WO2023016543A1 - 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用 - Google Patents
脲类多靶点酪氨酸激酶抑制剂及其多种医药应用 Download PDFInfo
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- WO2023016543A1 WO2023016543A1 PCT/CN2022/112014 CN2022112014W WO2023016543A1 WO 2023016543 A1 WO2023016543 A1 WO 2023016543A1 CN 2022112014 W CN2022112014 W CN 2022112014W WO 2023016543 A1 WO2023016543 A1 WO 2023016543A1
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- alkyl
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- 230000008685 targeting Effects 0.000 description 1
- 229940066453 tecentriq Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 150000004886 thiomorpholines Chemical class 0.000 description 1
- 229940121514 toripalimab Drugs 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P11/00—Drugs for disorders of the respiratory system
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
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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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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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
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/02—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 two hetero rings
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- 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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Definitions
- the invention relates to a new class of urea compounds formed by "multi-substituted aromatic amines and alkyl amines". More specifically, the present invention relates to polysubstituted aryl aminourea compounds useful as multi-target tyrosine kinase inhibitors and various medical applications thereof.
- Protein tyrosine kinases are the largest known protein superfamily, and protein tyrosine kinases are an important hub for the transmission of extracellular signals into cells. Tyrosine kinases play an important role in regulating cell proliferation and differentiation. Abnormal expression of PTK will activate a series of downstream signaling pathways, causing cascade reactions, resulting in disordered cell proliferation regulation, and eventually leading to tumor formation. Tyrosine kinases can be divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).
- RTKs receptor tyrosine kinases
- nRTKs non-receptor tyrosine kinases
- Receptor tyrosine kinases include vascular endothelial growth factor receptor (VEGFR, Vascular Endothelial Growth Factor Receptor), Fibroblast Growth Factor Receptor (FGFR, Fibroblast growth Gactor Receptor), Epidermal Growth Factor Receptor [Epidermal growth factor receptor, referred to as EGFR, HER1, or ErbB-1, is epidermal growth factor receptor HER family member], tyrosine kinase membrane receptor (c-Met), platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), and RET and other members, these RTKs are related to tumor diseases and their target Treatment is closely related.
- VEGFR Vascular Endothelial Growth Factor Receptor
- FGFR Fibroblast Growth Factor Receptor
- FGFR Fibroblast Growth Factor Receptor
- Epidermal Growth Factor Receptor Receptor Epidermal Growth Factor Receptor
- EGFR vascular endothelial growth factor receptor
- TKIs protein tyrosine kinase inhibitors
- TKIs protein tyrosine kinase inhibitors
- TKIs protein tyrosine kinase inhibitors
- clinical Small molecule urea compound anticancer drugs for the treatment of liver cancer include Sorafenib (Sorafenib, Ref-1), Regorafenib (Regorafenib, Ref-2), and tyrosine kinases VEGFR1-3 and FGFR1- Lenvatinib (Lenvatinib, Ref-3), all of which have good inhibitory effects, has a good anti-tumor effect in clinical treatment.
- the purpose of the present invention is to develop a novel multi-target tyrosine kinase inhibitor (TKI) with higher activity of inhibiting tyrosine kinase and lower toxicity and side effects through the innovative design of small molecule structure and functional groups thereof. It is effectively used to treat various tumors such as pancreatic cancer, lung cancer, kidney cancer, liver cancer, gastric cancer, cervical cancer and leukemia and related cancer diseases.
- TKI multi-target tyrosine kinase inhibitor
- the present invention relates to a class of multi-substituted anilaminourea compounds of the formula IIIb containing novel multi-substituted aniline groups as the focus of innovation.
- TKI multi-target tyrosine kinase inhibitor
- VEGFR1, VEGFR2, VEGFR3 and fibroblast growth factor receptors (FGFR1-4) vascular endothelial growth factor receptors
- FGFR1-4 fibroblast growth factor receptors
- Tyrosine kinases such as but not limited to EGFR, RET, PDGFR ⁇ and other tyrosine kinases, can produce relatively strong angiogenesis inhibitory effects, and are more effective in preventing and treating various abnormal proliferations accompanied by angiogenesis. It has better applications in diseases such as tumors.
- the structure of the urea compound containing multiple substituted aniline groups disclosed in the present invention is based on the structural characteristics of the tyrosine kinase target, by introducing more substituents into aniline for structural modification innovation and optimization, thereby developing a A multi-target tyrosine kinase inhibitor (TKI) with better inhibitory effect can more effectively treat various types of tumors.
- TKI multi-target tyrosine kinase inhibitor
- the core problem solved by the present invention is to develop a novel urea compound containing multi-substituent aniline as an innovative feature, which is effective for pancreatic cancer (BXPC3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep3B2. 1-7), gastric cancer (SNU16), cervical cancer (Hela), and leukemia (K562) and other tumor cell lines and kinase targets such as VEGFR1-3, FGFR1-4, EGFR, RET have good inhibitory effects, the results It shows that the suppression effect is better, the application prospect is better, and it has better security.
- the first aspect of the present invention provides a compound represented by formula IIIb, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, or pharmaceutically Acceptable salts or hydrates, and deuterated or isotopically substituted compounds:
- E is nitrogen (N), or CH;
- G is hydrogen, deuterium (D), halogen, -CN, C 1-20 alkyl, C 1-20 alkoxy, or C 1-20 alkylamino;
- G2 is halogen, -CN, C 1-20 alkylamino, C 1-20 hydroxyalkyleneamine, C 1-20 nitrile alkyleneamine, C 1-20 aminoalkyleneamine group, C 3-20 aminocycloalkyleneamine group, C 1-20 carboxyalkyleneamine group, C 3-20 carboxycycloalkyleneamine group, 3-6 membered heterocyclylamine group, or -OR 6 ;
- R 6 is selected from: hydrogen, deuterium, C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 cyanoalkylene, C 3-20 cyanocycloalkylene, C 2-20 hydroxyalkylene, C 2-20 aminoalkylene, C 3-20 aminocycloalkylene, C 2-20 carboxyalkylene, C 3-20 carboxycycloalkylene, C 3-6 cycloalkyl, C 3-6 amino cycloalkylene, C 1-20 amino (C 3-20 cycloalkyl) alkylene, 3-6 membered heterocycl
- G 3 is -CN, -C(O)OR, -C(O)NH 2 , deuterated -C(O)ND 2 , C 1-20 alkoxy, C 1-20 alkylamino, or - C(O)NR 4 R 5 ; wherein, R is hydrogen, or C 1-20 alkyl, R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-20 alkyl, C 1-20 haloalkane C 1-20 cyanoalkylene, C 3-20 cyanocycloalkylene, C 2-20 hydroxyalkylene, C 3-20 hydroxycycloalkylene, C 2-20 aminoalkylene Group, C 3-20 aminocycloalkylene, C 2-20 carboxyalkylene, C 3-20 carboxycycloalkylene, C 3-20 cycloalkenyl, C 3-20 cycloalkyl, 3- 6-membered heterocyclic group, 3-6-membered heterocyclic alkylene group, C 6-20 aryl group, C 3-20 heterocycl
- G 4 and G 5 are each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-20 alkyl, C 1-20 alkoxy, or C 1-20 alkylamino;
- R 1 is selected from: hydrogen, deuterium, C 1-20 alkyl, C 3-20 cycloalkyl, or C 3-20 deuterated cycloalkyl;
- R 2 and R 3 are each independently selected from: hydrogen, deuterium, C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 deuterated cycloalkyl, or 3-6 membered heterocyclyl;
- X 1 , X 2 and X 3 are each independently selected from: halogen, -CN, -NH 2 , C 1-20 alkoxy, or C 1-20 alkylamine;
- X 4 is selected from: hydrogen, deuterium, halogen, -CN, -NH 2 , C 1-20 alkoxy, or C 1-20 alkylamine.
- E is nitrogen (N), or CH;
- G is hydrogen, deuterium (D), halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino;
- G2 is halogen, -CN, C 1-6 alkylamino, C 1-6 hydroxyalkyleneamine, C 1-6 nitrile alkyleneamine, C 1-6 aminoalkyleneamine C 3-6 aminocycloalkyleneamine, C 1-6 carboxyalkyleneamine, C 3-6 carboxycycloalkyleneamine, 3-6 membered heterocyclylamine, or -OR 6 ;
- R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 carboxycycloalkylene, C 3-6 cycloalkyl, C 3-6 amino cycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclic group, or 3-6
- G 3 is -CN, -C(O)OR, -C(O)NH 2 , deuterated -C(O)ND 2 , C 1-6 alkoxy, C 1-6 alkylamino, or - C(O)NR 4 R 5 ; wherein, R is hydrogen, or C 1-6 alkyl, R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkane C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 3-6 hydroxycycloalkylene, C 2-6 aminoalkylene Group, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 carboxycycloalkylene, C 3-6 cycloalkenyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclic group, 3-6-membered heterocyclic alkylene group, C 6-10 aryl group, C 3-10 heterocycl
- G 4 and G 5 are each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino;
- R 1 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, or C 3-6 deuterated cycloalkyl;
- R 2 and R 3 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, or 3-6 membered heterocyclyl;
- X 1 , X 2 and X 3 are each independently selected from: halogen, -CN, -NH 2 , C 1-6 alkoxy, or C 1-6 alkylamine;
- X 4 is selected from: hydrogen, deuterium, halogen, -CN, -NH 2 , C 1-6 alkoxy, or C 1-6 alkylamine.
