式中，R1为5-6元杂环基，其任选被一个或多个R6取代，其中每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基羰基、杂环基羰基、杂环基氧基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：羟基、C1-8脂烃基、C1-8脂烃基氧基、氨基、C1-8脂烃基羰基；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ib化合物的一些实施方式中，R1为5元杂环基，优选选自于吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且R1任选被一个或两 个R6取代；其中每个R6独立地选自卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基或杂环基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，优选选自于吗啉基、哌啶基、哌嗪基或四氢吡喃基，每个杂环基任选地被一个或多个选自C1-8脂烃基的取代基取代，以及其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在式Ib化合物的一些实施方式中，R1为5元杂环基，优选选自于吡唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且R1任选被一个或两个R6取代；其中每个R6独立地选自C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基羰基、杂环基或杂环基C1-8脂烃基，其中：杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自吗啉基或四氢吡喃基，其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在式Ib化合物的一些实施方式中，R1为5元杂环基，优选选自于吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且R1任选被一个或两个R6取代；其中每个R6独立地选自甲基、乙基、异丙基、正丁基、羟基乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、环丁基、环戊基、二甲基氨基乙基、吗啉-4-基乙基、四氢吡喃-4-基或甲基羰基。
在式Ib化合物的一些实施方式中，R1为5元杂环基，优选选自于吡唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且R1任选被一个或两个R6取代；其中每个R6独立地选自甲基、乙基、异丙基、环丁烷、环戊烷、甲氧基甲基、甲氧基乙基、甲氧基丙基、二甲基氨基乙基、吗啉-4-基乙基、四氢吡喃-4-基或甲基羰基。
在式Ib化合物的一些实施方式中，R1选自于：
Figure PCTCN2014086820-appb-000057
Figure PCTCN2014086820-appb-000058
在式Ib化合物的一些实施方式中，l选自于0、1或2。
在式Ib化合物的一些实施方式中，m选自于0、1、2或3。
在式Ib化合物的一些实施方式中，n选自于0、1或2。
在式Ib化合物的一些实施方式中，m和n不同时为0。
在式Ib化合物的一些实施方式中，各基团具有以下含义：
W选自于
Figure PCTCN2014086820-appb-000059
X选自于O、S或NR4；
Y选自于CH、O或S；
Z选自于CH、O、S或NR5；
l选自0、1或2；
m选自于0、1、2或3；
n选自于0、1或2；
R1为5-6元杂芳基，其任选地被一个或多个R6取代；
R3a、R3b和R3c均为氢；
R4选自于氢或C1-8脂烃基；
R5选自氢或C1-8脂烃基；
每个R6独立地选自卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基或杂环基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自C1-8脂烃基的取代基取代；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ib化合物的一些实施方式中，各基团具有以下含义：
W选自于
Figure PCTCN2014086820-appb-000060
X选自于O或NR4；
Y选自于CH或S；
Z选自于CH、O或S；
l选自0、1或2；
m选自于0、1、2或3；
n选自于0、1或2；
R1为5元杂芳基，其任选地被一个或多个R6取代；
R3a、R3b和R3c均为氢；
R4选自于氢或C1-8脂烃基；
每个R6独立地选自卤素、C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基或杂环基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，每个杂环基任选被一个或多个选自C1-8脂烃基的取代基取代；
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在式Ib化合物的一些实施方式中，式Ib化合物选自于：
Figure PCTCN2014086820-appb-000061
Figure PCTCN2014086820-appb-000062
Figure PCTCN2014086820-appb-000063
Figure PCTCN2014086820-appb-000064
在式I化合物的又一些实施方式中，式I化合物具有结构式Ic：
Figure PCTCN2014086820-appb-000065
其中：
X、W、R1均如式I中所定义；
l选自于0、1、2、3或4；其中当l是0时，
Figure PCTCN2014086820-appb-000066
为
Figure PCTCN2014086820-appb-000067
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086820-appb-000068
为
Figure PCTCN2014086820-appb-000069
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086820-appb-000070
为
Figure PCTCN2014086820-appb-000071
在式Ic化合物的一些实施方式中，各基团具有如下定义：
W选自
Figure PCTCN2014086820-appb-000072
X选自于O、S或NR4；
l选自于0、1、2、3或4；其中当l是0时，
Figure PCTCN2014086820-appb-000073
为
Figure PCTCN2014086820-appb-000074
m选自于0、1、2、3或4；其中当m是0时，
Figure PCTCN2014086820-appb-000075
为
Figure PCTCN2014086820-appb-000076
n选自于0、1、2或3；其中当n是0时，
Figure PCTCN2014086820-appb-000077
为
Figure PCTCN2014086820-appb-000078
R1为5-6元杂芳基，其任选地被一个或多个R6取代；
R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
R4选自于氢或C1-8脂烃基；
每个R6独立地选自于卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂 烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自卤素或C1-8脂烃基的取代基取代，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ic化合物的一些实施方式中，W选自
Figure PCTCN2014086820-appb-000079
其中R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基，其中，C1-8脂烃基选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在式Ic化合物的一些实施方式中，W选自
Figure PCTCN2014086820-appb-000080
其中R3a、R3b和R3c均为氢。
在式Ic化合物的一些实施方式中，W选自
Figure PCTCN2014086820-appb-000081
在式Ic化合物的一些实施方式中，X为O。在式Ic化合物的另一些实施方式中，X为S。在式Ic化合物的又一些实施方式中，X为NR4，其中R4选自于氢或C1-8脂烃基，其中C1-8脂烃基独立地选自于C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。在又一些实施方式中，X为NR4，其中R4选自于氢或C1-8烷基。在又一些实施方式中，X为NR4，其中R4选自于氢或甲基。在又一些实施方式中，X为NR4，其中R4为氢。
在式Ic化合物的一些实施方式中，R1为5-6元杂芳基，优选选自吡啶基、吡咯 基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，其任选被一个或多个R6取代，其中每个R6独立地选自于卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中：
杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；
C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自卤素或C1-8脂烃基的取代基取代，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ic化合物的一些实施方式中，R1为5元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，其任选被一个或多个R6取代，其中每个R6独立地选自于卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基或杂环基，其中：杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，优选选自于哌啶基、哌嗪基、吗啉基或四氢吡喃基，每个杂环基任选被一个或多个选自C1-8脂烃基的取代基取代；其中C1-8脂烃基在每次出现时独立地选自C1-8烷基和C3-8环烷基。
在式Ic化合物的一些实施方式中，R1为5元杂芳基，优选选自吡唑基或异噻唑基，其任选被一个或多个R6取代，其中每个R6独立地选自卤素或C1-8脂烃基。
在式Ic化合物的一些实施方式中，R1为5元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基和异噻唑基，其任选被一个或多个R6取代，其中每个R6独立地选自甲基、乙基、异丙基、正丁基、羟基乙基、甲氧基甲基、 甲氧基乙基、甲氧基丙基、二甲基氨基乙基、吗啉-4-基乙基、四氢吡喃-4-基、环丁基、环戊基、甲基羰基，更优选选自甲基。
在式Ic化合物的一些实施方式中，R1选自于：
Figure PCTCN2014086820-appb-000082
在式Ic化合物的一些实施方式中，l选自于0、1或2，更优选选自0或1。
在式Ic化合物的一些实施方式中，m选自于0、1、2或3，优选选自1、2或3。
在式Ic化合物的一些实施方式中，n选自于0、1或2，更优选选自0。
在式Ic化合物的一些实施方式中，m和n不同时为0。
在式Ic化合物的一些实施方式中，各基团具有以下的定义：
W选自
Figure PCTCN2014086820-appb-000083
X为NR4；
l选自于0、1或2；
m选自于0、1、2或3；
n选自于0、1或2；
R1为5-6元杂芳基，其任选地被一个或多个R6取代；
R3a、R3b和R3c均为氢；
R4为氢；
每个R6独立地选自于卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基或C1-8脂烃基羰基，其中：杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自 卤素或C1-8脂烃基的取代基取代，
其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ic化合物的一些实施方式中，各基团具有以下的定义：
W选自
Figure PCTCN2014086820-appb-000084
X为NR4；
l选自于0、1或2；
m选自于0、1、2或3；
n选自于0、1或2；
R1为5元杂芳基，其任选地被一个或多个R6取代；
R3a、R3b和R3c均为氢；
R4为氢；
每个R6独立地选自于C1-8脂烃基，
其中，C1-8脂烃基选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
在式Ic化合物的一些实施方式中，式Ic化合物选自于：
Figure PCTCN2014086820-appb-000085
本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其药学上可接受的盐可能含一个或多个手性碳原子，每个不对称碳原子可以是R或S构型，两种构型都在本发明范围之内。因此，化合物可以作为对映异构体、非对映异构体或它们的混合物存在。上述化合物可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术拆分，例如通过手性色谱法或者分段结晶法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法解析外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH Ed.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
本发明的另一方面涉及药物组合物，其包含一种或多种本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明的药物组合物可以被配制为固态、半固态、液态或气态制剂，如片剂、胶囊、粉剂、颗粒剂、膏剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶。
