WO2018108079A1 - 多激酶抑制剂化合物、其晶型及用途 - Google Patents
多激酶抑制剂化合物、其晶型及用途 Download PDFInfo
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- WO2018108079A1 WO2018108079A1 PCT/CN2017/115698 CN2017115698W WO2018108079A1 WO 2018108079 A1 WO2018108079 A1 WO 2018108079A1 CN 2017115698 W CN2017115698 W CN 2017115698W WO 2018108079 A1 WO2018108079 A1 WO 2018108079A1
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- 0 CC*(CC1)CCS1(=O)=O Chemical compound CC*(CC1)CCS1(=O)=O 0.000 description 12
- RCVCFESJQJFXAL-UHFFFAOYSA-N CCN1CCN(Cc(nc2)cc(Nc3n[nH]c(C)c3[N+]([O-])=O)c2C(c(cccc2)c2Cl)=O)CC1 Chemical compound CCN1CCN(Cc(nc2)cc(Nc3n[nH]c(C)c3[N+]([O-])=O)c2C(c(cccc2)c2Cl)=O)CC1 RCVCFESJQJFXAL-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N CCN1CCNCC1 Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N CCN1CCOCC1 Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- ULZCOWMSBOJCLT-UHFFFAOYSA-N CN(CC1)CCS1(=O)=O Chemical compound CN(CC1)CCS1(=O)=O ULZCOWMSBOJCLT-UHFFFAOYSA-N 0.000 description 1
- RXYPXQSKLGGKOL-UHFFFAOYSA-N CN1CCN(C)CC1 Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- HNRUZNJUGBZKPP-UHFFFAOYSA-N Cc([nH]nc1Nc2c3)c1N=C(c1ccccc1Cl)c2cnc3N1CC2(CC2)N(C)CC1 Chemical compound Cc([nH]nc1Nc2c3)c1N=C(c1ccccc1Cl)c2cnc3N1CC2(CC2)N(C)CC1 HNRUZNJUGBZKPP-UHFFFAOYSA-N 0.000 description 1
- DZNXMHJMXLSNIR-UHFFFAOYSA-N Cc(cncc1)c1Cl Chemical compound Cc(cncc1)c1Cl DZNXMHJMXLSNIR-UHFFFAOYSA-N 0.000 description 1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention belongs to the technical field of medicine, and in particular relates to a multi-kinase inhibitor compound, its crystal form and use.
- Aurora kinases are one of the mitotic kinases that were discovered in 1995 and were first observed in human tumor tissues in 1998. It has become a hot target for studying anti-tumor.
- the Aurora kinase family includes three highly homologous kinases: Aurora A, Aurora B, and Aurora C. Among them, Aurora A and Aurora B are currently at detectable levels.
- Aurora A has now been shown to be an oncogene whose overexpression blocks the correct assembly of mitotic checkpoint complexes, resulting in genetic instability and tumor formation.
- Aurora B is an important kinase that regulates the normal progression of cell mitosis. Aurora B is widely expressed in tumors. When Aurora B is inhibited, tumor cells become more sensitive.
- anti-tumor drugs targeting Aurora kinase has attracted more and more attention.
- Aurora kinases are expressed and activated during mitosis, and they are ineffective against non-proliferating cells. Therefore, Aurora kinase inhibitors are targeted anti-tumor drugs, which will have greater advantages than other non-specific cytotoxic drugs.
- VEGFR vascular endothelial growth factor/vascular endothelial growth factor receptor
- VEGFR2 The conformation of VEGFR binds to VEGF, resulting in receptor dimerization, autophosphorylation of the intracellular tyrosine site, and activation of downstream signaling pathways.
- VEGFR2 (KDR) is mainly distributed in vascular endothelial cells and hematopoietic stem cells, and hematopoietic system dysfunction before malignant proliferative lesions, such as thrombocytosis, thrombocythemia, myelofibrosis (MF), chronic congenital Myelofibrosis (IMF), polycythemia (PV), and myelodysplastic syndromes and hematological malignancies are closely related.
- hematological malignancies include, but are not limited to, leukemia (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma, for example, acute lymphocytic leukemia (ALL), acute Myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), and the like.
- ALL acute lymphocytic leukemia
- AML acute Myeloid leukemia
- APL acute promyelocytic leukemia
- CLL chronic lymphocytic leukemia
- CML chronic myelogenous leukemia
- CML chronic neutrophilic leukemia
- WO2013123840A1 discloses a class of azabenzo[f]indole derivatives having antitumor effects, but does not disclose its therapeutic mechanism.
- the present invention provides a compound (multi-kinase inhibitor) capable of inhibiting, regulating and/or regulating the activity of one or more protein kinases such as Aurora kinase and VEGFR kinase as shown in the following formulas (I), (II) or A pharmaceutically acceptable salt, a stereoisomer, a crystalline form I of a compound represented by the following formula (III), and a pharmaceutical preparation and a pharmaceutical composition comprising the above compound and/or crystalline form I for treating these kinase abnormalities Diseases mediated, especially cancer-related diseases.
- the invention also provides methods of preparing the above compounds and crystalline forms, and methods of using the compounds, crystalline forms, pharmaceutical formulations and/or pharmaceutical compositions to treat the above-described diseases in mammals, particularly humans.
- the present invention first provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof:
- X is selected from CH or N;
- R 1 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy;
- R 2 is selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl
- Y is selected from CR 3 or N;
- P is selected from CR 4 or N;
- W is selected from CR 5 or N;
- R 3 , R 4 , R 5 are independently selected from the group consisting of hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy , oxa C 5-8 cycloalkyloxy, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkylamino, C 1- 6 alkylsulfonyl, C 3-8 cycloalkylsulfonyl, C 1-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, -NR 11 -(CH 2 ) n -N(R 7 )(R 8 ), C 1-6 alkylthio-(CH 2 ) n -, -(CH 2 ) n -(3-14) membered cycloalkyl, -(CH 2 ) n -(
- R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halogenated C 1-6 alkoxy base;
- P, W, and Y are not N at the same time.
- R 4 cannot be selected from a C 1-6 alkyl group.
- R 4 or R 5 When Y is CR 3 , P is CR 4 , and W is CR 5 , one of R 4 or R 5 must be selected from H;
- Ar is selected from a 3-14 membered cycloalkyl group, a 6-14 membered aryl group, a 5-14 membered heterocyclic group or a 5-14 membered heteroaryl group, a cycloalkyl group, an aryl group, a heterocyclic group or a heteroaryl group.