- E is CH
- G1 is hydrogen
- G 2 is -OR 6 , wherein R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkylene, C 3-6 aminocycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene ;
- G 3 is -C(O)OR, -C(O)NH 2 , or -C(O)NR 4 R 5 ; wherein, R is hydrogen, or C 1-6 alkyl, and R 4 and R 5 are independently is selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, 3-6 heterocyclyl, C 1-6 alkylene (3-6 hetero ring), C 3-6 heterocyclic aryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2-6 heterocycloalkylsulfonyl; between R 4 and R 5 Occasionally connected to each other to form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 heteroatoms;
- G4 and G5 are each independently selected from: hydrogen;
- R is selected from: hydrogen
- R is selected from: hydrogen
- R 3 are each independently selected from: C 3-6 cycloalkyl
- X 1 , X 2 and X 3 are each independently selected from: halogen;
- X4 is selected from: hydrogen.
- the compound of formula IIIb described in the present invention is selected from the following structures, characterized by including but not limited to any of the following structures:
- the second aspect of the present invention provides a method for preparing a compound represented by formula IIIb, characterized in that: it can be prepared by any of the following two methods:
- R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 2-6 hydroxyalkylene, C 2 -6 aminoalkylene, C 2-6 carboxyalkylene, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, 3 -6-membered heterocyclylalkylene, C 6-12 aryl, C 3-10 heterocyclic aryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2- 6 heterocycloalkylsulfonyl groups, or R 4 and R 5 are connected to each other to form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 heteroatoms.
- R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene Alkyl, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, C 3-6 aminocycloalkylene group, C 1-6 amino group (C 3-6 cycloalkyl) alkylene group, 3-6 membered heterocyclyl group, or 3-6 membered heterocyclylalkylene group.
- Another aspect of the present invention further provides a synthetic preparation method for the following intermediate compound RM1b-01:
- Another aspect of the present invention further provides the synthetic preparation method of the following compound SM2-01 and its application in the synthetic preparation of the compound of formula IIIb:
- Another aspect of the present invention provides a compound represented by formula IIIb or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent and/or excipient.
- Another aspect of the present invention provides an application of a compound represented by formula IIIb or a composition thereof in the preparation of a medicament for preventing or treating blood system diseases.
- Another aspect of the present invention provides an application of a compound represented by formula IIIb or a composition thereof in the preparation of a medicament for treating cancer, wherein the cancer is selected from: pancreatic cancer, lung cancer, kidney cancer, liver cancer, gastric cancer , cervical cancer and leukemia and other cancer diseases.
- Another aspect of the present invention provides a combination drug product comprising a compound according to any one of formula IIIb or a compound according to claim 6, and an additional pharmaceutically active agent selected from the group consisting of: (1 ) immunomodulators; (2) PD-1; (3) PD-L1; or (4) other compounds that do not belong to the above (1)-(3).
- the additional pharmaceutical active agent is selected from: (1) immunomodulator; (2) PD-1; (3) PD-L1; or (4) not belonging to the above (1)-( 3) other compounds.
- the immunomodulator includes but not limited to Car-T or other immunomodulators.
- the PD-1 contains active agents that have been marketed or are in clinical trials, including but not limited to: Opdivo, Keytruda, JS001, SHR-1210, BGB-A317, ICI308, BAT1306, toripalimab, or sintilimab.
- the PD-L1 contains active agents that have been marketed or are in clinical trials, including but not limited to: recombinant fully human anti-PD-L1 monoclonal antibody injection, Tecentriq, Bavencio , lIctayo, Imfinzi or Acradine soft capsules.
- the compound or composition of the present invention is especially suitable for the treatment of cancer or related inhibition of angiogenesis, prevention and treatment of blood system diseases.
- the compound of the present invention has better multi-target selectivity and inhibitory activity.
- the "alkyl” refers to a branched chain, straight chain, monocyclic and polycyclic saturated alkane group including 1 to 20 carbon atoms, which consists only of carbon and hydrogen atomic composition.
- the alkyl group has one to twelve carbon atoms (C1C12 alkyl), one to eight carbon atoms (C1C8 alkyl) or one to six carbon atoms (C1C6 alkyl), and it is passed through a single Bonds connect to the rest of the molecule.
- An alkyl group can be unsubstituted or substituted with one or more substituents.
- the alkyl group contains 1-9 carbon atoms (eg, 1-6 carbon atoms, 1-4 carbon atoms, or 1-2 carbon atoms).
- Exemplary alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and each isomers etc.
- the alkyl group including one or more carbons thereof, may optionally be linked to one or more groups including, but not limited to, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl group, carboxyl group, amino group (NH2), amino group, alkylamino group, aminocarbonyl group, aminocarbonyl group, alkyl group, alkoxy group, alkoxycarbonyl group, alkylcarbonylamino group, alkoxycarbonylamino group , Alkylaminocarbonyl, Cycloalkyl, Cycloalkenyl, Cycloalkoxy, Cycloalkoxycarbonyl, Cycloalkylamino, Cycloalkylaminocarbonyl, Cycloalkenyl, Cycloether, Heterocyclyl , alkyl ureido, aryl, aryloxy, heteroaryl, heteroaryloxy, fused aryl, fused heteroaryl, fused epoxy, fuse
- cycloalkyl refers to a ring system containing only carbon atoms in the ring system backbone, eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
- a carbocyclyl can include multiple fused rings.
- a carbocyclyl can have any degree of saturation provided at least one ring in the ring system is not aromatic.
- a carbocyclyl group can be unsubstituted or substituted with one or more substituents.
- a carbocyclyl group contains 3 to 10 carbon atoms, such as 3 to 6 carbon atoms.
- the "aryl” refers to any stable monocyclic, bicyclic, tricyclic or tetracyclic rings containing up to 7 carbon atoms in each ring, wherein at least one ring It is a hydrocarbon ring system group of an aromatic ring.
- exemplary aryl groups are hydrocarbon ring system groups comprising hydrogen and 6-9 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups comprising hydrogen and 9-12 carbon atoms and at least one aromatic ring; comprising hydrogen and a hydrocarbon ring system group of 12-15 carbon atoms and at least one aromatic ring; or a hydrocarbon ring system group comprising hydrogen and 15-18 carbon atoms and at least one aromatic ring.
- an aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
- Aryl groups include, but are not limited to, aryl groups derived from benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, and the like.
- the "heterocyclic group” has 3-16 ring atoms, including 1-3 (if it is a monocyclic ring), and 1-6 (if it is a bicyclic ring) or 1-9 (if tricyclic or polycyclic) one or more of heteroatoms selected from O, N and S are aromatic or non-aromatic heterocycles containing 0 to 3 carbon-carbon double bonds, and Included are bicyclic and tricyclic fused ring groups.
- "Heterocyclic” moieties may contain from 3 to 14 carbon atoms, eg 3 to 8 carbon atoms in monocyclic systems and 7 to 14 carbon atoms in polycyclic systems.
- Heterocycle encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties.
- the heterocyclyl can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, iso Oxazolidines, thiazolidines, isothiazolidines, piperidines, morpholines, thiomorpholines, piperazines and tetrahydropyrans.
- heterocyclic group includes the above-mentioned heterocyclic aryl groups and their dihydro or tetrahydro analogs, and includes but is not limited to the following “heterocyclic groups”: benzimidazolyl, benzofuranyl, benzopyrazolyl , benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuryl, pyridopyridyl, and heterocyclic groups can be combined with other organic small molecule groups through carbon atoms or heteroatoms Groups are connected into new compounds with medicinal effects.
- halogen refers to fluorine, chlorine, bromine and iodine.
- the present invention first designs and introduces a new type of "multi-substituted arylamine and alkylamine” functional groups, and synthesizes a class of drugs that can more effectively treat various tumors and other diseases that are accompanied by abnormal proliferation of blood vessels. Polysubstituted anilinourea compounds.
- the present invention generally relates to compounds covered by formula IIIb, and cis-trans isomers, enantiomers, diastereoisomers, racemates, tautomers, or pharmaceutically acceptable Salts or hydrates, and deuterated or other isotopically substituted compounds:
- the compound of formula IIIb, E, G 1 , G 2 , G 3 , G 4 , G 5 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 etc. are as defined in the claims and described in the manual. Specific embodiments of the compound of formula IIIb are also described below.
- the compounds of the present invention can exist in multiple isomeric forms, and one or more tautomeric forms, including two single tautomers, and a mixture of tautomers.
- the term "isomer" is intended to cover all isomeric forms of the compounds of the invention, including tautomeric forms of said compounds.
- pharmaceutically acceptable salt is a pharmaceutically acceptable, organic or inorganic acid or base salt of the compound of the present invention.
- typical pharmaceutically acceptable salts are selected from but not limited to any of the following acids or bases: inorganic acid salts are mainly selected from: hydrochloride, bromate, iodate, phosphate, sulfate, bicarbonate Salt, bisulfate, borate, or nitrate; organic acid salt is mainly selected from: acetate, benzoate, methanesulfonate, tosylate or valerate.
- Compounds of the invention may be isotopically labeled in which one or more atoms are replaced by atoms having a different atomic mass or mass number.
