WO2019057112A1 - 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用 - Google Patents

2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用 Download PDF

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WO2019057112A1
WO2019057112A1 PCT/CN2018/106694 CN2018106694W WO2019057112A1 WO 2019057112 A1 WO2019057112 A1 WO 2019057112A1 CN 2018106694 W CN2018106694 W CN 2018106694W WO 2019057112 A1 WO2019057112 A1 WO 2019057112A1
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amino
pyrimidine
pyrazol
carboxamide
methyl
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PCT/CN2018/106694
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French (fr)
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张强
刘彦生
李兰涛
李兴福
胡晨明
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北京赛特明强医药科技有限公司
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Priority to US16/642,552 priority Critical patent/US11344549B2/en
Priority to CA3076276A priority patent/CA3076276C/en
Priority to EP18857913.0A priority patent/EP3686197B1/en
Priority to AU2018337138A priority patent/AU2018337138B2/en
Priority to JP2020516537A priority patent/JP7117029B2/ja
Publication of WO2019057112A1 publication Critical patent/WO2019057112A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention belongs to the field of chemical medicine, and in particular relates to a compound having JAK kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and pharmaceutical compositions containing the same and these compounds Or the use of a composition in the preparation of a medicament.
  • JAK kinase and its downstream effectors, signal transduction and activator proteins form an important cytokine signaling pathway, the JAK-STAT pathway.
  • JAK-STAT pathway can be activated by a variety of cytokines, growth factors and receptors, involved in cell proliferation, differentiation, apoptosis, angiogenesis and immune regulation.
  • JAK kinase is a key kinase in the JAK-STAT signaling pathway.
  • JAK kinase inhibitor (tofacitinib) was approved for the treatment of rheumatoid arthritis in 2012 [Norman] P., Selective JAK inhibitors in development for rheumatoid arthritis, Expert Opin Investig Drugs, 2014, 23: 1067-1077].
  • JAK1 is a kinase domain, highly conserved in the JAK family
  • JH2 is a kinase-like region or a "pseudo" kinase domain, the pseudokinase domain It is a unique property of JAK protein which is different from other tyrosine proteins.
  • JH3-JH4 is the SH2 domain (Src homology 2 domain), which contains about 100 amino acid residues, which can specifically recognize and bind to phosphorylated tyrosine residues on the ligand.
  • JH5-JH7 is a FERM domain, which is conserved and mainly regulates the binding of JAK to the receptor.
  • JAK3 structurally contains the above-mentioned kinase domain, and mutations of specific amino acids in different domains also cause changes in its kinase activity.
  • JAK-STAT signaling pathway is an important intracellular signal transduction pathway in the process of cell growth, activation, differentiation, apoptosis and its function.
  • STAT is a cytoplasmic protein that binds to the DNA of the target gene regulatory region and is a downstream substrate for JAK.
  • the STAT family includes seven members including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.
  • the interaction between JAKs and STATs plays an important role in the cytokine receptor signaling pathway [O'Sullivan LA et al., Cytokine receptor signaling through the JAK-Stat-Socs pathway in disease, Mol Immunol, 2007, 44: 2497-2506].
  • the JAK-STAT signaling pathway is a signal transduction pathway stimulated by a variety of cytokine receptors. JAK kinase mediates the signaling of most cytokines in cells, such as interleukin (IL) and interferon (IFN).
  • IL interleukin
  • IFN interferon
  • EPO Erythropoietin
  • GMCSF granulocyte and macrophage colony-stimulating factor
  • GH somatotropin
  • PRL prolactin
  • TPO thrombopoietin
  • PDGF platelet-derived factor
  • EGF epidermal cells Growth factors
  • JAK1 and JAK2 are expressed in various tissues of human body.
  • JAK3 is mainly expressed in various hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells, activated B lymphocytes and T lymphocytes. Deletions such as JAK1 and JAK2 cause fatal damage in humans, and loss of JAK3 can avoid toxic adverse reactions that damage other tissue cells [Yamaoka K., et al., JAK3 negatively regulates dendritic-cell cytokine production and survival, Blood, 2005, 106 :3227-3233]. Based on the functional characteristics of various subtypes of the JAK kinase family and specific tissue distribution, JAK3 has become a popular target for the treatment of autoimmune diseases.
  • Tofacitinib has shown good clinical efficacy in clinical studies. In the clinical trial of rheumatoid arthritis, the 5 mg or 10 mg Tofacitinib measurement group showed significant statistical differences compared with the same placebo group, but it was found in clinical trials. The use of Tofacitinib is associated with an increased risk of serious infections, and its long-term safety remains to be further studied.
  • JAK-STAT signaling pathway plays an important role in cell differentiation and proliferation. Changes in JAK activity will also lead to changes in signaling pathways in this pathway, which in turn affect cell function. Based on the key role of JAK kinase in JAK-STAT signaling, and the specific tissue cell distribution of JAK3 kinase, JAK3 is a good therapeutic target for diseases such as rheumatoid arthritis.
  • JAK3 inhibitors are mainly used for the treatment of patients with moderate to severe rheumatoid arthritis. These drugs show good therapeutic effect and good safety in treatment, but their long-term safety needs to be further improved. During the clinical study of Tofacitinib, it was found that the use of this drug may cause certain adverse reactions, including infection, tuberculosis, tumor and liver damage. Therefore, improving the efficacy and reducing side effects of JAK3 inhibitors is a key issue to be solved in this research field. .
  • JAK kinase Several subtypes of JAK kinase have high ATP binding site homology and small structural differences, which is an important reason for the low selectivity of JAK inhibitors. There is still room for improvement in the efficacy, selectivity, and safety of a series of published JAK kinase inhibitors, and there is still a need to develop a more effective and safer JAK inhibitor.
  • highly selective JAK inhibitors are currently the focus of research in the field, in view of the fact that each member of the JAK kinase family is closely related to JAK-STAT signaling, pan-JAK inhibitors will significantly improve the efficacy and greatly reduce the dose. To achieve the purpose of controlling toxic side effects.
  • a significant increase in efficacy will help to develop anti-inflammatory drugs that are administered transdermally.
  • the development of such drugs will be autoimmune diseases such as psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, and leukemia, lymphoma, and multiple
  • the treatment of cancers such as myeloma provides new avenues.
  • the compounds of the invention exhibit excellent biological activity as JAK kinase inhibitors.
  • the present invention provides a 2-(1-substituted pyrazole-4-)amino-4-substituted amino-5-pyrimidinecarboxamide compound, and a preparation thereof for use in the preparation of a therapeutic or prophylactic tyrosine kinase (eg, JAK1) Use of a drug for a disease caused by JAK2, JAK3, TYK2) or a variant thereof.
  • a therapeutic or prophylactic tyrosine kinase eg, JAK1
  • the present invention provides a compound, or an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or in the form of a pharmaceutical composition of an effective polymorphic form thereof, which has the structural formula (I):
  • R 1 is n 1 is 0-1, n 2 is 0-1, and n 3 is 0-5.
  • L 1 is R 4 and/or R 5 is H, C 1 -C 3 linear alkyl
  • R 2 is n 4 is 0-3, n 5 is 0-1, and n 6 is 0-5.
  • L 2 is R 7 and/or R 8 are H, C 1 -C 3 linear alkyl
  • a 5-7 membered heterocyclic ring preferably the 5-7 membered heterocyclic ring contains 1-2 heteroatoms, the hetero atom of which is selected from O and/or N and/or S, when the heteroatom is N, N H or C 1 -C 4 alkyl, C 1 -C 3 acyl, preferably acetyl, trifluoroacetyl, propionyl, N,N-diformyl, when the hetero atom is S, S is attached to 0 - 2 oxygen atoms,
  • a substituted or unsubstituted five-membered aryl or heteroaryl group preferably, the structural formula of the substituted or unsubstituted five-membered aryl or heteroaryl group is Wherein: J 1 and/or J 2 and/or J 3 and/or J 4 are C, N, S, O; R 9 is a C 1 -C 3 linear or branched alkyl group,
  • J 1 , J 2 , J 3 , and J 4 are each independently C, N, S, and O,
  • R 20 and R 21 are each independently a C 1 -C 3 linear or branched alkyl group
  • the structural formula of the substituted or unsubstituted six-membered aryl or heteroaryl group is among them:
  • Q 1 , Q 2 , Q 3 , Q 4 , Q 5 are N or C;
  • R 10 and/or R 11 and/or R 12 are:
  • R', R" are H, C 1 -C 3 alkyl
  • R 15 and R 16 are linear alkyl groups
  • Q 1 , Q 2 , Q 3 , Q 4 , Q 5 are N or C;
  • R 17 and R 18 are each independently:
  • R', R" are H, C 1 -C 3 alkyl
  • R 13 is H, C 1 -C 3 alkyl
  • R 15 and R 16 are C 1 -C 3 linear alkyl groups
  • a 5- or 6-membered ring containing 0-3 heteroatoms of a 6-membered aromatic ring and a 5- or 6-membered heterocyclic ring containing 1-3 heteroatoms preferably from:
  • R', R" are H, C 1 -C 3 alkyl
  • heterocyclic group preferably, the heterocyclic group is a 5- or 6-membered heterocyclic group containing oxygen and/or nitrogen, such as
  • the present invention also provides a compound, or an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, which has the structural formula (I):
  • R 1 is n 1 is 0-2, n 2 is 0-1, and n 3 is 0-5.
  • L 1 is R 4 and/or R 5 is H, C 1 -C 3 linear alkyl
  • R 2 is n 4 is 0-3, n 5 is 0-1, and n 6 is 0-5.
  • L 2 is R 7 and/or R 8 are H, C 1 -C 3 linear alkyl
  • R 3 is R 22 -substituted C 1 -C 3 alkoxy or R 22 -substituted C 1 -C 3 alkylthio
  • R 22 is hydroxy, C 1 -C 3 alkoxy, C 1 -C 3 alkane a group, -NR'R", a hydroxy-substituted C 1 -C 3 alkoxy group, an amino-substituted C 1 -C 3 alkoxy group, a hydroxy-substituted C 1 -C 3 alkylthio group, an amino-substituted C 1 - a C 3 alkylthio group, wherein R', R" are H, C 1 - C 3 alkyl;
  • R 6 is a) H, hydroxyl
  • R', R" are H, C 1 -C 3 alkyl
  • One aspect of the present invention provides an alkenyl group-containing pyrimidinecarboxamide compound, an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, which has the structural formula (I):
  • n 1 is an integer of 0-8, n 2 is an integer of 0-1, n 3 is an integer of 0-8, and the sum of n 1 , n 2 , n 3 is 10 or less;
  • R 4 and R 5 are each independently H, C 1 -C 3 alkyl, and R 4 and R 5 are the same or different.
  • R 3 is an unsubstituted or C 1 -C 3 alkyl substituted C 2 -C 8 alkenyl group or an unsubstituted or C 1 -C 3 alkyl substituted C 4 -C 8 cycloalkenyl group;
  • n 4 is an integer of 0-8, n 5 is an integer of 0-1, n 6 is an integer of 0-8, and the sum of n 4 , n 5 , n 6 is 10 or less;
  • R 7 and R 8 are each independently H, C 1 -C 3 alkyl, and R 7 and R 8 are the same or different.
  • R 6 is -H, hydroxyalkyl, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxyalkyl, C 1 -C 5 alkylthioalkyl, 5 to 6 membered heterocyclic group, or -NR'R ", wherein R ', R" are each independently H, C 1 -C 3 alkyl is.
  • R 3 is
  • R 9 , R 10 , R 11 , R 12 and R 13 are each independently H, C 1 -C 3 alkyl, and m is an integer of 0 to 2.
  • n 1 is an integer of 0 to 5
  • m 2 is an integer of 0 to 5
  • the sum of m 1 , m 2 is less than or equal to 5.
  • n 1 is an integer of 0-2
  • n 2 is a 0-1 integer
  • n 3 is an integer of 0-3
  • R 4 and R 5 are each independently H, methyl, R 4 and R 5 are the same or different;
  • R 9 , R 10 , R 11 , R 12 and R 13 are each independently H, methyl or ethyl, and m is 0 or 1. More preferably, the sum of n 1 , n 2 , and n 3 is 5 or less.
  • R 9 , R 11 , R 12 and R 13 are each independently H, methyl or ethyl.
  • R 3 is
  • R 9 and R 10 are each independently H, C 1 -C 3 alkyl, and any of R 11 , R 12 and R 13 is C 4 -C 6 alkyl, and the others are each independently H, C 1 -C 3 alkyl, m is an integer from 0 to 2.
  • n 4 is an integer of 0-3, n 5 is a 0-1 integer, n 6 is an integer of 0-5, and R 7 and R 8 are each independently H, methyl, R 7 and R 8 are the same or different;
  • R 6 is -H, hydroxyethyl, hydroxypropyl, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxyethyl, C 1 -C 5 alkoxy A propyl group, a C 1 -C 5 alkylthioethyl group, a 5-6 membered heterocyclic group, or —NR′R′′, wherein R′ and R′′ are each independently H, C 1 -C 3 alkyl. More preferably, the sum of n 4 , n 5 , and n 6 is 5 or less.
  • R 6 is H, hydroxyethyl, hydroxypropyl, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl , isopropoxypropyl, methylthioethyl, ethylthioethyl, propylthioethyl, isopropylthioethyl, 5-6 membered heterocyclyl, or -NR'R", wherein R ', R" are independently H, methyl, ethyl;
  • the 5-6 membered heterocyclic group is unsubstituted or substituted with 1-2 substituents selected from a hydroxyl group, a C 1 -C 3 alkyl group, a C 1 -C 3 acyl group, and contains 1-2 selected from N a heterocyclic group of a hetero atom of O or S.
  • heterocyclic group having 1 to 2 hetero atoms selected from N, O, and S is any one selected from the group consisting of the following:
  • R 14 is H, methyl, ethyl, propyl or isopropyl.
  • the pharmaceutically acceptable salt of the pyrimidinecarboxamide compound is a hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate selected from the compound , nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, Fumar Acid salt, gluconate, benzoate, mandelate, methanesulfonate, isethionate, besylate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluene Acid salt, cyclohexylamine sulfonate, salicylate, hexanoate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylene
  • Another aspect of the invention relates to the pyrimidinecarboxamides, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof for the preparation of therapeutic and tyrosine kinases JAK1, JAK2, JAK3,
  • autoimmune diseases associated with tyrosine kinases JAK1, JAK2, JAK3, TYK2, and cancers include fundus diseases, dry eye syndrome, psoriasis, vitiligo , dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small Cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pyrimidine carboxamide compound, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and One or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may also include one or more additional therapeutic agents.
  • Alkyl means an aliphatic hydrocarbon group. Alkyl groups are saturated or unsaturated. The alkyl moiety, whether saturated or unsaturated, can be branched or straight chain. "Alkyl” may have from 1 to 5 carbon atoms, preferably from 1 to 3 carbon atoms. In one aspect, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, allyl, Vinyl, acetylene, but-2-enyl, but-3-enyl and the like.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each atom (ie, a backbone atom) that constitutes a ring is a carbon atom.
  • the cycloalkyl group can be saturated or partially unsaturated.
  • the cycloalkyl group may be fused to the aromatic ring and the point of attachment is on a carbon other than the aromatic ring carbon atom.
  • the cycloalkyl group includes a group having 3 to 10 ring atoms.
  • the cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • the cycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group may be a monovalent group or a divalent group (ie, a cycloalkylene group such as, but not limited to, cyclopropane-1,1-diyl, cyclobut-1,1-diyl, cyclopentyl) -1,1-diyl, cyclohex-1,1-diyl, cyclohexa-1,4-diyl, cyclohepta-1,1-diyl, etc.).
  • the cycloalkyl is a C 3 -C 6 cycloalkyl.
  • Alkenyl or “cycloalkenyl” refers to a straight or cyclic hydrocarbon chain radical consisting solely of carbon atoms and hydrogen atoms containing at least one double bond.
  • Alkoxyalkyl means an (alkyl)O(alkyl)- group and "alkylthio" means an (alkyl)S(alkyl)- group wherein alkyl is as defined herein.
  • the alkoxyalkyl group is a C 1 -C 5 alkoxyalkyl group, more preferably a C 1 -C 5 alkoxy C 1 -C 3 alkyl group, more preferably a C 1 -C 5 alkane Oxyethyl or C 1 -C 5 alkoxypropyl.
  • the alkylthioalkyl group is a C 1 -C 5 alkylthioalkyl group, more preferably a C 1 -C 5 alkylthio C 1 -C 3 alkyl group, more preferably a C 1 -C 5 alkane Thioethyl.
  • heterocyclyl refers to an aromatic heterocycle (also referred to as heteroaryl) and a heterocycloalkyl ring (also known as heteroaliphatic) containing one or more heteroatoms in the ring.
  • a cyclic group wherein each heteroatom in the ring is selected from the group consisting of O, S and N, wherein each heterocyclic group contains 5-6 atoms in its ring system.