本发明的药物组合物可以通过制药领域中公知的方法制备。例如，旨在注射给药的药物组合物可以通过将本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其药学上可接受的盐或前药与灭菌的蒸馏水组合来制备，从而形成溶液剂。可添加表面活性剂以促进形成均匀溶液或混悬液。制备药物组合物的实际方法为本领域技术人员所已知，例如可参见The Science and Practice of Pharmacy(制药科学与实践)，20th Edition(Philadelphia College of Pharmacy and Science,2000)。
本发明的药物组合物的给药途径包括但不限于口服、局部、经皮、肌肉、静脉、吸入、肠胃外、舌下、直肠、阴道及鼻内。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，可以是固体粉末或颗粒；水性或非水性液体中的溶液或混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其它辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括但不限于水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或混悬液。具体的给药方式和剂型取决于化合物本身的理化性质以及待治疗疾病的严重程度等。本领域技术人员能够根据上述因素并结合其自身具有的知识来确定具体的给药途径。例如可参见：李俊，《临床药理学》，人民卫生出版社，2008.06；丁玉峰，论临床剂型因素与合理用药，医药导报，26(5)，2007；Howard C.Ansel,Loyd V.Allen,Jr.,Nicholas G.Popovich著，江志强主译，《药物剂型与给药体系》，中国医药科技出版社，2003.05。
本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或者包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物的药物组合物还可以与一种或多种其它药物联合或组合使用。可以与本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或者与包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物的药物组合物联用的药物包括但不限于：
1)免疫抑制剂如甲氨蝶呤和环磷酰胺等药物；
2)糖皮质激素如地塞米松和倍他米松等药物；
3)非甾体抗炎药如水杨酸盐和芳基链烷酸等药物；
4)Cox-2特异性抑制剂如罗非昔布和塞来昔布等药物；
5)TNF-α结合蛋白如英利昔单抗和阿达木单抗等药物；
6)干扰素(例如干扰素-β、干扰素γ)和白细胞介素(例如白细胞介素-2)等药物。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，用于预防和/或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于抑制BTK和/或JAK3的活性。
本发明的另一方面涉及包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物，用于预防和/或治疗BTK和/或JAK3介导的疾病。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐或者包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的药物组合物在制备用于抑制BTK和/或JAK3活性的药物中的用途。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的的药物组合物在制备用于治疗和/或预防BTK和/或JAK3介导的疾病的药物中的用途。
本发明的另一方面涉及本发明的式I化合物，特别是式Ia、式Ib和式Ic化合 物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐的的药物组合物在制备用于治疗和/或预防BTK和/或JAK3介导的疾病的药物中的用途。
本发明的另一方面涉及在生物体系中抑制BTK和/或JAK3活性的方法，该方法包括使所述生物体系接触本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，或者包含上述化合物的药物组合物。在一些实施方式中，所述生物体系是酶、细胞、哺乳动物。哺乳动物的实例包括但不限于：人；非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。
本发明的另一方面涉及抑制哺乳动物(尤其是人)的BTK和/或JAK3的方法，所述方法包括对有需要的哺乳动物(尤其是人)给予治疗有效量的本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上接受的盐或者包含上述化合物的药物组合物。
本发明的另一方面涉及治疗和/或预防BTK和/或JAK3介导的疾病的方法，所述方法包括对有需要的哺乳动物(尤其是人)给予治疗有效量的本发明的式I化合物，特别是式Ia、式Ib和式Ic化合物，或其立体异构体、互变异构体、溶剂化物或其药学上接受的盐或者包含上述化合物的药物组合物。
在本申请中，所提及的BTK和/或JAK3介导的疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病和癌症。所述自身免疫性疾病和炎性疾病选自类风湿性关节炎、骨关节炎、青少年关节炎、慢性阻塞性肺疾病、多重硬化、系统性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎和肠道易激综合症等。所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤等。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。本发明化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。通常，经胃肠外给药的剂量可以是1-200mg/kg，口服给药的剂量可以是1-1000mg/kg。
本文中所提供的有效剂量的范围并非意图限制本发明的范围，而是代表优选的剂量范围。但是，最优选的剂量可针对个别个体而进行调整，这是本领域技术人员所了解且可决定的(例如参阅Berkow等人编著，Merck手册，第16版，Merck公司，Rahway,N.J.,1992)。
本发明化合物的制备
以下反应方案以式Ia、式Ib和式Ic化合物为例示例性地说明本发明的式I化合物的制备方法。
本领域技术人员应当理解，在以下描述中，只有当取代基的组合可以得到稳定的化合物时，这类取代基的组合才是允许的。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基“PG”保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。
保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis(有机合成中的保护基),(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
本发明的式Ia、式Ib和式Ic化合物可按照下列反应路线I所示的方法进行制备：
反应路线I
Figure PCTCN2014086820-appb-000086
其中，各式中的基团X、Y、Z、W、R1和R2均如上文对式Ia中所定义的；
或
Figure PCTCN2014086820-appb-000087
其中，各式中的基团X、Y、Z、W、R1、l、m和n均如上文对式Ib中所定义的；
或
Figure PCTCN2014086820-appb-000088
其中，各式中的基团X、Y、Z、W、R1、l、m和n均如上文对式Ic中所定义的。
反应路线I中包括如下步骤：
步骤1：使式1a、式1b或式1c化合物分别与式2a、式2b或式2c化合物发生取代反应制备式3a、式3b或式3c化合物。
在该步骤中，优选在碱的存在下进行，用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等有机碱，用于该反应的碱也可以选自碳酸钠、碳酸钾、氢氧化钠等无机碱。该反应也可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇、异丙醇、丁醇等。
步骤2：脱除式3a、式3b或式3c化合物的保护基PG制备式4a、式4b或式4c化合物。
式3a、式3b或式3c化合物中的保护基PG可以是叔丁氧羰基、苄氧羰基、苄基等。用于该反应的脱保护条件可以在酸催化下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在酸性 或者中性条件下，使用钯催化剂进行催化氢化，本发明的钯催化剂可以选自钯碳和氢氧化钯，该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、乙醇等。
步骤3：使式4a、式4b或式4c化合物发生缩合反应得到式5a、式5b或式5c化合物。
在该步骤中，缩合试剂可以选自羰基二咪唑(CDI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)等。用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶、氢化钠等。反应温度为0℃至80℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯等。
步骤4：使式5a、式5b或式5c化合物发生取代反应得到相应的式Ia、式Ib或式Ic化合物。
在该步骤中，反应可以在酸的存在或者中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在碱的存在下进行，用于该反应的碱可以选自氢氧化钠、碳酸铯、叔丁醇钠、氢化钠等强碱。该反应也可以在钯催化剂的存在下进行。可以用于本发明的钯催化剂选自二(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯(Pd(OAc)2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)。该条件下可用的碱优选为无机碱，例如碳酸钠、碳酸钾、磷酸钾、碳酸铯等。反应温度为80℃至160℃。用于该反应的溶剂可以选自1,4-二氧六环、甲苯、乙醇、异丙醇、丁醇、2-丁醇、水及其混合物。
本发明的式Ia、式Ib和式Ic化合物也可按照下列反应路线II所示的方法进行制备：
反应路线II
Figure PCTCN2014086820-appb-000089
其中，各式中的基团X、Y、Z、W、R1和R2均如上文对式Ia中所定义的；
或
Figure PCTCN2014086820-appb-000090
其中，各式中的基团X、Y、Z、W、R1、l、m和n均如上文对式Ib中所定义的；
或
Figure PCTCN2014086820-appb-000091
其中，各式中的基团X、Y、Z、W、R1、l、m和n均如上文对式Ic中所定义的。
反应路线II中包括如下步骤：
步骤1：使式1a、式1b或式1c化合物分别与式2a、式2b或式2c化合物发生取代反应制备式3a、式3b或式3c化合物。
在该步骤中，优选在碱的存在下进行，用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等有机碱，用于该反应的碱也可以选自碳酸钠、碳酸钾、氢氧化钠等无机碱。该反应也可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇、异丙醇、丁醇等。
步骤5：使式3a、式3b或式3c化合物发生取代反应得到式6a、式6b或式6c化合物。
在该步骤中，反应可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也 可以在碱的存在下进行，用于该反应的碱可以选自氢氧化钠、叔丁醇钠、氢化钠等强碱。该反应也可以在钯催化剂的存在下进行，可以用于本发明的钯催化剂选自二(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯(Pd(OAc)2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)。该条件下可用的碱优选为无机碱，例如碳酸钠、碳酸钾、磷酸钾、碳酸铯等。反应温度为80℃至160℃。用于该反应的溶剂可以选自1,4-二氧六环、甲苯、乙醇、异丙醇、丁醇、2-丁醇、水及其混合物。
步骤6：脱除式6a、式6b或式6c化合物的保护基PG制备式7a、式7b或式7c化合物。
式6a、式6b或式6c化合物中的保护基PG可以是叔丁氧羰基、苄氧羰基、苄基等。用于该反应的脱保护条件可以在酸催化下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在酸性或者中性条件下，使用钯催化剂进行催化氢化，本发明的钯催化剂选自钯碳和氢氧化钯，该反应的酸可以选自盐酸、氯化氢的1,4-二氧六环溶液、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇等。
步骤7：使式7a、式7b或式7c化合物发生缩合反应得到相应的式Ia、式Ib或式Ic化合物。
在该步骤中，缩合试剂可以选自羰基二咪唑(CDI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)等。用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等。反应温度为0℃至80℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯等。
本发明的式Ia化合物还可按照下列反应路线III所示的方法进行制备：
反应路线III
Figure PCTCN2014086820-appb-000092
其中，各式中的基团X、Y、Z、W、R1和R2均如上文对式Ia中所定义的。
反应路线III中包括如下步骤：
步骤8：使式1a化合物与式8a化合物发生取代反应制备式4a化合物。
在该步骤中，优选在碱的存在下进行，用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等有机碱，用于该反应的碱也可以选自碳酸钠、碳酸钾、氢氧化钠等无机碱。该反应也可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。反应温度为-80℃至120℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯、甲醇、乙醇、异丙醇、丁醇等。
步骤3：使式4a化合物发生缩合反应得到式5a化合物。