- isotopes that can be incorporated into compounds of formula IIIb include: isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, or chlorine. Examples of such isotopes are respectively: 2 H(D), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 36 Cl.
- These radiolabeled compounds can be used to measure the biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissues, including subjects administered the labeled compounds.
- Labeled compounds are also used to determine therapeutic efficacy, site or mode of action, and binding affinity of candidate therapeutics to pharmacologically important targets. Certain radioactively labeled compounds of formula IIIb are therefore useful in drug and/or tissue distribution studies.
- the radioisotopes tritium, ie3H , and carbon-14, ie14C are particularly useful for this purpose because of their ease of incorporation and ready means of detection.
- D deuterium
- 2H can confer certain therapeutic advantages resulting from greater metabolic stability (eg, increased in vivo half-lives of deuterium-containing compounds).
- Substituting deuterium for hydrogen can reduce the dosage required to achieve a therapeutic effect and thus may be preferred for use in a discovery or clinical setting.
- Isotopically-labeled compounds of formula IIIb can generally be prepared by conventional techniques known to those skilled in the art or in a manner analogous to those described in the Preparations and Examples sections described hereinafter, using suitable isotopically-labeled reagents.
- Embodiments of the invention described herein are also intended to encompass in vivo metabolites of compounds of formula IIIb. These products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. processes which are primarily attributable to the enzymatic activity of the compounds of the invention upon administration.
- the present invention also provides pharmaceutically acceptable salt forms of the compound of formula IIIb.
- the scope of this invention encompasses acid addition salts which are formed by contacting a pharmaceutically suitable acid with a compound of this invention.
- “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed using inorganic acids such as, but not limited to , hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, etc.;
- solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more molecules of a solvent.
- the solvent may be water, in which case the solvate may be a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present invention may exist in hydrated forms, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms.
- the compounds of the invention may be true solvates, while in other cases the compounds of the invention may retain only adventitious water or a mixture of water plus some adventitious solvent.
- the compound of formula IIIb is formulated in the form of a pharmaceutically acceptable composition comprising an amount of the compound of formula IIIb which is effective after administration of the pharmaceutical composition to a mammal. for the treatment of a particular disease or condition of interest.
- the pharmaceutical compositions of the present invention may comprise a compound of formula IIIb in combination with a pharmaceutically acceptable carrier, diluent or excipient.
- a compound of the invention, or a pharmaceutically acceptable salt thereof may also be administered prior to, concurrently with, or subsequent to the administration of one or more other therapeutic agents.
- Such combination therapy includes the administration of a single pharmaceutical dosage formulation comprising the compound of the invention and one or more other active substances, as well as the administration of the compound of the invention and each active substance in separate pharmaceutical dosage formulations.
- the present invention optimizes and synthesizes some novel tyrosine kinase (RTK) inhibitor formula IIIb urea compounds from the structure of urea anticancer drugs, and has several important RTK targets (such as: VEGFR1, VEGFR2 ( KDR), VEGFR3, FGFR2, RET, etc.) have better inhibitory effects.
- RTK tyrosine kinase
- Some novel formula IIIb urea compounds of the present invention are effective against various tumor cell lines [such as: pancreatic cancer (BXPC3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer ( SNU16), cervical cancer (Hela), and leukemia (K562), etc.] have better inhibitory effects, can be used as targeted drugs to effectively treat some tumors or related cancers mediated by RTK kinases, and have better RTK target to selectivity and security.
- tumor cell lines such as: pancreatic cancer (BXPC3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer ( SNU16), cervical cancer (Hela), and leukemia (K562), etc.
- All raw materials for example: SM1, SM2, SM3, SM4
- reagents and solvents used in the present invention can be obtained commercially or by order.
- the synthetic reaction routes, methods and conditions involved in the preparation of various new compounds of general formula IIIb are the conventional well-known reaction routes, methods and conditions in the art. According to the following synthetic preparation methods disclosed in the present invention, those in the art A skilled person can use the same principle and method to prepare each specific compound involved in each general formula compound in the present invention.
- the synthetic reaction routes, methods and conditions involved in the preparation of various new compounds of formula IIIb are conventional routes, methods and conditions in the art. According to the following synthetic preparation methods disclosed in the present invention, those skilled in the art can use According to the same principle and method, different reagents such as SM1 (Table 1), SM2 (Table 2), SM3 (Table 4a), SM4 (Table 4b) can be selected respectively by the conventional synthetic method shown in the following synthetic reaction scheme 1
- SM1 Table 1
- SM2 Table 2
- SM3 Table 4a
- SM4 Table 4b
- the present invention optimizes the following three methods for synthesizing the compounds of formula IIIb series through the study of synthesis-related reaction conditions.
- R 4 , R 5 and R 6 are the same as those of R 4 , R 5 and R 6 in claims 1 to 5 respectively;
- intermediate RM2 (1.0eq) and reagent SM3 (1.0 ⁇ 5.0eq), pyridine (1.0 ⁇ 5.0eq) in a round bottom reaction flask dissolved in DMF (5 ⁇ 10x), react at 20 ⁇ 80°C, wait until HPLC After the completion of the reaction, the intermediate RM3 was obtained after routine operations such as post-treatment, column chromatography purification, and drying.
- R 4 , R 5 and R 6 are the same as those of R 4 , R 5 and R 6 in claims 1 to 5;
- Table 3a Structural formulas of the "RM1" series of substitution etherification reaction products in the first step of synthesis method
- Table 5a Structural formulas of deuterated isotope compounds of formula IIIb polysubstituted aryl ureas
- the mass spectrometry data was analyzed by using liquid phase 1260 and mass spectrometer 6120 produced by Agilent.
- the molecular weight of the compound of formula IIIb in the present invention is mainly based on positive ion mode ESI-MS [(M+H) + ].
- the special raw materials and intermediates involved in the present invention are provided by Shanghai Zannan Technology Co., Ltd., etc., and all other chemical reagents are purchased from reagent suppliers such as Shanghai Reagent Company, Aldrich Company, and Acros Company. If the intermediates or products required for the reaction in the synthesis process are not enough for the next step and other tests, the synthesis is repeated many times until a sufficient amount is obtained.
- the activity test, pharmacology, toxicology and other tests of the compounds prepared in the present invention are completed by CRO service companies in Shanghai, Beijing and other places according to industry regulations.
- CDI N,N'-carbonyldiimidazole
- HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- HMTA Hexamethylenetetramine
- PE petroleum ether
- Preparation of the diazonium salt of p-aminobenzenesulfonic acid Add p-aminobenzenesulfonic acid (60g, 1.00eq), water (500mL) and Na2CO3 (20.0g) into a 1L three-necked flask, stir until clear, and control the internal temperature to 0°C , drop NaNO2 (25.0g) in water (75mL) solution, after dropping, add concentrated hydrochloric acid (86mL) dropwise, control internal temperature ⁇ 5°C, then stir for 40 minutes (refrigerate for later use).
- Fluorine nuclear magnetic resonance spectrum data of product SM2-01 hydrochloride 19F-NMR (377MHz, d4CD3OD) ⁇ : -132.36/-132.40/-133.09/-133.13.
- intermediate RM1-23 (3.95g, 10mmol), DMF (20mL) and pyridine (30mmol), control the ice-water bath not to exceed 10°C, drop in phenyl chloroformate (30mmol), and drop
- HPLC HPLC shows that the reaction is over
- the reaction liquid is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain intermediate RM2-23 (3.45g ), yield: 67%;
- Step 1 In a 50mL single-necked bottle, add raw material SM1-01 (2.52g, 10mmol), SM2-01 (2.12g, 13mmol), potassium tert-butoxide (1.46g, 13mmol) and DMSO (20mL), nitrogen Protection, reaction at 85°C, after HPLC showed that the reaction was over, the reaction solution was cooled to room temperature, slowly poured into 100mL ice water, solids were precipitated, filtered, washed with water, and fully dried to obtain intermediate RM1-24 (2.95 g), yield: 78%;
- the second step in the three-neck flask of 100mL, add intermediate RM1-24 (3.78g, 10mmol), DMF (20mL) and pyridine (30mmol), ice-water bath control does not exceed 10 °C, drop into chloroformate phenyl ester (30mmol ), react at room temperature after dripping, after the HPLC shows that the reaction is over, the reaction solution is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain the intermediate RM2- 24 (3.64g), yield: 73%;
- Step 3 Add intermediate RM2-24 (4.98g, 10mmol), MeCN (50mL) and SM3-01 (30mmol) to a 100mL single-necked bottle, and react at 60°C. After the reaction, HPLC shows that there is solid precipitation , filtered, washed and dried, purified by column chromatography to obtain solid product RM3-02 (2.63g), yield: 57%.
- Step 4 Add intermediate RM3-02 (4.61g, 10mmol), THF (10mL), MeOH (10mL) and sodium hydroxide (30mmol) to a 100mL single-necked bottle, react at 40°C, HPLC shows that the reaction is complete Finally, after adjusting the pH to about 6 with dilute acid, a solid precipitated out, filtered, washed and dried to obtain the solid product RM4-02 (3.53g), yield: 79%.
- Step 5 Add intermediate RM4-02 (447mg, 1.0mmol), DMF (5mL), HATU (1.3mmol) and SM4-01 (1.5mmol) to a 100mL single-necked bottle, and drop into DIEA (3.0mmol) , reacted at 20°C, HPLC showed that after the reaction was completed, solids were precipitated after adding water, filtered, washed and dried, and purified by column chromatography to obtain solid product IIIb-02 (308mg), yield: 67%.