- the ring-forming S atom may be optionally oxidized to S(O) or S(O) 2
- the ring-forming C atom may be optionally oxidized to C(O)
- Ar may be optionally substituted with 1-3 R 6 ;
- Each R 6 is independently selected from the group consisting of hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 Cycloalkyloxy, halo C 1-6 alkoxy, halo C 1-6 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, -NR 11 -(CH 2 ) n -N(R 9 )(R 10 ), amino C 1-6 alkyl, C 3-6 cycloalkylamino, C 1-6 alkylsulfonyl, C 3-8 cycloalkyl Sulfonyl, C 1-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 1-6 alkylthio, -(CH 2 ) n -(6-14)membered cycloalkyl, -(CH 2 n
- R 9 and R 10 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halo C 1-6 alkoxy base;
- R 11 is selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.
- One embodiment of the present invention relates to the compound of the above formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- R 1 is selected from C 1-3 alkyl, preferably methyl or ethyl
- R 2 is selected from the group consisting of hydrogen, methyl, and ethyl
- X is selected from N.
- One embodiment of the present invention relates to the compound of the above formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- Ar is selected from a 6-14 membered aryl group or a 5-14 membered heteroaryl group, and any ring-forming S atom in the aryl group or heteroaryl group may be optionally oxidized to S(O) or S(O) 2 to form a ring.
- C atoms may optionally be oxidized to C (O)
- Ar 6 may be optionally substituted with 1-3 R <
- One embodiment of the present invention relates to the compound of the above formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- X is N
- R 1 is selected from C 1-3 alkyl, preferably methyl or ethyl
- R 2 is selected from the group consisting of hydrogen, methyl or ethyl
- Y is selected from CR 3 or N;
- P is selected from CR 4 or N;
- W is selected from CR 5 or N;
- R 3 , R 4 , R 5 are independently selected from the group consisting of hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy , oxa C 5-8 cycloalkyloxy, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkylamino, C 1- 6 alkylsulfonyl, C 3-8 cycloalkylsulfonyl, C 1-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, -NR 11 -(CH 2 ) n -N(R 7 )(R 8 ), C 1-6 alkylthio-(CH 2 ) n -, -(CH 2 ) n -(3-14) membered cycloalkyl, -(CH 2 ) n -(
- R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halo C 1-6 alkyl or halogenated C 1-6 alkoxy base;
- the three atoms P, W, and Y are not N at the same time.
- R 4 cannot be selected from a C 1-6 alkyl group.
- R 4 or R 5 When Y is CR 3 , P is CR 4 , and W is CR 5 , one of R 4 or R 5 must be selected from H;
- R 11 is selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl
- Ar is selected from a 6-14 membered aryl group or a 5-10 membered heteroaryl group, and the ring-forming S atom in the aryl group or heteroaryl group may be optionally oxidized to S(O) or S(O) 2 to form a ring C.
- the atom may be optionally oxidized to C(O), wherein Ar may be optionally substituted with 1-3 R 6 ,
- One embodiment of the present invention relates to the aforementioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which has the structural formula shown in (II):
- Ar is selected from a 5-6 membered aryl group or a 5-6 membered heteroaryl group, and the ring-forming S atom in the aryl group or heteroaryl group may be optionally oxidized to S(O) or S(O) 2 to form a ring C. atoms may optionally be oxidized to C (O), Ar 6 may be optionally substituted with 1-3 R <
- Each R 6 is independently selected from the group consisting of hydrogen, amino, cyano, halogen, C 1-4 alkyl, trifluoromethyl or methylsulfonyl, and halogen is preferably chlorine;
- Y is selected from CR 3 or N;
- P is selected from CR 4 or N;
- W is selected from CR 5 or N;
- R 3 , R 4 , R 5 are independently selected from the group consisting of hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy , oxa C 5-8 cycloalkyloxy, halo C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkylamino, C 1- 4 -alkylsulfonyl, C 3-8 cycloalkylsulfonyl, C 1-4 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, -NR 11 -(CH 2 ) n -N(R 7 )(R 8 ), -(CH 2 ) n -(3-14)membered cycloalkyl, -(CH 2 ) n -(5-11)membered heterocyclyl or -(CH 2
- R 7 and R 8 are independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl;
- the three atoms P, W, and Y are not N at the same time, and at least one of P, W, and Y is N;
- R 4 may not be selected from C 1-4 alkyl
- R 11 is selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.
- Y is selected from CR 3 ;
- P is selected from CR 4 ;
- W is selected from N;
- R 4 may not be selected from a C 1-4 alkyl group.
- One embodiment of the present invention relates to a compound represented by the above formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- Ar may be selected from the group consisting of:
- Y is selected from CR 3 or N;
- P is selected from CR 4 or N;
- W is selected from CR 5 or N;
- R 3, R 4, R 5 are independently selected from the group:
- the three atoms P, W, and Y are not N at the same time, and at least one of P, W, and Y is N;
- Y is selected from CR 3 ;
- P is selected from CR 4 ;
- W is selected from N;
- Ar is selected from phenyl or 5-6 membered heteroaryl, and Ar may be optionally substituted with from 1 to 3 R 6 , and each R 6 is independently selected from the group consisting of hydrogen, amino, cyano, halogen, C 1-4 alkyl, Trifluoromethyl or methylsulfonyl;
- Y is selected from CR 3 ;
- P is selected from CR 4 ;
- W is selected from N;
- R 3 is selected from hydrogen or C 1-4 alkyl
- One embodiment of the present invention relates to a compound represented by the above formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- Ar is selected from phenyl or pyridyl, and Ar may be optionally substituted with from 1 to 3 R 6 , and each R 6 is independently selected from hydrogen, amino, cyano, halogen, C 1-4 alkyl, trifluoromethyl or Methanesulfonyl;
- Y is selected from CR 3 ;
- P is selected from CR 4 ;
- W is selected from N;
- R 3 is selected from hydrogen or C 1-4 alkyl
- the 5-6 membered monoheterocyclic group is preferably a 5-6 membered saturated monoheterocyclic group
- the 7-11 membered fused heterocyclic group is preferably a 7-11 membered saturated fused heterocyclic group, further preferably 7 to 11 members.
- the compound represented by the above formula (I) or (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof is shown in Table 1:
- the crystal form of the compound differs greatly from the other forms in terms of stability and solubility.
- the present inventors studied the compound of the following formula (III) and obtained a crystal form of the compound. Based on this, the present invention also provides the crystalline form I of the compound of the formula (III):
- the compound of formula (III) is 4-(5-(2-chlorophenyl)-3-methyl-2,10-dihydropyrazole[4,3-b]pyrido[4,3-e][ 1,4] two Form I of azaporine-8-yl)morpholine, in the X-ray powder diffraction pattern of Form I, at 7.4 ⁇ 0.2 °, 17.9 ⁇ 0.2 °, 18.9 ⁇ 0.2 °, 19.4 ⁇ 0.2 °, 21.5 ⁇ a characteristic peak at 0.2°, 23.7 ⁇ 0.2°; in the X-ray powder diffraction embodiment of the present invention, X-ray powder diffraction may use Cu-K ⁇ radiation, and characteristic peaks are represented by 2 ⁇ angles;
- the crystalline form I of the compound of the formula (III), in addition to the characteristic peaks described above, is also 14.0 ⁇ 0.2 °, 15.0 ⁇ 0.2 °, 20.7 ⁇ 0.2 °, 25.4. There are characteristic peaks at ⁇ 0.2°.