在该步骤中，缩合试剂可以选自羰基二咪唑(CDI)、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDCI)等。用于该反应的碱可以选自三乙胺、N,N-二异丙基乙胺、吡啶等。反应温度为0℃至80℃。用于该反应的溶剂可以选自1,4-二氧六环、四氢呋喃、二氯甲烷、甲苯等。
步骤4：使式5a化合物发生取代反应得到相应的式Ia化合物。
在该步骤中，反应可以在酸的存在下或者在中性条件下进行，用于该反应的酸可以选自盐酸、三氟乙酸、氯化氢的1,4-二氧六环溶液、醋酸、硫酸等。该反应也可以在碱的存在下进行，用于该反应的碱可以选自氢氧化钠、叔丁醇钠、氢化钠等强碱。该反应也可以在钯催化剂的存在下进行。可以用于本发明的钯催化剂选自二(三苯基磷)二氯化钯(Pd(PPh3)2Cl2)、三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯(Pd(OAc)2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)。该条件下可用的碱优选为无机碱，例如碳酸钠、碳酸钾、磷酸钾、碳酸铯等。反应温度为80℃至160℃。用于该反应的溶剂可以选自1,4-二氧六环、甲苯、乙醇、异丙醇、丁醇、2-丁醇、水及其混合物。
本领域技术人员可以理解，上述反应路线和制备方法仅用于简明和清楚说明的目的，并不是限制性的，通过选择合理的反应原料(其可以是商购获得到的或者采用本领域公知的方法制备得到的)，采用上述类似的方法也可以得到本发明的式I化合物。
实施例
下文所描述的实验、合成方法以及所涉及的中间体是对本发明的阐明，并不限制本发明的范围。
本发明中实验所使用的起始原料或购买自试剂供应商或经由本领域公知的方法 由已知原料制备。除非另外特别指明，本文的实施例应用下述条件：
温度的单位是摄氏度(℃)；室温的定义是18-25℃；
有机溶剂使用无水硫酸镁或无水硫酸钠干燥；使用旋转蒸发仪在减压升温条件下旋干(例如：15mmHg，30℃)；
柱层析分离时使用200-300目硅胶作为载体，TLC表示薄层色谱法；
通常情况下，反应的进度通过TLC或LC-MS监测；
最终产品的鉴定由核磁共振(Bruker AVANCE 300，300MHz)和LC-MS(Bruker esquine 6000，Agilent 1200series)完成。
实施例1
N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000093
步骤1：顺式-4-((2-氯噻吩[3,2-d]嘧啶-4-基)氨基)环己基氨基羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000094
将2,4-二氯噻吩[3,2-d]嘧啶(678mg,3.31mmol)和顺式-4-氨基环己基氨基羧酸叔丁酯(849mg,3.97mmol)溶于四氢呋喃(10mL)中，加入N,N-二异丙基乙胺(0.9mL,4.97mmol)。反应液在70℃下过夜反应，之后浓缩。残余物加入水(20mL)，用乙酸乙酯(20mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝1:5)，得到1.07g白色固体。收率：84.7％。MS(ESI,m/z):[M+H]+:383.4；1H-NMR(300MHz,CDCl3)δ:7.74(d,1H,J＝5.4Hz),7.35(d,1H,J＝5.4Hz),5.00(s,1H),4.59(s,1H),4.31-4.38(m,1H),3.72-3.74(m,1H),1.62-2.04(m,8H),1.45(s,9H)。
步骤2：顺式-N1-(2-氯噻吩[3,2-d]嘧啶-4-基)环己基-1,4-二胺的制备
Figure PCTCN2014086820-appb-000095
将步骤1所得产物(840mg,2.2mmol)溶于二氯甲烷(10mL)中，缓慢加入三氟乙酸(2mL,30.8mmol)，反应液在室温下反应2小时。浓缩反应液，所得粗产物无需进一步的纯化，直接用于下一步反应。MS(ESI,m/z):[M+H]+:282.9。
步骤3：N-(顺式-4-((2-氯噻吩[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000096
将步骤2所得产物(620mg,2.20mmol)溶于二氯甲烷(10mL)中，加入三乙胺(440mg,4.4mmol)。在0℃下将溶于二氯甲烷(5mL)的丙烯酰氯(0.2mL,2.42mmol)溶液滴加在上述溶液中。反应液在室温下反应过夜。反应液经水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到0.56g白色固体。收率：75.8％。MS(ESI,m/z):[M+H]+:337.2；1H-NMR(300MHz,DMSO-d6)δ:7.76(d,1H,J＝5.4Hz),7.36(d,1H,J＝5.4Hz),6.07-6.35(m,2H),5.65-5.69(m,2H),5.23(bs,1H),4.34-4.38(m,1H),4.09-4.13(m,1H),1.68-2.02(m,8H)。
步骤4：N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
将步骤3所得产物(54mg,0.162mmol)和1-甲基-1H-吡唑-4-胺(23mg,0.244mmol)溶于1,4-二氧六环(2mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到32mg淡黄色固体。收率：49.8％。MS(ESI,m/z):[M+H]+:398.3；1H-NMR(300MHz,CDCl3)δ:7.66-7.69(m,3H),6.99-7.19(m,2H),6.32(dd,1H,J＝1.5Hz,J＝16.8Hz),6.15(dd,1H,J＝10.2Hz,J＝16.8Hz),5.89-5.91(m,2H),5.66(dd,1H,J＝1.5Hz,J＝10.2Hz),4.23-4.38(m,1H),4.08-4.16(m,1H),3.88(s,3H),1.75-2.05(m,8H)。
下列化合物(表一)利用类似起始原料通过类似于实施例1的合成方法制备。
表一
Figure PCTCN2014086820-appb-000097
Figure PCTCN2014086820-appb-000098
Figure PCTCN2014086820-appb-000099
Figure PCTCN2014086820-appb-000100
Figure PCTCN2014086820-appb-000101
Figure PCTCN2014086820-appb-000102
Figure PCTCN2014086820-appb-000103
Figure PCTCN2014086820-appb-000104
Figure PCTCN2014086820-appb-000105
Figure PCTCN2014086820-appb-000106
Figure PCTCN2014086820-appb-000107
Figure PCTCN2014086820-appb-000108
Figure PCTCN2014086820-appb-000109
Figure PCTCN2014086820-appb-000110
实施例57
N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)呋喃[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000111
步骤1：顺式-N1-(2-氯呋喃[3,2-d]嘧啶-4-基)环己基-1,4-二胺的制备
Figure PCTCN2014086820-appb-000112
将2,4-二氯呋喃[3,2-d]嘧啶(188mg,1mmol)溶于二氯甲烷(5mL)，滴加到顺式-1,4-环己二胺(456mg,4.0mmol)的二氯甲烷(10mL)溶液中。反应液室温搅拌过夜，之后浓缩。残余物加入水(20mL)，用乙酸乙酯(20mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝1:1)，得到140mg淡黄色固体。收率：52.6％。MS(ESI,m/z):[M+H]+:267.1；1H-NMR(300MHz,CD3OD):8.01-8.00(d,1H,J＝2.1Hz),6.78-6.77(d,1H,J＝2.1Hz),4.24-2.22(m,1H),3.07-3.03(m,1H),1.91-1.66(m,8H)。
步骤2：N-(顺式-4-((2-氯呋喃[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000113
将步骤1所得产物(120mg,0.45mmol)和三乙胺(188μL,1.36mmol)溶于二氯甲烷(20mL)中，加入丙烯酰氯(53μL,0.54mmol)，反应液在室温下反应过夜。浓缩后残留物用硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)，得到0.13g橘黄色固体。收率：90.3％。MS(ESI,m/z):[M+H]+:321.1；1H-NMR(300MHz,DMSO-d6):8.24-8.21(d,1H,J＝6.3Hz),7.99-7.97(d,1H,J＝6.3Hz),6.41-6.32(dd,2H,J＝10.2Hz,J＝17.1Hz),5.68-5.64(dd,1H,J＝2.4Hz,J＝17.1Hz),5.59-5.55(dd,1H,J＝2.1Hz,J＝10.2Hz),4.11-4.09(m,1H),3.09-3.05(m,1H),1.81-1.61(m,8H)。
步骤3：N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)呋喃[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
将步骤2所得产物(25mg,0.078mmol)和1-甲基-1H-吡唑-4-胺(8.4mg,0.086mmol)溶于异丙醇(2mL)中，加入三氟乙酸(250mg,2.2mmol)。反应液在微波辐射90℃下反应1小时。反应液冷却至室温，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到10mg褐色固体。收率：33.7％。MS(ESI,m/z):[M+H]+:382.2；1H-NMR(300MHz,CD3OD)δ:7.94-7.93(d,1H,J＝2.1Hz),7.86(s,1H),7.60(s,1H),6.76-6.75(d,1H,J＝2.1Hz),6.44-6.35(t,1H,J＝10.2Hz,J＝17.1Hz),6.26-6.20(dd,1H,J＝2.1Hz,J＝17.1Hz),5.67-5.63(dd,1H,J＝2.1Hz,J＝10.2Hz),4.23-4.21(m,1H),4.02-4.01(m,1H),3.90(s,3H),1.90-1.74(m,8H)。
实施例58
N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)-5H-吡咯[3,2-d]嘧啶-4-基)氨基)环己 基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000114
步骤1：顺式-N1-(2-氯-5H-吡咯[3,2-d]嘧啶-4-基)环己基-1,4-二胺的制备
Figure PCTCN2014086820-appb-000115
将2,4-二氯吡咯[3,2-d]嘧啶(187mg,1mmol)溶于二氯甲烷(5mL)，滴加到顺式-1,4-环己二胺(456mg,4.0mmol)的二氯甲烷(10mL)溶液中。反应液室温搅拌过夜，之后浓缩。残余物加入水(20mL)，用乙酸乙酯(10mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝1:1)，得到150mg淡黄色固体。收率：56.6％。MS(ESI,m/z):[M+H]+:266.1；1H-NMR(300MHz,CD3OD):7.41-7.40(d,1H,J＝3.0Hz),6.62-8.61(d,1H,J＝3.0Hz),4.31(s,1H),3.09(s,1H),2.01-1.70(m,8H)。
步骤2：N-(顺式-4-((2-氯-5H-吡咯[3,2-d]吡啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000116
将步骤1所得产物(120mg,0.45mmol)和三乙胺(188μL,1.36mmol)溶于二氯甲烷(20mL)中，加入丙烯酰氯(53μL,0.54mmol)，反应液在室温下反应过夜。浓缩后残留物用硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)，得到0.1g淡黄色固体。收率：69.7％。MS(ESI,m/z):[M+H]+:320.1；1H-NMR(300MHz,CDCl3):7.40-7.38(d,1H,J＝7.8Hz),7.29-7.21(m,1H),6.73-6.70(d,1H,J＝7.8Hz),6.24-6.20(m,1H),5.57-5.53(m,1H),4.41(s,1H),3.97(s,1H),1.84-1.72(m,8H)。
步骤3：N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)-5H-吡咯[3,2-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
将步骤2所得产物(25mg,0.078mmol)和1-甲基-1H-吡唑-4-胺(8.4mg,0.086mmol)溶于异丙醇(2mL)中，加入三氟乙酸(250mg,2.2mmol)。反应液在微波辐射90℃下反应1小时。反应液冷却至室温，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到12mg褐色固体。收率：40.5％。MS(ESI,m/z):[M+H]+:381.2；1H-NMR(300MHz,CD3OD)δ:7.86(s,1H),7.64(s,1H),7.43(s,1H),6.43-6.34(m,1H),6.29-6.21(m,1H),5.69-5.65(m,1H),4.46-4.35(m,1H),4.01-4.95(m,1H),3.94(s, 3H),1.99-1.61(m,8H)。
实施例59
N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)-噻吩[2,3-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000117