- the synthetic method for preparing compound IIIb-05 is the same as in Example 2, wherein in the fifth step reaction, compound SM4-11 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, which is dried after the same post-treatment, Purified by column chromatography to obtain solid product IIIb-05 (401 mg), yield: 77%.
- intermediate RM1-25 (3.62g, 10mmol), DMF (20mL) and pyridine (30mmol), control the ice-water bath not to exceed 10°C, drop in phenyl chloroformate (30mmol), and drop
- HPLC HPLC shows that the reaction is over
- the reaction liquid is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain intermediate RM2-25 (4.10g ), yield: 85%;
- intermediate RM1-26 (3.74g, 10mmol), DMF (20mL) and pyridine (30mmol), control the ice-water bath not to exceed 10°C, drop in phenyl chloroformate (30mmol), and drop
- HPLC HPLC shows that the reaction is over
- the reaction liquid is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain intermediate RM2-26 (3.95g ), yield: 80%;
- the synthetic method for preparing compound IIIb-31 is the same as that of Example 2, wherein in the fifth step reaction, compound SM4-25 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, which is subjected to the same aftertreatment and Purified by column chromatography to obtain a solid.
- the synthetic method for preparing compound IIIb-36 is the same as that of Example 2, wherein in the fifth step reaction, the compound SM4-30 (1.5 mmol) is used to react with the intermediate RM4-01 to form an amide bond product, which is dried after the same post-treatment. Purified by column chromatography to obtain solid product IIIb-36 (387 mg), yield: 69%.
- the synthetic method for preparing compound IIIb-51 is the same as the first four steps of Example 1, wherein in the fifth step reaction, compound SM4-45 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, and after the same After work-up, purification by column chromatography yielded a solid.
- the synthetic method for preparing compound IIIb-61 is the same as in Example 55, wherein in the third step reaction, compound SM1-08 (1.0mmol) is used to react with intermediate RM1b-01 (1.3mmol), and column chromatography after the same post-treatment Purification afforded a solid product.
- SM1-14 (10.0g, 35mmol), RM1b-01 (11.8g, 45mmol), potassium tert-butoxide (5.0g, 45mmol) and dimethyl sulfoxide (100mL) in a 1.0L three-necked flask, heated to 65°C for reaction , after the reaction, cold cut and drop into ice water (1L), stirred, filtered, washed with appropriate amount of water, dried to obtain IIIb-50 (12.8g), yield: 71%.
- Embodiment 69 In vitro inhibitory activity drug effect test
- the compounds prepared by the present invention can be preliminarily determined and screened for their effects on pancreatic cancer (BXPC3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer (SNU16), cervical cancer (Hela), and leukemia (K562) and other seven tumor cell line target inhibition effects, and further through the inhibition of VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET and other RTK targets.
- the determination of the activity screens better new anti-cancer drugs, and then finally confirms the efficacy of the new drugs through clinical trials. Other methods will also be apparent to those of ordinary skill in the art.
- each compound to be tested and a positive reference drug were prepared with 10 concentration points, diluted in the culture medium at a concentration gradient of 1:3, and duplicated. Add 5ul of the test compound or positive reference drug to the cell plate, the final concentration of the test compound is up to 10uM, the final concentration of the positive reference drug is up to 3uM, and the DMSO concentration is controlled below 0.2%, and then the cell plate is placed in the cell culture incubator Incubate for 72 hours.
- Buffer configuration 50mM HEPES, pH 7.5, 0.00015% Brij-35.
- the kinase is diluted to the optimal concentration with the following buffer: 50mM HEPES, pH 7.5, 0.00015% Brij-35, 2mM DTT (final concentration of enzyme reaction: VEGFR-1 (FLT1): 2nM; VEGFR-2 (KDR): 1.2 FGFR-3 (FLT4): 1.5 nM; FGFR1: 2 nM; FGFR2: 9 nM; FGFR3: 8 nM; FGFR4: 10 nM; PDGFR ⁇ : 3.5 nM; c-MET: 10 nM; RET: 7 nM; EGFR: 6 nM). Transfer 10 ⁇ l to a 384-well plate and incubate with compound for 10 minutes.
- buffer 50mM HEPES, pH 7.5, 0.00015% Brij-35, 2mM DTT (final concentration of enzyme reaction: VEGFR-1 (FLT1): 2nM; VEGFR-2 (KDR): 1.2 FGFR-3 (
- VEGFR1 (FLT1) 3 ⁇ M Peptide30 (5-FAM-KKKKEEIYFFFCONH 2 ), 278 ⁇ M ATP, 10 mM MgCl 2 ;
- VEGFR2 (KDR): 3 ⁇ M Peptide22 (5-FAM-EEPLYWSFPAKKKCONH 2 ), 92 ⁇ M ATP, 10 mM MgCl 2 ;
- VEGFR3 (FLT4): 3 ⁇ M Peptide30 (5-FAM-KKKKEEIYFFFCONH 2 ), 84 ⁇ M ATP, 10 mM MgCl 2 ;
- FGFR2 3 ⁇ M Peptide22 (5-FAM-EEPLYWSFPAKKKCONH 2 ), 1.9 ⁇ M ATP, 10 mM MgCl 2 ;
- RET 3 ⁇ M Peptide22 (5-FAM-EEPLYWSFPAKKKCONH 2 ), 23 ⁇ M ATP, 10 mM MgCl 2
- hERG potassium ion channel
- K + potassium ion channel
- IKr three-phase rapid repolarization current
- LQTS long QT syndromes
- the compound may have the above-mentioned hidden dangers and risk. Therefore, the in vitro inhibitory effect (IC 50 ) of drugs on hERG channels has been recommended by the International Conference on Harmonization of Drug Registration as part of the preclinical safety evaluation (ICHS7B Expert Working Group, '02).
- the stably transfected cells were dropped on a round glass slide and placed in a petri dish at a cell density below 50%, and cultured overnight.
- the cells used in the experiment were transferred to a bath of about 1 ml embedded in the inverted microscope platform, and the extracellular fluid was perfused at a rate of 2.7 ml/min.
- the experiment can be started after 5 minutes of stabilization.
- Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were done at room temperature (22-24°C).
- the electrode (BF150-110-10) was straightened using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) in the experiment.
- the inner diameter of the electrode is 1-1.5mm, and the water resistance after being filled with inner liquid is 2-4M ⁇ .
- the electrophysiological stimulation scheme of the hERG potassium channel is to first clamp the membrane voltage at -80mV, give the cells a continuous 2s, +20mV voltage stimulation, activate the hERG potassium channel, and then repolarize to -50mV for 5s to generate an outward tail current.
- the stimulation frequency was once every 15s.
- the current value is the peak value of the tail current.
- the channel current was recorded in the whole-cell recording mode.
- perfuse the extracellular fluid about 2 ml per minute
- keep recording and wait for the current to stabilize (the current decay (Run-Down) is less than 5% within 5 minutes)
- the peak value of the tail current is the control current value.
- perfuse the extracellular fluid containing the drug to be tested and keep recording until the inhibitory effect of the drug on the hERG current reaches a steady state.
- the peak value of the tail current is the current value after adding the drug.
- the standard of steady state is judged by whether the latest three consecutive current recording lines coincide.
- Some preferred compounds such as formula IIIb (such as: IIIb-06, IIIb-08, IIIb-09, IIIb-21, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61, IIIb-65) inhibit various tumor cell lines [such as: pancreatic cancer (BXPC3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer ( SNU16), cervical cancer (Hela), prostate cancer (PC-3), and leukemia (K562), etc.] and tyrosine kinase (such as: VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET) activity test results respectively Listed in Table 6, Table 7 and Table 8 below.
- the activity range (IC 50 ) of each compound in inhibiting pancreatic cancer cell line (BXPC3) is ⁇ 5.0uM marked as "A", the activity range of 5.0-10.0uM is marked as “B”, and the activity range > 10.0uM is marked as "C";
- the activity range (IC 50 ) of each compound against lung cancer cell line (A549) is marked as “A” when it is ⁇ 2.5uM, "B” when the activity range is 2.5-5.0uM, and "C” when the activity range is >5.0uM ";
- the activity range (IC 50 ) of each compound in inhibiting kidney cancer cell line (Caki-1) is marked as "A” when it is ⁇ 2.5uM, "B” when the activity range is 2.5-5.0uM, and marked as “B” when the activity range is >5.0uM for "C”;
- the activity range (IC 50 ) of each compound in inhibiting liver cancer cell lines is marked as "A” when it is ⁇ 2.5uM, "B” when the activity range is 2.5-5.0uM, and marked as “B” when the activity range is >5.0uM for "C”;
- the activity range (IC 50 ) of each compound in inhibiting gastric cancer cell line (SNU16) is ⁇ 5.0uM marked as "A", the activity range of 5.0-10.0uM is marked as “B”, and the activity range > 10.0uM is marked as "C”";
- the activity range (IC 50 ) of each compound against cervical cancer cell line (Hela) is marked as "A” when it is ⁇ 5.0uM, "B” when the activity range is 5.0-10uM, and "C” when the activity range is >10uM ;
- the activity range (IC 50 ) of each compound in inhibiting the leukemia cell line (K562) is marked as "A” when it is ⁇ 5.0uM, "B” when the activity range is 5.0-10uM, and "C” when the activity range is >10uM;
- the activity range (IC 50 ) of each compound in inhibiting prostate cancer cell line (PC-3) is marked as "A” at ⁇ 5.0uM, "B” is marked at the activity range of 5.0-10uM, and "B” is marked at the activity range>10uM C".
