WO2021233236A1 - Substituted heteroaryl compound, and composition and use thereof - Google Patents

Substituted heteroaryl compound, and composition and use thereof Download PDF

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WO2021233236A1
WO2021233236A1 PCT/CN2021/094020 CN2021094020W WO2021233236A1 WO 2021233236 A1 WO2021233236 A1 WO 2021233236A1 CN 2021094020 W CN2021094020 W CN 2021094020W WO 2021233236 A1 WO2021233236 A1 WO 2021233236A1
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alkyl
pyrrolo
cycloalkyl
phenyl
pyrimidin
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PCT/CN2021/094020
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French (fr)
Chinese (zh)
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习宁
许世民
王婷瑾
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北京范恩柯尔生物科技有限公司
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • 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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a new class of substituted heteroaryl compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds, and the use of the compounds and the pharmaceutical compositions in preparing and treating mammals Use in medicines for proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer, viral infectious diseases or other diseases. More specifically, the compounds of the present invention can regulate the activity of AXL kinase, thereby regulating signal transduction inside and outside the cell.
  • the protein kinase family includes a large class of structurally related enzymes that control various signal transduction processes in cells and catalyze the phosphorylation of target protein substrates.
  • Many diseases are related to abnormal cellular responses triggered by protein kinase-mediated events. These diseases include benign and malignant proliferative diseases, diseases caused by inappropriate activation of the immune system, allograft rejection, graft-versus-host diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological diseases And neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases.
  • the medical field has developed protein kinase inhibitors that are effective in treating the diseases.
  • kinases can be classified into multiple families by phosphorylated substrates (eg, protein-tyrosine, protein-serine/threonine, lipid, etc.). Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival. Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets.
  • phosphorylated substrates eg, protein-tyrosine, protein-serine/threonine, lipid, etc.
  • Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival.
  • Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets.
  • kinases in the protein kinase family include, but are not limited to, Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fyn, AXL, IGF-1R, INS-R, KDR, Lck, Lyn, MEK, Mer, p38, PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, Tyro3 and Zap70, etc. (Robin
  • Cancer and other hyperproliferative diseases is characterized by uncontrolled cell proliferation. Compared with normal tissues, the activity of many protein kinases in human tumors is increased, and this increased activity may be due to many factors, including increased kinase levels, mutations in the expression of co-activators or inhibitory proteins .
  • AXL is a membrane-bound receptor tyrosine kinase, belonging to the TAM (Tyro3, AXL, Mer) family. It is characterized by their two immunoglobulin-like domains and the double fibronectin repeats in their extracellular domains and the kinase domain with related tyrosines in their cytoplasmic domains. (Linger, R.M.et al., TAM receptor tyrosinekinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Advances in cancer research 2008, 100, 35-83.).
  • TAM receptor tyrosine kinase is involved in cell growth, migration, aggregation and apoptosis in a variety of normal cells.
  • GAS6 growth arrest specific 6
  • protein S protein S
  • the binding of Gas6 to AXL leads to receptor dimerization and AXL autophosphorylation.
  • Stitt, T.N.et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptors. Cell 1995, 80(4), 661-70.).
  • AXL is present in a variety of organs and cells, including epithelial cell lines, mesenchymal and hematopoietic origins, and untransformed cells.
  • AXL kinase is overexpressed or activated in a variety of cancers, including ovarian cancer, melanoma, renal cell carcinoma, uterine leiomyoma, endometrial cancer, thyroid cancer, gastric cancer, breast cancer, NSCLC, CML, AML, colon Cancer, prostate cancer, various lymphomas, and esophageal cancer.
  • Immunotherapy refers to a treatment method that artificially enhances or suppresses the immune function of the body to achieve the purpose of curing diseases. There are many immunotherapy methods, and they are applicable to the treatment of many diseases. Tumor immunotherapy aims to activate the human immune system and kill cancer cells and tumor tissues by relying on autoimmune functions (Myers et al. Molecular Cancer, 2019, 18:94). Unlike previous surgery, chemotherapy, radiotherapy, and targeted therapy, the target of immunotherapy is not tumor cells and tissues, but the body's own immune system.
  • Protein kinase inhibitors have attracted a lot of attention as new immunomodulatory, anti-inflammatory and anti-cancer drugs. Therefore, new or improved agents that inhibit protein kinases such as AXL kinase can be used as immunomodulators, antitumor agents, analgesics, and anti-organ fibrosis drugs for organ transplantation, and new or improved agents for AXL kinase can also be used for prevention and/ Or treat autoimmune diseases (e.g., multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn’s disease, polycythemia vera, essential thrombocytosis Disease, myelofibrosis, autoimmune thyroid disease, Alzheimer’s disease), diseases involving excessive activation of inflammatory response (e.g., eczema), allergies, chronic obstructive pulmonary disease, bronchitis, fibrosis, cancer (e.g., gastric cancer
  • TAM receptor tyrosine kinases Tyro3, Axl and Mer and their homologous ligand proteins S (Protein S) and Gas6 promote immunity, phagocytosis and clearance of apoptotic cells in the nervous and reproductive systems. They also drive a key negative feedback loop that down-regulates the host's innate immune response mediated by Toll-like receptors (TLR) and type I interferon signaling pathways.
  • TLR Toll-like receptors
  • the TAM receptor-ligand interaction is also related to the promotion of cell entry of enveloped viruses: it has been found that the ectopic introduction of one or more TAM receptors into anti-infective cell lines can enhance filovirus and lentivirus infection.
  • the TAM ligand proteins S and Gas6 both contain a glutamate-rich Gla domain at their amino terminus, which is compatible with those exposed to apoptotic cells and membranes. Phosphatidylserine (PtdSer) on the surface of the virus particle binds.
  • Phosphatidylserine (PtdSer) on the surface of the virus particle binds.
  • the enveloped virus contains a high level of PtdSer on its surface and binds to the TAM ligand protein S and Gas6 through the PtdSer-Gla domain interaction.
  • the function of TAM receptor-ligand interaction is considered to be limited to promoting the binding of the virus to the target cell, thereby promoting virus infection.
  • Membrane-bound TAM ligands are significantly more effective than free ligands in activating TAM receptor signal transduction, indicating that TAM ligands change the ligand's influence on TAM signal transduction through the PtdSer binding of its gla domain.
  • AXL kinase inhibitors can block the interaction between AXL ligand and phosphatidylserine (PtdSer) in the membrane. Therefore, new reagents or improved reagents that inhibit protein kinases such as AXL kinase can be used as drugs for the treatment and/or prevention of viral infectious diseases, such as anti-Zika virus (iScience, 2019, 13,339-350), coronavirus, new coronavirus ( Such as covid-19, etc.) and hepatitis B virus (HBV) (Journal of Hepatology 2015 vol.63 j670-678).
  • viral infectious diseases such as anti-Zika virus (iScience, 2019, 13,339-350), coronavirus, new coronavirus ( Such as covid-19, etc.) and hepatitis B virus (HBV) (Journal of Hepatology 2015 vol.63 j670-678).
  • the present invention provides a class of compounds that inhibit, modulate and/or modulate the activity of AXL kinase for the treatment and/or prevention of proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, pain, fibrosis, Transplant rejection, or viral infectious disease or its complications.
  • the compound of the present invention has better pharmacological activity.
  • the compound of the present invention shows excellent inhibitory activity and kinase selectivity for the target kinase.
  • the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
  • the articles “a”, “an” and “said” used in the present invention are intended to include “at least one” or “one or more”. Therefore, these articles used in the present invention refer to articles of one or more than one (ie, at least one) object.
  • a component refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis/trans) isomers, atropisomers, etc. .
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula of the present invention, or special examples, subclasses, and the present invention includes A class of compounds.
  • C 1 -C 6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted with one or more substituents described in this invention.
  • alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • the alkyl group may be optionally substituted with one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, which includes “cis” and ""Reverse” positioning, or “E” and “Z” positioning.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents described in this invention.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • Examples of alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
  • the alkynyl group may be optionally substituted with one or more substituents described in this invention.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the definition as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted by one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ) and so on.
  • -CF 3 trifluoromethyl
  • -OCF 3 Trifluoromethoxy
  • difluoroethyl -CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F
  • trifluoroethyl -CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2
  • hydroxyalkyl or "hydroxy-substituted alkyl” and “hydroxyalkoxy” or “hydroxy-substituted alkoxy” respectively denote an alkyl or alkoxy group, as the case may be, with one or more A hydroxyl group is substituted, where "hydroxyalkyl” and “hydroxyalkyl” can be used interchangeably.
  • Examples of this include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl ( -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxyprop-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane Group (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2Methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OCH 2 OH), etc.
  • cyano substituted alkyl or "cyanoalkyl” includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
  • the cyanoalkyl group is a C 1-6 "lower cyanoalkyl group” substituted with one or more cyano groups.
  • the cyanoalkyl group is substituted by one or more cyano groups.
  • C 1-4 "lower cyanoalkyl" substituted by one or more cyano groups such examples include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -etc.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls, and bridged bicycloalkyls.
  • the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-10 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms.
  • the cycloalkyl group contains 3-7 carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms; still in some embodiments, the cycloalkyl group is C 7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spiro bicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl.
  • the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • the term "monocyclic cycloalkyl” or “monocyclic alkyl” refers to a cycloalkyl of a monocyclic system, wherein the cycloalkyl has the definition as described above, and the monocyclic cycloalkyl group may independently Unsubstituted or substituted by one or more substituents described in the present invention.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • cycloalkylalkyl includes cycloalkyl substituted alkyl groups.
  • a cycloalkylalkyl group refers to a "lower cycloalkylalkyl” group, that is, a cycloalkyl group is attached to a C1-6 alkyl group.
  • the cycloalkylalkyl group refers to a "phenylalkylene" containing a C 1-3 alkyl group.
  • cyclopropylmethyl cyclobutylmethyl
  • cyclopentylmethyl cyclohexylmethyl
  • cyclopentylethyl cyclohexylethyl
  • the cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described in the present invention.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 3-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 4-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-8 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-7 ring atoms.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • the heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl) and a partially unsaturated heterocyclic group.
  • the heterocyclic group has one or more points of attachment to the rest of the molecule.
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazoline, pyrazole Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, dithiocyclopentyl, tetrahydropyranyl , Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithia Alkyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl,
  • 1,4-thiazepine Base 1,2-thiazepine Group
  • indolinyl 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptan- 5-yl, 2-azaspiro[4.4]nonyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5 ]Decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindyl Dolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydrofuro[3,2-b]
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which refers to a monovalent or multivalent, saturated or partially unsaturated non-aromatic monocyclic ring containing 4-7 ring atoms Or a bicyclic ring, where at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • the heterocyclic group consisting of 4-7 atoms has one or more connection points to connect to the rest of the molecule.
  • examples of monocyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, 2H -Pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl, 1,2-
  • heterocyclylalkyl includes heterocyclyl-substituted alkyl groups, wherein both heterocyclyl and alkyl have the meanings described in the present invention. Examples of this include, but are not limited to, tetrahydrofurylmethyl, pyrrole- 2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl, etc.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and has one or more points of attachment to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • arylalkyl or “aralkyl” includes aryl substituted alkyl groups.
  • an arylalkyl group refers to a "lower arylalkyl” group, that is, the aryl group is attached to a C1-6 alkyl group.
  • the arylalkyl group refers to a "phenylalkylene” containing a C 1-3 alkyl group. Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenethyl and the like.
  • the aryl group on the arylalkyl group may be further substituted with one or more substituents described in the present invention.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring is aromatic, and At least one aromatic ring contains one or more heteroatoms, and each ring system contains a ring composed of 5-7 atoms, and there are one or more connection points connected to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is a heteroaryl group consisting of 5-12 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • heteroarylalkyl means that an alkyl group is substituted by one or more heteroaryl groups, wherein both the heteroaryl group and the alkyl group have the meanings described in the present invention.
  • heteroarylalkyl include, but not Limited to pyridine-2-methyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, etc.
  • halogen refers to F, Cl, Br or I.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • the present invention discloses a class of novel compounds, which can be used as inhibitors of protein kinase activity, especially AXL kinase activity.
  • Compounds that are protein kinase inhibitors can be used to treat and/or prevent diseases, disorders, or conditions associated with inappropriate protein kinase activity, particularly inappropriate AXL kinase activity.
  • the compound of the present invention has better pharmacological activity.
  • the compound of the present invention shows excellent inhibitory activity and kinase selectivity for the target kinase.
  • the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
  • the compounds disclosed in the present invention can show strong inhibitory activity against one or more protein kinases.
  • the present invention relates to a compound having a structure represented by formula (I):
  • U 1 and U 2 are each independently N or -C(R a )-;
  • R 1 and R 2 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkane C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12
  • R 4 is C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-6 alkyl; wherein each of the C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl and C 2 -7 heterocyclyl C 1-6 alkyl is independently optionally substituted with 0, 1, 2, 3 or 4 R 11a ;
  • R a , R 3 , R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each -NR c R d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl,
  • R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-12 atoms, wherein the heterocyclic ring consisting of 4-12 atoms optionally includes 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4 or 5 R 13 ;
  • n 0, 1, or 2.
  • R 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl and C 1-4 cyanoalkyl are independently optionally 0, 1, 2, 3 or 4 R 11 substitutions;
  • R 3 is H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl And C 1-4 cyanoalkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ;
  • R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-7 atoms, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4, or 5 R 13 .
  • R 2 and R 3 are each independently H, D, methyl, ethyl, or propyl, or R 2 and R 3 together with the carbon atom and nitrogen atom to which they are attached are optionally
  • a heterocyclic ring consisting of 5-7 atoms is formed, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 or 3 N, O, and/or S atoms and is optionally substituted by 0, 1 , 2, 3, 4, or 5 R 13 substitutions.
  • the compound of the present invention has a structure represented by formula (II):
  • Each t1 and t2 are independently 0, 1, 2, or 3;
  • n 0, 1, 2, 4, or 5.
  • each t1 and t2 are independently 0, 1, 2, or 3; and m is 0, 1, 2, or 4, respectively.
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, or C 1-9 heteroaryl; wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 amino Alkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl and C 1-9 heteroaryl are independently optionally substituted with 0, 1, 2, 3 or 4 R 11 .
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or 5-atom heteroaryl; wherein each C 1-4 alkyl, C 1-4 haloalkane Group, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidine
  • the group and the 5-atom heteroaryl group are independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl or triazolyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, Pyrazolyl and triazolyl are independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
  • U 1 and U 2 are each independently N or -C(R a )-;
  • Each R a and R 8 are each independently H, D, F, Cl, Br, -OH, -CN, -NO 2, -NH 2, or C 1-4 alkyl; wherein each of said C 1-4 Alkyl groups are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ; and
  • n 0, 1, or 2.
  • R 4 is C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl, C 1-4 alkyl, C 3-6 heterocyclyl, or C 3-6 heterocyclyl C 1-4 alkyl; wherein each C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl C 1-4 alkyl, C 3- 6 heterocyclyl and C 3-6 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3, or 4 R 11a .
  • R 4 is Wherein R 4 is optionally substituted with 0, 1, 2, 3 or 4 R 11a .
  • R 5 is H, D, -NR c R d , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, Or C 1-4 cyanoalkyl.
  • R 6 and R 7 are each independently H, D, F, Cl, Br, -OH, -NR c R d , -CN, -NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl.
  • the compound of the present invention is a compound having one of the following structures:
  • the compounds disclosed in the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms.
  • the present invention aims to make all stereoisomers forms of compounds represented by formula (I) or (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or Conformation) isomers, and their mixtures, such as racemic mixtures, form part of the present invention.
  • stereochemistry of any specific chiral atom when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention .
  • stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.
  • the compound represented by formula (I) or (II) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, and can be used to prepare and/or purify the compound of formula (I) or (II) and/or to isolate the compound of formula (I) Or an intermediate of the enantiomer of the compound shown in (II).
  • the present invention relates to intermediates for the preparation of compounds represented by formula (I) and (II).
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) and (II).
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further includes pharmaceutically acceptable excipients, diluents or carriers, or a combination thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • the pharmaceutical composition of the present invention further comprises an additional therapeutic agent.
  • the present invention relates to a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and/or treatment of diseases and/or disorders mediated by AXL protein kinase .
  • the disease and/or condition is selected from proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, or viral infectious diseases.
  • the disease and/or disorder is selected from treatment and/or prevention of AXL kinase, mediated diseases involving signaling pathways.
  • diseases and/or disorders include proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and their complications.
  • the compounds of the present invention can be used to treat and/or prevent the following diseases and/or disorders, including, but not limited to, cancer (including solid tumors and blood cancers), polycythemia vera, essential thrombocythemia, and myelofibrosis , Myelogenous leukemia, acute lymphocytic leukemia, chronic myeloid leukemia (CML), chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes, respiratory allergic diseases, sinusitis, eczema, measles, food allergy, insect venom allergy, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile joints Inflammation, psoriatic arthritis, organ transplant rejection, tissue transplant rejection
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound disclosed in the present invention, or the compound listed in the examples, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites or pharmaceutically Acceptable salts; and pharmaceutically acceptable excipients, diluents, carriers, vehicles, or combinations thereof.
  • the amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect the inhibition of protein kinase in biological samples or patients.
  • certain compounds of the present invention may exist in free form for treatment, or, if appropriate, may exist in the form of their pharmaceutically acceptable derivatives.
  • Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, and salts of these esters, or can directly or indirectly provide the compound of the present invention or its compounds when administered to a patient in need. Any additional adducts or derivatives of metabolites or residues.
  • the pharmaceutical composition provided by the present invention can be formulated with other active ingredients that do not impair the expected therapeutic effect, or with substances that supplement the expected effect.
  • the present invention provides the use of the compounds and pharmaceutical compositions disclosed in the present invention to treat, prevent, or ameliorate diseases or conditions that are mediated or otherwise affected by one or more protein kinases, such as AXL kinase, or are affected by AXL kinase.
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention for the treatment, prevention or amelioration of inappropriate AXL kinase behavior mediated or otherwise affected Or one or more symptoms of a disease or disorder that is mediated or otherwise affected by inappropriate AXL kinase behavior.
  • Inappropriate AXL kinase behavior refers to AXL kinase behavior that deviates from normal AXL kinase behavior in a specific patient. Inappropriate AXL kinase behavior can take the form of, for example, an abnormal increase in activity, or a deviation in the time point and control of AXL kinase behavior. This inappropriate kinase behavior stems from, for example, inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinase. Therefore, the present invention provides methods for treating these diseases and conditions.
  • myeloproliferative diseases such as polycythemia vera (PCV), idiopathic thrombocythemia, idiopathic myelofibrosis (IMF); leukemia,
  • myeloid leukemia includes chronic myeloid leukemia (CML), imatinib-resistant CML forms, acute myeloid leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as Acute lymphocytic leukemia (ALL) and myeloma
  • cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, urothelial cancer, liver cancer, stomach cancer and kidney cancer Etc.
  • inflammatory diseases or disorders related to immune dysfunction, immune deficiency, immune regulation, autoimmune diseases, tissue transplant rejection include inflammatory diseases or disorders related to immune dysfunction, immune deficiency, immune regulation,
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention, which are used to prevent and/or treat proliferative diseases, autoimmune diseases, and allergic diseases in mammals (including humans). Disease, inflammatory disease, or transplant rejection.
  • the present invention provides a method of treating a mammal suffering from or at risk of suffering from the disease disclosed in the present invention, the method comprising administering an amount effective to treat the disorder or an amount effective to prevent the disorder in one or more of the present disclosures
  • the pharmaceutical composition or compound is administered to a mammal suffering from or at risk of suffering from the disease disclosed in the present invention, the method comprising administering an amount effective to treat the disorder or an amount effective to prevent the disorder in one or more of the present disclosures.
  • the proliferative disease is selected from cancers such as colon cancer, malignant glioma, endometrial cancer, liver cancer, lung cancer, melanoma, kidney cancer, thyroid cancer, lymphoma, lymphoproliferative disorder, small cell Lung cancer, squamous cell lung cancer, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, etc.; hematological malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic disease ( MPD), chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin's lymphoma (NHL), B-cell lymphoma; Polycythemia vera, essential thrombocythemia, myelofibrosis, multiple myeloma, etc.
  • cancers such as colon cancer
  • the present invention provides a method for treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present invention Pharmaceutical composition or compound.
  • the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes and inflammatory bowel disease.
  • the present invention provides a method of treating and/or preventing mammals susceptible to or suffering from allergic diseases, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present invention Pharmaceutical composition or compound.
  • the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
  • the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
  • the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the disclosed Pharmaceutical composition or compound.
  • the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from a viral infectious disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present disclosures
  • the pharmaceutical composition or compound is administered to a mammal susceptible to or suffering from a viral infectious disease.
  • the viral infectious disease is selected from influenza, coronavirus infection, new coronavirus infection, dengue virus infection, Zika virus infection, Ebola virus infection, respiratory syncytial virus infection, or HBV.
  • the present invention provides a class of compounds disclosed in the present invention for use as a medicament, especially as a medicament for the treatment and/or prevention of the diseases and/or disorders described in the present invention.
  • the present invention also provides the use of the compounds disclosed in the present invention to prepare drugs for the treatment and/or prevention of the diseases and/or disorders described in the present invention.
  • the compounds of the present invention can be administered as a single active agent, or can be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combined administration.
  • the present invention provides a method for treating, preventing or ameliorating a disease or condition, which comprises administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents.
  • the combination drug contains one or two other therapeutic agents.
  • therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressive agents.
  • the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent, which can be prepared as a combination for simultaneous, separate or sequential administration during treatment.
  • the treatment is for the treatment of diseases or symptoms mediated by the activity of one or more protein kinases, such as AXL kinase, or NTRK kinase.
  • the products provided by the joint preparation include a composition containing the compound disclosed in the present invention and other therapeutic agents in the same pharmaceutical composition, or the compound disclosed in the present invention and other therapeutic agents in different forms, for example, a kit.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound disclosed in the present invention and another one or more therapeutic agents.
  • the pharmaceutical composition may include pharmaceutically acceptable excipients as described above.
  • the present invention provides a kit containing two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains the compound disclosed in the present invention.
  • the kit includes means for separately holding the composition, such as a container, a separate bottle, or a separate foil box.
  • a container such as a container, a separate bottle, or a separate foil box.
  • An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
  • the compounds disclosed in the present invention can be administered as a single active ingredient or as, for example, adjuvants, co-administered with other therapeutic agents.
  • the other therapeutic agents include chemotherapeutic agents and/or anti-proliferative agents.
  • chemotherapeutics include, but are not limited to, other therapies that can be used in combination with the compounds of the present invention or anticancer drugs, surgery, and radiotherapy (a few examples are gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton Therapies, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (taxol, docetaxel, etc.), platinum derivatives (cisplatin, carboplatin) ), biological response modifiers (interferon, interleukin), tumor necrosis factor (TNF, TRAIL receptor target), hyperthermia and cryotherapy, agents to reduce any adverse reactions (such as antiemetics), and other drugs Approved chemotherapy drugs, including but not limited to alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide)
  • Anti-angiogenic agents (avastin, etc.). Monoclonal antibodies (belimumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, panitumumab) Monoclonal antibody (ranibizumab), rituximab (rituximab), tositumomab (tositumomab), trastuzumab (trastuzumab)).
  • kinase inhibitors imatinib, sunitinib, sorafenib, erlotinib, gefitinib, dasatinib
  • nilotinib lapatinib
  • crizotinib ruxolitinib
  • vemurafenib vandetanib
  • par Zopanib pazopanib, etc.
  • Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia inducible factor) pathway and others.
  • the compound disclosed in the present invention can also be combined with other treatment processes to improve curative effect. For example, administering hormone therapy or special radiation therapy.
  • the compounds disclosed in the present invention are especially useful as radiosensitizers, especially for the treatment of tumors that are less sensitive to radiotherapy.
  • “Combination” means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compound disclosed in the present invention and the combination partner can be administered independently at the same time or can be administered separately within a certain time interval , Especially for joint partners to show cooperation, such as synergy.
  • the terms "co-administration” or “co-administration” and the like are intended to encompass the administration of a selected joint partner to a single individual (for example, a patient) in need thereof, and are intended to include substances in which the substance does not have to pass through the same route of administration or Simultaneous administration of the treatment plan.
  • the treatment methods disclosed in the present invention include administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • the various embodiments disclosed in the present invention include methods for treating the diseases or disorders described in the present invention by administering to a patient in need a safe and effective amount of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention.
  • the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention may be administered at one time, or according to the dosage regimen, administered several times at different time intervals within a specified time period. For example, it may be administered once, twice, three or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely.
  • the appropriate dosage regimen of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by a skilled person.
  • the appropriate dosage regimen of the compound disclosed in the present invention or the pharmaceutical composition containing the compound disclosed in the present invention depends on the disease being treated, the severity of the disease being treated, the age of the patient being treated, and The physical condition, medical history of the patient being treated, the nature of simultaneous therapy, the desired therapeutic effect, and other factors that are within the scope of the technician’s knowledge and experience.
  • an appropriate dosing regimen may be required to be adjusted.
  • the compounds disclosed in the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them.
  • the compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula (I) or (II).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous THF, dioxane, DCM, toluene and DMF were all purchased from commercial suppliers, such as Energy Chemical Company and Aldrich Chemical Company.
  • EtOAc, PE, CH 3 CN, NMP and DMSO were all treated with anhydrous Na 2 SO 4 before use.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • LC/MS was performed on Agilent 1260 (binary pump/DAD detector) coupled with Agilent 6120/6125 mass spectrometer.
  • MeCN aqueous solution (0.1% HCOOH), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm.
  • the sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
  • MeCN aqueous solution (0.1% trifluoroacetic acid), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm.
  • the sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
  • MeCN aqueous solution (0.1% NH 3 -H 2 O/10mM NH 4 AC), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm.
  • the sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , U 1 , U 2 and n has the definition as described in the present invention;
  • PG 1 and PG 2 is a protecting group.
  • the compound of the present invention having the structure represented by formula (6) can be prepared by the general synthesis method described in Synthetic Scheme 1, and the specific steps can be referred to the examples.
  • the boron ester derivative (1) in a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd( Under the action of dppf) 2 Cl 2 or Pd 2 (dba) 3, etc.
  • the compound (3) can be obtained by coupling reaction with the substituted heteroaryl compound (2 ).
  • an aromatic amine derivative (4) is obtained .
  • the carboxylic acid derivative (5) is condensed with the compound (4) in the presence of a condensing agent (such as EDCI or HATU) to obtain the target kinase inhibitor (6) .
  • a condensing agent such as EDCI or HATU
  • Carboxylic acid derivatives (5) can be found in the literature (see, for example, "Practical synthesis of bicyclic pyrazol-5-one derivatives.” Xuejin Feng, Michael A. Xi, Yanjun Wu, Xiaogang Wang, Ning Xi Tetrahedron Lett. 2017, 58, 46-49; Facile synthesis of bicyclic1-arylpyrazol-5-ones.”Wu,Y.;Wang,K.;Li,Z.;Bai,X.; Xi,N.Tetrahedron Lett.2014,55,142-147) The synthesis method described is obtained.
  • the compound of the present invention having the structure represented by formula (6) can also be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can be referred to the examples.
  • the aryl or heteroaryl compound (7) is condensed with the compound (5) in the presence of a condensing agent (such as EDCI or HATU) to obtain the compound (8) .
  • a condensing agent such as EDCI or HATU
  • the boronic ester derivative (10) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2) Or under the action of Pd 2 (dba) 3, etc.), the compound (9) can be obtained by coupling reaction with the substituted heteroaryl compound (8 ).
  • the boronic ester derivative (9) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2) Or under the action of Pd 2 (dba) 3, etc.), a coupling reaction occurs with the substituted heteroaryl derivative (2) to obtain the target kinase inhibitor (6) .
  • a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2
  • Step 2 tert-Butyl 2-(2-(2-hydroxyethoxy)acetyl)-1-phenylhydrazino-1-carboxylate
  • Step 2) (4-(4-chloro-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • Step 2) 1-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one
  • Step 2) (R)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide
  • Step 2) 4-(4-Chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
  • Step 2) 4-(4-Chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
  • Step 2) 4-(4-Chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
  • Step 2) 4-(4-Chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
  • the resulting mixture was stirred at 40°C for 3 h, and after cooling to room temperature, the reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 ⁇ 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Example 21 was isolated by the method described in Example 20 as a white solid (106.0 mg, 10.5% yield). LCMS (ES, m/z) 510.2 [M+H] + .
  • Step 2) (4-(4-Chloro-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)tert-butyl carbamate ester
  • Step 2) (4-(4-chloro-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • Step 4) 4-(4-Amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester
  • the LC/MS/MS system used for analysis includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column thermostat, Agilent G6430 three-stage quadrupole mass spectrometer with electrospray ionization (ESI) source . Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
  • the Agilent XDB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ M column was used for analysis, and 5 ⁇ L of sample was injected. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL/min.
  • the mobile phase gradient is shown in Table B:
  • Agilent 6330 series LC/MS/MS spectrometer is used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer uses ESI radiation source.
  • the Capcell MP-C18 column was used, the specification was: 100 ⁇ 4.6mm I.D., 5 ⁇ M (Phenomenex, Torrance, California, USA).
  • the mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 ⁇ L of sample.
  • the kinase test is done by detecting myelin base protein (MBP) incorporated into ⁇ -33 P-ATP.
  • MBP myelin base protein
  • TBS Tris Buffered Salt Solution
  • Greiner high binding white 384-well plate
  • kinase reaction in a total volume of 34 ⁇ L kinase buffer (prepared as needed, for example, 5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl 2 , 1mM DTT, 0.02% TritonX -100).
  • the compound was dissolved in DMSO and added to each well.
  • the final concentration of the compound in the DMSO solution was 1%. At least two tests are carried out for the determination of each compound. For example, the final concentration of the enzyme is 10 nM or 20 nM.
  • the reaction started after the MgATP mixture was added. After incubating for 40 minutes at room temperature, a phosphoric acid solution was added to it to a concentration of 0.5% to terminate the reaction. Distribute 10 ⁇ L of the reaction solution on the P30 filter in the form of spots, wash 4 times with 0.425% phosphoric acid solution in 4 minutes, and wash once with methanol. After drying, use a scintillation counter to measure.
  • the reagents used in the experiment are AXL (Carna Bioscience, Cat No.: 08-107) and FLPeptide 30 (PerkinElmer, Cat No.: 760430).
  • the instruments involved are incubator (Thermo Scientific), oscillator (QILINBEIER), EZ Reader (PerkinElmer, Cat No.: 122919), non-contact level pipetting system (Labcyte Inc., Cat No.: Echo 550), And non-contact nano-upgraded pipetting system (TECAN, Cat No.: EVO200).
  • Compound dilution 1) Dissolve the compound in DMSO to an appropriate concentration; 2) Use TECAN EVO200 to 3-fold 10 concentrations in a 384 microwell plate, the highest concentration is 1mM; use Echo550 to transfer 20nL solution from the dilution plate to the experiment In the board.
  • Reagent name Solution 1 MgCl 2 10mM Brij-35 0.050% DTT 2mM BSA 0.05% EGTA 1mM HEPE(pH7.5) 50mM AXL 1.333nM
  • Reagent name Solution 2 MgCl 2 10mM Brij-35 0.050% DTT 2mM BSA 0.05% EGTA 1mM HEPE(pH7.5) 50mM FLPeptide 6 ⁇ M ATP 400 ⁇ M
  • Test method described above can be obtained IC 50 and / or suppression of the inhibitory constant K i.
  • the IC 50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the test conditions.
  • Use the 1/2log dilution factor to make a curve containing 10 concentration points, and estimate the IC 50 value (for example, make a typical curve with the following compound concentrations: 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M , 0.003 ⁇ M, 0.001 ⁇ M, 0.0003 ⁇ M, 0 ⁇ M), or 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M, 0 ⁇ M).
  • This test is done by testing the compound's inhibitory effect on the growth of the Ba/F3 AXL cell line and the Ba/F3 parent cell line.
  • cell survival rate (%) (Lum test drug-Lum culture medium control )/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • Table 1 below provides the AXL(h) kinase test results of the compounds of the present invention, indicating that the compounds of the present invention have a very good inhibitory effect on AXL kinase.

Abstract

The present invention belongs to the pharmaceutical field, and specifically relates to a substituted heteroaryl compound as represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and the use of the compound and the pharmaceutical composition thereof in the preparation of drugs for treating and/or preventing proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancers, viral infectious diseases, or other diseases in mammals. The compound provided by the present invention exhibits an excellent inhibitory activity and kinase selectivity against a target kinase.

Description

取代的杂芳基化合物及其组合物和用途Substituted heteroaryl compound and its composition and use 发明领域Field of invention
本发明属于药物领域，具体涉及一类新的取代的杂芳基化合物、其药学上可接受的盐和包含所述化合物的药物组合物以及使用所述化合物及其药物组合物在制备治疗哺乳动物的增殖性疾病、自身免疫性疾病、过敏性疾病、炎性疾病、移植排斥、癌症、病毒感染性疾病或其他疾病的药物中的用途。更具体地说，本发明所述的化合物可以调节AXL激酶的活性，进而调节细胞内外的信号转导。The present invention belongs to the field of medicine, and specifically relates to a new class of substituted heteroaryl compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds, and the use of the compounds and the pharmaceutical compositions in preparing and treating mammals Use in medicines for proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer, viral infectious diseases or other diseases. More specifically, the compounds of the present invention can regulate the activity of AXL kinase, thereby regulating signal transduction inside and outside the cell.
发明背景Background of the invention
蛋白激酶家族包含一大类结构相关的酶，它们控制细胞内的各种信号转导过程，催化靶标蛋白质底物的磷酸化。许多疾病与蛋白激酶介导的事件引发的异常细胞应答有关。这些疾病包括良性的和恶性的增殖性疾病、免疫***不适当激活导致的疾病、同种异体移植排斥、移植物抗宿主疾病、自身免疫性疾病、炎性疾病、骨疾病、代谢病、神经疾病和神经变性疾病、癌症、心血管疾病、***反应和哮喘、阿尔茨海默病和激素相关疾病。相应地，医药领域已研发出治疗所述疾病有效的蛋白激酶抑制剂。The protein kinase family includes a large class of structurally related enzymes that control various signal transduction processes in cells and catalyze the phosphorylation of target protein substrates. Many diseases are related to abnormal cellular responses triggered by protein kinase-mediated events. These diseases include benign and malignant proliferative diseases, diseases caused by inappropriate activation of the immune system, allograft rejection, graft-versus-host diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological diseases And neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Correspondingly, the medical field has developed protein kinase inhibitors that are effective in treating the diseases.
激酶可以通过磷酸化的底物分为多个家族(例如，蛋白质-酪氨酸、蛋白质-丝氨酸/苏氨酸、脂质等)。酪氨酸磷酸化是调节各种生物学过程比如细胞增殖、迁移、分化和生存的中心事件之一。多个家族的受体和非受体酪氨酸激酶控制催化磷酸从ATP转移至特定细胞蛋白质靶标的酪氨酸基团。目前，已确认上述各个激酶家族一般相应的基序(Hanks et al.,FASEB J.,1995,9,576-596；Knighton et.al.,Science,1991,253,407-414；Garcia-Bustos en al.EMBO J.,1994,13:2352-2361)。蛋白激酶家族中的激酶的实例包括，但不限于，Aurora、Axl、abl、Akt、bcr-abl、Blk、Brk、Btk、c-Met、c-src、c-fms、CDKl、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、CDK10、cRafl、CSF1R、CSK、EGFR、ErbB2、ErbB3、ErbB4、Erk、Flt-3、Fak、fes、FGFRl、FGFR2、FGFR3、FGFR4、FGFR5、Fgr、Fyn、AXL、IGF-1R、INS-R、KDR、Lck、Lyn、MEK、Mer、p38、PDGFR、PIK、PKC、PYK2、ros、Tie、Tie-2、TRK、Yes、Tyro3和Zap70等(Robinson,D.R.；Wu,Y.M.；Lin,S.F.The protein tyrosine kinase family of the human genome.Oncogene 2000,19,5548-5557)。Kinases can be classified into multiple families by phosphorylated substrates (eg, protein-tyrosine, protein-serine/threonine, lipid, etc.). Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival. Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets. At present, the general corresponding motifs of the above-mentioned kinase families have been confirmed (Hanks et al., FASEB J., 1995, 9,576-596; Knighton et al., Science, 1991, 253, 407-414; Garcia-Bustos en al. EMBO) J., 1994, 13: 2352-2361). Examples of kinases in the protein kinase family include, but are not limited to, Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fyn, AXL, IGF-1R, INS-R, KDR, Lck, Lyn, MEK, Mer, p38, PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, Tyro3 and Zap70, etc. (Robinson ,DR; Wu,YM; Lin,SF The protein tyrosine kinase family of the human gene.Oncogene 2000,19,5548-5557).
癌症(和其它过度增殖性疾病)的特征在于不受控制的细胞增殖。与正常组织相比，在人体肿瘤中许多蛋白质激酶的活性升高，并且这种升高的活性可能是由于许多因素所致，包括激酶水平升高，共活化剂或抑制性蛋白质的表达发生突变。Cancer (and other hyperproliferative diseases) is characterized by uncontrolled cell proliferation. Compared with normal tissues, the activity of many protein kinases in human tumors is increased, and this increased activity may be due to many factors, including increased kinase levels, mutations in the expression of co-activators or inhibitory proteins .
AXL是一种膜结合受体酪氨酸激酶，属于TAM(Tyro3、AXL、Mer)家族。其特征在于它们的两个免疫球蛋白样结构域和在其胞外结构域中双纤连蛋白重复序列以及相关的酪氨酸在其胞质结构域中的激酶结构域。(Linger,R.M.et al.,TAM receptor tyrosine kinases:biologic functions,signaling,and potential therapeutic targeting in human cancer.Advances in cancer research 2008,100,35-83.)。TAM受体酪氨酸激酶介导的细胞信号传导在多种正常细胞中参与细胞的生长、迁移、聚集和凋亡等进程。TAM家族有两种已知的配体GAS6(生长停滞特异性6)和蛋白S。Gas6与AXL结合会导致受体二聚化和AXL自磷酸化。(Stitt,T.N.et al.,The anticoagulation factor protein S and its relative,Gas6,are ligands for the Tyro 3/Axl family of receptor tyrosine kinases.Cell 1995,80(4),661-70.)。AXL存在于多种器官和细胞中，包括上皮细胞系、间充质和造血起源、以及未转化的细胞。AXL is a membrane-bound receptor tyrosine kinase, belonging to the TAM (Tyro3, AXL, Mer) family. It is characterized by their two immunoglobulin-like domains and the double fibronectin repeats in their extracellular domains and the kinase domain with related tyrosines in their cytoplasmic domains. (Linger, R.M.et al., TAM receptor tyrosinekinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Advances in cancer research 2008, 100, 35-83.). Cell signal transduction mediated by TAM receptor tyrosine kinase is involved in cell growth, migration, aggregation and apoptosis in a variety of normal cells. There are two known ligands in the TAM family, GAS6 (growth arrest specific 6) and protein S. The binding of Gas6 to AXL leads to receptor dimerization and AXL autophosphorylation. (Stitt, T.N.et al., The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptors. Cell 1995, 80(4), 661-70.). AXL is present in a variety of organs and cells, including epithelial cell lines, mesenchymal and hematopoietic origins, and untransformed cells.
AXL激酶在多种癌症中均存在超表达或激活，包括卵巢癌、黑色素瘤、肾细胞癌、子宫平滑肌瘤、子宫内膜癌、甲状腺癌、胃癌、乳腺癌、NSCLC、CML、AML、结肠癌、***癌、各种淋巴瘤、和食道癌。近期研究表明，在经过化疗和受体酪氨酸激酶抑制剂(TKI)治疗后产生抗药性的癌细胞中，AXL的超表达现象尤为严重，是产生耐药性的重要原因之一(Zhang,Z.；Lee,J.C.；Lin,L.；et al Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer.Nat.Genet.2012,44,852-860)。目前，癌症病人出现耐药性仍然是癌症治疗过程中的难点，而抑制AXL活性可以增强化疗敏感度及延缓耐药性的发生，因此，AXL原癌基因是用于发现和开发新治疗剂的极具吸引力和有价值的靶标(Feneyrolles C,Spenlinhauer A,Guiet L,et al.Axl Kinase as a Key Target for Oncology:Focus on Small Molecule Inhibitors.Mol Cancer Ther,2014,13(9):2141-2148)。基于在多种人恶性肿瘤中的牵连，需要设计特异性和选择性的 抑制剂来治疗癌症以及AXL激酶介导的和/或与之相关的其它疾病或病况。本发明满足了这些需要并且提供了其它相关利益。AXL kinase is overexpressed or activated in a variety of cancers, including ovarian cancer, melanoma, renal cell carcinoma, uterine leiomyoma, endometrial cancer, thyroid cancer, gastric cancer, breast cancer, NSCLC, CML, AML, colon Cancer, prostate cancer, various lymphomas, and esophageal cancer. Recent studies have shown that in cancer cells that have developed drug resistance after chemotherapy and receptor tyrosine kinase inhibitor (TKI) treatment, the overexpression of AXL is particularly serious, which is one of the important reasons for drug resistance (Zhang, Z.; Lee, JC; Lin, L.; et al Activation of the AXL kind causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 2012, 44, 852-860). At present, the emergence of drug resistance in cancer patients is still a difficult point in the process of cancer treatment, and inhibition of AXL activity can enhance the sensitivity of chemotherapy and delay the onset of drug resistance. Therefore, AXL proto-oncogenes are used to discover and develop new therapeutic agents. Very attractive and valuable targets (Feneyrolles C, Spenlinhauer A, Guiet L, et al. Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors. Mol Cancer Ther, 2014, 13(9): 2141 2148). Based on the involvement in a variety of human malignancies, it is necessary to design specific and selective inhibitors to treat cancer and other diseases or conditions mediated by and/or related to AXL kinase. The present invention satisfies these needs and provides other related benefits.
免疫疗法是指针对机体低下或亢进的免疫状态，人为地增强或抑制机体的免疫功能以达到治疗疾病目的的治疗方法。免疫治疗的方法有很多，并适用于多种疾病的治疗。肿瘤的免疫治疗旨在激活人体免疫***，依靠自身免疫机能杀灭癌细胞和肿瘤组织(Myers et al.Molecular Cancer，2019，18:94)。与以往的手术、化疗、放疗和靶向治疗不同的是，免疫治疗针对的靶标并非肿瘤细胞和组织，而是人体自身的免疫***。Immunotherapy refers to a treatment method that artificially enhances or suppresses the immune function of the body to achieve the purpose of curing diseases. There are many immunotherapy methods, and they are applicable to the treatment of many diseases. Tumor immunotherapy aims to activate the human immune system and kill cancer cells and tumor tissues by relying on autoimmune functions (Myers et al. Molecular Cancer, 2019, 18:94). Unlike previous surgery, chemotherapy, radiotherapy, and targeted therapy, the target of immunotherapy is not tumor cells and tissues, but the body's own immune system.
蛋白激酶抑制剂作为新的免疫调节、抗炎作用药和抗癌症药聚集了众多关注。因此，抑制蛋白激酶如AXL激酶的新试剂或改进试剂可作为器官移植的免疫调节剂、抗肿瘤剂、止痛剂、抗器官纤维化药物，AXL激酶的新试剂或改进试剂也可用于预防和/或治疗自体免疫性疾病(例如，多发性硬化症、银屑病、类风湿性关节炎、哮喘、I型糖尿病、炎症性肠病、克罗恩病、真性红细胞增多症、原发性血小板增多症、骨髓纤维化、自身免疫性甲状腺病、阿尔兹海默病)，涉及过度活化炎症反应的疾病(例如，湿疹)，过敏，慢性阻塞性肺病，支气管炎，纤维化，癌症(例如，胃癌、肝癌、肺癌、结肠直肠癌、***癌、急性髓细胞性白血病、慢性髓细胞性白血病、急性淋巴细胞白血病、白血病、多发性骨髓瘤)和其他治疗引起的免疫反应(例如，皮疹、接触性皮炎或腹泻)，慢性疼痛和急性疼痛，或者其中所述疼痛与癌症、外科手术、骨折、由肿瘤转移引起的骨痛、骨关节炎、银肩病关节炎、类风湿性关节炎、间质性膀胱炎、慢性胰腺炎、内脏痛、偏头痛、慢性腰背痛、膀胱疼痛综合征或神经性疼痛相关，等等。Protein kinase inhibitors have attracted a lot of attention as new immunomodulatory, anti-inflammatory and anti-cancer drugs. Therefore, new or improved agents that inhibit protein kinases such as AXL kinase can be used as immunomodulators, antitumor agents, analgesics, and anti-organ fibrosis drugs for organ transplantation, and new or improved agents for AXL kinase can also be used for prevention and/ Or treat autoimmune diseases (e.g., multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn’s disease, polycythemia vera, essential thrombocytosis Disease, myelofibrosis, autoimmune thyroid disease, Alzheimer’s disease), diseases involving excessive activation of inflammatory response (e.g., eczema), allergies, chronic obstructive pulmonary disease, bronchitis, fibrosis, cancer (e.g., gastric cancer) , Liver cancer, lung cancer, colorectal cancer, prostate cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, leukemia, multiple myeloma) and other treatment-induced immune reactions (e.g., skin rash, contact Dermatitis or diarrhea), chronic pain and acute pain, or where the pain is related to cancer, surgery, fractures, bone pain caused by tumor metastasis, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, interstitial Related to cystitis, chronic pancreatitis, visceral pain, migraine, chronic low back pain, bladder pain syndrome or neuropathic pain, etc.
TAM受体酪氨酸激酶Tyro3、Axl和Mer及其同源配体蛋白S(Protein S)和Gas6促进免疫，神经和生殖***中凋亡细胞的吞噬清除。它们同时驱动一个关键的负反馈回路，该回路下调了由Toll样受体(TLR)和I型干扰素信号传导途径介导的宿主先天免疫应答。TAM受体-配体的相互作用也与促进包膜病毒的细胞进入有关：已发现将一种或多种TAM受体异位引入抗感染细胞系可增强丝状病毒和慢病毒的感染。除了通过羧基末端结构域与TAM受体结合外，TAM配体蛋白S和Gas6在其氨基末端均含有富含谷氨酸的Gla结构域，所述结构域与暴露于凋亡细胞和膜包裹的病毒颗粒表面的磷脂酰丝氨酸(PtdSer)结合。(G.Lemke,C.V.Rothlin,Nat Rev Immunol 8,327(May,2008)；G.Lemke,T.Burstyn-Cohen,Ann N Y Acad Sci 1209,23(Oct,2010).)TAM receptor tyrosine kinases Tyro3, Axl and Mer and their homologous ligand proteins S (Protein S) and Gas6 promote immunity, phagocytosis and clearance of apoptotic cells in the nervous and reproductive systems. They also drive a key negative feedback loop that down-regulates the host's innate immune response mediated by Toll-like receptors (TLR) and type I interferon signaling pathways. The TAM receptor-ligand interaction is also related to the promotion of cell entry of enveloped viruses: it has been found that the ectopic introduction of one or more TAM receptors into anti-infective cell lines can enhance filovirus and lentivirus infection. In addition to binding to the TAM receptor through the carboxy-terminal domain, the TAM ligand proteins S and Gas6 both contain a glutamate-rich Gla domain at their amino terminus, which is compatible with those exposed to apoptotic cells and membranes. Phosphatidylserine (PtdSer) on the surface of the virus particle binds. (G. Lemke, C.V. Rothlin, Nat Rev Immunol 8,327 (May, 2008); G. Lemke, T. Burstyn-Cohen, Ann N Y Acad Sci 1209, 23 (Oct, 2010).)