步骤1：(顺式-4-((2-氯噻吩[2,3-d]嘧啶-4-基)氨基)环己基)氨基羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000118
将2,4-二氯噻吩[2,3-d]嘧啶(204mg,1mmol)和顺式-4-氨基环己基氨基羧酸叔丁酯(215mg,1mmol)溶于四氢呋喃(10mL)中，加入N,N-二异丙基乙胺(0.4mL,2mmol)。反应液在70℃下过夜反应，之后浓缩。残余物加入水(20mL)，用乙酸乙酯(20mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝1:5)，得到150mg淡黄色固体。收率：56.6％。MS(ESI,m/z):[M+H]+:383.1；1H-NMR(300MHz,DMSO-d6):7.74-7.72(d,1H,J＝6.0Hz),7.58-7.56(d,1H,J＝6.0Hz),4.03(s,1H),3.46(m,1H),1.81-1.55(m,8H),1.40(s,9H)。
步骤2：N-(顺式-4-((2-氯噻吩[2,3-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
Figure PCTCN2014086820-appb-000119
将步骤1所得产物(50mg,0.13mmol)溶于甲醇(2mL)中，加入4N的氯化氢的1,4-二氧六环溶液(4mL,1mmol)，反应液在室温下反应2小时。反应液浓缩后，将剩余的粘稠液体溶于二氯甲烷(5mL)中，加入三乙胺(54μL,0.39mmol)。在0℃下将丙烯酰氯(14μL,0.14mmol)滴加在上述溶液中。反应液在室温下反应过夜。反应液经水(10mL)洗，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝8:1)，得到40mg白色固体。收率：91.5％。MS(ESI,m/z):[M+H]+:337.1；1H-NMR(300MHz,DMSO-d6):7.75-7.73(d,1H,J＝6.0Hz),7.57-7.55(d,1H,J＝6.0Hz),6.38-6.29(dd,1H,J＝10.2Hz,J＝17.1Hz),6.11-6.04(dd,1H,J＝2.4Hz,J＝17.1Hz),5.57-5.53(dd,1H,J＝2.1Hz,J＝10.2Hz),4.05-4.03(m,1H),3.09-3.05(m,1H),1.97-1.61(m,8H)。
步骤3：N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[2,3-d]嘧啶-4-基)氨基)环己基)丙烯酰胺的制备
将步骤2所得产物(25mg,0.078mmol)和1-甲基-1H-吡唑-4-胺(8.4mg,0.086mmol)溶于异丙醇(2mL)中，加入三氟乙酸(250mg,2.2mmol)。反应液在微波辐射90℃下反应1小时。反应液冷却至室温，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到10mg褐色固体。收率：33.7％。MS(ESI,m/z):[M+H]+:398.3；1H-NMR(300MHz,DMSO-d6)δ:10.51(s,1H),9.08(s,1H),8.20(d,1H,J＝5.1Hz),8.02(d,1H,J＝6.0Hz),7.87(s,1H),7.57(s,1H),7.21(d,1H,J＝5.4Hz),6.32-8.41(m,1H),6.07(dd,1H,J＝2.1Hz,J＝17.1Hz),5.57(dd,1H,J＝2.4Hz,J＝9.9Hz),4.14(d,1H,J＝5.4Hz),3.84(s,3H),1.25-1.64(m,8H)。
实施例60
N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)环己基)丙炔酰胺的制备
Figure PCTCN2014086820-appb-000120
步骤1：(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)环己基)氨基羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000121
将实施例1中步骤1所得产物(120mg,0.31mmol)和1-甲基-1H-吡唑-4-胺(52mg,0.62mmol)混悬于异丙醇(2mL)中，然后加入两滴三氟乙酸，混合液在微波条件下(反应温度为90℃)反应25分钟。往体系中加入饱和碳酸钠溶液中和至反应液的pH值为8左右，浓缩，硅胶柱层析分离(洗脱液：二氯甲烷：甲醇＝20:1)得到120mg黄色固体。收率：87.4％。MS(ESI,m/z):[M+H]+:444.3。
步骤2：N4-(顺式-4-氨基环己基)-N2-(1-甲基-1H-吡唑-4-基)噻吩[3,2-d]嘧啶-2,4-二胺的制备
Figure PCTCN2014086820-appb-000122
将上述步骤1所得产物(120mg,0.27mmol)溶于二氯甲烷(10mL)中，然后滴入4N的氯化氢的二氧六环溶液(675μL,2.7mmol)，反应液在室温下反应2小时。浓缩 反应液，所得粗产物无需进一步的纯化，直接用于下一步反应。MS(ESI,m/z):[M+H]+:344.2。
步骤3：N-(顺式-4-((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)环己基)丙炔酰胺的制备
将步骤2所得产物(38mg，0.10mmol)和丙炔酸(8.4mg，0.12mmol)溶于四氢呋喃(10mL)中，然后加入N,N-二异丙基乙胺(53μL)。混合液在室温下搅拌30分钟，然后再加入TBTU(4mg)，混合液在室温下搅拌过夜。浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到2.45mg淡黄色固体。收率：6.2％。MS(ESI,m/z):[M+H]+:396.2；1H-NMR(300MHz,CD3OD)δ:7.93(d,1H,J＝5.4Hz),7.85(s,1H),7.61(s,1H),7.16(d,1H,J＝5.4Hz),3.91(s,3H),3.54-3.61(m,2H),1.74-2.01(m,8H)。
实施例61
1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000123
步骤1：3-(((2-氯噻吩[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000124
将2,4-二氯噻吩[3,2-d]嘧啶(205mg,1mmol)、3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯(186mg,1mmol)溶于四氢呋喃(5mL)中，加入N,N-二异丙基乙胺(258mg,2mmol)。反应液在70℃下过夜反应，之后浓缩。残余物加入水(20mL)，用乙酸乙酯(10mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝5:1)，得到340mg白色固体。收率：96.0％。MS(ESI,m/z):[M+H]+:355.1；1H-NMR(300MHz,CDCl3):7.76(d,1H,J＝5.4Hz),7.37(d,1H,J＝5.4Hz),5.49(s,1H),4.05-4.09(m,2H),3.87-3.91(m,2H),3.71-3.75(m,2H),2.94(m,1H),1.44(s,9H)。
步骤2：N-(氮杂环丁烷-3-基甲基)-2-氯噻吩[3,2-d]嘧啶-4-胺的制备
Figure PCTCN2014086820-appb-000125
将步骤1所得产物(340mg,0.96mmol)溶于二氯甲烷(10mL)中，加入4N的氯化氢的1,4-二氧六环溶液(2.5mL,10mmol)，反应液在室温下反应2小时。浓缩反应液，所得粗产物无需进一步的纯化，直接用于下一步反应。MS(ESI,m/z):[M+H]+:254.9。
步骤3：1-(3-(((2-氯噻吩[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000126
将步骤2所得产物(1.22g,4.80mmol)溶于二氯甲烷(10mL)中，加入三乙胺(0.969g,9.60mmol)。在0℃下将溶于二氯甲烷(5mL)的丙烯酰氯(0.434g,4.80mmol)溶液滴加在上述溶液中。反应液在室温下反应过夜。反应液经水(10mL)洗，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到1.00g白色固体。收率：67.6％。MS(ESI,m/z):[M+H]+:309.0；1H-NMR(300MHz,DMSO-d6):8.50-8.53(m,1H),8.19(d,1H,J＝5.1Hz),7.35(d,1H,J＝5.4Hz),6.25-6.34(m,1H),6.05-6.12(m,1H),5.63-5.68(m,1H),4.27-4.33(m,1H),3.97-4.03(m,2H),3.67-3.75(m,3H),2.89-2.98(m,1H)。
步骤4：1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
将步骤3所得产物(50mg,0.162mmol)、1-甲基-1H-吡唑-4-胺(23mg,0.244mmol)溶于1,4-二氧六环(2mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到15mg黄色固体。收率：25.4％。MS(ESI,m/z):[M+H]+:370.2；1H-NMR(300MHz,DMSO-d6)δ:7.83(s,1H),7.60(d,1H,J＝5.4Hz),7.52(s,1H),7.18(d,1H,J＝5.4Hz),7.12(s,1H),6.31-6.37(m,1H),6.13-6.22(m,1H),5.65-5.69(m,1H),5.53(s,1H),4.01-4.35(m,3H),3.81-3.93(m,6H),3.07(m,1H)。
下列化合物(表二)利用类似起始原料通过类似于实施例61的合成方法制备。
表二
Figure PCTCN2014086820-appb-000128
Figure PCTCN2014086820-appb-000129
Figure PCTCN2014086820-appb-000130
Figure PCTCN2014086820-appb-000131
Figure PCTCN2014086820-appb-000132
Figure PCTCN2014086820-appb-000133
Figure PCTCN2014086820-appb-000134
实施例92
1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)呋喃[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000135
步骤1：3-(((2-氯呋喃[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000136
将2,4-二氯呋喃[3,2-d]嘧啶(189mg,1mmol)、3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯(186mg,1mmol)溶于四氢呋喃(20mL)中，加入N,N-二异丙基乙胺(258mg,2mmol)，反应液在回流条件下反应过夜。然后冷却至室温，反应液浓缩。残余物加入水(20mL)，用乙酸乙酯(10mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝6:1)，得到283mg白色固体。收率：83.5％。MS(ESI,m/z):[M+H]+:339.1。
步骤2：N-(氮杂环丁烷-3-基甲基)-2-氯呋喃[3,2-d]嘧啶-4-胺的制备
Figure PCTCN2014086820-appb-000137
将步骤1所得化合物(283mg,0.84mmol)溶于二氯甲烷(2mL)中，冰浴下缓慢滴加三氟乙酸(1.43g,12.5mmol)的二氯甲烷溶液(1mL)，反应液在室温下反应1小时。浓缩反应液，所得粗产物无需进一步的纯化，直接用于下一步反应。MS(ESI,m/z):[M+H]+:238.9。
步骤3：1-(3-(((2-氯呋喃[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000138
将步骤2所得产物(0.84mmol)溶于二氯甲烷(10mL)中，加入三乙胺(254mg,2.51mmol)。在冰浴条件下将溶于二氯甲烷(5mL)的丙烯酰氯(83.1mg,0.92mmol)溶液滴加在上述溶液中。反应液在室温下反应过夜。反应液经水(10mL)洗，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到176mg白色固体。收率：72.0％。MS(ESI,m/z):[M+H]+:293.0。
步骤4：1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)呋喃[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
将步骤3所得化合物(29.3mg,0.1mmol)、1-甲基-1H-吡唑-4-胺(14.6mg,0.15mmol)溶于异丙醇(2mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到15.5mg黄色固体。收率：43.9％。MS(ESI,m/z):[M+H]+:354.2；1H-NMR(300MHz,DMSO-d6)δ:7.80(s,1H),7.61(d,1H,J＝2.1Hz),7.49(s,1H),7.04(s,1H),6.66(d,1H,J＝1.8Hz),6.33(dd,1H,J＝1.8Hz,J＝17.1Hz),6.12-6.21(m,1H),5.67(dd,1H,J＝2.1Hz,J＝10.2Hz),4.00-4.35(m,3H),3.87(s,3H),3.79-3.92(m,3H),3.01-3.06(m,1H)。
下列化合物(表三)利用类似起始原料通过类似于实施例92的合成方法制备。
表三
Figure PCTCN2014086820-appb-000139
Figure PCTCN2014086820-appb-000140
实施例97
1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000141
步骤1：3-(((2-氯-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯 的制备