  • the 5-6 membered heterocyclic group may be unsubstituted or substituted with 1-2 substituents selected from a hydroxyl group, a C 1 -C 3 alkyl group, a C 1 -C 3 acyl group, and 1-2 selected from the group consisting of a heterocyclic group of a hetero atom of N, O or S.
  • heterocyclic group having 1 to 2 hetero atoms selected from N, O, and S is any one selected from the group consisting of the following:
  • R 14 is H, methyl, ethyl, propyl or isopropyl.
  • “Stereoisomers” are isomers in which only atoms are arranged in a different manner in space. Certain compounds described herein contain one or more asymmetric centers and, therefore, may give rise to enantiomers, diastereomers, and other stereoisomers that may be defined as (R)- or (S)- depending on absolute stereochemistry. form.
  • the chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation assays, and the degree of advantage of one stereoisomer over other isomers can be determined.
  • the structure contains a chiral carbon atom.
  • the structure is meant to include all possible isomers, including racemic mixtures, optically pure forms of optically active (R)- and (S)-isomers, etc., ie, when R 4 and R 5 are different, L 1 is include And racemate; when R 7 and R 8 are different, L 2 is include And racemates.
  • Tautomers are structurally distinct isomers that are interchangeable by tautomerization.
  • Tautomerization is a form of isomerization and includes proton shifting or proton transfer tautomerization, which is considered a subset of acid-base chemistry.
  • Proton-shifting tautomerization or “proton-transfer tautomerization” refers to proton migration accompanied by a bond-level transformation, often the exchange of a single bond with an adjacent double bond.
  • tautomerization is possible (for example, in solution), the chemical equilibrium of the tautomers can be achieved.
  • An example of tautomerization is keto-enol tautomerization.
  • the compounds, isomers, crystals or prodrugs of the formula (I) and pharmaceutically acceptable salts thereof may exist in solvated as well as unsolvated forms.
  • the solvated form can be in a water soluble form.
  • the invention includes all such solvated and unsolvated forms.
  • One aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I).
  • the composition can be applied to autoimmune diseases such as psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, leukemia, lymphoma, multiple Cancers such as myeloma, including those that are resistant to treatment with Tofacitinib, Pefitintinib, Decernotinib or other kinase inhibitors, are resistant to autoimmune diseases, cancer, and the like.
  • autoimmune diseases such as psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, leukemia,
  • It is a further object of the present invention to provide a method for treating an autoimmune disease and cancer comprising administering to a subject a method of administering a therapeutically effective amount of a composition comprising a compound of the present invention.
  • Autoimmune diseases, cancers that can be treated as such are noted elsewhere herein, including autoimmune diseases, cancers, and the like that are resistant to treatment with Tofacitinib, Pefitintinib, Roxolitinib, Decernotinib, or other kinase inhibitors.
  • One or more other therapies may also be used in combination with cancer treatment, including surgery, radiation therapy (such as gamma-ray, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes).
  • radiation therapy such as gamma-ray, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.
  • Endocrine therapy biological response modifiers (eg, interferons, interleukins and tumor necrosis factor (TNF)), hyperthermia, cryotherapy, attenuating any adverse effects (eg, antiemetics), and other therapeutic agents.
  • TNF tumor necrosis factor
  • the invention further encompasses the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a fundus disease, dry eye, psoriasis, rheumatoid arthritis, rash, eczema, alopecia areata, atherosclerosis Agents for autoimmune diseases such as pulmonary fibrosis, liver fibrosis, myelofibrosis, enteritis, and diseases such as tumors, including treatment of resistance to one or more other therapeutic agents as indicated elsewhere herein. disease.
  • the compounds of the invention are also useful for reducing or preventing disease in a drug by inhibiting one or more kinases (e.g., JAK1, JAK2, JAK3, TYK2).
  • the present invention also provides a method of preparing the corresponding compound, and specific examples can be prepared by the following exemplary methods.
  • the synthetic route for the series (I) compounds is as follows:
  • Reagents and reaction conditions (a) DIEA, THF; (b) s-BuOH, TFA.
  • Step 2) Preparation of 4-benzylamino-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide:
  • Step 2) Preparation of 4-[(2-methoxybenzyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide:
  • Step 2) 4-[(2-Fluoro-6-methoxybenzyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide preparation:
  • Step 2) 4-[(2,6-Dimethylbenzyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino] 4.74 (s, 2H), 3.90 (s, 3H), 2.32 (s, 6H).
  • LCMS: m/z 352.2 (M+H) + .
  • Step 2) Preparation of 4-[(2,6-dichlorobenzyl)amino]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide:
  • Step 2) 4-[(2,6-Difluorobenzyl)amino]-2-[[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino]pyrimidine-5 -
  • Step 2) 4-[(2-Fluoro-6-methoxybenzyl)amino]-2-[[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino]
  • pyrimidine-5-carboxamide 4-[(2-Fluoro-6-methoxybenzyl)amino]-2-[[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino]
  • Step 1) Step 2) and the same embodiment 8
  • Example 2 The synthesis of the subsequent specific examples was carried out in the same manner as in Example 1, and the corresponding intermediate A and the target compound B were synthesized in the same manner as in Example 1, using the starting materials having different substituents, as shown in Table 3 and Table 4 below.
  • Reaction conditions 1) R 1 CH 2 NH 2 , DIEA, THF, 25 ° C, 2 to 16 h; 2) TFA, s-BuOH, 60 ⁇ 100 ° C, 2 ⁇ 16h.
  • Step 2) 4-(Butyl-3-en-1-ylamino)-2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide preparation:
  • Example 228 The same procedure as in Example 228 was followed by replacing the step 1) with 2-methylpropyl-2-en-1-amine.
  • Step 1) Preparation of 2-chloro-4-((cyclopentyl-3-en-1-ylmethyl)amino)pyrimidine-5-carboxamide:
  • Step 2) 2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-4-((cyclopentyl-3-en-1-ylmethyl)amino)pyrimidine- Preparation of 5-formamide:
  • Example 237 4-((Cyclopentyl-3-en-1-ylmethyl)amino)-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole- Preparation of 4-yl)amino)pyrimidine-5-carboxamide:
  • Step 1 Same as Example 236) Step 1;
  • Step 2 4-((Cyclopentyl-3-en-1-ylmethyl)amino)-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4 Preparation of -yl)amino)pyrimidine-5-carboxamide:
  • Example 236, step 2 The same procedure as in Example 236, step 2), was used to replace 1-tert-butyl-1H-pyrazol-4-amine with 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine. A white solid was obtained.
  • Example 236 The same procedure as in Example 236 was carried out, using 3-methylbutyl-3-en-1-amine instead of cyclopentyl-3-en-1-ylmethylamine hydrochloride to give a white solid.
  • 1 H NMR 400MHz, DMSO- d 6) ⁇ 9.40 (s, 1H), 9.17 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.82-7.59 (m, 1H), 7.52 (s, 1H), 7.18-6.87 (m, 1H), 4.84-4.77 (m, 1H), 4.77-4.72 (m, 1H), 3.67-3.50 (m, 2H), 2.39-2.22 (m, 2H) ), 1.73 (s, 3H), 1.49 (s, 9H).
  • Example 236 The same procedure as in Example 236 was carried out, using 5-methylhexane-4-en-l-amine as the title compound as a white solid.
  • 1 H NMR 400MHz, DMSO- d 6) ⁇ 9.40 (s, 1H), 9.21 (s, 1H), 8.44 (s, 1H), 7.98 (s, 1H), 7.82-7.54 (m, 1H), 7.52 (s, 1H), 7.26-6.84 (m, 1H), 5.21-5.01 (m, 1H), 2.07-1.99 (m, 2H), 1.64 (s, 6H), 1.57-1.53 (m, 4H), 1.49 (s, 9H).
  • JAK3 As an example. The specific experimental conditions of JAK1, JAK2, JAK3, and TYK2 are described later.
  • EDTA (0.5M pH 8.0) solution preparation Accurately weigh 14.612g EDTA powder, add ultrapure water and dilute to 100mL (if insoluble, heat to 37 °C, adjust pH to 8.0 with 1N NaOH solution)
  • 1 ⁇ Kinase Assay Buffer Add 25 mL HEPES solution (1M), 190.175mg EGTA, 5mL MgCl 2 solution (1M), 1mL DTT, 50 ⁇ L Tween-20 to the reagent bottle, and add 500mL to the pH of the ultrapure water. To 7.5).
  • 1 ⁇ Detection Buffer Take 1 mL of 10 ⁇ Detection Buffer and add 9 mL of water to mix.
  • 4 ⁇ stop solution 0.8 mL of the above EDTA (0.5 M, pH 8.0) solution, 1 mL of 10 ⁇ Detection Buffer and 8.2 mL of ultrapure water were mixed.
  • 4 ⁇ JAK3 kinase solution The kinase stock solution was diluted with 1 ⁇ Kinase Assay Buffer to a concentration of 0.36 nM, mixed, and stored on ice.
  • 4 ⁇ ATP solution Dilute the ATP stock solution with 1 ⁇ Kinase Assay Buffer to a concentration of 40 ⁇ M and mix.
  • the detection antibody Europium-anti-phospho-tyrosine antibody (PT66) was diluted with 1 ⁇ Detection Buffer to a concentration of 8 nM and mixed.
  • 2 ⁇ substrate/ATP mixture 4 ⁇ substrate solution and 600 ⁇ l 4 ⁇ ATP solution were mixed in equal amounts (prepared before use).
  • the compound solution diluted with ultrapure water in the above 96-well plate was placed in a corresponding well of a 384-well plate according to a standard well of 2 duplicate wells.
  • Add 2 ⁇ substrate/ATP mixture Take 5 ⁇ l of the above 2 ⁇ substrate/ATP mixture into the corresponding reaction well of a 384-well plate with a lance.
  • Negative control a negative control well was placed in a 384-well plate, which was added with 2.5 ⁇ l/well 4 ⁇ substrate, 2.5 ⁇ l 4 ⁇ enzyme solution, 2.5 ⁇ l 1 ⁇ Kinase Assay Buffer, and 2.5 ⁇ l of 4% DMSO-containing super Pure water.
  • Inhibition rate [1- (experimental well reading - negative control well reading) / (positive control well reading - negative control well reading)] * 100%
  • the drug concentration and corresponding inhibition rate were input into the GraphPad Prism 5 treatment to calculate the corresponding IC 50 value.
  • JAK1 kinase activity test JAK1 kinase activity test
  • JAKl final concentration 10nM
  • ATP final concentration 10 ⁇ M
  • ULight TM -labeled JAK1 Tyr1023
  • Peptide final concentration 10OnM
  • enzymatic reaction time was 2 hours.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient with a minimum final concentration of 0.042 nM.
  • the final concentration of DMSO was 1%.
  • the JAK2 final concentration 0.25nM
  • ATP final concentration 5 ⁇ M
  • ULight TM -labeled JAK- 1 (Tyr1023) Peptide final concentration 50 nM
  • enzymatic reaction time was 1 hour.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient with a minimum final concentration of 0.042 nM.
  • the final concentration of DMSO was 1%.
  • JAK3 final concentration 0.36nM
  • ATP final concentration 10 ⁇ M
  • ULight TM -labeled JAK- 1 (Tyr1023) Peptide final concentration 50 nM
  • enzymatic reaction time was 1 hour.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient with a minimum final concentration of 0.042 nM.
  • the final concentration of DMSO was 1%.
  • TYK2 final concentration 8nM
  • ATP final concentration 20 ⁇ M
  • ULight TM -labeled JAK- 1 (Tyr1023) Peptide final concentration 10OnM
  • enzymatic reaction time was 2 hours.
  • the maximum final concentration of the compound was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient with a minimum final concentration of 0.042 nM.
  • the final concentration of DMSO was 1%.
  • Tables 6 and 7 show the results of measurement of the inhibitory activities of some of the compounds of the present invention against tyrosine kinases JAK1, JAK2, JAK3 and TYK2.
  • the IC 50 values in the table below indicate the concentration of the compound at the highest inhibition rate of the enzyme of 50%, and NT indicates that the corresponding enzyme was not tested.
  • HEL cells were treated with different concentrations of Tofacitinib and S1 compounds, and then stimulated with 100 ng/mL IL-4 to detect pSTAT5 signal by AlphaLISA.
  • the specific test methods are as follows:
  • Donor Mix For current use, mix Dilution Buffer and Donor Beads in a ratio of 49:1 and place on an ice box (low light operation, use within 30 minutes).
  • Positive control lysate lyophilized powder + 250 ⁇ L of water, which was dispensed (10.5 ⁇ L per tube) and stored at -20 °C. (Used within one month)
  • HEL cells Collect HEL cells, wash them three times with PBS (1000 rpm, 4 min), inoculate cells in a 96-well plate according to 100,000 cells/well/45 ⁇ L DMEM (no phenol red), and make two duplicate wells at each concentration. Cultivate for 1 h;
  • each well was added 15 ⁇ L of different concentrations of Tofacitinib, mixed with a row of guns and cultured for 1h;
  • Inhibition rate [1- (experimental well reading - negative control well reading) / (positive control well reading - negative control well reading)] * 100%
  • the drug concentration and corresponding inhibition rate were input into the GraphPad Prism 5 treatment to calculate the corresponding IC 50 value.
  • Table 9 Lists the results of quantitative AlphaLISA assays for phosphorylation of STAT5 in HEL cells by some of the compounds of the invention.
  • mice were euthanized with carbon dioxide, soaked in 75% alcohol for 1 minute, placed in a safety cabinet, and cut a small opening in the left ventral middle part of the mouse to expose the abdominal wall and find the spleen;
  • the cell suspension was inoculated into a 96-well plate, and each well was inoculated with 80 ⁇ l of a cell suspension having a density of 100,000 cells/well;
  • Table 10 and Table 11 List the results of tests on the proliferation inhibitory activity of the compounds of the present invention on mouse spleen cells, wherein A indicates an IC 50 of less than or equal to 100 nM, B indicates an IC 50 of greater than 100 nM but less than or equal to 500 nM, and C indicates an IC 50 . Greater than 500 nM but less than or equal to 1000 nM, D indicates an IC 50 greater than 1000 nM.
  • the biological data provided by the present invention indicate that the compounds of the present invention are useful for treating or preventing diseases caused by abnormalities of tyrosine kinases (JAK1, JAK2, JAK3, TYK2). More than one-fifth of the compounds of the present invention have been shown to strongly inhibit JAK tyrosine kinase activity, and the JAK kinase family is closely related to the occurrence and metastasis of autoimmune diseases and cancer.
  • JAK1, JAK2, JAK3, TYK2 tyrosine kinases
  • the compounds of the invention are useful in the treatment of autoimmune diseases including, but not limited to, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease.
  • the compounds of the invention are also advantageous for the treatment of cancer, including primary and metastatic cancers, including solid tumors.
  • Such cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma.
  • the compounds of the invention also include cancers that are resistant to one or more other therapeutic methods.
  • the compounds of the invention are also useful in diseases other than autoimmune diseases and cancer associated with JAK1 kinase and/or JAK2 and/or JAK3 kinase, including but not limited to fundus diseases, pulmonary fibrosis, liver fibrosis, and the like.
  • the compounds of the present invention may be administered as a monotherapy or a combination therapy, in combination with a plurality of compounds of the present invention or in combination with other drugs other than the present invention.
  • Pharmaceutical methods of the invention comprise determining a therapeutically effective amount of a subject in need of a compound of the invention.
  • the "therapeutically effective dose” will vary depending on the stage, progression or severity of the disease.
  • the daily dosage of the compounds and compositions of the present invention will depend on a variety of factors of the patient, including the condition being treated, the severity of the condition, the efficacy of the particular compound employed, the particular composition, age, weight, general Health status, gender and diet, route and schedule of administration, metabolism and/or excretion rate of the compound, duration of treatment, and the like.
  • the desired dose of the compound of the present invention can be administered to humans and other animals after it has been formulated with a pharmaceutically acceptable carrier.
  • Modes of administration include oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (e.g., by transdermal patches, powders, ointments, or drops), sublingual, buccal, or nasal sprays, and the like.
  • the effective dose of the compound of the present invention is usually measured in an amount per mg of the patient's body weight, preferably from 0.1 to 125 mg/kg of body weight, usually from 0.01 to 500 mg/kg of body weight.
  • Administration can be one or more times, daily, weekly, every other day or every other day, or an intermittent schedule. For example, the compound can be administered daily, weekly (eg, every Monday), indefinitely, or for several weeks (eg, 4-10 weeks).
  • the effective dosage of a compound of the invention will vary depending upon the compound employed, the mode of administration, the severity of the condition, the condition to be treated, and the various physical factors of the subject. In most cases, a satisfactory therapeutic effect can be achieved when the preferred dosage of the preferred compound of the invention is from about 0.01 to 500 mg/kg. A preferred dose is from 0.1 to 125 mg/kg, and a more preferred dose is from 1 to 25 mg/kg.
  • the parenteral dose is usually at an oral dosage level of about 10% to 20%.