包膜病毒在其表面上含有高水平的PtdSer，并通过PtdSer-Gla结构域相互作用与TAM配体蛋白S和Gas6结合。在包膜病毒感染期间，TAM受体-配体相互作用的功能被认为仅限于促进病毒与靶细胞的结合，从而促进病毒感染。膜结合的TAM配体在活化TAM受体信号传导方面比游离配体明显更有效，表明TAM配体通过其gla结构域的PtdSer结合改变了配体对TAM信号转导的影响。AXL激酶抑制剂可以阻断膜中AXL配体与磷脂酰丝氨酸(PtdSer)之间的相互作用。因此，抑制蛋白激酶如AXL激酶的新试剂或改进试剂可作为治疗和/或预防病毒感染性疾病药物，例如作为抗寨卡病毒(iScience，2019，13,339–350)、冠状病毒、新冠状病毒(如covid-19等)和乙型肝炎病毒(HBV)(Journal of Hepatology 2015 vol.63 j670–678)的药物。The enveloped virus contains a high level of PtdSer on its surface and binds to the TAM ligand protein S and Gas6 through the PtdSer-Gla domain interaction. During enveloped virus infection, the function of TAM receptor-ligand interaction is considered to be limited to promoting the binding of the virus to the target cell, thereby promoting virus infection. Membrane-bound TAM ligands are significantly more effective than free ligands in activating TAM receptor signal transduction, indicating that TAM ligands change the ligand's influence on TAM signal transduction through the PtdSer binding of its gla domain. AXL kinase inhibitors can block the interaction between AXL ligand and phosphatidylserine (PtdSer) in the membrane. Therefore, new reagents or improved reagents that inhibit protein kinases such as AXL kinase can be used as drugs for the treatment and/or prevention of viral infectious diseases, such as anti-Zika virus (iScience, 2019, 13,339-350), coronavirus, new coronavirus ( Such as covid-19, etc.) and hepatitis B virus (HBV) (Journal of Hepatology 2015 vol.63 j670-678).
本发明描述的化合物、组合物和方法直接对应上述这些需要和其他目的。具体地，本发明提供了一类抑制、调节和/或调控AXL激酶活性的化合物，用于治疗和/或预防增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、疼痛、纤维化、移植排斥、或病毒感染性疾病或其并发症。与已有的同类化合物相比，本发明的化合物具有更好的药理活性，具体而言，本发明化合物对目标激酶显示出优异的抑制活性和激酶选择性。此外，本发明化合物还具有优良的透膜性质，在动物体内显示出优良的药代动力学性质，因此，本发明化合物具有非常好的开发前景。The compounds, compositions and methods described in the present invention directly correspond to the above-mentioned needs and other purposes. Specifically, the present invention provides a class of compounds that inhibit, modulate and/or modulate the activity of AXL kinase for the treatment and/or prevention of proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, pain, fibrosis, Transplant rejection, or viral infectious disease or its complications. Compared with existing similar compounds, the compound of the present invention has better pharmacological activity. Specifically, the compound of the present invention shows excellent inhibitory activity and kinase selectivity for the target kinase. In addition, the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
发明内容Summary of the invention
术语定义Definition of Terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在所附权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the scope of the present invention defined by the appended claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to this application (including but not limited to the defined terms, term application, described technology, etc.), this Application shall prevail.
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise stated or there is an obvious conflict in context, the articles "a", "an" and "said" used in the present invention are intended to include "at least one" or "one or more". Therefore, these articles used in the present invention refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis/trans) isomers, atropisomers, etc. .
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversion through the recombination of some bond-forming electrons. Specific examples of keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如本发明的通式化合物，或者像实施例里面特殊的例子、子类，以及本发明所包含的一类化合物。As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula of the present invention, or special examples, subclasses, and the present invention includes A class of compounds.
应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。“任选地”除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" can be used interchangeably. Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. "Optionally" Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
术语“任选地被……所取代”，可以与术语“未取代或被……所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基所取代，本发明所述的取代基包括，但不限于H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)R 9、-OC(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-OS(＝O) 1-2R 9、-S(＝O) 1-2OR 9a、-N(R 10a)C(＝O)R 10、-C(＝O)NR 10aR 10、-OC(＝O)NR 10aR 10、-N(R 10a)S(＝O) 1-2R 10、-S(＝O) 1-2NR 10aR 10、-N(R 10a)C(＝O)NR 10aR 10、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代等等。其中，R c、R d、R 9、R 9a、R 10和R 10a具有如本发明所述的含义。 The term "optionally substituted by" can be used interchangeably with the term "unsubstituted or substituted by", that is, the structure is unsubstituted or is replaced by one or more substituents described in the present invention Substitution, the substituents in the present invention include, but are not limited to H, D, oxo (=O), F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , -C( ＝O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -OS(=O) 1-2 R 9 , -S (=O) 1-2 OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , -OC(=O)NR 10a R 10 , -N(R 10a )S(=O) 1-2 R 10 , -S(=O) 1-2 NR 10a R 10 , -N(R 10a )C(=O)NR 10a R 10 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein Said each C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6- 12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3 Or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkane Substitution of oxy groups and so on. Among them, R c , R d , R 9 , R 9a , R 10 and R 10a have the meanings as described in the present invention.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C 1 -C 6 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。所述烷基基团可任选地被一个或多个本发明描述的取代基所取代。The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted with one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described in the present invention.
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基 (-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-Methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl(-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and so on.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其包括“顺”和“反”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, which includes "cis" and ""Reverse" positioning, or "E" and "Z" positioning. In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), and the like. The alkenyl group may be optionally substituted with one or more substituents described in this invention.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 ), etc. . The alkynyl group may be optionally substituted with one or more substituents described in this invention.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的定义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the definition as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基(-CF 3)、三氟甲氧基(-OCF 3)、二氟乙基(-CH 2CHF 2,-CF 2CH 3,-CHFCH 2F)、三氟乙基(-CH 2CF 3,-CF 2CH 2F,-CFHCHF 2)等。 The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted by one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ) and so on.
术语“羟基烷基”或“羟基取代的烷基”和“羟基烷氧基”或“羟基取代的烷氧基”分别表示烷基或烷氧基基团，视情况而定，被一个或多个羟基基团所取代，其中，“羟基烷基”与“羟烷基”可以交换使用，这样的实例包含，但并不限于，羟甲基(-CH 2OH)、2-羟乙基(-CH 2CH 2OH)、1-羟乙基(-CH(OH)CH 3)、2-羟基丙-2-基(-COH(CH 3) 2)、2-羟基-2-甲基丙基(-CH 2COH(CH 3) 2)、3-羟丙基(-CH 2CH 2CH 2OH)、2-羟丙基(-CH 2CH(OH)CH 3)、2-羟基-2甲基丙基(-CH 2CH(OH)(CH 3)CH 3)、羟基甲氧基(-OCH 2OH)等。 The terms "hydroxyalkyl" or "hydroxy-substituted alkyl" and "hydroxyalkoxy" or "hydroxy-substituted alkoxy" respectively denote an alkyl or alkoxy group, as the case may be, with one or more A hydroxyl group is substituted, where "hydroxyalkyl" and "hydroxyalkyl" can be used interchangeably. Examples of this include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl ( -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxyprop-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane Group (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2Methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OCH 2 OH), etc.
术语“氰基取代烷基”或“氰基烷基”包括被一个或多个氰基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氰基烷基是被一个或多个氰基基团所取代的C 1-6“较低级的氰基烷基”，另一些实施例是，氰基烷基是被一个或多个氰基基团所取代的C 1-4“较低级的氰基烷基”，这样的实例包括，但并不限于，CNCH 2-、CNCH 2CH 2-、CNCH 2CH 2CH 2-、CNCH 2CHCNCH 2-等。 The term "cyano substituted alkyl" or "cyanoalkyl" includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups. In some embodiments, the cyanoalkyl group is a C 1-6 "lower cyanoalkyl group" substituted with one or more cyano groups. In other embodiments, the cyanoalkyl group is substituted by one or more cyano groups. C 1-4 "lower cyanoalkyl" substituted by one or more cyano groups, such examples include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -etc.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环环烷基包含螺双环烷基、稠合双环烷基和桥双环烷基。在一些实施方案，环烷基包含3-12个碳原子；在另一些实施方案中，环烷基包含3-10个碳原子；在另一些实施方案中，环烷基包含3-8个碳原子；在另一些实施方案中，环烷基包含3-7个碳原子；在另一些实施方案中，环烷基包含3-6个碳原子；还在一些实施方案，环烷基为C 7-C 12环烷基，其包含C 7-C 12单环烷基、C 7-C 12双环烷基(如C 7-C 12螺双环烷基、C 7-C 12稠合双环烷基和C 7-C 12桥双环烷基)或C 7-C 12三环烷基。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。术语“单环环烷基”或“单环烷基”表示单环体系的环烷基，其中所述环烷基具有如前所述的定义，所述单环环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。 The term "cycloalkyl" refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls, and bridged bicycloalkyls. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-10 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms. Atoms; in other embodiments, the cycloalkyl group contains 3-7 carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms; still in some embodiments, the cycloalkyl group is C 7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spiro bicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl. The cycloalkyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention. The term "monocyclic cycloalkyl" or "monocyclic alkyl" refers to a cycloalkyl of a monocyclic system, wherein the cycloalkyl has the definition as described above, and the monocyclic cycloalkyl group may independently Unsubstituted or substituted by one or more substituents described in the present invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
术语“环烷基烷基”包括环烷基取代的烷基基团。在一些实施方案，环烷基烷基基团是指“较低级的环烷基烷基”基团，即环烷基基团连接到C 1-6的烷基基团上。在另一些实施方案，环烷基烷基基团是指含C 1-3的烷基的“苯烷撑”。其中具体实例包括，但不限于，环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环戊基乙基、环己基乙基等。环烷基烷基上的环烷基可进一步被一个或多个本发明所描述的取代基所取代。 The term "cycloalkylalkyl" includes cycloalkyl substituted alkyl groups. In some embodiments, a cycloalkylalkyl group refers to a "lower cycloalkylalkyl" group, that is, a cycloalkyl group is attached to a C1-6 alkyl group. In other embodiments, the cycloalkylalkyl group refers to a "phenylalkylene" containing a C 1-3 alkyl group. Specific examples thereof include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexylethyl and the like. The cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described in the present invention.
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的，单价或多价的，饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子。在一些实施方 案，杂环基或杂环包含4-12个环原子。在一些实施方案，杂环基或杂环包含5-12个环原子。在一些实施方案，杂环基或杂环包含5-8个环原子。在一些实施方案，杂环基或杂环包含5-7个环原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代，环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。杂环基包含饱和的杂环基(杂环烷基)和部分不饱和的杂环基。所述的杂环基具有一个或多个连接点与分子的其余部分相连。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氮单杂环庚烷、氧氮杂
Figure PCTCN2021094020-appb-000001
基(如，1,4-氧氮杂
Figure PCTCN2021094020-appb-000002
基、1,2-氧氮杂
Figure PCTCN2021094020-appb-000003
基)、二氮杂
Figure PCTCN2021094020-appb-000004
基(如，1,4-二氮杂
Figure PCTCN2021094020-appb-000005
基、1,2-二氮杂
Figure PCTCN2021094020-appb-000006
基)、二氧杂
Figure PCTCN2021094020-appb-000007
基(如，1,4-二氧杂
Figure PCTCN2021094020-appb-000008
基、1,2-二氧杂
Figure PCTCN2021094020-appb-000009
基)、硫氮杂
Figure PCTCN2021094020-appb-000010
基(如1,4-硫氮杂
Figure PCTCN2021094020-appb-000011
基、1,2-硫氮杂
Figure PCTCN2021094020-appb-000012
基)、吲哚啉基、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基、2-氮杂螺[4.4]壬烷基、1,6-二氧杂螺[4.4]壬烷基、2-氮杂螺[4.5]癸烷基、8-氮杂螺[4.5]癸烷基、7-氮杂螺[4.5]癸烷基、3-氮杂螺[5.5]十一烷基、2-氮杂螺[5.5]十一烷基、八氢-1H-异吲哚基、八氢环戊烷并[c]吡咯基、二氢吲哚基、1,2,3,4-四氢异喹啉基、六氢呋喃并[3,2-b]呋喃基和十二氢异喹啉基，等。杂环基中-CH2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 The terms "heterocyclic group" and "heterocyclic ring" are used interchangeably herein, and both refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 3-12 ring atoms. A bicyclic or tricyclic ring system in which at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. In some embodiments, the heterocyclyl or heterocyclic ring contains 4-12 ring atoms. In some embodiments, the heterocyclyl or heterocyclic ring contains 5-12 ring atoms. In some embodiments, the heterocyclyl or heterocyclic ring contains 5-8 ring atoms. In some embodiments, the heterocyclyl or heterocyclic ring contains 5-7 ring atoms. Unless otherwise specified, the heterocyclic group can be a carbon group or a nitrogen group, and the -CH 2 -group can be optionally replaced by -C(=O)-, and the sulfur atom of the ring can be optionally oxidized to S-oxidation The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. The heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl) and a partially unsaturated heterocyclic group. The heterocyclic group has one or more points of attachment to the rest of the molecule. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazoline, pyrazole Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, dithiocyclopentyl, tetrahydropyranyl , Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithia Alkyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl, Azacycloheptane, Oxazepine
Figure PCTCN2021094020-appb-000001
Base (e.g., 1,4-oxazepine
Figure PCTCN2021094020-appb-000002
Base, 1,2-oxazepine
Figure PCTCN2021094020-appb-000003
Base), diaza
Figure PCTCN2021094020-appb-000004
Base (e.g., 1,4-diazepine
Figure PCTCN2021094020-appb-000005
Base, 1,2-diazepine
Figure PCTCN2021094020-appb-000006
Base), dioxane
Figure PCTCN2021094020-appb-000007
Base (e.g., 1,4-dioxa
Figure PCTCN2021094020-appb-000008
Base, 1,2-dioxane
Figure PCTCN2021094020-appb-000009
Base), thiazepine
Figure PCTCN2021094020-appb-000010
Base (e.g. 1,4-thiazepine
Figure PCTCN2021094020-appb-000011
Base, 1,2-thiazepine
Figure PCTCN2021094020-appb-000012
Group), indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptan- 5-yl, 2-azaspiro[4.4]nonyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5 ]Decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindyl Dolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydrofuro[3,2-b]furyl and Dodecahydroisoquinolinyl, etc. Examples of the -CH2- group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone And 3,5-dioxopiperidinyl. Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
还在一实施方案中，杂环基为4-7个原子组成的杂环基，是指包含4-7个环原子的单价或多价的，饱和或部分不饱和的非芳香性的单环或双环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，4-7个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述4-7个原子组成的杂环基具有一个或多个连接点与分子的其余部分相连。其中，4-7个原子组成的单环杂环基的实例包括，但不限于：氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂
Figure PCTCN2021094020-appb-000013
基(1,4-氧氮杂
Figure PCTCN2021094020-appb-000014
基、1,2-氧氮杂
Figure PCTCN2021094020-appb-000015
基)、二氮杂
Figure PCTCN2021094020-appb-000016
基(1,4-二氮杂
Figure PCTCN2021094020-appb-000017
基、1,2-二氮杂
Figure PCTCN2021094020-appb-000018
基)和硫氮杂
Figure PCTCN2021094020-appb-000019
基(1,4-硫氮杂
Figure PCTCN2021094020-appb-000020
基、1,2-硫氮杂
Figure PCTCN2021094020-appb-000021
基)等；4-7个原子组成的双环杂环基的实例包括，但不限于：3-氮杂双环[3,2,0]庚烷、3-氧代双环[3,2,0]庚烷等；4-7个原子组成的杂环基中-CH2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基；4-7个原子组成的杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代四氢噻吩、1,1-二氧代四氢噻喃、1,1-二氧代硫代吗啉基。所述的4-7个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In another embodiment, the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which refers to a monovalent or multivalent, saturated or partially unsaturated non-aromatic monocyclic ring containing 4-7 ring atoms Or a bicyclic ring, where at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclic group consisting of 4-7 atoms may be a carbon group or a nitrogen group, and the -CH 2 -group may be optionally replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. The heterocyclic group consisting of 4-7 atoms has one or more connection points to connect to the rest of the molecule. Among them, examples of monocyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, 2H -Pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine
Figure PCTCN2021094020-appb-000013
Base (1,4-oxazepine
Figure PCTCN2021094020-appb-000014
Base, 1,2-oxazepine
Figure PCTCN2021094020-appb-000015
Base), diaza
Figure PCTCN2021094020-appb-000016
Base (1,4-diazepine
Figure PCTCN2021094020-appb-000017
Base, 1,2-diazepine
Figure PCTCN2021094020-appb-000018
Base) and thiazepine
Figure PCTCN2021094020-appb-000019
Base (1,4-thiazepine
Figure PCTCN2021094020-appb-000020
Base, 1,2-thiazepine
Figure PCTCN2021094020-appb-000021
Examples of bicyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: 3-azabicyclo[3,2,0]heptane, 3-oxobicyclo[3,2,0] Heptane, etc.; examples in which the -CH2- group is replaced by -C(=O)- in a heterocyclic group consisting of 4-7 atoms include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3,5-dioxopiperidinyl; examples of oxidized sulfur atoms in 4-7-atom heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxotetrahydrothiophene, 1,1-dioxotetrahydrothiopyran, 1,1-dioxothiomorpholinyl. The heterocyclic group composed of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention.
术语“杂环基烷基”包括杂环基取代的烷基，其中杂环基和烷基均具有如本发明所述的含义，这样的实例包括，但并不限于四氢呋喃基甲基、吡咯-2-基甲基、吗啉-4-基乙基、哌嗪-4-基乙基、哌啶-4-基乙基等。The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl groups, wherein both heterocyclyl and alkyl have the meanings described in the present invention. Examples of this include, but are not limited to, tetrahydrofurylmethyl, pyrrole- 2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl, etc.
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
术语“芳基烷基”或“芳烷基”包括芳基取代的烷基基团。在一些实施方案，芳基烷基基团是指“较低级的芳基烷基”基团，即芳基基团连接到C 1-6的烷基基团上。在另一些实施方案，芳基烷基基团是指含C 1-3的烷基的“苯烷撑”。其中具体实例包括，但不限于，苄基、二苯基甲基、苯乙基等。芳基烷基上的芳基可进一步被一个或多个本发明所描述的取代基所取代。 The term "arylalkyl" or "aralkyl" includes aryl substituted alkyl groups. In some embodiments, an arylalkyl group refers to a "lower arylalkyl" group, that is, the aryl group is attached to a C1-6 alkyl group. In other embodiments, the arylalkyl group refers to a "phenylalkylene" containing a C 1-3 alkyl group. Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenethyl and the like. The aryl group on the arylalkyl group may be further substituted with one or more substituents described in the present invention.
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个芳香环包含一个或多个杂原子，其中每一个环体系包含5-7个原 子组成的环，且有一个或多个连接点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-12个原子组成的杂芳基。在另一实施案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个原子组成的杂芳基。在另一实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个原子组成的杂芳基。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring is aromatic, and At least one aromatic ring contains one or more heteroatoms, and each ring system contains a ring composed of 5-7 atoms, and there are one or more connection points connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In one embodiment, the heteroaryl group is a heteroaryl group consisting of 5-12 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. The heteroaryl group is optionally substituted with one or more substituents described in the present invention.
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、***基(如2-***基和5-***基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-***基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基，等等。Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes the following bicyclics, but not limited to these bicyclics: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (Such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And [1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]Triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole And [1,5-a]pyridyl, etc.
术语“杂芳基烷基”表示烷基基团被一个或多个杂芳基所取代，其中杂芳基和烷基基团均具有本发明所述的含义，这样的实例包括，但并不限于，吡啶-2-甲基、咪唑-2-甲基、呋喃-2-乙基、吲哚-3-甲基等。The term "heteroarylalkyl" means that an alkyl group is substituted by one or more heteroaryl groups, wherein both the heteroaryl group and the alkyl group have the meanings described in the present invention. Such examples include, but not Limited to pyridine-2-methyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, etc.
术语“卤素”是指F，Cl，Br或I。The term "halogen" refers to F, Cl, Br or I.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法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，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。 The "pharmaceutically acceptable salt" used in the present invention refers to the organic and inorganic salts of the compound of the present invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to the association formed by the solvent molecule being water.
本发明化合物的描述Description of the compounds of the invention
本发明公开了一类新颖的化合物，可作为蛋白激酶活性，特别是AXL激酶活性的抑制剂。作为蛋白激酶抑制剂的化合物可用于治疗和/或预防与不适当的蛋白激酶活性，特别是不适当的AXL激酶活性相关的疾病、病症、或病况。与已有的同类化合物相比，本发明的化合物具有更好的药理活性，具体而言，本发明化合物对目标激酶显示出优异的抑制活性和激酶选择性。此外，本发明化合物还具有优良的透膜性质，在动物体内显示出优良的药代动力学性质，因此，本发明化合物具有非常好的开发前景。The present invention discloses a class of novel compounds, which can be used as inhibitors of protein kinase activity, especially AXL kinase activity. Compounds that are protein kinase inhibitors can be used to treat and/or prevent diseases, disorders, or conditions associated with inappropriate protein kinase activity, particularly inappropriate AXL kinase activity. Compared with existing similar compounds, the compound of the present invention has better pharmacological activity. Specifically, the compound of the present invention shows excellent inhibitory activity and kinase selectivity for the target kinase. In addition, the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
本发明公开化合物可显示对一种或多种蛋白激酶表现出较强的抑制活性。一方面，本发明涉及一种化合物，其具有式(I)所示结构：The compounds disclosed in the present invention can show strong inhibitory activity against one or more protein kinases. In one aspect, the present invention relates to a compound having a structure represented by formula (I):
Figure PCTCN2021094020-appb-000022
Figure PCTCN2021094020-appb-000022
或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
其中，in,
U 1和U 2分别独立地为N或-C(R a)-； U 1 and U 2 are each independently N or -C(R a )-;
R 1和R 2分别独立地为H、C 1-6烷基、C 1-6卤代烷基、C 2-6羟基烷基、C 2-6氨基烷基、C 1-6氰基烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 2-6羟基烷基、C 2-6氨基烷基、C 1-6氰基烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 11取代； R 1 and R 2 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkane C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl And C 1-9 heteroaryl C 1-6 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 11 ;
R 4是C 2-6羟基烷基、C 4-10环烷基、C 4-10环烷基C 1-6烷基、C 2-7杂环基、或C 2-7杂环基C 1-6烷基；其中所述各C 2-6羟基烷基、C 4-10环烷基、C 4-10环烷基C 1-6烷基、C 2-7杂环基和C 2-7杂环基C 1-6烷基独立任选地被0、1、2、3或4个R 11a取代； R 4 is C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-6 alkyl; wherein each of the C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl and C 2 -7 heterocyclyl C 1-6 alkyl is independently optionally substituted with 0, 1, 2, 3 or 4 R 11a ;
各R a、R 3、R 5、R 6、R 7和R 8分别独立地为H、D、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各-NR cR d、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 12取代； Each of R a , R 3 , R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each -NR c R d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 cycloalkyl, C 3- 8 Cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 Alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ;
或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成4-12个原子组成的杂环，其中所述4-12个原子组成的杂环任选地包含1、2或3个N、O、和/或S原子并任选地被0、1、2、3、4或5个R 13取代； Or R 2 and R 3, together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-12 atoms, wherein the heterocyclic ring consisting of 4-12 atoms optionally includes 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4 or 5 R 13 ;
各R 11、R 11a、R 12和R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)R 9、-OC(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-OS(＝O) 1-2R 9、-S(＝O) 1-2OR 9a、-N(R 10a)C(＝O)R 10、-C(＝O)NR 10aR 10、-OC(＝O)NR 10aR 10、-N(R 10a)S(＝O) 1-2R 10、-S(＝O) 1-2NR 10aR 10、-N(R 10a)C(＝O)NR 10aR 10、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各-NR cR d、-C(＝O)R 9、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代； Each of R 11 , R 11a , R 12 and R 13 is independently H, D, oxo (=O), F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d ,- C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -OS(=O) 1-2 R 9 , -S(=O) 1-2 OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , -OC(=O)NR 10a R 10 , -N (R 10a )S(=O) 1-2 R 10 , -S(=O) 1-2 NR 10a R 10 , -N(R 10a )C(=O)NR 10a R 10 , C 1-6 alkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1 -6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclic group, C 2-7 heterocyclic group C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl ; Wherein each of -NR c R d , -C(=O)R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1 -6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8 Cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 Alkyl, C 1-9 heteroaryl, and C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3, or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy group substitution;
各R c、R d、R 9、R 9a、R 10和R 10a分别独立地为H、D、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；和 Each R c , R d , R 9 , R 9a , R 10 and R 10a is independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1 -6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1- 9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each of the C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 hetero Aryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3, or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy group substitution; and
n是0、1、或2。n is 0, 1, or 2.
在一些实施方案，其中，In some embodiments, where
R 2是H、C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、或C 1-4氰基烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基和C 1-4氰基烷基独立任选地被0、1、2、3或4个R 11取代； R 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl and C 1-4 cyanoalkyl are independently optionally 0, 1, 2, 3 or 4 R 11 substitutions;
R 3是H、D、F、Cl、Br、-OH、-CN、-NO 2、-NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、或C 1-4氰基烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基独立任选地被0、1、2、3或4个R 12取代； R 3 is H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl And C 1-4 cyanoalkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ;
或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成4-7个原子组成的杂环，其中所述4-7个原子组成的杂环任选地包含1、2或3个N、O、和/或S原子并任选地被0、1、2、3、4或5个R 13取代。 Or R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-7 atoms, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4, or 5 R 13 .
在一些实施方案，其中，R 2和R 3各自独立地为H、D、甲基、乙基、或丙基，或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成5-7个原子组成的杂环，其中所述4-7个原子组成的杂环任选地包含1、2或3个N、O、和/或S原子并任选地被0、1、2、3、4或5个R 13取代。 In some embodiments, wherein R 2 and R 3 are each independently H, D, methyl, ethyl, or propyl, or R 2 and R 3 together with the carbon atom and nitrogen atom to which they are attached are optionally A heterocyclic ring consisting of 5-7 atoms is formed, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 or 3 N, O, and/or S atoms and is optionally substituted by 0, 1 , 2, 3, 4, or 5 R 13 substitutions.
在一些实施方案，本发明所述化合物具有式(II)所示结构：In some embodiments, the compound of the present invention has a structure represented by formula (II):
Figure PCTCN2021094020-appb-000023
Figure PCTCN2021094020-appb-000023
其中，in,
X 1是O、S、-N(R 13a)-、-C(＝O)-、-(CH 2) t1-、-X 2-(CH 2) t1-、或-(CH 2) t1-X 2-(CH 2) t2-； X 1 is O, S, -N(R 13a )-, -C(=O)-, -(CH 2 ) t1 -, -X 2 -(CH 2 ) t1 -, or -(CH 2 ) t1- X 2 -(CH 2 ) t2 -;
X 2是O、S、-N(R 13a)-、或-C(＝O)-； X 2 is O, S, -N(R 13a )-, or -C(=O)-;
各R 13a分别独立地为H、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基、-C(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-S(＝O) 1-2OR 9a、-S(＝O) 1-2NR 10aR 10、或-C(＝O)NR 10aR 10，其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代； Each R 13a is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 Heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-6 alkane Base, -C(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -S(=O) 1-2 OR 9a , -S(=O) 1-2 NR 10a R 10 , or -C(=O)NR 10a R 10 , wherein each C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 hetero Aryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3, or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy group substitution;
各t1和t2分别独立地为0、1、2、或3；和Each t1 and t2 are independently 0, 1, 2, or 3; and
m是0、1、2、4、或5。m is 0, 1, 2, 4, or 5.
在一些实施方案，其中，X 1是O、S、-N(R 13a)-、-C(＝O)-、-(CH 2) t1-、-X 2-(CH 2) t1-、或-(CH 2) t1-X 2-(CH 2) t2-；和X 2是O、S、或-N(R 13a)-。 In some embodiments, X 1 is O, S, -N(R 13a )-, -C(=O)-, -(CH 2 ) t1 -, -X 2 -(CH 2 ) t1 -, or -(CH 2 ) t1 -X 2 -(CH 2 ) t2 -; and X 2 is O, S, or -N(R 13a )-.
在一些实施方案，R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 In some embodiments, R 13 is each independently H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkane Oxy, C 1-4 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 2-7 heterocyclic group, C 2-7 heterocyclic group C 1 -4 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 Cyanoalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-4 alkyl, C 2-7 heterocyclyl , C 2-7 heterocyclyl C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-4 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-4 alkyl is independently optionally selected by 0, 1, 2, 3, or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 ,- CN, -NO 2 , C 1-4 alkyl and C 1-4 alkoxy groups are substituted.
在一些实施方案，各R 13a分别独立地为H、C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4 烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1，2，3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代。 In some embodiments, each R 13a is independently H, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-4 alkyl, C 2-7 heterocyclyl , C 2-7 heterocyclyl C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl Group C 1-4 alkyl; wherein each C 1-4 alkyl C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 2-7 heterocyclyl, C 2 -7 heterocyclyl C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl C 1-4 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1- 4 alkyl groups are independently optionally 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN,- NO 2 , C 1-6 alkyl and C 1-6 alkoxy groups are substituted.
在一些实施方案，各t1和t2分别独立地为0、1、2、或3；和m是0、1、2、或4。In some embodiments, each t1 and t2 are independently 0, 1, 2, or 3; and m is 0, 1, 2, or 4, respectively.
在一些实施方案，其中，R 1是C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、或C 1-9杂芳基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基和C 1-9杂芳基独立任选地被0、1，2，3或4个R 11取代。 In some embodiments, wherein R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, or C 1-9 heteroaryl; wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 amino Alkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl and C 1-9 heteroaryl are independently optionally substituted with 0, 1, 2, 3 or 4 R 11 .
在一些实施方案，其中，R 1是C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、或5个原子组成的杂芳基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基和5个原子组成的杂芳基独立任选地被0、1、2、3或4个R 11取代。 In some embodiments, wherein R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or 5-atom heteroaryl; wherein each C 1-4 alkyl, C 1-4 haloalkane Group, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidine The group and the 5-atom heteroaryl group are independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
在一些实施方案，其中，R 1是C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡唑基或***基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡唑基和***基独立任选地被0、1、2、3或4个R 11取代。 In some embodiments, wherein R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl or triazolyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, Pyrazolyl and triazolyl are independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
在一些实施方案，其中，In some embodiments, where
U 1和U 2分别独立地为N或-C(R a)-； U 1 and U 2 are each independently N or -C(R a )-;
各R a和R 8分别独立地为H、D、F、Cl、Br、-OH、-CN、-NO 2、-NH 2、或C 1-4烷基；其中所述各C 1-4烷基独立任选地被0、1，2，3或4个R 12取代；和 Each R a and R 8 are each independently H, D, F, Cl, Br, -OH, -CN, -NO 2, -NH 2, or C 1-4 alkyl; wherein each of said C 1-4 Alkyl groups are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ; and
n是0、1、或2。n is 0, 1, or 2.
在一些实施方案，其中，R 4是C 2-4羟基烷基、C 4-6环烷基、C 4-6环烷基C 1-4烷基、C 3-6杂环基、或C 3-6杂环基C 1-4烷基；其中所述各C 2-4羟基烷基、C 4-6环烷基、C 4-6环烷基C 1-4烷基、C 3-6杂环基和C 3-6杂环基C 1-4烷基独立任选地被0、1、2、3或4个R 11a取代。 In some embodiments, wherein R 4 is C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl, C 1-4 alkyl, C 3-6 heterocyclyl, or C 3-6 heterocyclyl C 1-4 alkyl; wherein each C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl C 1-4 alkyl, C 3- 6 heterocyclyl and C 3-6 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3, or 4 R 11a .
在一些实施方案，其中，R 4是
Figure PCTCN2021094020-appb-000024
Figure PCTCN2021094020-appb-000025
其中R 4任选地被0、1、2、3或4个R 11a取代。 In some embodiments, wherein R 4 is
Figure PCTCN2021094020-appb-000024
Figure PCTCN2021094020-appb-000025
Wherein R 4 is optionally substituted with 0, 1, 2, 3 or 4 R 11a .
在一些实施方案，其中，R 5是H、D、-NR cR d、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、或C 1-4氰基烷基。 In some embodiments, wherein R 5 is H, D, -NR c R d , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, Or C 1-4 cyanoalkyl.
在一些实施方案，其中，R 6和R 7分别独立地为H、D、F、Cl、Br、-OH、-NR cR d、-CN、-NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、或C 1-4氰基烷基。 In some embodiments, wherein R 6 and R 7 are each independently H, D, F, Cl, Br, -OH, -NR c R d , -CN, -NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl.
在一些实施方案，其中，各R 11、R 12和R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、或C 1-4烷基氨基；其中所述各-NR cR d、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基和C 1-4烷基氨基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2和C 1-4烷氧基的基团取代。 In some embodiments, wherein each R 11 , R 12 and R 13 are each independently H, D, oxo (=O), F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, Or C 1-4 alkylamino; wherein each -NR c R d , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy and C 1-4 alkylamino are independently optionally 0, 1, 2, 3 or 4 independently selected from H, D, oxo (= O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 and C 1-4 alkoxy groups are substituted.
在一些实施方案，其中，各R c、R d、R 9、R 9a、R 10和R 10a分别独立地为H、D、C 1-4烷基、C 3-6环烷基、或C 2-7杂环基；其中所述各C 1-4烷基C 3-6环烷基和C 2-7杂环基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代。 In some embodiments, wherein each R c , R d , R 9 , R 9a , R 10 and R 10a are each independently H, D, C 1-4 alkyl, C 3-6 cycloalkyl, or C 2-7 heterocyclyl; wherein each C 1-4 alkyl, C 3-6 cycloalkyl and C 2-7 heterocyclyl are independently optionally selected from 0, 1, 2, 3, or 4 independently Substitution from groups of H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy .
在一些实施方案，其中，各R 11a分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)C 1-4烷基、-OC(＝O)C 1-4烷基、-C(＝O)O-C 1-4烷基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、或C 1-4烷基氨基。 在一些实施方案，本发明所述化合物为具有以下结构之一的化合物： In some embodiments, wherein each R 11a is independently H, D, oxo (=O), F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , -C( =0)C 1-4 alkyl, -OC(=O)C 1-4 alkyl, -C(=O)OC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, or C 1 -4 Alkylamino. In some embodiments, the compound of the present invention is a compound having one of the following structures:
Figure PCTCN2021094020-appb-000026
Figure PCTCN2021094020-appb-000026
Figure PCTCN2021094020-appb-000027
Figure PCTCN2021094020-appb-000027
Figure PCTCN2021094020-appb-000028
Figure PCTCN2021094020-appb-000028
或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物或药学上可接受的盐。Or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites or pharmaceutically acceptable salts.
除非另有说明，式(I)和(II)所示化合物的立体异构体、互变异构体、溶剂化物、代谢产物或药学上可接受的盐均包含在本发明范围内。Unless otherwise specified, the stereoisomers, tautomers, solvates, metabolites or pharmaceutically acceptable salts of the compounds represented by formula (I) and (II) are all included in the scope of the present invention.
本发明公开化合物可含有不对称或手性中心，因此可以不同的立体异构体形式存在。本发明旨在使式(I)或(II)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。The compounds disclosed in the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms. The present invention aims to make all stereoisomers forms of compounds represented by formula (I) or (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or Conformation) isomers, and their mixtures, such as racemic mixtures, form part of the present invention.
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体均考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In the structure disclosed in the present invention, when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention . When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.
式(I)或(II)所示化合物可以盐的形式存在。在一实施方案，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)或(II)所示化合物和/或用于分离本式(I)或(II)所示化合物的对映体的中间体。The compound represented by formula (I) or (II) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and can be used to prepare and/or purify the compound of formula (I) or (II) and/or to isolate the compound of formula (I) Or an intermediate of the enantiomer of the compound shown in (II).
另一方面，本发明涉及制备式(I)和(II)所示化合物的中间体。In another aspect, the present invention relates to intermediates for the preparation of compounds represented by formula (I) and (II).
另一方面，本发明涉及式(I)和(II)所示化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) and (II).
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物。在一实施方案中，本发明所述药物组合物，更进一步包括药学上可接受的辅料、稀释剂或载体、或其组合。在另一实施方案，所述药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further includes pharmaceutically acceptable excipients, diluents or carriers, or a combination thereof. In another embodiment, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
在一些实施方案，本发明所述药物组合物进一步包含附加治疗剂。In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent.
另一方面，本发明涉及一种使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防和/或治疗AXL蛋白激酶介导的疾病和/或病症的药物中的用途。In another aspect, the present invention relates to a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and/or treatment of diseases and/or disorders mediated by AXL protein kinase .
在一些实施方案，所述疾病和/或病症选自增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、移植排斥、或病毒感染性疾病。In some embodiments, the disease and/or condition is selected from proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, or viral infectious diseases.
在一些实施方案，所述疾病和/或病症选自治疗和/或预防涉及信号通路的AXL激酶、介导的疾病。此类疾病和/或病症包括增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、移植排斥、以及它们的并发症。特别地，本发明化合物可用来治疗和/或预防下列疾病和/或病症，包括但不限于，癌症(包括实体肿瘤和血液癌症)、真性红细胞增多症、原发性血小板增多症、骨髓纤维化、性髓细胞性白血病、急性淋巴细胞白血病、慢性髓细胞性白血病(CML)、慢性阻塞性肺疾病(COPD)、哮喘、***性红斑狼疮、皮肤型红斑狼疮、狼疮性肾炎、皮肌炎、干燥综合征、银屑病、I型糖尿病、呼吸道过敏性疾病、鼻窦炎、湿疹、麻疹、食物过敏、昆虫毒液过敏、炎性肠病、克罗恩病、类风湿性关节炎、幼年型关节炎、银屑病性关节炎、器官移植排斥、组织移植排斥、细胞移植排斥、流感、冠状病毒感染、新冠状病毒感染、登革热病毒感染、寨卡病毒感染、埃博拉病毒感染、呼吸道合胞病毒感染、或HBV。In some embodiments, the disease and/or disorder is selected from treatment and/or prevention of AXL kinase, mediated diseases involving signaling pathways. Such diseases and/or disorders include proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and their complications. In particular, the compounds of the present invention can be used to treat and/or prevent the following diseases and/or disorders, including, but not limited to, cancer (including solid tumors and blood cancers), polycythemia vera, essential thrombocythemia, and myelofibrosis , Myelogenous leukemia, acute lymphocytic leukemia, chronic myeloid leukemia (CML), chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes, respiratory allergic diseases, sinusitis, eczema, measles, food allergy, insect venom allergy, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile joints Inflammation, psoriatic arthritis, organ transplant rejection, tissue transplant rejection, cell transplant rejection, influenza, coronavirus infection, new coronavirus infection, dengue virus infection, Zika virus infection, Ebola virus infection, respiratory syncytia Viral infection, or HBV.
本发明化合物的药物组合物、制剂和给药Pharmaceutical composition, formulation and administration of the compound of the present invention
本发明提供了一种药物组合物，其包含本发明公开化合物，或实施例中所列化合物，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物或药学上可接受的盐；和药学上可接受的辅料、稀释剂、载体、溶媒或其组合。本发明公开的药物组合物中化合物的量是指能有效检测到抑制生物样本或患者体内蛋白激酶的量。The present invention provides a pharmaceutical composition comprising the compound disclosed in the present invention, or the compound listed in the examples, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites or pharmaceutically Acceptable salts; and pharmaceutically acceptable excipients, diluents, carriers, vehicles, or combinations thereof. The amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect the inhibition of protein kinase in biological samples or patients.
也应认识到，本发明的某些化合物可以以游离形式存在用于治疗，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的盐、酯、这些酯的盐、或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。It should also be recognized that certain compounds of the present invention may exist in free form for treatment, or, if appropriate, may exist in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, and salts of these esters, or can directly or indirectly provide the compound of the present invention or its compounds when administered to a patient in need. Any additional adducts or derivatives of metabolites or residues.
在文献例如Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明公开化合物不相容的任何常用载体外，关注其应用属于本发明的范围。In the literature such as Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, York discloses various carriers for preparing pharmaceutically acceptable compositions, and well-known techniques for their preparation, and the contents of each of these documents are incorporated into the present invention by reference. Except for any commonly used carriers that are incompatible with the disclosed compounds of the present invention due to any undesired biological effects or interactions with any other ingredients in a pharmaceutically acceptable composition in a harmful manner, the application of concern falls under The scope of the invention.
本发明提供的药物组合物可以与不会损害预期治疗作用的其它活性成分共同配制，或者与补充预期作用的物质共同配制。The pharmaceutical composition provided by the present invention can be formulated with other active ingredients that do not impair the expected therapeutic effect, or with substances that supplement the expected effect.
本发明化合物和组合物的用途Uses of the compounds and compositions of the present invention
本发明提供了使用本发明所公开的化合物和药物组合物治疗、预防、或改善由一种或多种蛋白激酶，如AXL激酶行为介导或以其他方式影响的疾病或病症，或者由AXL激酶行为介导或以其他方式影响的疾病或病症的一种或多种症状的方法。The present invention provides the use of the compounds and pharmaceutical compositions disclosed in the present invention to treat, prevent, or ameliorate diseases or conditions that are mediated or otherwise affected by one or more protein kinases, such as AXL kinase, or are affected by AXL kinase. A method of behavior-mediated or otherwise affected one or more symptoms of a disease or condition.
在一些实施方案，本发明提供了一类本发明所公开的化合物或包含本发明所公开化合物的药物组合物，用于治疗、预防或改善由不适当的AXL激酶行为介导或以其他方式影响的疾病或病症或者由不适当的AXL激酶行为介导或以其他方式影响的疾病或病症的一种或多种症状。In some embodiments, the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention for the treatment, prevention or amelioration of inappropriate AXL kinase behavior mediated or otherwise affected Or one or more symptoms of a disease or disorder that is mediated or otherwise affected by inappropriate AXL kinase behavior.
“不适当的AXL激酶行为”是指发生在特定患者身上偏离正常AXL激酶行为的AXL激酶行为。不适当的AXL激酶行为可以表现为例如活性的不正常增长、或AXL激酶行为时间点和控制上的偏差的形式。这种不适当的激酶行为源于，例如，蛋白激酶的过度表达或突变而导致的不适当或不受控的行为。因此，本发明提供治疗这些疾病和病症的方法。"Inappropriate AXL kinase behavior" refers to AXL kinase behavior that deviates from normal AXL kinase behavior in a specific patient. Inappropriate AXL kinase behavior can take the form of, for example, an abnormal increase in activity, or a deviation in the time point and control of AXL kinase behavior. This inappropriate kinase behavior stems from, for example, inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinase. Therefore, the present invention provides methods for treating these diseases and conditions.
同上面的描述相一致，这样的疾病或病症包括但不限于：骨髓增殖性疾病，例如真性红细胞增多症(PCV)、特发性血小板增多症、特发性骨髓纤维化(IMF)；白血病，例如髓系白血病包括慢性髓系白血病(CML)、耐伊马替尼的CML形式、急性髓系白血病(AML)和AML的亚型、急性成巨核细胞白血病(AMKL)；淋巴增殖性疾病，例如急性淋巴细胞白血病(ALL)和骨髓瘤等；癌症包括头颈部癌、***癌、乳癌、卵巢癌、黑素瘤、肺癌、脑肿瘤、胰腺癌、尿路上皮癌、肝癌、胃癌和肾癌等；和与免疫功能紊乱、免疫缺陷、免疫调节有关的炎症性疾病或病症、自身免疫性疾病、组织移植排斥、移植物抗宿主病、伤口愈合、肾病、多发性硬化、甲状腺炎、I型糖尿病、结节病、银屑病、变应性鼻炎、炎症性肠病包括克罗恩病和溃疡性结肠炎(UC)、***性红斑狼疮(SLE)、关节炎、骨关节炎、类风湿性关节炎、骨质疏松症、哮喘和慢性阻塞性肺病(COPD)和干眼综合征(或干燥性角膜结膜炎(KCS))。Consistent with the above description, such diseases or disorders include but are not limited to: myeloproliferative diseases, such as polycythemia vera (PCV), idiopathic thrombocythemia, idiopathic myelofibrosis (IMF); leukemia, For example, myeloid leukemia includes chronic myeloid leukemia (CML), imatinib-resistant CML forms, acute myeloid leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as Acute lymphocytic leukemia (ALL) and myeloma; cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, urothelial cancer, liver cancer, stomach cancer and kidney cancer Etc.; and inflammatory diseases or disorders related to immune dysfunction, immune deficiency, immune regulation, autoimmune diseases, tissue transplant rejection, graft versus host disease, wound healing, nephropathy, multiple sclerosis, thyroiditis, type I Diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid Arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
一方面，本发明提供一类本发明所公开的化合物或包含本发明所公开化合物的药物组合物，用于预防和/或治疗哺乳动物(包括人类)的增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、或移植排斥。In one aspect, the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention, which are used to prevent and/or treat proliferative diseases, autoimmune diseases, and allergic diseases in mammals (including humans). Disease, inflammatory disease, or transplant rejection.
在另一方面，本发明提供一种治疗罹患或有风险罹患本发明所公开疾病的哺乳动物的方法，所述方法包括给予有效治疗病症量或有效预防病症量的一种或多种本发明公开的药物组合物或化合物。In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of suffering from the disease disclosed in the present invention, the method comprising administering an amount effective to treat the disorder or an amount effective to prevent the disorder in one or more of the present disclosures The pharmaceutical composition or compound.
在特定实施方案中，增殖性疾病选自癌症，如结肠癌，恶性胶质瘤，子宫内膜癌，肝癌，肺癌，黑色素瘤，肾癌，甲状腺癌，淋巴瘤，淋巴增生性障碍，小细胞肺癌，鳞状细胞肺癌，胶质瘤，乳腺癌，***癌，卵巢癌，***等；恶性血液病，如急性骨髓性白血病(AML)，脊髓发育异常综合征(MDS)，骨髓增生病(MPD)，慢性骨髓性白血病(CML)，T细胞急性淋巴细胞白血病(T-ALL)，B细胞急性淋巴细胞白血病(B-ALL)，非霍奇金淋巴瘤(NHL)，B细胞淋巴瘤；真性红细胞增多症、原发性血小板增多症、骨髓纤维化、多发性骨髓瘤等。In a specific embodiment, the proliferative disease is selected from cancers such as colon cancer, malignant glioma, endometrial cancer, liver cancer, lung cancer, melanoma, kidney cancer, thyroid cancer, lymphoma, lymphoproliferative disorder, small cell Lung cancer, squamous cell lung cancer, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, etc.; hematological malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic disease ( MPD), chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin's lymphoma (NHL), B-cell lymphoma; Polycythemia vera, essential thrombocythemia, myelofibrosis, multiple myeloma, etc.
在另一方面，本发明了提供治疗和/或预防易患或患有自体免疫疾病的哺乳动物的方法，所述方法包括施用有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。In another aspect, the present invention provides a method for treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present invention Pharmaceutical composition or compound.
在特定实施方案中，自体免疫疾病选自COPD，哮喘，***性红斑狼疮，皮肤型红斑狼疮，狼疮性肾炎，皮肌炎，干燥综合征，银屑病，I型糖尿病和炎性肠病。In a specific embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes and inflammatory bowel disease.
在另一方面，本发明提供了治疗和/或预防易患或患有过敏性疾病的哺乳动物的方法，所述方法包括施用有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。在特定的实施方案中，过敏性疾病选自呼吸道过敏性疾病，鼻窦炎，湿疹和麻疹，食物过敏和昆虫毒液过敏。In another aspect, the present invention provides a method of treating and/or preventing mammals susceptible to or suffering from allergic diseases, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present invention Pharmaceutical composition or compound. In a specific embodiment, the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
在特定的实施方案中，过敏性疾病选自呼吸道过敏性疾病，鼻窦炎，湿疹和麻疹，食物过敏和昆虫毒液过敏。In a specific embodiment, the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
在另一方面，本发明提供了治疗和/或预防易患或患有炎性疾病的哺乳动物的方法，所述方法包括施用有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the disclosed Pharmaceutical composition or compound.
在另一方面，本发明提供了治疗和/或预防易患或患有病毒感染性疾病的哺乳动物的方法，所述方法包括施用有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from a viral infectious disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present disclosures The pharmaceutical composition or compound.