- the crystalline form I of the compound of the formula (III), X-ray powder diffraction expressed in terms of 2 ⁇ angle, in addition to the characteristic peaks described above, is also 11.7 ⁇ 0.2°, There are characteristic peaks at 22.8 ⁇ 0.2° and 27.8 ⁇ 0.2°.
- the present invention also provides a process for the preparation of the crystalline form I of the compound of the formula (III), which may comprise:
- the compound of the formula (III) is dissolved in a single or mixed solvent under heating, and the crystal form I is cooled and precipitated;
- the single or mixed solvent may be selected from the group consisting of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and dichloroethane.
- dimethyl sulfoxide ⁇ water as used in the present invention means a mixture of dimethyl sulfoxide and water;
- methanol / tetrahydrofuran is a nail a mixture of an alcohol and tetrahydrofuran;
- methanol ⁇ 2-methyltetrahydrofuran means a mixture of methanol and 2-methyltetrahydrofuran,
- methanol / dichloromethane means a mixture of methanol and dichloromethane,
- ethanol ⁇ 2-methyltetrahydrofuran It refers to a mixture of ethanol and 2-methyltetrahydrofuran, and "dichloromethane ⁇ water” means a mixture of dichloromethane and water.
- the amount of the single or mixed solvent used is a volume required to ensure dissolution of all the feeds, for example, a volume of a single or mixed solvent used for the amount of the compound represented by the formula (III): 1 g. It is 90-200mL.
- the volume ratio of the mixed solvent to be used may be from 0.1 to 20:1, preferably from 1 to 10:1, more preferably from 1 to 5:1, for example, ethanol ⁇ 2-methyltetrahydrofuran is 5:1, dichloromethane ⁇
- the water is 2:1, methanol/dichloromethane is 5:1, and the like.
- the present invention also provides a process for the preparation of the crystalline form I of the compound of the formula (III), which may comprise:
- the compound represented by the formula (III) is slurried by adding an appropriate amount of a single or mixed solvent, stirred, filtered (preferably filtered under reduced pressure), and dried to give a crystal form I.
- the single or mixed solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, dimethyl sulfoxide, water, methanol.
- ⁇ Tetrahydrofuran methanol ⁇ 2-methyltetrahydrofuran, methanol ⁇ dichloromethane, ethanol ⁇ 2-methyltetrahydrofuran, dichloromethane / water in one or a mixture of several, preferably methanol, ethanol, tetrahydrofuran, 2-methyl Tetrahydrofuran, dimethyl sulfoxide, dimethyl sulfoxide ⁇ water, methanol ⁇ tetrahydrofuran, methanol ⁇ 2-methyltetrahydrofuran, ethanol ⁇ 2-methyltetrahydrofuran, dichloromethane ⁇ water.
- the invention also provides a preparation method of the compound represented by the above formula (III), which comprises:
- PMB p-methoxybenzyl
- the present invention also provides a preparation intermediate of the compound represented by the above formula (III), which has the following structural formula:
- the present invention also provides a crystalline form comprising the compound represented by the above formula (I) or (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and/or a compound represented by the above formula (III) A pharmaceutical preparation of I.
- the pharmaceutical preparation may comprise one or more pharmaceutically acceptable carriers, which may be administered orally, parenterally, rectally or via pulmonary administration to a patient or subject in need of such treatment.
- the pharmaceutical composition can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule, etc.; or an oral liquid preparation such as an oral solution or an oral suspension. , syrup, and the like.
- a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
- the pharmaceutical composition can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
- the injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is placed, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
- the pharmaceutical composition For rectal administration, can be formulated as a suppository or the like.
- the pharmaceutical composition For pulmonary administration, can be formulated as an inhalant or a spray.
- the pharmaceutical preparation may further comprise one or more second therapeutically active agents, and the second therapeutically active agent is an antimetabolite, a growth factor inhibitor, and a silk classification.
- the second therapeutically active agent is an antimetabolite, a growth factor inhibitor, and a silk classification.
- Inhibitors, anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immunological checkpoints or tumor immunotherapy-related antibodies or small molecules drug are examples of drugs.
- the present invention also provides a crystalline form comprising the compound represented by the above formula (I) or (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and/or a compound represented by the above formula (III) A pharmaceutical composition of I and one or more second therapeutically active agents.
- the composition may be a "therapeutically effective amount" of the compound of the above formula (I) or (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof And/or the crystalline form I containing the compound of the above formula (III) and one or more second therapeutically active agents are used in combination, for example, sequentially, simultaneously, or therapeutically active.
- the ingredients are administered as a combination preparation.
- the second therapeutically active agent is an antimetabolite, a growth factor inhibitor, a silk classification inhibitor, an antitumor hormone, an alkylating agent, a metal, a topoisomerase inhibitor, a hormone drug, an immunomodulator , tumor suppressor genes, cancer vaccines, immune checkpoints or antibodies or small molecule drugs related to tumor immunotherapy.
- the present invention also provides the compound of the above formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the crystal form I of the compound of the above formula (III), or the aforementioned
- a pharmaceutical preparation for the preparation of a medicament for treating a multi-kinase-mediated cancer including lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer , endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma , neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma
- the present invention also provides a method for treating a disease, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of the above formula (I) or (II) or a pharmaceutically acceptable salt thereof or a stereo thereof Isomer, Form I of the compound of the above formula (III), or a pharmaceutical preparation as described above, wherein the disease includes cancer mediated by a multi-kinase including lung cancer, squamous cell carcinoma , bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, nerve Glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal
- a “therapeutically effective amount” as used herein refers to an amount of the aforementioned compound, Form I and/or pharmaceutical formulation that is at least capable of alleviating the symptoms of a patient's condition when administered to a patient .
- the actual amount comprising a "therapeutically effective amount” will vary depending on a variety of circumstances including, but not limited to, the particular condition being treated, the severity of the condition, the physique and health of the patient, and the route of administration. Skilled medical practitioners can readily determine the appropriate amount using methods known in the medical arts.
- halogen as used in the present invention means fluorine, chlorine, bromine, iodine or the like, preferably fluorine and chlorine.