  • the components of each composition will be administered during a desired treatment period. Whether as a separate dosage unit or as a single dosage form comprising two components, the components of the composition may be administered simultaneously during the treatment period, or may be administered at different times during the treatment period, or some may be pretreated as another Apply.
  • the compounds of the invention may be used in the free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment.
  • pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting a compound isolated and purified in the present invention with a suitable free base or acid.
  • a pharmaceutically non-toxic acid-forming salt including, but not limited to, with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,
  • a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid
  • These salts are obtained by the amino salt formed from succinic acid or malonic acid, or by using a method well known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentane, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphoric acid Salt, gluconate, hemisulfate, heptano, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectic acid Salt, persul
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and the use of such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • prodrug as used herein means that a compound can be converted into a compound of the formula (I) of the present invention in vivo. This transformation is converted to the parent compound by hydrolysis of the prodrug in the blood or by enzymatic action in the blood or tissue.
  • composition of the present patent is any one of the compounds (or prodrugs, or pharmaceutically acceptable salts thereof, or other pharmaceutically acceptable derivatives thereof) described herein, and one or more pharmaceutically acceptable It consists of a carrier or an excipient. These compositions may optionally further comprise one or more additional therapeutic agents.
  • the compounds of the invention may be combined with one or more other therapeutic regimens (eg, Tofacitinib or other kinase inhibitors, interferons, bone marrow transplants, farnesyl transferase inhibitors, bisphosphonates, thalidomide) , cancer vaccines, hormone therapy, antibodies, radiation, etc.) are co-administered to the desired patient.
  • the pharmaceutical composition of the compound may be another anti-inflammatory agent or anti-cancer agent.
  • compositions of the present invention comprise a compound of the present invention and a pharmaceutically acceptable carrier, including any and all solvents, diluents or other carriers, dispersion or suspending aids, surfactants, isotonic agents, Thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., to suit the particular dosage form desired.
  • a pharmaceutically acceptable carrier including any and all solvents, diluents or other carriers, dispersion or suspending aids, surfactants, isotonic agents, Thickeners or emulsifiers, preservatives, solid binders, lubricants, etc.
  • Some pharmaceutically acceptable carrier materials include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose And cellulose acetate; scutellaria powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and large Soybean oil; ethylene glycol, such as propylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution ; ethanol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and
  • the invention also encompasses a class of compositions (collectively referred to herein as "carrier” materials) for use in combination with one or more pharmaceutically acceptable carriers and/or diluents and/or adjuvants in the present invention. And, if necessary, other active ingredients.
  • carrier materials
  • the active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such administration, for the effective dosage required for the intended treatment.
  • the compounds and compositions of the invention may be administered orally, mucosally, topically, rectally, transpulmonarily, such as by inhalation spray, or parenterally, including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, Intrasternal and infusion techniques.
  • Administration is in the form of a dosage unit and contains a pharmaceutically acceptable carrier, adjuvant, and vehicle.
  • the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension or a liquid.
  • dosage units are tablets or capsules.
  • they may contain the active ingredient in an amount of from 1 to 2000 mg, preferably from 1 to 500 mg, more usually from 5 to 200 mg.
  • a suitable daily dose for a human or other mammal may vary depending on the patient and other factors, but may be determined again using conventional methods.
  • the amount of compound in the administration and dosage regimen of the compounds and/or compositions of the present invention will depend on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, The severity of the disease, the route and frequency of administration, and the particular compound used. Therefore, the dosage regimen can vary widely, but can be determined using standard methods.
  • a typical daily dose is from 0.01 to 500 mg/kg body weight, preferably from 0.1 to 125 mg/kg body weight, more preferably from 1 to 25 mg/kg body weight.
  • the active compounds of the invention will usually be formulated with one or more adjuvants, excipients or carriers. If administered orally, the compound can be combined with lactose, sucrose, starch powder, cellulose alkanoate, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium phosphate and sulfuric acid. Calcium salts, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol are mixed and then tableted or capsuled for ease of administration. Such capsules or tablets may contain a controlled release formulation which may be provided by dispersing the active compound in hydroxypropylmethylcellulose.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations (such as elixirs, lotions, ointments, creams or pastes) suitable for permeation through the skin, and drops suitable for administration to the eye, ear or nose.
  • Suitable compounds for topical administration of the compounds of the invention are from 0.1 to 150 mg, one to four times daily, preferably from one to two times daily.
  • the active ingredient can be combined with any paraffin or water miscible ointment.
  • the active ingredient can be formulated as a water-in-oil emulsion base cream.
  • the aqueous phase of the cream base can include, for example, at least 30% by weight of a polyol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol, and mixtures thereof.
  • Topical formulations may include compounds which enhance absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the compound can also be administered by a transdermal device. Preferably, transdermal administration will be accomplished using a patch containing a reservoir and a porous membrane or solid matrix.
  • the oil phase of the emulsion of the invention may be constituted in a known manner from known ingredients, comprising a mixture of at least one emulsifier and a fat or oil or a mixture of fats and oils of both.
  • the hydrophilic emulsifier can be used in combination with a lipophilic emulsifier as a stabilizer, and it is also preferred that it can also be combined with oil and fat.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, single two Glyceryl stearate or a mixture thereof with an emulsifying wax, or other materials known in the art.
  • the cream should preferably be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from the tube or other container.
  • Linear or branched, mono or dialkyl alkyl esters such as diisoadipate, isohexadecyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, palm Isopropyl acrylate, butyl stearate, 2-ethylhexyl palmitate or a mixed branched ester can also be used.
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially aqueous solvent for the active ingredient.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be administered from one or more sterile powders or granules, by using the formulations mentioned herein for oral administration or using other suitable dispersing or wetting agents and suspending agents. And prepared.
  • the compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical arts.
  • the active ingredient can also be administered by injection, with a suitable carrier including a combination of saline, dextrose or water, or with cyclodextrin (captisol), cosolvent solubilization (ie propylene glycol) or micelle solubilization (ie spit Temperature 80).
  • a suitable carrier including a combination of saline, dextrose or water, or with cyclodextrin (captisol), cosolvent solubilization (ie propylene glycol) or micelle solubilization (ie spit Temperature 80).
  • the formulation may also be a sterile injectable solution or a suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. Solvents which can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspension medium. Any mild fixed oil used for this purpose
  • the pharmaceutical composition can be administered in the form of an aerosol or with an inhaler, including a dry powder aerosol.
  • Suppositories for rectal administration can be prepared by combining the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperatures but liquid at the rectal temperature and therefore will melt in the rectum And release the drug.
  • the pharmaceutical composition may be added to conventional pharmaceutical operations such as sterilization and/or tablets and pills which may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like, and enteric coatings may also be used. preparation.
  • Such compositions may also contain adjuvants such as wetting agents, sweetening, flavoring, and perfuming agents.
  • the pharmaceutical composition of the present invention comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an antibiotic
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • An additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound comprises a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • compositions may optionally comprise one or more additional therapeutic agents including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents , antifungal, antibiotic or anti-vascular hyperproliferative compound.
  • additional therapeutic agents including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents , antifungal, antibiotic or anti-vascular hyperproliferative compound.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that can be administered to a patient with a compound of the invention, and which does not destroy the activity of the drug, and at a dose sufficient to deliver a therapeutic amount. It is non-toxic.
  • compositions of the invention can be used in the pharmaceutical compositions of the invention, including but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) Such as d-atocopHerol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymer delivery matrix, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine , sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, using surfactants, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, Colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-poly
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkyl groups, including 2 and 3-hydroxypropyl-cyclodextrin, or other dissolved derivatives may also be advantageous It is used to enhance the delivery of compounds of the formulae described herein.
  • the pharmaceutical compositions can be administered orally, optionally, in acceptable dosage forms including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are usually used include lactose and corn starch.
  • Lubricants such as, for example, magnesium stearate, are also commonly added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient When orally administered with an aqueous suspension and/or emulsion, the active ingredient may be suspended or dissolved in the oily phase with emulsifying and/or suspending agents. Some sweeteners, flavoring agents and/or coloring agents can be added if desired.
  • the pharmaceutical compositions may include the use of liposomes or microencapsulation techniques, various examples of which are found in the literature.
  • the pharmaceutical composition can be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other solubilizers or dispersants, examples of which are also well known in the art.
  • the compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
  • the therapeutic agents can be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • “combination therapy” is meant the use of a compound of the invention in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose Achieve the best results of the drug.