Figure PCTCN2014086820-appb-000142
将2,4-二氯-5H-吡咯[3,2-d]嘧啶(360mg,1.92mmol)和3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯(374mg,2.01mmol)溶解于甲醇(20mL)中。室温搅拌下加入N,N-二异丙基乙胺(667μL,3.83mmol)。加热回流3小时。将反应液浓缩后，重新溶解于二氯甲烷(50mL)，用水(30mL)洗后浓缩得到350mg白色固体。收率：51.2％。MS(ESI,m/z):[M+H]+:338.2。
步骤2：1-(3-(((2-氯-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000143
将步骤1所得产物(222mg,0.66mmol)溶解于二氯甲烷(5mL)，室温搅拌下加入三氟乙酸(2mL)，搅拌3小时后，减压浓缩反应液，除去大部分三氟乙酸后，重新溶解于二氯甲烷(30mL)，室温搅拌下加入N,N-二异丙基乙胺(229μL,1.31mmol)，冰浴下缓慢滴加丙烯酰氯(59μL,0.66mmol)的二氯甲烷(10mL)溶液。5小时后，向反应体系中加入水(50mL)，分离出有机相，用无水硫酸钠干燥后浓缩得到淡黄色固体。硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到150mg白色固体。收率：77.7％。MS(ESI,m/z):[M+H]+:292.0。
步骤3：1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
将步骤2所得化合物(40mg,0.14mmol)、1-甲基-1H-吡唑-4-胺(15mg,0.15mmol)溶于异丙醇(2mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到2mg黄色固体。收率：4.1％。MS(ESI,m/z):[M+H]+:353.2；1H-NMR(300MHz,DMSO-d6)δ:7.52(s,2H),7.41(s,1H),6.98(d,1H,J＝3.0Hz),6.13-6.19(m,2H),5.98(d,1H,J＝3.0Hz),5.67(dd,1H,J＝2.4Hz,J＝9.6Hz),4.25-4.35(m,1H),4.04-4.08(m,2H),3.80-3.85(m,2H),3.74(s,3H),3.65-3.73(m,1H),2.95-3.05(m,1H)。
实施例98
1-(3-(((5-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000144
步骤1：3-(((2-氯-5-甲基-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000145
将2,4-二氯-5-甲基-5H-吡咯[3,2-d]嘧啶(300mg,1.48mmol)、3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯(290mg,1.56mmol)溶于四氢呋喃(10mL)中，加入N,N-二异丙基乙胺(258mg,2mmol)，反应液在回流条件下反应过夜。然后冷却至室温，反应液浓缩。残余物加入水(50mL)，用乙酸乙酯(20mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝6:1)，得到300mg无色液体。收率：50.7％。MS(ESI,m/z):[M+H]+:352.2。
步骤2：1-(3-(((2-氯-5-甲基-5H-吡咯[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000146
将步骤1所得产物(229mg)溶于二氯甲烷(4mL)中，室温搅拌下加入三氟乙酸(1.5mL)，搅拌3小时后，减压浓缩反应液，除去大部分三氟乙酸后，重新溶解于二氯甲烷(20mL)，室温搅拌下加入N,N-二异丙基乙胺(276μL,1.59mmol)，冰浴下缓慢滴加丙烯酰氯(64μL,0.66mmol)的二氯甲烷(10mL)溶液。5小时后，向反应体系中加入水(50mL)，分离出有机相，用无水硫酸钠干燥后浓缩得到淡黄色固体。硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到180mg白色固体。收率：90.5％。MS(ESI,m/z):[M+H]+:306.1。
步骤3：1-(3-(((5-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)-5H-吡咯[3,2-d]嘧啶-4-基) 氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
将步骤2所得化合物(50mg,0.16mmol)、1-甲基-1H-吡唑-4-胺(18mg,0.18mmol)溶于异丙醇(2mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到3mg淡黄色固体。收率：5％。MS(ESI,m/z):[M+H]+:367.3；1H-NMR(300MHz,DMSO-d6)δ:7.59(d,1H,J＝3.0Hz),7.54(s,1H),6.89(d,1H,J＝3.0Hz),6.77(bs,1H),6.11-6.30(m,3H),5.68(dd,1H,J＝1.8Hz,J＝10.2Hz),4.31-4.37(m,1H),4.11-4.18(m,1H),3.90-4.06(m,5H),3.83(s,3H),3.70-3.80(m,2H),3.05-3.17(m,1H)。
实施例99
1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[2,3-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000147
步骤1：3-(((2-氯噻吩[2,3-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000148
将2,4-二氯噻吩[2,3-d]嘧啶(300mg,1.46mmol)、3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯(272mg,1.46mmol)溶于四氢呋喃(25mL)中，加入N,N-二异丙基乙胺(258mg,2mmol)。反应液在70℃下过夜反应，然后浓缩。残余物加入水(50mL)，用乙酸乙酯(20mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷：乙酸乙酯＝1:5)，得到425mg白色固体。收率：81.9％。MS(ESI,m/z):[M+H]+:355.2。
步骤2：1-(3-(((2-氯噻吩[2,3-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000149
将步骤1所得产物(425mg,1.20mmol)溶解于二氯甲烷(10mL)，室温搅拌下加入三氟乙酸(3mL)，搅拌3小时后，减压浓缩反应液，除去大部分三氟乙酸后，重新溶解于二氯甲烷(30mL)，室温搅拌下加入N,N-二异丙基乙胺(417μL,2.40mmol)，冰浴下缓慢滴加丙烯酰氯(140μL，1.73mmol)的二氯甲烷(20mL)溶液。5小时后，向反应体系中加入水(50mL)，分离出有机相，用无水硫酸钠干燥后浓缩得到淡黄色固体。硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到300mg白色固体。收率：81.1％。MS(ESI,m/z):[M+H]+:309.1。
步骤3：1-(3-(((2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[2,3-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
将步骤2所得产物(40mg,0.13mmol)、1-甲基-1H-吡唑-4-胺(19mg,0.19mmol)、三(二亚苄基丙酮)二钯(12mg,0.013mmol)、(±)-2,2'-双-(二苯膦基)-1,1'-联萘(12mg,0.019mmol)和碳酸铯(127mg,0.39mmol)混悬于1,4-二氧六环(1.5mL)中，加入水(300μL)，氩气置换空气后，微波辅助，100℃下反应半小时。反应液经硅藻土过滤后，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)，得到9mg黄色固体。收率：18.8％。MS(ESI,m/z):[M+H]+:370.2；1H-NMR(300MHz,CDCl3)δ:7.79(bs,1H),7.07(s,1H),6.97(d,1H,J＝6.0Hz),6.91(s,1H),6.82(d,1H,J＝6.0Hz),6.75(bs,1H),6.26(dd,1H,J＝1.8Hz,J＝16.8Hz),6.10(dd,1H,J＝10.2Hz,J＝16.8Hz),5.60(dd,1H,J＝1.8Hz,J＝10.2Hz),4.21-4.27(m,1H),4.08-4.14(m,1H),3.92-3.97(m,1H),3.78-3.86(m,5H),3.65-3.76(m,1H),2.95-3.05(m,1H)。
下列化合物(表四)利用类似起始原料通过类似于实施例99的合成方法制备。
表四
Figure PCTCN2014086820-appb-000150
Figure PCTCN2014086820-appb-000151
实施例105
(R)-1-(3-(甲基(2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000152
步骤1：(R)-3-((2-氯噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000153
将2,4-二氯噻吩[3,2-d]嘧啶(2.26g,0.011mol)、(R)-3-氨基吡咯烷-1-基羧酸叔丁酯(2.25g,0.012mol)溶于四氢呋喃(50mL)中。加入N,N-二异丙基乙胺(2.838g,0.022mol)。反应液在70℃下过夜反应，之后浓缩。残余物加入水(50mL)，用乙酸乙酯(50mL*3)萃取。有机相经无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷:乙酸乙酯＝5:1)，得到3.8g白色固体。收率：97.4％。MS(ESI,m/z):[M+H]+:355.1；1H-NMR(300MHz,DMSO-d6):8.05(d,1H,J＝6.3Hz),8.02(d,1H,J＝5.4Hz),7.35(d,1H,J＝6.3Hz),4.60-4.48(m,1H),3.60-3.67(m,1H),3.22-3.48(m,3H),2.15-2.19(m,1H),1.91-2.01(m,1H),1.40(s,9H)。
步骤2：(R)-2-氯-N-(吡咯烷-3-基)噻吩[3,2-d]嘧啶-4-胺的制备
Figure PCTCN2014086820-appb-000154
将步骤1所得化合物(0.3g,0.845mmol)溶于乙醇(10mL)中，加入4N的氯化氢的1,4-二氧六环溶液(2mL,8mmol)。反应液在80℃反应4小时。浓缩反应液，所得粗产物无需进一步的纯化，直接用于下一步反应。MS(ESI,m/z):[M+H]+:254.9。
步骤3：(R)-1-(3-((2-氯噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000155
将步骤2所得化合物(0.497g,1.96mmol)溶于二氯甲烷(10mL)中，加入三乙胺(0.396g,3.92mmol)。在0℃下将溶于二氯甲烷(5mL)的丙烯酰氯(0.195g,2.15mmol)溶液滴加在上述溶液中。反应液在室温下反应过夜。反应液经水(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到0.44g白色固体。收率：72.8％。MS(ESI,m/z):[M+H]+:309.0；1H-NMR(300MHz,DMSO-d6):8.52-8.55(m,1H),8.20(m,1H),7.35(m,1H),6.52-6.67(m,1H),6.11-6.19 (m,1H),5.64-5.71(m,1H),4.63-4.80(m,1H),3.43-3.97(m,4H),2.00-2.23(m,2H)。
步骤4：(R)-1-(3-((2-氯噻吩[3,2-d]嘧啶-4-基)甲基)氨基)吡咯烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000156
将碘甲烷(24μL，0.39mmol)加入到步骤3所得化合物(100mg,0.32mmol)与氢化钠(60％，分散在矿物油中，39mg,0.97mmol)的四氢呋喃(15mL)溶液中。室温下搅拌3小时。浓缩反应液后用硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝30:1)，得到80mg白色固体。收率：76.5％。MS(ESI,m/z):[M+H]+:323.1；1H-NMR(300MHz,CDCl3):7.79-7.82(m,1H),7.36-7.38(m,1H),6.40-6.54(m,1H),5.58-5.77(m,1H),3.81-4.03(m,2H),3.48-3.70(m,2H),3.40(s,3H),2.12-2.40(m,2H)。
步骤5：(R)-1-(3-(甲基(2-((1-甲基-1H-吡唑-4-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2-烯-1-丙酮的制备
将步骤4所得化合物(40mg,0.12mmol)、1-甲基-1H-吡唑-4-胺(13mg,0.14mmol)和三氟乙酸(20mg,0.18mmol)溶解于2-丁醇(1.2mL)中，在微波100℃条件下反应40分钟。经硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝20:1)，得到22mg棕色固体。收率：46.3％。MS(ESI,m/z):[M+H]+:384.3；1H-NMR(300MHz,CDCl3):δ:7.79(d,1H,J＝9.9Hz),7.68(d,1H,J＝5.4Hz),7.50(d,1H,J＝5.7Hz),7.22(d,1H,J＝5.7Hz),6.42-6.48(m,2H),5.70-5.77(m,1H),5.47-5.56(m,1H),3.79-3.98(m,5H),3.49-3.67(m,2H),3.35(d,3H,J＝5.4Hz),2.12-2.34(m,2H)。