在特定实施方案中，病毒感染性疾病选自流感、冠状病毒感染、新冠状病毒感染、登革热病毒感染、寨卡病毒感染、埃博拉病毒感染、呼吸道合胞病毒感染、或HBV。In a specific embodiment, the viral infectious disease is selected from influenza, coronavirus infection, new coronavirus infection, dengue virus infection, Zika virus infection, Ebola virus infection, respiratory syncytial virus infection, or HBV.
在另一方面，本发明提供了一类用作药物尤其用作治疗和/或预防本发明所述疾病和/或病症的药物的 本发明公开的化合物。本发明也提供了使用本发明公开化合物来制备治疗和/或预防本发明所述疾病和/或病症的药物。In another aspect, the present invention provides a class of compounds disclosed in the present invention for use as a medicament, especially as a medicament for the treatment and/or prevention of the diseases and/or disorders described in the present invention. The present invention also provides the use of the compounds disclosed in the present invention to prepare drugs for the treatment and/or prevention of the diseases and/or disorders described in the present invention.
联合治疗Combination therapy
本发明化合物可以作为单独的活性试剂给药，或者可以与其它治疗剂联合给药，包括具有相同或相似治疗活性并且对于此类联合给药确定为安全且有效的其它化合物。The compounds of the present invention can be administered as a single active agent, or can be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combined administration.
一方面，本发明提供治疗、预防或改善疾病或病症的方法，包括施用安全有效量的包含本发明公开化合物与一种或多种治疗活性剂的联合药物。在一些实施方案，联合药物包含一种或两种其他治疗剂。In one aspect, the present invention provides a method for treating, preventing or ameliorating a disease or condition, which comprises administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents. In some embodiments, the combination drug contains one or two other therapeutic agents.
其它治疗剂的实例包括包括但不限于：抗癌剂，包括化疗剂和抗增殖剂；抗炎剂；和免疫调剂剂或免疫抑制剂。Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressive agents.
另一方面，本发明提供了包括本发明化合物和至少一种其它治疗剂的产品，可制备成在治疗中同时、分别或顺序施用的组合。在一些实施方案，治疗是针对由一种或多种蛋白激酶，如AXL激酶、或NTRK激酶活性介导的疾病或病征的治疗。联合制备提供的产品包括存在于同一药物组合物中、并包含本发明公开化合物和其他治疗剂的组合物，或以不同形式存在的本发明公开化合物和其他治疗剂，例如，药盒。In another aspect, the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent, which can be prepared as a combination for simultaneous, separate or sequential administration during treatment. In some embodiments, the treatment is for the treatment of diseases or symptoms mediated by the activity of one or more protein kinases, such as AXL kinase, or NTRK kinase. The products provided by the joint preparation include a composition containing the compound disclosed in the present invention and other therapeutic agents in the same pharmaceutical composition, or the compound disclosed in the present invention and other therapeutic agents in different forms, for example, a kit.
另一方面，本发明提供了一种包含本发明公开化合物和另外一种或多种治疗剂的药物组合物。在一些实施方案，药物组合物可包含如上所述的药学上可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising the compound disclosed in the present invention and another one or more therapeutic agents. In some embodiments, the pharmaceutical composition may include pharmaceutically acceptable excipients as described above.
另一方面，本发明提供了包含两种或两种以上的单独药物组合物的药盒，其中至少一种药物组合物包含本发明公开化合物。在一些实施方案，药盒包括单独保持所述组合物的工具，例如容器、分开的瓶或分开的箔盒。这类药盒的实例是泡罩包装，其通常用于包装片剂、胶囊剂等。In another aspect, the present invention provides a kit containing two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains the compound disclosed in the present invention. In some embodiments, the kit includes means for separately holding the composition, such as a container, a separate bottle, or a separate foil box. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
本发明公开化合物可以作为单一活性组分施用或作为例如佐剂，与其它治疗剂共同施用。The compounds disclosed in the present invention can be administered as a single active ingredient or as, for example, adjuvants, co-administered with other therapeutic agents.
在一些实施方案，所述其它治疗剂包括，化疗剂和/或抗增殖剂。已知的化疗药物包括，但并不限于，可与本发明化合物联合使用的其他疗法或抗癌药物、手术、放射疗法(少许例子如γ辐射，中子束放射疗法，电子束放射疗法，质子疗法，近距离放射疗法和***放射性同位素疗法)，内分泌疗法、紫杉烷类(紫杉醇(taxol)，多西紫杉醇(taxotere)等)、铂衍生物(顺铂(cisplatin)、卡铂(carboplatin))、生物反应调节剂(干扰素，白细胞间素)、肿瘤坏死因子(TNF，TRAIL受体靶向物)、过热和冷冻疗法、减轻任何不良反应的试剂(如止吐药)、和其他被认可的化疗药物、包括但并不限于，烷化药物(氮芥(mechlorethamine)，苯丁酸氮芥(chlorambucil)、环磷酰胺(cyclophosphamide)、马法兰(melphalan)、异环磷酰胺(ifosfamide))、抗代谢物(甲氨蝶呤(methotrexate)、培美曲塞(pemetrexed)等等)、嘌呤拮抗剂和嘧啶拮抗剂(6-巯嘌呤(6-mercaptopurine)、5-氟尿嘧啶(5-fluorouracil)、阿糖胞苷(cytarabile)、吉西他滨(gemcitabine))、纺锤体抑制剂(长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine))、鬼臼毒素(依托泊苷(etoposide)、伊立替康(irinotecan)、托泊替康(topotecan))、抗生素(多柔比星(doxorubicin)、博莱霉素(bleomycin)、丝裂霉素(mitomycin))、亚硝基脲(卡莫司汀(carmustine)、洛莫司汀(lomustine))、细胞***周期抑制剂(KSP通过有丝***驱动蛋白抑制剂，CENP-E和CDK抑制剂)、酶(天门冬酰胺酶(asparaginase))、激素(它莫昔芬(tamoxifen)、亮丙瑞林(leuprolide)、氟他胺(flutamide)、甲地孕酮(megestrol)、***(dexamethasone)等等)。抗血管生成试剂(阿瓦斯丁(avastin)等)。单抗(贝利单抗(belimumab)，brentuximab、西妥昔单抗(cetuximab)、吉妥单抗(gemtuzumab)、伊匹单抗(ipilimumab)、ofatumumab、帕尼单抗(panitumumab)、雷珠单抗(ranibizumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab))。激酶抑制剂(伊马替尼(imatinib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、达沙替尼(dasatinib)、尼洛替尼(nilotinib)、拉帕替尼(lapatinib)、克卓替尼(crizotinib)、鲁索替尼(ruxolitinib)、维罗非尼(vemurafenib)、凡德他尼(vandetanib)、帕唑帕尼(pazopanib)等等)。药物抑制或激活癌症的途径如mTOR，HIF(缺氧诱导因子)途径及其他。In some embodiments, the other therapeutic agents include chemotherapeutic agents and/or anti-proliferative agents. Known chemotherapeutics include, but are not limited to, other therapies that can be used in combination with the compounds of the present invention or anticancer drugs, surgery, and radiotherapy (a few examples are gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton Therapies, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (taxol, docetaxel, etc.), platinum derivatives (cisplatin, carboplatin) ), biological response modifiers (interferon, interleukin), tumor necrosis factor (TNF, TRAIL receptor target), hyperthermia and cryotherapy, agents to reduce any adverse reactions (such as antiemetics), and other drugs Approved chemotherapy drugs, including but not limited to alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide) , Antimetabolites (methotrexate, pemetrexed, etc.), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil) , Cytarabile, gemcitabine), spindle inhibitors (vinblastine, vincristine, vinorelbine), podophyllotoxin (etoposide) ), irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosourea ( Carmustine, lomustine), cell division cycle inhibitors (KSP through mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase) , Hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone, etc.). Anti-angiogenic agents (avastin, etc.). Monoclonal antibodies (belimumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, panitumumab) Monoclonal antibody (ranibizumab), rituximab (rituximab), tositumomab (tositumomab), trastuzumab (trastuzumab)). Kinase inhibitors (imatinib, sunitinib, sorafenib, erlotinib, gefitinib, dasatinib) ), nilotinib, lapatinib, crizotinib, ruxolitinib, vemurafenib, vandetanib, par Zopanib (pazopanib, etc.). Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia inducible factor) pathway and others.
本发明公开的化合物还可与其它治疗过程联合，提高疗效。例如，施用激素治疗或者特殊的放射治疗。本发明公开的化合物尤其被用作放射增敏剂，特别用于对那些放射治疗敏感性弱的肿瘤治疗。The compound disclosed in the present invention can also be combined with other treatment processes to improve curative effect. For example, administering hormone therapy or special radiation therapy. The compounds disclosed in the present invention are especially useful as radiosensitizers, especially for the treatment of tumors that are less sensitive to radiotherapy.
“联合”表示在单个剂量单位形式中的固定联合或用于联合给药的部分的药盒，其中本发明公开的化合物和联合伴侣可在同一时间独立施用或者可在一定的时间间隔内分别施用，特别是使联合伴侣表现出合作、例如协同作用。如本发明所用的术语“共同给药”或“联合给药”等意欲囊括将所选的联合伴侣施用于需 要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同给药途径或同时给药的治疗方案。"Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compound disclosed in the present invention and the combination partner can be administered independently at the same time or can be administered separately within a certain time interval , Especially for joint partners to show cooperation, such as synergy. As used in the present invention, the terms "co-administration" or "co-administration" and the like are intended to encompass the administration of a selected joint partner to a single individual (for example, a patient) in need thereof, and are intended to include substances in which the substance does not have to pass through the same route of administration or Simultaneous administration of the treatment plan.
治疗方法treatment method
在一些实施方案，本发明公开的治疗方法包括对有需要的患者施用安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明公开的各实施方案包括通过对有需要的患者给予安全有效量的本发明公开化合物或包含本发明公开化合物的药物组合物，来治疗本发明所述疾病或病症的方法。In some embodiments, the treatment methods disclosed in the present invention include administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need. The various embodiments disclosed in the present invention include methods for treating the diseases or disorders described in the present invention by administering to a patient in need a safe and effective amount of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention.
在一些实施方案，本发明公开化合物或包含本发明公开化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。在其中一个实施方案，每天给药一次。在又一实施方案，每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案取决于所述化合物的药代动力学性质，例如稀释、分布和半衰期，这些可由技术人员测定。此外，本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病、被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等那些在技术人员知识和经验范围内的因素。所述领域技术人员还应理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整适宜的给药方案。In some embodiments, the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention may be administered at one time, or according to the dosage regimen, administered several times at different time intervals within a specified time period. For example, it may be administered once, twice, three or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosage regimen of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by a skilled person. In addition, the appropriate dosage regimen of the compound disclosed in the present invention or the pharmaceutical composition containing the compound disclosed in the present invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age of the patient being treated, and The physical condition, medical history of the patient being treated, the nature of simultaneous therapy, the desired therapeutic effect, and other factors that are within the scope of the technician’s knowledge and experience. Those skilled in the art should also understand that for the individual patient's response to the dosing regimen, or when the individual patient's needs change over time, an appropriate dosing regimen may be required to be adjusted.
本发明公开化合物可与一种或多种其它治疗剂同时、或在其之前或之后进行给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别进行给药，或与之以同一药物组合物形式给药。The compounds disclosed in the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition.
一般合成方案General synthesis scheme
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To describe the present invention, examples are listed below. However, it needs to be understood that the present invention is not limited to these embodiments, but only provides methods for practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)或(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula (I) or (II). The following reaction schemes and examples are used to further illustrate the content of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购自商品供应商，例如Aldrich Chemical Company，Alfa Chemical Company，上海韶远试剂有限公司，SAIN化学技术(上海)有限公司，上海拜德制药技术有限公司，上海浩宏生物医学技术有限公司，除非另有说明，否则本发明所使用的试剂无需进一步纯化即可使用。常用溶剂购自北京海之源伟业科技有限公司等商品供应商。In the examples described below, all temperatures are set to degrees Celsius unless otherwise indicated. Reagents are purchased from commodity suppliers, such as Aldrich Chemical Company, Alfa Chemical Company, Shanghai Shaoyuan Reagent Co., Ltd., SAIN Chemical Technology (Shanghai) Co., Ltd., Shanghai Baide Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., unless Otherwise, the reagents used in the present invention can be used without further purification. Common solvents are purchased from commodity suppliers such as Beijing Haizhiyuan Weiye Technology Co., Ltd.
无水THF、二氧六环、DCM、甲苯和DMF均购自商品供应商，例如能源化工公司(Energy chemical company)和Aldrich化学公司。EtOAc、PE、CH 3CN、NMP和DMSO在使用前均用无水Na 2SO 4处理。 Anhydrous THF, dioxane, DCM, toluene and DMF were all purchased from commercial suppliers, such as Energy Chemical Company and Aldrich Chemical Company. EtOAc, PE, CH 3 CN, NMP and DMSO were all treated with anhydrous Na 2 SO 4 before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under a positive pressure of nitrogen or argon or a drying tube on an anhydrous solvent (unless otherwise indicated), the reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. The glassware is all dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
1H NMR谱和 13C/2D数据是在Bruker Avance III 400MHz上收集得到。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽单峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 1 H NMR spectrum and 13 C/2D data were collected on Bruker Avance III 400MHz. The 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide Peak), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets, doublet of triplets). Coupling constant, expressed in Hertz (Hz).
LC/MS是在与Agilent 6120/6125质谱仪耦合的Agilent 1260(二元泵/DAD检测器)上进行。LC/MS was performed on Agilent 1260 (binary pump/DAD detector) coupled with Agilent 6120/6125 mass spectrometer.
方法1：method 1:
柱：HALO C18 2.7μm，4.6mm×30mm，流动相：MeCN(0.05％HCOOH)-Water(0.05％HCOOH)；Column: HALO C18 2.7μm, 4.6mm×30mm, mobile phase: MeCN(0.05%HCOOH)-Water(0.05%HCOOH);
梯度：从5％至95％的MeCN，洗脱0.8min，保持0.8min，总运行时间是2.0min；流速：1.8mL/min；Gradient: from 5% to 95% MeCN, elution 0.8min, hold 0.8min, total running time is 2.0min; flow rate: 1.8mL/min;
柱温：45℃；Column temperature: 45℃;
方法2：Method 2:
柱：HALO C18 2.7μm，4.6mm×50mm，流动相：MeCN(0.025％三氟乙酸)-水(0.025％三氟乙酸)；梯度：从5％至95％的MeCN，洗脱1.0min，保持1.0min，总运行时间是2.5min；流速：1.8mL/min；柱温：45℃。Column: HALO C18 2.7μm, 4.6mm×50mm, mobile phase: MeCN (0.025% trifluoroacetic acid)-water (0.025% trifluoroacetic acid); gradient: from 5% to 95% MeCN, elution for 1.0 min, hold 1.0min, total running time is 2.5min; flow rate: 1.8mL/min; column temperature: 45°C.
由RP-HPLC进行纯度测试：Purity test by RP-HPLC:
在RP-HPLC上进行化合物纯度测试(Shimadzu 2010/2030)Perform compound purity test on RP-HPLC (Shimadzu 2010/2030)
方法1：method 1:
柱：Gemini 4.6×150mm 5um；流动相：H 2O(0.05％三氟乙酸)-MeCN(0.05％三氟乙酸)。梯度：从10％至100％的MeCN，洗脱8分钟，保持2分钟。流速：1.2mL/min，柱温：35℃/40℃。 Column: Gemini 4.6×150mm 5um; mobile phase: H 2 O (0.05% trifluoroacetic acid)-MeCN (0.05% trifluoroacetic acid). Gradient: MeCN from 10% to 100%, elution for 8 minutes, hold for 2 minutes. Flow rate: 1.2 mL/min, column temperature: 35°C/40°C.
方法2：Method 2:
柱：XBRIDGE 2.1×50mm，3.5um；流动相：H 2O(0.05％三氟乙酸)-MeCN(0.05％三氟乙酸)。梯度：从10％至100％的MeCN，洗脱7分钟，保持1分钟。流速：0.8mL/min，柱温：35℃/40℃。 Column: XBRIDGE 2.1×50mm, 3.5um; mobile phase: H 2 O (0.05% trifluoroacetic acid)-MeCN (0.05% trifluoroacetic acid). Gradient: MeCN from 10% to 100%, elution for 7 minutes, hold for 1 minute. Flow rate: 0.8 mL/min, column temperature: 35°C/40°C.
由SFC进行化合物纯化：Compound purification by SFC:
在配备UV检测器的Thar P80上进行SFC纯化。SFC purification was performed on Thar P80 equipped with UV detector.
方法：柱CHIRALPAK AD-H 250mm，20mm，5μm，改性剂：30％EtOH(0.2％NH 4OH)。 Method: Column CHIRALPAK AD-H 250mm, 20mm, 5μm, modifier: 30% EtOH (0.2% NH 4 OH).
由RP-HPLC进行化合物纯化：Purification of the compound by RP-HPLC:
在Gilson纯化***(322或306泵和GX-281馏分收集器)，Shimadzu LC20Ap和Waters MS触发纯化***上进行RP-HPLC纯化；Perform RP-HPLC purification on Gilson purification system (322 or 306 pump and GX-281 fraction collector), Shimadzu LC20Ap and Waters MS trigger purification system;
方法1：method 1:
柱Gemini C18 21x150mm，5μm Xbrige C18 19x150mm，5μm，Spolar C18 20x150mm和Ultimate AQ-C18 30x250mm，10μmColumn Gemini C18 21x150mm, 5μm Xbrige C18 19x150mm, 5μm, Spolar C18 20x150mm and Ultimate AQ-C18 30x250mm, 10μm
流动相：Mobile phase:
1.MeCN的水溶液(0.1％HCOOH)，流速：20ml/min，50ml/min，柱30x250mm，10μm；波长：210-400nm。将样品注入DMSO(+任选的甲酸和水)中，从10％至95％MeCN的线性梯度，洗脱10分钟。1. MeCN aqueous solution (0.1% HCOOH), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10μm; wavelength: 210-400nm. The sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
2.MeCN的水溶液(0.1％三氟乙酸)，流速：20ml/min，50ml/min，柱30x250mm，10μm；波长：210-400nm。将样品注入DMSO(+任选的甲酸和水)中，从10％至95％MeCN的线性梯度，洗脱10分钟。2. MeCN aqueous solution (0.1% trifluoroacetic acid), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10μm; wavelength: 210-400nm. The sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
3.MeCN的水溶液(0.1％NH 3-H 2O/10mM NH 4AC)，流速：20ml/min，50ml/min，柱30x250mm，10μm；波长：210-400nm。将样品注入DMSO(+任选的甲酸和水)中，从10％至95％MeCN的线性梯度，洗脱10分钟。 3. MeCN aqueous solution (0.1% NH 3 -H 2 O/10mM NH 4 AC), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10μm; wavelength: 210-400nm. The sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
制备本发明公开化合物的典型合成步骤如下面的合成方案1～2所示。除非另外说明，各R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、U 1、U 2和n均具有如本发明所述的定义；PG 1和PG 2是保护基团。 The typical synthetic steps for preparing the compounds disclosed in the present invention are shown in the following synthetic schemes 1-2. Unless otherwise specified, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , U 1 , U 2 and n has the definition as described in the present invention; PG 1 and PG 2 is a protecting group.
合成方案1：Synthesis scheme 1:
Figure PCTCN2021094020-appb-000029
Figure PCTCN2021094020-appb-000029
具有如式 (6)所示结构的本发明化合物可以通过合成方案1描述的一般合成方法制备得到，具体步骤可参考实施例。合成方案1中，在碱性条件下，硼酯衍生物 (1)在合适的碱(如碳酸铯，碳酸钾，碳酸钠等)，以及合适的Pd催化剂(如Pd(OAc) 2、Pd(dppf) 2Cl 2或Pd 2(dba) 3等)的作用下，与取代的杂芳基化合物 (2)发生偶联反应得到化合物 (3)。脱除保护基团PG 1后得到芳香胺衍生物 (4)。羧酸衍生物 (5)在缩合剂(如EDCI或HATU)存在下与化合物 (4)缩合得到目标激酶抑制剂 (6)。 The compound of the present invention having the structure represented by formula (6) can be prepared by the general synthesis method described in Synthetic Scheme 1, and the specific steps can be referred to the examples. In the synthesis scheme 1, under basic conditions, the boron ester derivative (1) in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd( Under the action of dppf) 2 Cl 2 or Pd 2 (dba) 3, etc.), the compound (3) can be obtained by coupling reaction with the substituted heteroaryl compound (2 ). After removing the protective group PG 1 , an aromatic amine derivative (4) is obtained . The carboxylic acid derivative (5) is condensed with the compound (4) in the presence of a condensing agent (such as EDCI or HATU) to obtain the target kinase inhibitor (6) .
羧酸衍生物 (5)可通过文献(例如参见，“Practical synthesis of bicyclic pyrazol-5-one derivatives.”Xuejin Feng,Michael A.Xi,Yanjun Wu,Xiaogang Wang,Ning Xi Tetrahedron Lett.2017,58,46-49；Facile synthesis of bicyclic1-arylpyrazol-5-ones.”Wu,Y.；Wang,K.；Li,Z.；Bai,X.；Xi,N.Tetrahedron Lett.2014,55,142-147)中描述的合成方法得到。 Carboxylic acid derivatives (5) can be found in the literature (see, for example, "Practical synthesis of bicyclic pyrazol-5-one derivatives." Xuejin Feng, Michael A. Xi, Yanjun Wu, Xiaogang Wang, Ning Xi Tetrahedron Lett. 2017, 58, 46-49; Facile synthesis of bicyclic1-arylpyrazol-5-ones."Wu,Y.;Wang,K.;Li,Z.;Bai,X.; Xi,N.Tetrahedron Lett.2014,55,142-147) The synthesis method described is obtained.
合成方案2：Synthesis scheme 2:
Figure PCTCN2021094020-appb-000030
Figure PCTCN2021094020-appb-000030
具有如式 (6)所示结构的本发明化合物还可以通过合成方案2描述的一般合成方法制备得到，具体步骤可参考实施例。合成方案2中，芳基或杂芳基化合物 (7)在缩合剂(如EDCI或HATU)存在下与化合物 (5)缩合得到化合物 (8)。在碱性条件下，硼酯衍生物 (10)在合适的碱(如碳酸铯，碳酸钾，碳酸钠等)，以及合适的Pd催化剂(如Pd(OAc) 2、Pd(dppf) 2Cl 2或Pd 2(dba) 3等)的作用下，与取代的杂芳基化合物 (8)发生偶联反应得到化合物 (9)。在碱性条件下，硼酯衍生物 (9)在合适的碱(如碳酸铯，碳酸钾，碳酸钠等)，以及合适的Pd催化剂(如Pd(OAc) 2、Pd(dppf) 2Cl 2或Pd 2(dba) 3等)的作用下，与取代的杂芳基衍生物 (2)发生偶联反应得到目标激酶抑制剂 (6)。 The compound of the present invention having the structure represented by formula (6) can also be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can be referred to the examples. In the synthesis scheme 2, the aryl or heteroaryl compound (7) is condensed with the compound (5) in the presence of a condensing agent (such as EDCI or HATU) to obtain the compound (8) . Under basic conditions, the boronic ester derivative (10) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2) Or under the action of Pd 2 (dba) 3, etc.), the compound (9) can be obtained by coupling reaction with the substituted heteroaryl compound (8 ). Under alkaline conditions, the boronic ester derivative (9) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2) Or under the action of Pd 2 (dba) 3, etc.), a coupling reaction occurs with the substituted heteroaryl derivative (2) to obtain the target kinase inhibitor (6) .
实施例Example
中间体的合成Synthesis of intermediates
中间体1 2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸Intermediate 1 2-Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid
Figure PCTCN2021094020-appb-000031
Figure PCTCN2021094020-appb-000031
步骤1) 2-(2-(2-(叔丁氧基羰基)-2-苯基肼基)-2-氧乙氧基)乙酸Step 1) 2-(2-(2-(tert-butoxycarbonyl)-2-phenylhydrazino)-2-oxoethoxy)acetic acid
向1-苯基肼-1-甲酸叔丁酯(3.7g，18mmol)的DMF(50mL)溶液中加入1,4-二氧六环-2,6-二酮(3.13g，27mmol)和碳酸钠(3.82g，36mmol)。将所得混合物保持在氮气下，并在室温搅拌16h。将混合物浓缩以除去有机物，用2N HCl调节pH至4～5，加入H 2O(50mL)，用EtOAc(150mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，得到2-(2-(2-(叔丁氧基羰基)-2-苯基肼基)-2-氧乙氧基)乙酸为白色固体(4.2g，64.4％)。MS(ESI)m/z 346.9[M+Na] +。 1H NMR(400MHz,DMSO-d 6)δ12.79(s,1H),10.63(s,1H),7.39–7.29(m,4H),7.15(ddd,J＝8.4,5.5,1.8Hz,1H),4.15(d,J＝2.2Hz,4H),1.42(s,9H)。 To a solution of tert-butyl 1-phenylhydrazine-1-carboxylate (3.7g, 18mmol) in DMF (50mL) was added 1,4-dioxane-2,6-dione (3.13g, 27mmol) and carbonic acid Sodium (3.82 g, 36 mmol). The resulting mixture was kept under nitrogen and stirred at room temperature for 16 h. The mixture was concentrated to remove organics, the pH was adjusted to 4-5 with 2N HCl, H 2 O (50 mL) was added, and the mixture was extracted with EtOAc (150 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain 2-(2-(2-(tert-butoxycarbonyl)-2-phenylhydrazino)-2-oxy Ethoxy)acetic acid was a white solid (4.2 g, 64.4%). MS (ESI) m/z 346.9 [M+Na] + . 1 H NMR(400MHz,DMSO-d 6 )δ12.79(s,1H),10.63(s,1H),7.39–7.29(m,4H),7.15(ddd,J=8.4,5.5,1.8Hz,1H ), 4.15 (d, J = 2.2 Hz, 4H), 1.42 (s, 9H).
步骤2) 2-(2-(2-羟基乙氧基)乙酰基)-1-苯基肼基-1-甲酸叔丁酯Step 2) tert-Butyl 2-(2-(2-hydroxyethoxy)acetyl)-1-phenylhydrazino-1-carboxylate
在0℃、氮气氛下，向2-(2-(2-(叔丁氧基羰基)-2-苯基肼基)-2-氧乙氧基)乙酸(4.2g，12.9mmol)的THF(60mL)溶液中加入BH 3的THF(19.4ml，19.35mmol)溶液。反应在室温下搅拌4h。将混合物用NH 4Cl水溶液淬灭，用H 2O(30mL)稀释，然后用EtOAc(130mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到2-(2-(2-羟基乙氧基)乙酰基)-1-苯基肼基-1-甲酸叔丁酯为白色固体(3.16g，70.54％)。MS(ESI)m/z 332.9[M+Na] +。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.37–7.30(m,4H),7.19-7.11(m,1H),4.06(s,2H),3.59-3.49(m,4H),1.42(s,9H)。 Under a nitrogen atmosphere at 0°C, add 2-(2-(2-(tert-butoxycarbonyl)-2-phenylhydrazino)-2-oxoethoxy)acetic acid (4.2g, 12.9mmol) in THF (60 mL) was added a solution of BH 3 in THF (19.4 ml, 19.35 mmol). The reaction was stirred at room temperature for 4h. The mixture was quenched with aqueous NH 4 Cl, diluted with H 2 O (30 mL), and then extracted with EtOAc (130 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to give 2-(2-(2- Hydroxyethoxy)acetyl)-1-phenylhydrazino-1-carboxylic acid tert-butyl ester is a white solid (3.16 g, 70.54%). MS (ESI) m/z 332.9 [M+Na] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 7.37-7.30 (m, 4H), 7.19-7.11 (m, 1H), 4.06 (s, 2H), 3.59-3.49 (m ,4H),1.42(s,9H).
步骤3) (3-氧吗啉基)(苯基)氨基甲酸叔丁酯Step 3) tert-butyl (3-oxomorpholinyl)(phenyl)carbamate
在0℃下，向2-(2-(2-羟基乙氧基)乙酰基)-1-苯基肼基-1-甲酸叔丁酯(3.16g，10.1mmol)的THF(60mL)混合物中加入三苯基膦(4.0g，15.2mmol)和DIAD(3.06g，15.2mmol)。反应在25℃下搅拌16h。LCMS显示得到产物。混合物中加入H 2O(30mL)，用EtOAc(130mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，所得残余物经硅胶柱色谱法纯化(PE/EA＝3/1)，得到(3-氧吗啉基)(苯基)氨基甲酸叔丁酯为白色固体(2.9g，78.2％)。MS(ESI)m/z 193[M-100+H] +。 1H NMR(400MHz,DMSO-d 6) δ7.37(d,J＝4.5Hz,4H),7.21(dt,J＝8.3,4.2Hz,1H),4.78(dq,J＝12.4,6.1Hz,1H),4.26(q,J＝16.5Hz,2H),3.97–3.88(m,2H),3.72–3.64(m,1H),3.51(dt,J＝11.2,4.0Hz,1H),1.44(d,J＝5.9Hz,9H)。 To a mixture of tert-butyl 2-(2-(2-hydroxyethoxy)acetyl)-1-phenylhydrazino-1-carboxylate (3.16g, 10.1mmol) in THF (60mL) at 0°C Triphenylphosphine (4.0 g, 15.2 mmol) and DIAD (3.06 g, 15.2 mmol) were added. The reaction was stirred at 25°C for 16h. LCMS showed the product was obtained. H 2 O (30 mL) was added to the mixture, and it was extracted with EtOAc (130 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE/EA=3/1) to obtain (3-oxomorpholinyl) (Phenyl) tert-butyl carbamate was a white solid (2.9 g, 78.2%). MS (ESI) m/z 193 [M-100+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.37 (d, J = 4.5 Hz, 4H), 7.21 (dt, J = 8.3, 4.2 Hz, 1H), 4.78 (dq, J = 12.4, 6.1 Hz, 1H), 4.26 (q, J = 16.5 Hz, 2H), 3.97–3.88 (m, 2H), 3.72–3.64 (m, 1H), 3.51 (dt, J = 11.2, 4.0 Hz, 1H), 1.44 (d , J=5.9Hz, 9H).
步骤4) 4-(苯氨基)吗啉-3-酮Step 4) 4-(phenylamino)morpholin-3-one
向(3-氧吗啉基)(苯基)氨基甲酸叔丁酯(2.9g，9.9mmol)的二氧六环(20mL)混合物中加入HCl的二氧六环(20ml)溶液。混合物在室温下搅拌3h。LCMS显示得到产物，将混合物浓缩，用Na 2CO 3水溶液调节pH至7～8，加入H 2O(50mL)稀释，用EtOAc(150mL×2)萃取。。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，得到4-(苯氨基)吗啉-3-酮为黄色油状物(1.9g，89.9％)。MS(ESI)m/z 193.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ7.18(dd,J＝8.4,7.4Hz,2H),6.76(t,J＝7.3Hz,1H),6.70–6.65(m,2H),4.19(s,2H),4.03–3.95(m,2H),3.58–3.51(m,2H)。 To a mixture of tert-butyl (3-oxomorpholinyl)(phenyl)carbamate (2.9 g, 9.9 mmol) in dioxane (20 mL) was added a solution of HCl in dioxane (20 mL). The mixture was stirred at room temperature for 3h. LCMS showed that the product was obtained. The mixture was concentrated, adjusted to pH 7-8 with aqueous Na 2 CO 3 , diluted with H 2 O (50 mL), and extracted with EtOAc (150 mL×2). . The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain 4-(phenylamino)morpholin-3-one as a yellow oil (1.9 g, 89.9%). MS (ESI) m/z 193.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.18 (dd, J = 8.4, 7.4 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.70–6.65 (m, 2H), 4.19 ( s, 2H), 4.03–3.95 (m, 2H), 3.58–3.51 (m, 2H).
步骤5) 3-氧-3-((3-氧吗啉基)(苯基)氨基)丙酸乙酯Step 5) Ethyl 3-oxo-3-((3-oxomorpholinyl)(phenyl)amino)propionate
向4-(苯氨基)吗啉-3-酮(1.9g，9.9mmol)的DCM(30mL)混合物中加入3-氯-3-氧丙酸乙酯(2.98g，19.8mmol)和碳酸钠(3.15g，29.7mmol)。混合物在0℃下搅拌5h。LCMS显示得到产物，将反应混合物过滤并用盐水(30ml)洗，滤液经无水Na 2SO 4干燥，过滤，浓缩，所得残余物经硅胶柱色谱法纯化(PE/EA＝2/1)，得到3-氧-3-((3-氧吗啉基)(苯基)氨基)丙酸乙酯为黄色油状物(1.35g，42.4％)。MS(ESI)m/z306.9[M+H] +。 To a mixture of 4-(phenylamino)morpholin-3-one (1.9g, 9.9mmol) in DCM (30mL) was added ethyl 3-chloro-3-oxopropionate (2.98g, 19.8mmol) and sodium carbonate ( 3.15g, 29.7mmol). The mixture was stirred at 0°C for 5h. LCMS showed product was obtained, the reaction mixture was filtered and washed with brine (30ml), dried Na 2 SO 4 the filtrate was dried over anhydrous, filtered, concentrated and the resulting residue was purified by silica gel column chromatography (PE / EA = 2/1 ) to afford Ethyl 3-oxo-3-((3-oxomorpholinyl)(phenyl)amino)propionate was a yellow oil (1.35 g, 42.4%). MS (ESI) m/z 306.9 [M+H] + .
步骤6) 2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酸乙酯Step 6) 2-Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid ethyl ester
将3-氧-3-((3-氧吗啉基)(苯基)氨基)丙酸乙酯(1.35g，4.4mmol)的DBU(5mL)混合物在50℃下搅拌1h。LCMS显示得到产物，将混合物用水(10ml)稀释，用2N HCl调节pH至7，加入H 2O(20mL)稀释，然后用EtOAc(50mL×2)萃取。有机层用盐水(20mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，所得残余物经硅胶柱色谱法纯化(PE/EA＝1/4)，得到2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酸乙酯为黄色油状物(770mg，56.8％)。MS(ESI)m/z 288.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ7.55(dd,J＝10.4,4.8Hz,2H),7.48–7.37(m,3H),4.98(s,2H),4.14(q,J＝7.1Hz,2H),4.04(dd,J＝9.8,4.5Hz,2H),3.60(t,J＝5.0Hz,2H),1.22(t,J＝7.1Hz,3H)。 A mixture of ethyl 3-oxo-3-((3-oxomorpholinyl)(phenyl)amino)propionate (1.35 g, 4.4 mmol) in DBU (5 mL) was stirred at 50° C. for 1 h. LCMS showed that the product was obtained. The mixture was diluted with water (10 ml), adjusted to pH 7 with 2N HCl, diluted with H 2 O (20 mL), and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE/EA = 1/4) to obtain 2-oxo-1-phenyl Ethyl -2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylate was a yellow oil (770mg, 56.8%). MS (ESI) m/z 288.9 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ7.55 (dd, J = 10.4, 4.8 Hz, 2H), 7.48–7.37 (m, 3H), 4.98 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.04 (dd, J = 9.8, 4.5 Hz, 2H), 3.60 (t, J = 5.0 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).
步骤7) 2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸Step 7) 2-Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid
向2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酸乙酯(770mg，2.67mmol)的EtOH/H 2O(20ml/5ml)混合物中加入NaOH(534mg，13.35mmol)，混合物在室温下搅拌16h，LCMS显示得到产物。将混合物浓缩以除去有机物，用2N HCl将pH调节至4～5，用H 2O(50mL)稀释，然后用EtOAc(50mL×2)萃取。有机层用盐水(20mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，得到2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸为黄色固体(660mg，90.21％)。MS(ESI)m/z 260.9[M+H] +。 1H NMR:(400MHz,DMSO-d 6)δ11.93(s,1H),7.57(dd,J＝10.2,4.7Hz,2H),7.52–7.42(m,3H),4.98(s,2H),4.10–4.01(m,2H),3.64(t,J＝5.0Hz,2H)。 To 2-oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid ethyl ester (770mg, 2.67 NaOH (534 mg, 13.35 mmol) was added to the EtOH/H 2 O (20 ml/5 ml) mixture of mmol), and the mixture was stirred at room temperature for 16 h. LCMS showed that the product was obtained. The mixture was concentrated to remove organics, the pH was adjusted to 4-5 with 2N HCl, diluted with H 2 O (50 mL), and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain 2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5 ,1-c][1,4]oxazine-3-carboxylic acid is a yellow solid (660 mg, 90.21%). MS (ESI) m/z 260.9 [M+H] + . 1 H NMR: (400MHz, DMSO-d 6 )δ11.93(s,1H), 7.57(dd,J=10.2,4.7Hz,2H), 7.52-7.42(m,3H), 4.98(s,2H) , 4.10-4.01 (m, 2H), 3.64 (t, J=5.0 Hz, 2H).
中间体2 2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸Intermediate 2 2-Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid
Figure PCTCN2021094020-appb-000032
Figure PCTCN2021094020-appb-000032
步骤1) 5-氯-N'-苯基戊酰肼Step 1) 5-Chloro-N'-phenylvaleryl hydrazide
在0℃下，向苯肼(1600mg，14.8mmol)和10％Na 2CO 3水溶液(25mL)的DCM(25mL)溶液中加入5-氯戊酰氯(2065mg，13.3mmol)，将混合物在20℃下搅拌16小时。混合物用DCM(50mL)稀释，分离的有机层先后用1N HCl水溶液(30mL)和盐水(50mL)洗，然后经Na 2SO 4干燥，过滤，蒸发浓缩，得到粗制的5-氯-N'-苯基戊酰肼为淡黄色油状物(2800mg，75.1％收率)。MS(ESI):226.9[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.45-7.39(m,1H),7.34-7.28(m,1H),7.25-7.21(m,1H),6.97-6.75(m,2H),3.58-3.45(m,2H),2.32-2.18(m,2H),1.89-1.82(m,2H),1.81-1.78(m,1H),1.75-1.71(m,1H)。 At 0°C, to a solution of phenylhydrazine (1600 mg, 14.8 mmol) and 10% Na 2 CO 3 aqueous solution (25 mL) in DCM (25 mL) was added 5-chlorovaleryl chloride (2065 mg, 13.3 mmol), and the mixture was heated at 20° C. Stir for 16 hours. The mixture was diluted with DCM (50mL), the separated organic layer was washed with 1N HCl aqueous solution (30mL) and brine (50mL) successively, then dried over Na 2 SO 4 , filtered, and concentrated by evaporation to give crude 5-chloro-N' -Phenylvaleryl hydrazide is a pale yellow oil (2800 mg, 75.1% yield). MS (ESI): 226.9 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.45-7.39 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.21 (m, 1H), 6.97-6.75 (m, 2H), 3.58-3.45 (m, 2H), 2.32-2.18 (m, 2H), 1.89-1.82 (m, 2H), 1.81-1.78 (m, 1H), 1.75-1.71 (m, 1H).
步骤2) 3-(2-(5-氯戊酰基)-1-苯基肼基)-3-氧丙酸乙酯Step 2) Ethyl 3-(2-(5-chloropentanoyl)-1-phenylhydrazino)-3-oxopropionate
向5-氯-N'-苯基戊酰肼(2.8g，0.012mol)和Na 2CO 3(1.57g，0.015mol)的DCM(50mL)溶液中加入3-氯-3-氧丙酸乙酯(1.86g，0.012mol)，混合物在20℃下搅拌16h。混合物用DCM(50mL)稀释，并用盐水(50mL×2)洗。有机层经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经硅胶柱色谱法纯化，得到粗制的3-(2-(5-氯戊酰基)-1-苯基肼基)-3-氧丙酸乙酯为黄色油状物(3.8g，81.2％收率)。MS(ESI):341.2[M+H] +。 1H NMR(300MHz,CDCl 3)δ7.47-7.36(m,5H),4.30-4.08(m,2H),3.54-3.35(m,4H),2.30-2.25(m,2H),1.85-1.73(m,4H),1.35–1.21(m,3H)。 To 5-chloro-N'-phenylvaleryl hydrazide (2.8g, 0.012mol) and Na 2 CO 3 (1.57g, 0.015mol) in DCM (50mL) was added ethyl 3-chloro-3-oxopropionate Ester (1.86g, 0.012mol), the mixture was stirred at 20°C for 16h. The mixture was diluted with DCM (50 mL) and washed with brine (50 mL×2). The organic layer was dried over Na 2 SO 4, filtered, and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography to obtain crude ethyl 3-(2-(5-chloropentanoyl)-1-phenylhydrazino)-3-oxopropionate as a yellow oil (3.8g, 81.2% yield). MS (ESI): 341.2 [M+H] + . 1 H NMR (300MHz, CDCl 3 ) δ7.47-7.36 (m, 5H), 4.30-4.08 (m, 2H), 3.54-3.35 (m, 4H), 2.30-2.25 (m, 2H), 1.85-1.73 (m,4H),1.35-1.21(m,3H).
步骤3) 3-氧-3-((2-氧哌啶-1-基)(苯基)氨基)丙酸乙酯Step 3) Ethyl 3-oxo-3-((2-oxopiperidin-1-yl)(phenyl)amino)propionate
向3-(2-(5-氯戊酰基)-1-苯基肼基)-3-氧丙酸乙酯的DMF(30mL)溶液中加入NaH(782mg，0.032mmol)，混合物在20℃下搅拌16小时。反应混合物用NaH 2PO 4水溶液(20mL)淬灭，然后用EtOAc(30mL×3)萃取。合并的有机层用盐水(50mL×2)洗，经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(EtOAc/PE＝1/1)，得到粗制的3-氧-3-((2-氧哌啶-1-基)(苯基)氨基)丙酸乙酯为黄色油状物(1.8g，51.7％收率)。MS(ESI):305.2[M+H] +。 1H NMR(300MHz,CDCl 3)δ7.62-7.30(m,5H),4.29-4.09(m,2H),3.79-3.75(m,1H),3.63-3.43(m,2H),3.28(s,2H),2.67-2.55(m,1H),2.46-2.35(m,1H),2.02-1.69(m,5H),1.34-1.23(m,3H)。 To the DMF (30 mL) solution of ethyl 3-(2-(5-chlorovaleryl)-1-phenylhydrazino)-3-oxopropionate was added NaH (782 mg, 0.032 mmol), and the mixture was kept at 20°C. Stir for 16 hours. The reaction mixture was quenched with aqueous NaH 2 PO 4 (20 mL), and then extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over Na 2 SO 4 , filtered, and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (EtOAc/PE=1/1) to obtain crude 3-oxo-3-((2-oxopiperidin-1-yl)(phenyl)amino)propionic acid ethyl ester The ester was a yellow oil (1.8 g, 51.7% yield). MS (ESI): 305.2 [M+H] + . 1 H NMR (300MHz, CDCl 3 ) δ 7.62-7.30 (m, 5H), 4.29-4.09 (m, 2H), 3.79-3.75 (m, 1H), 3.63-3.43 (m, 2H), 3.28 (s , 2H), 2.67-2.55 (m, 1H), 2.46-2.35 (m, 1H), 2.02-1.69 (m, 5H), 1.34-1.23 (m, 3H).
步骤4) 2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯Step 4) 2-Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester
将2-((2-氧哌啶-1-基)(苯基)氨基甲酰基)乙酸乙酯(1.7g，5.59mmol)的DBU(20mL)混合物在50℃下搅拌2h。混合物用水(20mL)稀释，并用EtAOc(50mL×3)萃取。合并的有机层用盐水(50mL×2)洗。有机层经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(EtOAc/PE＝1/1)，得到粗制的2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯为棕色固体(1.5g，89％收率)。MS(ESI):287.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.48-7.44(m,1H),7.38-7.33(m,1H),7.32-7.29(m,2H),4.31(q,J＝7.2Hz,1H),3.51(t,J＝6.0Hz,1H),3.20(t,J＝6.4Hz,1H),2.08-1.99(m,1H),1.91-1.87(m,1H),1.36(t,J＝7.2Hz,3H)。 A mixture of ethyl 2-((2-oxopiperidin-1-yl)(phenyl)carbamoyl)acetate (1.7 g, 5.59 mmol) in DBU (20 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EtAOc (50 mL×3). The combined organic layer was washed with brine (50 mL×2). The organic layer was dried over Na 2 SO 4, filtered, and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (EtOAc/PE=1/1) to obtain crude 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[ 1,5-a] Ethyl pyridine-3-carboxylate was a brown solid (1.5 g, 89% yield). MS (ESI): 287.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.48-7.44 (m, 1H), 7.38-7.33 (m, 1H), 7.32-7.29 (m, 2H), 4.31 (q, J = 7.2Hz, 1H), 3.51(t,J=6.0Hz,1H), 3.20(t,J=6.4Hz,1H),2.08-1.99(m,1H),1.91-1.87(m,1H),1.36(t,J=7.2Hz ,3H).
步骤5) 2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑[1,5-a]吡啶-3-羧酸Step 5) 2-Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazole[1,5-a]pyridine-3-carboxylic acid
将2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯(1.5g，5.24mmol)和NaOH(1.048g，26.2mmol)的EtOH(20mL)和H 2O(10mL)混合物在25℃下搅拌16h。将混合物真空浓缩，所得残余物溶于水(20mL)。将混合物用1N HCl酸化至pH 4-5，然后用EtOAc(20mL×3)萃取。合并的有机层用盐水(40mL×2)洗，经Na 2SO 4干燥，过滤，蒸发浓缩，得到2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑[1,5-a]吡啶-3-羧酸为棕色固体(1.3g，91％收率)。MS(ESI):259.2[M+H] +。 1H NMR(300MHz,CDCl 3)δ11.84(s,1H),7.57-7.48(m,3H),7.38-7.34(m,2H),3.59(t,J＝5.7Hz,2H),3.26(t,J＝6.3Hz,2H),2.11-2.05(m,2H),1.96-1.90(m,2H)。 Combine 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (1.5g, 5.24mmol) and NaOH A mixture of EtOH (20 mL) and H 2 O (10 mL) (1.048 g, 26.2 mmol) was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in water (20 mL). The mixture was acidified with 1N HCl to pH 4-5, and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (40 mL×2), dried over Na 2 SO 4 , filtered, and concentrated by evaporation to obtain 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyridine The azole [1,5-a]pyridine-3-carboxylic acid was a brown solid (1.3 g, 91% yield). MS (ESI): 259.2 [M+H] + . 1 H NMR (300MHz, CDCl 3 ) δ 11.84 (s, 1H), 7.57-7.48 (m, 3H), 7.38-7.34 (m, 2H), 3.59 (t, J = 5.7 Hz, 2H), 3.26 ( t, J = 6.3 Hz, 2H), 2.11-2.05 (m, 2H), 1.96-1.90 (m, 2H).
中间体3 2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-羧酸Intermediate 3 2-Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid
Figure PCTCN2021094020-appb-000033
Figure PCTCN2021094020-appb-000033
步骤1) 4-氯-N'-苯基丁酰肼Step 1) 4-Chloro-N'-phenylbutyryl hydrazide
在0℃下，向苯肼(1600mg，14.8mmol)和10％Na 2CO 3水溶液(25mL)的DCM(25mL)溶液中加入4-氯丁酰氯(2087mg，14.8mmol)，混合物在20℃下搅拌16小时。混合物用DCM(50mL)稀释，分离的有机层用1N HCl水溶液(30mL)洗，然后用盐水(50mL)洗，经Na 2SO 4干燥，过滤，蒸发浓缩，得到粗制的4-氯-N'-苯基丁酰肼为淡黄色油状物(2.9g，78.3％收率)。MS(ESI):213.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.37-7.28(m,2H),7.25-7.22(m,1H),6.96-6.90(m,1H),6.86-6.83(m,2H),5.78(s,1H),3.66-3.61(m,2H),2.48(t,J＝7.2Hz,2H),2.20-2.13(m,2H)。 To a solution of phenylhydrazine (1600 mg, 14.8 mmol) and 10% Na 2 CO 3 aqueous solution (25 mL) in DCM (25 mL) at 0° C., 4-chlorobutyryl chloride (2087 mg, 14.8 mmol) was added, and the mixture was kept at 20° C. Stir for 16 hours. The mixture was diluted with DCM (50 mL), the separated organic layer was washed with 1N aqueous HCl (30 mL), then brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated by evaporation to give crude 4-chloro-N '-Phenylbutyryl hydrazide is a pale yellow oil (2.9 g, 78.3% yield). MS (ESI): 213.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 7.37-7.28 (m, 2H), 7.25-7.22 (m, 1H), 6.96-6.90 (m, 1H), 6.86-6.83 (m, 2H), 5.78 (s , 1H), 3.66-3.61 (m, 2H), 2.48 (t, J=7.2 Hz, 2H), 2.20-2.13 (m, 2H).