  • Co-administration includes simultaneous delivery of the dosage form, as well as separate dosage forms for each compound.
  • administration of the compounds of the invention can be used in conjunction with other therapies known in the art, for example, in the treatment of cancer using radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like to improve Cancer-like.
  • the invention is not limited to the order of administration; the compounds of the invention may be administered previously, simultaneously, or after other anticancer or cytotoxic agents.

Abstract

本发明涉及作为JAK抑制剂的一类新化合物、组合物及其应用。具体地，本发明提供了一类具有强力JAK抑制活性的化合物(如式(1)所示)或其异构体、溶剂化物、水合物、在药学上可接受的盐、前药，及包含所述化合物的药物组合物。本发明还公开了本发明化合物或药物组合物在制备药物中的应用，该药物用于治疗自身免疫疾病或癌症。

Description

2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用 技术领域
本发明属于化学医药领域，具体涉及一类具有JAK激酶抑制活性的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。
背景技术
JAK激酶(Janus kinase)和其下游的效应器、信号转导及转录激活蛋白形成了重要的细胞因子信号传导途径——JAK-STAT通路。研究发现JAK-STAT通路可由多种细胞因子、生长因子以及受体激活，参与细胞增殖、分化、凋亡、血管生成以及免疫调节等过程。JAK激酶是JAK-STAT信号通路中的关键激酶，该酶被发现二十多年后，第一种JAK激酶抑制剂(tofacitinib)于2012年才被批准用于类风湿性关节炎的治疗[Norman P.，Selective JAK inhibitors in development for rheumatoid arthritis，Expert Opin Investig Drugs，2014，23：1067-1077]。
在哺乳动物体内，JAK激酶家族中的三成员：JAK1、JAK2、JAK3和TYK2由超过1100个氨基酸组成，相对分子质量可达120000-140000，同源性达40％-70％，这些JAK激酶家族成员从C端到N端依次可分为7个同源结构域(JH)：JH1为激酶区，在JAK家族中高度保守；JH2为激酶样区或“假”激酶区，该假激酶结构域是JAK蛋白区别于其他酪氨酸蛋白的独特属性，该激酶区虽不具有催化活性，但对JH1的活性起调节作用，该结构域内的突变常可导致JAK激酶活性的增强或者减弱，并进而导致某些疾病的发生；JH3-JH4为SH2结构域(Src homology 2 domain)，该结构域含有约100个氨基酸残基，其可以特异性地识别和结合配基上磷酸化的酪氨酸残基；JH5-JH7为FERM结构域，该结构域保守，主要调节JAK与受体的结合。JAK3作为JAK激酶家族成员之一，在结构上，同样含有上述的激酶区，其不同结构域内特定氨基酸的突变也会造成其激酶活性的改变。
JAK-STAT信号通路是多种细胞生长、活化、分化、凋亡及其功能发挥过程中重要的一条细胞内信号转导途径。STAT是一类能与靶基因调控区DNA结合的胞质蛋白，是JAK的下游底物。STAT家族中包括STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B及STAT6等7个成员。JAKs与STATs之间的相互作用在细胞因子受体信号通路中起着重要作用[O′Sullivan LA et al.，Cytokine receptor signaling through the JAK-Stat-Socs  pathway in disease，Mol Immunol，2007，44：2497-2506]。当细胞表面的细胞因子受体与其各自的细胞因子配体结合后引起受体分子的二聚化，使得与受体偶联的JAK激酶相互靠近并通过交互的酪氨酸磷酸化作用而活化。JAK-STAT信号通路是一条由多种细胞因子受体刺激的信号转导通路，JAK激酶介导细胞内大多数细胞因子的信号传导，如白介素(IL)类、干扰素(IFN)类、***(EPO)、粒细胞和巨噬细胞集落刺激因子(GMCSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)、血小板衍生因子(PDGF)以及表皮细胞生长因子(EGF)等，而且不同受体可激活不同亚型的JAK激酶，从而表现差异化的生物学功能[Pesu M.et al.，Therapeutic targeting of Janus kinases，Immunol Rev，2008，223：132-142]。
JAK1和JAK2在人体各组织细胞中均有表达，JAK3主要表达于各造血组织细胞中，主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。JAK1和JAK2等缺失会造成人体致死性损伤，JAK3缺失则可避免损伤其他组织细胞的毒性不良反应[Yamaoka K.，et al.，JAK3 negatively regulates dendritic-cell cytokine production and survival，Blood，2005，106：3227-3233]。基于JAK激酶家族中各亚型的功能特点和特殊的组织分布，JAK3已成为治疗自身免疫性疾病的热门靶标，越来越多临床研究也将类风湿性关节炎的治疗聚焦于阻断JAK3信号转导通路上。2012年，选择性JAK3抑制剂Tofacitinib通过了临床试验，被批准用于类风湿性关节炎的治疗。
Tofacitinib(CP690550)是Pfizer公司研发的一种吡咯并嘧啶类选择性JAK3激酶抑制剂，对JAK3的抑制活性(IC 50＝1nmol/L)是JAK2(IC 50＝20nmol/L)的20倍及JAK1(IC 50＝112nmol/L)的100倍。研究Tofacitinib的立体化学结构发现其手性结构决定其能够特异性地结合到JAK3分子上，从而抑制JAK3磷酸化，进一步导致STAT磷酸化受阻，造成下游炎性细胞因子合成受到抑制。Tofacitinib在临床研究中表现出良好的临床疗效，在类风湿性关节炎临床试验研究中，5mg或10mg Tofacitinib计量组与等量安慰剂组对比呈现出显著的统计学差异，但临床试验研究中发现使用Tofacitinib与严重感染风险增高相关，其长期安全性有待进一步研究。
JAK-STAT信号通路在细胞分化及增殖过程中起到了重要的作用，JAK活性的改变也将导致该通路信号传递的改变，进而影响细胞功能。基于JAK激酶在JAK-STAT信号传递中的关键作用，以及JAK3激酶特定的组织细胞分布，使得JAK3成为类风湿性关节炎等疾病良好的治疗靶点。
目前JAK3抑制剂主要用于中重度类风湿性关节炎患者的治疗，该类药物在治疗中表现出良好的治疗效果和较好的安全性，但其长期安全性仍有待进一步提高。Tofacitinib临床研究过程中发现，使用该药物后会导致一定的不良反应，包括感染、结核、肿瘤和肝损伤等，所以提高JAK3抑制剂的药效、减少毒副作用是该研究领域亟待解决的关键问题。
JAK激酶几个亚型的ATP结合位点同源性较高，结构差异性较小，这是导致JAK抑制剂选择性不高的重要原因。目前已公开的一系列JAK激酶抑制剂在疗效、选择性和安全性方面还有改进的空间，仍需要开发出药效更佳和安全性更好的JAK抑制剂。尽管高选择性JAK抑制剂是目前本领域的研究重点，但鉴于JAK激酶家族每一个成员都与JAK-STAT信号传递密切相关，泛JAK抑制剂将会显著提高药效，大大降低用药剂量，从而达到控制毒副作用的目的。另外，药效的显著提高将有助于开发经皮肤给药的抗炎类药物。而此类药物的研发将为银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病等自身免疫疾病以及白血病、淋巴瘤、多发性骨髓瘤等癌症的治疗提供新的途径。本发明的化合物作为JAK激酶抑制剂表现出极佳的生物活性。
发明内容
本发明提供了一种2-(1-取代吡唑-4-)氨基-4-取代氨基-5-嘧啶甲酰胺类化合物，以及其用作制备治疗或预防由酪氨酸激酶(例如JAK1、JAK2、JAK3、TYK2)或其变种引起的疾病的药物的用途。
本发明提供了一种化合物或其异构体、溶剂化物或其药学上可接受的盐，或者以其有效的多晶型的药物组合物的形式提供，该化合物具有结构式(I)：
Figure PCTCN2018106694-appb-000001
其中，
R 1为
Figure PCTCN2018106694-appb-000002
n 1为0-1，n 2为0-1，n 3为0-5，
L 1为
Figure PCTCN2018106694-appb-000003
R 4和/或R 5为H、C 1-C 3直链烷基；
R 2为
Figure PCTCN2018106694-appb-000004
n 4为0-3，n 5为0-1，n 6为0-5，
L 2为
Figure PCTCN2018106694-appb-000005
R 7和/或R 8为H、C 1-C 3直链烷基；
化合物式(I)中取代基R 3为：
a)H，羟基，氰基，
b)C 1-C 5直链或支链烷基，
c)C 3-C 8环烷基，更优选为C 3-C 7环烷基，
d)C 1-C 5直链或支链烷氧基，
e)C 1-C 5直链或支链烷硫基，
f)5-7元杂环，优选地所述5-7元杂环含有1-2个杂原子，其杂原子选自O和/或N和/或S，当杂原子为N时，N上连接H或C 1-C 4烷基、C 1-C 3酰基，优选乙酰基、三氟乙酰基、丙酰基、N，N-二甲酰基，当杂原子为S时，S上连接0-2个氧原子，
g)取代或非取代的五元芳基或者杂芳基，优选地，所述取代或非取代的五元芳基或者杂芳基的结构式为
Figure PCTCN2018106694-appb-000006
其中：J 1和/或J 2和/或J 3和/或J 4为C、N、S、O；R 9为C 1-C 3直链或支链烷基，
或者所述取代或非取代的五元芳基或者杂芳基的结构式为
Figure PCTCN2018106694-appb-000007
其中：
J 1、J 2、J 3、J 4各自独立地为C、N、S、O，
R 20、R 21各自独立地为C 1-C 3直链或支链烷基，
h)取代或非取代的六元芳基或者杂芳基，
优选地，所述取代或非取代的六元芳基或者杂芳基的结构式为
Figure PCTCN2018106694-appb-000008
其中：
Q 1、Q 2、Q 3、Q 4、Q 5为N或C；
R 10和/或R 11和/或R 12为：
1)-F、-Cl、-Br、-CF 3、-OCF 3、氰基；
2)-NR′R″，R′、R″为H、C 1-C 3的烷基；
3)C 1-C 3烷基、C 2-C 5炔基、C 3-C 5环烷基；
4)SO 2R 13，其中R 13为H、C 1-C 3烷基；
5)
Figure PCTCN2018106694-appb-000009
其中q为0-2，M为O、S，R 14为H，C 1-C 5直链或支链烷基；
6)
Figure PCTCN2018106694-appb-000010
其中R 15、R 16为直链烷基，
或者，所述取代或非取代的六元芳基或者杂芳基的结构式为
Figure PCTCN2018106694-appb-000011
其中：
Q 1、Q 2、Q 3、Q 4、Q 5为N或C；
R 17、R 18各自独立地为：
a)-H，
b)-F、-Cl、-Br、-CF 3、-OCF 3、氰基，
c)-NR′R″，R′、R″为H、C 1-C 3的烷基，
d)C 1-C 3烷基、C 2-C 5炔基、C 2-C 5烯基、C 3-C 5环烷基，
e)SO 2R 13，其中R 13为H、C 1-C 3烷基，
f)
Figure PCTCN2018106694-appb-000012
其中q为0-2，M为O、S，R 14为H，C 1-C 5直链或支链烷基，
g)
Figure PCTCN2018106694-appb-000013
其中R 15、R 16为C 1-C 3的直链烷基，
h)-(CH 2) t-R 19，t为1-2，R 19为C 3-C 5环烷基；
i)含0-3个杂原子六元芳环并五元或六元环或含1-3个杂原子五元杂芳环并五元或六元环，优选自：
Figure PCTCN2018106694-appb-000014
式(I)中取代基R 6为：
a)H、羟基，
b)-NR′R″，R′、R″为H、C 1-C 3的烷基，
c)C 1-C 5直链或支链烷基，
d)C 3-C 8环烷基，
e)C 1-C 5直链或支链烷氧基，
f)C 1-C 5直链或支链烷硫基，
g)杂环基，优选地，所述杂环基为五元或六元含氧和/或氮的杂环基，如
Figure PCTCN2018106694-appb-000015
本发明还提供了一种化合物或其异构体、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 PCTCN2018106694-appb-000016
其中，
R 1为
Figure PCTCN2018106694-appb-000017
n 1为0-2，n 2为0-1，n 3为0-5，
L 1为
Figure PCTCN2018106694-appb-000018
R 4和/或R 5为H、C 1-C 3直链烷基；
R 2为
Figure PCTCN2018106694-appb-000019
n 4为0-3，n 5为0-1，n 6为0-5，
L 2为
Figure PCTCN2018106694-appb-000020
R 7和/或R 8为H、C 1-C 3直链烷基；
R 3为R 22取代的C 1-C 3烷氧基或者R 22取代的C 1-C 3烷硫基，R 22为羟基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR′R″、羟基取代的C 1-C 3烷氧基、氨基取代的C 1-C 3烷氧基、羟基取代的C 1-C 3烷硫基、氨基取代的C 1-C 3烷硫基，其中R′、R″为H、C 1-C 3的烷基；
R 6为a)H、羟基，
b)-NR′R″，R′、R″为H、C 1-C 3的烷基，
c)C 1-C 5直链或支链烷基，
d)C 3-C 8环烷基，
e)C 1-C 5直链或支链烷氧基，
f)C 1-C 5直链或支链烷硫基，或者
g)
Figure PCTCN2018106694-appb-000021
本发明的一个方面提供了一种含烯基的嘧啶甲酰胺类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，该化合物具有结构式(I)：
Figure PCTCN2018106694-appb-000022
其中，X为N；
R 1为
Figure PCTCN2018106694-appb-000023
n 1为0-8的整数，n 2为0-1的整数，n 3为0-8的整数，且n 1、n 2、n 3之和为10以下；
L 1为
R 4、R 5各自独立地为H、C 1-C 3烷基，R 4、R 5相同或者不同，
R 3为未取代或者C 1-C 3烷基取代的C 2-C 8链烯基或者未取代或者C 1-C 3烷基取代的C 4-C 8的环烯基；
R 2为
Figure PCTCN2018106694-appb-000025
n 4为0-8的整数，n 5为0-1的整数，n 6为0-8的整数，且n 4、n 5、n 6之和为10以下；
L 2为
Figure PCTCN2018106694-appb-000026
R 7、R 8各自独立地为H、C 1-C 3烷基，R 7、R 8相同或者不同，
R 6为-H、羟基烷基、C 1-C 5烷基、C 3-C 8环烷基、C 1-C 5烷氧基烷基、C 1-C 5烷硫基烷基、5-6元杂环基、或-NR′R″，其中R′、R″各自独立地为H、C 1-C 3的烷基。
优选地，该式(I)的化合物中，R 3为
Figure PCTCN2018106694-appb-000027
R 9、R 10、R 11、R 12、R 13各自独立地为H、C 1-C 3烷基，m为0至2的整数，
m 1为0至5的整数，m 2为0至5的整数，且m 1，m 2之和小于或等于5。
优选地，该式(I)的化合物中，n 1为0-2整数，n 2为0-1整数，n 3为0-3整数，R 4、R 5各自独立地为H、甲基，R 4、R 5相同或者不同；
R 9、R 10、R 11、R 12、R 13各自独立地为H、甲基或乙基，m为0或1。更优选地，n 1、n 2、n 3之和为5以下。
更优选地，该式(I)的化合物中，所述R 3为
Figure PCTCN2018106694-appb-000028
R 9、R 11、R 12、R 13各自独立地为H、甲基或乙基。
优选地，R 3为
Figure PCTCN2018106694-appb-000029
R 9、R 10各自独立地为H、C 1-C 3烷基，R 11、R 12、R 13中任一为C 4-C 6烷基，其余各自独立地为H、C 1-C 3烷基，m为0至2的整数。
优选地，该式(I)的化合物中，n 4为0-3整数，n 5为0-1整数，n 6为0-5整数，R 7、R 8各自独立地为H、甲基，R 7、R 8相同或者不同；
R 6为-H、羟乙基、羟丙基、C 1-C 5烷基、C 3-C 8环烷基、C 1-C 5烷氧基乙基、C 1-C 5烷氧基丙基、C 1-C 5烷硫基乙基、5-6元杂环基、或-NR′R″，其中R′、R″各自独立地为H、C 1-C 3的烷基。更优选地，n 4、n 5、n 6之和为5以下。
更优选地，该式(I)的化合物中，R 6为H、羟乙基、羟丙基、甲基、乙基、丙基、异丙基、叔丁基、环丙基、环丁基、环戊基、环己基、甲氧基乙基、乙氧基乙基、丙氧基乙基、异丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、异丙氧基丙基、甲硫基乙基、乙硫基乙基、丙硫基乙基、异丙硫基乙基、5-6元杂环基、或-NR′R″，其中R′、R″分别独立地为H、甲基、乙基；
所述5-6元杂环基为未取代或被1-2个选自羟基、C 1-C 3烷基、C 1-C 3酰基的取代基所取代的含有1-2个选自N、O、S的杂原子的杂环基。
更具体地，所述含有1-2个选自N、O、S的杂原子的杂环基为选自以下基团中的任一种：
Figure PCTCN2018106694-appb-000030
其中R 14为H、甲基、乙基、丙基、异丙基。
根据本申请的一些实施方案，所述嘧啶甲酰胺类化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己胺基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
本发明的另一方面涉及所述的嘧啶甲酰胺类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症的药物中的应用，其中，所述与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子***、结肠直肠癌、黑色素瘤、子宫内膜癌、***癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
本发明的又一方面提供了一种药物组合物，该药物组合物包括本申请的嘧啶甲酰胺类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。
根据本申请的一些实施方案，该药物组合物还可以包括一种或多种其他治疗剂。
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
“烷基”是指脂肪族烃基。烷基是饱和或不饱和的。烷基部分，不管是饱和的还是不饱和的，可以是支链的或直链的。“烷基”可以具有1-5个碳原子，优选具有1-3个碳原子。在一个方面，烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。典型的烷基包括但绝不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、己基、烯丙基、乙烯基、乙炔、丁-2-烯基、丁-3-烯基等。
术语“环烷基”是指单环或多环脂肪族非芳香族基团，其中构成环的每个原子(即骨架原子)是碳原子。环烷基可以是饱和或部分不饱和的。环烷基可以与芳环稠合，并且连接点处于不是芳环碳原子的碳上。环烷基包括具有3-10个环原子的基团。在一些实施方案中，环烷基选自环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。环烷基可以是取代或未取代的。取决于结构，环烷基可以是单价基团或双价基团(即亚环烷基，例如但不限于环丙-1，1-二基、环丁-1，1-二基、环戊-1，1-二基、环己-1，1-二基、环己-1，4-二基、环庚-1，1-二基等)。在一个方面，环烷基是C 3-C 6环烷基。
“链烯基”或者“环烯基”是指仅由碳原子和氢原子组成的直链或环状烃链基团，其含有至少一个双键。
“烷氧基烷基”是指(烷基)O(烷基)-基团，“烷硫基”是指(烷基)S(烷基)-基团，其中烷基如本文所定义。优选地，所述烷氧基烷基为C 1-C 5烷氧基烷基，更优选为C 1-C 5烷氧基C 1-C 3烷基，更优选为C 1-C 5烷氧基乙基或者C 1-C 5烷氧基丙基。优选地，所述烷硫基烷基为C 1-C 5烷硫基烷基，更优选为C 1-C 5烷硫基C 1-C 3烷基，更优选为C 1-C 5烷硫基乙基。
术语“5-6元杂环基”中“杂环基”是指环中含有一个或多个杂原子的芳香杂环(也称作杂芳基)和杂环烷基环(也称作杂脂环基团)，其中环中的各个杂原子选自O、S和N，其中各个杂环基团在其环体系中含有5-6个原子。而且该5-6元杂环基可以为未取代或被1-2个选自羟基、C 1-C 3烷基、C 1-C 3酰基的取代基所取代的含有1-2个选自N、O、S的杂原子的杂环基。
更具体地，所述含有1-2个选自N、O、S的杂原子的杂环基为选自以下基团中的任一种：
Figure PCTCN2018106694-appb-000031
其中R 14为H、甲基、乙基、丙基、异丙基。
本申请中术语“异构体”为具有相同分子式的不同化合物，可以包括立体异构、互变异构等各种异构形式。“立体异构体”是仅原子在空间的排列方式不同的异构体。本文描述的某些化合物含有一个或多个不对称中心，且因此可以产生对映体、非对映体和其他依据绝对立体化学可以被定义为(R)-或(S)-的立体异构形式。本发明的化学实体、药物组合物和方法旨在包括所有这些可能的异构体，包括外消旋混合物、光学纯形式和中间的混合物。旋光(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备，或使用常规技术来拆分。化合物的光学活性可以通过任何合适的方法进行分析，包括但不限于手性色谱法和旋光测定法，且可确定一种立体异构体超越其他异构体的优势程度。
具体地，例如，对于本申请结构式(I)的化合物，当n 2或者n 5不为0，且R 4、R 5不同或者R 7、R 8不同时，
Figure PCTCN2018106694-appb-000032
结构中包含手性碳原子，此时，
Figure PCTCN2018106694-appb-000033
Figure PCTCN2018106694-appb-000034
的结构意指包括所有可能的异构体，包括外消旋混合物、光学纯形式的旋光(R)-和(S)-异构体等，即R 4、R 5不同时，L 1为
Figure PCTCN2018106694-appb-000035
包括
Figure PCTCN2018106694-appb-000036
和外消旋体；R 7、R 8不同时，L 2为
Figure PCTCN2018106694-appb-000037
包括
Figure PCTCN2018106694-appb-000038
和外消旋体。
当本文所述的化合物含有烯烃双键时，除非另有说明，其意指该化合物包括各种顺反异构体。
“互变异构体”是可通过互变异构化互相转换的结构上不同的异构体。“互变异构化”是异构化的一种形式，且包括质子移变或质子转移互变异构化，可认为它是酸碱化学的子集。“质子移变互变异构化”或“质子转移互变异构化”涉及伴有键级变换的质子迁移，往往是单键与相邻的双键的互换。当可能发生互变异构化时(例如，在溶液中)，可达到互变异构体的化学平衡。互变异构化的一个实例为酮-烯醇互变异构化。
本申请中，结构式(I)的化合物、异构体、结晶或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本发明的一个方面是一种药物组合物，其包含结构式(I)的化合物。这种组合物可施用于银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病等自身免疫疾病以及白血病、淋巴瘤、多发性骨髓瘤等癌症，包括那些经过Tofacitinib、Peficitinib、Decernotinib或其他激酶抑制剂治疗有抗药性的类自身免疫疾病、癌症等。
本发明的又一目的是在于提供一种用于治疗自身免疫疾病和癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。可被这样治疗的自身免疫 疾病、癌症在本文别处会注明，包括具有对Tofacitinib、Peficitinib、Roxolitinib、Decernotinib或其他激酶抑制剂治疗有抗药性的自身免疫疾病、癌症等。
在癌症治疗中也可以组合使用一个或多个其他疗法，包括手术、放疗(如γ-射线、中子束放射疗法、电子束放射治疗、质子治疗、近距离放射治疗和全身放射性同位素等)、内分泌疗法、生物应答调节剂(例如，干扰素、白介素和肿瘤坏死因子(TNF))、热疗、冷冻疗法、减弱任何不良影响(例如，止吐剂)以及其他的治疗药物。
本发明还包括本发明的化合物或其药学上可接受的衍生物的使用，制造用于治疗眼底疾病、干眼症、银屑病、类风湿性关节炎、皮疹、湿疹、斑秃、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、性肠炎等自身免疫疾病以及肿瘤等疾病的药剂，包括治疗那些如本文在别处所指出的对一种或多种其它治疗剂产生耐药的疾病。本发明的化合物也可用于在药物中通过抑制一种或多种激酶(例如JAK1、JAK2、JAK3、TYK2)来减轻或预防疾病。
本发明还提供了制备相应化合物的方法，具体例可通过下述示例性的方法制备。系列(I)化合物的合成路线如下所示：
Figure PCTCN2018106694-appb-000039
试剂及反应条件：(a)DIEA，THF；(b)s-BuOH，TFA.
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本申请中所使用的部分中间体的合成，参见中国专利申请号2017108562180.
中间体的合成方法如下：
中间体1 1-(2-甲氧基乙基)-1H-吡唑-4-胺的制备：
Figure PCTCN2018106694-appb-000040
DMSO-d 6)δ8.85(s，1H)，8.27(s，1H)，4.35(t，J＝5.1Hz，2H)，3.73(t，J＝5.2Hz，2H)，3.24(s，3H).LCMS：m/z＝172.1(M+H) +.
Figure PCTCN2018106694-appb-000041
2H)，3.58(t，J＝5.4Hz，2H)，3.20(s，3H).LCMS：m/z＝142.1(M+H) +.
中间体2 1-[2-(甲硫基)乙基]-1H-吡唑-4-胺的制备：
Figure PCTCN2018106694-appb-000042
(石油醚∶乙酸乙酯＝4∶1)，得到黄色油状物180mg，产率54％。LCMS：m/z＝188.0(M+H) +.
Figure PCTCN2018106694-appb-000043
2H)，2.79(t，J＝6.9Hz，2H)，1.99(s，3H).LCMS：m/z＝158.1(M+H) +.
表1中间体3-22的合成(参考中间体1或2的合成方法)
Figure PCTCN2018106694-appb-000044
Figure PCTCN2018106694-appb-000045
Figure PCTCN2018106694-appb-000046
Figure PCTCN2018106694-appb-000047
中间体23 1-环丙基-1H-吡唑-4-胺的制备：
Figure PCTCN2018106694-appb-000048
加入环丙基硼酸(320mg，3.72mmol)、醋酸铜(326mg，1.79mmol)、吡啶(144mg，1.82mmol)、碳酸钠(432mg，4.08mmol)，70℃氩气保护条件下，反应4小时。反应液浓缩柱层析(石油醚∶乙酸乙酯＝4∶1)，得到黄色油状物110mg，产率41％。LCMS：m/z＝154.1(M+H) +.