- oxo means that any of the C atoms in the substituent structure can be oxidized to "-C(O)-"; if a hetero atom is contained, the hetero atom can form an oxide, such as Can be oxidized into S is optionally oxidized to S(O) or S(O) 2 .
- halo means that any hydrogen atom in the substituent may be taken by one or more of the same or different halogens. generation.
- Halogen is as defined above.
- C 1-6 alkyl refers to a hydrocarbon moiety containing from 1 to 6 carbon atoms, a straight-chain or branched alkyl group removing one hydrogen atom chain-derived, such as methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and
- C 2-8 alkenyl refers to an olefin moiety containing 2-8 carbon-carbon double bond carbon atoms, derived by removing one hydrogen atom of the alkene group, straight or branched chain, such as vinyl, 1- Propylene, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3 a pentadienyl group, a 1,4-pentadienyl group, a 1-hexenyl group, a 1,4-hexadienyl group or the like.
- C 2-8 alkynyl means an alkynyl hydrocarbon moiety containing 2-8 carbon-carbon triple bond of carbon atoms, derived by removing one hydrogen atom of the alkynyl group is a linear or branched chain, such as ethynyl, propynyl Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, and the like.
- C 1-6 alkylcarbonylamino means C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-NH-C(O)-, C 1-6 alkyl-S, respectively. O) 2 -, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S-; the "C 1-6 alkyl” is as defined above, preferably “C 1-4" alkyl”.
- C 1-6 alkoxy refers to the present invention as hereinbefore defined "C 1-6 alkyl” group attached through an oxygen atom to the parent, i.e., "C 1-6 alkyl -O-" A group such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy and n-hexyloxy.
- the "C 1-4 alkoxy group” refers to the above-mentioned example having 1 to 4 carbon atoms, that is, a "C 1-4 alkyl-O-” group.
- cycloalkyl include a single ring system and a fused ring system (bicyclic system or polycyclic system), and a single ring means only It exists in the form of a ring, and the fused ring refers to a polycyclic structure in which two or more rings are formed by a joint of a snail, a snail, and a bridge.
- the parallel ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (ie, sharing one bond).
- the bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
- the spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other.
- the present invention is a cycloalkyl group, an aryl group, a heterocyclic group or a heteroaryl group defined by the number of atoms, and includes, unless otherwise specified, a monocyclic ring and a fused ring structure which can be formed.
- cycloalkyl group as used in the present invention means a monocyclic cycloalkyl group, a bicyclic cycloalkyl system or a polycyclic cycloalkyl system. These groups may be saturated or unsaturated, but not aromatic.
- the monocyclic cycloalkyl group may be a C 3-8 cycloalkyl group, a C 3-6 cycloalkyl group, a C 5-8 cycloalkyl group or the like, and examples include, but are not limited to, a cyclopropyl group, a cyclobutane group, a cyclopentane.
- cyclohexane cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4 a cycloheptadienyl group, a cyclooctenyl group, a 1,5-cyclooctadienyl group or the like.
- the cyclocycloalkyl group may be a 6-12 membered cyclocycloalkyl group, a 7-10 membered cyclocycloalkyl group, and representative examples thereof include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] Heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] decane, bicyclo [3.3.1] decane and bicyclo [4.2.1] decane.
- the spirocyclic cycloalkyl group may be a 6-12 membered spiro group, a 7-11 membered spiro group or the like, and examples thereof include, but are not limited to:
- the bridged cycloalkyl group may be a 6-12 membered bridged ring group and a 7-11 membered bridged ring group, and examples thereof include, but are not limited to:
- the "3-14 membered cycloalkyl group”, “3-10 membered cycloalkyl group”, and “3-6 membered cycloalkyl group” as described in the present invention include a single ring which can be formed unless otherwise specified. And fused ring structure.
- heterocyclic group as used in the present invention means a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a hetero atom selected from O, S, N, preferably 1-3 hetero atoms, and includes The carbon atom, the nitrogen atom and the sulfur atom may be substituted by oxo.
- Heterocyclyl means a monocyclic heterocyclyl, bicyclic heterocyclyl or polycyclic heterocyclyl system, including saturated, partially saturated heterocyclic, but excluding aromatic rings.
- the monoheterocyclic group may be a 3-8 membered heterocyclic group, a 3-8 membered saturated heterocyclic group, a 3-6 membered heterocyclic group, a 4-7 membered heterocyclic group, a 5-7 membered heterocyclic group, 5-6.
- Examples of monoheterocyclyl groups include, but are not limited to, aziridine, oxacyclopropane, thietyl, azetidinyl, oxacyclobutane, thietane, Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1, 4-oxathianyl; examples of partially saturated heterocyclic groups include, but are not limited to, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazo
- the fused heterocyclic ring includes a heterocyclic group, a spiroheterocyclic group, a bridged heterocyclic group, and may be saturated, partially saturated or unsaturated, but not aromatic.
- the fused heterocyclic group is a monocyclic cycloalkyl group, a 5- or 6-membered monocyclic cycloalkenyl group, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered fused ring to a benzene ring, 5- or 6-membered member.
- the heterocyclic group may be 6-12 members and a cyclic group, 7-11 members and a cyclic group, 6-10 members and a cyclic group, 6-12 members saturated with a cyclic group, and 7-11 members saturated with a cyclic group.
- Examples thereof include, but are not limited to, 3-azabicyclo[3.10.]hexane, 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0 Xin Alkyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrole [3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridine, 2,3-dihydrobenzofuran-2-yl, 2,3- Dihydrobenzofuranyl-3-yl, indan-1-yl, indan-2-yl, indan-3-yl, 2,3 dihydrobenzothiophen-2-yl, VIII Hydrogen-1H-indenyl, octahydr
- the spiroheterocyclyl group may be a 6-12 membered spiroheterocyclyl group, a 7-11 membered spiroheterocyclyl group, a 7-11 membered saturated spiroheterocyclyl group, a 6-12 membered saturated spirocyclic group, and examples thereof include not limited to:
- bridged heterocyclic group which may be a 6-12 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, a 6-12 membered saturated bridged ring group, and a 7-11 membered saturated bridged heterocyclic group include but Limited to:
- the heterocyclic group includes, unless otherwise specified, a monocyclic ring and a fused ring structure which can be formed.
- the aryl group as used in the present invention refers to an aromatic cyclic group, including a monocyclic system, a bicyclic system or a polycyclic system, and may be a 6-14 membered aryl group, including a "6-8 membered monocyclic aryl group. ", for example, phenyl, cyclooctenyl, etc.; includes “8-14 membered fused ring aryl", such as pentylene, naphthalene, phenanthrene, and the like.
- heteroaryl refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a hetero atom selected from O, S, N, preferably from 1 to 3 heteroatoms, including carbon atoms, In the case where the sulfur atom is oxo, for example, the carbon atom is replaced by C(O), S(O), S(O) 2 .