步骤2) 3-(2-(4-氯丁酰基)-1-苯基肼基)-3-氧丙酸乙酯Step 2) Ethyl 3-(2-(4-chlorobutyryl)-1-phenylhydrazino)-3-oxopropionate
向4-氯-N'-苯基丁酰肼(2.6g，0.012mol)和Na 2CO 3(1.55g，1.13mol)的DCM(50mL)溶液中加入3-氯-3-氧丙酸乙酯(1.84g，0.012mol)，混合物在20℃下搅拌16h。反应混合物用DCM(50mL)稀 释，并用盐水(50mL×2)洗。有机层经Na 2SO 4干燥，蒸发浓缩。所得残余物经硅胶柱色谱法纯化，得到粗制的3-(2-(4-氯丁酰基)-1-苯基肼基)-3-氧丙酸乙酯为黄色油状物(3.0g，63.9％收率)。MS(ESI):327.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.54-7.30(m,5H),4.28-4.08(m,2H),3.65-3.55(m,2H),3.43-3.34(m,1H),2.43(t,J＝7.2Hz,2H),2.16-2.07(m,2H),1.34-1.20(m,3H)。 To 4-chloro-N'-phenylbutyryl hydrazide (2.6g, 0.012mol) and Na 2 CO 3 (1.55g, 1.13mol) in DCM (50mL) was added 3-chloro-3-oxopropionate ethyl Ester (1.84g, 0.012mol), the mixture was stirred at 20°C for 16h. The reaction mixture was diluted with DCM (50 mL) and washed with brine (50 mL×2). The organic layer was dried over Na 2 SO 4 and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography to obtain crude ethyl 3-(2-(4-chlorobutyryl)-1-phenylhydrazino)-3-oxopropionate as a yellow oil (3.0g, 63.9% yield). MS(ESI): 327.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 7.54-7.30 (m, 5H), 4.28-4.08 (m, 2H), 3.65-3.55 (m, 2H), 3.43-3.34 (m, 1H), 2.43 (t , J = 7.2 Hz, 2H), 2.16-2.07 (m, 2H), 1.34-1.20 (m, 3H).
步骤3) 3-氧-3-((2-氧吡咯烷-1-基)(苯基)氨基)丙酸乙酯Step 3) Ethyl 3-oxo-3-((2-oxopyrrolidin-1-yl)(phenyl)amino)propionate
在0℃下，向3-(2-(4-氯丁酰基)-1-苯基肼基)-3-氧丙酸乙酯(3.0g，0.0092mol)的DMF(20mL)溶液中加入NaH(0.66g，0.027mol)，然后混合物在20℃下搅拌16小时。反应混合物用NaH 2PO 4水溶液(30mL)淬灭，并用EtOAc(40mL x 3)萃取。合并的有机层经Na 2SO 4干燥，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(EA/PE＝1/1)，得到3-氧-3-((2-氧吡咯烷-1-基)(苯基)氨基)丙酸乙酯为棕色油状物(1.7g，54％收率)。MS(ESI):291.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.51-7.26(m,5H),4.28-4.10(m,2H),3.87-3.44(m,2H),3.29(s,2H),2.58-2.30(m,2H),2.22-1.94(m,2H),1.32-1.23(m 3H)。 Add NaH to the solution of ethyl 3-(2-(4-chlorobutyryl)-1-phenylhydrazino)-3-oxopropionate (3.0g, 0.0092mol) in DMF (20mL) at 0°C (0.66g, 0.027mol), then the mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched with aqueous NaH 2 PO 4 (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layer was dried over Na 2 SO 4 and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (EA/PE=1/1) to obtain ethyl 3-oxo-3-((2-oxopyrrolidin-1-yl)(phenyl)amino)propionate as brown Oil (1.7 g, 54% yield). MS (ESI): 291.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.51-7.26 (m, 5H), 4.28-4.10 (m, 2H), 3.87-3.44 (m, 2H), 3.29 (s, 2H), 2.58-2.30 (m , 2H), 2.22-1.94 (m, 2H), 1.32-1.23 (m 3H).
步骤4) 2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酸乙酯Step 4) 2-Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid ethyl ester
将3-氧-3-((2-氧吡咯烷-1-基)(苯基)氨基)丙酸乙酯(1.8g，0.0062mmol)的DBU(10mL)混合物在50℃下加热6h。混合物用水(30mL)稀释，并用EtOAc(50mL×3)萃取。合并的有机层经Na 2SO 4干燥，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(EA/EA＝1/1)，得到2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酸乙酯为黄色固体(0.6g，33.8％收率)。MS(ESI):273.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.45(t,J＝7.6Hz,2H),7.38-7.36(m,2H),7.31-7.26(m,1H),4.32(q,J＝7.2Hz,2H),3.67(t,J＝6.8Hz,2H),3.19(t,J＝7.2Hz,2H),2.52-2.39(m,2H),1.36(t,J＝7.2Hz,3H)。 A mixture of ethyl 3-oxo-3-((2-oxopyrrolidin-1-yl)(phenyl)amino)propionate (1.8 g, 0.0062 mmol) in DBU (10 mL) was heated at 50° C. for 6 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was dried over Na 2 SO 4 and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (EA/EA=1/1) to obtain 2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b ] Ethyl pyrazole-3-carboxylate was a yellow solid (0.6 g, 33.8% yield). MS (ESI): 273.2 [M+H] + . 1 H NMR(400MHz, CDCl 3 )δ7.45(t,J=7.6Hz,2H), 7.38-7.36(m,2H),7.31-7.26(m,1H), 4.32(q,J=7.2Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.52-2.39 (m, 2H), 1.36 (t, J=7.2 Hz, 3H).
步骤5) 2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-羧酸Step 5) 2-Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid
将2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酸乙酯(600mg，2.2mmol)和氢氧化钠(264mg，6.6mmol)的EtOH(10mL)、THF(10mL)和H 2O(10mL)混合物在20℃下搅拌16h。然后将其真空浓缩，残余物用水(20mL)稀释。混合物用1N HCl酸化至pH 4至5，然后用EtOAc(20mL×3)萃取。合并的有机层用盐水(40mL×2)洗，经Na 2SO 4干燥，蒸发浓缩，得到粗制的2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-羧酸为棕色固体(500mg，88.4％收率)。MS(ESI):245.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ11.42(s,1H),7.53(t,J＝7.6Hz,2H),7.43-7.38(m,3H),3.80(t,J＝7.2Hz,2H),3.27(t,J＝7.2Hz,2H),2.60-2.51(m,2H)。 Combine 2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid ethyl ester (600mg, 2.2mmol) and sodium hydroxide A mixture of EtOH (10 mL), THF (10 mL) and H 2 O (10 mL) (264 mg, 6.6 mmol) was stirred at 20° C. for 16 h. It was then concentrated in vacuo, and the residue was diluted with water (20 mL). The mixture was acidified with 1N HCl to pH 4 to 5, and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (40 mL×2), dried over Na 2 SO 4 and concentrated by evaporation to obtain crude 2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrole And [1,2-b]pyrazole-3-carboxylic acid is a brown solid (500 mg, 88.4% yield). MS(ESI): 245.1 [M+H] + . 1 H NMR(400MHz, CDCl 3 )δ11.42(s,1H), 7.53(t,J=7.6Hz,2H),7.43-7.38(m,3H), 3.80(t,J=7.2Hz,2H) , 3.27 (t, J = 7.2 Hz, 2H), 2.60-2.51 (m, 2H).
实施例1 N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 1 N-(4-(4-Amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000034
Figure PCTCN2021094020-appb-000034
步骤1) 1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮Step 1) 1-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one
在25℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(5.6g，20.0mmol)的DMF(50mL)混合物中加入1-溴丙烷-2-酮(5.48g，40.0mmol)和Cs 2CO 3(13.03g，10.0mmol)。反应在25℃下搅拌16h，LCMS显示得到产物。混合物用H 2O(100mL)稀释，再用EtOAc(100mL×2)萃取。有机层用盐水(100mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(PE/EtOAc＝1/1)，得到1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮为白色固体(3.8g，57％)。MS(ESI)m/z 335.9[M+H] +。 1H NMR:(400MHz,DMSO-d 6)δ8.62(s,1H),7.85(s,1H),5.28(s,2H),2.24(s,3H)。 At 25°C, to 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.6g, 20.0mmol) in DMF (50mL) was added 1-bromopropan-2-one ( 5.48 g, 40.0 mmol) and Cs 2 CO 3 (13.03 g, 10.0 mmol). The reaction was stirred at 25°C for 16 h, LCMS showed that the product was obtained. The mixture was diluted with H 2 O (100 mL), and extracted with EtOAc (100 mL×2). The organic layer was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (PE/EtOAc=1/1) to obtain 1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propane- The 2-ketone was a white solid (3.8 g, 57%). MS (ESI) m/z 335.9 [M+H] + . 1 H NMR: (400MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 7.85 (s, 1H), 5.28 (s, 2H), 2.24 (s, 3H).
步骤2) (4-(4-氯-7-(2-氧丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯Step 2) (4-(4-chloro-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
向1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮(948mg，2.83mmol)的二氧六环/H 2O(20mL/4mL)溶液中加入N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]氨基甲酸叔丁酯(1085mg，3.40mmol)、碳酸钠(449mg，4.25mmol)和Pd(PPh 3) 4(327mg，0.283mmol)。将所得混合物保持在氮气下，并在80℃下搅拌6小时。合物用H 2O(50mL)稀释，再用EtOAc(50mL×2)萃取。有机层用盐水 (50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到(4-(4-氯-7-(2-氧丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯为白色固体(872mg，77％)。MS(ESI)m/z 401.1[M+H] +。 1H NMR:(400MHz,DMSO-d 6)δ9.47(s,1H),8.63(s,1H),7.56–7.54(m,3H),7.40(d,J＝8.6Hz,2H),5.33(s,2H),2.26(s,3H),1.50(s,9H)。 To 1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one (948mg, 2.83mmol) in dioxane/H 2 O( 20mL/4mL) add N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamic acid tert Butyl ester (1085 mg, 3.40 mmol), sodium carbonate (449 mg, 4.25 mmol) and Pd(PPh 3 ) 4 (327 mg, 0.283 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 6 hours. The mixture was diluted with H 2 O (50 mL), and extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain (4-(4-chloro-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidine) Tert-butyl -5-yl)phenyl)carbamate was a white solid (872 mg, 77%). MS (ESI) m/z 401.1 [M+H] + . 1 H NMR: (400MHz,DMSO-d 6 )δ9.47(s,1H),8.63(s,1H),7.56-7.54(m,3H),7.40(d,J=8.6Hz,2H),5.33 (s, 2H), 2.26 (s, 3H), 1.50 (s, 9H).
步骤3) (4-(4-氨基-7-(2-氧丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯Step 3) (4-(4-amino-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
向N-(4-(4-氯-7-(2-氧丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯(1.08g，2.51mmol)的二氧六环混合物中加入氢氧化铵(10mL)。反应在130℃下在密封管中搅拌16h。将混合物浓缩以除去有机物，得到(4-(4-氨基-7-(2-氧丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯为黄色固体(950mg，92％)。MS(ESI)m/z 382.1[M+H] +。 To N-(4-(4-chloro-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate (1.08g, 2.51 mmol) of dioxane mixture was added with ammonium hydroxide (10 mL). The reaction was stirred in a sealed tube at 130°C for 16 h. The mixture was concentrated to remove organics to give (4-(4-amino-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) t-butyl carbamate The ester was a yellow solid (950 mg, 92%). MS (ESI) m/z 382.1 [M+H] + .
步骤4) 1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮Step 4) 1-(4-Amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one
向N-(4-(4-氨基-7-(2-氧丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯(950mg，粗品)的二氧六环(10mL)溶液中加入HCl(2.5mL，4M的二氧六环溶液)，混合物在25℃下搅拌6h。将混合物浓缩以除去有机物，用H 2O(20mL)稀释，然后用1M NaOH处理至pH约为9，用H 2O(50mL)稀释，再用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮为白色固体(188mg，30％)。MS(ESI)m/z 282.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.08(s,1H),7.11(d,J＝8.3Hz,2H),7.02(s,1H),6.67(d,J＝8.3Hz,2H),6.06(s,2H),5.22(s,2H),5.08(s,2H),2.18(s,3H)。 To tert-butyl N-(4-(4-amino-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)carbamate (950mg, crude HCl (2.5 mL, 4M dioxane solution) was added to the dioxane (10 mL) solution of ), and the mixture was stirred at 25° C. for 6 h. The mixture was concentrated to remove organics, diluted with H 2 O (20 mL), then treated with 1 M NaOH to a pH of about 9, diluted with H 2 O (50 mL), and extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 1-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)propan-2-one is a white solid (188 mg, 30%). MS (ESI) m/z 282.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.08(s,1H), 7.11(d,J=8.3Hz,2H), 7.02(s,1H), 6.67(d,J=8.3Hz,2H) , 6.06(s, 2H), 5.22(s, 2H), 5.08(s, 2H), 2.18(s, 3H).
步骤5) 1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇Step 5) 1-(4-Amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol
在0℃下，向1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮(203mg，0.72mmol)的MeOH(10mL)混合物中加入NaBH 4(28mg，0.72mmol)。反应在0℃下搅拌2h。将混合物浓缩以除去有机物，混合物用H 2O(30mL)稀释，用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩，得到1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇为白色固体(190mg，97％)。MS(ESI)m/z 284.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.11(s,1H),7.10(d,J＝8.8Hz,3H),6.66(d,J＝8.4Hz,2H),6.30-5.85(m,2H),5.44(s,2H),4.97(s,1H),4.10-3.93(m,3H),1.04(d,J＝6.0Hz,3H)。 At 0℃, to 1-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one (203mg, 0.72mmol NaBH 4 (28 mg, 0.72 mmol) was added to the MeOH (10 mL) mixture of ). The reaction was stirred at 0°C for 2h. The mixture was concentrated to remove organics, the mixture was diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain 1-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d ]Pyrimidine-7-yl)propan-2-ol is a white solid (190 mg, 97%). MS (ESI) m/z 284.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.11(s,1H), 7.10(d,J=8.8Hz,3H), 6.66(d,J=8.4Hz,2H), 6.30-5.85(m, 2H), 5.44 (s, 2H), 4.97 (s, 1H), 4.10-3.93 (m, 3H), 1.04 (d, J=6.0 Hz, 3H).
步骤6) N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 6) N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
向1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(57mg，0.20mmol)的DCM/THF(10mL/10mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(52mg，0.2mmol)、EDCI(58mg，0.3mmol)、HOAT(41mg，0.3mmol)和DIEA(78mg，0.6mmol)，然后混合物在50℃下搅拌16h。反应混合物用H 2O(30mL)稀释，再用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)10％-40％)纯化，得到N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(62.1mg，59％)。MS(ESI)m/z 526.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),8.13(s,1H),7.70(d,J＝8.6Hz,2H),7.62–7.58(m,2H),7.56-7.50(m,3H),7.41(d,J＝8.5Hz,2H),7.28(s,1H),6.08(s,2H),5.13(s,2H),4.98(s,1H),4.12–4.02(m,5H),3.69(t,J＝4.9Hz,2H),1.05(d,J＝6.0Hz,3H)。 To 1-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (57mg, 0.20mmol) in DCM/THF (10mL/10mL) Add 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (52mg, 0.2mmol), EDCI (58mg , 0.3mmol), HOAT (41mg, 0.3mmol) and DIEA (78mg, 0.6mmol), and then the mixture was stirred at 50°C for 16h. The reaction mixture was diluted with H 2 O (30 mL), and then extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 10%-40%) to obtain N-(4-(4-amino-7-( 2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H- Pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (62.1 mg, 59%). MS (ESI) m/z 526.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.13 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.62–7.58 (m, 2H), 7.56 7.50(m,3H),7.41(d,J=8.5Hz,2H),7.28(s,1H),6.08(s,2H),5.13(s,2H),4.98(s,1H),4.12-4.02 (m, 5H), 3.69 (t, J = 4.9 Hz, 2H), 1.05 (d, J = 6.0 Hz, 3H).
实施例2 (S)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 2 (S)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000035
Figure PCTCN2021094020-appb-000035
步骤1) 1-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮Step 1) 1-(5-(4-Amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one
向1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮(336mg，1.0mmol)的二氧六环/H 2O(10mL/2mL)溶液中加入N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯(285mg，1.2mmol)、碳酸钠(159mg，1.5mmol)和Pd(PPh 3) 4(116mg，0.1mmol)。所得混合物保持在氮气下，并在80℃下搅拌6h。将混合物浓缩以除去有机物，用H 2O(50mL)稀释，再用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到1-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮为白色固体(300mg，94％)。MS(ESI)m/z 319.0[M+H] +。 1H NMR:(400MHz,DMSO-d 6)δ8.60(s,1H),7.55(s,1H),7.06(t,J＝8.6Hz,1H),6.46–6.41(m,2H),5.53(s,2H),5.32(s,2H),2.26(s,3H)。 To 1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one (336mg, 1.0mmol) in dioxane/H 2 O( 10mL/2mL) add N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl to the solution ) Tert-butyl carbamate (285 mg, 1.2 mmol), sodium carbonate (159 mg, 1.5 mmol) and Pd(PPh 3 ) 4 (116 mg, 0.1 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 6 h. The mixture was concentrated to remove organics, diluted with H 2 O (50 mL), and extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 1-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3- d] Pyrimidine-7-yl)propan-2-one as a white solid (300 mg, 94%). MS (ESI) m/z 319.0 [M+H] + . 1 H NMR: (400MHz,DMSO-d 6 )δ8.60(s,1H),7.55(s,1H),7.06(t,J=8.6Hz,1H),6.46-6.41(m,2H),5.53 (s, 2H), 5.32 (s, 2H), 2.26 (s, 3H).
步骤2) 1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮Step 2) 1-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one
向N-(4-(4-氯-4-(2-氧丙基))吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)氨基甲酸叔丁酯(300mg，0.72mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，用H 2O(30mL)稀释，再用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮为白色固体(105mg，37％)。MS(ESI)m/z300.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.07(s,1H),7.07–7.02(m,2H),6.51-6.43(m,2H),5.96(s,2H),5.55(s,2H),5.10(s,2H),2.18(s,3H)。 To N-(4-(4-chloro-4-(2-oxopropyl))pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)tert-butyl carbamate (300mg , 0.72mmol) of dioxane (10mL) mixture was added ammonium hydroxide (10mL). The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3- d] Pyrimidine-7-yl)propan-2-one as a white solid (105 mg, 37%). MS (ESI) m/z 300.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.07(s,1H), 7.07-7.02(m,2H), 6.51-6.43(m,2H), 5.96(s,2H), 5.55(s,2H) ), 5.10 (s, 2H), 2.18 (s, 3H).
步骤3) (S)-1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇Step 3) (S)-1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol
在0℃下，向1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-酮(485mg，1.62mmol)的MeOH(20mL)混合物中加入NaBH 4(62mg，1.62mmol)。反应在0℃下搅拌2h。将混合物浓缩以除去有机物，用H 2O(30mL)稀释，然后用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经SFC(CHIRALPAK AD-H 250mm，20mm，5μm，30％ETOH(0.2％NH 4OH))纯化，得到(S)-1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(180mg)。MS(ESI)m/z 302.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.12(s,1H),7.02(t,J＝8.6Hz,1H),6.49–6.42(m,2H),6.13-5.71(m,2H),5.52(s,2H),4.96(d,J＝4.7Hz,1H),4.09–3.99(m,3H),1.03(d,J＝6.4Hz,3H)。 At 0 ℃, to 1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one( NaBH 4 (62 mg, 1.62 mmol) was added to a mixture of 485 mg, 1.62 mmol) in MeOH (20 mL). The reaction was stirred at 0°C for 2h. The mixture was concentrated to remove organics, diluted with H 2 O (30 mL), and then extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by SFC (CHIRALPAK AD-H 250mm, 20mm, 5μm, 30% ETOH (0.2% NH 4 OH)) to obtain (S)-1-(4-amino-5-(4-amino-2- (Fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (180 mg). MS (ESI) m/z 302.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.09 (s, 1H), 7.12 (s, 1H), 7.02 (t, J = 8.6 Hz, 1H), 6.49-6.42 (m, 2H), 6.13 5.71 (m, 2H), 5.52 (s, 2H), 4.96 (d, J = 4.7 Hz, 1H), 4.09-3.99 (m, 3H), 1.03 (d, J = 6.4 Hz, 3H).
步骤4) (S)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡咯并[5,1-c][1,4]噁嗪-3-甲酰胺Step 4) (S)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide
向(S)-1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(60mg，0.20mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(52mg，0.2mmol)、EDCI(58mg，0.3mmol)、HOAT(41mg，0.3mmol)和DIEA(78mg，0.6mmol)，然后混合物在45℃下搅拌16h。反应混合物用H 2O(30mL)稀释，再用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)，10％-40％)纯化，得到(S)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡咯并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(75.3mg，69％)。MS(ESI)m/z 544.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.13(s,2H),7.85–7.81(m,1H),7.63–7.58(m,2H),7.56-7.51(m,3H),7.35–7.28(m,3H),6.03(s,2H),5.12(s,2H),4.97(s,1H),4.11–4.00(m,4H),3.70(t,J＝5.0Hz,2H),1.05(d,J＝6.0Hz,3H)。 To (S)-1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (60mg , 0.20mmol) in DCM (20mL) was added 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (52mg, 0.2mmol) , EDCI (58mg, 0.3mmol), HOAT (41mg, 0.3mmol) and DIEA (78mg, 0.6mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was diluted with H 2 O (30 mL), and then extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA), 10%-40%) to obtain (S)-N-(4-(4- Amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4, 6,7-Tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (75.3 mg, 69%). MS (ESI) m/z 544.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H),8.13(s,2H),7.85-7.81(m,1H),7.63-7.58(m,2H),7.56-7.51(m ,3H),7.35–7.28(m,3H),6.03(s,2H),5.12(s,2H),4.97(s,1H),4.11–4.00(m,4H),3.70(t,J=5.0 Hz, 2H), 1.05 (d, J=6.0 Hz, 3H).
实施例3 (R)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡咯并[5,1-c][1,4]噁嗪-3-甲酰胺Example 3 (R)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000036
Figure PCTCN2021094020-appb-000036
步骤1) (R)-1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇Step 1) (R)-1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol
根据实施例2步骤(3)中所述方法，分离得到(R)-1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(170mg)。According to the method described in step (3) of Example 2, (R)-1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d ]Pyrimidin-7-yl)propan-2-ol (170 mg).
步骤2) (R)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡咯并[5,1-c][1,4]噁嗪-3-甲酰胺Step 2) (R)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide
向(R)-1-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(60mg，0.20mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(52mg，0.2mmol)、EDCI(58mg，0.3mmol)、HOAT(41mg，0.3mmol)和DIEA(78mg，0.6mmol)，然后混合物在45℃下搅拌16h。反应混合物用H 2O(30mL)稀释，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)，10％-40％)纯化，得到(R)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡咯并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(60.2mg，55％)。MS(ESI)m/z 544.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.13(s,1H),7.85–7.81(m,1H),7.64-7.58m,2H),7.55–7.51(m,3H),7.37–7.28(m,3H),6.03(s,2H),5.12(s,2H),4.97(s,1H),4.13–4.00(m,5H),3.70(t,J＝4.8Hz,2H),1.05(d,J＝6.0Hz,3H)。 To (R)-1-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (60mg , 0.20mmol) in DCM (20mL) was added 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (52mg, 0.2mmol) , EDCI (58mg, 0.3mmol), HOAT (41mg, 0.3mmol) and DIEA (78mg, 0.6mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was diluted with H 2 O (30 mL) and extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA), 10%-40%) to obtain (R)-N-(4-(4- Amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4, 6,7-Tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (60.2 mg, 55%). MS (ESI) m/z 544.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H),8.13(s,1H),7.85-7.81(m,1H),7.64-7.58m,2H),7.55-7.51(m, 3H), 7.37–7.28(m,3H), 6.03(s,2H), 5.12(s,2H), 4.97(s,1H), 4.13–4.00(m,5H), 3.70(t,J=4.8Hz , 2H), 1.05 (d, J=6.0 Hz, 3H).
实施例4 N-(4-(4-氨基-7-(2-羟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 4 N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000037
Figure PCTCN2021094020-appb-000037
步骤1) 2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇Step 1) 2-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1-ol
将4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2g，0.01mol)、2-溴乙醇(1.5g，0.012mol)和Cs 2CO 3(4.89g，0.015mol)的DMF(30mL)混合物在20℃下搅拌16h。将反应混合物用EtOAc(80mL)稀释，并用盐水(40mL×2)洗。有机层经Na 2SO 4干燥，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(EA/PE＝1/1)，得到2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇为黄色固体(1.5g，44％收率)。MS(ESI):m/z 324.0[M+1] +。 1H NMR(400MHz,CDCl 3)δ8.61(s,1H),7.50(s,1H),4.43(t,J＝4.8Hz,2H),4.02(t,J＝4.8Hz,2H)。 Combine 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2g, 0.01mol), 2-bromoethanol (1.5g, 0.012mol) and Cs 2 CO 3 (4.89g, 0.015mol) ) DMF (30 mL) mixture was stirred at 20°C for 16 h. The reaction mixture was diluted with EtOAc (80 mL) and washed with brine (40 mL×2). The organic layer was dried over Na 2 SO 4 and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (EA/PE=1/1) to obtain 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane -1-ol is a yellow solid (1.5 g, 44% yield). MS (ESI): m/z 324.0 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ 8.61 (s, 1H), 7.50 (s, 1H), 4.43 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H).
步骤2) 2-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇Step 2) 2-(5-(4-Amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1-ol
将2-(5-碘-4-甲基吡咯并[2,3-d]嘧啶-7-基)乙醇(1.5g，4.63mmol)、3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.209g，5.1mmol)、碳酸钠(982mg，9.23mmol)和四(三苯基膦)钯(268mg，0.23mmol)的二氧六环(80mL)和H 2O(20mL)混合物在90℃下加热反应16h。然后将混合物真空浓缩，残余物用EtOAc(50mL)稀释，并用盐水(30mL×3)洗。有机层经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到2-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇为黄色固体(1g，66.8％收率)。MS(ESI):307.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),7.67(s,1H),7.05(t,J＝8.6Hz,1H),6.46-6.38(m,2H),5.51(s,2H),4.98(s,1H),4.35(t,J＝5.6Hz,2H),3.79(t,J＝5.2Hz,2H)。 Combine 2-(5-iodo-4-methylpyrrolo[2,3-d]pyrimidin-7-yl)ethanol (1.5g, 4.63mmol), 3-fluoro-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.209g, 5.1mmol), sodium carbonate (982mg, 9.23mmol) and tetrakis(triphenylphosphine) palladium A mixture of (268 mg, 0.23 mmol) of dioxane (80 mL) and H 2 O (20 mL) was heated at 90° C. for 16 h. The mixture was then concentrated in vacuo, and the residue was diluted with EtOAc (50 mL) and washed with brine (30 mL×3). The organic layer was dried over Na 2 SO 4, filtered, and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 2-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3- d] Pyrimidine-7-yl)ethane-1-ol is a yellow solid (1 g, 66.8% yield). MS (ESI): 307.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H), 7.67(s,1H), 7.05(t,J=8.6Hz,1H), 6.46-6.38(m,2H), 5.51( s, 2H), 4.98 (s, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H).
步骤3) 2-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇Step 3) 2-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1-ol
将2-(5-(4-氨基-2-氟苯基)-4-氯吡咯并[2,3-d]嘧啶-7-基)乙醇(500mg，1.63mmol)的二氧六环(5mL)和25％NH 4OH(5mL)混合物在120℃下加热反应16h。然后将其冷却至室温，并将混合物真空浓缩。所得残余物用MeOH(5mL)和H 2O(2mL)处理，过滤。滤饼用水(2mL)洗，经真空干燥，得到粗制的2-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇为白色固体(260mg，52.7％收率)。MS(ESI):288.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.10(s,1H),7.15(s,1H),7.02(t,J＝9.3Hz,1H), 6.52-6.40(m,2H),5.91(s,1H),5.54(s,2H),4.96(t,J＝5.1Hz,1H),4.19(t,J＝5.7Hz,2H),3.73(q,J＝5.4Hz,2H)。 Combine 2-(5-(4-amino-2-fluorophenyl)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl)ethanol (500mg, 1.63mmol) in dioxane (5mL ) And 25% NH 4 OH (5 mL) were heated to react at 120° C. for 16 h. It was then cooled to room temperature, and the mixture was concentrated in vacuo. The resulting residue was treated with MeOH (5 mL) and H 2 O (2 mL) and filtered. The filter cake was washed with water (2 mL) and dried under vacuum to obtain crude 2-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)ethane-1-ol is a white solid (260 mg, 52.7% yield). MS(ESI): 288.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.15 (s, 1H), 7.02 (t, J = 9.3 Hz, 1H), 6.52-6.40 (m, 2H), 5.91 ( s, 1H), 5.54 (s, 2H), 4.96 (t, J = 5.1 Hz, 1H), 4.19 (t, J = 5.7 Hz, 2H), 3.73 (q, J = 5.4 Hz, 2H).
步骤4) N-(4-(4-氨基-7-(2-羟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 4) N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
将2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸的混合物(50mg，0.19mmol)、2-(4-氨基-5-(4-氨基-2-氟苯基)吡咯并[2,3-d]嘧啶-7-基)乙醇(55mg，0.19mmol)、N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(55mg，0.29mmol)、HOAt(31.5mg，0.23mmol)和DIEA(74.5mg，0.58mmol)的DCM(20mL)和THF(20mL)混合物于40℃下加热反应16h。然后将混合物用EtOAc(30mL)稀释，并用盐水(20mL×2)洗。有机层经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经制备型HPLC(ACN-H 2O(0.1％FA)，梯度15％-40％)纯化，得到N-(4-(4-氨基-7-(2-羟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(52.8mg，50.9％收率)。MS(ESI):530.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.13(s,1H),7.87-7.79(m,1H),7.63-7.58(m,2H),7.54-7.52(m,3H),7.39-7.29(m,3H),6.03(s,2H),5.12(s,2H),4.97(t,J＝5.2Hz,1H),4.22(t,J＝5.6Hz,2H),4.11-4.08(m,2H),3.78-3.68(m,4H)。 A mixture of 2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid (50mg, 0.19mmol), 2-(4-amino-5-(4-amino-2-fluorophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (55mg, 0.19mmol), N-( 3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (55mg, 0.29mmol), HOAt (31.5mg, 0.23mmol) and DIEA (74.5mg, 0.58mmol) in DCM (20mL A mixture of) and THF (20 mL) was heated to react at 40°C for 16 h. Then the mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL×2). The organic layer was dried over Na 2 SO 4, filtered, and concentrated by evaporation. The obtained residue was purified by preparative HPLC (ACN-H 2 O (0.1% FA), gradient 15%-40%) to obtain N-(4-(4-amino-7-(2-hydroxyethyl)-7H -Pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[ 5,1-c][1,4]oxazine-3-carboxamide is a white solid (52.8 mg, 50.9% yield). MS (ESI): 530.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.13 (s, 1H), 7.87-7.79 (m, 1H), 7.63-7.58 (m, 2H), 7.54-7.52 (m ,3H),7.39-7.29(m,3H),6.03(s,2H),5.12(s,2H),4.97(t,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H) , 4.11-4.08 (m, 2H), 3.78-3.68 (m, 4H).
实施例5 N-(4-(4-氨基-7-(2-羟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 5 N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000038
Figure PCTCN2021094020-appb-000038
步骤1) 2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇Step 1) 2-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1-ol
将4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2.0g，0.01mol)、2-溴乙醇(1.5g，0.012mol)和Cs 2CO 3(4.89g，0.015mol)的DMF(30mL)混合物在20℃下搅拌16h。混合物用EtOAc(80mL)稀释，并用盐水(40mL×2)洗。有机层经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(EA/PE＝1/1)，得到2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇为黄色固体(1.5g，44％收率)。MS(ESI):324.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.61(s,1H),7.50(s,1H),4.43(t,J＝4.8Hz,2H),4.02(t,J＝4.8Hz,2H)。 Combine 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.0g, 0.01mol), 2-bromoethanol (1.5g, 0.012mol) and Cs 2 CO 3 (4.89g, 0.015 mol) of DMF (30 mL) was stirred at 20°C for 16 h. The mixture was diluted with EtOAc (80 mL) and washed with brine (40 mL×2). The organic layer was dried over Na 2 SO 4, filtered, and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (EA/PE=1/1) to obtain 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane -1-ol is a yellow solid (1.5 g, 44% yield). MS (ESI): 324.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 8.61 (s, 1H), 7.50 (s, 1H), 4.43 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H).
步骤2) 2-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇Step 2) 2-(5-(4-Amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1-ol
将2-(5-碘-4-甲基吡咯并[2,3-d]嘧啶-7-基)乙醇(1.5g，4.63mmol)、3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.209g，5.1mmol)、碳酸钠(982mg，9.23mmol)和四(三苯基膦)钯(268mg，0.23mmol)的二氧六环(80mL)和H 2O(20mL)混合物在90℃下加热反应16h。然后将混合物真空浓缩，残余物用EtOAc(50mL)稀释，并用盐水(30mL×3)洗。有机层经Na 2SO 4干燥，蒸发浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到2-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇为黄色固体(1g，66.8％收率)。MS(ESI):307.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),7.67(s,1H),7.05(t,J＝8.6Hz,1H),6.46-6.38(m,2H),5.51(s,2H),4.98(s,1H),4.35(t,J＝5.6Hz,2H),3.79(t,J＝5.2Hz,2H)。 Combine 2-(5-iodo-4-methylpyrrolo[2,3-d]pyrimidin-7-yl)ethanol (1.5g, 4.63mmol), 3-fluoro-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.209g, 5.1mmol), sodium carbonate (982mg, 9.23mmol) and tetrakis(triphenylphosphine) palladium A mixture of (268 mg, 0.23 mmol) of dioxane (80 mL) and H 2 O (20 mL) was heated at 90° C. for 16 h. The mixture was then concentrated in vacuo, and the residue was diluted with EtOAc (50 mL) and washed with brine (30 mL×3). The organic layer was dried over Na 2 SO 4 and concentrated by evaporation. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 2-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3- d] Pyrimidine-7-yl)ethane-1-ol is a yellow solid (1 g, 66.8% yield). MS (ESI): 307.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H), 7.67(s,1H), 7.05(t,J=8.6Hz,1H), 6.46-6.38(m,2H), 5.51( s, 2H), 4.98 (s, 1H), 4.35 (t, J = 5.6 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H).
步骤3) 2-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇Step 3) 2-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethane-1-ol
将2-(5-(4-氨基-2-氟苯基)-4-氯吡咯并[2,3-d]嘧啶-7-基)乙醇(500mg，1.63mmol)的二氧六环(5mL)和25％NH 4OH(5mL)混合物在120℃下加热反应16h。然后将混合物冷却至室温，真空浓缩。所得残余物用MeOH(5mL)和H 2O(2mL)处理，过滤。滤饼用水(2mL)洗，经真空干燥，得到粗制的2-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙烷-1-醇为白色固体(260mg，52.7％收率)。MS(ESI):288.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.10(s,1H),7.15(s,1H),7.02(t,J＝9.3Hz,1H),6.52-6.40(m,2H),5.91(s,1H),5.54(s,2H),4.96(t,J＝5.1Hz,1H),4.19(t,J＝5.7Hz,2H),3.73(q,J＝5.4Hz,2H)。 Combine 2-(5-(4-amino-2-fluorophenyl)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl)ethanol (500mg, 1.63mmol) in dioxane (5mL ) And 25% NH 4 OH (5 mL) were heated to react at 120° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was treated with MeOH (5 mL) and H 2 O (2 mL) and filtered. The filter cake was washed with water (2 mL) and dried under vacuum to obtain crude 2-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)ethane-1-ol is a white solid (260 mg, 52.7% yield). MS(ESI): 288.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.15 (s, 1H), 7.02 (t, J = 9.3 Hz, 1H), 6.52-6.40 (m, 2H), 5.91 ( s, 1H), 5.54 (s, 2H), 4.96 (t, J = 5.1 Hz, 1H), 4.19 (t, J = 5.7 Hz, 2H), 3.73 (q, J = 5.4 Hz, 2H).
步骤4) N-(4-(4-氨基-7-(2-羟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯 并[1,2-b]吡唑-3-甲酰胺Step 4) N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
将2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-羧酸(100mg，0.41mmol)、2-(4-氨基-5-(4-氨基-2-氟苯基)吡咯并[2,3-d]嘧啶-7-基)乙醇(129mg，0.45mmol)、N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(101.6mg，0.53mmol)、HOAt(67.4mg，0.49mmol)和DIEA(159mg，1.23mmol)的DCM(20mL)和THF(20mL)混合物在40℃下加热反应16h。然后将混合物用EtOAc(30mL)稀释，并用盐水(20mL×2)洗。有机层经Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物经制备型HPLC纯化(ACN-H 2O(0.1％FA)，梯度15％-40％)，得到产物N-(4-(4-氨基-7-(2-羟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺为白色固体(61.6mg，29％收率)。MS(ESI):513.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.13(s,1H),7.87(d,J＝12.4Hz,1H),7.60-7.49(m,4H),7.44-7.40(m,1H),7.35-7.32(m,3H),6.04(brs,2H),4.97(t,J＝5.2Hz,1H),4.22(t,J＝5.6Hz,2H),3.82(t,J＝6.8Hz,2H),3.74(q,J＝5.2Hz,2H),3.18(t,J＝7.2Hz,2H),2.46-2.42(m,2H)。 The 2-oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (100mg, 0.41mmol), 2-(4 -Amino-5-(4-amino-2-fluorophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (129mg, 0.45mmol), N-(3-dimethylaminopropyl) )-N'-ethylcarbodiimide hydrochloride (101.6mg, 0.53mmol), HOAt (67.4mg, 0.49mmol) and DIEA (159mg, 1.23mmol) in DCM (20mL) and THF (20mL) mixture in The reaction was heated at 40°C for 16h. Then the mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL×2). The organic layer was dried over Na 2 SO 4, filtered, and concentrated by evaporation. The residue obtained was purified by preparative HPLC (ACN-H 2 O (0.1% FA), gradient 15%-40%) to obtain the product N-(4-(4-amino-7-(2-hydroxyethyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[ 1,2-b]pyrazole-3-carboxamide is a white solid (61.6 mg, 29% yield). MS (ESI): 513.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 12.4 Hz, 1H), 7.60-7.49 (m, 4H), 7.44 7.40(m,1H),7.35-7.32(m,3H),6.04(brs,2H),4.97(t,J=5.2Hz,1H),4.22(t,J=5.6Hz,2H),3.82(t , J = 6.8 Hz, 2H), 3.74 (q, J = 5.2 Hz, 2H), 3.18 (t, J = 7.2 Hz, 2H), 2.46-2.42 (m, 2H).
实施例6 N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 6 N-(4-(4-Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000039
Figure PCTCN2021094020-appb-000039
步骤1) 4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶Step 1) 4-Chloro-5-iodo-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2.8g，10.0mmol)的THF(40mL)混合物中加入氧杂环戊烷-3-醇(1.76g，20.0mmol)、三苯基膦(5.3g，20.0mmol)和DIAD(4.04g，20.0mmol)。反应在25℃下搅拌16h。LCMS显示得到产物。反应混合物用H 2O(30mL)稀释，EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶为白色固体(1.977g，56％)。MS(ESI)m/z349.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),7.95(s,1H),5.51-5.44(m,1H),4.15–4.10(m,1H),3.97-3.88(m,2H),3.86-3.77(m,1H),2.49-2.45(m,1H),2.25-2.16(m,1H)。 Add oxolane-3-ol to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.8g, 10.0mmol) in THF (40mL) at 0°C (1.76 g, 20.0 mmol), triphenylphosphine (5.3 g, 20.0 mmol) and DIAD (4.04 g, 20.0 mmol). The reaction was stirred at 25°C for 16h. LCMS showed the product was obtained. The reaction mixture was diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-chloro-5-iodo-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine It is a white solid (1.977 g, 56%). MS (ESI) m/z 349.9 [M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.66(s,1H), 7.95(s,1H), 5.51-5.44(m,1H), 4.15-4.10(m,1H), 3.97-3.88(m , 2H), 3.86-3.77 (m, 1H), 2.49-2.45 (m, 1H), 2.25-2.16 (m, 1H).
步骤2) 4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2) 4-(4-Chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
向4-氯-5-碘-7-(氧杂环戊烷-3-基)吡咯并[2,3-d]嘧啶(700mg，2.0mmol)的二氧六环/H 2O(10mL/2mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(526mg，2.4mmol)、碳酸钠(318mg，3.0mmol)、和Pd(PPh 3) 4(232mg，0.2mmol)。所得混合物保持在氮气下，并在25℃下搅拌16h。将混合物浓缩以除去有机物，用H 2O(50mL)稀释，然后用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺为白色固体(350mg，55％)。MS(ESI)m/z 315.1[M+H] +。 1H NMR(300MHz,DMSO-d 6)δ8.62(s,1H),7.61(s,1H),7.18(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),5.56–5.48(m,1H),5.17(s,2H),4.16-4.08(m,1H),4.01–3.91(m,2H),3.87-3.80(m,1H),2.49-2.41(m,1H),2.27-2.21(m,1H)。 To 4-chloro-5-iodo-7-(oxolane-3-yl)pyrrolo[2,3-d]pyrimidine (700mg, 2.0mmol) in dioxane/H 2 O (10mL/ 2mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (526mg, 2.4mmol), sodium carbonate ( 318 mg, 3.0 mmol), and Pd(PPh 3 ) 4 (232 mg, 0.2 mmol). The resulting mixture was kept under nitrogen and stirred at 25°C for 16 h. The mixture was concentrated to remove organics, diluted with H 2 O (50 mL), and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-(4-chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-yl)aniline is a white solid (350 mg, 55%). MS (ESI) m/z 315.1 [M+H] + . 1 H NMR(300MHz,DMSO-d 6 )δ8.62(s,1H), 7.61(s,1H), 7.18(d,J=8.4Hz,2H), 6.61(d,J=8.4Hz,2H) ,5.56–5.48(m,1H),5.17(s,2H),4.16-4.08(m,1H),4.01–3.91(m,2H),3.87-3.80(m,1H),2.49-2.41(m, 1H), 2.27-2.21 (m, 1H).
步骤3) 5-(4-氨基苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺Step 3) 5-(4-Aminophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
向4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺(350mg，1.11mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，加入H 2O(30mL)稀释，然后用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到5-(4-氨基苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺为白色固体(260mg，79％)。MS(ESI)m/z 296.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.11(s,1H),7.13–7.11(m,3H),6.66(d,J＝8.4Hz,2H),6.25-5.72(m,2H),5.40–5.35(m,1H),5.21(s,2H),4.11–4.06(m,1H),3.97–3.93(m,1H),3.88–3.80(m,2H),2.46–2.41(m,1H), 2.19–2.12(m,1H)。 To 4-(4-chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline (350mg, 1.11mmol) in dioxane (10mL) Ammonium hydroxide (10 mL) was added to the mixture. The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, diluted with H 2 O (30 mL), and then extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 5-(4-aminophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d ] Pyrimidine-4-amine is a white solid (260 mg, 79%). MS (ESI) m/z 296.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.11(s,1H), 7.13–7.11(m,3H), 6.66(d,J=8.4Hz,2H), 6.25-5.72(m,2H), 5.40–5.35(m,1H), 5.21(s,2H), 4.11–4.06(m,1H), 3.97–3.93(m,1H), 3.88–3.80(m,2H), 2.46–2.41(m,1H) ), 2.19–2.12(m,1H).
步骤4) N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 4) N-(4-(4-Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
向5-(4-氨基苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(56mg，0.19mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(50mg，0.19mmol)、EDCI(58mg，0.3mmol)、HOAT(41mg，0.3mmol)和DIEA(78mg，0.6mmol)，然后混合物在45℃下搅拌16h。反应混合物中加入H 2O(30mL)稀释，然后用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(15-30)(0.1％FA))纯化，得到N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(82.4mg，79.78％)。MS(ESI)m/z 537.7[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),8.15(s,1H),7.70(d,J＝8.6Hz,2H),7.61(dd,J＝10.5,4.5Hz,2H),7.53(dt,J＝7.0,2.9Hz,3H),7.44(d,J＝8.5Hz,2H),7.31(s,1H),6.13(s,2H),5.45-5.37(m,1H),5.13(s,2H),4.09(dd,J＝9.3,5.4Hz,3H),4.01-3.94(m,1H),3.92-3.79(m,2H),3.69(t,J＝4.9Hz,2H),2.48-2.41(m,1H),2.25-2.13(m,1H)。 Into a mixture of 5-(4-aminophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (56 mg, 0.19 mmol) in DCM (20 mL) Add 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (50mg, 0.19mmol), EDCI (58mg, 0.3mmol), HOAT ( 41 mg, 0.3 mmol) and DIEA (78 mg, 0.6 mmol), and then the mixture was stirred at 45°C for 16 h. The reaction mixture was diluted by adding H 2 O (30 mL), and then extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (15-30) (0.1% FA)) to obtain N-(4-(4-amino-7-( Tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H- Pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (82.4 mg, 79.78%). MS (ESI) m/z 537.7 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.15 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.61 (dd, J = 10.5, 4.5 Hz, 2H),7.53(dt,J=7.0,2.9Hz,3H),7.44(d,J=8.5Hz,2H),7.31(s,1H),6.13(s,2H),5.45-5.37(m,1H) ), 5.13(s,2H),4.09(dd,J=9.3,5.4Hz,3H),4.01-3.94(m,1H),3.92-3.79(m,2H),3.69(t,J=4.9Hz, 2H), 2.48-2.41 (m, 1H), 2.25-2.13 (m, 1H).
实施例7 N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 7 N-(4-(4-Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000040
Figure PCTCN2021094020-appb-000040
步骤1) 4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶Step 1) 4-Chloro-5-iodo-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
根据实施例6步骤(1)所述方法制备得到4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶为白色固体(1.977g，56％)。MS(ESI)m/z 349.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),7.95(s,1H),5.51-5.44(m,1H),4.15–4.10(m,1H),3.97-3.88(m,2H),3.86-3.77(m,1H),2.49-2.45(m,1H),2.25-2.16(m,1H)。 According to the method described in step (1) of Example 6, 4-chloro-5-iodo-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine was prepared as a white solid (1.977g, 56%). MS (ESI) m/z 349.9 [M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.66(s,1H), 7.95(s,1H), 5.51-5.44(m,1H), 4.15-4.10(m,1H), 3.97-3.88(m , 2H), 3.86-3.77 (m, 1H), 2.49-2.45 (m, 1H), 2.25-2.16 (m, 1H).