Figure PCTCN2018106694-appb-000049
酸乙酯(2mL)的混合溶液中，加入雷尼镍(15mg)，氢气环境下反应3小时。硅藻土过滤，滤液蒸干，得棕色油状物90mg，产率90％。 1H NMR(400MHz，DMSO-d 6)δ7.02(s，1H)，6.86(s，1H)，3.89-3.61(m，2H)，3.50-3.45(m，1H)，0.91-0.73(m，4H).LCMS：m/z＝124.1(M+H) +.
中间体24 1-(6-甲氧基己基)-1H-吡唑-4-胺的制备：
Figure PCTCN2018106694-appb-000050
3.54mmol)，80℃反应3小时。反应液倒入冰水中，乙酸乙酯萃取，无水硫酸钠干燥，过滤蒸干柱层析(石油醚∶乙酸乙酯＝5∶1)，得到无色油状物300mg，产率61％。LCMS：m/z＝276.0(M+H) +.
Figure PCTCN2018106694-appb-000051
应液饱和食盐水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤蒸干反相柱层析(石油醚∶乙酸乙酯＝5∶1)，得无色油230mg，产率93％。LCMS：m/z＝228.1(M+H) +.
Figure PCTCN2018106694-appb-000052
雷尼镍(25mg)，氢气环境下反应3小时。硅藻土过滤，滤液蒸干，得棕色油状物190mg，产率95％。LCMS：m/z＝198.2(M+H) +.
中间体25 4-甲基-1-戊胺的制备：
将3-甲基戊腈(400mg，4.11mmol)溶于无水四氢呋喃(5mL)中，0℃氩气
Figure PCTCN2018106694-appb-000053
1.08(m，2H)，0.95(d，6H).LCMS：m/z＝102.1(M+H) +.
表2中间体26-28的合成(参考中间体29的合成)
Figure PCTCN2018106694-appb-000054
中间体29[2-(甲氧甲基)苯基]甲胺的制备：
步骤1)：2-(甲氧甲基)苯甲腈的制备：
Figure PCTCN2018106694-appb-000055
＝148.1(M+H) +.
步骤2)：[2-(甲氧甲基)苯基]甲胺的制备：
Figure PCTCN2018106694-appb-000056
LCMS：m/z＝152.1(M+H) +.
中间体30(2-甲基吡啶-3-基)甲胺的制备：
将2-甲基烟酰胺(200mg，1.47mmol)溶于无水四氢呋喃(5mL)中，0℃氩气
Figure PCTCN2018106694-appb-000057
123.1(M+H) +.
中间体31[3-(二甲氨基甲酰基)苄基]氨基盐酸盐的制备：
将3-(((叔丁氧羰基)氨基)甲基)苯甲酸(400mg，1.59mmol)溶于四氢呋喃
Figure PCTCN2018106694-appb-000058
得到白色固体263mg，产率77％。LCMS：m/z＝179.1(M+H) +.
实施例
实施例1 4-苄基氨基-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-(苄基氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000059
-7.33(m，5H)，4.82(s，2H).LCMS：m/z＝263.1(M+H) +.
步骤2)：4-苄基氨基-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000060
(s，1H)，7.42-7.36(m，5H)，4.79(s，2H)，3.79(s，3H).LCMS：m/z＝324.1(M+H) +.
实施例2 4-[(2-甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-[(2-甲氧基苄基)氨基]嘧啶-5-甲酰胺的制备：
将2，4-二氯嘧啶-5-甲酰胺(80mg，0.42mmol)溶于四氢呋喃(3mL)
Figure PCTCN2018106694-appb-000061
166.77，157.63，156.84，148.52，147.71，130.55，129.68，122.97，121.08，111.64，96.61，56.12，42.39.LCMS：m/z＝293.1(M+H) +.
步骤2)：4-[(2-甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
将2-氯-4-[(2-甲氧基苄基)氨基]嘧啶-5-甲酰胺(116mg，0.40mmol)
Figure PCTCN2018106694-appb-000062
DMSO-d 6+DCl/D 2O)δ166.86，161.02，157.36，149.69，144.70，131.25，129.45，128.42，124.82，123.12，120.85，119.52，111.38，100.76，56.01，40.98，39.31.LCMS：m/z＝354.2(M+H) +.
实施例3 4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-[(2-氟-6-甲氧基苄基)氨基]嘧啶-5-甲酰胺的制备：
将2，4-二氯嘧啶-5-甲酰胺(210mg，1.09mmol)溶于四氢呋喃
Figure PCTCN2018106694-appb-000063
MHz，DMSO-d 6+DCl/D 2O)δ8.82(s，1H)，7.50-7.40(m，1H)，7.03-6.96(m，1H)，6.95-6.87(m，1H)，4.77(s，2H)，3.88(s，3H).LCMS：m/z＝311.1(M+H) +.
步骤2)：4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000064
1H)，6.93-6.83(m，1H)，4.83(s，2H)，3.89(s，3H)，3.88(s，3H).LCMS：m/z＝372.2(M+H) +.
实施例4 4-[(2，6-二甲基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-[(2，6-二甲基苄基)氨基]嘧啶-5-甲酰胺的制备：
将2，4-二氯嘧啶-5-甲酰胺(70mg，0.36mmol)溶于四氢呋喃(4mL)
Figure PCTCN2018106694-appb-000065
DCl/D 2O)δ166.98，157.34，148.46，147.77，137.93，131.33，129.36，129.10，96.61，41.68，19.77.LCMS：m/z＝291.1(M+H) +.
步骤2)：4-[(2，6-二甲基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]
Figure PCTCN2018106694-appb-000066
4.74(s，2H)，3.90(s，3H)，2.32(s，6H).LCMS：m/z＝352.2(M+H) +.
实施例5 4-[(2，6-二氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-[(2，6-二氯苄基)氨基]嘧啶-5-甲酰胺：
将2，4-二氯嘧啶-5-甲酰胺(70mg，0.36mmol)溶于四氢呋喃(4mL)
Figure PCTCN2018106694-appb-000067
149.16，147.94，135.98，132.68，130.34，129.74，96.46，42.77.LCMS：m/z＝331.0(M+H) +.
步骤2)：4-[(2，6-二氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000068
2H)，3.89(s，3H).LCMS：m/z＝392.1(M+H) +.
实施例6 4-[(2，6-二氟苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-[(2，6-二氟苄基)氨基]嘧啶-5-甲酰胺的制备：
将2，4-二氯嘧啶-5-甲酰胺(210mg，1.09mmol)溶于四氢呋
Figure PCTCN2018106694-appb-000069
7.38(m，1H)，7.38-7.08(m，2H)，4.93(s，2H).LCMS：m/z＝299.0(M+H) +.
步骤2)：4-[(2，6-二氟苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000070
Hz，2H)，3.70(t，J＝5.1Hz，2H)，3.21(s，3H).LCMS：m/z＝404.2(M+H) +.
实施例7 4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-[(2-氟-6-甲氧基苄基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000071
7.50-7.40(m，1H)，7.03-6.96(m，1H)，6.95-6.87(m，1H)，4.77(s，2H)，3.88(s，3H).LCMS：m/z＝311.1(M+H) +.
步骤2)：4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺的制备：
将2-氯-4-[(2-氟-6-甲氧基苄基)氨基]嘧啶-5-甲酰胺
Figure PCTCN2018106694-appb-000072
1H)，6.95-6.73(m，1H)，4.83(s，2H)，4.32(t，J＝5.1Hz，2H)，3.89(s，3H)，3.70(t，J＝5.1Hz，2H)，3.21(s，3H).LCMS：m/z＝416.2(M+H) +.
实施例8 4-[(5-羟基戊基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000073
1H)，7.68(s，1H)，3.87(s，3H)，3.60-3.47(m，2H)，3.39(t，J＝6.3Hz，2H)，1.69-1.54(m，2H)，1.51-1.40(m，2H)，1.40-1.29(m，2H).LCMS：m/z＝320.2(M+H) +.
实施例9 4-[(5-甲氧基戊基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
步骤1)、步骤2)同实施例8
Figure PCTCN2018106694-appb-000074
产率95％。LCMS：m/z＝382.1(M+H) +.
Figure PCTCN2018106694-appb-000075
DMSO-d 6+DCl/D 2O)δ8.69(s，1H)，8.02(s，1H)，7.76(s，1H)，3.90(s，3H)，3.53(t，J＝6.7Hz，2H)，3.31(t，J＝6.1Hz，2H)，3.20(s，3H)，1.69-1.57(m，2H)，1.57-1.44(m，2H)，1.44-1.30(m，2H).LCMS：m/z＝334.2(M+H) +.
实施例10 4-[(3-羟基-3-甲基丁基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000076
率72％。LCMS：m/z＝320.1(M+H) +.
Figure PCTCN2018106694-appb-000077
和食盐水洗，无水硫酸钠干燥，过滤蒸干，薄层层析(二氯甲烷∶甲醇＝10∶1)，粗产物用乙腈洗涤，得到白色固体15mg，产率19％。 1H NMR(400MHz，DMSO-d 6+DCl/D 2O)δ8.57(s，1H)，8.01(s，1H)，7.62(s，1H)，3.78(s，3H)，3.63-3.47(m，2H)，1.71-1.56(m，2H)，1.08(s，6H).LCMS：m/z＝320.2(M+H) +.
实施例11 4-[[(1-乙酰基哌啶-4-基)甲基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000078
固体150mg，产率79％。LCMS：m/z＝370.2(M+H) +.
Figure PCTCN2018106694-appb-000079
产率66％。LCMS：m/z＝431.2(M+H) +.
Figure PCTCN2018106694-appb-000080
(160mg，1.58mmol)，搅拌2分钟后，滴入乙酰氯(63mg，0.80mmol)，25℃反应2小时。反应液浓缩，薄层层析层析(二氯甲烷∶甲醇＝10∶1)， 得到白色固体30mg，两步产率30％。 1H NMR(400MHz，DMSO-d 6+DCl/D 2O)δ8.72(s，1H)，8.02(s，1H)，7.75(s，1H)，4.47-4.25(m，1H)，3.90(s，3H)，3.48(d，J＝6.7Hz，2H)，3.17-3.02(m，1H)，2.54(s，3H)，2.13-2.07(m，2H)，2.04-1.89(m，1H)，1.80-1.63(m，2H)，1.32-1.05(m，2H).LCMS：m/z＝373.2(M+H) +.
实施例12 4-[[2-(1-乙酰基哌啶-4-基)乙基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000081
搅拌15分钟后过滤，滤饼用石油醚洗涤，得白色固体270mg，产率68％。LCMS：m/z＝384.2(M+H) +.
Figure PCTCN2018106694-appb-000082
滤，乙腈洗涤，得到白色固体170mg，产率54％。LCMS：m/z＝445.3(M+H) +.
Figure PCTCN2018106694-appb-000083
搅拌2分钟后，滴入乙酰氯(69mg，0.88mmol)，25℃反应2小时。反应液浓缩，薄层层析层析(二氯甲烷∶甲醇＝10∶1)，得到浅黄色固体10mg，两步产率7％。 1H NMR(400MHz，DMSO-d 6+DCl/D 2O)δ8.58(s，1H)，7.90(s，1H)，7.63(s，1H)，4.34-4.08(m，1H)，3.79(s，3H)，3.77-3.64(m， 1H)，3.53-3.37(m，2H)，3.04-2.83(m，1H)，2.45-2.38(m，1H)，1.98(s，3H)，1.69-1.55(m，2H)，1.52-1.37(m，3H)，1.11-0.79(m，2H).LCMS：m/z＝387.2(M+H) +.
实施例13 4-[[4-氨基-2-氟苄基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000084
产率70％。 1H NMR(400MHz，DMSO-d 6+DCl/D 2O)δ8.76(s，1H)，7.70(s，1H)，7.60-7.47(m，1H)，7.47-7.34(m，2H)，7.32-7.19(m，1H)，4.83(s，2H)，3.81(s，3H).LCMS：m/z＝357.2(M+H) +.
实施例14-227的合成
后续具体实施例的合成按照如下所示合成路线，以与实施例1相似的方法，采用具有不同取代基的原料，合成相应的中间体A和目标化合物B，如下表3和表4所示。
Figure PCTCN2018106694-appb-000085
反应条件：1)R 1CH 2NH 2，DIEA，THF，25℃，2～16h；2)
Figure PCTCN2018106694-appb-000086
TFA，s-BuOH，60～100℃，2～16h.
表3实施例14-180的中间体化合物A和目标化合物B的结构和表征
Figure PCTCN2018106694-appb-000087
Figure PCTCN2018106694-appb-000088
Figure PCTCN2018106694-appb-000089
Figure PCTCN2018106694-appb-000090
Figure PCTCN2018106694-appb-000091
Figure PCTCN2018106694-appb-000092
Figure PCTCN2018106694-appb-000093
Figure PCTCN2018106694-appb-000094
Figure PCTCN2018106694-appb-000095
Figure PCTCN2018106694-appb-000096
Figure PCTCN2018106694-appb-000097
Figure PCTCN2018106694-appb-000098
Figure PCTCN2018106694-appb-000099
Figure PCTCN2018106694-appb-000100
Figure PCTCN2018106694-appb-000101
Figure PCTCN2018106694-appb-000102
Figure PCTCN2018106694-appb-000103
Figure PCTCN2018106694-appb-000104
Figure PCTCN2018106694-appb-000105
Figure PCTCN2018106694-appb-000106
Figure PCTCN2018106694-appb-000107
Figure PCTCN2018106694-appb-000108
Figure PCTCN2018106694-appb-000109
Figure PCTCN2018106694-appb-000110
Figure PCTCN2018106694-appb-000111
Figure PCTCN2018106694-appb-000112
Figure PCTCN2018106694-appb-000113
Figure PCTCN2018106694-appb-000114
Figure PCTCN2018106694-appb-000115
Figure PCTCN2018106694-appb-000116
Figure PCTCN2018106694-appb-000117
Figure PCTCN2018106694-appb-000118
Figure PCTCN2018106694-appb-000119
Figure PCTCN2018106694-appb-000120
Figure PCTCN2018106694-appb-000121
Figure PCTCN2018106694-appb-000122
Figure PCTCN2018106694-appb-000123
表4实施例181-227的中间体化合物A和目标化合物B的结构和表征
Figure PCTCN2018106694-appb-000124
Figure PCTCN2018106694-appb-000125
Figure PCTCN2018106694-appb-000126
Figure PCTCN2018106694-appb-000127
Figure PCTCN2018106694-appb-000128
Figure PCTCN2018106694-appb-000129
Figure PCTCN2018106694-appb-000130
Figure PCTCN2018106694-appb-000131
Figure PCTCN2018106694-appb-000132
Figure PCTCN2018106694-appb-000133
Figure PCTCN2018106694-appb-000134
实施例228 4-(丁基-3-烯-1-基氨基)-2-((1-(叔丁基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000135
步骤2)：4-(丁基-3-烯-1-基氨基)-2-((1-(叔丁基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000136
2H)，2.43-2.28(m，2H)，1.52(s，9H).化学式：C 16H 23N 7O，MS：330(M+H) +.
实施例229 2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-甲基烯丙基)氨基)嘧啶-5-甲酰胺的制备：
操作同实施例228，用2-甲基丙基-2-烯-1-胺代替步骤1)中丁
Figure PCTCN2018106694-appb-000137
实施例230 2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-((3-甲基丁基-2-烯-1-基)氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000138
实施例231 2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-(戊基-4-烯-1-基氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000139
实施例232 4-((2-甲基烯丙基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备：
操作同实施例228，用2-甲基丙基-2-烯-1-胺代替步骤1)中
Figure PCTCN2018106694-appb-000140
(m，4H)，1.76(s，3H).化学式：C 17H 23N 7O 2，MS：358(M+H) +.
实施例233 4-((3-甲基丁基-2-烯-1-基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备：
操作同实施例228，用3-甲基丁基-2-烯-1-胺代替步骤1)中
Figure PCTCN2018106694-appb-000141
(M+H) +.
实施例234 4-(丁基-3-烯-1-基氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000142
实施例235 2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-4-(戊基-4-烯-1-基氨基)嘧啶-5-甲酰胺的制备：
操作同实施例228，用戊基-4-烯-1-胺代替步骤1)中丁基-3-
Figure PCTCN2018106694-appb-000143
C 18H 25N 7O 2，MS：372(M+H) +.