下列化合物(表五)利用类似起始原料通过类似于实施例105的合成方法制备：
表五
Figure PCTCN2014086820-appb-000157
Figure PCTCN2014086820-appb-000158
实施例108
1-(3-(((2-((1-异丙基-1H-吡唑-4-基氨基)噻吩[3,2-d]嘧啶-4-基)氨基)甲基)氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000159
步骤1：1-异丙基-4-硝基-1H-吡唑的制备
Figure PCTCN2014086820-appb-000160
4-硝基-1H-吡唑(226mg,2mmol)、2-碘丙烷(340mg,2mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(276mg,2mmol)，反应液在70℃下反应2小时。将反应液倾倒入水(20mL)中，用乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析分离(洗脱液：正己烷/乙酸乙酯＝5:1)，得到250mg白色固体。收率：80.0％。MS(ESI,m/z):[M+H]+:155.8；1H-NMR(300MHz,CDCl3)δ:8.16(s,1H),8.08(s,1H),4.48-4.57(m,1H),1.57(s,3H),1.55(s,3H)。
步骤2：1-异丙基-1H-吡唑-4-胺的制备
Figure PCTCN2014086820-appb-000161
将步骤1所得产物(250mg,1.61mmol)溶于乙醇(10mL)中，加入钯碳(25mg)，通氢气，在室温下反应2小时。反应液过滤浓缩，所得粗产物直接用于下一步反应。MS(ESI,m/z):[M+H]+:125.9。
步骤3：1-(3-(((2-((1-异丙基-1H-吡唑-4-基-氨基)噻吩[3,2-d]嘧啶-4-基)氨基)甲基) 氮杂环丁烷-1-基)-2-烯-1-丙酮的制备
将实施例61中步骤3所得产物(30mg,0.1mmol)、1-异丙基-1H-吡唑-4-胺(19mg,0.15mmol)溶于的1,4-二氧六环(2mL)中。反应液用三氟乙酸调节pH至5，微波辐射90℃下反应0.5小时。反应液冷却至室温，用1N的氢氧化钠溶液调节pH至8。用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩，制备硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝20:1)得到15mg黄色固体。收率：37.8％。MS(ESI,m/z):[M+H]+:398.3；1H-NMR(300MHz,DMSO-d6)δ:7.81(s,1H),7.64(d,1H,J＝5.4Hz),7.60(s,1H),7.20(d,1H,J＝5.4Hz),6.31-6.37(m,1H),6.13-6.22(m,1H),5.66-5.70(m,1H),4.31-4.37(m,1H),4.18-4.24(m,1H),4.00-4.05(m,1H),3.81-3.95(m,3H),3.09(m,1H),1.53(s,3H),1.51(s,3H)。
下列化合物(表六)利用类似起始原料通过类似于实施例108的合成方法制备：
表六
Figure PCTCN2014086820-appb-000162
Figure PCTCN2014086820-appb-000163
Figure PCTCN2014086820-appb-000164
Figure PCTCN2014086820-appb-000165
Figure PCTCN2014086820-appb-000166
Figure PCTCN2014086820-appb-000167
实施例132
(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000168
步骤1：(R)-3-((2-((3-甲基异噻唑-5-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000169
将实施例105中步骤1所得产物(35.6g,0.1mol)和3-甲基异噻唑-5-胺盐酸盐(16.3g,0.11mol)溶于1,4-二氧六环/水中(700mL,20:1)，加入三(二亚苄基丙酮)二钯(7.3g,8mmol)、(±)-2,2'-双-(二苯膦基)-1,1'-联萘(7.5g,12mmol)和碳酸铯(130g,0.4mol)，氮气保护，在100℃下回流过夜。反应液冷却至室温，经硅藻土过滤，滤液减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷：甲醇＝30:1)，得44g黄色固体粗品。向粗品中加入混合溶剂(正己烷：二氯甲烷：乙酸乙酯＝3:1:1)(500mL)。混合液在70℃下搅拌1小时，冰浴冷却，过滤，得到35g淡黄色固体。收率：80.6％。MS(ESI,m/z):[M+H]+:433.3；1H-NMR(300MHz,CDCl3)δ:7.69(d,1H,J＝3.6Hz),7.22(s,1H),6.46(s,1H),5.00-5.30(m,2H),3.46-3.87(m,4H),2.37-2.40(m,4H),2.12(m,1H),1.84-1.86(m,1H),1.49(s,9H)。
步骤2：(R)-N2-(3-甲基异噻唑-5-基)-N4-(吡咯烷-3-基)噻吩[3,2-d]嘧啶-2,4-二胺的制备
Figure PCTCN2014086820-appb-000170
将上述步骤1所得产物(35g,0.081mol)溶于二氯甲烷(1.5L)，加入甲醇(1L)助溶。加入4N的氯化氢的1,4-二氧六环溶液(200mL,0.8mol)，室温下反应2小时。反应液减压浓缩，直接投入下一步。MS(ESI,m/z):[M+H]+:333.1。
步骤3：(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2-烯-1-丙酮的制备
将步骤2所得产物(26.9g,0.081mol)溶于二氯甲烷(500mL)中，冰浴下加入三乙胺(16.36g,0.162mol)，继续冰浴下滴加丙烯酰氯(7.33g,0.081mol)的二氯甲烷(50mL)溶液，室温下反应过夜。反应液减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝30:1)，得到15g白色固体。收率：47.9％。MS(ESI,m/z):[M+H]+:387.2；1H-NMR(300MHz,DMSO-d6)δ:8.06-8.14(m,2H),7.23(s,1H),6.53-6.70(m,2H),6.12-6.20(m,1H),5.64-5.72(m,1H),4.88(s,1H),3.51-4.09(m,4H),2.05-2.66(m,6H)。
实施例133
(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)噻吩[3,2-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2-炔-1-丙酮的制备
Figure PCTCN2014086820-appb-000171
将实施例132中步骤2所得产物(33mg,0.10mmol)和丙炔酸(8.4mg,0.12mmol)溶于四氢呋喃(10mL)中，然后加入N,N-二异丙基乙胺(53μL)。混合液在室温下搅拌30分钟，然后再加入TBTU(4mg)，混合液在室温下搅拌过夜。浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到6.4mg淡黄色固体。收率：16.7％。MS(ESI,m/z):[M+H]+:385.2；1H-NMR(300MHz,CD3OD)δ:7.89-7.92(m,1H),7.22(d,1H,J＝5.1Hz),6.62(s,1H),5.04(s,1H),3.53-4.86(m,5H),2.42-2.50(m,1H),2.35(s,3H),2.20-2.28(m,1H)。
实施例134
(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000172
步骤1：(R)-3-((2-氯吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000173
将2,4-二氯吡咯[2,1-f][1,2,4]三嗪(325mg,1.73mmol)和(R)-1-叔丁氧基羰基-3-氨基哌啶(364mg,1.80mmol)溶解于四氢呋喃(50mL)溶液中。室温搅拌下加入N,N-二异丙基乙胺(603μL,3.46mmol)，回流3小时。将反应液浓缩后，重新溶解于二氯甲烷(50mL)，水(30mL)洗后浓缩，无水硫酸钠干燥后得到640mg粗产物。MS(ESI,m/z):[M+H]+:352.2。
步骤2：(R)-1-(3-((2-氯吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)-2-烯-1-丙酮的制备
Figure PCTCN2014086820-appb-000174
将步骤1得到的粗产物(640mg)溶解于二氯甲烷(3mL)，室温搅拌下加入三氟乙酸(1.5mL)，搅拌3小时后，减压浓缩反应液，除去大部分三氟乙酸后，重新溶解 于二氯甲烷(30mL)，室温搅拌下加入N,N-二异丙基乙胺(603μL,3.46mmol)，冰浴下缓慢滴加丙烯酰氯(140μL,1.73mmol)的二氯甲烷(20mL)溶液。5小时后，向反应体系中加入水(50mL)，分离出有机相，用无水硫酸钠干燥后浓缩得到淡黄色固体。硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝70:1)，得到408mg白色固体。收率：77.14％。MS(ESI,m/z):[M+H]+:306.2。
步骤3：(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)-2-烯-1-丙酮的制备
将步骤2所得产物(31mg,0.1mmol)、3-甲基-异噻唑-5-胺盐酸盐(15mg,0.1mmol)、三(二亚苄基丙酮)二钯(9mg,0.01mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(9mg,0.015mmol)和碳酸铯(130mg,0.4mmol)混悬于1,4-二氧六环(1.5mL)中，加入水(300μL)，氩气置换空气后，微波辅助，100℃下反应半小时。反应液经硅藻土过滤后，用硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝30:1)，得到20mg黄色固体。收率：51.44％。MS(ESI,m/z):[M+H]+:384.3；1H-NMR(300MHz,CD3OD)δ:7.43(s,1H),6.70-6.89(m,2H),6.52-6.56(m,2H),6.20(dd,1H,J＝16.8Hz,J＝40.2Hz),5.71(dd,1H,J＝10.8Hz,J＝55.5Hz),4.78-4.82(m,1H),4.08-4.46(m,2H),2.82-3.46(m,2H),2.34(s,3H),2.18-2.30(m,1H),1.90-2.02(m,1H),1.60-1.85(m,2H)。
下列化合物(表七)利用类似起始原料，通过类似于实施例134的合成方法制备。
表七
Figure PCTCN2014086820-appb-000175
Figure PCTCN2014086820-appb-000176
实施例139
(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)-2-炔-1-丙酮的制备
Figure PCTCN2014086820-appb-000177
步骤1：(R)-3-((2-((3-甲基异噻唑-5-基)氨基)吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2014086820-appb-000178
将实施例134中步骤1所得产物(352mg,1mmol)和3-甲基异噻唑-5-胺盐酸盐(163mg,1.1mmol)溶于1,4-二氧六环/水中(21mL,20:1)，加入三(二亚苄基丙酮)二钯(46mg,0.05mmol)、(±)-2,2'-双-(二苯膦基)-1,1'-联萘(63mg,0.1mmol)和碳酸铯(650 mg,2mmol)，氮气保护，在100℃下回流过夜。反应液冷却至室温，经硅藻土过滤，滤液减压浓缩，硅胶柱层析分离(洗脱液：二氯甲烷：甲醇＝30:1)，得到349mg淡黄色固体。收率：81.2％。MS(ESI,m/z):[M+H]+:430.2。
步骤2：(R)-N2-(3-甲基异噻唑-5-基)-N4-(哌啶-3-基)吡咯[2,1-f][1,2,4]三嗪-2,4-二胺的制备
Figure PCTCN2014086820-appb-000179
将上述步骤1所得产物(64mg,0.2mmol)溶于二氯甲烷(15mL)，加入甲醇(10mL)助溶。加入4N的氯化氢的1,4-二氧六环溶液(0.5mL,2mmol)，室温下反应2小时。反应液减压浓缩，直接投入下一步。MS(ESI,m/z):[M+H]+:330.1。
步骤3：(R)-1-(3-((2-((3-甲基异噻唑-5-基)氨基)吡咯[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)-2-炔-1-丙酮的制备
将步骤2所得产物(33mg,0.10mmol)和丙炔酸(8.4mg,0.12mmol)溶于四氢呋喃(10mL)中，然后加入N,N-二异丙基乙胺(53μL)。混合液在室温下搅拌30分钟，然后再加入TBTU(4mg)，混合液在室温下搅拌过夜。浓缩，硅胶柱层析分离(洗脱液：二氯甲烷/甲醇＝10:1)得到6.1mg淡黄色固体。收率：16.1％。MS(ESI,m/z):[M+H]+:382.2。
下列化合物(表八)利用类似起始原料，通过类似于实施例139的合成方法制备
表八
Figure PCTCN2014086820-appb-000180
生物活性评价
测试实施例1：BTK激酶活性抑制实验
将BTK激酶(购自Invitrogen，货号：PV3363)用反应缓冲液(40mM Tris-HCl，pH 7.5；20mM MgCl2,0.1mg/ml BSA；1mM DTT；2mM MnCl2)稀释到2倍终浓度(终浓度为1.1ng/μL)并以5μL/孔加入96孔板。将本发明的化合物用去离子水梯度稀释为终浓度(分别为10μM,1μM,0.1μM,20nM,4nM,0.8nM)的4倍(即，40μM,4μM,0.4μM,80nM,16nM,3.2nM)，并以2.5μL/孔加入96孔板实验孔。于25℃孵育10分钟后，以2.5μL/孔加入ATP(50μM)(购自Promega，货号：V9102)和0.2μg/μL 酶反应底物Poly E4Y1(购自Sigma，货号：P0275-25MG)，于25℃反应120分钟。反应结束后，每孔加入10μL ADP-Glo试剂(ADP-GloTM激酶检测试剂盒购自Promega，货号：V9102)，于25℃反应40分钟后，每孔再加入20μL ADP-Glo激酶检测试剂并于25℃反应30分钟，按照ADP-Glo激酶检测试剂盒说明书采用发光法进行激酶活性检测，并计算本发明化合物的IC50，结果见表九。