步骤2) 4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺Step 2) 4-(4-Chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
向4-氯-5-碘-7-(氧杂环戊烷-3-基)吡咯并[2,3-d]嘧啶(700mg，2.0mmol)的二氧六环/H 2O(10mL/2mL)溶液中加入N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯(569mg，2.4mmol)、碳酸钠(318mg，3.0mmol)、和Pd(PPh 3) 4(232mg，0.2mmol)。所得混合物保持在氮气下，并在80℃下搅拌16h。将混合物浓缩以除去有机物，加入H 2O(50mL)稀释，然后用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺为白色固体(550mg，82％)。MS(ESI)m/z 333.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.64(s,1H),7.66(s,1H),7.11–7.05(m,1H),6.46–6.39(m,2H),5.69–5.34(m,3H),4.15–4.09(m,1H),4.02–3.94(m,2H),3.89-3.81(m,1H),2.59-2.52(m,1H),2.28–2.20(m,1H)。 To 4-chloro-5-iodo-7-(oxolane-3-yl)pyrrolo[2,3-d]pyrimidine (700mg, 2.0mmol) in dioxane/H 2 O (10mL/ 2mL) Add N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino to the solution Tert-butyl formate (569 mg, 2.4 mmol), sodium carbonate (318 mg, 3.0 mmol), and Pd(PPh 3 ) 4 (232 mg, 0.2 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 16 h. The mixture was concentrated to remove organics, diluted by adding H 2 O (50 mL), and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-(4-chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-yl)-3-fluoroaniline is a white solid (550 mg, 82%). MS (ESI) m/z 333.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.64 (s, 1H), 7.66 (s, 1H), 7.11-7.05 (m, 1H), 6.46-6.39 (m, 2H), 5.69-5.34 (m ,3H), 4.15–4.09(m,1H), 4.02–3.94(m,2H), 3.89-3.81(m,1H), 2.59-2.52(m,1H), 2.28–2.20(m,1H).
步骤3) 5-(4-氨基-2-氟苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺Step 3) 5-(4-Amino-2-fluorophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
向4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺(550mg，1.65mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，加入H 2O(30mL)稀释，然后用EA(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到5-(4-氨基-2-氟苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺为白色固体(400mg，77％)。MS(ESI)m/z 314.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.12(s,1H),7.15(s,1H),7.04(t,J＝8.8Hz,1H),6.49–6.43(m,2H),6.16-5.76(m,2H),5.54(s,2H),5.40–5.35(m,1H),4.12-4.04(m,1H),3.98–3.94(m,1H),3.88–3.80(m,2H), 2.47–2.41(m,1H),2.18–2.13(m,1H)。 To 4-(4-chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline (550mg, 1.65mmol) in dioxane Ammonium hydroxide (10 mL) was added to the ring (10 mL) mixture. The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, diluted by adding H 2 O (30 mL), and then extracted with EA (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 5-(4-amino-2-fluorophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-amine is a white solid (400 mg, 77%). MS (ESI) m/z 314.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.12(s,1H),7.15(s,1H),7.04(t,J=8.8Hz,1H),6.49–6.43(m,2H),6.16- 5.76 (m, 2H), 5.54 (s, 2H), 5.40-5.35 (m, 1H), 4.12-4.04 (m, 1H), 3.98-3.94 (m, 1H), 3.88-3.80 (m, 2H), 2.47–2.41(m,1H), 2.18–2.13(m,1H).
步骤4) N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 4) N-(4-(4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
向5-(4-氨基-2-氟苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(60mg，0.19mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(50mg，0.19mmol)、EDCI(58mg，0.3mmol)、HOAT(41mg，0.3mmol)和DIEA(78mg，0.6mmol)，然后混合物在45℃下搅拌16h。反应混合物中加入H 2O(30mL)稀释，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(15-50)(0.05％NH 3))纯化，得到N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(46.3mg，43.34％)。MS(ESI)m/z 555.7[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),8.15(s,1H),7.83(dd,J＝12.4,1.8Hz,1H),7.64–7.58(m,2H),7.53(dd,J＝7.1,4.8Hz,3H),7.41-7.29(m,3H),6.08(s,2H),5.45-5.37(m,1H),5.12(s,2H),4.13-4.04(m,3H),3.97(dd,J＝9.4,6.0Hz,1H),3.91-3.79(m,2H),3.70(t,J＝4.9Hz,2H),2.47-2.41(m,1H),2.23-2.12(m,1H)。 To 5-(4-amino-2-fluorophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60mg, 0.19mmol) in DCM ( 20mL) was added 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (50mg, 0.19mmol), EDCI (58mg, 0.3mmol) to the mixture ), HOAT (41mg, 0.3mmol) and DIEA (78mg, 0.6mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was diluted with H 2 O (30 mL), and extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (15-50) (0.05% NH 3 )) to obtain N-(4-(4-amino-7- (Tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4,6,7- Tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (46.3 mg, 43.34%). MS (ESI) m/z 555.7 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 8.15 (s, 1H), 7.83 (dd, J = 12.4, 1.8 Hz, 1H), 7.64–7.58 (m, 2H), 7.53(dd,J=7.1,4.8Hz,3H),7.41-7.29(m,3H),6.08(s,2H),5.45-5.37(m,1H),5.12(s,2H),4.13-4.04( m, 3H), 3.97 (dd, J = 9.4, 6.0 Hz, 1H), 3.91-3.79 (m, 2H), 3.70 (t, J = 4.9 Hz, 2H), 2.47-2.41 (m, 1H), 2.23 -2.12 (m, 1H).
实施例8 N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 8 N-(4-(4-Amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000041
Figure PCTCN2021094020-appb-000041
向1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(43mg，0.15mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-3-羧酸(39mg，0.15mmol)、EDCI(43mg，0.23mmol)、HOAT(31mg，0.23mmol)和DIEA(59mg，0.45mmol)，然后混合物在45℃下搅拌16h。反应混合物用H 2O(30mL)稀释，然后用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)25％-30％)纯化，得到N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(37.6mg，48％)。MS(ESI)m/z 524.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.68(s,1H),8.13(s,1H),7.69(d,J＝8.6Hz,2H),7.61-7.56(m,2H),7.54-7.50(m,1H),7.49–7.45(m,2H),7.40(d,J＝8.4Hz,2H),7.27(s,1H),6.18-5.98(m,2H),5.05-4.92(m,1H),4.10–4.01(m,3H),3.57(t,J＝5.8Hz,2H),3.22(t,J＝6.2Hz,2H),2.02–1.96(m,2H),1.85–1.80(m,2H),1.05(d,J＝6.0Hz,3H)。 To 1-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (43mg, 0.15mmol) in DCM (10mL ) Add 2-oxo-1-phenyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyridine-3-carboxylic acid (39mg, 0.15mmol), EDCI (43mg, 0.23mmol) to the mixture ), HOAT (31mg, 0.23mmol) and DIEA (59mg, 0.45mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was diluted with H 2 O (30 mL), and then extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 25%-30%) to obtain N-(4-(4-amino-7-( 2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-1,2,4,5,6,7-hexa Hydropyrazolo[1,5-a]pyridine-3-carboxamide is a white solid (37.6 mg, 48%). MS (ESI) m/z 524.2 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H),8.13(s,1H),7.69(d,J=8.6Hz,2H),7.61-7.56(m,2H),7.54- 7.50(m,1H),7.49–7.45(m,2H),7.40(d,J=8.4Hz,2H),7.27(s,1H),6.18-5.98(m,2H),5.05-4.92(m, 1H),4.10–4.01(m,3H),3.57(t,J=5.8Hz,2H),3.22(t,J=6.2Hz,2H),2.02–1.96(m,2H),1.85–1.80(m , 2H), 1.05 (d, J=6.0 Hz, 3H).
实施例9 (S)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 9 (S)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000042
Figure PCTCN2021094020-appb-000042
向1-(4-氨基-5-(4-氨基-2-氟苯基)吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(45mg，0.15mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-3-羧酸(39mg，0.15mmol)、EDCI(43mg，0.23mmol)、HOAT(31mg，0.23mmol)和DIEA(59mg，0.45mmol)，然后混合物在42℃下搅拌16h。反应混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA) 25％-30％)纯化，得到(S)-N-(4-(4-氨基-7-(2-羟丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(35.5mg，44％)。MS(ESI)m/z 542.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.81(s,1H),8.12(s,1H),7.84(dd,J＝12.6,1.9Hz,1H),7.62-7.56(m,2H),7.54-7.49(m,1H),7.49–7.45(m,2H),7.36–7.27(m,3H),6.12-5.90(m,2H),5.95-4.90(m,1H),4.12–4.00(m,3H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.02–1.95(m,2H),1.85–1.79(m,2H),1.05(d,J＝6.0Hz,3H)。 To 1-(4-amino-5-(4-amino-2-fluorophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (45mg, 0.15mmol) in DCM ( 10mL) was added 2-oxo-1-phenyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyridine-3-carboxylic acid (39mg, 0.15mmol), EDCI (43mg, 0.23 mmol), HOAT (31 mg, 0.23 mmol) and DIEA (59 mg, 0.45 mmol), and then the mixture was stirred at 42°C for 16 h. The reaction mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 25%-30%) to obtain (S)-N-(4-(4-amino -7-(2-Hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-1,2,4 ,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide was a white solid (35.5 mg, 44%). MS (ESI) m/z 542.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.12 (s, 1H), 7.84 (dd, J = 12.6, 1.9 Hz, 1H), 7.62-7.56 (m, 2H), 7.54-7.49(m,1H),7.49-7.45(m,2H),7.36-7.27(m,3H),6.12-5.90(m,2H),5.95-4.90(m,1H),4.12-4.00(m ,3H),3.58(t,J=5.8Hz,2H),3.21(t,J=6.2Hz,2H),2.02–1.95(m,2H),1.85–1.79(m,2H),1.05(d, J = 6.0 Hz, 3H).
实施例10 N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 10 N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000043
Figure PCTCN2021094020-appb-000043
步骤1) 4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶Step 1) 4-Chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2.79g，10.0mmol)的THF(20mL)混合物中加入氧杂环丁烷-3-醇(1.48g，10.0mmol)、三苯基膦(5.25g，10.0mmol)和DEAD(4.04g，20.0mmol)。反应在85℃下搅拌16h。LCMS显示得到产物。混合物加入H 2O(30mL)稀释，再用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶为白色固体(3.0g，89％)。MS(ESI)m/z 335.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),8.41(s,1H),5.96–5.88(m,1H),4.99(dt,J＝14.7,7.0Hz,4H)。 At 0°C, add oxetane-3-ol to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.79g, 10.0mmol) in THF (20mL) (1.48g, 10.0mmol), triphenylphosphine (5.25g, 10.0mmol) and DEAD (4.04g, 20.0mmol). The reaction was stirred at 85°C for 16h. LCMS showed the product was obtained. The mixture was diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3 -d] Pyrimidine is a white solid (3.0 g, 89%). MS (ESI) m/z 335.9 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 8.41 (s, 1H), 5.96-5.88 (m, 1H), 4.99 (dt, J=14.7, 7.0 Hz, 4H).
步骤2) 4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2) 4-(4-Chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
向4-氯-5-碘-7-(氧杂环丁烷-3-基)吡咯并[2,3-d]嘧啶(670mg，2.0mmol)的二氧六环/H 2O(20mL/4mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(439mg，2.0mmol)、碳酸钠(318mg，3.0mmol)、和Pd(PPh 3) 4(232mg，0.2mmol)。将所得混合物保持在氮气下，并在80℃下搅拌16h。将混合物浓缩以除去有机物，用H 2O(50mL)稀释，然后用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺为白色固体(350mg，58％)。MS(ESI)m/z 301.1[M+H] +。 To 4-chloro-5-iodo-7-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidine (670mg, 2.0mmol) in dioxane/H 2 O (20mL/ 4mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (439mg, 2.0mmol), sodium carbonate ( 318 mg, 3.0 mmol), and Pd(PPh 3 ) 4 (232 mg, 0.2 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 16 h. The mixture was concentrated to remove organics, diluted with H 2 O (50 mL), and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-(4-chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3- d] Pyrimidine-5-yl)aniline as a white solid (350 mg, 58%). MS (ESI) m/z 301.1 [M+H] + .
步骤3) 5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺Step 3) 5-(4-Aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
向4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺(470mg，1.56mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，用H 2O(30mL)稀释，然后用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺为白色固体(70mg，15％)。MS(ESI)m/z 282.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.11(s,1H),7.52(s,1H),7.15(d,J＝8.4Hz,2H),6.67(d,J＝8.4Hz,2H),6.26-5.91(m,2H),5.87–5.82(m,1H),5.22(s,2H),5.03-4.93(m,4H)。 To 4-(4-chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline (470mg, 1.56mmol) in dioxane Ammonium hydroxide (10 mL) was added to the ring (10 mL) mixture. The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, diluted with H 2 O (30 mL), and then extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-amine is a white solid (70 mg, 15%). MS (ESI) m/z 282.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.11(s,1H),7.52(s,1H),7.15(d,J=8.4Hz,2H), 6.67(d,J=8.4Hz,2H) , 6.26-5.91 (m, 2H), 5.87-5.82 (m, 1H), 5.22 (s, 2H), 5.03-4.93 (m, 4H).
步骤4) N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 4) N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
向5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(40mg，0.14mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(37mg，0.14mmol)、EDCI(41mg，0.24mmol)、HOAT(29mg，0.21mmol)和DIEA(55mg，0.42mmol)，然后混合物在45℃下搅拌16h。反应混合物用H 2O(30mL)稀释，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA) 20％-30％)纯化，得到N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(25.7mg，37％)。MS(ESI)m/z 524.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.14(s,1H),7.74–7.70(m,3H),7.63–7.59(m,2H),7.56-7.50(m,3H),7.47(d,J＝8.8Hz,2H),6.30-6.04(m,2H),5.92-5.83(m,1H),5.13(s,2H),5.04–4.96(m,4H),4.10(t,J＝4.8Hz,2H),3.70(t,J＝4.8Hz,2H)。 To 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40mg, 0.14mmol) in DCM ( 10mL) was added 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (37mg, 0.14mmol), EDCI (41mg, 0.24mmol) to the mixture ), HOAT (29mg, 0.21mmol) and DIEA (55mg, 0.42mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was diluted with H 2 O (30 mL) and extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 20%-30%) to obtain N-(4-(4-amino-7-( Oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-2,4,6,7-tetra Hydrogen-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide is a white solid (25.7 mg, 37%). MS (ESI) m/z 524.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.14 (s, 1H), 7.74-7.70 (m, 3H), 7.63-7.59 (m, 2H), 7.56-7.50 (m ,3H),7.47(d,J=8.8Hz,2H),6.30-6.04(m,2H),5.92-5.83(m,1H),5.13(s,2H),5.04-4.96(m,4H), 4.10 (t, J = 4.8 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H).
实施例11 N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 11 N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000044
Figure PCTCN2021094020-appb-000044
步骤1) 4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶Step 1) 4-Chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
根据实施例10步骤(1)所述方法制备得到4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶为白色固体(3.0g，89％)。MS(ESI)m/z 335.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),8.41(s,1H),5.96–5.88(m,1H),4.99(dt,J＝14.7,7.0Hz,4H)。 Prepared according to the method described in step (1) of Example 10 to obtain 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine as a white solid (3.0g, 89%). MS (ESI) m/z 335.9 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 8.41 (s, 1H), 5.96-5.88 (m, 1H), 4.99 (dt, J=14.7, 7.0 Hz, 4H).
步骤2) 4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺Step 2) 4-(4-Chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
向4-氯-5-碘-7-(氧杂环丁烷-3-基)吡咯并[2,3-d]嘧啶(670mg，2.0mmol)的二氧六环/H 2O(20mL/4mL)溶液中加入N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯(475mg，2.0mmol)、碳酸钠(318mg，3.0mmol)、和Pd(PPh 3) 4(232mg，0.2mmol)。将所得混合物保持在氮气下，并在80℃下搅拌6h。将混合物浓缩以除去有机物，加入H 2O(50mL)稀释，用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺为白色固体(400mg，62％)。MS(ESI)m/z 319.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.65(s,1H),8.08(s,1H),7.10(t,J＝8.6Hz,1H),6.47–6.40(m,2H),6.02–5.94(m,1H),5.54(s,2H),5.04(dt,J＝14.8,7.1Hz,4H)。 To 4-chloro-5-iodo-7-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidine (670mg, 2.0mmol) in dioxane/H 2 O (20mL/ 4mL) Add N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino to the solution Tert-butyl formate (475 mg, 2.0 mmol), sodium carbonate (318 mg, 3.0 mmol), and Pd(PPh 3 ) 4 (232 mg, 0.2 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 6 h. The mixture was concentrated to remove organics, diluted with H 2 O (50 mL), and extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-(4-chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3- d] Pyrimidine-5-yl)-3-fluoroaniline as a white solid (400 mg, 62%). MS (ESI) m/z 319.0 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,1H), 8.08(s,1H), 7.10(t,J=8.6Hz,1H), 6.47–6.40(m,2H), 6.02– 5.94 (m, 1H), 5.54 (s, 2H), 5.04 (dt, J=14.8, 7.1 Hz, 4H).
步骤3) 5-(4-氨基-2-氟苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺Step 3) 5-(4-Amino-2-fluorophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
向4-(4-氯-7-(氧杂环丁烷-3-基)吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺(500mg，1.57mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，加入H 2O(30mL)稀释，然后用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到5-(4-氨基-2-氟苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺为白色固体(70mg，15％)。MS(ESI)m/z 300.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.11(s,1H),7.53(s,1H),7.07(t,J＝8.6Hz,1H),6.50–6.43(m,2H),6.115-5.90(m,2H),5.87–5.82(m,1H),5.56(s,2H),5.02–4.94(m,4H)。 To 4-(4-chloro-7-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline (500mg, 1.57mmol) in dioxy Ammonium hydroxide (10 mL) was added to the hexacyclic (10 mL) mixture. The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, diluted with H 2 O (30 mL), and then extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 5-(4-amino-2-fluorophenyl)-7-(oxetan-3-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-amine is a white solid (70 mg, 15%). MS (ESI) m/z 300.1 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.11(s,1H),7.53(s,1H),7.07(t,J=8.6Hz,1H),6.50-6.43(m,2H),6.115- 5.90 (m, 2H), 5.87-5.82 (m, 1H), 5.56 (s, 2H), 5.02-4.94 (m, 4H).
步骤4) N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 4) N-(4-(4-amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
向5-(4-氨基-2-氟苯基)-7-(氧杂环丁烷-3-基)吡咯并[2,3-d]嘧啶-4-胺(35mg，0.12mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(32mg，0.12mmol)、EDCI(35mg，0.18mmol)、HOAT(25mg，0.18mmol)和DIEA(46mg，0.36mmol)，然后混合物在45℃下搅拌16h。反应混合物加入H 2O(30mL)，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)15％-40％)纯化，得到N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(23.4mg，37％)。MS(ESI)m/z 542.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.14(s,1H),7.85(d,J＝12.0Hz,1H),7.70(s,1H),7.63–7.58(m,2H),7.53(d,J＝8.0Hz,3H),7.43-7.32(m,2H),6.24-6.00(m,2H),5.90–5.84(m,1H),5.13 (s,2H),5.54-4.94(m,4H),4.10(t,J＝4.8Hz,2H),3.71(t,J＝4.6Hz,2H)。 To 5-(4-amino-2-fluorophenyl)-7-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-4-amine (35mg, 0.12mmol) in DCM (10mL) Add 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (32mg, 0.12mmol), EDCI (35mg, 0.18 mmol), HOAT (25 mg, 0.18 mmol) and DIEA (46 mg, 0.36 mmol), and then the mixture was stirred at 45°C for 16 h. The reaction mixture was added with H 2 O (30 mL), and extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 15%-40%) to obtain N-(4-(4-amino-7-( Oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4,6 ,7-Tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (23.4 mg, 37%). MS (ESI) m/z 542.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.55 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 12.0 Hz, 1H), 7.70 (s, 1H), 7.63-7.58 ( m,2H),7.53(d,J=8.0Hz,3H),7.43-7.32(m,2H),6.24-6.00(m,2H),5.90-5.84(m,1H),5.13 (s,2H) , 5.54-4.94 (m, 4H), 4.10 (t, J = 4.8 Hz, 2H), 3.71 (t, J = 4.6 Hz, 2H).
实施例12 N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 12 N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000045
Figure PCTCN2021094020-appb-000045
向5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(40mg，0.14mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(37mg，0.14mmol)、EDCI(41mg，0.24mmol)、HOAT(29mg，0.21mmol)和DIEA(55mg，0.42mmol)，然后混合物在45℃下搅拌16h。反应混合物加入H 2O(30mL)，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)25％-30％)纯化，得到N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(10.8mg，15％)。MS(ESI)m/z 522.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.70(s,1H),8.14(s,1H),7.73–7.70(m,3H),7.62-7.56(m,2H),7.52(d,J＝7.2Hz,1H),7.49–7.45(m,4H),6.127-6.08(m,2H),5.92-5.83(m,1H),5.04-4.95(m,4H),3.57(t,J＝6.0Hz,2H),3.22(t,J＝6.4Hz,2H),2.01–1.96(m,2H),1.85–1.80(m,2H)。 To 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40mg, 0.14mmol) in DCM ( 10mL) Add 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (37mg, 0.14mmol) to the mixture , EDCI (41mg, 0.24mmol), HOAT (29mg, 0.21mmol) and DIEA (55mg, 0.42mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was added with H 2 O (30 mL), and extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 25%-30%) to obtain N-(4-(4-amino-7-( Oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-1,2,4,5,6 ,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide is a white solid (10.8 mg, 15%). MS (ESI) m/z 522.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.14 (s, 1H), 7.73-7.70 (m, 3H), 7.62-7.56 (m, 2H), 7.52 (d, J =7.2Hz,1H),7.49–7.45(m,4H),6.127-6.08(m,2H),5.92-5.83(m,1H),5.04-4.95(m,4H),3.57(t,J=6.0 Hz, 2H), 3.22 (t, J = 6.4 Hz, 2H), 2.01-1.96 (m, 2H), 1.85-1.80 (m, 2H).
实施例13 N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 13 N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000046
Figure PCTCN2021094020-appb-000046
向5-(4-氨基-2-氟苯基)-7-(氧杂环丁烷-3-基)吡咯并[2,3-d]嘧啶-4-胺(35mg，0.12mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-4H,5H,6H,7H-吡唑并[1,5-a]吡啶-3-羧酸(31mg，0.12mmol)、EDCI(35mg，0.18mmol)、HOAT(25mg，0.18mmol)和DIEA(46mg，0.36mmol)，然后混合物在45℃下搅拌16h。反应混合物加入H 2O(30mL)，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(0.1％FA)25％-30％)纯化，得到N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(22.7mg，36％)。MS(ESI)m/z 540.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.83(s,1H),8.14(s,1H),7.89-7.84(m,1H),7.69(s,1H),7.59(t,J＝7.5Hz,2H),7.54–7.44(m,3H),7.38(t,J＝8.6Hz,1H),7.33–7.28(m,1H),6.22-6.12(m,2H),5.89–5.84(m,1H),5.04-4.94(m,4H),3.58(t,J＝6.0Hz,2H),3.21(t,J＝6.4Hz,2H),2.02–1.97(m,2H),1.85–1.78(m,2H)。 To 5-(4-amino-2-fluorophenyl)-7-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-4-amine (35mg, 0.12mmol) in DCM (10mL) was added 2-oxo-1-phenyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyridine-3-carboxylic acid (31mg, 0.12mmol), EDCI (35mg, 0.18mmol), HOAT (25mg, 0.18mmol) and DIEA (46mg, 0.36mmol), and then the mixture was stirred at 45°C for 16h. The reaction mixture was added with H 2 O (30 mL), and extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (0.1% FA) 25%-30%) to obtain N-(4-(4-amino-7-( Oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-1,2,4 ,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide was a white solid (22.7 mg, 36%). MS (ESI) m/z 540.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.14 (s, 1H), 7.89-7.84 (m, 1H), 7.69 (s, 1H), 7.59 (t, J = 7.5 Hz,2H),7.54-7.44(m,3H),7.38(t,J=8.6Hz,1H),7.33-7.28(m,1H),6.22-6.12(m,2H),5.89-5.84(m, 1H),5.04-4.94(m,4H),3.58(t,J=6.0Hz,2H),3.21(t,J=6.4Hz,2H),2.02-1.97(m,2H),1.85-1.78(m ,2H).
实施例14 N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 14 N-(4-(4-Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000047
Figure PCTCN2021094020-appb-000047
将2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(43.9mg，0.17mmol)、5-(4-氨基苯基)-7-(氧杂环戊烷-3-基)吡咯并[2,3-d]嘧啶-4-胺(50mg，0.17mmol)、N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(49mg，0.255mmol)、HOAT(27.8mg，0.204mmol)和DIEA(66mg，0.51mmol)的DCM(20mL)混合物在40℃下加热反应16h。反应混合物用DCM(20mL)稀释，然后用盐水(30mL×2)洗。有机层经无水Na 2SO 4干燥，蒸发浓缩。所得残余物用MeOH(3mL)重结晶，过滤，滤饼用MeOH(1mL)洗，真空干燥，得到N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(43.7mg，48％收率)。MS(ESI):536.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.69(s,1H),8.16(s,1H),7.70(d,J＝8.4Hz,2H),7.61-7.57(m,2H),7.52(d,J＝7.2Hz,1H),7.48-7.41(m,4H),7.32(s,1H),6.19(s,2H),5.42-5.40(m,1H),4.10(q,J＝7.6Hz,1H),3.99-6.95(m,1H),3.90-3.81(m,2H),3.57(t,J＝5.6Hz,2H),3.22(t,J＝6.0Hz,2H),2.50-2.41(m,1H),2.22-2.15(m,1H),2.05-1.95(m,2H),1.86-1.78(m,2H)。 The 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (43.9mg, 0.17mmol), 5- (4-Aminophenyl)-7-(oxolane-3-yl)pyrrolo[2,3-d]pyrimidin-4-amine (50mg, 0.17mmol), N-(3-dimethyl Aminopropyl)-N'-ethylcarbodiimide hydrochloride (49mg, 0.255mmol), HOAT (27.8mg, 0.204mmol) and DIEA (66mg, 0.51mmol) in DCM (20mL) mixture at 40°C The reaction was heated for 16h. The reaction mixture was diluted with DCM (20 mL), and then washed with brine (30 mL×2). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated by evaporation. The obtained residue was recrystallized with MeOH (3 mL), filtered, and the filter cake was washed with MeOH (1 mL) and dried in vacuo to obtain N-(4-(4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a] Pyridine-3-carboxamide was a white solid (43.7 mg, 48% yield). MS (ESI): 536.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 8.16 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.61-7.57 (m, 2H), 7.52 ( d,J=7.2Hz,1H),7.48-7.41(m,4H),7.32(s,1H),6.19(s,2H),5.42-5.40(m,1H),4.10(q,J=7.6Hz ,1H),3.99-6.95(m,1H),3.90-3.81(m,2H),3.57(t,J=5.6Hz,2H),3.22(t,J=6.0Hz,2H),2.50-2.41( m, 1H), 2.22-2.15 (m, 1H), 2.05-1.95 (m, 2H), 1.86-1.78 (m, 2H).
实施例15 N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 15 N-(4-(4-Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2- Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000048
Figure PCTCN2021094020-appb-000048
将2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(41.3mg，0.16mmol)、5-(4-氨基-2-氟苯基)-7-(氧杂环戊烷-3-基)吡咯并[2,3-d]嘧啶-4-胺(50mg，0.16mmol)、N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(46mg，0.24mmol)、HOAT(26.3mg，0.19mmol)和DIEA(62mg，0.48mmol)的DCM(20mL)混合物在40℃下加热反应16h。反应混合物用DCM(20mL)稀释，然后用盐水(30mL×2)洗。有机层经无水Na 2SO 4干燥，过滤，蒸发浓缩。所得残余物用MeOH(3mL)重结晶，过滤，滤饼用MeOH(1mL)洗，真空干燥，得到N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(41.3mg，46％收率)。MS(ESI):554.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.82(s,1H),8.14(s,1H),7.85(d,J＝12.4Hz,1H),7.62-7.57(m,2H),7.52(d,J＝7.2Hz,1H),7.50-7.46(m,2H),7.36(t,J＝8.4Hz,1H),7.33-7.26(m,2H),6.09(s,2H),5.43-5.37(m,1H),4.09(q,J＝8.0Hz,1H),3.99-3.95(m,1H),3.90-3.79(m,2H),3.58(t,J＝5.6Hz,2H),3.21(t,J＝6Hz,2H),2.50-2.42(m,1H),2.21-2.13(m,1H),2.02-1.97(m,2H),1.86-1.82(m,2H)。 The 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (41.3mg, 0.16mmol), 5- (4-Amino-2-fluorophenyl)-7-(oxolane-3-yl)pyrrolo[2,3-d]pyrimidin-4-amine (50mg, 0.16mmol), N-(3 -Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (46mg, 0.24mmol), HOAT (26.3mg, 0.19mmol) and DIEA (62mg, 0.48mmol) in DCM (20mL) mixture The reaction was heated at 40°C for 16h. The reaction mixture was diluted with DCM (20 mL), and then washed with brine (30 mL×2). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated by evaporation. The obtained residue was recrystallized with MeOH (3 mL), filtered, and the filter cake was washed with MeOH (1 mL) and dried in vacuo to obtain N-(4-(4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1, 5-a] Pyridine-3-carboxamide as a white solid (41.3 mg, 46% yield). MS (ESI): 554.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 12.4 Hz, 1H), 7.62-7.57 (m, 2H), 7.52 ( d,J=7.2Hz,1H),7.50-7.46(m,2H),7.36(t,J=8.4Hz,1H),7.33-7.26(m,2H),6.09(s,2H),5.43-5.37 (m,1H),4.09(q,J=8.0Hz,1H),3.99-3.95(m,1H),3.90-3.79(m,2H),3.58(t,J=5.6Hz,2H),3.21( t, J=6Hz, 2H), 2.50-2.42 (m, 1H), 2.21-2.13 (m, 1H), 2.02-1.97 (m, 2H), 1.86-1.82 (m, 2H).
实施例16 N-(4-(4-氨基-7-(3-羟基环戊基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 16 N-(4-(4-amino-7-(3-hydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2 -Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000049
Figure PCTCN2021094020-appb-000049
步骤1) 3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇Step 1) 3-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(900mg，3.22mmol)的THF(40mL)混合物中加入环戊烷-1,3-二醇(493mg，4.83mmol)、三苯基膦(1.7g，6.44mmol)和DIAD(1.3g，6.44mmol)。反应在25℃下搅拌16h。LCMS显示得到产物。混合物中加入H 2O(30mL)，再用EA(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇为白色固体(800mg，粗品)。MS(ESI)m/z 363.7[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.14(s,1H),5.34-5.26(m,1H),4.85-4.68(m, 1H),4.27(s,1H),2.45-2.31(m,1H),2.24–2.13(m,1H),2.05-1.91(m,1H),1.83–1.75(m,3H)。 Add cyclopentane-1,3-diol to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (900mg, 3.22mmol) in THF (40mL) at 0°C (493 mg, 4.83 mmol), triphenylphosphine (1.7 g, 6.44 mmol) and DIAD (1.3 g, 6.44 mmol). The reaction was stirred at 25°C for 16h. LCMS showed the product was obtained. H 2 O (30 mL) was added to the mixture, and then extracted with EA (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane Alkan-1-ol is a white solid (800 mg, crude product). MS (ESI) m/z 363.7 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.63(s,1H), 8.14(s,1H),5.34-5.26(m,1H),4.85-4.68(m, 1H), 4.27(s,1H) ), 2.45-2.31 (m, 1H), 2.24-2.13 (m, 1H), 2.05-1.91 (m, 1H), 1.83-1.75 (m, 3H).
步骤2) 3-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇Step 2) 3-(5-(4-Amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol
向3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇(800mg，2.2mmol)的二氧六环/H 2O(10mL/2mL)溶液中加入3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(340mg，1.43mmol)、碳酸钠(466mg，4.4mmol)和Pd(PPh 3) 4(254mg，0.22mmol)。将所得混合物保持在氮气下，并在80℃下搅拌2小时。将混合物浓缩以除去有机物，然后用EA(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇为白色固体(320mg，41.94％)。MS(ESI)m/z 346.7[M+H] +。 To 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol (800mg, 2.2mmol) dioxane/H 2 Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (340mg , 1.43 mmol), sodium carbonate (466 mg, 4.4 mmol) and Pd(PPh 3 ) 4 (254 mg, 0.22 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 2 hours. The mixture was concentrated to remove organics, and then extracted with EA (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 3-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3- d] Pyrimidine-7-yl)cyclopentane-1-ol is a white solid (320 mg, 41.94%). MS (ESI) m/z 346.7 [M+H] + .
步骤3) 3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇Step 3) 3-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol
向3-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇(320mg，0.92mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，加入H 2O(30mL)稀释，用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝10/1)，得到3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇为白色固体(200mg，66.2％)。MS(ESI)m/z 327.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.36–7.21(m,2H),7.03(t,J＝8.7Hz,1H),6.68(s,1H),6.51–6.41(m,2H),5.89(s,2H),4.71(d,J＝3.5Hz,1H),4.35(d,J＝2.6Hz,1H),4.10(q,J＝5.3Hz,1H),2.26–1.96(m,5H),1.88-1.77(m,1H)。 To 3-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol (320mg, 0.92 Ammonium hydroxide (10 mL) was added to a mixture of dioxane (10 mL) in mmol). The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=10/1) to obtain 3-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3- d] Pyrimidine-7-yl)cyclopentane-1-ol is a white solid (200 mg, 66.2%). MS (ESI) m/z 327.9 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ8.09(s,1H), 7.36–7.21(m,2H), 7.03(t,J=8.7Hz,1H), 6.68(s,1H), 6.51– 6.41 (m, 2H), 5.89 (s, 2H), 4.71 (d, J = 3.5 Hz, 1H), 4.35 (d, J = 2.6 Hz, 1H), 4.10 (q, J = 5.3 Hz, 1H), 2.26–1.96 (m, 5H), 1.88-1.77 (m, 1H).
步骤4) N-(4-(4-氨基-7-(3-羟基环戊基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Step 4) N-(4-(4-amino-7-(3-hydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2 -Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
向3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇(62.2mg，0.19mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(50mg，0.19mmol)、EDCI(52mg，0.28mmol)、HOAT(37mg，0.28mmol)和DIEA(74mg，0.57mmol)，然后混合物在45℃下搅拌16h。混合物中加入H 2O(30mL)，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(15-40)(0.1％FA))纯化，得到N-(4-(4-氨基-7-(3-羟基环戊基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(43.2mg，40.1％)。MS(ESI)m/z 567.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.81(s,1H),8.12(s,1H),7.84(dd,J＝12.5,2.0Hz,1H),7.59(t,J＝7.4Hz,2H),7.53–7.46(m,3H),7.39(s,1H),7.35–7.27(m,2H),6.00(s,2H),5.34–5.28(m,1H),4.71(s,1H),4.36(s,1H),3.58(t,J＝5.9Hz,2H),3.20(t,J＝6.3Hz,2H),2.54-2.21(m,1H),2.17–2.08(m,2H),2.03–1.96(m,3H),1.89-1.78(m,3H),1.64-1.58(m,1H)。 To 3-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol (62.2mg, 0.19mmol) in DCM (20mL) was added 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (50mg, 0.19mmol), EDCI (52mg, 0.28mmol), HOAT (37mg, 0.28mmol) and DIEA (74mg, 0.57mmol), then the mixture was stirred at 45°C for 16h. H 2 O (30 mL) was added to the mixture, and it was extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (15-40) (0.1% FA)) to obtain N-(4-(4-amino-7-( 3-hydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-1,2,4,5, 6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide was a white solid (43.2 mg, 40.1%). MS (ESI) m/z 567.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.12 (s, 1H), 7.84 (dd, J = 12.5, 2.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 2H), 7.53 - 7.46 (m, 3H), 7.39 (s, 1H), 7.35 - 7.27 (m, 2H), 6.00 (s, 2H), 5.34 - 5.28 (m, 1H), 4.71 (s, 1H) , 4.36 (s, 1H), 3.58 (t, J = 5.9 Hz, 2H), 3.20 (t, J = 6.3 Hz, 2H), 2.54-2.21 (m, 1H), 2.17-2.08 (m, 2H), 2.03–1.96 (m, 3H), 1.89-1.78 (m, 3H), 1.64-1.58 (m, 1H).
实施例17 N-(4-(4-氨基-7-(3-羟基环戊基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 17 N-(4-(4-amino-7-(3-hydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2 -Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000050
Figure PCTCN2021094020-appb-000050
向3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环戊烷-1-醇(63mg，0.19mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸(50mg，0.19mmol)、EDCI(52mg，0.28mmol)、HOAT(37mg，0.28mmol)和DIEA(74mg，0.57mmol)，然后混合物在45℃下搅拌16h。反应混合物中加入H 2O(30mL)，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(20-30)(0.1％FA))纯化，得到N-(4-(4-氨基-7-(3-羟基环戊基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3- 氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(43.8mg，40.2％)。MS(ESI)m/z 569.7[M+H] +。 1H NMR:(400MHz,DMSO-d 6)δ10.53(s,1H),8.12(s,1H),7.83(dd,J＝12.4,1.9Hz,1H),7.63–7.58(m,2H),7.53(dd,J＝7.1,5.0Hz,3H),7.41–7.31(m,3H),6.01(s,2H),5.35–5.28(m,1H),5.12(s,2H),4.72(s,1H),4.36(s,1H),4.10(t,J＝5.0Hz,2H),3.70(t,J＝4.9Hz,2H),2.24-2.01(m,4H),1.88–1.80(m,1H),1.63–1.56(m,1H)。 To 3-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1-ol (63mg, 0.19 mmol) in DCM (20mL) was added 2-oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine- 3-carboxylic acid (50mg, 0.19mmol), EDCI (52mg, 0.28mmol), HOAT (37mg, 0.28mmol) and DIEA (74mg, 0.57mmol), then the mixture was stirred at 45°C for 16h. H 2 O (30 mL) was added to the reaction mixture, and it was extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (20-30) (0.1% FA)) to obtain N-(4-(4-amino-7-( 3-hydroxycyclopentyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4,6,7- Tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (43.8 mg, 40.2%). MS (ESI) m/z 569.7 [M+H] + . 1 H NMR: (400MHz, DMSO-d 6 )δ10.53(s,1H), 8.12(s,1H), 7.83(dd,J=12.4,1.9Hz,1H), 7.63–7.58(m,2H) ,7.53(dd,J=7.1,5.0Hz,3H),7.41-7.31(m,3H),6.01(s,2H),5.35-5.28(m,1H),5.12(s,2H),4.72(s ,1H), 4.36(s,1H), 4.10(t,J=5.0Hz,2H), 3.70(t,J=4.9Hz,2H),2.24-2.01(m,4H),1.88–1.80(m, 1H), 1.63-1.56 (m, 1H).
实施例18 N-(4-(4-氨基-7-((1R,4R)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 18 N-(4-(4-amino-7-((1R,4R)-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000051
Figure PCTCN2021094020-appb-000051
步骤1) 4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇Step 1) 4-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2.0g，7.2mmol)的THF(40mL)混合物中加入环己烷-1,4-二醇(1.67g，14.4mmol)、三苯基膦(3.7g，14.4mmol)和DIAD(2.9g，14.4mmol)。反应在25℃下搅拌16h。LCMS显示得到产物。混合物加入H 2O(30mL)，再用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇为白色固体(2g，74.07％)。MS(ESI)m/z 377.7[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.10(s,1H),4.72-4.61(m,1H),4.53(d,J＝3.7Hz,1H),3.90(d,J＝2.4Hz,1H),2.29-2.15(m,2H),1.81(d,J＝12.2Hz,2H),1.65(dd,J＝23.2,11.5Hz,4H)。 At 0°C, to 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.0g, 7.2mmol) in THF (40mL) was added cyclohexane-1,4-di Alcohol (1.67 g, 14.4 mmol), triphenylphosphine (3.7 g, 14.4 mmol) and DIAD (2.9 g, 14.4 mmol). The reaction was stirred at 25°C for 16h. LCMS showed the product was obtained. The mixture was added with H 2 O (30 mL), and then extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane Alkan-1-ol is a white solid (2g, 74.07%). MS (ESI) m/z 377.7 [M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.63(s,1H), 8.10(s,1H), 4.72-4.61(m,1H), 4.53(d,J=3.7Hz,1H), 3.90( d, J = 2.4 Hz, 1H), 2.29-2.15 (m, 2H), 1.81 (d, J = 12.2 Hz, 2H), 1.65 (dd, J = 23.2, 11.5 Hz, 4H).
步骤2) (1R,4R)-4-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇Step 2) (1R,4R)-4-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol
向4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(250mg，0.66mmol)的二氧六环/H 2O(10mL/2mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(144.6mg，0.66mmol)、碳酸钠(210mg，1.98mmol)和Pd(PPh 3) 4(38mg，0.032mmol)。将所得混合物保持在氮气下，并在80℃下搅拌2小时。将混合物浓缩以除去有机物，然后用EtOAc(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到(1R,4R)-4-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇为白色固体(100mg，44.05％)。MS(ESI)m/z 342.8[M+H] +。 To 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol (250mg, 0.66mmol) dioxane/H 2 Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (144.6mg, 0.66mmol) to O(10mL/2mL) solution ), sodium carbonate (210 mg, 1.98 mmol) and Pd(PPh 3 ) 4 (38 mg, 0.032 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 2 hours. The mixture was concentrated to remove organics, and then extracted with EtOAc (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain (1R,4R)-4-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)cyclohexane-1-ol is a white solid (100 mg, 44.05%). MS (ESI) m/z 342.8 [M+H] + .
步骤3) (1R,4R)-4-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇Step 3) (1R,4R)-4-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol
向(1R,4R)-4-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(95mg，0.27mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，然后用EtOAc(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝10/1)，得到(1R,4R)-4-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇为白色固体(31mg，34.6％)。MS(ESI)m/z 323.9[M+H] +。 To (1R,4R)-4-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol (95mg , 0.27mmol) of dioxane (10mL) was added ammonium hydroxide (10mL). The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, and then extracted with EtOAc (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=10/1) to obtain (1R,4R)-4-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)cyclohexane-1-ol is a white solid (31 mg, 34.6%). MS (ESI) m/z 323.9 [M+H] + .
步骤4) N-(4-(4-氨基-7-((1R,4R)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Step 4) N-(4-(4-amino-7-((1R,4R)-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
向(1R,4R)-4-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(30mg，0.09mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(23.2mg，0.09mmol)、EDCI(26mg，0.14mmol)、HOAT(18.5mg，0.14mmol)和DIEA(35mg，0.27mmol)，然后混合物在45℃下搅拌16h。反应混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(15-40)(0.1％FA))纯化，得到N-(4-(4-氨基-7-((1R,4R)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(19.2mg，35.6％)。MS(ESI)m/z 563.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.68(s,1H),8.12(s,1H),7.69(d,J＝8.6Hz,2H),7.59(t,J＝7.5 Hz,2H),7.52(d,J＝7.4Hz,1H),7.46(dt,J＝16.7,6.4Hz,4H),7.36(s,1H),6.07(s,2H),4.59(t,J＝12.1Hz,1H),4.50(s,1H),3.90(s,1H),3.57(t,J＝5.9Hz,2H),3.22(t,J＝6.3Hz,2H),2.19(dd,J＝24.1,11.8Hz,2H),2.03-1.94(m,2H),1.87-1.76(m,4H),1.72-1.56(m,4H)。 To (1R,4R)-4-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol (30mg , 0.09mmol) in DCM (20mL) was added 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxy Acid (23.2mg, 0.09mmol), EDCI (26mg, 0.14mmol), HOAT (18.5mg, 0.14mmol) and DIEA (35mg, 0.27mmol), then the mixture was stirred at 45°C for 16h. The reaction mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (15-40) (0.1% FA)) to obtain N-(4-(4-amino-7-( (1R,4R)-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-1,2,4,5 ,6,7-Hexahydropyrazolo[1,5-a]pyridine-3-carboxamide was a white solid (19.2 mg, 35.6%). MS (ESI) m/z 563.8 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H), 8.12(s,1H), 7.69(d,J=8.6Hz,2H), 7.59(t,J=7.5 Hz,2H) ,7.52(d,J=7.4Hz,1H),7.46(dt,J=16.7,6.4Hz,4H),7.36(s,1H),6.07(s,2H),4.59(t,J=12.1Hz, 1H), 4.50 (s, 1H), 3.90 (s, 1H), 3.57 (t, J = 5.9 Hz, 2H), 3.22 (t, J = 6.3 Hz, 2H), 2.19 (dd, J = 24.1, 11.8 Hz, 2H), 2.03-1.94 (m, 2H), 1.87-1.76 (m, 4H), 1.72-1.56 (m, 4H).
实施例19 N-(4-(4-氨基-7-((1R,4R)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 19 N-(4-(4-amino-7-((1R,4R)-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoro (Phenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000052
Figure PCTCN2021094020-appb-000052
步骤1) (1R,4R)-4-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇Step 1) (1R,4R)-4-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane -1-ol
在0℃下，向4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(250mg，0.66mmol)的二氧六环/H 2O(10mL/2mL)溶液中加入3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(156.5mg，0.66mmol)、碳酸钠(140mg，1.32mmol)和Pd(PPh 3) 4(38mg，0.032mmol)。将所得混合物保持在氮气下，并在80℃下搅拌2小时。将混合物浓缩以除去有机物，然后用EtOAc(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到(1R,4R)-4-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇为白色固体(130mg，54.4％)。MS(ESI)m/z 360.8[M+H] +。 At 0 ℃, to 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol (250mg, 0.66mmol) of dioxy six ring / H 2 O (10mL / 2mL ) was added 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2- Yl)aniline (156.5 mg, 0.66 mmol), sodium carbonate (140 mg, 1.32 mmol) and Pd(PPh 3 ) 4 (38 mg, 0.032 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 2 hours. The mixture was concentrated to remove organics, and then extracted with EtOAc (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain (1R,4R)-4-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrole And [2,3-d]pyrimidin-7-yl)cyclohexane-1-ol was a white solid (130 mg, 54.4%). MS (ESI) m/z 360.8 [M+H] + .
步骤2) (1R,4R)-4-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇Step 2) (1R,4R)-4-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane -1-ol
向(1R,4R)-4-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(130mg，0.36mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应在密闭管中于130℃下搅拌16h。将混合物浓缩以除去有机物，然后用EtOAc(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(DCM/MeOH＝10/1)，得到(1R,4R)-4-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇为白色固体(51mg，35.28％)。MS(ESI)m/z 341.9[M+H] +。 To (1R,4R)-4-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1 -Ammonium hydroxide (10 mL) was added to a mixture of alcohol (130 mg, 0.36 mmol) in dioxane (10 mL). The reaction was stirred at 130°C for 16h in a closed tube. The mixture was concentrated to remove organics, and then extracted with EtOAc (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (DCM/MeOH=10/1) to obtain (1R,4R)-4-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrole And [2,3-d]pyrimidin-7-yl)cyclohexane-1-ol was a white solid (51 mg, 35.28%). MS (ESI) m/z 341.9 [M+H] + .
步骤3) N-(4-(4-氨基-7-((1R,4R)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Step 3) N-(4-(4-amino-7-((1R,4R)-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoro (Phenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
向(1R,4R)-4-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(51mg，0.15mmol)的DCM(20mL)混合物中加入2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸(39mg，0.15mmol)、EDCI(43mg，0.23mmol)、HOAT(31mg，0.23mmol)和DIEA(58mg，0.45mmol)，然后将混合物在45℃下搅拌16h。反应混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，浓缩。所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN-H 2O(18-35)(0.1％FA))纯化，得到N-(4-(4-氨基-7-((1R,4R)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(29.5mg，32.67％)。MS(ESI)m/z 583.7[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.12(s,1H),7.83(dd,J＝12.5,1.9Hz,1H),7.64–7.58(m,2H),7.57-7.49(m,3H),7.40–7.28(m,3H),6.02(s,2H),5.12(s,2H),4.64-4.45(m,2H),4.10(t,J＝4.9Hz,2H),3.90(s,1H),3.70(t,J＝4.9Hz,2H),2.17(dd,J＝24.6,12.2Hz,2H),1.81(d,J＝11.8Hz,2H),1.65(dd,J＝25.2,12.0Hz,4H)。 To (1R,4R)-4-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1 -Add 2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4] Oxazine-3-carboxylic acid (39mg, 0.15mmol), EDCI (43mg, 0.23mmol), HOAT (31mg, 0.23mmol) and DIEA (58mg, 0.45mmol), then the mixture was stirred at 45°C for 16h . The reaction mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN-H 2 O (18-35) (0.1% FA)) to obtain N-(4-(4-amino-7-( (1R,4R)-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4 ,6,7-Tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (29.5 mg, 32.67%). MS (ESI) m/z 583.7 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.12 (s, 1H), 7.83 (dd, J = 12.5, 1.9 Hz, 1H), 7.64–7.58 (m, 2H), 7.57-7.49(m,3H),7.40-7.28(m,3H),6.02(s,2H),5.12(s,2H),4.64-4.45(m,2H),4.10(t,J=4.9Hz, 2H), 3.90 (s, 1H), 3.70 (t, J = 4.9 Hz, 2H), 2.17 (dd, J = 24.6, 12.2 Hz, 2H), 1.81 (d, J = 11.8 Hz, 2H), 1.65 ( dd, J=25.2, 12.0 Hz, 4H).