实施例236 2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-((环戊基-3-烯-1-基甲基)氨基)嘧啶-5-甲酰胺的制备：
步骤1)：2-氯-4-((环戊基-3-烯-1-基甲基)氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000144
将2，4-二氯嘧啶-5-甲酰胺(400mg，2.08mmol)和三乙胺(633mg，6.25mmol)溶于四氢呋喃(10mL)中，加入环戊基-3-烯-1-基甲基胺盐酸盐(281mg，2.1mmol)，25℃反应3小时。加入饱和食盐水(200mL)，搅拌15分钟后，过滤，滤饼用石油醚洗涤，得白色固体380mg，MS：253[M+H] +。
步骤2)：2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-((环戊基-3-烯-1-基甲基)氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000145
将2-氯-4-((环戊基-3-烯-1-基甲基)氨基)嘧啶-5-甲酰胺(127mg，0.5mmol)溶于仲丁醇(3mL)中，加入1-叔丁基-1H-吡唑-4-胺(84mg，0.6mmol)和三氟乙酸(0.1mL)，100℃封管反应2小时。反应液浓缩，柱层析纯化，得白色固体50mg。 1H NMR(400MHz，DMSO-d 6)δ10.58(s，1H)，10.16(s，1H)，8.55(s，1H)，8.37-8.14(m，1H)，8.02(s，1H)，7.71-7.52(m，2H)，5.75-5.63(m，2H)，3.57-3.44(m，2H)，2.72-2.56(m，1H)，2.49-2.39(m，2H)，2.15-2.01(m，2H)，1.52(s，9H).MS：356[M+H] +。
实施例237：4-((环戊基-3-烯-1-基甲基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备：
步骤1：同实施例236)步骤1；
步骤2)4-((环戊基-3-烯-1-基甲基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000146
操作同实施例236步骤2)，用1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-胺代替1-叔丁基-1H-吡唑-4-胺，得白色固体。 1H NMR(400MHz，DMSO-d 6)δ10.62(s，1H)，10.16(s，1H)，8.56(s，1H)，8.26(s，1H)，7.98(s，1H)，7.71-7.53(m，2H)，5.75-5.65(m，2H)，4.46-4.31(m，1H)，4.01-3.90(m，2H)，3.57-3.39(m，4H)，2.70-2.55(m，1H)，2.48-2.36(m，2H)，2.17-2.04(m，2H)，2.03-1.82(m，4H).MS：384[M+H] +。
实施例238：4-(烯丙氨基)-2-((1-(叔丁基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺的制备：
Figure PCTCN2018106694-appb-000147
操作同实施例236，用烯丙胺盐酸盐代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ10.71(s，1H)，10.16(s，1H)，8.62(s，1H)，8.31(s，1H)，8.00(s，1H)，7.77-7.54(m，2H)，6.07-5.89(m，1H)，5.27-5.11(m，2H)，4.25-4.12(m，2H)，1.51(s，9H).MS：316[M+H] +。
实施例239：(Z)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((戊烷-2-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000148
操作同实施例236，用(Z)-戊烷-2-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.44(s，1H)，9.18(d，J＝28.1Hz，1H)，8.46(s，1H)，8.02(d，J＝9.3Hz，1H)，7.83-7.56(m，1H)，7.48(s，1H)，7.23-6.97(m，1H)，5.72-5.52(m，2H)，4.14-4.03(m，2H)，2.14-1.98(m，2H)，1.49(s，9H)，0.99-0.91(m，3H).MS：344[M+H] +。
实施例240：(E)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((4-甲基戊烷-2-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000149
操作同实施例236，用(E)-4-甲基戊烷-2-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.45(s，1H)，9.24(s，1H)，8.46(s，1H)，8.01(s，1H)，7.87-7.51(m，1H)，7.48(s，1H)，7.39-6.79(m，1H)，5.75-5.39(m，2H)，4.25-3.86(m，2H)，2.40-2.10(m，1H)，1.49(s，9H)，0.94(d，J＝6.7Hz，6H).MS：358[M+H] +。
实施例241：(E)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((戊烷-3-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000150
操作同实施例236，用(E)-戊烷-3-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.41(s，1H)，9.19(s，1H)，8.44(s，1H)，8.00(s，1H)，7.67-7.53(m，1H)，7.50(s，1H)，7.21-6.93(m，1H)，5.58-5.36(m，2H)，3.52-3.47(m，2H)，2.37-2.20(m，2H)，1.63(d，J＝5.9Hz，3H)，1.49(s，9H).MS：344[M+H] +。
实施例242：2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((3-甲基丁基-3-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000151
操作同实施例236，用3-甲基丁基-3-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.40(s，1H)，9.17(s，1H)，8.44(s，1H)，7.97(s，1H)，7.82-7.59(m，1H)，7.52(s，1H)，7.18-6.87(m，1H)，4.84-4.77(m，1H)，4.77-4.72(m，1H)，3.67-3.50(m，2H)，2.39-2.22(m，2H)，1.73(s，3H)，1.49(s，9H).MS：344[M+H] +。
实施例243：2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((4-甲基戊烷-3-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000152
操作同实施例236，用4-甲基戊烷-3-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.41(s，1H)，9.16(s，1H)，8.45(s，1H)，8.01(s，1H)， 7.82-7.55(m，1H)，7.50(s，1H)，7.24-6.87(m，1H)，5.21-5.11(m，1H)，3.54-3.43(m，2H)，2.36-2.22(m，2H)，1.67(s，3H)，1.57(s，3H)，1.49(s，9H).MS：358[M+H] +。
实施例244：2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((4-甲基戊烷-4-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000153
操作同实施例236，用4-甲基戊烷-4-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.46(s，1H)，9.27(s，1H)，8.45(s，1H)，8.00(s，1H)，7.86-7.59(m，1H)，7.51(s，1H)，7.31-6.76(m，1H)，4.78-4.63(m，2H)，3.52-3.44(m，2H)，2.06(t，J＝7.7Hz，2H)，1.80-1.70(m，2H)，1.69(s，3H)，1.50(s，9H).MS：358[M+H] +。
实施例245：2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((5-甲基己烷-4-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000154
操作同实施例236，用5-甲基己烷-4-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.40(s，1H)，9.21(s，1H)，8.44(s，1H)，7.98(s，1H)，7.82-7.54(m，1H)，7.52(s，1H)，7.26-6.84(m，1H)，5.21-5.01(m，1H)，2.07-1.99(m，2H)，1.64(s，6H)，1.57-1.53(m，4H)，1.49(s，9H).MS：372[M+H] +。
实施例246：(E)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((5-甲基己烷-2-烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000155
操作同实施例236，用(E)-5-甲基己烷-2-烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.40(s，1H)，9.18(s，1H)，8.44(s，1H)，8.01(s，1H)，7.77-7.54(m，1H)，7.50(s，1H)，7.22-6.80(m，1H)，5.56-5.44(m，1H)，5.44-5.31(m，1H)， 3.55-3.42(m，2H)，2.35-2.14(m，3H)，1.50(s，9H)，0.93(d，J＝6.7Hz，6H).MS：372[M+H] +。
实施例247：2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-(((2E，4E)-己烷-2，4-二烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000156
操作同实施例236，用(2E，4E)-己烷-2，4-二烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.48(s，1H)，9.29(s，1H)，8.47(s，1H)，7.98(s，1H)，7.86-7.58(m，1H)，7.49(s，1H)，7.34-6.92(m，1H)，6.22-5.99(m，2H)，5.82-5.70(m，1H)，5.70-5.55(m，1H)，4.19-4.02(m，2H)，1.69(d，J＝6.7Hz，3H)，1.48(s，9H).MS：356[M+H] +。
实施例248：2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-(((2E，4E)-庚烷-2，4-二烯-1-基)氨基)嘧啶-5-甲酰胺的制备
Figure PCTCN2018106694-appb-000157
操作同实施例236，用(2E，4E)-庚烷-2，4-二烯-1-胺代替环戊基-3-烯-1-基甲基胺盐酸盐，得类白色固体。 1H NMR(400MHz，DMSO-d 6)δ9.44(s，1H)，9.25(s，1H)，8.47(s，1H)，7.98(s，1H)，7.88-7.58(m，1H)，7.48(s，1H)，7.32-6.86(m，1H)，6.16(dd，J＝15.1，10.4Hz，1H)，6.04(dd，J＝15.1，10.5Hz，1H)，5.86-5.60(m，2H)，4.21-4.05(m，2H)，2.12-1.96(m，2H)，1.48(s，9H)，0.94(t，J＝7.5Hz，3H).MS：370[M+H] +。
实验例1.本发明化合物抑制JAK1，JAK2，JAK3，TYK2激酶活性的测试
在体外组装的酶促反应中，加入不同浓度的化合物检测化合物对特异性酶促反应的抑制作用，具体测试方法如下：
一、测试用仪器、材料和试剂
表5.测试用仪器、材料和试剂
Figure PCTCN2018106694-appb-000158
Figure PCTCN2018106694-appb-000159
二.测试方法
下述将以JAK3为例，JAK1、JAK2、JAK3、TYK2具体的实验条件见后文。
1.试剂配制：
EDTA(0.5M pH8.0)溶液配制：准确称量14.612g EDTA粉末，加入超纯水后定容到100mL(若有不溶则加热到37℃，用1N NaOH溶液调pH至8.0)
1×Kinase Assay Buffer：于试剂瓶中分别加入25mL HEPES溶液(1M)、190.175mg EGTA、5mL MgCl 2溶液(1M)、1mL DTT、50μL Tween-20，加超纯水定容到500mL(调pH至7.5)。
1×Detection Buffer：取1mL 10×Detection Buffer加入9mL水混匀。
4×终止液：将0.8mL上述EDTA(0.5M，pH8.0)溶液、1mL 10×Detection Buffer及8.2mL超纯水混匀。
4×JAK3激酶溶液：用1×Kinase Assay Buffer稀释激酶原液到浓度为0.36nM，混匀，冰上保存。
4×底物溶液：用1×Kinase Assay Buffer稀释底物ULight TM-labeled JAK-1(Tyr1023)Peptide原液到200nM，混匀。
4×ATP溶液：用1×Kinase Assay Buffer稀释ATP原液到浓度为40μM，混匀。
4×检测液：用1×Detection Buffer稀释检测抗体Europium-anti-phospho-tyrosine antibody(PT66)到浓度为8nM，混匀。
2×底物/ATP混合液：4×底物溶液和600μl 4×ATP溶液等量混匀(使用前配制)。
2、实验步骤
1)化合物的稀释，
在96孔板中，将化合物用DMSO溶液按3倍比例稀释，形成11个梯度，另一纯DMSO溶液作为阳性对照；取一块新的96孔板，将上述溶液用超纯水稀释25倍(DMSO浓度为4％)
2)将化合物转盘到384孔板
将上述96孔板中用超纯水稀释过的化合物溶液按照2复孔的标准转盘到384孔板相应的孔中。
3)加4×激酶溶液：用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中，混匀室温预反应5分钟。
4)加2×底物/ATP混合液：用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照：在384孔板中设置阴性对照孔，该孔加入2.5μl/孔4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含4％DMSO的超纯水。
6)离心混匀，避光室温反应60min。
7)终止酶促反应：
吸取5μl上述4×终止液到384孔板相应孔中，离心混匀，室温反应5分钟。
8)显色反应：
吸取5μl上述4×检测液加入到384孔板中孔中，离心混匀，室温反应60min。
9)将384孔板放入读板仪，调取相应的程序检测信号。
10)抑制率和IC 50计算：
孔读值＝10000*EU665值/EU615值
抑制率＝[1-(实验孔读值-阴性对照孔读值)/(阳性对照孔读值-阴性对照孔读值)]*100％
将药物浓度和相应抑制率输入GraphPad Prism5处理计算出相应的IC 50值。
三.测试条件：
JAK1激酶活性测试：
JAK1(终浓度10nM)；ATP(终浓度10μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度100nM)；酶促反应时间为2小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
JAK2激酶活性测试：
JAK2(终浓度0.25nM)；ATP(终浓度5μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度50nM)；酶促反应时间为1小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
JAK3激酶活性测试：
JAK3(终浓度0.36nM)；ATP(终浓度10μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度50nM)；酶促反应时间为1小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
TYK2激酶活性测试：
TYK2(终浓度8nM)；ATP(终浓度20μM)；ULight TM-labeled JAK-1(Tyr1023)Peptide(终浓度100nM)；酶促反应时间为2小时。化合物最大终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
表6和7列出了本发明中部分化合物对酪氨酸激酶JAK1、JAK2、JAK3和TYK2抑制活性的测定结果。下表中IC 50值表示酶最高抑制率50％时的化合物浓度，NT表示没有测试相对应的酶。
表6、本发明部分化合物对JAK1、JAK2、JAK3和TYK2酪氨酸激酶抑制活性测定结果
Figure PCTCN2018106694-appb-000160
Figure PCTCN2018106694-appb-000161
Figure PCTCN2018106694-appb-000162
Figure PCTCN2018106694-appb-000163
Figure PCTCN2018106694-appb-000164
Figure PCTCN2018106694-appb-000165
表7、本发明部分化合物对JAK1、JAK2、JAK3、TYK2酪氨酸激酶抑制活性测定结果
Figure PCTCN2018106694-appb-000166
Figure PCTCN2018106694-appb-000167
实验例2.本发明化合物对HEL细胞中STAT5的磷酸化定量AlphaLISA检测
用不同浓度的Tofacitinib和S1部分化合物处理HEL细胞，再用100ng/mL IL-4进行刺激后采用AlphaLISA定量检测pSTAT5信号，具体测试方法如下：
表8.测试试剂：
Figure PCTCN2018106694-appb-000168
一、相关溶液的稀释及配置
1、Acceptor Mix：现用现配，将Reaction Buffer1、Reaction Buffer2、Activation Buffer、Acceptor Beads按照47∶47∶4∶2的比例混合，放置于冰盒上(30min内使用)
Donor Mix：现用现配，将Dilution Buffer和Donor Beads按照49∶1的比例混合，放置冰盒上(弱光操作，30min内使用)。
2、Positive control lysate：冻干粉+250μL水，将其进行分装(每管10.5μL)，放于-20℃保存。(一个月之内使用完)
二、实验过程
1、收集HEL细胞，用PBS离心洗三遍(1000rpm，4min)，在96孔板中按照10万cell/well/45μL DMEM(无酚红)进行细胞接种，每个浓度做两个复孔，培养1h；
2、每孔加入15μL不同浓度的Tofacitinib，用排枪混匀后培养1h；
3、每孔加入20μL400ng/mL的IL-4，混匀，培养15min；
4、随后于每孔加入20μL5×Lysis buffer，在混匀小精灵上混匀，350rpm，10min；裂解后，低速离心，800rpm，1min；
5、吸取上述裂解产物10μL分别加至384板中；
6、每孔加入5μL Acceptor Mix，密封，用锡箔纸包裹避光，混匀1-2min，室温孵育2h；(孵育时在混匀小精灵上低速摇动)
7、每孔加入5μL Donor Mix，密封，用锡箔纸包裹，混匀1-2min，室温孵育2h；(弱光操 作，孵育时在混匀小精灵上低速摇动)
8、在多功能读板机Envision中打开相应程序读取孔板读值。
9、抑制率和IC 50计算：
抑制率＝[1-(实验孔读值-阴性对照孔读值)/(阳性对照孔读值-阴性对照孔读值)]*100％
将药物浓度和相应抑制率输入GraphPad Prism5处理计算出相应的IC 50值。
表9.列出了本发明部分化合物对HEL细胞中STAT5的磷酸化定量AlphaLISA检测结果。
表9、本发明部分化合物对HEL细胞中STAT5的磷酸化定量检测结果
Figure PCTCN2018106694-appb-000169
实验例3.本发明化合物对小鼠脾细胞增殖抑制活性的测试
具体实验步骤如下：
1)化合物稀释：从最高浓度5000nM开始进行3倍梯度稀释后共9个浓度(本实验使用的药物的最大终浓度为5000nM，最低终浓度为0.76nM)。
2)取一直径6厘米的培养皿，在其中放置一孔径为70μm的细胞过滤筛，然后在筛中加入2mL HBSS溶液，使其浸润培养皿底部；
3)将成年Balb/c小鼠用二氧化碳安乐死，在75％酒精中浸泡1分钟，放入安全柜，在小鼠左腹侧中部剪开小口，暴露腹壁，找到脾脏；
4)取脾脏，去除周围的脂肪组织后将脾脏放入培养皿中的细胞过滤筛上，适当剪切；
5)用注射器活塞的顶端扁平部轻轻研磨脾脏，得到细胞悬浮液；
6)从培养皿中收集细胞悬液，将细胞悬液缓慢加入盛有5ml Ficoll-Paque PLUS的15ml离心管中；
7)以400g的速度，在室温下离心30分钟；
8)离心结束后，用吸管缓慢移除上层，再缓慢吸出中间层，即脾细胞；
9)将搜集的脾细胞悬液置于另一15ml离心管中并加入10ml RPMI1640完全培养基，300g，4℃，离心4分钟；
10)弃去上清液，加入完全培养基重悬细胞，然后进行细胞计数。细胞悬液按第九步重复洗一次；
11)将细胞以200万/mL至500万/mL的细胞密度转移至培养皿中(含2.5μg/mL刀豆蛋白A)培养过夜；
12)第二天，将细胞转移至15mL离心管中，以300g的速度离心5min；
13)弃去上清液，加入5mL RPMI 1640完全培养液，吹打均匀，取10μL细胞悬浮液和10μL胎盼蓝混匀，用细胞计数仪进行计数，记录细胞数及存活率。
14)细胞悬液接种到96孔板中，每孔接种80μl细胞悬液，其密度为100000细胞/孔；
15)在每孔中加入20μL对应的上述用培养液稀释过的5×化合物溶液，混匀；
16)培养72小时后每孔加入10μL CCK-8试剂，孵育2小时(可以根据颜色深浅来调节反应时间)；
17)在多功能读板机于450nm处读其OD值。
18)数据处理：
细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]*100％
As：实验孔(含有细胞的培养基、CCK-8、化合物)的OD值，
Ac：对照孔(含有细胞的培养基、CCK-8)的OD值，
Ab：空白孔(不含细胞和化合物的培养基、CCK-8)的OD值，
然后将数值导入Graphpad Prism5软件进行曲线拟合，计算IC50。
表10和表11.列出了本发明化合物对小鼠脾细胞增殖抑制活性的测试结果，其中A表示IC 50小于或等于100nM，B表示IC 50大于100nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于1000nM，D表示IC 50大于1000nM。
表10、本发明化合物对小鼠脾细胞增殖抑制活性的测试结果
Figure PCTCN2018106694-appb-000170
Figure PCTCN2018106694-appb-000171
Figure PCTCN2018106694-appb-000172
Figure PCTCN2018106694-appb-000173
表11、本发明部分化合物对小鼠脾细胞增殖抑制活性的测试结果
Figure PCTCN2018106694-appb-000174
用途，制剂，给药
医药用途、适应症
本发明所提供的生物学数据表明，本发明的化合物有利于治疗或预防由于酪氨酸激酶(JAK1、JAK2、JAK3、TYK2)异常而引起的疾病。超过五分之一的本发明的化合物已被证实能够强力抑制JAK酪氨酸激酶活性，而JAK激酶家族与自身免疫疾病及癌症的发生及转移有密切关系。因此，本发明的化合物有利于治疗自身免疫疾病，包括但不限于：银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病。本发明的化合物还有利于治疗癌症，包括原发性和转移性癌症，包括实体瘤。此类癌症包括但不限于：非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子***、结肠直肠癌、黑色素瘤、子宫内膜癌、***癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。本发明的化合物也包括治疗耐一种或多种其它治疗方法的癌症。本发明的化合物还可用于与JAK1激酶和/或JAK2和/或JAK3激酶有关的除了自身免疫疾病和癌症以外的其他疾病，包括但不限于眼底疾病，肺纤维化、肝纤维化等。本发明的化合物可以作为单一疗法或联合疗法，可以与多个本发明的化合物联合用药或与本发明以外的其他药物联合用药。