- Table 7 Some preferred compounds of formula IIIb inhibit the activity results of four cell lines of liver cancer, gastric cancer, cervical cancer and leukemia
- Some preferred compounds in formula IIIb are respectively used to inhibit the activity results of RTK targets such as VEGFR1-3, FGFR2, RET, etc. in Table 8 below; wherein, each compound inhibits various tyrosine kinases VEGFR1,
- the active effect range (IC 50 ) of KDR (VEGFR2) and VEGFR3 is marked as "A” when it is ⁇ 5nM, "B” when the activity range is 5-10nM, and “C” when the activity range is >10nM; each compound inhibits each The active effect range (IC 50 ) of a tyrosine kinase FGFR2 is marked as "A” at ⁇ 50nM, "B” when the activity range is 50-100nM, and “C” when the activity range is >100nM; each compound inhibits each The activity effect range (IC 50 ) of a tyrosine kinase RET ⁇ 5nM is marked as "A”, the activity range of 5-10nM is marked as "B", and
- IIIb-61 A A A A A A IIIb-65 A A A A A A Sorafenib C C C C Regorafenib C C C B C Lenvatinib B B A B B
- Embodiment 70 Compound Toxicity Screening Test
- the present invention respectively carried out the MTD toxicity test (150mg/kg, QD) of rats, taking the medicine for 14 consecutive days without death and other abnormalities. No abnormal changes were found in the heart, liver, lung, kidney, stomach, intestine and other organs in the rat autopsy results. It is generally believed that the tested compound is safe and non-toxic within an appropriate dose.
- the present invention designs and synthesizes the preferred compound "IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61, IIIb-65" not only has better inhibitory effect, but also has better safety and druggability, and has application value for further preclinical research and clinical trials such as drug toxicology.
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Abstract
本发明公开了式IIIb所示的化合物,其顺反异构体、外消旋体、氘代或药学上可接受的盐或它们的混合物,含有该化合物的药物组合物以及所述化合物作为多个酪氨酸激酶(RTK)重要靶点抑制剂及其用于治疗多种伴有血管形成的肿瘤等疾病的用途。本发明的化合物可以作为抑制活性更好的RTK靶向多抗药物用于有效治疗胰腺癌、肺癌、肾癌、肝癌、胃癌、宫颈癌和白血病等多种癌症疾病,其中E、G1、G2、G3、G4、G5、R1、R2、R3、X1、X2、X3、X4以及化合物中各元素可能的同位素取代标记如说明书中所定义。
Description
本发明涉及一类新型含“多取代芳胺与烷基胺”形成的脲类化合物。更具体地,本发明涉及可用作多靶点酪氨酸激酶抑制剂的多取代芳胺基脲类化合物及其多种医药应用。
蛋白酪氨酸激酶(protein tyrosine kinases,PTKs)是已知的最大的蛋白质超家族,蛋白酪氨酸激酶是胞外信号传递到细胞内的重要枢纽。酪氨酸激酶在调控细胞的增殖、分化方面起着重要作用,PTK异常表达会激活一系列下游信号途径,引起级联反应,致使细胞增殖调节紊乱,最终导致肿瘤的形成。酪氨酸激酶可分为受体型酪氨酸激酶(RTK)和非受体型酪氨酸激酶(nRTK)两种,受体型酪氨酸激酶(RTK)包括血管内皮细胞生长因子受体(VEGFR,Vascular Endothelial Growth Factor Receptor)、成纤维细胞生长因子受体(FGFR,Fibroblast growth gactor receptor)、表皮生长因子受体[Epidermal growth factor receptor,简称EGFR、HER1、或ErbB-1,是表皮生长因子受体(HER)家族成员之一]、酪氨酸激酶膜受体(c-Met)、血小板衍生生长因子受体α(PDGFRα)、以及RET等成员,这些RTKs与肿瘤疾病及其靶向治疗密切相关。
迄今为止,超过80%的激酶已被作为治疗性药物开发的靶标,有关报道指出血管内皮形成的病理性增加与各种疾病的发病或发展过程有关,实体瘤的增殖依赖于血管形成,因此有效抑制上述的一些酪氨酸激酶VEGFR1-3、FGFR1-4、EGFR、RET、c-MET等酪氨酸激酶(RTK)靶点的药物己成为针对难治性实体瘤的主要靶向治疗方法。目前已上市的大部分分子靶向抗肿瘤药物均为以PTK为靶标的蛋白酪氨酸激酶抑制剂(TKI)。
目前,国内外已上市的大部分分子靶向抗肿瘤药物均为以PTK为靶标的蛋白酪氨酸激酶抑制剂(TKI),例如对酪氨酸激酶VEGFR1-3具有较好抑制作用的、 临床用于治疗肝癌的小分子脲类化合物抗癌药有索拉非尼(Sorafenib,Ref-1)、瑞戈非尼(Regorafenib,Ref-2),以及对酪氨酸激酶VEGFR1-3和FGFR1-4均具有较好抑制作用的仑伐替尼(Lenvatinib,乐伐替尼,Ref-3),临床治疗中具有较好的抗肿瘤效果。
本发明的目的是通过小分子结构及其功能团的创新设计,研制出一种抑制酪氨酸激酶活性更高、毒性副作用更低的新型多靶点酪氨酸激酶抑制剂(TKI),更有效地用于治疗胰腺癌、肺癌、肾癌、肝癌、胃癌、宫颈癌和白血病等多种肿瘤及其相关癌症疾病。
本发明涉及一类含新型的多取代苯胺基团为创新重点的式IIIb多取代苯胺基脲类化合物作为多靶点酪氨酸激酶抑制剂(TKI),不仅能高效抑制血管内皮生长因子受体(VEGFR1、VEGFR2、VEGFR3)和成纤维细胞生长因子受体(FGFR1-4),而且也能高效抑制除了其正常的细胞功能的其它可能导致血管生成和肿瘤生长致病的多个重要受体酪氨酸激酶(RTK),例如包括但不限于EGFR、RET、PDGFRα等酪氨酸激酶,从而可以产生比较强的血管生成抑制作用,在更有效预防和治疗伴有血管形成的异常增殖的各种肿瘤等疾病中具有更好的应用。
本发明所公开的含多取代苯胺基团的脲类化合物的结构是根据酪氨酸激酶靶点的结构特征,通过在苯胺中引入含较多取代基进行结构修饰创新和优化,从而研制出一种抑制效果更好的多靶点酪氨酸激酶抑制剂(TKI),能够更有效地治疗多种类型的肿瘤。
发明内容
本发明解决的核心问题是研制出一种新型含有多取代基苯胺为创新特征的脲类化合物,其对于胰腺癌(BXPC3)、肺癌(A549)、肾癌(Caki-1)、肝癌(Hep3B2.1-7)、胃癌(SNU16)、宫颈癌(Hela)、和白血病(K562)等多种肿瘤细胞株和VEGFR1-3、FGFR1-4、EGFR、RET等激酶靶子具有较好的抑制作用,结果显示抑制效果更好、应用前景更佳,并且具有较好的安全性。
本发明的第一方面提供一种式IIIb所示的化合物,其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、或药学上可接受的盐或水合物、以及氘代或同位素取代的化合物:
其中,
E是氮(N)、或CH;
G
1是氢、氘(D)、卤素、-CN、C
1-20烷基、C
1-20烷氧基、或C
1-20烷基胺基;
G