- Heteroaryl includes monoheteroaryl and fused heteroaryl, which may be 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-7 membered heteroaryl, 5-6 membered heteroaryl, 8- Representative examples of 10-membered heteroaryl, monoheteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl.
- a heteroheteroaryl group refers to a bicyclic or polycyclic ring system fused to a phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl group.
- the fused heteroaryl group may be an 8-12 membered heteroaryl group, an 8-10 membered heteroaryl group, a 9-10 membered heteroaryl group, and representative examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiophene Benzo, benzothienyl, benzooxadiazolyl, benzothiazolyl, porphyrinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, anthracene Azyl, fluorenyl, isoquinolyl, naphthyridinyl, fluorenyl, quinolinyl, 5,6,7,8-tetrahydroquino
- the fused heteroaryl is fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclic ring.
- 5- or 6-membered monocyclic heteroaryl ring of a 5- or 6-membered monocyclic heteroaryl group is fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclic ring.
- the 5-14 membered heteroaryl group, the 5-10 membered heteroaryl group, the 6-10 membered heteroaryl group, the 5-6 membered heteroaryl group, and the 8-10 membered heteroaryl group of the present invention are not specifically indicated. In this case, it includes the monocyclic and fused ring structures that can be formed.
- the "pharmaceutically acceptable salt” as used in the present invention means a pharmaceutically acceptable acid and base addition salt and solvate.
- Such pharmaceutically acceptable salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid. , hydroiodic, alkanoic acid (such as acetic, HOOC- (CH 2) n- COOH ( wherein n 0 ⁇ 4)) and the like.
- Such pharmaceutically acceptable salts also include salts of the bases such as sodium, potassium, calcium, ammonium, and the like.
- a variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.
- the "stereoisomer" of the compound of the formula (I), (II) of the present invention means that when the compound of the formula (I), (II) has an asymmetric carbon atom, an enantiomer is produced; when the compound has carbon and carbon In the case of a double bond or a cyclic structure, a cis-trans isomer is produced; when a compound has a ketone or a oxime, a tautomer is produced, and all of the compounds of the formula (I), (II) are enantiomers, non- Enantiomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.
- the crystalline form I of the compound represented by the formulas (I) and (II) and the compound of the formula (III) of the present invention is a dual inhibitor of mitosis and angiogenesis inhibition.
- the drug is more potent and has better pharmacological activities such as enzymology, cell and pharmacodynamics.
- the compound of the present invention has better pharmacokinetic properties, physicochemical properties and/or toxicological properties, and has superior drug-forming properties.
- Figure 1 is an X-ray powder diffraction (XRPD) pattern of Form I of the compound of formula (III).
- DSC differential scanning thermal analysis
- Anhydrous tetrahydrofuran (500 mL) and 2,5-dibromopyridine (100.0 g, 0.42 mol, 1.0 eq) were added to a 2 L four-necked flask, and the mixture was cooled to 2 ° C with stirring in an ice water bath, and isopropylmagnesium chloride (210.5 mL) was added dropwise. , 2.0 M, 0.42 mol, 1.0 eq), the controlled temperature does not exceed 10 ° C, and the dropping is completed in about 0.5 h.
- a tetramethylpiperidine lithium/magnesium chloride solution (281 mL, 1.5 mol/L, 0.43 mol, 2.5 eq) was added to a 2 L four-necked flask, and the temperature was lowered to -65 ° C in a dry ice/ethanol bath, and added dropwise (6- A solution of bromopyridin-3-yl)(2-chlorophenyl)methanone (50.0 g, 0.17 mol, 1.0 eq) in tetrahydrofuran (50 mL).
- Step 1 Intermediates 1-3 were prepared in the same manner as in Preparation 2.
- Step 2 Intermediate 1-4 was prepared according to the method in Preparation 3.
- Step 1 (2-Chlorophenyl)(4-((1-(4-methoxybenzyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)amino)-6 Synthesis of (4-methylpiperazin-1-yl)pyridin-3-yl)methanone
- Step 1 Synthesis of (6-bromo-4-((5-methyl-4-nitro-1H-pyrazol-3-yl)amino)pyridin-3-yl)(2-chlorophenyl)methanone
- Step 1 Weigh 500mg of intermediate 1-4, add 15ml of acetonitrile to dissolve, add 200mg of triethylamine, 200mg of BOC piperazine, heat reflux for 3h, end the reaction of the plate, and spin dry to obtain yellow solid intermediate 37-1,400mg Yield 80%;
- Step 2 The intermediate 37-1 was dissolved in 15 ml of TFA, and the mixture was refluxed for 6h. The reaction was purified by LC-MS, and then evaporated to dryness. After filtration, the methyl tert-ether was obtained as a yellow solid compound 37-2 (300 mg, yield >100%).
- Step 3 Intermediate 37-2 was dissolved in 15 ml of methyltetrahydrofuran, 500 ml of tin dichloride dihydrate was added, the temperature was raised to 90 ° C, and refluxed for 5 hours, and the reaction was completed to obtain compound 37 (16 mg, yield 5%).
- Step 1 Weigh boc piperazine 300mg, 450mg intermediate 33-2, potassium carbonate 300mg, add acetonitrile 20ml dissolved, warm to 60 ° C, reaction 6h, LC-MS detection reaction is finished, add water 300ml dichloromethane 50ml, points The liquid and oil phase were dried and dried to give intermediate 38-1, 300 mg.
- Step 2 Pour 15 ml of trifluoroacetic acid into 300 mg of compound 38-1, warm to 90 ° C, reflux for 4 h, LC-MS reaction is completed, spin dry to obtain 200 mg of compound 38-2;
- Step 3 Weigh 1.10g of tin dichloride dihydrate, add to intermediate 38-2, add 15ml of methyltetrahydrofuran, 0.2ml of water, and warm up to 90 ° C. After 16h, the reaction is finished, adjust the pH to 10, and filter. After spinning and drying, 36 mg of compound 38 was obtained in a yield of 21%.
- the synthetic route is as follows:
- Step 1 (2-Chlorophenyl)(4-((1-(4-methoxybenzyl)-5-methyl-4-nitro-1H-pyrazol-3-yl)amino)-6 Synthesis of morpholinopyridin-3-yl)methanone (Intermediate III-E)
- the formula (III-F) can also be prepared to obtain the transition state of the formula (III-F'), and the prepared crude product is subjected to an acidic treatment process (for example, treatment with hydrochloric acid) to finally obtain the target intermediate formula (III-F). ).
- an acidic treatment process for example, treatment with hydrochloric acid
- the crystal form of this sample was determined by X-ray powder diffraction, and the crystal form was the same as the crystal form obtained in the preparation methods of Examples 13, 14, 15, and 16.