表九 BTK激酶的活性抑制分析结果
化合物 BTK 化合物 BTK 化合物 BTK
1 +++ 62 +++ 104 +++
2 +++ 65 +++ 105 +++
4 +++ 69 +++ 108 +++
8 +++ 70 ++ 111 +++
12 +++ 71 +++ 112 +++
13 +++ 72 +++ 114 +++
14 +++ 73 +++ 115 +++
15 +++ 74 ++ 116 +++
16 +++ 75 +++ 118 +++
17 ++ 76 +++ 119 +++
18 +++ 77 +++ 120 +++
30 ++ 78 ++ 121 +++
31 +++ 79 + 122 +++
33 ++ 80 +++ 123 +++
34 +++ 81 +++ 124 +++
35 +++ 82 +++ 125 +++
36 ++ 83 +++ 126 +++
43 +++ 84 +++ 127 +++
44 +++ 85 ++ 128 +++
45 ++ 88 ++ 129 +++
46 +++ 92 +++ 130 +++
47 +++ 93 +++ 131 +++
49 +++ 94 +++ 132 +++
50 +++ 95 +++ 134 +++
51 +++ 96 +++ 135 +++
52 ++ 99 ++ 136 +++
57 +++ 101 ++ 137 +++
60 +++ 102 +++ 138 +++
61 +++ 103 +++    
表九显示在BTK的活性抑制分析中所选本发明化合物的活性，其中活性指定为“+++”的化合物提供的IC50≤50nM；活性指定为“++”的化合物提供的IC50为50<IC50≤100nM；活性指定为“+”的化合物提供的IC50为100<IC50<1000nM。
测试实施例2：JAK3激酶活性抑制实验
将JAK3激酶(购自SignalChem，货号：J03-11G)用反应缓冲液(40mM Tris-HCl，pH 7.5；20mM MgCl2；0.1mg/ml BSA；1mM DTT)稀释到2倍终浓度(终浓度为0.5ng/μL)，并以5μL/孔加入96孔板。将本发明的化合物用去离子水梯度稀释为终浓度(分别为10μM,1μM,0.1μM,20nM,4nM,0.8nM)的4倍(即，40μM,4μM,0.4μM,80nM,16nM,3.2nM)，并以2.5μL/孔加入96孔板实验孔。于25℃孵育10分钟后，以2.5μL/孔加入10μM ATP(购自Promega，货号：V9102)和0.2μg/μL酶反应底物Poly E4Y1(购自Sigma，货号：P0275-25MG)，于25℃反应60分钟。反应结束后，每孔加入10μL ADP-Glo试剂(ADP-GloTM激酶检测试剂盒购自Promega，货号：V9102)，于25℃反应40分钟后，每孔再加入20μL ADP-Glo激酶检测试剂并于25℃反应30分钟，按照ADP-Glo激酶检测试剂盒说明书采用发光法进行激酶活性检测，并计算本发明化合物的IC50，结果见表十。
表十 JAK3激酶的活性抑制分析结果
化合物 JAK3 化合物 JAK3 化合物 JAK3
61 +++ 85 ++ 118 ++
62 ++ 88 ++ 119 ++
65 ++ 92 + 120 ++
69 ++ 93 ++ 121 ++
70 ++ 94 +++ 122 +++
71 +++ 95 ++ 123 ++
72 ++ 96 +++ 124 ++
73 ++ 99 ++ 125 +++
74 + 101 + 126 ++
75 ++ 102 ++ 127 +++
76 ++ 103 + 128 ++
77 ++ 104 ++ 129 ++
78 ++ 105 ++ 130 ++
79 ++ 108 +++ 131 ++
80 ++ 111 ++ 132 +++
81 ++ 112 ++ 134 +++
82 +++ 114 ++ 135 ++
83 +++ 115 ++ 137 +++
84 ++ 116 ++ 138 ++
表十显示在JAK3的活性抑制分析中所选本发明化合物的活性，其中活性指定为“+++”的化合物提供的IC50≤10nM；活性指定为“++”的化合物提供的IC50为10<IC50≤100nM；活性指定为“+”的化合物提供的IC50为100<IC50<1000nM。
测试实施例3：IL-2诱导的CTLL-2细胞增殖实验
用RPMI-1640完全培养基(购自Gibco，货号：22440)梯度稀释本发明的化合物至终浓度(分别为：1μM,0.2μM,40nM,8nM,1.6nM和0.32nM)的3倍(即，3μM,0.6μM,120nM,24nM,4.8nM和0.96nM)，以50μL化合物/孔加入96孔板实验孔，设置含有IL-2(简称IL-2+)(IL-2购自R&D，货号：402-ML-020/CF)和不含IL-2(简称IL-2-)的对照孔(加50μL培养基)。对数生长期CTLL-2细胞(购自ATCC，货号：TIB-214)用PBS缓冲液(pH 7.2)洗后，重悬于不含IL-2的RPMI-1640完全培养基，以50000细胞/50μL/孔接种于96孔板的实验孔和对照孔，并将实验板置于37℃，5％CO2预孵育1小时。此后，在实验孔和IL-2+对照孔中加入含有IL-2的RPMI-1640完全培养基(50μL/孔)，IL-2-对照孔中加不含IL-2的RPMI-1640完全培养基(50μL/孔)，在37℃条件下，使用5％的CO2刺激24小时。作用完毕后，自培养箱内取出96孔板，每孔加入15μL CCK-8试剂(购自DOJINDO，货号：DOJINDO-CK04)，然后放回培养箱内，继续培养1-4小时，在450nm波长下测定光吸收，并据此计算本发明化合物的IC50，结果见表十一。
表十一 IL-2诱导的CTLL-2细胞增殖实验结果
化合物 CTLL-2
134 +++
137 ++
表十二显示在CTLL-2细胞增殖实验中所选本发明化合物的活性，其中活性指定为“+++”的化合物提供的IC50≤100nM；活性指定为“++”的化合物提供的IC50为100<IC50<1000nM。
测试实施例4：Ramos细胞p-BTK和p-PCL-γ2抑制实验(蛋白质印迹法(Western blot))
饥饿培养1小时的Ramos细胞(购自北京协和医学院)用本发明的化合物处理1小时后，用PBS缓冲液(pH 7.2)洗去化合物。并重悬于100μL含1μM抗人IgM F(ab’)2(购自SBA公司，货号：2022-01)无血清培养基，置于冰上刺激10分钟。用PBS缓冲液(pH 7.2)洗去IgM，重悬于100μL蛋白裂解液(购自Sigma，货号：C2978)， 制备并定量蛋白样品。取100μg蛋白样品，在200V电压下进行聚丙烯酰胺凝胶电泳。电泳结束后，将蛋白转印到PVDF膜上，并用3％BSA室温封闭2小时。加入相应抗体(抗-p-BTK(pY223)(购自CST，货号：5082S)；抗-BTK(购自Abcam，货号：ab118156)；抗-p-PLCγ2(pY1217)(购自CST，货号：3871S)；抗-PLCγ2(购自CST，货号：3872S)；抗-β-actin(购自CWBIO，货号：CW0096A))，4℃孵育过夜，再用辣根过氧化物酶标记的IgG二抗(购自CWBIO，货号：CW0103A)，孵育1小时，加ECL底物(购自GE，货号：RPN2109)显色，检测蛋白表达。
按上述方案测试本发明的化合物132，结果表明化合物132能显著抑制Ramos细胞中p-BTK和p-PLCγ2的表达，并呈现剂量依赖性。
结果显示于图1中。
测试实施例5：二型胶原诱导的DBA/1J小鼠关节炎模型(CIA)
CIA模型是一个被广泛用于研究人类类风湿关节炎治疗药物的动物模型。本试验所用的实验动物是DBA/1J小鼠(雄性，6～8周龄，购买于中国上海斯莱克实验动物有限公司)，饲养在IVC系统中。
为了诱导小鼠CIA模型，首先将牛二型胶原溶液(CII)(购买于Chondrex公司，货号：20022)与等体积完全弗氏佐剂(CFA)(购买于Sigma-Aldrich公司，货号：F5881)用电子匀浆器进行乳化，制备成乳剂，然后将70μL制备好的乳剂经皮内注射，注入小鼠尾根部，进行初次免疫。初次免疫三周后，加强免疫一次。用牛二型胶原溶液与等体积不完全弗氏佐剂(IFA)(购买于Sigma-Aldrich公司，货号：F5506)进行乳化，制备成乳剂，然后背部单点皮内注射70μL制备好的乳剂，完成免疫。小鼠的关节炎严重程度按以下标准分为0到4分(0分：没有水肿或者肿胀；1分：轻度水肿和发红，限于踝关节或跗骨；2分：轻度水肿和发红，从踝关节到跗骨；3分：中度水肿和发红，从踝关节到跖骨；4分：严重水肿和发红，从脚踝到整个脚面、脚趾，或者踝关节或腕关节僵直)，对每只小鼠的四肢进行评分后加和，最高评分为16分(4×4)。
根据关节炎评分进行分组，共分为3组，分别为1组模型对照组和2组给药组，每组5到7只小鼠，治疗开始时每组小鼠关节炎严重程度评分的平均值约1-2分。分别设计3mg/kg和10mg/kg两种剂量，口服，每天给药1次，连续给药14天。同时设置正常对照组，测试结果和正常对照组、模型对照组的结果进行比较，以确定待测化合物对该模型的关节炎治疗效果。
通过对关节炎严重程度分数的对比，证实本发明的化合物132在设定的给药剂量下，在CIA模型中有很好的关节炎治疗作用，并呈现剂量依赖性。
结果见图2。
测试实施例6：佐剂性大鼠关节炎模型(AIA)
准确称量100mg灭活的结核分枝杆菌(购自BD Difco，货号：231141)，溶于5mL不完全弗氏佐剂(IFA)(购自Sigma，货号：F5506)，然后加入5mL生理盐水，均质乳化成10mg/mL的完全弗氏佐剂(CFA)。为了诱导大鼠AIA模型，取SPF级的Lewis大鼠50只(购自北京维通利华实验动物技术有限公司(Vital River Laboratories(VRL)，动物生产许可证号码：SCXK(京)2012-0001)，雄性，体重180-200克，适应性饲养7天后，在大鼠尾根部注射含灭活的结核分枝杆菌(H37RA，10mg/ml)的完全弗氏佐剂0.1ml/只，进行大鼠关节炎的诱导。同时，留取3只未免疫大鼠为正常对照组。关节炎严重程度按照0-4分评价如下：0＝无红斑或红肿；l＝轻微的红斑或肿胀，其中的一个足趾关节有红斑或肿胀；2＝多于一只趾出现红斑或肿胀；3＝踝或腕关节的肿胀；4＝包括踝关节在内的全部足趾的肿胀。其中大鼠四只足趾分别评分，最高评分为16。
采用足趾容积仪排水法测量大鼠的足趾体积，测定自踝关节以下的容积(mL)(PV-200型足趾容积测量仪，成都泰盟科技有限公司)。大鼠足趾体积从免疫第10天，也就是给药第一天起开始测量，每两天测量一次。每只大鼠测出的四肢体积相加，再除以4，以得到平均值。分别设计30mg/kg和100mg/kg两种剂量，口服，每天给药1次，连续给药7天。同时，设置正常对照组和模型对照组，测试结果和正常对照组、模型对照组的结果进行比较，以确定待测化合物对该模型的关节炎治疗效果。
通过对关节炎严重程度分数的对比，证实本发明的化合物132在设定的给药剂量下，在AIA模型中有很好的关节炎治疗作用。
结果见图3。

Claims (27)

  1. 一种化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式I：
    Figure PCTCN2014086820-appb-100001
    其中：
    R选自被-NR2W取代的C3-8环烷基；4-10元饱和的氮杂环基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；或被4-10元饱和的氮杂环基取代的C1-4烷基，其中该氮杂环基环上仅含一个氮原子，且该氮原子被W取代；
    W选自
    Figure PCTCN2014086820-appb-100002
    V选自C或N；
    X选自于NR4、O或S；
    Y选自CH、S或O；
    Z选自CH、S、O或NR5；
    R1选自于C6-12芳基或5-12元杂芳基，其任选地被一个或多个R6取代；
    R2选自于氢或C1-8脂烃基；
    R3a、R3b和R3c独立地选自于氢、卤素或二(C1-8脂烃基)氨基甲基；
    R4选自于氢或C1-8脂烃基；
    R5选自于氢或C1-8脂烃基；
    每个R6独立地选自卤素、硝基、氰基、杂环基、C6-12芳基、5-12元杂芳基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)膦酰基C1-8脂烃基、羟基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基C1-8脂烃基氧 基、C1-8脂烃基氨基C1-8脂烃基氧基、二(C1-8脂烃基)氨基C1-8脂烃基氧基、C1-8脂烃基酰基氨基C1-8脂烃基氧基、C1-8脂烃基羰基C1-8脂烃基氧基、氨基酰基C1-8脂烃基氧基、C1-8脂烃基氨基酰基C1-8脂烃基氧基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、杂环基C1-8脂烃基氨基、羟基C1-8脂烃基氨基、C1-8脂烃基氧基C1-8脂烃基氨基、氨基C1-8脂烃基氨基、C1-8脂烃基氨基C1-8脂烃基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基酰基氨基C1-8脂烃基氨基、C1-8脂烃基羰基C1-8脂烃基氨基、氨基酰基C1-8脂烃基氨基、C1-8脂烃基氨基酰基C1-8脂烃基氨基、二(C1-8脂烃基)氨基酰基C1-8脂烃基氨基、C1-8脂烃基酰基氨基、杂环基C1-8脂烃基酰基氨基、杂环基酰基氨基、羟基C1-8脂烃基酰基氨基、C1-8脂烃基氧基C1-8脂烃基酰基氨基、氨基C1-8脂烃基酰基氨基、C1-8脂烃基氨基C1-8脂烃基酰基氨基、二(C1-8脂烃基)氨基C1-8脂烃基酰基氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、杂环基C1-8脂烃基氧基羰基、二(C1-8脂烃基)氨基C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、杂环基C1-8脂烃基氨基酰基、杂环基氨基酰基、羟基C1-8脂烃基氨基酰基、C1-8脂烃基氧基C1-8脂烃基氨基酰基、氨基C1-8脂烃基氨基酰基、C1-8脂烃基氨基C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基酰基、C1-8脂烃基巯基、杂环基巯基、杂环基C1-8脂烃基巯基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、杂环基C1-8脂烃基氨基磺酰基、杂环基氨基磺酰基、二(C1-8脂烃基)氨基C1-8脂烃基氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基C1-8脂烃基氨基亚磺酰基、杂环基氨基亚磺酰基、二(C1-8脂烃基)膦酰基，其中：