制药方法
本发明的制药方法包括对需要本发明化合物的受试者确定治疗有效量。“治疗有效剂量”依疾病的阶段、进展或严重程度而不同。本发明的化合物和组合物的每日剂量将取决于患者的多种因素，包括所治疗的病症、该病症的严重程度、所采用的具体化合物的药效、特定组合物、年龄、体重、一般健康状况、性别和饮食、给药的途径和时间表、代谢和/或所述化合物的***速率、治疗的持续时间等。此外，本发明的化合物所需剂量与药学上可接受的载体制成药剂后，可施用于人和其他动物。给药模式包括口服、直肠、肠胃外、脑池内、***内、腹膜内、局部(如通过透皮贴剂、粉剂、软膏、或滴剂)、舌下、经颊、或 鼻喷雾等。本发明的化合物的有效剂量通常以每公斤患者体重所施药量来计量，优选于0.1～125毫克/千克体重，一般为0.01～500毫克/千克体重。给药可以是一次或多次、每天、每周、每隔一日或每隔多日、或一个间歇时间表。例如，所述化合物可以每天给药、每周给药(例如，每周一)、无限期给药或延续数周给药(例如4-10周)。本发明的化合物的有效剂量将根据所使用的化合物，给药模式、疾病的严重性、所治疗条件以及相关的患者的各种物理因素而变化。在多数情况下，当本发明的优选化合物的每日剂量约为0.01～500毫克/公斤时，可以达到令人满意的治疗效果。优选剂量为0.1～125毫克/千克，更优选的剂量为1～25毫克/千克。肠胃外给药剂量通常是在大约10％-20％的口服剂量水平。当本发明的化合物被用作组合治疗方案的一部分时，每一个组合物的组分将在一个所需的治疗期间被施用。无论是作为单独的剂量单元或者作为单一剂型包含两种组分，组合物中的组分可以在治疗期中同时施用，也可以在治疗期中的不同时间施用，或者某个可以作为另一个的预处理施用。
关于化合物
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明中分离纯化的化合物与合适的游离碱或酸反应而成。
药学上无毒的酸形成的盐，包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的氨基盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁、等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化是通过前体药物在血液中水解或在血液或组织中经酶作用而转化为母体化合物的。
组合物
本专利所述组合物是由本文所述任何一个化合物(或前药、或其药学上可接受的盐、或其他药学上可接受的衍生物)，以及一种或多种药学上可接受的载体或赋形剂所组成。这些组合物可任选进一步包含一种或多种另外的治疗剂。本发明的化合物可以与一种或多种其它治疗方案(例如，Tofacitinib或其他激酶抑制剂、干扰素、骨髓移植、法尼基转移酶抑制剂、二膦酸盐、沙利度胺的施用组合、癌症疫苗、激素疗法、抗体、辐射等)共同施用于所需患者。化合物的药物组合物可以是另一种或多种抗炎剂或抗癌剂。
如本文所述，本发明的组合物包含本发明的化合物与药学上可接受的载体，包括任何和所有溶剂、稀释剂或其它载体、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等，以适合于所需的特定剂型。一些药学上可接受的载体材料的实例包括，但不限于，糖，如乳糖、葡萄糖和蔗糖；淀粉如玉米淀粉和马铃薯淀粉；纤维素及其衍生物如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；西黄蓍胶粉；麦芽；明胶；滑石粉；赋形剂，例如可可脂和栓剂蜡；油如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；乙二醇，例如丙二醇；酯类如油酸乙酯和月桂酸乙酯、琼脂；缓冲剂例如氢氧化镁和氢氧化铝；藻酸；无热原水；等渗盐水；林格氏溶液；乙醇，和磷酸盐缓冲溶液，以及其它无毒的相容性润滑剂如月桂基硫酸钠和硬脂酸镁、以及着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以可存在于组合物中。
配方
本发明还涵盖本发明中的活性化合物与一种或多种药学上可接受的载体和/或稀释剂和/或佐剂联合使用的一类组合物(在本文中统称为“载体”材料)，并且如果需要的话，也包括其它活性成分。本发明的活性化合物可以通过任何合适的途径给药，优选以适合这种给药途径的药物组合物的形式用于预期治疗所需的有效剂量。本发明的化合物和组合物的给药形式可以是，口服，粘膜，局部，直肠，经肺，如通过吸入喷雾，或胃肠外，包括血管内，静脉内，腹膜内，皮下，肌内，胸骨内和输注技术。其给药是以剂量单位为准的制剂形式并含有药学上可接受的载体，佐剂，和赋形剂。对于口服给药，药物组合物可以是下列形式，例如，片剂、胶囊剂、混悬剂或液体。所述剂量单位的实例是片剂或胶囊。例如，它们可以包含活性成分的量为1至2000毫克，优选为1至500毫克，更常见的为5至200毫克。一个人或其它哺乳动物合适的每日剂量可根据患者和其他因素有所不同，但可以使用常规方法来再次确定。如前所述，本发明所涉及的化合物和/或组合物的给药和剂量方案中化合物的量取决于多种因素，包括受试者的年龄，体重，性别和医疗条件，疾病类型，该疾病严重程度，给药途径和频率，以及所使用的特定化合物。因此，剂量方案可以变化很大，但可使用标准方法来确定。典型的日剂量为0.01～500毫克/公斤体重，优选为0.1～125毫克/公斤体重，更优选为1～25毫克/公斤体重。
本发明的活性化合物通常与一种或多种佐剂、赋形剂或载体来组成给药途径。如果口服给药，所述化合物可以与乳糖、蔗糖、淀粉粉末、链烷酸纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠和钙盐、明胶、金合欢胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇相混合，然后压片或制成胶囊以方便给药。这样的胶囊剂或片 剂可以包含一种控释制剂，可将活性化合物分散于羟丙基甲基纤维素来提供。适合于局部给药的制剂包括适于渗透穿过皮肤的液体或半液体制剂(如搽剂、洗剂、软膏剂、乳膏剂或糊剂)和适合施用于眼、耳或鼻的滴液。本发明的化合物适宜的局部给药剂量为0.1～150毫克，每日一至四次，优选每日1至2次。对于局部给药，使用软膏剂时，活性成分可与任何石蜡或水混溶性软膏为基质。或者，活性成分可以配制成油包水乳剂基质霜剂。如果需要，乳膏基质的水相可包括例如至少30％重量比的多元醇，如丙二醇、丁烷-1，3-二醇、甘露醇、山梨醇、甘油、聚乙二醇和它们的混合物。局部制剂可以包括能使通过皮肤或其它受影响区域增强活性成分吸收或渗透的化合物。此类真皮渗透增强剂的实例包括二甲基亚砜和相关类似物。化合物还可以通过透皮装置给药。优选透皮给药将使用含有储液器和多孔质膜或者固体基质的贴剂来实现。本发明的乳剂的油相可以由已知成分以已知方式构成，包含至少一种乳化剂与脂肪或油的混合物或与两者的脂肪和油的混合物。优选地，亲水性乳化剂可同时与作为稳定剂的亲脂性乳化剂合用，另外优选的是它也可以与油和脂肪合用。适合于在本发明的制剂中使用的乳化剂和乳液稳定剂包括吐温60、司盘80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、月桂基硫酸钠、单一的二硬脂酸甘油酯或与其与乳化蜡的混合物，或本领域中公知的其他材料。乳膏应当优选不油腻、不着色和可洗的产品，并具有合适的稠度以避免从管或其他容器中渗漏。直链或支链、一元或二元烷基酯如二异己二酸酯、异十六烷基硬脂酸酯、椰子脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、2-乙基己基棕榈酸酯或混合的支链的酯也可使用。作为选择，高熔点脂质如白色软石蜡和/或液体石蜡或其它矿物油都可以使用。适于局部给药至眼部的制剂还包括滴眼剂，其中活性成分溶解或悬浮于合适的载体，特别是对于活性成分的水性溶剂。活性成分在这些制剂中重量比优选为0.5％至20％，更有利的比例是0.5～10％，最佳为约1.5％的浓度。制剂用于肠胃外给药可以是以水性或非水性的等渗无菌注射溶液或悬浮液的形式。这些溶液和悬浮液可以从一个或多个无菌粉末或颗粒，通过使用本文提到的用于口服给药的制剂或使用其他合适的分散剂或润湿剂和助悬剂的载体或稀释剂而制备。化合物可以溶解在水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠、黄蓍胶、和/或各种缓冲液。其它辅助剂和给药方式是在制药领域中众所周知的。
所述活性成分还可以通过注射给药、与合适的载体包括盐水、葡萄糖或水的组合物、或者与环糊精(Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即吐温80)。制剂还可以是无菌注射溶液或在无毒的肠胃外可接受的稀释剂或溶剂中的悬浮液，例如1，3-丁二醇。可使用的溶剂有水、林格氏溶液和等渗氯化钠溶液。此外，无菌、不挥发性油通常用作溶剂或悬浮介质。用于此目的的任何温和的固定油都可以使用，包括合成的单或二甘油酯。
对于肺部给药，所述药物组合物可以施用以气雾剂的形式或用吸入器，包括干粉气雾剂。用于直肠给药的栓剂可通过将药物与适宜的无刺激性赋形剂来制备，如可可脂和聚乙二醇在常温下是固体，但在直肠温度为液体，因此将在直肠中融化并释放出药物。该药物 组合物可以加入常规的药物操作如灭菌和/或可以含有常规的佐剂，如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等的片剂和丸剂还可用肠溶衣制备。这样的组合物还可以包含佐剂，如润湿剂、甜味剂、矫味剂和芳香剂。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。本发明的可替代的组合物包括具有本文所述式(I)的化合物或其药学上可接受的盐和药学上可接受的载体，佐剂或赋形剂。这样的组合物可任选地包含一种或多种额外治疗剂，包括，例如，激酶抑制剂(小分子，多肽，抗体等)，免疫抑制剂，抗癌剂，抗病毒剂，抗炎剂，抗真菌剂，抗生素或抗血管过度增生化合物。
术语“药学上可接受的载体或佐剂”是指一种可与本发明的化合物一起被施用给患者的载体或佐剂，并且其不破坏药物活性，并且在剂量足以递送给药治疗量时是无毒的。药学上可接受的载体、佐剂和赋形剂可用于本发明的药物组合物，包括但不限于、离子交换剂、氧化铝、硬脂酸铝、卵磷脂、自乳化药物传递***(SEDDS)、如d-atocopHerol聚乙二醇1000琥珀酸盐，药物剂型中使用的表面活性剂，如吐温或其他类似的聚合物递送基质，血清蛋白如人血清白蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的偏甘油酯混合物中使用表面活性剂，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体二氧化硅，三硅酸镁，聚乙烯吡咯烷酮，基于纤维素的物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜡，聚乙烯-聚氧丙烯嵌段聚合物，聚乙二醇和羊毛脂。环糊精如α-，β-，和γ-环糊精，或化学改性衍生物如羟基烷基，包括2和3-羟丙基-环糊精，或者其它溶解的衍生物也可有利地用于提高递送本文所述结构式的化合物。所述药物组合物可以任意使用可接受的剂型口服给药，包括但不限于胶囊，片剂，乳剂和水性悬浮液，分散体和溶液。在用于口服使用的片剂的情况下，通常使用的载体包括乳糖和玉米淀粉。润滑剂，诸如如硬脂酸镁，也通常被加入。对于以胶囊形式的口服给药，有用的稀释剂包括乳糖和干燥的玉米淀粉。当使用水性悬浮液和/或乳状液口服给药时，活性成分可与乳化和/或悬浮剂悬浮或溶解于油相中。如果需要，某些甜味剂，矫味剂和/或着色剂可以被加入。该药物组合物可以包括使用脂质体或微胶囊化技术，其不同的实施例在文献中可以查到。所述药物组合物可通过鼻气雾剂或吸入给药。这样的组合物是根据药物制剂领域中的已知技术制备的，并且可以在盐水中制备成溶液，采用苯甲醇或其它合适的防腐剂，吸收促进剂以提高生物利用度，碳氟化合物，和/或其它增溶剂或分散剂，其例子也是众所周知的现有技术。
联合用药
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明 的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原则的前提下，本发明的实施方式还可以作出若干改进和修饰，这些改进和修饰也应视为本发明的保护范围。

Claims (24)

  1. 一种化合物或其异构体、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 PCTCN2018106694-appb-100001
    其中，
    R 1为
    Figure PCTCN2018106694-appb-100002
    n 1为0-2，n 2为0-1，n 3为0-5，
    L 1为
    Figure PCTCN2018106694-appb-100003
    R 4和/或R 5为H、C 1-C 3直链烷基；
    R 2为
    Figure PCTCN2018106694-appb-100004
    n 4为0-3，n 5为0-1，n 6为0-5，
    L 2为
    Figure PCTCN2018106694-appb-100005
    R 7和/或R 8为H、C 1-C 3直链烷基；
    R 3为a)H，羟基，氰基，
    b)C 1-C 5直链或支链烷基，
    c)C 3-C 7环烷基，
    d)C 1-C 5直链或支链烷氧基，
    e)C 1-C 5直链或支链烷硫基，
    f)5-7元杂环，
    g)取代或非取代的五元芳基或者杂芳基，
    h)取代或非取代的六元芳基或者杂芳基，
    i)含0-3个杂原子六元芳环或杂芳环并五元或六元环，或含1-3个杂原子五元芳杂环并五元或六元环，如：
    Figure PCTCN2018106694-appb-100006
    R 6为a)H、羟基，
    b)-NR′R″，R′、R″为H、C 1-C 3的烷基，
    c)C 1-C 5直链或支链烷基，
    d)C 3-C 8环烷基，
    e)C 1-C 5直链或支链烷氧基，
    f)C 1-C 5直链或支链烷硫基，
    g)杂环基。
  2. 根据权利要求1所述的化合物或其异构体、溶剂化物或其药学上可接受的盐，其中，所述5-7元杂环含有1-2个杂原子，其杂原子选自O和/或N和/或S，当杂原子为N时，N上连接H或C 1-C 4烷基、C 1-C 3酰基，优选乙酰基、三氟乙酰基、丙酰基、N，N-二甲酰基；当杂原子为S时，S上连接0-2个氧原子。
  3. 根据权利要求1所述的化合物或其异构体、溶剂化物或其药学上可接受的盐，其中，所述取代的五元芳基或者杂芳基的结构式为
    Figure PCTCN2018106694-appb-100007
    其中：
    J 1和/或J 2和/或J 3和/或J 4为C、N、S、O，
    R 9为C 1-C 3直链或支链烷基。
  4. 根据权利要求1所述的化合物或其异构体、溶剂化物或其药学上可接受的盐，其中，所述取代或非取代的五元芳基或者杂芳基的结构式为
    Figure PCTCN2018106694-appb-100008
    其中：
    J 1、J 2、J 3、J 4各自独立地为C、N、S、O，
    R 20、R 21各自独立地为C 1-C 3直链或支链烷基。
  5. 根据权利要求1所述的化合物或其异构体、溶剂化物或其药学上可接受的盐，其中，所述取代或非取代的六元芳基或者杂芳基的结构式为
    Figure PCTCN2018106694-appb-100009
    其中：
    Q 1、Q 2、Q 3、Q 4、Q 5为N或C；
    R 10和/或R 11和/或R 12为：
    a)-F、-Cl、-Br、-CF 3、-OCF 3、氰基，
    b)-NR′R″，R′、R″为H、C 1-C 3的烷基，
    c)C 1-C 3烷基、C 2-C 5炔基、C 3-C 5环烷基，
    d)SO 2R 13，其中R 13为H、C 1-C 3烷基，
    e)
    Figure PCTCN2018106694-appb-100010
    其中q为0-2，M为O、S，R 14为H，C 1-C 5直链或支链烷基，
    f)
    Figure PCTCN2018106694-appb-100011
    其中R 15、R 16为直链烷基。
  6. 根据权利要求1所述的化合物或其异构体、溶剂化物或其药学上可接受的盐，其中，所述取代或非取代的六元芳基或者杂芳基的结构式为
    Figure PCTCN2018106694-appb-100012
    其中：
    Q 1、Q 2、Q 3、Q 4、Q 5为N或C；
    R 17、R 18各自独立地为：
    a)-H，
    b)-F、-Cl、-Br、-CF 3、-OCF 3、氰基，
    c)-NR′R″，R′、R″为H、C 1-C 3的烷基，
    d)C 1-C 3烷基、C 2-C 5炔基、C 2-C 5烯基、C 3-C 5环烷基，
    e)SO 2R 13，其中R 13为H、C 1-C 3烷基，
    f)
    Figure PCTCN2018106694-appb-100013
    其中q为0-2，M为O、S，R 14为H，C 1-C 5直链或支链烷基，
    g)
    Figure PCTCN2018106694-appb-100014
    其中R 15、R 16为C 1-C 3的直链烷基，
    h)-(CH 2) t-R 19，t为1-2，R 19为C 3-C 5环烷基。
  7. 根据权利要求1所述的化合物或其异构体、溶剂化物或其药学上可接受的盐，其中，所述杂环基为五元或六元含氧和/或氮的杂环基，如：
    Figure PCTCN2018106694-appb-100015
  8. 一种化合物或其异构体、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 PCTCN2018106694-appb-100016
    其中，
    R 1为
    Figure PCTCN2018106694-appb-100017
    n 1为0-2，n 2为0-1，n 3为0-5，
    L 1为
    Figure PCTCN2018106694-appb-100018
    R 4和/或R 5为H、C 1-C 3直链烷基；
    R 2为
    Figure PCTCN2018106694-appb-100019
    n 4为0-3，n 5为0-1，n 6为0-5，
    L 2为
    Figure PCTCN2018106694-appb-100020
    R 7和/或R 8为H、C 1-C 3直链烷基；
    R 3为R 22取代的C 1-C 3烷氧基或者R 22取代的C 1-C 3烷硫基，R 22为羟基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR′R″、羟基取代的C 1-C 3烷氧基、氨基取代的C 1-C 3烷氧基、羟基取代的 C 1-C 3烷硫基、氨基取代的C 1-C 3烷硫基，其中R′、R″为H、C 1-C 3的烷基；
    R6为 a)H、羟基，
    b)-NR′R″，R′、R″为H、C 1-C 3的烷基，
    c)C 1-C 5直链或支链烷基，
    d)C 3-C 8环烷基，
    e)C 1-C 5直链或支链烷氧基，
    f)C 1-C 5直链或支链烷硫基，或者
    g)
    Figure PCTCN2018106694-appb-100021
  9. 一种化合物或其异构体、溶剂化物或其药学上可接受的盐，所述化合物选自：
    4-苄基氨基-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二甲基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[[4-氨基-2-氟苄基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-正丁氨基-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-(正戊氨基)嘧啶-5-甲酰胺；
    4-异丁氨基-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-新戊氨基嘧啶-5-甲酰胺；
    4-(异戊氨基)-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(3，3-二甲基丁基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(4-甲基戊基)氨基)嘧啶-5-甲酰胺；
    4-[(环丙基甲基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(环丁基甲基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(环戊基甲基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(环己基甲基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-环丙基乙基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-环戊基乙基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(4-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(4-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(3-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(3-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(3-甲基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(2-甲基苄基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(2-乙基苄基)氨基]嘧啶-5-甲酰胺；
    4-[(2-环丙基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(2-三氟甲基苄基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氰基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-乙氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-异丙氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(2-三氟甲氧基苄基)氨基]嘧啶-5-甲酰胺；