- Test substance Compound 1-4 in the present invention (see Table 1 for the number and structure of the compound), dilution concentration: 0.03 ⁇ M - 3 ⁇ M, a total of 10 concentration gradients.
- Test method Aurora kinase (including Aurora A, Aurora B) and VEGFR2 (KDR) enzymatic activity tests were performed using a multi-function microplate reader.
- the Aurora A kinase protein and compound were sequentially added to the following reaction system: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 ⁇ M LRRASLG (Kemptide), 10 mM magnesium acetate and [ ⁇ - 33 P]-ATP (radioactive activity was about 500 cpm/pmol) Then, ATP was added to the above reaction system to start the reaction, and then incubated at room temperature for 40 minutes, and then the reaction was terminated by adding a 3% phosphoric acid solution.
- the Aurora B kinase protein and compound were sequentially added to the following reaction system: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 ⁇ M AKRRRLSSLRA, 10 mM magnesium acetate and [ ⁇ - 33 P]-ATP (radioactive activity at about 500 cpm/pmol), then ATP was added to the above reaction system to start the reaction, and then incubated at room temperature for 40 minutes, and then the reaction was terminated by adding a 3% phosphoric acid solution.
- the KDR kinase protein and the compound were sequentially added to the following reaction system: 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM magnesium acetate, and [ ⁇ - 33 P]-ATP (radioactive activity was about 500 cpm). /pmol), then ATP was added to the above reaction system to start the reaction, then incubated at room temperature for 40 minutes, and then the reaction was stopped by adding a 3% phosphoric acid solution.
- the compounds of the present invention have good inhibitory activity against polykinase, indicating that the compounds of the present invention have a therapeutic effect on diseases mediated by abnormal expression of Aurora kinase (including Aurora A, Aurora B) and VEGFR2 (KDR). Good clinical application potential.
- Aurora kinase including Aurora A, Aurora B
- VEGFR2 VEGFR2
- Test substance the compound of the present invention (the number and structure of the compound are shown in Table 1), and the dilution concentration is 0.03 ⁇ M - 3 ⁇ M. 10 concentration gradients.
- Control drug Compound 1-2 disclosed in WO2013123840A1
- Test method Aurora kinase (including Aurora A, Aurora B) and VEGFR2 (KDR) enzymatic activity tests were performed using a multi-function microplate reader.
- Aurora A, Aurora B and KDR were dissolved in 1x kinase buffer and configured to be 2.5 times enzymatic solution. After reacting each concentration of compound with 2.5 times of enzyme solution for 10 min at room temperature, FAM-labeled peptide substrate was added to initiate reaction with ATP. After incubation for 40 minutes, 25 ⁇ L of stop solution (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) was added to terminate the reaction, and Caliper read the final data. The test results are shown in Table 3.
- the compounds of the present invention have good inhibitory activity against polykinase, indicating that the compounds of the present invention have a therapeutic effect on diseases mediated by abnormal expression of Aurora kinase (including Aurora A, Aurora B) and VEGFR2 (KDR). Good clinical application potential.
- Aurora kinase including Aurora A, Aurora B
- VEGFR2 VEGFR2
- Test substance The compound of the present invention (the number and structure of the compound are shown in Table 1).
- Control drug Compound 1-2 disclosed in WO2013123840A1
- Cell line name source Cell line name source OVCAR-8 Ovarian cancer cells ATCC Hep3B liver cancer cells ATCC OVCAR-3 Ovarian cancer cells ATCC KG-1 Leukemia cell ATCC Caov-3 Ovarian cancer cells ATCC Kasumi-1 Leukemia cell ATCC A2780 Ovarian cancer cells CEACC BT-549 Breast cancer cell ATCC TOV-112D Ovarian cancer cells ATCC MDA-MB-468 Breast cancer cell ATCC D4475 Breast cancer cell ATCC A549 Lung cancer cell ATCC HCC1954 Breast cancer cell ATCC HCC38 Breast cancer cell ATCC HCC70 Breast cancer cell ATCC
- Test method The effect of compounds on cell proliferation of different cell lines was examined by Cell Titer-Glo method.
- the compounds of the present invention have good inhibitory activity against various cancer cells and can be used for the treatment of corresponding cancer diseases.
- Test substance Form I prepared in Example 13, dilution concentration: 0.03 ⁇ M - 3 ⁇ M, a total of 10 concentration gradients.
- Test method The enzymatic activity test of the kinase shown in Table 1 was carried out using a multi-function microplate reader.
- the kinases shown in Table 6 were separately dissolved in 1 ⁇ kinase buffer to prepare 2.5 times the enzyme solution, and the crystal form I was reacted with 2.5 times of the enzyme solution at room temperature for 10 minutes, and then the FAM-labeled polypeptide substrate was added to initiate reaction with ATP. The reaction was stopped by incubating for 40 minutes by adding 25 ⁇ L of stop solution (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA), and Caliper read the final data. The test results are shown in Table 6.
- Test substance Form I prepared in Example 17 (Compound 29 Form I).
- Kasumi-1 cells derived from ATCC.
- Kasumi-1 cells were cultured in vitro in a single layer, and culture conditions were 10% heat-inactivated fetal bovine serum and 1% penicillin-streptomycin double antibody in RPMI1640 medium, and cultured at 37 ° C, 5% CO 2 . Passaged two to three times a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
- a 0.2 mL cell suspension containing about 1 x 10 7 Kasumi-1 cells (cell suspension in 1:1 basal RPMI 1640 medium and nutrient gel) was subcutaneously inoculated into the right back of female CB17 SCID mice. Group administration was started when the average tumor volume reached 100-150 mm 3 . Grouping method: Animals were weighed prior to dosing and tumor volume was measured. Groups were grouped according to the tumor volume, with 8 mice per group.
- TWc control tumor weight
- TWT tumor weight of treatment group. According to the NIH guidelines, TGI ⁇ 58%, the drug is considered effective.
- TGI tumor weight inhibition rate
- Test substance Form I prepared in Example 17 (Compound 29 Form I).
- Beagle dogs were given a single oral dose of 2 mg/kg of Compound 29 Form I (prescription: 10% DMA + 20% (30% Solutol) + 70 %saline), blood was collected at 0h before administration and 0.25, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24h after administration. 200 ⁇ L of blood was taken from the saphenous vein and placed in the dried EDTA-K2 tube. .
- Plasma preparation The whole blood sample was centrifuged at a low speed (1800 g, 5 min, 4 ° C) to separate the plasma (the whole blood was collected and placed in an ice bath, and the plasma separation was completed within 30 min), and the separated plasma was stored in - Waiting for analysis in a refrigerator at 20 °C.