2是卤素、-CN、C
1-20烷基胺基、C
1-20羟基亚烷基胺基、C
1-20腈基亚烷基胺基、C
1-20胺基亚烷基胺基、C
3-20胺基环亚烷基胺基、C
1-20羧基亚烷基胺基、C
3-20羧基环亚烷基胺基、3-6元的杂环基胺基、或-OR
6;其中,R
6选自:氢、氘、C
1-20烷基、C
1-20卤代烷基、C
1-20氰基亚烷基、C
3-20氰基环亚烷基、C
2-20羟基亚烷基、C
2-20胺基亚烷基、C
3-20胺基环亚烷基、C
2-20羧基亚烷基、C
3-20羧基环亚烷基、C
3-6环烷基、C
3-6胺基环亚烷基、C
1-20胺基(C
3-20环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;
G
3是-CN、-C(O)OR、-C(O)NH
2、氘代-C(O)ND
2、C
1-20烷氧基、C
1-20烷基胺基、或-C(O)NR
4R
5;其中,R是氢、或C
1-20烷基,R
4和R
5各自独立地选自:氢、氘、C
1-20烷基、C
1-20卤代烷基、C
1-20腈基亚烷基、C
3-20氰基环亚烷基、C
2-20羟基亚烷基、C
3-20羟基环亚烷基、C
2-20胺基亚烷基、C
3-20胺基环亚烷基、C
2-20羧基亚烷基、C
3-20羧基环亚烷基、C
3-20环烯基、C
3-20环烷基、3-6元的杂环基、3-6元的杂环基亚烷基、C
6-20芳基、C
3-20杂环芳基、C
1-20烷基磺酰基、C
3-20环烷基磺酰基、或C
2-20杂环烷基磺酰基;R
4和R
5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;
G
4和G
5各自独立地选自:氢、氘(D)、卤素、-CN、C
1-20烷基、C
1-20烷氧基、或C
1-20烷基胺基;
R
1选自:氢、氘、C
1-20烷基、C
3-20环烷基、或C
3-20氘代环烷基;
R
2和R
3各自独立地选自:氢、氘、C
1-20烷基、C
3-20环烷基、C
3-20氘代环烷基、或3-6元的杂环基;
X
1、X
2和X
3各自独立地选自:卤素、-CN、-NH
2、C
1-20烷氧基、或C
1-20烷 基胺基;
X
4选自:氢、氘、卤素、-CN、-NH
2、C
1-20烷氧基、或C
1-20烷基胺基。
在一些优选的实施方式中,
E是氮(N)、或CH;
G
1是氢、氘(D)、卤素、-CN、C
1-6烷基、C
1-6烷氧基、或C
1-6烷基胺基;
G
2是卤素、-CN、C
1-6烷基胺基、C
1-6羟基亚烷基胺基、C
1-6腈基亚烷基胺基、C
1-6胺基亚烷基胺基、C
3-6胺基环亚烷基胺基、C
1-6羧基亚烷基胺基、C
3-6羧基环亚烷基胺基、3-6元的杂环基胺基、或-OR
6;其中,R
6选自:氢、氘、C
1-6烷基、C
1-6卤代烷基、C
1-6氰基亚烷基、C
3-6氰基环亚烷基、C
2-6羟基亚烷基、C
2-6胺基亚烷基、C
3-6胺基环亚烷基、C
2-6羧基亚烷基、C
3-6羧基环亚烷基、C
3-6环烷基、C
3-6胺基环亚烷基、C
1-6胺基(C
3-6环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;
G
3是-CN、-C(O)OR、-C(O)NH
2、氘代-C(O)ND
2、C
1-6烷氧基、C
1-6烷基胺基、或-C(O)NR
4R
5;其中,R是氢、或C
1-6烷基,R
4和R
5各自独立地选自:氢、氘、C
1-6烷基、C
1-6卤代烷基、C
1-6腈基亚烷基、C
3-6氰基环亚烷基、C
2-6羟基亚烷基、C
3-6羟基环亚烷基、C
2-6胺基亚烷基、C
3-6胺基环亚烷基、C
2-6羧基亚烷基、C
3-6羧基环亚烷基、C
3-6环烯基、C
3-6环烷基、3-6元的杂环基、3-6元的杂环基亚烷基、C
6-10芳基、C
3-10杂环芳基、C
1-6烷基磺酰基、C
3-6环烷基磺酰基、或C
2-6杂环烷基磺酰基;R
4和R
5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;
G
4和G
5各自独立地选自:氢、氘(D)、卤素、-CN、C
1-6烷基、C
1-6烷氧基、或C
1-6烷基胺基;
R
1选自:氢、氘、C
1-6烷基、C
3-6环烷基、或C
3-6氘代环烷基;
R
2和R
3各自独立地选自:氢、氘、C
1-6烷基、C
3-6环烷基、C
3-6氘代环烷基、或3-6元的杂环基;
X
1、X
2和X
3各自独立地选自:卤素、-CN、-NH
2、C
1-6烷氧基、或C
1-6烷基胺基;
X
4选自:氢、氘、卤素、-CN、-NH
2、C
1-6烷氧基、或C
1-6烷基胺基。
在一些更优选的实施方式中,
E是CH;
G
1是氢;
G
2是-OR
6,其中R
6选自:氢、氘、C
1-6烷基、C
1-6卤代烷基、C
1-6氰基亚烷基、C
3-6氰基环亚烷基、C
2-6羟基亚烷基、C
2-6胺基亚烷基、C
3-6胺基环亚烷基、C
2-6羧基亚烷基、C
3-6环烷基、C
3-6胺基环亚烷基、C
1-6胺基(C
3-6环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;
G
3是-C(O)OR、-C(O)NH
2、或-C(O)NR
4R
5;其中,R是氢、或C
1-6烷基,R
4和R
5各自独立地选自:氢、C
1-6烷基、C
1-6卤代烷基、C
1-6氰基亚烷基、C
3-6氰基环亚烷基、C
2-6羟基亚烷基、C
2-6胺基亚烷基、C
2-6羧基亚烷基、C
3-6环烷基、3-6元的杂环基、C
1-6亚烷基(3-6元的杂环基)、C
3-6杂环芳基、C
1-6烷基磺酰基、C
3-6环烷基磺酰基、或C
2-6杂环烷基磺酰基;R
4和R
5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;
G
4和G
5各自独立地选自:氢;
R
1选自:氢;
R
2选自:氢;
R
3各自独立地选自:C
3-6环烷基;
X
1、X
2和X
3各自独立地选自:卤素;
X
4选自:氢。
在一些具体的实施方式中,本发明所述的式IIIb化合物选自下列结构,其特征为包括但不限于如下任一结构:
本发明的第二方面提供一种式IIIb所示的化合物的制备方法,其特征在于:其可以通过下述二种方法的任一种方法制得:
方法一包括下述五个步骤,反应方程式如下:
方法二包括下述三个步骤,反应方程式如下:
其中,
R
4和R
5各自独立地选自:氢、氘、C
1-6烷基、C
1-6卤代烷基、C
1-6氰基亚烷基、C
2-6羟基亚烷基、C
2-6胺基亚烷基、C
2-6羧基亚烷基、C
2-6烯基、C
3-6环烯基、C
3-6环烷基、3-6元的杂环基、3-6元的杂环基亚烷基、C
6-12芳基、C
3-10杂环芳基、C
1-6烷基磺酰基、C
3-6环烷基磺酰基、或C
2-6杂环烷基磺酰基,或R
4和R
5之间相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基。
R
6选自:氢、氘、C
1-6烷基、C
1-6卤代烷基、C
1-6氰基亚烷基、C
3-6氰基环亚 烷基、C
2-6羟基亚烷基、C
2-6胺基亚烷基、C
3-6胺基环亚烷基、C
2-6羧基亚烷基、C
3-6环烷基、C
3-6胺基环亚烷基、C
1-6胺基(C
3-6环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基。
本发明的另一方面进一步提供了下列中间体化合物RM1b-01的合成制备方法:
本发明的另一方面进一步提供了下列化合物SM2-01的合成制备方法及其在式IIIb化合物的合成制备中的应用:
反应一:
反应二:
本发明的另一方面提供一种式IIIb所示的化合物或其药学上可以接受的盐以及药学上可接受的稀释剂和/或赋形剂。
本发明的另一方面提供一种式IIIb所示的化合物或其组合物在制备用于预防或治疗血液系统疾病的药物中的应用。
本发明的另一方面提供一种式IIIb所示的化合物或其组合物在制备用于治疗癌症的药物中的应用,其中,所述癌症选自:胰腺癌、肺癌、肾癌、肝癌、胃癌、宫颈癌和白血病等多种癌症疾病。
本发明的另一方面提供一种联合药物产品,其包含如式IIIb中任一项所述的化合物或权利要求6所述的化合物,以及选自以下的另外的药学上的活性剂:(1)免疫调节剂;(2)PD-1;(3)PD-L1;或(4)不属于上述(1)-(3)的其他化合物。
在优选的实施方式中,另外的药物上的活性剂选自:(1)免疫调节剂;(2)PD-1;(3)PD-L1;或(4)不属于上述(1)-(3)的其他化合物。
在本发明所述的上述联合药物产品中,所述的免疫调节剂包含但不限于Car-T或其它免疫调节剂。
在本发明所述的上述联合药物产品中,所述的PD-1包含己上市或正在临床试验的活性剂,包括但不限于:Opdivo、Keytruda、JS001、SHR-1210、BGB-A317、ICI308、BAT1306、特瑞普利单抗、或信迪利单抗。
在本发明所述的上述联合药物产品中,所述的PD-L1包含己上市或正在临床试验的活性剂,包括但不限于:重组全人抗PD-L1单克隆抗体注射液、Tecentriq、Bavencio、lIctayo、Imfinzi或阿可拉定软胶囊。