    杂环基，作为独立的基团或其它基团的一部分，表示含有一个或多个选自N、O、S的杂原子的饱和或部分不饱和的3-12元杂环基团，每个杂环基任选独立地被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、杂环基、5-12元杂芳基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、C1-8脂烃基羰基、杂环基羰基、杂环基C1-8脂烃基羰基、羟基C1-8脂烃基羰基、C1-8脂烃基氧基C1-8脂烃基羰基、二(C1-8脂烃基)氨基C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、杂环基磺酰基、杂环基亚磺酰基、杂环基C1-8脂烃基磺酰基、杂环基C1-8脂烃基亚磺酰基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基；
    C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自以下的取代基取代：卤 素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基或二(C1-8脂烃基)氨基；
    其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，该化合物具有结构式Ia：
    Figure PCTCN2014086820-appb-100003
    其中，X、Y、Z、W、R1和R2均如权利要求1中所定义。
  3. 根据权利要求2所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    R1选自于苯基或5-12元杂芳基，其任选地被一个或多个R6取代；
    每个R6独立地选自卤素、杂环基、C1-8脂烃基、C1-8卤代脂烃基、杂环基C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、C1-8脂烃基氧基、杂环基氧基、杂环基C1-8脂烃基氧基、羟基C1-8脂烃基氧基、C1-8脂烃基氧基C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基、杂环基氨基、二(C1-8脂烃基)氨基C1-8脂烃基氨基、C1-8脂烃基羰基、杂环基羰基、C1-8脂烃基氨基酰基、杂环基氨基酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基或杂环基氨基亚磺酰基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或多个选自以下的取代基取代：卤素、C1-8脂烃基、羟基、C1-8脂烃基氧基、氨基、C1-8脂烃基氨基、二(C1-8脂烃基)氨基和C1-8脂烃基羰基；
    其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  4. 根据权利要求2或3所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中R1选自于：
    Figure PCTCN2014086820-appb-100004
  5. 根据权利要求2至4中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2014086820-appb-100005
    Figure PCTCN2014086820-appb-100006
  6. 根据权利要求1所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中所述化合物具有结构式Ib：
    Figure PCTCN2014086820-appb-100007
    其中：
    X、Y、Z、W、R1均如权利要求1中所定义；
    l选自0、1、2、3或4，其中当l是0时，
    Figure PCTCN2014086820-appb-100008
    为
    Figure PCTCN2014086820-appb-100009
    m选自于0、1、2、3或4；其中当m是0时，
    Figure PCTCN2014086820-appb-100010
    为
    Figure PCTCN2014086820-appb-100011
    n选自于0、1、2或3；其中当n是0时，
    Figure PCTCN2014086820-appb-100012
    为
    Figure PCTCN2014086820-appb-100013
  7. 根据权利要求6所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    R1为5-6元杂芳基，其任选地被一个或多个R6取代；
    每个R6独立地选自卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基独立地任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；C6-12芳基或5-12元杂芳基任选被一个或多个选自卤素或C1-8脂烃基的取代基取代，
    其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  8. 根据权利要求6或7所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中R1为5元杂芳基，优选选自吡咯基、吡唑基、咪唑基、噻吩基、异噁唑基、噻唑基或异噻唑基，并且R1任选被一个或两个R6取代；每个R6独立地选自C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基或杂环基，其中杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的5-6元杂环基团，每个杂环基独立地任选被一个或多个选自C1-8脂烃基的取代基取代，其中C1-8脂烃基独立地选自C1-8烷基和C3-8环烷基。
  9. 根据权利要求6至8任一项所述的化合物或其立体异构体、互变异构体、溶剂化 物或其药学上可接受的盐，其中R1选自于：
    Figure PCTCN2014086820-appb-100014
  10. 根据权利要求6至9中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中所述化合物选自于：
    Figure PCTCN2014086820-appb-100015
    Figure PCTCN2014086820-appb-100016
    Figure PCTCN2014086820-appb-100017
    Figure PCTCN2014086820-appb-100018
  11. 根据权利要求1所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中所述化合物具有结构式Ic：
    Figure PCTCN2014086820-appb-100019
    其中：
    X、W、R1均如权利要求1中所定义；
    l选自于0、1、2、3或4；其中当l是0时，
    Figure PCTCN2014086820-appb-100020
    为
    Figure PCTCN2014086820-appb-100021
    m选自于0、1、2、3或4；其中当m是0时，
    Figure PCTCN2014086820-appb-100022
    为
    Figure PCTCN2014086820-appb-100023
    n选自于0、1、2或3；其中当n是0时，
    Figure PCTCN2014086820-appb-100024
    为
    Figure PCTCN2014086820-appb-100025
  12. 根据权利要求11所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    R1为5-6元杂芳基，其任选地被一个或多个R6取代；
    每个R6独立地选自于卤素、硝基、氰基、C1-8脂烃基、C1-8卤代脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基C1-8脂烃基、C1-8脂烃基氧基羰基C1-8脂烃基、C1-8脂烃基羰基氧基C1-8脂烃基、氨基酰基C1-8脂烃基、C1-8脂烃基氨基酰基C1-8脂烃基、二(C1-8脂烃基)氨基酰基C1-8脂烃基、C1-8脂烃基酰基氨基C1-8脂烃基、C1-8脂烃基磺酰基C1-8脂烃基、C1-8脂烃基亚磺酰基C1-8脂烃基、C1-8脂烃基磺酰基氨基C1-8脂烃基、氨基磺酰基C1-8脂烃基、C1-8脂烃基氨基磺酰基C1-8脂烃基、二(C1-8脂烃基)氨基磺酰基C1-8脂烃基、C1-8脂烃基羰基、C1-8脂烃基氧基羰基、氨基酰基、C1-8脂烃基氨基酰基、二(C1-8脂烃基)氨基酰基、C1-8脂烃基氧基、C1-8脂烃基磺酰基、C1-8脂烃基亚磺酰基、C1-8脂烃基磺酰基氨基、氨基磺酰基、C1-8脂烃基氨基磺酰基、二(C1-8脂烃基)氨基磺酰基、氨基亚磺酰基、C1-8脂烃基氨基亚磺酰基、二(C1-8脂烃基)氨基亚磺酰基、杂环基氨基亚磺酰基、杂环基、C6-12芳基或5-12元杂芳基，其中：
    杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自以下的取代基取代：卤素、羟基、C1-8脂烃基、C1-8脂烃基氧基或C1-8脂烃基羰基；
    C6-12芳基和5-12元杂芳基独立地任选被一个或多个选自卤素或C1-8脂烃基的取代基取代，
    其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  13. 根据权利要求11或12所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中：
    R1为5元杂芳基，其任选地被一个或两个R6取代；
    每个R6独立地选自于C1-8脂烃基、羟基C1-8脂烃基、C1-8脂烃基氧基C1-8脂烃基、氨基C1-8脂烃基、C1-8脂烃基氨基C1-8脂烃基、二(C1-8脂烃基)氨基C1-8脂烃基、杂环基C1-8脂烃基、C1-8脂烃基羰基或杂环基，其中，杂环基，作为独立的基团或其它基团的一部分，表示含有一个或两个选自N、O、S的杂原子的饱和或部分不饱和的3-8元杂环基团，每个杂环基任选被一个或多个选自C1-8脂烃基的取代基取代；
    其中，C1-8脂烃基在每次出现时独立地选自C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基和C4-8环烯基。
  14. 根据权利要求11至13中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中R1选自于：
    Figure PCTCN2014086820-appb-100026
  15. 根据权利要求11至14中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2014086820-appb-100027
  16. 一种药物组合物，包含如权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐以及药学上可接受的辅料。
  17. 根据权利要求16所述的药物组合物，还包含一种或多种选自以下的药物：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
  18. 如权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备抑制BTK和/或JAK3活性的药物中的用途。
  19. 如权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐在制备用于预防或治疗由BTK和/或JAK3介导的疾病的药物中的用途。
  20. 根据权利要求19所述的用途，其中所述疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病和癌症。
  21. 根据权利要求19所述的用途，其中所述疾病选自类风湿性关节炎、骨关节炎、青少年关节炎、慢性阻塞性肺疾病、多重硬化、系统性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎和肠道易激综合症。
  22. 根据权利要求21所述的用途，其中所述癌症选自B细胞性慢性淋巴细胞白血病、急性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓性白血病、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤。
  23. 一种在生物体系中抑制BTK和/或JAK3活性的方法，包含使生物体系接触权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐或权利要求16或17所述的药物组合物。
  24. 根据权利要求23所述的方法，其中所述生物体系是酶、细胞或哺乳动物。
  25. 一种预防或治疗BTK和/或JAK3介导的疾病的方法，包含给予有需要的受试者 治疗有效剂量的权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐或权利要求16或17所述的药物组合物。
  26. 根据权利要求25所述的方法，其中所述疾病选自自身免疫性疾病、炎性疾病、异种免疫性情况或疾病、血栓栓塞疾病或癌症。
  27. 权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐与一种或多种选自以下的活性物质在制备用于治疗BTK和/或JAK3介导的疾病的药物中的应用：免疫抑制剂、糖皮质激素、非甾体抗炎药、Cox-2特异性抑制剂、TNF-α结合蛋白、干扰素和白细胞介素。
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