实施例20 (S)-N-(4-(4-氨基-7-(2-羟基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 20 (S)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000053
Figure PCTCN2021094020-appb-000053
步骤1) 6-羟基-3-氧己酸乙酯Step 1) Ethyl 6-hydroxy-3-oxohexanoate
将在-78℃下由二异丙胺(16.42mL，116.158mmol)和正丁基锂(46.46mL，116.158mmol，2.5M的正己烷溶液)生成的二异丙基酰胺锂溶液在0℃搅拌20分钟，然后冷却至-78℃。向混合物中逐滴加入乙酸乙酯(11.35mL，116.198mmol，1.0当量)，并将反应混合物在-78℃下保持1h。然后加入4-丁内酯(10g，116.158mmol)，将溶液在-78℃下再搅拌3h，然后用乙醇淬灭并温热至20℃。将产物在***和水之间分层。用1M HCl中和水层后，将所得混合物用乙酸乙酯(3×500mL)萃取，合并有机层，经无水硫酸钠干燥，过滤，浓缩。所得残余物经硅胶柱色谱法(0-35％乙酸乙酯/石油醚)纯化，得到6-羟基-3-氧己酸乙酯为黄色油状物(12.0g，59.31％收率)。The lithium diisopropylamide solution generated from diisopropylamine (16.42mL, 116.158mmol) and n-butyllithium (46.46mL, 116.158mmol, 2.5M n-hexane solution) at -78°C was stirred at 0°C for 20 minutes , And then cooled to -78°C. Ethyl acetate (11.35 mL, 116.198 mmol, 1.0 equivalent) was added dropwise to the mixture, and the reaction mixture was kept at -78°C for 1 h. Then 4-butyrolactone (10 g, 116.158 mmol) was added, and the solution was stirred for another 3 h at -78°C, then quenched with ethanol and warmed to 20°C. The product was partitioned between ether and water. After neutralizing the aqueous layer with 1M HCl, the resulting mixture was extracted with ethyl acetate (3×500 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (0-35% ethyl acetate/petroleum ether) to obtain ethyl 6-hydroxy-3-oxohexanoate as a yellow oil (12.0 g, 59.31% yield).
步骤2) 5-(3-羟基丙基)-2-苯基-1H-吡唑-3-酮Step 2) 5-(3-hydroxypropyl)-2-phenyl-1H-pyrazol-3-one
向6-羟基-3-氧己酸乙酯(3.0g，17.222mmol)的1,4-二氧六环(50mL)溶液中加入乙酸钠(4.69g，34.444mmol)、AcOH(1.48mL，24.650mmol)、和苯肼(2.05g，18.944mmol)。将所得混合物在110℃下搅拌3小时。混合物冷却至室温后，将固体滤出。滤液真空浓缩。所得残余物经硅胶柱色谱法(0-8％MeOH/DCM)纯化，得到5-(3-羟基丙基)-2-苯基-1H-吡唑-3-酮为黄色油状物(3.3g，87.79％收率)。MS(ESI)m/z 219.10[M+H] +。 To a solution of ethyl 6-hydroxy-3-oxohexanoate (3.0g, 17.222mmol) in 1,4-dioxane (50mL) was added sodium acetate (4.69g, 34.444mmol), AcOH (1.48mL, 24.650) mmol), and phenylhydrazine (2.05 g, 18.944 mmol). The resulting mixture was stirred at 110°C for 3 hours. After the mixture was cooled to room temperature, the solid was filtered off. The filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (0-8% MeOH/DCM) to obtain 5-(3-hydroxypropyl)-2-phenyl-1H-pyrazol-3-one as a yellow oil (3.3g , 87.79% yield). MS (ESI) m/z 219.10 [M+H] + .
步骤3) 1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-2-酮Step 3) 1-Phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazol-2-one
在0℃、N 2(g)气氛下，向5-(3-羟基丙基)-2-苯基-1H-吡唑-3-酮(3.0g，13.745mmol)的THF(300mL)溶液中加入PPh 3(3.97g，15.120mmol)。在0℃下滴加DIAD(3.06g，15.120mmol)。混合物在25℃下搅拌3h。混合物在真空下浓缩，所得残余物经硅胶柱色谱法(0-3％MeOH/DCM)纯化，得到1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-2-酮为黄色固体(1.6g，58.13％收率)。MS(ESI)m/z 201.10[M+H] +。 To a solution of 5-(3-hydroxypropyl)-2-phenyl-1H-pyrazol-3-one (3.0g, 13.745mmol) in THF (300mL) at 0°C under N 2 (g) atmosphere Add PPh 3 (3.97 g, 15.120 mmol). DIAD (3.06 g, 15.120 mmol) was added dropwise at 0°C. The mixture was stirred at 25°C for 3h. The mixture was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (0-3% MeOH/DCM) to give 1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-2 -The ketone is a yellow solid (1.6 g, 58.13% yield). MS (ESI) m/z 201.10 [M+H] + .
步骤4) 2-氧-1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-3-甲醛Step 4) 2-Oxy-1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde
向1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-2-酮(1.60g，7.990mmol)的乙腈(15mL)溶液中加入N-(氯亚甲基)-N-甲基甲基氯化铵(1.53g，11.986mmol)。将所得混合物在25℃下搅拌过夜。然后加入NaOH(水溶液)。将所得混合物在25℃下搅拌2h。反应用水(100mL)淬灭。所得混合物用DCM(3×100mL)萃取。合并有机层，经无水硫酸钠干燥，过滤，浓缩。所得残余物经硅胶柱色谱法纯化(0-100％乙酸乙酯/石油醚)，得到2-氧-1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-3-甲醛为黄色固体(1.2g，65.80％收率)。MS(ESI)m/z 229.10[M+H] +。 Add N-(chloromethylene) to the solution of 1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazol-2-one (1.60g, 7.990mmol) in acetonitrile (15mL) -N-Methylmethylammonium chloride (1.53 g, 11.986 mmol). The resulting mixture was stirred at 25°C overnight. Then NaOH (aqueous solution) was added. The resulting mixture was stirred at 25°C for 2 h. The reaction was quenched with water (100 mL). The resulting mixture was extracted with DCM (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate/petroleum ether) to obtain 2-oxo-1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole- 3-Formaldehyde is a yellow solid (1.2 g, 65.80% yield). MS (ESI) m/z 229.10 [M+H] + .
步骤5) 2-氧-1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-3-羧酸Step 5) 2-Oxy-1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid
在0℃下，向2-氧-1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-3-甲醛(1.5g，6.572mmol)的t-BuOH(24mL)混合物中加入2-甲基-2-丁烯(4.51g，64.403mmol)，然后加入亚氯酸钠(1.72g，19.058mmol)的H 2O(8mL)溶液。然后向混合物中加入KH 2PO 4(4.38g，32.201mmol)的H 2O(8mL)溶液，并将混合物温热至室温。将混合物搅拌18小时，冷却至室温后，将混合物过滤，所得固体用MeCN重结晶，得到2-氧-1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-3-羧酸为黄色固体(1.0g，62.30％收率)。MS(ESI)m/z 245.10[M+H] +。 At 0℃, add 2-oxo-1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde (1.5g, 6.572mmol) in t-BuOH (24mL) To the mixture was added 2-methyl-2-butene (4.51 g, 64.403 mmol) and then sodium chlorite (1.72 g, 19.058 mmol) in H 2 O (8 mL). Then a solution of KH 2 PO 4 (4.38 g, 32.201 mmol) in H 2 O (8 mL) was added to the mixture, and the mixture was warmed to room temperature. The mixture was stirred for 18 hours. After cooling to room temperature, the mixture was filtered. The resulting solid was recrystallized from MeCN to obtain 2-oxo-1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole- The 3-carboxylic acid was a yellow solid (1.0 g, 62.30% yield). MS (ESI) m/z 245.10 [M+H] + .
步骤6) (S)-N-(4-(4-氨基-7-(2-羟基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Step 6) (S)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
向2-氧-1-苯基-4H,5H,6H-吡咯并[1,2-b]吡唑-3-羧酸(500mg，2.047mmol)的DCM(20mL)溶液中加入HOAT(334.36mg，2.456mmol)、DIEA(793.71mg，6.141mmol)、1-(4-氨基-5-(4-氨基苯基)吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(580.01mg，2.047mmol)、和EDCI(510.16mg，2.661mmol)。将所得混合物在40℃下搅拌3h，冷却至室温后，将反应用水(100mL)淬灭。所得混合物用乙酸乙酯(3×100mL)萃取。合并有机层，经无水硫酸钠干燥，过滤，浓缩。所得残余物经手性HPLC在以下条件下纯化(柱：CHIRAL ART Cellulose-SB，3*25cm，5μm；流动相A：己烷：DCM＝1：1(0.5％2M NH 3-MeOH)--HPLC，流动相B：MeOH—HPLC；流速：50mL/min；梯度：20分钟内从85B至85B；220/254nm；RT：19；进样量： 1mL；运行次数：15)，得到(S)-N-(4-(4-氨基-7-(2-羟基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺为白色固体(106.1mg，10.15％收率)。LCMS(ES,m/z)510.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ:10.25(s,1H),8.13(s,1H),7.72(d,J＝4.2Hz,2H),7.52–7.58(m,4H),7.40–7.43(m,3H),7.27(s,1H),6.06(br,2H),4.95(d,J＝2.4Hz,1H),4.00-4.13(m,3H),3.80(t,J＝6.8Hz,2H),3.17(t,J＝7.2Hz,2H),2.41-2.50(m,2H),1.03(d,J＝2.8Hz,3H)。 To 2-oxy-1-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (500mg, 2.047mmol) in DCM (20mL) was added HOAT (334.36mg) , 2.456mmol), DIEA (793.71mg, 6.141mmol), 1-(4-amino-5-(4-aminophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (580.01 mg, 2.047 mmol), and EDCI (510.16 mg, 2.661 mmol). The resulting mixture was stirred at 40°C for 3 h, and after cooling to room temperature, the reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SB, 3*25cm, 5μm; mobile phase A: hexane: DCM=1:1 (0.5% 2M NH 3 -MeOH)-HPLC , Mobile phase B: MeOH-HPLC; Flow rate: 50mL/min; Gradient: from 85B to 85B in 20 minutes; 220/254nm; RT: 19; Injection volume: 1mL; Number of runs: 15) to obtain (S)- N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl- 2,4,5,6-Tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide was a white solid (106.1 mg, 10.5% yield). LCMS (ES, m/z) 510.2 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:10.25(s,1H),8.13(s,1H),7.72(d,J=4.2Hz,2H),7.52-7.58(m,4H),7.40- 7.43(m,3H), 7.27(s,1H), 6.06(br,2H), 4.95(d,J=2.4Hz,1H), 4.00-4.13(m,3H), 3.80(t,J=6.8Hz , 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.41-2.50 (m, 2H), 1.03 (d, J = 2.8 Hz, 3H).
实施例21 (R)-N-(4-(4-氨基-7-(2-羟基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 21 (R)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000054
Figure PCTCN2021094020-appb-000054
由实施例20所述方法分离得到实施例21为白色固体(106.0mg，10.15％收率)。LCMS(ES,m/z)510.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ:10.25(s,1H),8.13(s,1H),7.72(d,J＝4.2Hz,2H),7.52–7.58(m,4H),7.40–7.43(m,3H),7.27(s,1H),6.06(br,2H),4.95(d,J＝2.4Hz,1H),4.00-4.13(m,3H),3.80(t,J＝6.8Hz,2H),3.17(t,J＝7.2Hz,2H),2.41-2.50(m,2H),1.03(d,J＝2.8Hz,3H)。 Example 21 was isolated by the method described in Example 20 as a white solid (106.0 mg, 10.5% yield). LCMS (ES, m/z) 510.2 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ:10.25(s,1H),8.13(s,1H),7.72(d,J=4.2Hz,2H),7.52-7.58(m,4H),7.40- 7.43(m,3H), 7.27(s,1H), 6.06(br,2H), 4.95(d,J=2.4Hz,1H), 4.00-4.13(m,3H), 3.80(t,J=6.8Hz , 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.41-2.50 (m, 2H), 1.03 (d, J = 2.8 Hz, 3H).
实施例22 N-(4-(4-氨基-7-(2-羟基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 22 N-(4-(4-Amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000055
Figure PCTCN2021094020-appb-000055
将EDCI(380.0mg，1.94mmol)和HOAT(33.0mg，0.238mmol)加至2-氧-1-苯基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-羧酸(308.0mg，1.261mmol)和1-(4-氨基-5-(4-氨基苯基)吡咯并[2,3-d]嘧啶-7-基)丙烷-2-醇(300.0mg，1.059mmol)的DCM(15mL)混合物中，将混合物回流过夜。TLC显示起始原料耗尽，将H 2O(20mL)加入混合物中，然后用DCM(100mL x 2)萃取。合并有机相，真空浓缩，得到黄色固体。所得固体经快速柱色谱法(DCM:MeOH＝1:0-20:1)纯化，得到标题化合物为黄色固体(79.6mg，13.7％收率)。HRMS(ESI+)510.2246[M+H] +。 1H NMR(400MHz,CDCl 3)δ10.28(s,1H),8.31(s,1H),7.79(d,J＝8.4Hz,2H),7.55(t,J＝7.8Hz,2H),7.42(dd,J＝18.0,9.3Hz,5H),7.02(s,1H),5.81(s,2H),4.35–4.29(m,1H),4.29–4.21(m,1H),4.20–4.13(m,1H),3.75(t,J＝6.9Hz,2H),3.35(t,J＝7.4Hz,2H),3.22(s,1H),2.61–2.50(m,2H),1.28(d,J＝6.1Hz,3H)。 Add EDCI (380.0mg, 1.94mmol) and HOAT (33.0mg, 0.238mmol) to 2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole- 3-carboxylic acid (308.0mg, 1.261mmol) and 1-(4-amino-5-(4-aminophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-ol (300.0 mg, 1.059 mmol) in a mixture of DCM (15 mL), the mixture was refluxed overnight. TLC showed that the starting material was consumed, H 2 O (20 mL) was added to the mixture, and then extracted with DCM (100 mL x 2). The organic phases were combined and concentrated in vacuo to obtain a yellow solid. The obtained solid was purified by flash column chromatography (DCM:MeOH=1:0-20:1) to obtain the title compound as a yellow solid (79.6 mg, 13.7% yield). HRMS(ESI+)510.2246[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 10.28 (s, 1H), 8.31 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.42 (dd,J=18.0,9.3Hz,5H),7.02(s,1H),5.81(s,2H), 4.35–4.29(m,1H), 4.29–4.21(m,1H), 4.20–4.13(m ,1H),3.75(t,J=6.9Hz,2H),3.35(t,J=7.4Hz,2H),3.22(s,1H),2.61-2.50(m,2H),1.28(d,J= 6.1Hz, 3H).
实施例23 N-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 23 N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000056
Figure PCTCN2021094020-appb-000056
将EDCI(116mg，0.593mmol)和HOAT(11mg，0.0792mmol)加至2-(4-氨基-5-(4-氨基苯基)吡咯并[2,3-d]嘧啶-7-基)乙醇(105mg，0.3899mmol)和2-氧-1-苯基-5,6-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸(112 mg，0.4304mmol)的DCM(6mL)混合物中，将混合物回流过夜。TLC显示起始原料耗尽，将H 2O(20mL)加入混合物中，然后用DCM(50mL x 2)萃取。合并有机相，真空浓缩，得到黄色固体。所得固体经快速柱色谱法(DCM:MeOH＝100:1-10:1)纯化，得到标题化合物为黄色固体(33.1mg，94.6质量％，0.0612mmol，15.7％收率)。MS(ESI,pos.ion)m/z:512.3([M+H] +)。HRMS(ESI+)512.2037[M+H] +。 1H NMR(400MHz,CDCl 3)δ10.28(s,1H),8.16(s,1H),7.61(d,J＝8.3Hz,2H),7.46(t,J＝7.5Hz,2H),7.38(t,J＝7.4Hz,1H),7.30(dd,J＝7.6,5.4Hz,4H),7.27(s,1H),6.93(d,J＝3.2Hz,1H),5.16(s,2H),4.85(s,1H),4.26–4.19(m,2H),4.09–4.02(m,2H),3.87(M,2H),3.60–3.53(m,2H)。 Add EDCI (116mg, 0.593mmol) and HOAT (11mg, 0.0792mmol) to 2-(4-amino-5-(4-aminophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (105mg, 0.3899mmol) and 2-oxo-1-phenyl-5,6-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid (112 mg , 0.4304 mmol) in a mixture of DCM (6 mL), the mixture was refluxed overnight. TLC showed that the starting material was consumed, H 2 O (20 mL) was added to the mixture, and then extracted with DCM (50 mL x 2). The organic phases were combined and concentrated in vacuo to obtain a yellow solid. The obtained solid was purified by flash column chromatography (DCM:MeOH=100:1-10:1) to obtain the title compound as a yellow solid (33.1 mg, 94.6% by mass, 0.0612 mmol, 15.7% yield). MS (ESI, pos.ion) m/z: 512.3 ([M+H] + ). HRMS(ESI+)512.2037[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 10.28 (s, 1H), 8.16 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (t,J=7.4Hz,1H), 7.30(dd,J=7.6,5.4Hz,4H), 7.27(s,1H), 6.93(d,J=3.2Hz,1H), 5.16(s,2H) , 4.85(s,1H), 4.26–4.19(m,2H), 4.09–4.02(m,2H), 3.87(M,2H), 3.60–3.53(m,2H).
实施例24 N-(4-(4-氨基-7-(2-羟基-2-甲基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 24 N-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2 -Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000057
Figure PCTCN2021094020-appb-000057
步骤1) 1-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇Step 1) 1-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(3.0g，11mmol)的DMF(10mL)溶液中加入60％油分散氢化钠(560mg，14.0012mmol)，然后将混合物搅拌30分钟。将2,2-二甲基环氧乙烷(5.0mL，56mmol)滴加至混合物中，再搅拌过夜。将反应混合物用水(10ml)淬灭，用EtOAc(100mL×3)萃取，合并有机相，用H2O(30mL)洗，浓缩，所得残余物经硅胶柱色谱法纯化(PE:EtOAC＝5:1-0:1)，得到白色固体(2.6g,69％收率)。MS(ESI,pos.ion)m/z:352.0[M+H]+。At 0°C, to 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0g, 11mmol) in DMF (10mL) was added 60% oil-dispersed sodium hydride (560mg, 14.0012) mmol), and then the mixture was stirred for 30 minutes. 2,2-Dimethyloxirane (5.0 mL, 56 mmol) was added dropwise to the mixture, and stirred overnight. The reaction mixture was quenched with water (10ml), extracted with EtOAc (100mL×3), the organic phases were combined, washed with H2O (30mL), concentrated, and the resulting residue was purified by silica gel column chromatography (PE:EtOAC=5:1- 0:1) to obtain a white solid (2.6 g, 69% yield). MS (ESI, pos.ion) m/z: 352.0 [M+H]+.
步骤2) (4-(4-氯-7-(2-羟基-2-甲基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯Step 2) (4-(4-Chloro-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)tert-butyl carbamate ester
向1-(4-氯-5-碘-吡咯并[2,3-d]嘧啶-7-基)-2-甲基-丙烷-2-醇(2.57g，7.31mmol)的二氧六环(50mL)和H 2O(10ml)溶液中加入N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯(2.8g，8.8mmol)、Pd(PPh 3) 4(852.0mg，0.734mmol)、和碳酸铯(6.0g，18mmol)。将反应混合物回流过夜。反应混合物用水(200mL)淬灭，并用EtOAc(250mL×3)萃取，合并的有机层用盐水(100mL×2)洗，经无水Na2SO4干燥，过滤，真空浓缩，残余物经硅胶柱色谱法纯化(PE:EtOAc＝1:1-0:1)，得到标题化合物，为黄色固体(2.8g，92％收率)。MS(ESI,pos.ion)m/z:417.15[M+H]+。 To the dioxane of 1-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propan-2-ol (2.57g, 7.31mmol) Add N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) to the solution of (50mL) and H 2 O (10ml) Phenyl) tert-butyl carbamate (2.8 g, 8.8 mmol), Pd(PPh 3 ) 4 (852.0 mg, 0.734 mmol), and cesium carbonate (6.0 g, 18 mmol). The reaction mixture was refluxed overnight. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (250 mL×3). The combined organic layer was washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=1:1-0:1) to obtain the title compound as a yellow solid (2.8g, 92% yield). MS (ESI, pos.ion) m/z: 417.15 [M+H]+.
步骤3) 1-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)-2-甲基丙烷-2-醇Step 3) 1-(4-Amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-2-ol
在压力容器中，向1-(5-(4-氨基苯基)-4-氯-吡咯并[2,3-d]嘧啶-7-基)-2-甲基-丙烷-2-醇(2.8g，8.8mmol)的二氧六环(10mL)溶液中加入NH 3(80mL，25％的水溶液)，将反应混合物在130℃下搅拌24小时。将反应混合物真空浓缩，残余物经硅胶柱色谱法纯化(PE:EtOAc＝1:1)，得到标题化合物为白色固体(1.56g，59％收率)。MS(ESI,pos.ion)m/z:297.5[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ8.09(s,1H),7.11(d,J＝8.3Hz,2H),7.10(s,1H),6.66(d,J＝8.3Hz,2H),6.00(s,2H),5.19(s,2H),4.81(s,1H),4.08(s,2H),1.07(s,6H)。 In a pressure vessel, add 1-(5-(4-aminophenyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propan-2-ol ( NH 3 (80 mL, 25% aqueous solution) was added to a solution of 2.8 g, 8.8 mmol) in dioxane (10 mL), and the reaction mixture was stirred at 130° C. for 24 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE:EtOAc=1:1) to obtain the title compound as a white solid (1.56 g, 59% yield). MS (ESI, pos.ion) m/z: 297.5 [M+H] + . 1 H NMR(600MHz,DMSO-d 6 )δ8.09(s,1H), 7.11(d,J=8.3Hz,2H), 7.10(s,1H), 6.66(d,J=8.3Hz,2H) , 6.00 (s, 2H), 5.19 (s, 2H), 4.81 (s, 1H), 4.08 (s, 2H), 1.07 (s, 6H).
步骤4) N-(4-(4-氨基-7-(2-羟基-2-甲基丙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Step 4) N-(4-(4-amino-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2 -Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
向2-氧-1-苯基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-羧酸(305mg，1.181mmol)的DCM(20ml)溶液中加入1-(4-氨基-5-(4-氨基苯基)吡咯并[2,3-d]嘧啶-7-基)-2-甲基-丙烷-2-醇(350mg，1.177mmol)、EDCI(92.8mg，0.476mmol)和HOAT(33mg，0.238mmol)。将反应混合物回流过夜。反应混合物用水(50ml)淬灭，并用DCM(100mL×2)萃取，合并的有机层用H 2O(50mL×2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩，残余物经硅胶柱色谱法纯化(DCM:MeOH＝100:1-10:1)，得到标题化合物为黄色固体(231.0mg，34.6％收率)。MS(ESI,pos.ion)m/z:538.25[M+H] +。HRMS(ESI)538.2569[M+H] +。 1H NMR(600MHz,CDCl 3)δ10.66(s,1H),8.25(s,1H),7.74(d,J＝8.3Hz,2H),7.53(t,J＝7.7Hz,2H),7.45(t,J＝7.4Hz,1H),7.40(d,J＝8.3Hz,2H),7.36(d,J＝7.8Hz,2H),6.94(s,1H),5.25(s,2H),4.72(s,1H),4.19(s,2H),3.56(t,J＝5.9Hz,2H),3.40(t,J＝6.4Hz,2H),2.07(dt,J＝11.5,5.7Hz,2H),1.94–1.89(m,2H),1.24(s,6H)。 13C NMR (151MHz,DMSO-d 6)δ168.58,160.46,158.39,155.73,155.12,146.71,145.34,137.37,133.12,129.71,128.16,122.81,121.68,118.43,116.80,50.00,49.59,45.97,41.15,36.53,21.56。 To a solution of 2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (305mg, 1.181mmol) in DCM (20ml) was added 1-(4-Amino-5-(4-aminophenyl)pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propane-2-ol (350mg, 1.177mmol), EDCI (92.8 mg, 0.476 mmol) and HOAT (33 mg, 0.238 mmol). The reaction mixture was refluxed overnight. The reaction mixture was quenched with water (50 ml) and extracted with DCM (100 mL×2). The combined organic layer was washed with H 2 O (50 mL×2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. Purified by silica gel column chromatography (DCM:MeOH=100:1-10:1) to obtain the title compound as a yellow solid (231.0 mg, 34.6% yield). MS (ESI, pos.ion) m/z: 538.25 [M+H] + . HRMS (ESI) 538.2569 [M+H] + . 1 H NMR (600MHz, CDCl 3 ) δ 10.66 (s, 1H), 8.25 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.53 (t, J = 7.7 Hz, 2H), 7.45 (t,J=7.4Hz,1H),7.40(d,J=8.3Hz,2H),7.36(d,J=7.8Hz,2H),6.94(s,1H),5.25(s,2H),4.72 (s, 1H), 4.19 (s, 2H), 3.56 (t, J = 5.9 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 2.07 (dt, J = 11.5, 5.7 Hz, 2H) ,1.94-1.89(m,2H),1.24(s,6H). 13 C NMR (151MHz, DMSO-d 6 ) δ168.58,160.46,158.39,155.73,155.12,146.71,145.34,137.37,133.12,129.71,128.16,122.81,121.68,118.43,116.80,50.00,49.59,45.97,41.15,36.53 ,21.56.
实施例25 N-(4-(4-氨基-7-(2-(羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6,7,8-六氢-1H-吡唑并[1,5-a]氮杂环庚烷-3-甲酰胺Example 25 N-(4-(4-amino-7-(2-(hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1 -Phenyl-2,4,5,6,7,8-hexahydro-1H-pyrazolo[1,5-a]azacycloheptane-3-carboxamide
Figure PCTCN2021094020-appb-000058
Figure PCTCN2021094020-appb-000058
步骤1) 8-羟基-3-氧代辛酸乙酯Step 1) Ethyl 8-hydroxy-3-oxooctanoate
在-78℃条件下，向含有LDA(33.0ml，65.70mmol，2mol/L)的四氢呋喃(300ml)溶液中加入乙酸乙酯(3.86g，43.80mmol)。将反应液保持低温搅拌1小时后加入氧杂环庚烷-2-酮(5.00g，43.80mmol)，继续搅拌3小时，用水(50ml)淬灭后，用乙酸乙酯(200mL x 3)萃取。合并有机相，并用盐水(100mL x2)洗，无水硫酸钠干燥，过滤并减压浓缩。所得残余物经硅胶柱层析纯化(EtOAc/PE(v/v)＝1/5)，得到标题化合物为黄色液体(4.00g，45.1％收率)。 1H NMR(400MHz,DMSO-d 6)δ(ppm):4.34(t,J＝5.1Hz,1H),4.09(q,J＝7.1Hz,2H),3.56(s,2H),3.40-3.35(m,2H),2.51(t,J＝7.2Hz,2H),1.52-1.36(m,4H),1.25-1.20(m,2H),1.19(t,J＝7.1Hz,3H)。 At -78°C, ethyl acetate (3.86g, 43.80mmol) was added to a tetrahydrofuran (300ml) solution containing LDA (33.0ml, 65.70mmol, 2mol/L). The reaction solution was kept at low temperature and stirred for 1 hour, and then oxepane-2-one (5.00g, 43.80mmol) was added. The stirring was continued for 3 hours. After quenching with water (50ml), it was extracted with ethyl acetate (200mL x 3). . The organic phases were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/PE(v/v)=1/5) to obtain the title compound as a yellow liquid (4.00 g, 45.1% yield). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 4.34 (t, J = 5.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 3.40-3.35 (m, 2H), 2.51 (t, J=7.2 Hz, 2H), 1.52-1.36 (m, 4H), 1.25-1.20 (m, 2H), 1.19 (t, J=7.1 Hz, 3H).
步骤2) 8-碘-3-氧代辛酸乙酯Step 2) Ethyl 8-iodo-3-oxooctanoate
向含有8-羟基-3-氧代辛酸乙酯(4.00g，19.80mmol)的二氯甲烷(100mL)溶液中加入1H-咪唑(4.03g，59.30mmol)、和三苯基膦(10.40g，39.60mmol)。将反应液降温至0℃，加入碘(10.00g，39.60mmol)，之后在室温下继续搅拌4小时，用饱和亚硫酸钠溶液(100ml)淬灭，用二氯甲烷(200mL x 3)萃取。合并有机相，用盐水(100mL x 2)洗，经无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(EtOAC/PE(v/v)＝1/20)，得到标题化合物为黄色液体(5.40g，87.5％收率)。MS(ESI,pos.ion)m/z:313.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):4.09(q,J＝7.1Hz,2H),3.57(s,2H),3.26(t,J＝6.9Hz,2H),2.53(dd,J＝12.7,5.4Hz,2H),1.74(dd,J＝14.5,7.1Hz,2H),1.53-1.44(m,2H),1.36-1.28(m,2H),1.19(t,J＝7.1Hz,3H)。 To a dichloromethane (100mL) solution containing ethyl 8-hydroxy-3-oxooctanoate (4.00g, 19.80mmol) was added 1H-imidazole (4.03g, 59.30mmol), and triphenylphosphine (10.40g, 39.60mmol). The reaction solution was cooled to 0°C, iodine (10.00 g, 39.60 mmol) was added, and then stirring was continued at room temperature for 4 hours, quenched with saturated sodium sulfite solution (100 ml), and extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAC/PE(v/v)=1/20) to obtain the title compound as a yellow liquid (5.40 g, 87.5% yield). MS (ESI, pos.ion) m/z: 313.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 4.09 (q, J = 7.1Hz, 2H), 3.57 (s, 2H), 3.26 (t, J = 6.9Hz, 2H), 2.53 (dd ,J=12.7,5.4Hz,2H),1.74(dd,J=14.5,7.1Hz,2H),1.53-1.44(m,2H),1.36-1.28(m,2H),1.19(t,J=7.1 Hz, 3H).
步骤3) 1-苯基-5,6,7,8-四氢-1H-吡唑并[1,5-a]氮杂环庚烷-2(4H)-酮Step 3) 1-Phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[1,5-a]azacycloheptane-2(4H)-one
向含有8-碘-3-氧代辛酸乙酯(5.20g，16.65mmol)的1,4-二氧六环(100ml)溶液中加入苯肼(1.98g，18.32mmol)、冰醋酸(3.00g，49.97mmol)和醋酸钠(4.10g，49.97mmol)。将反应液加热至回流，搅拌24小时，减压浓缩，所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到标题化合物为黄色液体(1.20g，31.6％收率)。MS(ESI,pos.ion)m/z:229.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):7.48(t,J＝7.8Hz,2H),7.32-7.27(m,3H),5.24(s,1H),2.74(s,2H),1.91(s,2H),1.68(s,4H),1.58(s,2H)。 To a 1,4-dioxane (100ml) solution containing ethyl 8-iodo-3-oxooctanoate (5.20g, 16.65mmol) was added phenylhydrazine (1.98g, 18.32mmol), glacial acetic acid (3.00g) , 49.97 mmol) and sodium acetate (4.10 g, 49.97 mmol). The reaction solution was heated to reflux, stirred for 24 hours, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to obtain the title compound as a yellow liquid (1.20g, 31.6 % Yield). MS (ESI, pos.ion) m/z: 229.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.48 (t, J = 7.8Hz, 2H), 7.32-7.27 (m, 3H), 5.24 (s, 1H), 2.74 (s, 2H) ,1.91(s,2H),1.68(s,4H),1.58(s,2H).
步骤4) 2-氧代-1-苯基-2,4,5,6,7,8-六氢-1H-吡唑并[1,5-a]氮杂环庚烷-3-甲醛Step 4) 2-oxo-1-phenyl-2,4,5,6,7,8-hexahydro-1H-pyrazolo[1,5-a]azacycloheptane-3-carbaldehyde
向含有1-苯基-5,6,7,8-四氢-1H-吡唑并[1,5-a]氮杂环庚烷-2(4H)-酮(1.00g，4.38mmol)的氯仿(50mL)溶液中加入(氯亚甲基)-二甲基氯化铵(3.36g，26.30mmol)。将反应液加热至回流搅拌6小时，用水(20ml)淬灭，用饱和碳酸氢钠溶液调节至pH＝7，之后用二氯甲烷(200mL x 3)萃取。合并有机相，用盐水(100mL x 2)洗，经无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到标题化合物为黄色液体(1.12g，100.0％收率)。MS(ESI,pos.ion)m/z:257.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):9.65(s,1H),7.56(t,J＝7.7Hz,2H),7.46(t,J＝7.4Hz,1H),7.33(d,J＝7.5Hz,2H),3.81-3.75(m,2H),3.32-3.25(m,2H),1.77-1.63(m,6H)。 To those containing 1-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[1,5-a]azepane-2(4H)-one (1.00g, 4.38mmol) To the chloroform (50 mL) solution was added (chloromethylene)-dimethylammonium chloride (3.36 g, 26.30 mmol). The reaction solution was heated to reflux and stirred for 6 hours, quenched with water (20 ml), adjusted to pH=7 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to obtain the title compound as a yellow liquid (1.12 g, 100.0% yield). MS (ESI, pos.ion) m/z: 257.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 9.65 (s, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.33 (d , J=7.5Hz, 2H), 3.81-3.75 (m, 2H), 3.32-3.25 (m, 2H), 1.77-1.63 (m, 6H).
步骤5) 2-氧代-1-苯基-2,4,5,6,7,8-六氢-1H-吡唑并[1,5-a]氮杂环庚烷-3-甲酸Step 5) 2-oxo-1-phenyl-2,4,5,6,7,8-hexahydro-1H-pyrazolo[1,5-a]azacycloheptane-3-carboxylic acid
向含有2-氧代-1-苯基-2,4,5,6,7,8-六氢-1H-吡唑并[1,5-a]氮杂环庚烷-3-甲醛(1.50g，5.85mmol)的二氯甲烷(30mL)溶液中加入二甲基亚砜(3.42g，43.90mmol)、磷酸(0.43g，3.51mmol，80％的水溶液)和水(3mL)。将反应液室温搅拌30分钟之后加入次氯酸钠(1.32g，11.70mmol，80％)和水(10ml)，继续室 温搅拌3小时，用二氯甲烷(10mL x 3)洗，并用饱和碳酸氢钠溶液调节至pH＝7。水相用浓盐酸(12M)调节至pH＝1，析出固体，过滤，收集滤饼，得到标题化合物为白色固体(0.40g，25.0％收率)。MS(ESI,pos.ion)m/z:273.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):12.30(s,1H),7.60(t,J＝7.5Hz,2H),7.52(t,J＝7.4Hz,1H),7.41(d,J＝7.4Hz,2H),3.84-3.76(m,2H),3.30(d,J＝4.3Hz,2H),1.81-1.68(m,4H),1.64(d,J＝4.3Hz,2H)。 To contain 2-oxo-1-phenyl-2,4,5,6,7,8-hexahydro-1H-pyrazolo[1,5-a]azacycloheptane-3-carbaldehyde (1.50 g, 5.85 mmol) in dichloromethane (30 mL) was added dimethyl sulfoxide (3.42 g, 43.90 mmol), phosphoric acid (0.43 g, 3.51 mmol, 80% aqueous solution) and water (3 mL). After stirring the reaction solution at room temperature for 30 minutes, add sodium hypochlorite (1.32g, 11.70mmol, 80%) and water (10ml), continue stirring at room temperature for 3 hours, wash with dichloromethane (10mL x 3), and adjust with saturated sodium bicarbonate solution To pH=7. The aqueous phase was adjusted to pH=1 with concentrated hydrochloric acid (12M), a solid was precipitated, filtered, and the filter cake was collected to obtain the title compound as a white solid (0.40 g, 25.0% yield). MS (ESI, pos.ion) m/z: 273.2 [M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ(ppm): 12.30(s,1H), 7.60(t,J=7.5Hz,2H), 7.52(t,J=7.4Hz,1H), 7.41(d ,J=7.4Hz,2H),3.84-3.76(m,2H),3.30(d,J=4.3Hz,2H),1.81-1.68(m,4H),1.64(d,J=4.3Hz,2H) .
步骤6) N-(4-(4-氨基-7-(2-(羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧代-1-苯基-2,4,5,6,7,8-六氢-1H-吡唑并[1,5-c]氮杂环庚烷-3-甲酰胺Step 6) N-(4-(4-amino-7-(2-(hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo- 1-Phenyl-2,4,5,6,7,8-hexahydro-1H-pyrazolo[1,5-c]azepane-3-carboxamide
向含有2-氧代-1-苯基-2,4,5,6,7,8-六氢-1H-吡唑并[1,5-a]氮杂环庚烷-3-甲酸(0.16g，0.59mmol)的二氯甲烷(30ml)溶液中加入2-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙醇(0.16g，0.59mmol)、EDCI(0.23g，1.18mmol)和HOAT(0.16g，1.18mmol)。将反应液加热至回流搅拌过夜，用水(50ml)淬灭后，用二氯甲烷(200mL x 3)萃取。合并有机相，用饱和碳酸氢钠溶液(50mL)和盐水(100mL x 2)洗，无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到标题化合物为黄色固体(0.080g，26.0％收率)。MS(ESI,pos.ion)m/z:524.2[M+H] +；HRMS(ESI +)524.2390[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.86(s,1H),8.14(s,1H),7.70(d,J＝8.5Hz,2H),7.60(t,J＝7.6Hz,2H),7.50(t,J＝7.4Hz,1H),7.41(dd,J＝7.8,3.3Hz,5H),7.30(s,1H),6.07(s,2H),4.22(t,J＝5.6Hz,2H),3.81(d,J＝8.3Hz,2H),3.79-3.73(m,2H),3.49(s,2H),1.76(s,4H),1.64(s,2H)。 13C NMR(151MHz,DMSO-d 6)δ(ppm):164.03,161.53,160.89,157.69,151.87,150.73,137.86,133.77,130.02,129.95,129.33,128.95,126.90,124.30,120.04,114.96,100.43,97.31,60.42,49.11,49.06,46.96,29.74,26.34,25.07,24.97。 To contain 2-oxo-1-phenyl-2,4,5,6,7,8-hexahydro-1H-pyrazolo[1,5-a]azepane-3-carboxylic acid (0.16 g, 0.59mmol) in dichloromethane (30ml), add 2-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (0.16g, 0.59mmol), EDCI (0.23g, 1.18mmol) and HOAT (0.16g, 1.18mmol). The reaction solution was heated to reflux and stirred overnight, and after quenching with water (50 ml), it was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to obtain the title compound as a yellow solid (0.080 g, 26.0% yield). MS (ESI, pos.ion) m/z: 524.2 [M+H] + ; HRMS (ESI + ) 524.2390 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 10.86(s,1H), 8.14(s,1H), 7.70(d,J=8.5Hz,2H), 7.60(t,J=7.6Hz , 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.41 (dd, J = 7.8, 3.3 Hz, 5H), 7.30 (s, 1H), 6.07 (s, 2H), 4.22 (t, J = 5.6 Hz, 2H), 3.81 (d, J = 8.3 Hz, 2H), 3.79-3.73 (m, 2H), 3.49 (s, 2H), 1.76 (s, 4H), 1.64 (s, 2H). 13 C NMR (151MHz, DMSO-d 6 ) δ (ppm): 164.03, 161.53, 160.89, 157.69, 151.87, 150.73, 137.86, 133.77, 130.02, 129.95, 129.33, 128.95, 126.90, 124.30, 120.04, 114.96, 100.43, 97.31, 60.42, 49.11, 49.06, 46.96, 29.74, 26.34, 25.07, 24.97.
实施例26 N-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2.3-d]嘧啶-5-基)苯基-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 26 N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2.3-d]pyrimidin-5-yl)phenyl-2-oxo-1-phenyl- 1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000059
Figure PCTCN2021094020-appb-000059
步骤1) 2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙醇Step 1) 2-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethanol
向含有4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(5.00g，17.89mmol)的DMF(50mL)溶液中加入2-溴乙醇(4.47g，35.78mmol)和氢氧化钾(3.00g，53.67mmol)。将反应液加热至70℃搅拌10小时，用水(200ml)淬灭，过滤，收集滤饼，得到标题化合物为黄色固体(3.0g，52.0％收率)。MS(ESI,pos.ion)m/z:324.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):8.63(s,1H),7.97(s,1H),4.93(t,J＝5.4Hz,1H),4.31(t,J＝5.4Hz,2H),3.75(q,J＝5.4Hz,2H)。 To a DMF (50 mL) solution containing 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.00 g, 17.89 mmol) was added 2-bromoethanol (4.47 g, 35.78 mmol) and hydrogen Potassium oxide (3.00 g, 53.67 mmol). The reaction solution was heated to 70° C. and stirred for 10 hours, quenched with water (200 ml), filtered, and the filter cake was collected to obtain the title compound as a yellow solid (3.0 g, 52.0% yield). MS (ESI, pos.ion) m/z: 324.0 [M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 8.63(s,1H),7.97(s,1H), 4.93(t,J=5.4Hz,1H),4.31(t,J=5.4Hz , 2H), 3.75 (q, J=5.4 Hz, 2H).
步骤2) (4-(4-氯-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁基酯Step 2) (4-(4-chloro-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
向含有2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙醇(2.80g，8.65mmol)的1,4-二氧六环(50mL)和水(10ml)的混合液中加入(4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)氨基甲酸叔丁基酯(2.76g，8.65mmol)、四(三苯基膦)钯(0)(1.00g，0.86mmol)和碳酸钠(2.75g，25.96mmol)。将反应液加热至回流搅拌6小时，用水(100ml)淬灭后，用乙酸乙酯(200mL x 3)萃取。合并有机相，用盐水(100mL x 2)洗，经无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到标题化合物为黄色固体(0.80g，24.0％收率)。MS(ESI,pos.ion)m/z:389.2[M+H] +。 To the 1,4-dioxane (50mL) containing 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (2.80g, 8.65mmol) Add (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) t-butyl carbamate to the mixture with water (10ml) Base ester (2.76 g, 8.65 mmol), tetrakis(triphenylphosphine)palladium(0) (1.00 g, 0.86 mmol) and sodium carbonate (2.75 g, 25.96 mmol). The reaction solution was heated to reflux and stirred for 6 hours, quenched with water (100 ml), and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to obtain the title compound as a yellow solid (0.80 g, 24.0% yield). MS (ESI, pos.ion) m/z: 389.2 [M+H] + .
步骤3) 2-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙醇Step 3) 2-(4-Amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethanol
在高压釜中，向含有(4-(4-氯-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁基酯(0.80g，2.06mmol)的1,4-二氧六环(5ml)溶液中加入氨水(25ml，25％的水溶液)。将反应液加热至130℃搅拌24h，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/20)，得到标题化合物为白色固体(0.25g，45.0％收率)。MS(ESI,pos.ion)m/z:270.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):8.10(s, 1H),7.14-7.09(m,3H),6.66(d,J＝8.3Hz,2H),5.99(s,2H),5.18(s,3H),4.19(t,J＝5.8Hz,2H),3.73(t,J＝5.8Hz,2H)。 In the autoclave, add tert-butyl containing (4-(4-chloro-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)carbamate Aqueous ammonia (25ml, 25% aqueous solution) was added to the 1,4-dioxane (5ml) solution of the ester (0.80g, 2.06mmol). The reaction solution was heated to 130°C, stirred for 24h, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/20) to obtain the title compound as a white solid (0.25 g, 45.0% yield). MS (ESI, pos.ion) m/z: 270.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.10 (s, 1H), 7.14-7.09 (m, 3H), 6.66 (d, J = 8.3 Hz, 2H), 5.99 (s, 2H) , 5.18 (s, 3H), 4.19 (t, J = 5.8 Hz, 2H), 3.73 (t, J = 5.8 Hz, 2H).
步骤4) N-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2.3-d]嘧啶-5-基)苯基-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Step 4) N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2.3-d]pyrimidin-5-yl)phenyl-2-oxo-1-phenyl -1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
向含有2-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙醇(0.12g，0.45mmol)的二氯甲烷(50ml)溶液中加入2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸(0.12g，0.45mmol)、EDCI(0.17g，0.89mmol)和HOAT(0.12g，0.89mmol)。将反应液加热至回流搅拌过夜，用水(50ml)淬灭后，用二氯甲烷(200mL x 3)萃取。合并有机相，用饱和碳酸氢钠溶液(50mL)和盐水(100mL x 2)洗，经无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到标题化合物为白色固体(100.0mg，45.1％收率)。MS(ESI,pos.ion)m/z:510.2[M+H] +。HRMS(ESI +)510.2248[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.67(s,1H),8.13(s,1H),7.70(d,J＝7.4Hz,2H),7.58(d,J＝6.7Hz,2H),7.51(d,J＝6.6Hz,1H),7.43(dd,J＝24.5,7.2Hz,4H),7.30(s,1H),6.07(s,2H),4.98(s,1H),4.22(s,2H),3.75(s,2H),3.56(s,2H),3.22(s,2H),1.98(s,2H),1.82(s,2H)。 13C NMR(151MHz,DMSO-d 6)δ(ppm):163.21,161.57,157.69,154.05,151.87,150.71,137.99,133.15,129.89,129.85,129.35,129.30,127.72,124.28,119.86,114.99,100.45,96.72,60.43,46.96,46.90,23.90,22.30,19.08。 To the dichloromethane (50ml) containing 2-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (0.12g, 0.45mmol) ) Add 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (0.12g, 0.45mmol) to the solution , EDCI (0.17g, 0.89mmol) and HOAT (0.12g, 0.89mmol). The reaction solution was heated to reflux and stirred overnight, and after quenching with water (50 ml), it was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to obtain the title compound as a white solid (100.0 mg, 45.1% yield). MS (ESI, pos.ion) m/z: 510.2 [M+H] + . HRMS(ESI + )510.2248[M+H] + ; 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 10.67(s,1H),8.13(s,1H),7.70(d,J=7.4 Hz, 2H), 7.58 (d, J = 6.7 Hz, 2H), 7.51 (d, J = 6.6 Hz, 1H), 7.43 (dd, J = 24.5, 7.2 Hz, 4H), 7.30 (s, 1H), 6.07(s,2H),4.98(s,1H),4.22(s,2H),3.75(s,2H),3.56(s,2H),3.22(s,2H),1.98(s,2H),1.82 (s, 2H). 13 C NMR (151MHz, DMSO-d 6 ) δ (ppm): 163.21, 161.57, 157.69, 154.05, 151.87, 150.71, 137.99, 133.15, 129.89, 129.85, 129.35, 129.30, 127.72, 124.28, 119.86, 114.99, 100.45, 96.72, 60.43, 46.96, 46.90, 23.90, 22.30, 19.08.