    4-[[2-(甲氧甲基)苄基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，3-二氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-3-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，3-二氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氯-3-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基-3-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，3-二甲基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，4-二氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-4-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氯-4-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基-4-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基-4-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲氧基-4-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，5-二氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-5-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氯-5-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基-5-氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基-5-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[[2-(三氟甲基)-5-氟苄基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲氧基-5-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，5-二甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-(三氟甲基)苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基-6-氯苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(3，5-二氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(3，5-二甲氧基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，3，6-三氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，3，5-三氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟-3-甲基苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氯-3，6-二氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，4，6-三氟苄基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-(苯乙氨基)嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(3-甲基苯乙基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(3-甲氧基苯乙基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟苯乙基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲基苯乙基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-甲氧基苯乙基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-氯苯乙基)氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(吡啶-4-基甲基)氨基]嘧啶-5-甲酰胺；
    4-[[(2-氟吡啶-3-基)甲基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[[(2-甲氧基吡啶-3-基)甲基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[[(2-乙氧基吡啶-3-基)甲基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[[(2-叔丁氧基吡啶-3-基)甲基]氨基]-2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[[2-(吡啶-3-基)乙基]氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[[(2，3-二氢苯并[b][1，4]二噁烷-5-基)甲基]氨基]嘧啶-5-甲酰胺；
    2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[[(1H-吲哚-3-基)甲基]氨基]嘧啶-5-甲酰胺；
    (S)-2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(2-苯基丙基)氨基]嘧啶-5-甲酰胺；
    (R)-2-[(1-甲基-1H-吡唑-4-基)氨基]-4-[(2-苯基丙基)氨基]嘧啶-5-甲酰胺；
    4-苄基氨基-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    2-[(1H-吡唑-4-基)氨基]-4-[(2，6-二氟苄基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[(1-乙基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[(1-异丙基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[(1-环丙基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[(1-环丁基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(四氢呋喃-3-基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-((四氢呋喃-2-基)甲基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-((四氢呋喃-3-基)甲基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(2-甲硫基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(2-(吗啉-1-基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟苄基)氨基]-2-[[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-氯苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-氯苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-氯苄基)氨基]-2-[[1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    2-[(1H-吡唑-4-基)氨基]-4-[(2-氟-6-甲氧基苄基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-乙基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-异丙基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-环丙基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-环丁基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-环戊基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-环己基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[(1-环庚基-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-甲硫基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-{[1-(1-甲基哌嗪-4-基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-(吡咯-1-基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-(哌啶-1-基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-(吗啉-1-基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(6-甲氧己基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-甲氧基苄基)氨基]-2-[[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[[2-氟-6-(三氟甲基)苄基]氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-(三氟甲基)苄基)氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氟-6-(三氟甲基)苄基)氨基]-2-[[1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-甲氧基苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-甲氧基-5-氯苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二甲基苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氯-6-甲基苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氯苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，3，6-三氟苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2，6-二氟-3-甲基苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[(2-氯-3，6-二氟苄基)氨基]-2-[[1-(2-羟乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺；
    4-[[2-氟-3-甲氧基苄基]氨基]-2-[[1-(2-甲氧基乙基)-1H-吡唑-4-基]氨基]嘧啶-5-甲酰胺。
  10. 一种化合物或其异构体、溶剂化物或其药学上可接受的盐，所述化合物选自：
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-(异戊基氨基)嘧啶-5-甲酰胺；
    4-(异戊基氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-(2-羟基乙氧基)乙基)氨基)嘧啶-5-甲酰胺；
    4-((2-(2-羟基乙氧基)乙基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-乙基-1H-吡唑-4-基)氨基)-4-((2-乙基苄基)氨基)嘧啶-5-甲酰胺；
    4-((2-乙基苄基)氨基)-2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-乙基苄基)氨基)-2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-环丙基-1H-吡唑-4-基)氨基)-4-((2-乙基苄基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-乙基苄基)氨基)嘧啶-5-甲酰胺；
    4-((2-乙基苄基)氨基)-2-((1-(四氢-2H-吡喃-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-甲基-1H-吡唑-4-基)氨基)-4-((2-丙基苄基)氨基)嘧啶-5-甲酰胺；
    4-((2-异丙基苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-(环丙基甲基)苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-甲氧基苄基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2，6-二氟苄基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-环丙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-氯-6-氟苄基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-环丁基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-环戊基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-环己基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氯-6-氟苄基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-溴-6-氟苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-溴-6-氟苄基)氨基)-2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氟-6-甲基苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-氟-6-甲基苄基)氨基)-2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-乙基-1H-吡唑-4-基)氨基)-4-((2-氟-6-(三氟甲基)苄基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-氟-6-(三氟甲基)苄基)氨基)嘧啶-5-甲酰胺；
    4-((2-乙基-6-氟苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-乙基-1H-吡唑-4-基)氨基)-4-((2-乙基-6-氟苄基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-乙基-6-氟苄基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-氟-6-甲氧基苄基)氨基)嘧啶-5-甲酰胺；
    4-((2，6-二甲基苄基)氨基)-2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2，6-二甲基苄基)氨基)-2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2，6-二甲基苄基)氨基)嘧啶-5-甲酰胺；
    4-((2，6-二甲基苄基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((2-乙炔基苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-甲基-1H-吡唑-4-基)氨基)-4-((2-乙烯基苄基)氨基)嘧啶-5-甲酰胺；
    2-((1-甲基-1H-吡唑-4-基)氨基)-4-((2-(丙基-1-烯-1-基)苄基)氨基)嘧啶-5-甲酰胺；4-((2-烯丙基苄基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺。
  11. 一种结构式(I)的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2018106694-appb-100022
    其中，
    X为N；
    R 1为
    Figure PCTCN2018106694-appb-100023
    n 1为0-8的整数，n 2为0-1的整数，n 3为0-8的整数，且n 1、n 2、n 3之和为10以下；
    L 1为
    Figure PCTCN2018106694-appb-100024
    R 4、R 5各自独立地为H、C 1-C 3烷基，R 4、R 5相同或者不同，
    R 3为未取代或者C 1-C 3烷基取代的C 2-C 8链烯基或者未取代或者C 1-C 3烷基取代的C 4-C 8的环烯基；
    R 2为
    Figure PCTCN2018106694-appb-100025
    n 4为0-8的整数，n 5为0-1的整数，n 6为0-8的整数，且n 4、n 5、n 6之和为10以下；
    L 2为
    Figure PCTCN2018106694-appb-100026
    R 7、R 8各自独立地为H、C 1-C 3烷基，R 7、R 8相同或者不同，
    R 6为-H、羟基烷基、C 1-C 5烷基、C 3-C 8环烷基、C 1-C 5烷氧基烷基、C 1-C 5烷硫基烷 基、5-6元杂环基、或-NR′R″，其中R′、R″各自独立地为H、C 1-C 3的烷基。
  12. 如权利要求11所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，
    其中，R 3为
    Figure PCTCN2018106694-appb-100027
    R 9、R 10、R 11、R 12、R 13各自独立地为H、C 1-C 3烷基，m为0至2的整数，
    m 1为0至5的整数，m 2为0至5的整数，且m 1，m 2之和小于或等于5。
  13. 如权利要求11所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，
    其中，R 3为
    Figure PCTCN2018106694-appb-100028
    R 9、R 10各自独立地为H、C 1-C 3烷基，R 11、R 12、R 13中任一为C 4-C 6烷基，其余各自独立地为H、C 1-C 3烷基，m为0至2的整数。
  14. 如权利要求12所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，n 1为0-2整数，n 2为0-1整数，n 3为0-3整数，R 4、R 5各自独立地为H、甲基，R 4、R 5相同或者不同；
    R 9、R 10、R 11、R 12、R 13各自独立地为H、甲基或乙基，m为0或1。
  15. 如权利要求14所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，所述R 3为
    Figure PCTCN2018106694-appb-100029
    R 9、R 11、R 12、R 13各自独立地为H、甲基或乙基。
  16. 如权利要求11所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，n 4为0-3整数，n 5为0-1整数，n 6为0-5整数，R 7、R 8各自独立地为H、甲基，R 7、R 8相同或者不同；
    R 6为-H、羟乙基、羟丙基、C 1-C 5烷基、C 3-C 8环烷基、C 1-C 5烷氧基乙基、C 1-C 5烷氧基丙基、C 1-C 5烷硫基乙基、5-6元杂环基、或-NR′R″，其中R′、R″各自独立地为H、C 1-C 3的烷基。
  17. 如权利要求16所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 6为H、羟乙基、羟丙基、甲基、乙基、丙基、异丙基、叔丁基、环丙基、环丁基、环戊基、环己基、甲氧基乙基、乙氧基乙基、丙氧基乙基、异丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、异丙氧基丙基、甲硫基乙基、乙硫基乙基、丙硫基乙基、异丙硫基乙基、5-6元杂环基、或-NR′R″，其中R′、R″分别独立地为H、甲基、乙基；
    所述5-6元杂环基为未取代或被1-2个选自羟基、C 1-C 3烷基、C 1-C 3酰基的取代基所取代的含有1-2个选自N、O、S的杂原子的杂环基。
  18. 如权利要求17所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，所述含有1-2个选自N、O、S的杂原子的杂环基为选自以下基团中的任一种：
    Figure PCTCN2018106694-appb-100030
    其中R 14为H、甲基、乙基、丙基、异丙基。
  19. 如权利要求11所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，所述式(I)的化合物选自：
    4-(丁基-3-烯-1-基氨基)-2-((1-(叔丁基)-1H-吡唑-4-基)氨基]嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((2-甲基烯丙基)氨基)嘧啶-5-甲酰胺；
    2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-((3-甲基丁基-2-烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-(戊基-4-烯-1-基氨基)嘧啶-5-甲酰胺；
    4-((2-甲基烯丙基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-((3-甲基丁基-2-烯-1-基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-(丁基-3-烯-1-基氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)-4-(戊基-4-烯-1-基氨基)嘧啶-5-甲酰胺。
  20. 如权利要求11所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，所述式(I)的化合物选自：
    2-((1-(叔丁基)-1H-吡唑-4-基)氨基)-4-((环戊基-3-烯-1-基甲基)氨基)嘧啶-5-甲酰胺；
    4-((环戊基-3-烯-1-基甲基)氨基)-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    4-(烯丙氨基)-2-((1-(叔丁基)-1H-吡唑-4-基)氨基)嘧啶-5-甲酰胺；
    (Z)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((戊烷-2-烯-1-基)氨基)嘧啶-5-甲酰胺；
    (E)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((4-甲基戊烷-2-烯-1-基)氨基)嘧啶-5-甲酰胺；
    (E)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((戊烷-3-烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((3-甲基丁基-3-烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((4-甲基戊烷-3-烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((4-甲基戊烷-4-烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((5-甲基己烷-4-烯-1-基)氨基)嘧啶-5-甲酰胺；
    (E)-2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-((5-甲基己烷-2-烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-(((2E，4E)-己烷-2，4-二烯-1-基)氨基)嘧啶-5-甲酰胺；
    2-((1-叔丁基-1H-吡唑-4-基)氨基)-4-(((2E，4E)-庚烷-2，4-二烯-1-基)氨基)嘧啶-5-甲酰胺。
  21. 如权利要求1至20中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己胺基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
  22. 权利要求1至20中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症的药物中的应用，其中，所述与酪氨酸激酶JAK1、JAK2、JAK3、TYK2相关的自身免疫疾病以及癌症包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子***、结肠直肠癌、黑色素瘤、子宫内膜癌、***癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
  23. 一种药物组合物，包括权利要求1至20中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。
  24. 如权利要求23所述的药物组合物，其中，所述药物组合物还包括一种或多种其他治疗剂。
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WO2020187292A1 (zh) * 2019-03-19 2020-09-24 北京赛特明强医药科技有限公司 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用

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