- the concentration of the test substance was output using AB's Analyst 1.6.1.
- Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (Analyst 1.6.1 direct output is not calculated), PK parameters are calculated using Pharsight Phoenix 6.1 software NCA.
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Abstract
Description
细胞株 | 名称 | 来源 | 细胞株 | 名称 | 来源 |
OVCAR-8 | 卵巢癌细胞 | ATCC | Hep3B | 肝癌细胞 | ATCC |
OVCAR-3 | 卵巢癌细胞 | ATCC | KG-1 | 白血病细胞 | ATCC |
Caov-3 | 卵巢癌细胞 | ATCC | Kasumi-1 | 白血病细胞 | ATCC |
A2780 | 卵巢癌细胞 | CEACC | BT-549 | 乳腺癌细胞 | ATCC |
TOV-112D | 卵巢癌细胞 | ATCC | MDA-MB-468 | 乳腺癌细胞 | ATCC |
D4475 | 乳腺癌细胞 | ATCC | A549 | 肺癌细胞 | ATCC |
HCC1954 | 乳腺癌细胞 | ATCC | HCC38 | 乳腺癌细胞 | ATCC |
HCC70 | 乳腺癌细胞 | ATCC |
Claims (17)
- 下述通式(I)表示的化合物或其药学上可接受的盐、立体异构体:其中,X选自CH或N;R1选自氢、C1-6烷基、C3-6环烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基;R2选自氢、C1-6烷基或C3-6环烷基;Y选自CR3或N;P选自CR4或N;W选自CR5或N;R3、R4、R5独立选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基氧基、氧杂C5-8环烷基氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C3-6环烷基氨基、C1-6烷基磺酰基、C3-8环烷基磺酰基、C1-6烷基羰基、C3-6环烷基羰基、-NR11-(CH2)n-N(R7)(R8)、C1-6烷基硫基-(CH2)n-、-(CH2)n-(3-14)元环烷基、-(CH2)n-(6-14)元芳基、-(CH2)n-(5-14)元杂环基或-(CH2)n-(5-14)元杂芳基,其中,n=0-6,环烷基、芳基、杂环基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),环烷基、芳基、杂芳基、杂环基可任选被一至多个独立的C1-3烷基、C3-6环烷基取代;R7、R8独立选自氢、C1-6烷基、C3-6环烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基;并且,P、W、Y不同时为N,当Y为CR3、P为CR4、W为N时,R4不能选自C1-6烷基;当Y为CR3、P为CR4、W为CR5时,R4或R5中必须有1个选自H;Ar选自3-14元环烷基、6-14元芳基、5-14元杂环基或5-14元杂芳基,环烷基、芳基、杂环基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),Ar可任选被1-3个R6取代;每个R6独立选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、卤代C1-6烷氧基、卤代C1-6烷基、C3-6环烷基、C2-8烯基、C2-8炔基、-NR11-(CH2)n-N(R9)(R10)、氨基C1-6烷基、C3-6环烷基氨基、C1-6烷基磺酰基、C3-8-环烷基磺酰基、C1-6烷基羰基、C3-6环烷基羰基、C1-6烷基硫基、-(CH2)n-(6-14)元环烷基、-(CH2)n-(6-14)元芳基、-(CH2)n-(5-14)元杂环基或-(CH2)n-(5-14)元杂芳基,其中,n=0-6,环烷基、芳基、杂芳基、杂环基可任选被一至多个独立的C1-3烷基取代;R9、R10独立选自氢、C1-6烷基、C3-6环烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基;R11选自氢、C1-6烷基或C3-6环烷基。
- 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体,其中,X为N;R1选自C1-3烷基,优选为甲基或乙基;R2选自氢、甲基或乙基;Y选自CR3或N;P选自CR4或N;W选自CR5或N;R3、R4、R5独立选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基氧基、氧杂C5-8环烷基氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C3-6环烷基氨基、C1-6烷基磺酰基、C3-8环烷基磺酰基、C1-6烷基羰基、C3-6环烷基羰基、-NR11-(CH2)n-N(R7)(R8)、C1-6烷基硫基-(CH2)n-、-(CH2)n-(3-14)元环烷基、-(CH2)n-(6-14)元芳基、-(CH2)n-(5-14)元杂环基或-(CH2)n-(5-14)元杂芳基,其中,n=0-6,环烷基、芳基、杂环基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),环烷基、芳基、杂芳基、杂环基可任选被一至多个独立的C1-3烷基、C3-6环烷基取代;R7、R8独立选自氢、C1-6烷基、C3-6环烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基;并且,P、W、Y三个原子不同时为N,当Y为CR3、P为CR4、W为N时,R4不能选自C1-6烷基;当Y为CR3,P为CR4、W为CR5时,R4或R5中必须有1个选自H;R11选自氢、C1-6烷基或C3-6环烷基;Ar选自6-14元芳基或5-10元杂芳基,芳基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),其中,Ar可任选被1-3个R6取代;每个R6独立选自氢、氨基、氰基、卤素、C1-4烷基、三氟甲基、甲磺酰基、-(CH2)n-(5-10)元杂环基或-(CH2)n-(5-10)元杂芳基,n=0-6,杂芳基、杂环基可任选被一至多个独立的C1-3烷基取代。
- 如权利要求2所述的化合物或其药学上可接受的盐、立体异构体,其结构通式如(II)所示:其中,Ar选自5-6元芳基或5-6元杂芳基,芳基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选地被氧化为C(O),Ar可任选被1-3个R6取代;每个R6独立的选自氢、氨基、氰基、卤素、C1-4烷基、三氟甲基或甲磺酰基,卤素优选氯;Y选自CR3或N;P选自CR4或N;W选自CR5或N;R3、R4、R5独立选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C1-4烷基、C1-4烷氧基、C3-6环烷基氧基、氧杂C5-8环烷基氧基、卤代C1-4烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基氨基、C1-4烷基磺酰基、C3-8环烷基磺酰基、C1-4烷基羰基、C3-6环烷基羰基、-NR11-(CH2)n-N(R7)(R8)、-(CH2)n-(3-14)元环烷基、-(CH2)n-(5-11)元杂环基或-(CH2)n-(5-10)元杂芳基,其中,n=0-6,环烷基、杂环基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),环烷基、杂芳基、杂环基可任选被一至多个独立的C1-3烷基、C3-6环烷基取代;R7、R8独立选自氢、甲基、乙基、异丙基或环丙基;并且,P、W、Y三个原子不同时为N,且P、W、Y中至少有一个为N;当Y为CR3、P为CR4、W为N时,R4不能选自C1-4烷基;R11选自氢、C1-6烷基或C3-6环烷基。