实施例27 N-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺Example 27 N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1,5-dimethyl 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
Figure PCTCN2021094020-appb-000060
Figure PCTCN2021094020-appb-000060
向含有2-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙醇(90mg，0.33mmol)的二氯甲烷(50ml)溶液中加入1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-甲酸(77mg，0.33mmol)、EDCI(130mg，0.67mmol)和HOAT(91mg，0.67mmol)。将反应液加热至回流搅拌过夜，用水(50ml)淬灭后，用二氯甲烷(200mL x 3)萃取。合并有机相，用饱和碳酸氢钠溶液(50mL)和盐水(100mL x 2)洗，经无水硫酸钠干燥，过滤，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到标题化合物为白色固体(50.0mg，31.0％收率)。MS(ESI,pos.ion)m/z:484.2[M+H] +。HRMS(ESI +)484.2091[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.82(s,1H),8.14(s,1H),7.70(d,J＝8.2Hz,2H),7.60(t,J＝7.3Hz,2H),7.53(d,J＝7.2Hz,1H),7.43(dd,J＝13.8,8.0Hz,4H),7.30(s,1H),6.07(s,2H),4.97(s,1H),4.22(s,2H),3.75(d,J＝5.0Hz,2H),2.72(s,3H),2.51(s,3H)。 13C NMR(151MHz,DMSO-d 6)δ(ppm):163.54,161.67,157.69,154.26,151.87,150.70,137.95,133.52,129.95,129.91,129.35,127.63,124.30,119.96,114.99,100.45,97.66,60.43,46.96,33.75,11.90。 To dichloromethane (50ml) containing 2-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethanol (90mg, 0.33mmol) Add 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (77mg, 0.33mmol) and EDCI (130mg, 0.67mmol) to the solution And HOAT (91 mg, 0.67 mmol). The reaction solution was heated to reflux and stirred overnight, and after quenching with water (50 ml), it was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to obtain the title compound as a white solid (50.0 mg, 31.0% yield). MS (ESI, pos.ion) m/z: 484.2 [M+H] + . HRMS(ESI + )484.2091[M+H] + ; 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 10.82(s,1H), 8.14(s,1H), 7.70(d,J=8.2 Hz, 2H), 7.60 (t, J = 7.3 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.43 (dd, J = 13.8, 8.0 Hz, 4H), 7.30 (s, 1H), 6.07 (s, 2H), 4.97 (s, 1H), 4.22 (s, 2H), 3.75 (d, J=5.0 Hz, 2H), 2.72 (s, 3H), 2.51 (s, 3H). 13 C NMR (151MHz, DMSO-d 6 ) δ (ppm): 163.54, 161.67, 157.69, 154.26, 151.87, 150.70, 137.95, 133.52, 129.95, 129.91, 129.35, 127.63, 124.30, 119.96, 114.99, 100.45, 97.66, 60.43, 46.96, 33.75, 11.90.
实施例28 N-(4-(4-氨基-7-(2-羟基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 28 N-(4-(4-amino-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1- Phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000061
Figure PCTCN2021094020-appb-000061
将EDCI(900.0mg，4.60mmol)和HOAT(86mg，0.619mmol)加至2-(4-氨基-5-(4-氨基苯基)吡咯并[2,3-d]嘧啶-7-基)乙醇(760mg，2.822mmol)和2-氧-1-苯基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-羧酸(831mg， 3.403mmol)的DCM(15mL)混合物中，将混合物回流过夜。TLC显示起始原料耗尽，将H 2O(20mL)加入混合物中，然后用DCM(50mL x 2)萃取。合并有机相，真空浓缩，得到黄色固体。所得固体经快速柱色谱法(DCM:MeOH＝100:1-10:1)纯化，得到标题化合物为黄色固体(366.4mg，0.6702mmol，23.75％收率)。MS(ESI,pos.ion)m/z:496.3([M+H] +)。 Add EDCI (900.0mg, 4.60mmol) and HOAT (86mg, 0.619mmol) to 2-(4-amino-5-(4-aminophenyl)pyrrolo[2,3-d]pyrimidin-7-yl) Ethanol (760mg, 2.822mmol) and 2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (831mg, 3.403mmol) in DCM (15 mL) of the mixture, reflux the mixture overnight. TLC showed that the starting material was consumed, H 2 O (20 mL) was added to the mixture, and then extracted with DCM (50 mL x 2). The organic phases were combined and concentrated in vacuo to obtain a yellow solid. The obtained solid was purified by flash column chromatography (DCM:MeOH=100:1-10:1) to obtain the title compound as a yellow solid (366.4mg, 0.6702mmol, 23.75% yield). MS (ESI, pos.ion) m/z: 496.3 ([M+H] + ).
实施例29 (1S,4S)-4-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯Example 29 (1S,4S)-4-(4-amino-5-(2-fluoro-4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazole And [5,1-c][1,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate
Figure PCTCN2021094020-appb-000062
Figure PCTCN2021094020-appb-000062
步骤1) (1S,4S)-4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯Step 1) (1S,4S)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate
室温下，向(1S,4S)-4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-醇(300mg,0.79mmol)、异丁酰氯(127mg,1.20mmol)和TEA(240.73mg,2.38mmol)的DCM(30mL)溶液中加入DMAP(9.71mg,0.079mmol)，混合物在40℃下搅拌反应24h。反应混合物用水(20mL)淬灭，然后用DCM(20mL×3)萃取。合并的有机层用盐水(10mL×2)洗，经Na 2SO 4干燥，减压浓缩。所得残余物经硅胶色谱法纯化(EA/PE＝1/1)，得到(1S,4S)-4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯为白色固体(260mg，62.13％收率)。MS(ESI,pos.ion)m/z:447.6[M+H] +。 At room temperature, to (1S,4S)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-ol (300mg, 0.79mmol ), isobutyryl chloride (127 mg, 1.20 mmol) and TEA (240.73 mg, 2.38 mmol) in DCM (30 mL) were added DMAP (9.71 mg, 0.079 mmol), and the mixture was stirred at 40°C for 24h. The reaction mixture was quenched with water (20 mL), and then extracted with DCM (20 mL×3). The combined organic layer was washed with brine (10 mL×2), dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EA/PE=1/1) to obtain (1S,4S)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7 -Cyclohexyl isobutyrate is a white solid (260 mg, 62.13% yield). MS (ESI, pos.ion) m/z: 447.6 [M+H] + .
步骤2) (1S,4S)-4-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯Step 2) (1S,4S)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate
向密封管中的(1S,4S)-4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯(260mg,0.58mmol)的二氧六环(6mL)溶液中加入NH 3溶液(25％，6mL)，所得混合物于120℃下搅拌反应16h。冷却后，将混合物减压浓缩，所得残余物经硅胶色谱法纯化(DCM/MeOH＝20/1)，得到(1S,4S)-4-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯为黄色固体(160mg，57.90％收率)。MS(ESI,pos.ion)m/z:428.7[M+H]+。 To the (1S,4S)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylisobutyrate (260mg, 0.58mmol) in the sealed tube ) Was added to the dioxane (6 mL) solution of NH 3 solution (25%, 6 mL), and the resulting mixture was stirred at 120° C. for 16 h. After cooling, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain (1S,4S)-4-(4-amino-5-iodo-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate is a yellow solid (160 mg, 57.90% yield). MS (ESI, pos.ion) m/z: 428.7 [M+H]+.
步骤3) (1S,4S)-4-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯Step 3) (1S,4S)-4-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyliso Butyrate
向(1S,4S)-4-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯(160mg，0.37mmol)、3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(115.1mg，0.49mmol)和碳酸钠(118.8mg，1.12mmol)的二氧六环(16mL)和H 2O(4mL)混合物中加入1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(43.17mg，0.037mmol)，所得混合物于N 2氛下在80℃下加热10h。冷却后，将混合物减压浓缩。残余物用水(30mL)稀释，然后用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL×2)洗，经Na 2SO 4干燥，减压浓缩。所得残余物经硅胶色谱法纯化(EA/PE＝1/1)，得到(1S,4S)-4-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯为淡黄色固体(120mg，80％收率)。MS(ESI,pos.ion)m/z:411.8[M+H] +。 To (1S,4S)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylisobutyrate (160mg, 0.37mmol), 3- Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (115.1mg, 0.49mmol) and sodium carbonate (118.8mg , 1.12mmol) of dioxane (16mL) and H 2 O (4mL) was added 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride (II) dichloromethane complex Compound (43.17mg, 0.037mmol), the resulting mixture was heated at 80°C for 10h under N 2 atmosphere. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL), and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL×2), dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (EA/PE=1/1) to obtain (1S,4S)-4-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo [2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate is a pale yellow solid (120 mg, 80% yield). MS (ESI, pos.ion) m/z: 411.8 [M+H] + .
步骤4) (1S,4S)-4-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯Step 4) (1S,4S)-4-(4-amino-5-(2-fluoro-4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazole And [5,1-c][1,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate
室温下，向(1S,4S)-4-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯(100mg,0.24mmol)、2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸(75.89mg，0.29mmol)、DIEA(94.04mg，0.73mmol)和HOAt(49.61mg，0.36mmol)的DCM(20mL)混合物中加入N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐(69.87mg，0.36mmol)，然后混合物于40℃下加热16h。冷却至室温后，将混合物用DCM(30mL)稀释，然后用盐水(30mL×3)洗。分离的有机层经Na 2SO 4干燥，减压浓缩。所得残余物经制备型HPLC纯化(Gemini-C18 150 x 21.2mm，5um.ACN--H2O(0.1％FA))，得到(1S,4S)-4-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡 咯并[2,3-d]嘧啶-7-基)环己基异丁酸酯为白色固体(31.4mg，19.55％收率)。MS(ESI,pos.ion)m/z:653.6[M+H] +。 1H NMR:(400MHz,DMSO)δ10.54(s,1H),8.13(s,1H),7.86-7.80(m,1H),7.64-7.58(m,2H),7.54(dd,J＝6.9,4.7Hz,3H),7.45(s,1H),7.39-7.29(m,2H),6.05(s,2H),5.12(s,2H),4.80-4.60(m,2H),4.10(t,J＝5.0Hz,2H),3.70(t,J＝4.8Hz,2H),2.11-1.90(m,6H),1.59(dd,J＝23.3,11.3Hz,2H),1.09(d,J＝7.0Hz,6H)。 At room temperature, to (1S,4S)-4-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl Isobutyrate (100mg, 0.24mmol), 2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine -3-carboxylic acid (75.89mg, 0.29mmol), DIEA (94.04mg, 0.73mmol) and HOAt (49.61mg, 0.36mmol) in DCM (20mL) was added N-(3-dimethylaminopropyl)- N'-Ethylcarbodiimide hydrochloride (69.87mg, 0.36mmol), and then the mixture was heated at 40°C for 16h. After cooling to room temperature, the mixture was diluted with DCM (30 mL), and then washed with brine (30 mL×3). The separated organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um.ACN--H2O (0.1% FA)) to obtain (1S,4S)-4-(4-amino-5-(2-fluoro -4-(2-Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamido) Phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl isobutyrate is a white solid (31.4 mg, 19.55% yield). MS (ESI, pos.ion) m/z: 653.6 [M+H] + . 1 H NMR:(400MHz,DMSO)δ10.54(s,1H),8.13(s,1H),7.86-7.80(m,1H),7.64-7.58(m,2H),7.54(dd,J=6.9 ,4.7Hz,3H),7.45(s,1H),7.39-7.29(m,2H),6.05(s,2H),5.12(s,2H),4.80-4.60(m,2H),4.10(t, J = 5.0Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 2.11-1.90 (m, 6H), 1.59 (dd, J = 23.3, 11.3 Hz, 2H), 1.09 (d, J = 7.0 Hz, 6H).
实施例30 3-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Example 30 3-(4-Amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021094020-appb-000063
Figure PCTCN2021094020-appb-000063
步骤1) 3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 1) tert-Butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(140mg，0.5mmol)的THF(20mL)溶液中加入3-羟基氮杂环丁烷-1-甲酸叔丁酯(131mg，0.75mmol)、三苯基膦(263mg，1.0mmol)、和DIAD(203mg，1.0mmol)。反应在25℃下搅拌16h，LCMS显示得到产物。将混合物减压浓缩以除去有机物，然后用EA(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(280mg，粗品)。MS(ESI,pos.ion)m/z:434.9[M+H] +。 1H NMR:(400MHz,DMSO)δ8.65(s,1H),8.34(s,1H),5.55(t,J＝7.0Hz,1H),4.32(d,J＝7.2Hz,4H),1.42(s,9H)。 Add 3-hydroxyazetidine-1 to 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (140mg, 0.5mmol) in THF (20mL) at 0°C -Tert-butyl formate (131 mg, 0.75 mmol), triphenylphosphine (263 mg, 1.0 mmol), and DIAD (203 mg, 1.0 mmol). The reaction was stirred at 25°C for 16 h, LCMS showed that the product was obtained. The mixture was concentrated under reduced pressure to remove organics, and then extracted with EA (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 3-(4-chloro- Tert-butyl 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate was a white solid (280 mg, crude product). MS (ESI, pos.ion) m/z: 434.9 [M+H] + . 1 H NMR:(400MHz,DMSO)δ8.65(s,1H),8.34(s,1H),5.55(t,J=7.0Hz,1H), 4.32(d,J=7.2Hz,4H),1.42 (s,9H).
步骤2) 3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 2) tert-Butyl 3-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
向3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(280mg，0.65mmol)的二氧六环/H 2O(20mL/4mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(141mg，0.65mmol)、碳酸钠(103mg，0.97mmol)、和Pd(PPh 3) 4(75mg，0.065mmol)。所得混合物保持在氮气下，并于80℃下搅拌反应6h。冷却后，将混合物减压浓缩以除去有机物，加入H 2O(50mL)，用EtOAc(50mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，然后所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(100mg，40％收率)。MS(ESI,pos.ion)m/z:400.1[M+H] +。 1H NMR:(400MHz,DMSO)δ8.62(s,1H),7.97(s,1H),7.21(d,J＝8.4Hz,2H),6.62(d,J＝8.4Hz,2H),5.65–5.60(m,1H),5.18(s,2H),4.36(d,J＝6.4Hz,4H),1.42(s,9H)。 To 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (280mg, 0.65mmol) in dioxane six ring / H 2 O (20mL / 4mL ) was added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline ( 141 mg, 0.65 mmol), sodium carbonate (103 mg, 0.97 mmol), and Pd(PPh 3 ) 4 (75 mg, 0.065 mmol). The resulting mixture was kept under nitrogen and stirred at 80°C for 6h. After cooling, the mixture was concentrated under reduced pressure to remove organics, H 2 O (50 mL) was added, and extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure, and then the resulting residue was purified by column chromatography (DCM/MeOH=20/1) to give 3-(5-( 4-Aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester is a white solid (100mg, 40% yield ). MS (ESI, pos.ion) m/z: 400.1 [M+H] + . 1 H NMR:(400MHz,DMSO)δ8.62(s,1H),7.97(s,1H), 7.21(d,J=8.4Hz,2H), 6.62(d,J=8.4Hz,2H), 5.65 -5.60 (m, 1H), 5.18 (s, 2H), 4.36 (d, J = 6.4 Hz, 4H), 1.42 (s, 9H).
步骤3) 3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 3) tert-Butyl 3-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
向3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(100mg，0.25mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。将反应于密闭管中在130℃下搅拌16h。冷却后，将混合物减压浓缩以除去有机物，加入H 2O(30mL)，然后用EtOAc(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，然后所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(40mg，40％)。MS(ESI,pos.ion)m/z:381.2[M+H] +。 1H NMR:(400MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.15(d,J＝8.4Hz,2H),6.66(d,J＝8.4Hz,2H),6.24-5.96(m,2H),5.50–5.45(m,1H),5.21(s,2H),4.36-4.25(m,4H),1.42(s,9H)。 To tert-butyl 3-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (100mg, Ammonium hydroxide (10 mL) was added to a mixture of 0.25 mmol) of dioxane (10 mL). The reaction was stirred at 130°C for 16 h in a closed tube. After cooling, the mixture was concentrated under reduced pressure to remove organics, H 2 O (30 mL) was added, and then extracted with EtOAc (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure, and then the resulting residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 3-(4-amino Tert-butyl-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate was a white solid (40 mg, 40%). MS (ESI, pos.ion) m/z: 381.2 [M+H] + . 1 H NMR: (400MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.15(d,J=8.4Hz,2H),6.66(d,J=8.4Hz,2H),6.24 -5.96 (m, 2H), 5.50-5.45 (m, 1H), 5.21 (s, 2H), 4.36 to 4.25 (m, 4H), 1.42 (s, 9H).
步骤4) 3-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 4) 3-(4-Amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester
向3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(40mg，0.1mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-4H,6H,7H-吡唑并[3,2-c]吗啉-3-羧酸(26mg，0.1mmol)、EDCI(29mg，0.15mmol)、HOAT(21mg，0.15mmol)、和DIEA(39mg，0.30mmol)，然后将混合物于50℃下搅拌反应16h。冷却后，混合物加入H 2O(30mL)，再用DCM(30mL×2)萃取。有机层用盐水(50mL) 洗，经无水Na 2SO 4干燥，过滤，减压浓缩，然后所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um,ACN--H 2O(0.1％FA))纯化，得到3-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(40mg，63％收率)。MS(ESI,pos.ion)m/z:623.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.43(s,1H),8.14(s,1H),7.71(d,J＝8.4Hz,2H),7.63–7.59(m,3H),7.55–7.51(m,3H),7.46(d,J＝8.8Hz,2H),6.23-6.11(m,2H),5.52–5.49(m,1H),5.13(s,2H),4.32(d,J＝8.0Hz,4H),4.12–4.09(t,J＝5.0Hz,2H),3.70(t,J＝4.8Hz,2H),1.42(s,9H)。 To tert-butyl 3-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (40mg, 0.1mmol) in DCM (10mL) mixture was added 2-oxo-1-phenyl-4H,6H,7H-pyrazolo[3,2-c]morpholine-3-carboxylic acid (26mg, 0.1mmol), EDCI (29mg, 0.15mmol), HOAT (21mg, 0.15mmol), and DIEA (39mg, 0.30mmol), then the mixture was stirred at 50°C for 16h. After cooling, the mixture was added with H 2 O (30 mL), and then extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. Then the resulting residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O( 0.1% FA)) was purified to obtain 3-(4-amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1 -c][1,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester It is a white solid (40 mg, 63% yield). MS (ESI, pos.ion) m/z: 623.1 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.43(s,1H), 8.14(s,1H), 7.71(d,J=8.4Hz,2H), 7.63–7.59(m,3H), 7.55–7.51( m,3H),7.46(d,J=8.8Hz,2H),6.23-6.11(m,2H),5.52-5.49(m,1H),5.13(s,2H),4.32(d,J=8.0Hz , 4H), 4.12-4.09 (t, J = 5.0 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 1.42 (s, 9H).
实施例31 N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 31 N-(4-(4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000064
Figure PCTCN2021094020-appb-000064
在0℃下，向3-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(26.6mg,0.04mmol)的二氧六环(10mL)混合物中加入HCl(0.5mL，0.52mmol，4M的二氧六环溶液)。反应在25℃下搅拌2h。将混合物减压浓缩以除去有机物，所得残余物经制备型HPLC纯化(Gemini-C18 150 x 21.2mm，5um,ACN--H 2O(0.1％FA)10％-40％)得到N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(6.4mg，33％收率)。MS(ESI,pos.ion)m/z:523.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.43(s,1H),8.33(s,1H),8.14(s,1H),7.72(d,J＝6.8Hz,2H),7.67(s,1H),7.60(d,J＝6.4Hz,2H),7.54(s,3H),7.45(d,J＝7.6Hz,2H),6.23-6.07(m,2H),5.54(s,1H),5.13(s,2H),4.13–4.03(m,4H),3.95–3.88(m,2H),3.72–3.69(m,2H)。 At 0 ℃, to 3-(4-amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c ][1,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester (26.6 mg, 0.04mmol) of dioxane (10mL) was added HCl (0.5mL, 0.52mmol, 4M dioxane solution). The reaction was stirred at 25°C for 2h. The mixture was concentrated under reduced pressure to remove organics, and the resulting residue was purified by preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1% FA) 10%-40%) to obtain N-(4 -(4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl- 2,4,6,7-Tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide was a white solid (6.4 mg, 33% yield). MS (ESI, pos.ion) m/z: 523.1 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.43(s,1H), 8.33(s,1H), 8.14(s,1H), 7.72(d,J=6.8Hz,2H), 7.67(s,1H) ,7.60(d,J=6.4Hz,2H),7.54(s,3H),7.45(d,J=7.6Hz,2H),6.23-6.07(m,2H),5.54(s,1H),5.13( s, 2H), 4.13–4.03 (m, 4H), 3.95–3.88 (m, 2H), 3.72–3.69 (m, 2H).
实施例32 N-(4-(4-氨基-7-(1-异丁酰基氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 32 N-(4-(4-amino-7-(1-isobutyrylazetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene Yl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000065
Figure PCTCN2021094020-appb-000065
向N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺(40mg,0.08mmol)的DCM(10mL)混合物中加入三乙胺(25mg，0.24mmol)和2-甲基丙酰氯(9mg，0.08mmol)，然后混合物于常温下搅拌反应2h。反应混合物中加入H 2O(30mL)，用DCM(30mL×2)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA)20％-30％)纯化，得到N-(4-(4-氨基-7-(1-异丁酰基氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(8.2mg，18％收率)。MS(ESI,pos.ion)m/z:593.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.43(s,1H),8.15(s,1H),7.71(d,J＝8.4Hz,2H),7.67(s,1H),7.63–7.58(m,2H),7.56–7.51(m,3H),7.46(d,J＝8.4Hz,2H),6.25-6.09(m,2H),5.60–5.55(m,1H),5.13(s,2H),4.69-4.63(m,1H),4.61-4.56(m,1H),4.37-4.31(m,1H),4.27–4.23(m,1H),4.10(t,J＝5.0Hz,2H),3.70(t,J＝5.0Hz,2H),2.54(s,1H),1.06–0.99(m,6H)。 To N-(4-(4-amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo- 1-Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide (40mg, 0.08mmol) in DCM (10mL ) Triethylamine (25mg, 0.24mmol) and 2-methylpropionyl chloride (9mg, 0.08mmol) were added to the mixture, and then the mixture was stirred and reacted at room temperature for 2h. H 2 O (30 mL) was added to the reaction mixture, and it was extracted with DCM (30 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1 %FA) 20%-30%) purification to obtain N-(4-(4-amino-7-(1-isobutyrylazetidin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxa The oxazine-3-carboxamide was a white solid (8.2 mg, 18% yield). MS (ESI, pos.ion) m/z: 593.1 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.43(s,1H), 8.15(s,1H), 7.71(d,J=8.4Hz,2H), 7.67(s,1H), 7.63–7.58(m, 2H), 7.56–7.51(m, 3H), 7.46(d, J=8.4Hz, 2H), 6.25-6.09(m, 2H), 5.60–5.55(m, 1H), 5.13(s, 2H), 4.69 -4.63(m,1H),4.61-4.56(m,1H),4.37-4.31(m,1H),4.27-4.23(m,1H),4.10(t,J=5.0Hz,2H),3.70(t , J=5.0Hz, 2H), 2.54(s, 1H), 1.06-0.99(m, 6H).
实施例33 N-(4-(4-氨基-7-(哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺盐酸盐Example 33 N-(4-(4-Amino-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1 -Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide hydrochloride
Figure PCTCN2021094020-appb-000066
Figure PCTCN2021094020-appb-000066
步骤1) 4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯Step 1) tert-Butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(500mg，1.79mmol)、4-羟基哌啶-1-甲酸叔丁酯(1.08g，5.3mmol)和三苯基膦(938mg，3.5mmol)的THF(20mL)混合物中加入DIAD(723mg,3.5mmol)，混合物在室温下搅拌反应16h。反应混合物用水(20mL)淬灭，然后用EtOAc(20mL×3)萃取。合并的有机层用盐水(40mL×2)洗，经Na 2SO 4干燥，减压浓缩。所得残余物经硅胶色谱法纯化(EtOAc/PE＝1/1)，得到4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯为白色固体(550mg，63％收率)。MS(ESI,pos.ion)m/z:463.1[M+H] +。 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),7.44(s,1H),4.90(t,J＝12.0Hz,1H),4.34(d,J＝12.3Hz,2H),2.93(t,J＝12.6Hz,2H),2.07-2.02(m,2H),1.98-1.84(m,2H),1.49(s,9H)。 At 0℃, to 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (500mg, 1.79mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.08g, 5.3 mmol) and triphenylphosphine (938mg, 3.5mmol) in THF (20mL) was added DIAD (723mg, 3.5mmol), and the mixture was stirred at room temperature for 16h. The reaction mixture was quenched with water (20 mL), and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (40 mL×2), dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/PE=1/1) to obtain 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine- Tert-Butyl 1-formate was a white solid (550 mg, 63% yield). MS (ESI, pos.ion) m/z: 463.1 [M+H] + . 1 H NMR(300MHz,CDCl 3 )δ8.62(s,1H),7.44(s,1H),4.90(t,J=12.0Hz,1H), 4.34(d,J=12.3Hz,2H), 2.93 (t, J=12.6 Hz, 2H), 2.07-2.02 (m, 2H), 1.98-1.84 (m, 2H), 1.49 (s, 9H).
步骤2) 4-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯Step 2) tert-Butyl 4-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate
向4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(200mg，0.43mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(94mg，0.43mmol)和碳酸钠(91mg，0.86mmol)的二氧六环(16mL)和H 2O(4mL)混合物中加入1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(35.5mg，0.043mmol)，所得混合物于N 2氛下、在60℃下加热反应16h。冷却后，将混合物减压浓缩。残余物用水(30mL)稀释，然后用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL×2)洗，经Na 2SO 4干燥，过滤，减压浓缩。所得残余物经硅胶色谱法纯化(EtOAc/PE＝1/1)，得到4-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯为浅黄色固体(160mg，82.6％收率)。MS(ESI,pos.ion)m/z:428.1[M+H] +。 1H NMR(300MHz,CDCl 3)δ8.63(s,1H),7.33(d,J＝8.4Hz,2H),7.23(s,1H),6.85(d,J＝8.1Hz,2H),4.99-4.91(m,1H),4.39-4.2(m,2H),3.0-2.92(m,2H),2.12-2.05(m,2H),1.97-1.92(m,2H),1.49(s,9H)。 To 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (200mg, 0.43mmol), 4-(4, Dioxane of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (94mg, 0.43mmol) and sodium carbonate (91mg, 0.86mmol) (16mL) and H 2 O (4mL) mixture was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (35.5mg, 0.043mmol) The resulting mixture was heated and reacted at 60° C. under N 2 atmosphere for 16 h. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL), and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL×2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EtOAc/PE=1/1) to obtain 4-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7 Tert-butyl-yl)piperidine-1-carboxylate was a pale yellow solid (160 mg, 82.6% yield). MS (ESI, pos.ion) m/z: 428.1 [M+H] + . 1 H NMR(300MHz, CDCl 3 )δ8.63(s,1H), 7.33(d,J=8.4Hz,2H), 7.23(s,1H), 6.85(d,J=8.1Hz,2H), 4.99 -4.91(m,1H),4.39-4.2(m,2H),3.0-2.92(m,2H),2.12-2.05(m,2H),1.97-1.92(m,2H),1.49(s,9H) .
步骤3) 4-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯Step 3) tert-Butyl 4-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate
向密封管中的4-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(160mg，0.37mmol)的二氧六环(2mL)溶液中加入NH 3溶液(25％,2mL)，混合物于130℃下搅拌反应16h。冷却后，将混合物减压浓缩，所得残余物经硅胶色谱法纯化(DCM/MeOH＝20/1)，得到4-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯为黄色固体(100mg，59％收率)。MS(ESI,pos.ion)m/z:409.0[M+H] +。 To the 4-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (160mg , 0.37 mmol) in dioxane (2mL) was added a solution of NH 3 (25%, 2mL) solution and the mixture reaction was stirred at 130 ℃ 16h. After cooling, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give 4-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[ Tert-butyl 2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate was a yellow solid (100 mg, 59% yield). MS (ESI, pos.ion) m/z: 409.0 [M+H] + .
步骤4) 4-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯Step 4) 4-(4-Amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester
室温下，向4-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(90mg，0.22mmol)、2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-羧酸(57mg，0.22mmol)、DIEA(85mg，0.66mmol)和HOAt(30mg，0.22mmol)的DCM(20mL)混合物中加入N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐(63mg，0.33mmol)，所得混合物于50℃下加热反应16h。冷却至室温后，将混合物用DCM(30mL)稀释，然后用盐水(30mL×3)洗。分离的有机层经Na 2SO 4干燥，过滤，减压浓缩。残余物经硅胶色谱法纯化(DCM/MeOH＝30/1)，得到4-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯为淡黄色固体(50mg，33％收率)。MS(ESI,pos.ion)m/z:651.3[M+H] +。 At room temperature, add tert-butyl 4-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (90mg, 0.22mmol), 2-oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid (57mg , 0.22mmol), DIEA (85mg, 0.66mmol) and HOAt (30mg, 0.22mmol) in DCM (20mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide salt Salt (63mg, 0.33mmol), the resulting mixture was heated at 50°C for 16h. After cooling to room temperature, the mixture was diluted with DCM (30 mL), and then washed with brine (30 mL×3). The separated organic layer was dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to give 4-(4-amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro -1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine Tert-Butyl-1-carboxylate was a pale yellow solid (50 mg, 33% yield). MS (ESI, pos.ion) m/z: 651.3 [M+H] + .
步骤5) N-(4-(4-氨基-7-(哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺盐酸盐Step 5) N-(4-(4-Amino-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1 -Phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide hydrochloride
向4-(4-氨基-5-(4-(2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(50mg，0.08mmol)的二氧六环(1mL)溶液中加入4N HCl的二氧六环(1mL)溶液，混合物于25℃下搅拌反应16h。然后将混合物减压浓缩，得到N-(4-(4-氨基-7-(哌啶-4- 基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺盐酸盐为淡黄色固体(45mg，97％收率)。MS(ESI):551.3[M+H] +。 1H NMR(400MHz,DMSO)δ10.48(s,1H),9.00(s,1H),8.77(s,1H),8.46(s,1H),7.75(d,J＝8.4Hz,2H),7.63-7.51(m,5H),7.46(d,J＝8.4Hz,2H),5.13(s,2H),5.00-4.94(m,1H),4.11(s,2H),3.70(s,2H),3.47-3.43(m,2H),3.21-3.13(m,2H),2.33-2.26(m,2H),2.17-2.13(m,2H)。 To 4-(4-amino-5-(4-(2-oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4 ]Oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (50mg, 0.08mmol) in dioxane A solution of 4N HCl in dioxane (1 mL) was added to the ring (1 mL) solution, and the mixture was stirred at 25° C. for 16 h. The mixture was then concentrated under reduced pressure to obtain N-(4-(4-amino-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 2-Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide hydrochloride is light yellow Solid (45 mg, 97% yield). MS (ESI): 551.3 [M+H] + . 1 H NMR (400MHz, DMSO) δ 10.48 (s, 1H), 9.00 (s, 1H), 8.77 (s, 1H), 8.46 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.63-7.51(m,5H),7.46(d,J=8.4Hz,2H),5.13(s,2H),5.00-4.94(m,1H),4.11(s,2H),3.70(s,2H) , 3.47-3.43 (m, 2H), 3.21-3.13 (m, 2H), 2.33-2.26 (m, 2H), 2.17-2.13 (m, 2H).
实施例34 N-(4-(4-氨基-7-(1-异丁酰基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺Example 34 N-(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 2-Oxy-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide
Figure PCTCN2021094020-appb-000067
Figure PCTCN2021094020-appb-000067
在0℃下，向N-(4-(4-氨基-7-(哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺盐酸盐(35mg，0.06mmol)和DIEA(16mg，0.13mmol)的DCM(10mL)溶液中加入2-甲基丙酰氯(6.8mg，0.06mmol)。混合物在室温搅拌2h。将混合物用DCM(20mL)稀释，然后用盐水(20mL×2)洗。分离的有机层经Na 2SO 4干燥，过滤，减压浓缩。所得残余物经制备型HPLC纯化(ACN-H 2O 0.1％FA，梯度80％至40％)，得到N-(4-(4-氨基-7-(1-异丁酰基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺为白色固体(19.9mg，48.3％收率)。MS(ESI,pos.ion)m/z:621.3[M+H] +。 1H NMR(400MHz,DMSO)δ10.46(s,1H),8.36(s,1H),7.77(s,1H),7.73(d,J＝8.4Hz,2H),7.64-7.58(m,2H),7.54-7.51(m,3H),7.44(d,J＝8.4Hz,2H),5.12(s,2H),4.96-4.87(m,1H),4.64-4.61(m,1H),4.10(s,2H),3.70(s,2H),3.28-3.23(m,2H),2.95-2.89(m,1H),2.75-2.72(m,1H),2.02-1.90(m,4H),1.06-1.01(m,6H)。 At 0 ℃, to N-(4-(4-amino-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxygen-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1,4]oxazine-3-carboxamide hydrochloride (35mg, 0.06mmol ) And DIEA (16 mg, 0.13 mmol) in DCM (10 mL) was added with 2-methyl propionyl chloride (6.8 mg, 0.06 mmol). The mixture was stirred at room temperature for 2h. The mixture was diluted with DCM (20 mL), and then washed with brine (20 mL×2). The separated organic layer was dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (ACN-H 2 O 0.1% FA, gradient 80% to 40%) to obtain N-(4-(4-amino-7-(1-isobutyrylpiperidine-4- Yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[ 5,1-c][1,4]oxazine-3-carboxamide is a white solid (19.9 mg, 48.3% yield). MS (ESI, pos.ion) m/z: 621.3 [M+H] + . 1 H NMR(400MHz,DMSO)δ10.46(s,1H),8.36(s,1H),7.77(s,1H),7.73(d,J=8.4Hz,2H),7.64-7.58(m,2H) ),7.54-7.51(m,3H),7.44(d,J=8.4Hz,2H),5.12(s,2H),4.96-4.87(m,1H),4.64-4.61(m,1H),4.10( s,2H),3.70(s,2H),3.28-3.23(m,2H),2.95-2.89(m,1H),2.75-2.72(m,1H),2.02-1.90(m,4H),1.06- 1.01 (m, 6H).
实施例35 N-(4-(4-氨基-7-(3-羟基环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-(哌啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 35 N-(4-(4-Amino-7-(3-hydroxycyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1 -(Piperidin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000068
Figure PCTCN2021094020-appb-000068
步骤1) 5-氯-N'-(吡啶-2-基)戊酰肼Step 1) 5-Chloro-N'-(pyridin-2-yl)valeryl hydrazide
在0℃下，向2-肼基吡啶(400mg，3.67mmol)和Na 2CO 3(621mg，5.8g mmol)的DCM(8mL)和H 2O(8mL)的混合物中加入5-氯戊酰氯(511.4mg，3.29mmol)，混合物在20℃下搅拌反应16h。将混合物用DCM(50mL)稀释，分离的有机层用盐水(20mL×3)洗，然后经Na 2SO 4干燥，减压浓缩，得到5-氯-N'-(吡啶-2-基)戊酰肼为淡黄色固体(800mg，86.3％收率)。MS(ESI,pos.ion)m/z:227.9[M+H] +。 1H NMR(300MHz,CDCl 3)δ8.14(d,J＝5.1Hz,1H),7.96(s,1H),7.56(t,J＝7.2Hz,1H),6.85-6.79(m,1H),6.71(d,J＝8.4Hz,1H),3.60-3.54(m,2H),2.40-2.34(m,2H),1.88-1.78(m,4H)。 At 0° C., to a mixture of 2-hydrazinopyridine (400 mg, 3.67 mmol) and Na 2 CO 3 (621 mg, 5.8 g mmol) in DCM (8 mL) and H 2 O (8 mL) was added 5-chloropentanoyl chloride (511.4mg, 3.29mmol), the mixture was stirred at 20°C for 16h. The mixture was diluted with DCM (50 mL), the separated organic layer was washed with brine (20 mL×3), then dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 5-chloro-N'-(pyridin-2-yl)pentan Hydrazide was a pale yellow solid (800 mg, 86.3% yield). MS (ESI, pos.ion) m/z: 227.9 [M+H] + . 1 H NMR(300MHz,CDCl 3 )δ8.14(d,J=5.1Hz,1H),7.96(s,1H),7.56(t,J=7.2Hz,1H),6.85-6.79(m,1H) , 6.71 (d, J = 8.4 Hz, 1H), 3.60-3.54 (m, 2H), 2.40-2.34 (m, 2H), 1.88-1.78 (m, 4H).
步骤2) 3-(2-(5-氯戊酰基)-1-(吡啶-2-基)肼基)-3-氧丙酸乙酯Step 2) Ethyl 3-(2-(5-chloropentanoyl)-1-(pyridin-2-yl)hydrazino)-3-oxopropionate
在0℃下，向5-氯-N'-(吡啶-2-基)戊酰肼(800mg，3.51mmol)和碳酸钠(558mg，5.3mmol)的DCM(20mL)混合物中加入3-氯-3-氧丙酸乙酯(528mg，3.51mmol)，混合物在20℃下搅拌反应16h。将反应混合物用DCM(40mL)稀释，然后用盐水(20mL×2)洗。分离的有机层经Na 2SO 4干燥，减压浓缩。所得残余物经硅胶色谱法纯化(EA/PE＝1/1)，得到3-(2-(5-氯戊酰基)-1-(吡啶-2-基)肼基)-3-氧丙酸乙酯为无色油状物(850mg，67.3％收率)。MS(ESI,pos.ion)m/z:342.1[M+H] +。 1H NMR(300MHz,CDCl 3)δ8.32(d,J＝4.2Hz,1H),8.22-8.10(m,2H),7.75(t,J＝7.2Hz,1H),7.19–7.10(m,1H),4.22(q,J＝7.2Hz,2H),3.79- 3.70(m,1H),3.58-3.48(m,3H),2.45-2.39(m,2H),1.91-1.84(m,4H),1.33–1.25(m,4H)。 At 0°C, to a mixture of 5-chloro-N'-(pyridin-2-yl)valeryl hydrazide (800 mg, 3.51 mmol) and sodium carbonate (558 mg, 5.3 mmol) in DCM (20 mL) was added 3-chloro- Ethyl 3-oxopropionate (528mg, 3.51mmol), the mixture was stirred at 20°C for 16h. The reaction mixture was diluted with DCM (40 mL), and then washed with brine (20 mL×2). The separated organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EA/PE=1/1) to obtain 3-(2-(5-chloropentanoyl)-1-(pyridin-2-yl)hydrazino)-3-oxopropionic acid The ethyl ester is a colorless oil (850 mg, 67.3% yield). MS (ESI, pos.ion) m/z: 342.1 [M+H] + . 1 H NMR(300MHz,CDCl 3 )δ8.32(d,J=4.2Hz,1H), 8.22-8.10(m,2H), 7.75(t,J=7.2Hz,1H), 7.19-7.10(m, 1H), 4.22 (q, J = 7.2Hz, 2H), 3.79- 3.70 (m, 1H), 3.58-3.48 (m, 3H), 2.45-2.39 (m, 2H), 1.91-1.84 (m, 4H) ,1.33-1.25(m,4H).
步骤3) 3-氧-3-((2-氧哌啶-1-基)(吡啶-2-基)氨基)丙酸乙酯Step 3) Ethyl 3-oxo-3-((2-oxopiperidin-1-yl)(pyridin-2-yl)amino)propionate
在0℃下，向3-(2-(5-氯戊酰基)-1-(吡啶-2-基)肼基)-3-氧丙酸乙酯(800mg，2.34mmol)的DMF(15mL)溶液中加入NaH(168mg，7mmol)，混合物在室温下搅拌反应2h。将反应混合物用NaH 2P 4水溶液(10mL)淬灭，然后用EtOAc(20mL×3)萃取。合并的有机层用盐水(20mL×3)洗，经Na 2SO 4干燥，减压浓缩。所得残余物经硅胶色谱法纯化(EA/PE＝1/1)，得到3-氧-3-((2-氧哌啶-1-基)(吡啶-2-基)氨基)丙酸乙酯为白色固体(600mg，79.8％收率)。MS(ESI,pos.ion)m/z:306.1[M+H] +。 1H NMR(400MHz,DMSO)δ8.38(d,J＝4.8Hz,1H),7.89-7.70(m,2H),7.26-7.22(m,1H),4.12(q,J＝7.2Hz,2H),3.55(t,J＝5.2Hz,2H),2.49-2.45(m,2H),1.92-1.87(m,2H),1.87-1.72(m,2H),1.20(t,J＝7.2Hz,3H)。 Add 3-(2-(5-chloropentanoyl)-1-(pyridin-2-yl)hydrazino)-3-oxopropionate (800mg, 2.34mmol) in DMF (15mL) at 0°C NaH (168mg, 7mmol) was added to the solution, and the mixture was stirred and reacted at room temperature for 2h. The reaction mixture was quenched with aqueous NaH 2 P 4 (10 mL), and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL×3), dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EA/PE=1/1) to obtain ethyl 3-oxo-3-((2-oxopiperidin-1-yl)(pyridin-2-yl)amino)propionate It is a white solid (600 mg, 79.8% yield). MS (ESI, pos.ion) m/z: 306.1 [M+H] + . 1 H NMR(400MHz,DMSO)δ8.38(d,J=4.8Hz,1H),7.89-7.70(m,2H),7.26-7.22(m,1H),4.12(q,J=7.2Hz,2H ),3.55(t,J=5.2Hz,2H),2.49-2.45(m,2H),1.92-1.87(m,2H),1.87-1.72(m,2H),1.20(t,J=7.2Hz, 3H).
步骤4) 2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯Step 4) 2-Oxy-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester
向乙醇钠(200mg，3.94mmol)的EtOH(10mL)溶液中加入3-氧-3-((2-氧哌啶-1-基)(吡啶-2-基)氨基)丙酸乙酯(300mg，0.98mmol)，混合物于70℃下加热16h。冷却至室温后，混合物减压浓缩。残余物用水(20mL)稀释，然后用EtOAc(20mL×3)萃取。合并的有机层经Na 2SO 4干燥，减压浓缩。所得残余物经硅胶色谱法纯化(EA/PE＝1/1)，得到2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯为棕色固体(200mg，56％收率)。MS(ESI,pos.ion)m/z:288.2[M+H] +。 To a solution of sodium ethoxide (200mg, 3.94mmol) in EtOH (10mL) was added ethyl 3-oxo-3-((2-oxopiperidin-1-yl)(pyridin-2-yl)amino)propionate (300mg , 0.98mmol), the mixture was heated at 70°C for 16h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), and then extracted with EtOAc (20 mL×3). The combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (EA/PE=1/1) to obtain 2-oxy-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo [1,5-a] Ethyl pyridine-3-carboxylate was a brown solid (200 mg, 56% yield). MS (ESI, pos.ion) m/z: 288.2 [M+H] + .
步骤5) 2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸Step 5) 2-Oxy-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid
向2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸乙酯(200mg，0.7mmol)的THF(5mL)和EtOH(5mL)溶液中加入NaOH(84mg，2mmol)的H 2O(5mL)溶液，混合物于25℃下搅拌反应16h。将混合物减压浓缩，残余物用水(10mL)稀释。混合物通过1N HCl酸化至pH 4-5，然后将混合物用EtOAc(20mL×3)萃取。合并的有机层经Na 2SO 4干燥，减压浓缩。所得残余物经制备型HPLC纯化(ACN-H 2O 0.1％FA，梯度20％至40％)，得到2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸为棕色固体(50mg，26％收率)。MS(ESI,pos.ion)m/z:260.0[M+H] +。 1H NMR(301MHz,DMSO)δ11.84(s,1H),8.57(d,J＝4.2Hz,1H),8.05(t,J＝7.8Hz,1H),7.67(d,J＝8.1Hz,1H),7.49-7.41(m,1H),3.89(t,J＝5.7Hz,2H),3.10(t,J＝6.3Hz,2H),1.99-1.95(m,2H),1.84-1.78(m,2H)。 To 2-oxo-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (200mg, 0.7 A solution of NaOH (84 mg, 2 mmol) in H 2 O (5 mL) was added to a THF (5 mL) and EtOH (5 mL) solution of mmol), and the mixture was stirred for reaction at 25° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The mixture was acidified to pH 4-5 by 1N HCl, and then the mixture was extracted with EtOAc (20 mL×3). The combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (ACN-H 2 O 0.1% FA, gradient 20% to 40%) to obtain 2-oxo-1-(pyridin-2-yl)-1,2,4,5,6 ,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid was a brown solid (50mg, 26% yield). MS (ESI, pos.ion) m/z: 260.0 [M+H] + . 1 H NMR(301MHz,DMSO)δ11.84(s,1H), 8.57(d,J=4.2Hz,1H), 8.05(t,J=7.8Hz,1H), 7.67(d,J=8.1Hz, 1H),7.49-7.41(m,1H),3.89(t,J=5.7Hz,2H),3.10(t,J=6.3Hz,2H),1.99-1.95(m,2H),1.84-1.78(m ,2H).
步骤6) N-(4-(4-氨基-7-(3-羟基环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Step 6) N-(4-(4-amino-7-(3-hydroxycyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1 -(Pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
向2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(25mg，0.1mmol)、3-[4-氨基-5-(4-氨基苯基)吡咯并[2,3-d]嘧啶-7-基]环丁烷-1-醇(29mg，0.1mmol)、HOAt(13.6mg，0.1mmol)和DIEA(38.8mg，0.3mmol)的DCM(20mL)溶液中加入N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐(28.8mg，0.15mmol)，混合物于40℃下搅拌反应16h。冷却至室温后，将混合物用DCM(30mL)稀释，然后用盐水(20mL×2)洗。分离的有机层经Na 2SO 4干燥，减压浓缩。所得残余物经制备型HPLC纯化(ACN-H 2O(0.1％FA)，梯度25％至50％)，得到N-(4-(4-氨基-7-(3-羟基环丁基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-(吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(16mg，28.6％收率)。MS(ESI,pos.ion)m/z:537.3[M+H] +。 1H NMR(400MHz,DMSO)δ10.53(s,1H),8.60(d,J＝4.0Hz,1H),8.12(s,1H),8.08(t,J＝7.6Hz,1H),7.76(d,J＝8Hz,1H),7.71(d,J＝8.4Hz,2H),7.54(s,1H),7.46(dd,J＝15.3,7.7Hz,3H),6.09(s,2H),5.44-5.37(m,1H),5.23(s,1H),4.47(s,1H),3.92(t,J＝5.4Hz,2H),3.30-3.26(m,2H),2.73-2.68(m,2H),2.41-2.32(m,2H),2.05-1.96(m,2H),1.88-1.82(m,2H)。 To 2-oxo-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (25mg, 0.1mmol ), 3-[4-amino-5-(4-aminophenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutan-1-ol (29mg, 0.1mmol), HOAt(13.6 mg, 0.1mmol) and DIEA (38.8mg, 0.3mmol) in DCM (20mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (28.8mg, 0.15mmol), the mixture was stirred at 40°C for 16h. After cooling to room temperature, the mixture was diluted with DCM (30 mL), and then washed with brine (20 mL×2). The separated organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (ACN-H 2 O (0.1% FA), gradient 25% to 50%) to obtain N-(4-(4-amino-7-(3-hydroxycyclobutyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyridine Azolo[1,5-a]pyridine-3-carboxamide was a white solid (16 mg, 28.6% yield). MS (ESI, pos.ion) m/z: 537.3 [M+H] + . 1 H NMR (400MHz, DMSO) δ 10.53 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.12 (s, 1H), 8.08 (t, J = 7.6 Hz, 1H), 7.76 ( d, J = 8Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.46 (dd, J = 15.3, 7.7 Hz, 3H), 6.09 (s, 2H), 5.44 -5.37(m,1H),5.23(s,1H),4.47(s,1H),3.92(t,J=5.4Hz,2H),3.30-3.26(m,2H),2.73-2.68(m,2H ), 2.41-2.32 (m, 2H), 2.05-1.96 (m, 2H), 1.88-1.82 (m, 2H).