- 如权利要求3或4所述的化合物或其药学上可接受的盐、立体异构体,其中,Y选自CR3;P选自CR4;W选自N;R4不能选自C1-4烷基。
- 如权利要求3所述的化合物或其药学上可接受的盐、立体异构体,其中,Ar选自苯基或5-6元杂芳基,Ar可任选被1-3个R6取代,每个R6独立选自氢、氨基、氰基、卤素、C1-4烷基、三氟甲基或甲磺酰基;Y选自CR3;P选自CR4;W选自N;R3选自氢或C1-4烷基;R4选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C1-4烷氧基、C3-6环烷基氧基、氧杂C5-8环烷基氧基、卤代C1-4烷氧基、C3-6环烷基氨基、C1-4烷基磺酰基、C3-6环烷基磺酰基、C1-4烷基羰基、C3-6环烷基羰基、-NR11-(CH2)n-N(R7)(R8)、-(CH2)n-C3-10环烷基、-(CH2)n-(5-11)元杂环基或-(CH2)n-(5-10)元杂芳基,其中,n=0-6,环烷基、杂环基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),环烷基、杂芳基、杂环基可任选被一至多个独立的C1-3烷基、C3-6环烷基取代。
- 如权利要求6所述的化合物或其药学上可接受的盐、立体异构体,其中,Ar选自苯基或吡啶基,Ar可任选被1-3个R6取代,每个R6独立选自氢、氨基、氰基、卤素、C1-4烷基、三氟甲基或甲磺酰基;Y选自CR3;P选自CR4;W选自N;R3选自氢或C1-4烷基;R4选自氢、羟基、氨基、羧基、氰基、硝基、卤素、C1-4烷氧基、C3-6环烷基氧基、卤代C1-4烷氧基、C3-6环烷基氨基、C1-4烷基磺酰基、C1-4烷基羰基、C3-6环烷基-羰基、-NR11-(CH2)n-N(R7)(R8)、-(CH2)n-C3-6环烷基、-(CH2)n-(5-6)元单杂环基、-(CH2)n-(7-11)元稠杂环基、-(CH2)n-(5-6)元单杂芳基、-(CH2)n-(8-10)元稠杂芳基,其中,n=0-6,环烷基、杂环基、杂芳基中的成环S原子可任选被氧化为S(O)或S(O)2,成环C原子可任选被氧化为C(O),环烷基、杂芳基、杂环基可任选被一至多个独立的C1-3烷基、C3-6环烷基取代。
- 权利要求9所述的晶型I的制备方法,其中,所述方法包括:将式(Ⅲ)所示的化合物在加热条件下溶于单一或混合溶剂,冷却析出晶型I;或将式(Ⅲ)所示的化合物悬浮于单一或混合溶剂中,搅拌,过滤得到晶型I;或将式(Ⅲ)所示的化合物溶解于单一或混合溶剂中,真空浓缩得到晶型I;或将式(Ⅲ)所示的化合物,加入适量单一或混合溶剂进行浆洗,搅拌,过滤,干燥,得到晶型I。
- 权利要求10所述的晶型I的制备方法,所述的单一或混合溶剂选自:甲醇、乙醇、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、二氯乙烷、乙酸乙酯、乙腈、二甲基亚砜、二甲基亚砜\水、甲醇\四氢呋喃、甲醇\2-甲基四氢呋喃、甲醇\二氯甲烷、乙醇\2-甲基四氢呋喃、 二氯甲烷\水中的一种或几种的混合。
- 含有权利要求1-8中任一项所述的化合物或其药学上可接受的盐或其立体异构体,和/或含有权利要求9所述的式(Ⅲ)所示的化合物的晶型I的药物制剂,优选地,所述药物制剂包含一种或多种药用载体。
- 含有权利要求14所述的药物制剂,其进一步包含一种或多种第二治疗活性剂,所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝分类抑制剂、抗肿瘤激素类、烷化剂类、金属类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点或肿瘤免疫治疗相关的抗体或小分子药物。
- 含有权利要求1-8中任一项所述的化合物或其药学上可接受的盐或其立体异构体,和/或含有权利要求9所述的式(Ⅲ)所示的化合物的晶型I及一种或多种第二治疗活性剂的药物组合物,所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝分类抑制剂、抗肿瘤激素类、烷化剂类、金属类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点或肿瘤免疫治疗相关的抗体或小分子药物。
- 权利要求1-8任一项所述的化合物或其药学上可接受的盐或其立体异构体、权利要求9所述的式(Ⅲ)所示的化合物的晶型I、或权利要求14-16任一项所述的药物制剂在制备治疗由多激酶异常介导的癌症的药物中的应用,其中,所述的癌症包括肺癌、鳞状上 皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113620949A (zh) * | 2020-05-08 | 2021-11-09 | 南京药捷安康生物科技有限公司 | 抗肿瘤化合物的合成方法及其中间体 |
WO2021223751A1 (zh) | 2020-05-08 | 2021-11-11 | 南京药捷安康生物科技有限公司 | 抗肿瘤化合物的合成方法及其中间体 |
WO2022206758A1 (zh) * | 2021-03-29 | 2022-10-06 | 药捷安康(南京)科技股份有限公司 | 多激酶抑制剂的联合应用 |
WO2022237765A1 (zh) | 2021-05-10 | 2022-11-17 | 药捷安康(南京)科技股份有限公司 | 多激酶抑制剂的药物组合物及其用途 |
WO2023093878A1 (zh) | 2021-11-27 | 2023-06-01 | 药捷安康(南京)科技股份有限公司 | 激酶抑制剂的新用途 |
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EP3447056A1 (en) | 2019-02-27 |
CN108218868A (zh) | 2018-06-29 |
CN108218868B (zh) | 2019-02-19 |
KR20190068626A (ko) | 2019-06-18 |
RU2723985C1 (ru) | 2020-06-18 |
CA3041155A1 (en) | 2018-06-21 |
KR102373577B1 (ko) | 2022-03-10 |
JP6594571B2 (ja) | 2019-10-23 |
US10208042B1 (en) | 2019-02-19 |
BR112019008295B1 (pt) | 2024-03-12 |
AU2017376353A2 (en) | 2019-06-27 |
BR112019008295A2 (pt) | 2019-07-09 |
JP2019518784A (ja) | 2019-07-04 |
CA3041155C (en) | 2021-12-14 |
EP3447056A4 (en) | 2019-09-18 |
RU2723985C9 (ru) | 2020-09-21 |
US11718620B2 (en) | 2023-08-08 |
US20210130354A1 (en) | 2021-05-06 |
US20190152972A1 (en) | 2019-05-23 |
US20190040064A1 (en) | 2019-02-07 |
US10889586B2 (en) | 2021-01-12 |
AU2017376353A1 (en) | 2019-05-16 |
AU2017376353B2 (en) | 2020-02-06 |
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