实施例36 3-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Example 36 3-(4-Amino-5-(2-fluoro-4-(2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b ]Pyrazole-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021094020-appb-000069
Figure PCTCN2021094020-appb-000069
步骤1) 3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯 Step 1) tert-Butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(140mg，0.5mmol)的THF(20mL)混合物中加入3-羟基氮杂环丁烷-1-甲酸叔丁酯(131mg，0.75mmol)、三苯基膦(263mg，1.0mmol)、和DIAD(203mg，1.0mmol)。反应在25℃下搅拌16h，LCMS显示得到产物。将混合物减压浓缩以除去有机物，然后用EA(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(280mg，粗品)为白色固体。LCMS:t R＝1.368min,色谱柱(HALO C18 4.6*50mm,2.7μm),MS(ESI,pos.ion)m/z:434.9[M+H] +。 1H NMR:(400MHz,DMSO)δ8.65(s,1H),8.34(s,1H),5.55(t,J＝7.0Hz,1H),4.32(d,J＝7.2Hz,4H),1.42(s,9H)。 Add 3-hydroxyazetidine-1 to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (140mg, 0.5mmol) in THF (20mL) at 0°C -Tert-butyl formate (131 mg, 0.75 mmol), triphenylphosphine (263 mg, 1.0 mmol), and DIAD (203 mg, 1.0 mmol). The reaction was stirred at 25°C for 16 h, LCMS showed that the product was obtained. The mixture was concentrated under reduced pressure to remove organics, and then extracted with EA (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 3-(4-chloro- Tert-butyl 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (280 mg, crude product) is a white solid. LCMS: t R =1.368 min, chromatographic column (HALO C18 4.6*50mm, 2.7 μm), MS (ESI, pos.ion) m/z: 434.9 [M+H] + . 1 H NMR:(400MHz,DMSO)δ8.65(s,1H),8.34(s,1H),5.55(t,J=7.0Hz,1H), 4.32(d,J=7.2Hz,4H),1.42 (s,9H).
步骤2) 3-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 2) 3-(5-(4-Amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid Tert-butyl ester
向3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(350mg，0.80mmol)的二氧六环/H 2O(20mL/4mL)溶液中加入3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺(190mg，0.80mmol)、碳酸钠(128mg，1.2mmol)、和Pd(PPh 3) 4(93mg，0.08mmol)。所得混合物保持在氮气下，并于60℃下搅拌6h。冷却后，将混合物减压浓缩以除去有机物，然后用DCM(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(380mg，95％)。MS(ESI,pos.ion)m/z:418.1[M+H] +。 To 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester (350mg, 0.80mmol) in dioxy Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl to the hexacyclic/H 2 O (20mL/4mL) solution ) Aniline (190 mg, 0.80 mmol), sodium carbonate (128 mg, 1.2 mmol), and Pd(PPh 3 ) 4 (93 mg, 0.08 mmol). The resulting mixture was kept under nitrogen and stirred at 60°C for 6 h. After cooling, the mixture was concentrated under reduced pressure to remove organics, and then extracted with DCM (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM/MeOH=20/1) to give 3-(5-(4 -Amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester as a white solid (380mg, 95 %). MS (ESI, pos.ion) m/z: 418.1 [M+H] + .
步骤3) 3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 3) 3-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid Tert-butyl ester
向3-(5-(4-氨基-2-氟苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(380mg，0.90mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应于密闭管中在130℃下搅拌16h。冷却后，将混合物减压浓缩以除去有机物，然后用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(120mg，30％)。MS(ESI,pos.ion)m/z:399.1[M+H] +。 1H NMR:(400MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.06(t,J＝8.8Hz,1H),6.49–6.43(m,2H),6.15-5.85(m,2H),5.55(s,2H),5.49-5.42(m,1H),4.35–4.24(m,4H),1.42(s,9H)。 To 3-(5-(4-amino-2-fluorophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl Ammonium hydroxide (10 mL) was added to the dioxane (10 mL) mixture of ester (380 mg, 0.90 mmol). The reaction was stirred at 130°C for 16h in a closed tube. After cooling, the mixture was concentrated under reduced pressure to remove organics, and then extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 3-(4-amino- 5-(4-Amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester is a white solid (120mg, 30 %). MS (ESI, pos.ion) m/z: 399.1 [M+H] + . 1 H NMR:(400MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.06(t,J=8.8Hz,1H),6.49-6.43(m,2H),6.15-5.85( m, 2H), 5.55 (s, 2H), 5.49-5.42 (m, 1H), 4.35-4.24 (m, 4H), 1.42 (s, 9H).
步骤4) 3-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 4) 3-(4-Amino-5-(2-fluoro-4-(2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b ]Pyrazole-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester
向3-(4-氨基-5-(4-氨基-2-氟苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(50mg，0.13mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-羧酸(32mg，0.13mmol)、EDCI(38mg，0.195mmol)、HOAT(27mg，0.195mmol)、和DIEA(51mg，0.39mmol)，所得混合物于50℃下搅拌反应16h。冷却后，混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA))纯化，得到3-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(40mg，49％)。MS(ESI,pos.ion)m/z:625.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.39(s,1H),8.13(s,1H),7.89–7.85(m,1H),7.61(s,1H),7.58-7.50(m,4H),7.43–7.36(m,3H),6.20-6.05(m,2H),5.51–5.48(m,1H),4.32(d,J＝8.4Hz,4H),3.83(t,J＝6.8Hz,2H),3.18(t,J＝7.2Hz,2H),2.46-2.41(m,2H),1.42(s,9H)。 To 3-(4-amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl Add 2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3 to the mixture of ester (50mg, 0.13mmol) in DCM (10mL) -Carboxylic acid (32mg, 0.13mmol), EDCI (38mg, 0.195mmol), HOAT (27mg, 0.195mmol), and DIEA (51mg, 0.39mmol), the resulting mixture was stirred at 50°C for 16h. After cooling, the mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1 %FA)) to obtain 3-(4-amino-5-(2-fluoro-4-(2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1 ,2-b]pyrazole-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester is a white solid (40mg, 49%). MS (ESI, pos.ion) m/z: 625.1 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.39(s,1H),8.13(s,1H),7.89-7.85(m,1H),7.61(s,1H),7.58-7.50(m,4H), 7.43–7.36(m,3H), 6.20-6.05(m,2H), 5.51–5.48(m,1H), 4.32(d,J=8.4Hz,4H), 3.83(t,J=6.8Hz,2H) , 3.18 (t, J = 7.2 Hz, 2H), 2.46-2.41 (m, 2H), 1.42 (s, 9H).
实施例37 N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 37 N-(4-(4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000070
Figure PCTCN2021094020-appb-000070
在0℃下，向3-(4-氨基-5-(2-氟-4-(2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(32.4mg，0.05mmol)的二氧六环(10mL)混合物中加入HCl(0.5mL，0.52mmol，4M的二氧六环溶液)。反应于25℃下搅拌2h。将混合物减压浓缩以除去有机物，所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA)10％-40％)，得到N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺为白色固体(14.3mg，53％)。MS(ESI,pos.ion)m/z:525.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.40(s,1H),8.33(s,1H),8.14(s,1H),7.88(d,J＝13.2Hz,1H),7.66(s,1H),7.60-7.51(m,4H),7.45–7.36(m,3H),6.19-6.05(m,2H),5.57–5.50(m,1H),4.09–4.00(m,2H),3.96–3.87(m,2H),3.82(t,J＝6.8Hz,2H),3.17(t,J＝7.2Hz,2H),2.46-2.41(m,2H)。 At 0 ℃, to 3-(4-amino-5-(2-fluoro-4-(2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1, 2-b]pyrazole-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester (32.4mg, Add HCl (0.5 mL, 0.52 mmol, 4M dioxane solution) to the 0.05 mmol) dioxane (10 mL) mixture. The reaction was stirred at 25°C for 2h. The mixture was concentrated under reduced pressure to remove organics, and the resulting residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1% FA) 10%-40%) to obtain N-(4 -(4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1 -Phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide is a white solid (14.3 mg, 53%). MS (ESI, pos.ion) m/z: 525.1 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.40(s,1H), 8.33(s,1H), 8.14(s,1H), 7.88(d,J=13.2Hz,1H), 7.66(s,1H) ,7.60-7.51(m,4H),7.45--7.36(m,3H),6.19-6.05(m,2H),5.57-5.50(m,1H),4.09-4.00(m,2H),3.96-3.87( m, 2H), 3.82 (t, J = 6.8 Hz, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.46-2.41 (m, 2H).
实施例38 N-(4-(4-氨基-7-(1-异丁酰基氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺Example 38 N-(4-(4-amino-7-(1-isobutyrylazetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 3-fluorophenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
Figure PCTCN2021094020-appb-000071
Figure PCTCN2021094020-appb-000071
向N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(80mg，0.15mmol)的DCM(10mL)混合物中加入三乙胺(46mg，0.45mmol)和2-甲基丙酰氯(16mg，0.15mmol)，所得混合物于RT下搅拌反应2h。反应混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA)20％-30％)纯化，得到N-(4-(4-氨基-7-(1-异丁酰基氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺为白色固体(22.1mg，25％)。MS(ESI,pos.ion)m/z:595.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.40(s,1H),8.14(s,1H),7.90–7.85(m,1H),7.65(s,1H),7.60-7.50(m,4H),7.45–7.35(m,3H),6.28-6.01(m,2H),5.61-5.52(m,1H),4.69–4.58(m,2H),4.34(t,J＝9.2Hz,1H),4.27-4.21(m,1H),3.82(t,J＝6.8Hz,2H),3.18(t,J＝7.2Hz,2H),2.56–2.51(m,1H),2.46-2.39(m,2H),1.06-0.99(m,6H)。 To N-(4-(4-amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)- 2-Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide (80mg, 0.15mmol) in DCM (10mL) mixture Triethylamine (46mg, 0.45mmol) and 2-methylpropionyl chloride (16mg, 0.15mmol) were added to the mixture, and the resulting mixture was stirred and reacted at RT for 2h. The reaction mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1% FA) 20%-30%) purification to obtain N-(4-(4-amino-7-(1-isobutyrylazetidin-3-yl)-7H-pyrrolo[2,3-d ]Pyrimidin-5-yl)-3-fluorophenyl)-2-oxo-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3 -Formamide is a white solid (22.1 mg, 25%). MS (ESI, pos.ion) m/z: 595.1 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.40(s,1H), 8.14(s,1H), 7.90-7.85(m,1H), 7.65(s,1H), 7.60-7.50(m,4H), 7.45–7.35(m,3H),6.28-6.01(m,2H),5.61-5.52(m,1H),4.69–4.58(m,2H), 4.34(t,J=9.2Hz,1H), 4.27- 4.21(m,1H),3.82(t,J=6.8Hz,2H),3.18(t,J=7.2Hz,2H),2.56–2.51(m,1H),2.46-2.39(m,2H),1.06 -0.99 (m, 6H).
实施例39 3-(4-氨基-5-(4-(2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Example 39 3-(4-Amino-5-(4-(2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine -3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021094020-appb-000072
Figure PCTCN2021094020-appb-000072
步骤1) 3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 1) tert-Butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
在0℃下，向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(140mg，0.5mmol)的THF(20mL)混合物中加入3-羟基氮杂环丁烷-1-甲酸叔丁酯(131mg，0.75mmol)、三苯基膦(263mg，1.0mmol)、和DIAD(203mg，1.0mmol)。反应于25℃下搅拌16h，LCMS显示得到产物。将混合物减压浓缩以除去有机物，然后用EA(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(280mg，粗品)。MS(ESI,pos.ion)m/z:434.9[M+H] +。 1H NMR:(400MHz,DMSO)δ8.65(s,1H),8.34(s,1H),5.55(t,J＝7.0Hz,1H),4.32(d,J＝7.2Hz,4H),1.42(s,9H)。 Add 3-hydroxyazetidine-1 to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (140mg, 0.5mmol) in THF (20mL) at 0°C -Tert-butyl formate (131 mg, 0.75 mmol), triphenylphosphine (263 mg, 1.0 mmol), and DIAD (203 mg, 1.0 mmol). The reaction was stirred at 25°C for 16 h, LCMS showed that the product was obtained. The mixture was concentrated under reduced pressure to remove organics, and then extracted with EA (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 3-(4-chloro-5 -Iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester is a white solid (280 mg, crude product). MS (ESI, pos.ion) m/z: 434.9 [M+H] + . 1 H NMR:(400MHz,DMSO)δ8.65(s,1H),8.34(s,1H),5.55(t,J=7.0Hz,1H), 4.32(d,J=7.2Hz,4H),1.42 (s,9H).
步骤2) 3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 2) tert-Butyl 3-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
向3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(280mg，0.65mmol)的二氧六环/H 2O(20mL/4mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(141mg，0.65mmol)、碳酸钠(103mg，0.97mmol)、和Pd(PPh 3) 4(75mg，0.065mmol)。所得混合物保持在氮气下，并于60℃下搅拌6h。冷却后，将混合物减压浓缩以除去有机物，然后用EA(50mL×2)和H 2O(50mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(100mg，40％)。MS(ESI,pos.ion)m/z:400.1[M+H] +。 1H NMR:(400MHz,DMSO)δ8.62(s,1H),7.97(s,1H),7.21(d,J＝8.4Hz,2H),6.62(d,J＝8.4Hz,2H),5.65–5.60(m,1H),5.18(s,2H),4.36(d,J＝6.4Hz,4H),1.42(s,9H)。 To 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (280mg, 0.65mmol) in dioxane six ring / H 2 O (20mL / 4mL ) was added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline ( 141 mg, 0.65 mmol), sodium carbonate (103 mg, 0.97 mmol), and Pd(PPh 3 ) 4 (75 mg, 0.065 mmol). The resulting mixture was kept under nitrogen and stirred at 60°C for 6 h. After cooling, the mixture was concentrated under reduced pressure to remove organics, and then extracted with EA (50 mL×2) and H 2 O (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM/MeOH=20/1) to give 3-(5-(4 -Aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester is a white solid (100 mg, 40%). MS (ESI, pos.ion) m/z: 400.1 [M+H] + . 1 H NMR:(400MHz,DMSO)δ8.62(s,1H),7.97(s,1H), 7.21(d,J=8.4Hz,2H), 6.62(d,J=8.4Hz,2H), 5.65 -5.60 (m, 1H), 5.18 (s, 2H), 4.36 (d, J = 6.4 Hz, 4H), 1.42 (s, 9H).
步骤3) 3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 3) tert-Butyl 3-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate
向3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(100mg，0.25mmol)的二氧六环(10mL)混合物中加入氢氧化铵(10mL)。反应于密闭管中在130℃下搅拌16h。冷却后，将混合物减压浓缩以除去有机物，然后用EA(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，所得残余物经柱色谱法纯化(DCM/MeOH＝20/1)，得到3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(40mg，40％)。MS(ESI,pos.ion)m/z:381.2[M+H] +。 1H NMR:(400MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.15(d,J＝8.4Hz,2H),6.66(d,J＝8.4Hz,2H),6.24-5.96(m,2H),5.50–5.45(m,1H),5.21(s,2H),4.36-4.25(m,4H),1.42(s,9H)。 To tert-butyl 3-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (100mg, Ammonium hydroxide (10 mL) was added to a mixture of 0.25 mmol) of dioxane (10 mL). The reaction was stirred at 130°C for 16h in a closed tube. After cooling, the mixture was concentrated under reduced pressure to remove organics, and then extracted with EA (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 3-(4-amino- Tert-butyl 5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate was a white solid (40 mg, 40%). MS (ESI, pos.ion) m/z: 381.2 [M+H] + . 1 H NMR: (400MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.15(d,J=8.4Hz,2H),6.66(d,J=8.4Hz,2H),6.24 -5.96 (m, 2H), 5.50-5.45 (m, 1H), 5.21 (s, 2H), 4.36 to 4.25 (m, 4H), 1.42 (s, 9H).
步骤4) 3-(4-氨基-5-(4-(2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 4) 3-(4-Amino-5-(4-(2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine -3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester
向3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(120mg，0.31mmol)的DCM(10mL)混合物中加入2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-羧酸(32mg，0.13mmol)、EDCI(90mg，0.47mmol)、HOAT(64mg，0.47mmol)、和DIEA(121mg，0.93mmol)，所得混合物于50℃下搅拌反应16h。冷却后，混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA))纯化，得到3-(4-氨基-5-(4-(2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯为白色固体(110mg，60％)。MS(ESI,pos.ion)m/z:621.6[M+H] +。 1H NMR:(400MHz,DMSO)δ10.69(s,1H),8.14(s,1H),7.72–7.69(m,2H),7.62–7.57(m,3H),7.53–7.51(m,1H),7.48–7.44(m,4H),6.23-6.13(m,2H),5.53–5.49(m,1H),4.36-4.28(m,4H),3.57(t,J＝5.6Hz,2H),3.22(t,J＝6.4Hz,2H),1.99(dd,J＝6.7,3.7Hz,2H),1.84–1.80(m,2H),1.42(s,9H)。 To tert-butyl 3-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (120mg, 0.31mmol) in the DCM (10mL) mixture was added 2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (32mg, 0.13mmol), EDCI (90mg, 0.47mmol), HOAT (64mg, 0.47mmol), and DIEA (121mg, 0.93mmol), the resulting mixture was stirred and reacted at 50°C for 16h. After cooling, the mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1% FA)) was purified to obtain 3-(4-amino-5-(4-(2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5- a]pyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester as a white solid (110mg, 60 %). MS (ESI, pos.ion) m/z: 621.6 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.69(s,1H), 8.14(s,1H), 7.72-7.69(m,2H), 7.62-7.57(m,3H), 7.53-7.51(m,1H) ),7.48–7.44(m,4H),6.23-6.13(m,2H),5.53–5.49(m,1H),4.36-4.28(m,4H),3.57(t,J=5.6Hz,2H), 3.22 (t, J = 6.4 Hz, 2H), 1.99 (dd, J = 6.7, 3.7 Hz, 2H), 1.84-1.80 (m, 2H), 1.42 (s, 9H).
实施例40 N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 40 N-(4-(4-amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2- Oxy-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000073
Figure PCTCN2021094020-appb-000073
在0℃下，向3-(4-氨基-5-(4-(2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯(30mg，0.05mmol)的二氧六环(10mL)混合物中加入HCl(0.5mL，0.52mmol，4M的二氧六环溶液)。反应于25℃下搅拌2h。将混合物减压浓缩以除去有机物，所得残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA)10％-40％)，得到N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(10.8mg，42％)。MS(ESI,pos.ion)m/z:520.8[M+H] +。 1H NMR:(400MHz,DMSO)δ10.70(s,1H),8.26(s,1H),8.16(s,1H),7.72(d,J＝8.4Hz,2H),7.66(s,1H),7.62-7.56(m,2H),7.54–7.41 (m,5H),6.30-6.06(m,2H),5.62-5.54(m,1H),4.29(t,J＝8.4Hz,,2H),4.13(t,J＝9.2Hz,2H),3.58(t,J＝5.8Hz,2H),3.21(t,J＝6.2Hz,2H),2.02-1.95(m,2H),1.86–1.79(m,2H)。 At 0 ℃, to 3-(4-amino-5-(4-(2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5- a]pyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylic acid tert-butyl ester (30mg, 0.05mmol) HCl (0.5 mL, 0.52 mmol, 4M dioxane solution) was added to the dioxane (10 mL) mixture. The reaction was stirred at 25°C for 2h. The mixture was concentrated under reduced pressure to remove organics, and the resulting residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1% FA) 10%-40%) to obtain N-(4 -(4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo-1-phenyl- 1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide was a white solid (10.8 mg, 42%). MS (ESI, pos.ion) m/z: 520.8 [M+H] + . 1 H NMR: (400MHz,DMSO)δ10.70(s,1H), 8.26(s,1H), 8.16(s,1H), 7.72(d,J=8.4Hz,2H), 7.66(s,1H) ,7.62-7.56(m,2H),7.54-7.41 (m,5H),6.30-6.06(m,2H),5.62-5.54(m,1H),4.29(t,J=8.4Hz,,2H), 4.13(t,J=9.2Hz,2H),3.58(t,J=5.8Hz,2H),3.21(t,J=6.2Hz,2H),2.02-1.95(m,2H),1.86-1.79(m ,2H).
实施例41 N-(4-(7-(1-乙酰基氮杂环丁烷-3-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺Example 41 N-(4-(7-(1-Acetylazetidin-3-yl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl )-2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2021094020-appb-000074
Figure PCTCN2021094020-appb-000074
向N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(60mg，0.12mmol)的DCM(10mL)混合物中加入三乙胺(37mg，0.36mmol)和乙酰氯(10mg，0.12mmol)，所得混合物于RT下搅拌反应2h。反应混合物用DCM(30mL×2)和H 2O(30mL)萃取。有机层用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，减压浓缩，残余物经制备型HPLC(Gemini-C18 150 x 21.2mm，5um，ACN--H 2O(0.1％FA)20％-30％)纯化，得到N-(4-(7-(1-乙酰基氮杂环丁烷-3-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(44.6mg，66％)。MS(ESI,pos.ion)m/z:563.1[M+H] +。 1H NMR:(400MHz,DMSO)δ10.70(s,1H),8.15(s,1H),7.72–7.68(m,3H),7.59(t,J＝7.4Hz,2H),7.52(d,J＝7.2Hz,1H),7.48–7.44(m,4H),6.32-6.10(m,2H),5.61-5.53(m,1H),4.63-4.57(m 1H),4.57–4.53(m,1H),4.37-4.31(m,1H),4.25-4.20(m,1H),3.57(t,J＝5.8Hz,2H),3.21(t,J＝6.4Hz,2H),2.01–1.96(m,2H),1.85–1.81(m,5H)。 To N-(4-(4-amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-2-oxo- 1-Phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide (60mg, 0.12mmol) in DCM (10mL) was added three Ethylamine (37mg, 0.36mmol) and acetyl chloride (10mg, 0.12mmol), the resulting mixture was stirred and reacted at RT for 2h. The reaction mixture was extracted with DCM (30 mL×2) and H 2 O (30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (Gemini-C18 150 x 21.2mm, 5um, ACN--H 2 O (0.1% FA) 20%-30%) purification to obtain N-(4-(7-(1-acetylazetidin-3-yl)-4-amino-7H-pyrrolo[2,3-d] (Pyrimidine-5-yl)phenyl)-2-oxo-1-phenyl-1,2,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide is White solid (44.6 mg, 66%). MS (ESI, pos.ion) m/z: 563.1 [M+H] + . 1 H NMR: (400MHz, DMSO)δ10.70(s,1H), 8.15(s,1H), 7.72–7.68(m,3H), 7.59(t,J=7.4Hz,2H), 7.52(d, J=7.2Hz,1H),7.48–7.44(m,4H),6.32-6.10(m,2H),5.61-5.53(m,1H),4.63-4.57(m 1H),4.57–4.53(m,1H) ), 4.37-4.31 (m, 1H), 4.25-4.20 (m, 1H), 3.57 (t, J = 5.8 Hz, 2H), 3.21 (t, J = 6.4 Hz, 2H), 2.01-1.96 (m, 2H), 1.85–1.81 (m, 5H).
生物试验Biological test
分析用的LC/MS/MS***包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离(ESI)源的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：The LC/MS/MS system used for analysis includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column thermostat, Agilent G6430 three-stage quadrupole mass spectrometer with electrospray ionization (ESI) source . Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
表ATable A
多反应检测扫描Multiple reaction detection scan 490.2→383.1490.2→383.1
碎裂电压Fragmentation voltage 230V230V
毛细管电压Capillary voltage 55V55V
干燥气温度Drying gas temperature 350℃350°C
雾化器Atomizer 0.276MPa0.276MPa
干燥气流速Drying gas flow rate 10L/min10L/min
分析使用Agilent XDB-C18，2.1×30mm，3.5μM柱，注入5μL样品。分析条件：流动相为0.1％的甲酸水溶液(A)和0.1％的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表B所示：The Agilent XDB-C18, 2.1×30mm, 3.5μM column was used for analysis, and 5μL of sample was injected. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL/min. The mobile phase gradient is shown in Table B:
表BTable B
时间time 流动相B的梯度Gradient of mobile phase B
0.5min0.5min 5％5%
1.0min1.0min 95％95%
2.2min2.2min 95％95%
2.3min2.3min 5％5%
5.0min5.0min 终止termination
此外，用于分析的还有Agilent 6330系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和G1314C UV检测器；LC/MS/MS光谱仪采用ESI放射源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Capcell MP-C18柱，规格为：100×4.6mm I.D.，5μM(Phenomenex,Torrance,California,USA)。流动相是5mM醋酸铵，0.1％甲醇水溶液(A)：5mM醋酸铵，0.1％甲醇乙腈溶液(B)(70:30，v/v)；流速为0.6mL/min；柱温保持在室温；注入20μL样品。In addition, Agilent 6330 series LC/MS/MS spectrometer is used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer uses ESI radiation source. Use standard solutions to perform appropriate cation model processing and MRM conversion for each analyte for optimal analysis. During the analysis, the Capcell MP-C18 column was used, the specification was: 100×4.6mm I.D., 5μM (Phenomenex, Torrance, California, USA). The mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 μL of sample.
实施例A激酶活性试验Example A Kinase activity test
本发明公开化合物作为蛋白激酶抑制剂的效用可以通过下面的实验来评价。The effectiveness of the compounds disclosed in the present invention as protein kinase inhibitors can be evaluated by the following experiments.
本发明化合物的AXL(h)激酶活性采用以下方法进行测试：The AXL(h) kinase activity of the compounds of the present invention was tested by the following method:
方法1：method 1:
激酶试验通过检测掺入γ- 33P-ATP的髓磷脂碱基蛋白(MBP)来完成的。制备20μg/ml的MBP(Sigma#M-1891)三羟甲基氨基甲烷缓冲盐溶液(TBS；50mM Tris pH＝8.0，138mM NaCl，2.7mM KCl)，包被高结合性的白384孔板(Greiner)，每孔60μL。4℃下，孵育24小时。之后用100μL TBS洗板3次。激酶反应在总体积为34μL的激酶缓冲液(根据需要配制，例如，5mM Hepes pH 7.6，15mM NaCl，0.01％牛血清白蛋白(Sigma#I-5506)，10mM MgCl 2，1mM DTT，0.02％TritonX-100)中进行。将化合物溶解在DMSO中，加入各孔中，DMSO溶液中化合物的最终浓度为1％。每个化合物的测定至少进行两次试验。比如，酶的最终浓度为10nM或20nM。加入没有标记的ATP(10μM)和γ- 33P标记的ATP(每孔2×10 6cpm，3000Ci/mmol)开始反应。反应在室温下震荡进行1个小时。384孔板用7×的PBS清洗，然后加入每孔50μL的闪烁液。用Wallac Trilux计数器检测结果。 The kinase test is done by detecting myelin base protein (MBP) incorporated into γ-33 P-ATP. Prepare 20μg/ml MBP (Sigma#M-1891) Tris Buffered Salt Solution (TBS; 50mM Tris pH=8.0, 138mM NaCl, 2.7mM KCl), and coat the high binding white 384-well plate ( Greiner), 60μL per well. Incubate for 24 hours at 4°C. After that, the plate was washed 3 times with 100 μL TBS. Kinase reaction in a total volume of 34μL kinase buffer (prepared as needed, for example, 5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl 2 , 1mM DTT, 0.02% TritonX -100). The compound was dissolved in DMSO and added to each well. The final concentration of the compound in the DMSO solution was 1%. At least two tests are carried out for the determination of each compound. For example, the final concentration of the enzyme is 10 nM or 20 nM. Add unlabeled ATP (10 μM) and γ- 33 P labeled ATP (2×10 6 cpm per well, 3000 Ci/mmol) to start the reaction. The reaction was carried out with shaking at room temperature for 1 hour. The 384-well plate was washed with 7× PBS, and then 50μL of scintillation fluid was added to each well. Check the results with a Wallac Trilux counter.
AXL(h)在8mM MOPS pH＝7.0，0.2mM EDTA，250μM KKSRGDYMTMQIG，10mM醋酸镁和[γ- 33P-ATP](比活性和浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入磷酸溶液至0.5％浓度来终止反应。将10μL的反应液呈斑点状分布于P30过滤器上，用4分钟以0.425％磷酸溶液清洗4次，甲醇清洗1次。干燥后用闪烁计数器测定。 AXL(h) was incubated in the presence of 8mM MOPS pH=7.0, 0.2mM EDTA, 250μM KKSRGDYMTMQIG, 10mM magnesium acetate and [γ- 33 P-ATP] (specific activity and concentration determined according to requirements). The reaction started after the MgATP mixture was added. After incubating for 40 minutes at room temperature, a phosphoric acid solution was added to it to a concentration of 0.5% to terminate the reaction. Distribute 10 μL of the reaction solution on the P30 filter in the form of spots, wash 4 times with 0.425% phosphoric acid solution in 4 minutes, and wash once with methanol. After drying, use a scintillation counter to measure.
方法2：Method 2:
在试验中所使用的试剂有AXL(Carna Bioscience,Cat No.:08-107)和FLPeptide30(PerkinElmer,Cat No.:760430)。所涉及的仪器有恒温箱(Thermo Scientific)，震荡器(QILINBEIER)，EZ Reader(PerkinElmer,Cat No.:122919)，非接触式级移液***(Labcyte Inc.,Cat No.:Echo 550)，和非接触式纳升级移液***(TECAN,Cat No.:EVO200)。The reagents used in the experiment are AXL (Carna Bioscience, Cat No.: 08-107) and FLPeptide 30 (PerkinElmer, Cat No.: 760430). The instruments involved are incubator (Thermo Scientific), oscillator (QILINBEIER), EZ Reader (PerkinElmer, Cat No.: 122919), non-contact level pipetting system (Labcyte Inc., Cat No.: Echo 550), And non-contact nano-upgraded pipetting system (TECAN, Cat No.: EVO200).
试验方法experiment method
化合物稀释：1)将化合物溶解于DMSO到适当的浓度；2)利用TECAN EVO200在384微孔板中3倍梯度稀释10个浓度，最高浓度为1mM；利用Echo550从稀释板中转移20nL溶液到实验板中。Compound dilution: 1) Dissolve the compound in DMSO to an appropriate concentration; 2) Use TECAN EVO200 to 3-fold 10 concentrations in a 384 microwell plate, the highest concentration is 1mM; use Echo550 to transfer 20nL solution from the dilution plate to the experiment In the board.
酶实验方法Enzyme test method
1)准备溶液1，如下表C所示1) Prepare solution 1, as shown in Table C below
表CTable C
试剂名称Reagent name 溶液1Solution 1
MgCl 2 MgCl 2 10mM10mM
Brij-35Brij-35 0.050％0.050%
DTTDTT 2mM2mM
BSABSA 0.05％0.05%
EGTAEGTA 1mM1mM
HEPE(pH7.5)HEPE(pH7.5) 50mM50mM
AXLAXL 1.333nM1.333nM
2)实验板中每个孔加入15uL溶液1，并室温孵育30分钟。2) Add 15uL solution 1 to each well of the experiment plate, and incubate at room temperature for 30 minutes.
3)准备溶液2，如下表D所示：3) Prepare solution 2, as shown in Table D below:
表DTable D
试剂名称Reagent name 溶液2Solution 2
MgCl 2 MgCl 2 10mM10mM
Brij-35Brij-35 0.050％0.050%
DTTDTT 2mM2mM
BSABSA 0.05％0.05%
EGTAEGTA 1mM1mM
HEPE(pH7.5)HEPE(pH7.5) 50mM50mM
FLPeptideFLPeptide 6μM6μM
ATPATP 400μM400μM
4)加入5μL溶液2启动反应，最终每孔的体积是20μL，体系中成分如下表E所示：4) Add 5μL of solution 2 to start the reaction, and the final volume of each well is 20μL. The composition of the system is shown in Table E below:
表ETable E
试剂名称Reagent name 终浓度Final concentration
MgCl 2 MgCl 2 10mM10mM
Brij-35Brij-35 0.050％0.050%
DTTDTT 2mM2mM
BSABSA 0.05％0.05%
EGTAEGTA 1mM1mM
HEPE(pH7.5)HEPE(pH7.5) 50mM50mM
FLPeptideFLPeptide 1.5μM1.5μM
ATPATP 100μM100μM
AXLAXL 1nM1nM
5)25℃下孵育90分钟，然后加入75μL的终止液(含0.5M EDTA)终止反应。5) Incubate at 25°C for 90 minutes, and then add 75μL of stop solution (containing 0.5M EDTA) to stop the reaction.
6)使用EZ reader分析每个孔的样品。6) Use EZ reader to analyze the samples of each well.
数据分析data analysis
1)通过测得的转化率(CR),根据下面的函数计算酶的保留活性(Remaining Activity(％))：1) Using the measured conversion rate (CR), calculate the enzyme's remaining activity (Remaining Activity (%)) according to the following function:
Figure PCTCN2021094020-appb-000075
Figure PCTCN2021094020-appb-000075
2)使用XLFit(方程201)软件拟合计算IC 50。 2) using the XLFit (Equation 201) fit calculation software IC 50.
上述试验方法可以得到抑制的IC 50和/或抑制常数K i。IC 50定义为在试验条件下，抑制50％酶活性时的化合物浓度。利用1/2log的稀释倍数做出包含10个浓度点的曲线，估算IC 50值(例如，通过以下化合物浓度做出一条典型的曲线：3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM、0.0003μM、0μM)，或者10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM、0μM)。 Test method described above can be obtained IC 50 and / or suppression of the inhibitory constant K i. The IC 50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the test conditions. Use the 1/2log dilution factor to make a curve containing 10 concentration points, and estimate the IC 50 value (for example, make a typical curve with the following compound concentrations: 3μM, 1μM, 0.3μM, 0.1μM, 0.03μM, 0.01μM , 0.003μM, 0.001μM, 0.0003μM, 0μM), or 10μM, 3μM, 1μM, 0.3μM, 0.1μM, 0.03μM, 0.01μM, 0.003μM, 0.001μM, 0μM).
对于所属领域的技术人员而言，这仅是众多检测方法中的两种，其他的方法亦可。For those skilled in the art, these are only two of the many detection methods, and other methods are also possible.
实施例B细胞活性试验Example B cell activity test
本试验是通过检测化合物对Ba/F3 AXL细胞系和Ba/F3亲代细胞系两株细胞生长的抑制作用来完成的。收获处于对数生长期的细胞并采用血小板计数器进行细胞计数，用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上；调整细胞浓度；分别添加90μL细胞悬液至96孔板中；将96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下培养过夜。配制10倍药物溶液，最高浓度为10μM，9个浓度，3.16倍稀释，在接种有细胞的96孔板中每孔加入10μL药物溶液，每个药物浓度设置三个复孔；将已加药的96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下继续培养72小时，之后进行CTG分析。融化CTG试剂并平衡细胞板至室温30分钟，每孔加入等体积的CTG溶液，在定轨摇床上振动5分钟使细胞裂解，将细胞板放置于室温20分钟以稳定冷光信号，读取冷光值。使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值，细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。 This test is done by testing the compound's inhibitory effect on the growth of the Ba/F3 AXL cell line and the Ba/F3 parent cell line. Harvest the cells in the logarithmic growth phase and use a platelet counter to count the cells. Use the trypan blue exclusion method to check the cell viability to ensure that the cell viability is above 90%; adjust the cell concentration; add 90 μL of cell suspension to a 96-well plate respectively; The cells in the 96-well plate were incubated overnight at 37°C, 5% CO 2 , and 95% humidity. Prepare a 10-fold drug solution, the highest concentration is 10μM, 9 concentrations, 3.16-fold dilution, add 10μL drug solution to each well of a 96-well plate seeded with cells, and set three multiple wells for each drug concentration; The cells in the 96-well plate were kept at 37°C, 5% CO 2 , and 95% humidity for 72 hours, after which CTG analysis was performed. Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes, add an equal volume of CTG solution to each well, shake on an orbital shaker for 5 minutes to lyse the cells, place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal, and read the luminescence value . Use GraphPad Prism 5.0 software to analyze the data, use nonlinear S-curve regression to fit the data to obtain the dose- response curve, and calculate the IC 50 value from this, cell survival rate (%) = (Lum test drug-Lum culture medium control )/(Lum cell control-Lum culture medium control)×100%.
下表1提供了本发明化合物的AXL(h)激酶实验结果，表明本发明化合物对AXL激酶有非常好的抑制作用。Table 1 below provides the AXL(h) kinase test results of the compounds of the present invention, indicating that the compounds of the present invention have a very good inhibitory effect on AXL kinase.
表1本发明化合物对AXL(h)激酶和Ba/F3AXL细胞的抑制活性Table 1 Inhibitory activity of the compounds of the present invention on AXL(h) kinase and Ba/F3AXL cells
+：>100nM；++：50-100nM；+++：10-50nM；++++：<10nM+: >100nM; ++: 50-100nM; +++: 10-50nM; ++++: <10nM
Figure PCTCN2021094020-appb-000076
Figure PCTCN2021094020-appb-000076
最后，需要注意的是，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。Finally, it should be noted that there are other ways to implement the present invention. Correspondingly, the embodiments of the present invention will be described as examples, but are not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention will serve as references in the present invention.

Claims (13)

  1. 化合物，其具有式(I)所示结构：Compound, which has the structure represented by formula (I):
    Figure PCTCN2021094020-appb-100001
    Figure PCTCN2021094020-appb-100001
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
    其中，in,
    U 1和U 2分别独立地为N或-C(R a)-； U 1 and U 2 are each independently N or -C(R a )-;
    R 1和R 2分别独立地为H、C 1-6烷基、C 1-6卤代烷基、C 2-6羟基烷基、C 2-6氨基烷基、C 1-6氰基烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 2-6羟基烷基、C 2-6氨基烷基、C 1-6氰基烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 11取代； R 1 and R 2 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkane C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl And C 1-9 heteroaryl C 1-6 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 11 ;
    R 4是C 2-6羟基烷基、C 4-10环烷基、C 4-10环烷基C 1-6烷基、C 3-7杂环基、或C 3-7杂环基C 1-6烷基；其中所述各C 2-6羟基烷基、C 4-10环烷基、C 4-10环烷基C 1-6烷基、C 3-7杂环基和C 3-7杂环基C 1-6烷基独立任选地被0、1、2、3或4个R 11a取代； R 4 is C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-6 alkyl; wherein each of the C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 3-7 heterocyclyl and C 3 -7 heterocyclyl C 1-6 alkyl is independently optionally substituted with 0, 1, 2, 3 or 4 R 11a ;
    各R a、R 3、R 5、R 6、R 7和R 8分别独立地为H、D、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各-NR cR d、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 12取代； Each of R a , R 3 , R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each -NR c R d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 cycloalkyl, C 3- 8 Cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 Alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ;
    或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成4-12个原子组成的杂环，其中所述4-12个原子组成的杂环任选地包含1、2或3个N、O、和/或S原子并任选地被0、1、2、3、4或5个R 13取代； Or R 2 and R 3, together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-12 atoms, wherein the heterocyclic ring consisting of 4-12 atoms optionally includes 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4 or 5 R 13 ;
    各R 11、R 11a、R 12和R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)R 9、-OC(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-OS(＝O) 1-2R 9、-S(＝O) 1-2OR 9a、-N(R 10a)C(＝O)R 10、-C(＝O)NR 10aR 10、-OC(＝O)NR 10aR 10、-N(R 10a)S(＝O) 1-2R 10、-S(＝O) 1-2NR 10aR 10、-N(R 10a)C(＝O)NR 10aR 10、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各-NR cR d、-C(＝O)R 9、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代； Each of R 11 , R 11a , R 12 and R 13 is independently H, D, oxo (=O), F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d ,- C(=O)R 9 , -OC(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -OS(=O) 1-2 R 9 , -S(=O) 1-2 OR 9a , -N(R 10a )C(=O)R 10 , -C(=O)NR 10a R 10 , -OC(=O)NR 10a R 10 , -N (R 10a )S(=O) 1-2 R 10 , -S(=O) 1-2 NR 10a R 10 , -N(R 10a )C(=O)NR 10a R 10 , C 1-6 alkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1 -6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclic group, C 2-7 heterocyclic group C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl ; Wherein each of -NR c R d , -C(=O)R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1 -6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8 Cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 Alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3 or 4 independently selected from H, D, oxo ( =O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy group substitution;
    各R c、R d、R 9、R 9a、R 10和R 10a分别独立地为H、D、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、 C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；和 Each R c , R d , R 9 , R 9a , R 10 and R 10a is independently H, D, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1 -6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1- 9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each of the C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 hetero Aryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3, or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy group substitution; and
    n是0、1、或2。n is 0, 1, or 2.
  2. 根据权利要求1所述的化合物，其具有式(II)所示结构：The compound according to claim 1, which has the structure represented by formula (II):
    Figure PCTCN2021094020-appb-100002
    Figure PCTCN2021094020-appb-100002
    其中，in,
    X 1是O、S、-N(R 13a)-、-C(＝O)-、-(CH 2) t1-、-X 2-(CH 2) t1-、或-(CH 2) t1-X 2-(CH 2) t2-； X 1 is O, S, -N(R 13a )-, -C(=O)-, -(CH 2 ) t1 -, -X 2 -(CH 2 ) t1 -, or -(CH 2 ) t1- X 2 -(CH 2 ) t2 -;
    X 2是O、S、-N(R 13a)-、或-C(＝O)-； X 2 is O, S, -N(R 13a )-, or -C(=O)-;
    各R 13a分别独立地为H、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基、-C(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-S(＝O) 1-2OR 9a、-S(＝O) 1-2NR 10aR 10、或-C(＝O)NR 10aR 10，其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代； Each R 13a is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 Heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-6 alkane Base, -C(=O)R 9 , -C(=O)OR 9a , -S(=O) 0-2 R 9 , -S(=O) 1-2 OR 9a , -S(=O) 1-2 NR 10a R 10 , or -C(=O)NR 10a R 10 , wherein each C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 Alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 hetero Aryl and C 1-9 heteroaryl C 1-6 alkyl are independently optionally 0, 1, 2, 3, or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl and C 1-6 alkoxy group substitution;
    各t1和t2分别独立地为0、1、2、或3；和Each t1 and t2 are independently 0, 1, 2, or 3; and
    m是0、1、2、4、或5。m is 0, 1, 2, 4, or 5.
  3. 根据权利要求1或2所述的化合物，其中，The compound of claim 1 or 2, wherein
    R 1是C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡唑基或***基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、C 1-4氰基烷基、C 3-8环烷基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡唑基和***基独立任选地被0、1、2、3或4个R 11取代。 R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, Phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl or triazolyl; wherein each of the C 1-4 alkyl group, C 1-4 haloalkyl group, C 2-4 hydroxyalkyl group , C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl and triazolyl Independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
  4. 根据权利要求1所述的化合物，其中，The compound of claim 1, wherein
    R 2是H、C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基、或C 1-4氰基烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 2-4羟基烷基、C 2-4氨基烷基和C 1-4氰基烷基独立任选地被0、1、2、3或4个R 11取代； R 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl and C 1-4 cyanoalkyl are independently optionally 0, 1, 2, 3 or 4 R 11 substitutions;
    R 3是H、D、F、-CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、或C 1-4氰基烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基独立任选地被0、1、2、3或4个R 12取代； R 3 is H, D, F, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl Group; wherein each of the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl and C 1-4 cyanoalkyl are independently optionally 0 , 1, 2, 3 or 4 R 12 substitutions;
    或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成4-7个原子组成的杂环，其中所述4-7个原子组成的杂环任选地包含1、2或3个N、O、和/或S原子并任选地被0、1、2、3、4或5个R 13取代。 Or R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-7 atoms, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4, or 5 R 13 .
  5. 根据权利要求1或2所述的化合物，其中，The compound of claim 1 or 2, wherein
    R 4是C 2-4羟基烷基、C 4-6环烷基、C 4-6环烷基C 1-4烷基、C 3-6杂环基、或C 3-6杂环基C 1-4烷基；其中所述各C 2-4羟基烷基、C 4-6环烷基、C 4-6环烷基C 1-4烷基、C 3-6杂环基和C 3-6杂环基C 1-4烷基独立任选地被0、1、2、3或4个R 11a取代。 R 4 is C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl, C 1-4 alkyl, C 3-6 heterocyclyl, or C 3-6 heterocyclyl C 1-4 alkyl; wherein each of the C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl, C 1-4 alkyl, C 3-6 heterocyclyl and C 3 The -6 heterocyclyl C 1-4 alkyl is independently optionally substituted with 0, 1, 2, 3, or 4 R 11a .
  6. 根据权利要求1或2所述的化合物，其中，The compound of claim 1 or 2, wherein
    R 4是
    Figure PCTCN2021094020-appb-100003
    Figure PCTCN2021094020-appb-100004
    其中R 4任选地被0、1、2、3或4个R 11a取代。     R 4 is
    Figure PCTCN2021094020-appb-100003
    Figure PCTCN2021094020-appb-100004
    Wherein R 4 is optionally substituted with 0, 1, 2, 3 or 4 R 11a .
  7. 根据权利要求1或2所述的化合物，其中，The compound of claim 1 or 2, wherein
    各R 11a分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)C 1-4烷基、-OC(＝O)C 1-4烷基、-C(＝O)O-C 1-4烷基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、或C 1-4烷基氨基。 Each R 11a is independently H, D, oxo (=O), F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , -C(=O)C 1-4 Alkyl, -OC(=O)C 1-4 alkyl, -C(=O)OC 1-4 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, or C 1-4 alkylamino.
  8. 根据权利要求1所述的化合物，其为具有以下结构之一的化合物：The compound according to claim 1, which is a compound having one of the following structures:
    Figure PCTCN2021094020-appb-100005
    Figure PCTCN2021094020-appb-100005
    Figure PCTCN2021094020-appb-100006
    Figure PCTCN2021094020-appb-100006
    Figure PCTCN2021094020-appb-100007
    Figure PCTCN2021094020-appb-100007
    Figure PCTCN2021094020-appb-100008
    Figure PCTCN2021094020-appb-100008
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐。Or its stereoisomers, tautomers, nitrogen oxides, solvates, or pharmaceutically acceptable salts.
  9. 药物组合物，所述药物组合物包含权利要求1-8中任一项所述的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐，以及药学上可接受的辅料、稀释剂或载体、或其组合。A pharmaceutical composition comprising the compound of any one of claims 1-8 or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof , And pharmaceutically acceptable excipients, diluents or carriers, or combinations thereof.
  10. 根据权利要求9所述的药物组合物，其进一步包含附加治疗剂。The pharmaceutical composition according to claim 9, which further comprises an additional therapeutic agent.
  11. 使用根据权利要求1-8任一项所述的化合物或权利要求9-10任一项所述的药物组合物在制备用于预防和/或治疗AXL激酶介导的疾病和/或病症的药物中的用途。Using the compound according to any one of claims 1-8 or the pharmaceutical composition according to any one of claims 9-10 in the preparation of a medicament for the prevention and/or treatment of AXL kinase-mediated diseases and/or disorders In the use.
  12. 根据权利要求11所述的用途，所述疾病和/或病症选自增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、移植排斥、或病毒感染性疾病。The use according to claim 11, wherein the diseases and/or conditions are selected from proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, or viral infectious diseases.
  13. 根据权利要求11所述的用途，所述疾病和/或病症选自癌症、真性红细胞增多症、原发性血小板增多症、急性髓细胞性白血病、急性淋巴细胞白血病、骨髓纤维化、急性髓细胞性白血病、慢性髓细胞性白血病、急性淋巴细胞白血病、慢性阻塞性肺疾病、哮喘、***性红斑狼疮、皮肤型红斑狼疮、狼疮性肾炎、皮肌炎、干燥综合征、银屑病、I型糖尿病、呼吸道过敏性疾病、鼻窦炎、湿疹、麻疹、食物过敏、昆虫毒液过敏、炎性肠病、克罗恩病、类风湿性关节炎、幼年型关节炎、银屑病性关节炎、器官移植排斥、组织移植排斥、细胞移植排斥、流感、冠状病毒感染、新冠状病毒感染、登革热病毒感染、寨卡病毒感染、埃博拉病毒感染、呼吸道合胞病毒感染、或HBV。The use according to claim 11, wherein the disease and/or condition is selected from cancer, polycythemia vera, essential thrombocythemia, acute myeloid leukemia, acute lymphocytic leukemia, myelofibrosis, acute myeloid cells Leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic obstructive pulmonary disease, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, type I Diabetes, respiratory allergic diseases, sinusitis, eczema, measles, food allergy, insect venom allergy, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, organs Transplant rejection, tissue transplant rejection, cell transplant rejection, influenza, coronavirus infection, new coronavirus infection, dengue virus infection, Zika virus infection, Ebola virus infection, respiratory syncytial virus infection, or HBV.
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