在优选的实施方式中,本发明的化合物或组合物尤其适用于癌症或相关抑制血管形成、预防和治疗血液系统疾病的治疗。同时,相对于三个同类对照药物而言,本发明的化合物具有更好的多靶点选择性和抑制活性。
在下面的详细描述中,本发明的上述实施方式和其他方面是显而易见的。为此,本文阐述了各种参考文献,其更详细地描述了某些背景信息,过程,化合物和/或组合物,并且各自通过引用整体并入本文。
发明详述
在以下描述中,为了提供对本发明各实施方式的透彻理解,陈述了一些具体的细节。然而,本领域技术人员应理解,可以在不要求这些细节的情况下实施本发明。除非上下文中另有说明,贯穿本发明说明书和权利要求书,词语“包含”及其变化形式,例如,“包含”和“包括”理解为开放、可兼形式(即,“包括(包含)但不限于”)。
说明书中提及的“一个实施方式”或“一种实施方式”表示连同实施方式描述的具体特征、结构或特性包括在本发明的至少一个实施方式中。因此,在说明书中各处出现的短语“在一个实施方式中”或“在一种实施方式中”不一定全部都涉及 同一个实施方式。而且,具体的特征、结构、或性质可以任何合适的方式组合在一个或多个实施方式中。
I.定义
本发明中,没有特别指定的时候,所述的“烷基”,意指包括1~20个碳原子的支链、直链、单环和多环的饱和烷烃基,其仅由碳和氢原子组成。在优选的实施方式中,所述烷基具有一至十二个碳原子(C1C12烷基)、一至八个碳原子(C1C8烷基)或一至六个碳原子(C1C6烷基),并且其通过单键与分子的剩余部分相连。烷基可以是未取代的或被一个或多个取代基取代。在一些实施方式中,烷基包含1-9个碳原子(例如,1-6个碳原子、1-4个碳原子,或1-2个碳原子)。示例性的烷基基团包括:甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基,及它们的各种异构体等。所述烷基包括其一个或多个碳可以任选地与包含但不限于下组的一个或多个基团连接:氘(D)、卤素、三氟甲基、三氟甲氧基、氰基、羟基、羧基、氨基(NH2)、胺基、烷基胺基、氨基羰基、胺基羰基、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷氧基羰基胺基、烷基胺基羰基、环烷基、环烯基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、烷基脲基、芳基、芳氧基、杂环芳基、杂环芳基氧基、稠环芳基、稠环杂环芳基、稠环氧基、稠环芳氧基、稠环杂环芳氧基、芳基脲基、或杂环芳基脲基。
如本文所用,“环烷基”是指在环体系骨架中仅含有碳原子的环体系,例如环丙基,环丁基,环戊基,环己基和环己烯基。碳环基可包括多个稠合环。碳环基可具有任何饱和度,前提是环体系中的至少一个环不是芳族的。碳环基基团可以是未取代的或被一个或多个取代基取代。在一些实施方式中,碳环基基团包含3至10个碳原子,例如3至6个碳原子。
本发明中,没有特别指定的时候,所述的“芳基”是指任何稳定的每个环可包含最高达7个碳原子的单环、二环、三环或四环,其中至少一个环是芳香环的烃环系基团。示例性的芳基是包含氢和6-9个碳原子和至少一个芳环的烃环系基团;包含氢和9-12个碳原子和至少一个芳环的烃环系基团;包含氢和12-15个碳原子和至少一个芳环的烃环系基团;或包含氢和15-18个碳原子和至少一个芳环的烃 环系基团。出于本发明目的,芳基基团可以是单环、双环、三环或四环环系,其可包括稠合或桥接环系。芳基基团包含但不限于,源自如下构成的芳基基团:苯、联苯、蒽、薁、芴、茚满、茚、萘、菲、芘等。
本发明中,没有特别指定的时候,所述的“杂环基”为具有3-16个环原子、含有1-3个(如果是单环的话)、1-6个(如果是双环的话)或1-9个(如果是三环或多环的话)选自O、N和S的杂原子中的一个或多个的芳香或者含有0~3个碳碳双键的非芳香杂环,并且包括二环和三环的稠环基团。“杂环”部分可以含有3至14个碳原子,例如单环体系中的3至8个碳原子和多环体系中的7至14个碳原子。“杂环”涵盖杂环烷基部分、杂环烯基部分和杂芳族部分。例如,杂环基可以是环氧乙烷、氮丙啶、氮杂环丁烷、氧杂环丁烷、四氢呋喃、吡咯烷、咪唑烷、琥珀酰亚胺、吡唑烷、噁唑烷、异噁唑烷、噻唑烷、异噻唑烷、哌啶、吗啉、硫代吗啉、哌嗪和四氢吡喃。因此,“杂环基”包括上述杂环芳基以及其二氢或者四氢类似物,并且包含但不限于以下“杂环基”:苯并咪唑基、苯并呋喃基、苯并吡唑基、苯并三唑基、苯并噻唑基、苯并噻吩基、苯并噁唑基、异苯并呋喃基、吡啶并吡啶基,杂环基可以通过碳原子或者杂原子与其它有机小分子基团进行连接成新的有药用效果的化合物。
术语“卤素”是指氟、氯、溴和碘。
II.本发明的化合物
1)本发明首先设计引入一种含新型“多取代芳胺基与烷基胺”功能基团,并且合成出了一类能够更有效治疗伴有血管形成的异常增殖的多种肿瘤等疾病的多取代苯胺基脲类化合物。
2)本发明一般涉及由式IIIb涵盖的化合物,及其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、或药学上可接受的盐或水合物、以及氘代或其它同位素取代的化合物:
其中,式IIIb的化合物,E、G
1、G
2、G
3、G
4、G
5、R
1、R
2、R
3、X
1、X
2、X
3、X
4等的定义如权利要求和说明书所述。下文还描述了式IIIb化合物的具体实施方式。
3)本发明化合物可以多种异构形式,以及一种或多种互变异构形式存在,包括两种单一互变异构体,和互变异构体的混合物。术语“异构体”意在涵盖本发明化合物的全部异构形式,包括所述化合物的互变异构形式。
本说明书中,″药学上可接受的盐″是本发明化合物的药学上可接受的、有机或无机酸或碱盐。其中,典型的药物上可接受的盐选自但不限于下列任何一种酸或碱:无机酸盐主要选自:盐酸盐、溴酸盐、碘酸盐、磷酸盐、硫酸盐、碳酸氢盐、硫酸氢盐、硼酸盐、或硝酸盐;有机酸盐主要选自:乙酸盐、苯甲酸盐、甲磺酸盐、甲苯磺酸盐或戊酸盐。
本发明的化合物可以是其中一个或多个原子被具有不同原子质量或质量数的原子代替的同位素标记。可被纳入式IIIb化合物的同位素的示例包括:氢、碳、氮、氧、氟、或氯的同位素。此类同位素的示例分别是:
2H(D)、
3H、
11C、
13C、
14C、
13N、
15N、
15O、
17O、
18O、
18F、
36Cl。这些带有放射性标记的化合物可用于检测生物分布、组织浓度,和从生物组织,包括给予该带标记的化合物的对象,运输和排出的动力学。带标记的化合物还用于确定治疗效果、作用位点或模式,以及候选治疗物对药理学上重要的靶标的结合亲和性。因此,式IIIb的某些放射性物质标记的化合物可用于药物和/或组织分布研究。放射性同位素氚,即
3H,和碳-14,即
14C,特别有用于该目的,因为它们易于纳入并且检测手段现成。
用重同位素如氘(D)即
2H取代能提供因代谢稳定性较高(例如含氘化合物的体内半衰期延长)而产生的某些治疗优势。用氘取代氢能减小获得疗效所需的剂量,并因此可优选用于发现或临床环境。
正电子发射型同位素(例如
11C,
18F,
15O和
13N)的取代能提供本发明化合物的经标记的类似物,其有用于正电子成象术(PET)研究,例如,用于检测物质受体占用率。同位素标记的式IIIb的化合物可一般地通过本领域技术人员已知的常规技术或通过与下文所述的制备和实施例部分中描述的那些类似的方式,采用合适的同位素标记试剂来制备。
本文所述的本发明实施方式还意在涵盖式IIIb化合物的体内代谢产物。这些产物可源自,例如,主要归因于本发明化合物给予后的酶促活性的氧化、还原、水解、酰胺化、酯化等过程。
本发明还提供式IIIb化合物的药学上可接受的盐形式。本发明范围涵盖酸加成盐,其通过使药学上合适的酸与本发明化合物接触来形成。
“药学上可接受的酸加成盐”指:保留生物有效性和游离碱的性质的那些盐,它们不是在生物或其它方面中不希望的,并且它们的形成采用无机酸,例如但不限于,盐酸、氢溴酸、硫酸、磷酸、硝酸、碳酸等;以及有机酸,例如但不限于,:乙酸、苯甲酸、甲磺酸、甲苯磺酸或戊酸等。
结晶化通常产生本发明化合物的溶剂合物。本文中所用术语“溶剂合物”指:包含本发明化合物的一个或多个分子与溶剂的一个分子或多个分子的聚集体。溶剂可以是水,此时溶剂合物可以是水合物。或者,溶剂可以是有机溶剂。因此,本发明化合物可以水合物形式存在,包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及对应的溶剂合物形式。本发明化合物可以是真溶剂合物,而在其它情况中,本发明化合物可以仅保留不定水或是水加上一些不定溶剂的混合物。
III.药物组合物
在一个实施方式中,式IIIb的化合物,以药学上可接受的组合物的形式配制,所述组合物包含一定量的式IIIb化合物,在给予所述药物组合物至哺乳动物后,该量有效于治疗感兴趣的特定疾病或病症。本发明的药物组合物可包含式IIIb化合物,其与药学上可接受的运载体、稀释剂或赋形剂相组合。
IV.治疗应用
本发明的化合物,或其药学上可接受的盐,也可在一种或多种其它治疗剂的给予之前、同时或之后给予。此类联合治疗包括给予单一药物剂量制剂,其包含本发明化合物和一种或多种其它活性物质,以及在分开的药物剂量制剂中给予本发明化合物和各活性物质。
本发明的积极进步效果在于:
1)本发明从脲类抗癌药物结构上优化合成了一些新型的酪氨酸激酶(RTK)抑制剂的式IIIb脲类化合物,并且对几个重要的RTK靶点(如:VEGFR1、VEGFR2(KDR)、VEGFR3、FGFR2、RET等)具有更好的抑制效果。
2)本发明的一些新型式IIIb脲类化合物对多种肿瘤细胞株[如:胰腺癌(BXPC3)、肺癌(A549)、肾癌(Caki-1)、肝癌(Hep3B 2.1-7)、胃癌(SNU16)、宫颈癌(Hela)、和白血病(K562)等]具有更好的抑制效果,可以作为靶向药物有效治疗由RTK激酶介导产生的一些肿瘤或相关癌症,并且具有更好的RTK靶向选择性和安全性。
3)本发明的一些新型式IIIb脲类化合物具有更好的安全性,例如:化合物IIIb-08、IIIb-09、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65不仅大鼠的MTD毒性剂量(QD)大于150mg/kg,而且其钾离子通道安全的参数hERG>30uM(仑伐替尼的大鼠的MTD毒性剂量为40mg/kg,hERG=11.9uM)。
本发明合成新型多取代苯胺为创新重点的芳基脲类化合物过程中的化学试剂和溶剂的英文缩写注释全部汇总列在实施例中仪器及原料说明部分。
本发明中所用的全部原料(例如:SM1、SM2、SM3、SM4)、试剂和溶剂等均可由市售或订购得到。
本发明中,制备通式IIIb的各类新化合物涉及的合成反应路线,方法及条件均为本领域常规熟知的反应路线、方法和条件,根据本发明公开的下述的合成制备方法,本领域技术人员可采用与之相同的原理和方法,制备本发明中各通式化合物所涉及的各个具体化合物。
下面通过实施例的方式进一步详细介绍本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规熟知的方法和条件,或按照商品说明书选择实施完成。
本发明中,制备各类式IIIb新化合物涉及的合成反应路线,方法及条件均为本领域常规路线、方法和条件,根据本发明公开的下述的合成制备方法,本领 域技术人员可采用与之相同的原理和方法,可以通过下列合成反应方案1所示的常规合成方法分别选择不同的SM1(表1)、SM2(表2)、SM3(表4a)、SM4(表4b)等试剂分别制备本发明中的各通式化合物涉及的各具体化合物(详见下列表6中式IIIb结构式系列中化合物IIIb-01至IIIb-65)。
本发明合成新型多取代芳基脲类化合物过程中的化学试剂和溶剂的英文缩写注释全部汇总列在实施例中仪器及原料说明部分。
本发明经合成有关的反应条件研究优化了以下三种合成式IIIb系列化合物的方法。
在上述合成方法1中,R
4、R
5和R
6各自的定义分别与权利要求1~5中的R
4、R
5和R
6相同;R
4和R
5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;具体合成反应实施步骤分别如下:
1.1、中间体RM1的合成:
在50mL的单口瓶中,加入原料SM1(1.0eq),SM2(13mmol)、叔丁醇钾(1.0~1.5eq)和DMSO(7~10x),氮气保护,85℃下反应,HPLC显示反应结束后,将反应液后处理,经柱层析纯化、干燥,得到中间体RM1。
1.2、中间体RM2的合成:
在100mL的三口瓶中,加入中间体RM1(1.0eq)、DMF(5x)和吡啶(5.0x),冰水浴控制不超过10℃,滴入氯甲酸苯酯(5.0eq),滴完以后室温反应,HPLC显示反应结束后,将反应液后处理,经柱层析纯化、干燥,得到中间体RM2。
1.3、中间体RM3的合成:
在圆底反应瓶中加入中间体RM2(1.0eq)和试剂SM3(1.0~5.0eq)、吡啶(1.0~5.0eq)溶于DMF(5~10x)中,在20~80℃反应,等到HPLC显示反应结束后,经后处理、柱层析纯化、干燥等常规操作后得到中间体RM3。
1.4、中间体RM4的合成:
在圆底反应瓶中加入中间体RM3(1.0eq)和THF(2~10x)、MeOH(2~10x)和氢氧化钠(2.0~10.0eq),在20~80℃反应,等到HPLC显示反应结束后,经3N-HCl调节至pH至约6后,有固体产物析出,然后通过过滤、纯化、干燥等常规操作得到中间体RM4。
1.5、目标产物IIIb的合成:
在圆底反应瓶中加入中间体RM4-02(1.0eq)、DMF(2~10x)、HATU(1.0~2.0eq)和试剂SM4(1.0~2.0eq),20~40℃下滴入DIEA(1.0~2.0eq),HPLC显示反应结束后,经后处理、柱层析纯化、干燥等常规操作后得到式IIIb目标产物。
在上述合成方法2中,R
4、R
5和R
6各自的定义分别与权利要求1~5中的 R
4、R
5和R
6相同;R
4和R
5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;具体合成反应实施步骤分别如下:
2.1、中间体RM1b的合成:
2.1-1、在圆底反应瓶中将上述得到的SM2、吡啶(4eq)分别加入DMF(5x)溶剂中,在低于10℃下滴加氯甲酸苯酯(3.0eq),滴加完成后室温反应。HPLC显示反应结束后,经后处理、柱层析纯化、干燥等常规操作后得到RM2b中间体。
2.1-2、在圆底反应瓶中将得到中间体RM2b和试剂SM3(3eq)、吡啶(3eq)溶于MeCN(20x)中,在60~80℃反应,等到HPLC显示反应结束后,,经后处理、柱层析纯化、干燥等常规操作后得到RM1b产物。
2.2、目标产物IIIb的合成:
在圆底反应瓶中将上述得到的RM1b(1.0eq)和SM1(1~1.5eq),叔丁醇钾(1.5eq)加入DMSO(10x)中,80~100℃下反应。HPLC显示反应结束后,经后处理、柱层析纯化、干燥,得到式IIIb的目标产物。
表1:原料SM1结构式
表2:原料SM2的结构
表3a:合成方法一中第一步取代醚化反应产物“RM1”系列的结构式
表3b:合成方法一中第二步偶联反应产物“RM2”系列的结构式
表3c:反应产物“RM3”系列结构式
表3d:合成方法一中第四步酯水解反应产物“RM4”系列结构式
表3e:合成方法三中第一步成脲反应产物“RM1b”系列的结构式
表4a:原料SM3系列结构式
表4b:原料SM4系列结构式
表5:式IIIb多取代芳基脲类化合物结构式
本发明中除了通过上述反应不仅能合成相应的实施例1~65制备得到了化合物IIIb-01至IIIb-65,而且还可以依据上述合成方法分别采用SM1(表1)、SM2(表2)、SM3(表4a)、SM4(表4b)中一个或多个氢被氘同位素取代的一些氘代试剂,在安全装置的保护下可以分别合成以下表5a中一些如权利要求1~5中所述化合物的部分“H”被氘(D)同位素取代的化合物(如:IIIb-66、IIIb-67、IIIb-68、IIIb-69、IIIb-70、IIIb-71、IIIb-72、IIIb-73、IIIb-74、IIIb-75、IIIb-76、IIIb-77、IIIb-78、IIIb-79、IIIb-80、IIIb-81、IIIb-82、IIIb-83、IIIb-84、IIIb-85、IIIb-86、IIIb-87、IIIb-88、IIIb-89)或式IIIb化合物中的部分或全部氢(H)被氘(D)同位素取代的化合物。
表5a:式IIIb多取代芳基脲类的氘代同位素化合物结构式
具体有关上述每个式IIIb的新型结构化合物的合成和分析结果,详见本发明最后的实施例,每个化合物的结构表征分别由LC-MS和/或核磁共振(
1H-NMR、和/或
19F-NMR)等分析确定。
以下通过实施例说明本发明各类中间体和化合物的合成和效果。
实施例中涉及到的仪器及原料说明如下:
核磁共振(氢谱和氟谱)是Bruker公司生产的Ascend 400m核磁仪分析得到。化学位移以四甲基硅烷为内标来记录,核磁分析时都使用氘代的DMSO、MeOH等溶剂,以ppm为单位来表示(CDCl
3:δ=7.26ppm)。记录的数据信息如下:化学位移及其裂分和偶合常数(s:单重峰;d:双重峰;t:三重峰;q:四重峰;br:宽峰;m:多重峰)。
质谱数据采用Agilent公司生产的液相1260和质谱6120联用进行分析。本发明中式IIIb化合物的分子量主要为阳离子模式ESI-MS[(M+H)
+]。
本发明中涉及的特殊原料和中间体由上海赞南科技有限公司等订制加工提供,其他所有化学试剂从上海试剂公司、Aldrich公司、Acros公司等试剂供应商购买。如合成过程中反应所需的中间体或产物不够下一步等试验,则重复多次合成至足够数量为止。本发明所制备化合物的活性测试以及药理、毒理等试验由上海和北京等地的CRO服务公司按行业规定完成。
本发明及其实施例中涉及的有关化学原料、试剂和溶剂的英文缩写注释如下:
Boc:叔丁氧基羰基
(Boc)
2O:二碳酸二叔丁酯
CDI:N,N′-羰基二咪唑
DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯
EDCI:N-乙基-N′-(3-二甲胺基丙基)碳二亚胺盐酸盐
HATU:2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯
NBS:N-溴代丁二酰亚胺
NCS:N-氯代丁二酰亚胺
SOCl
2:氯化亚砜
Pd/C:钯炭
DIEA:N,N-二异丙基乙胺
DMAP:4-二甲胺基吡啶
HMTA:六亚甲基四胺
Py:吡啶
HBr:氢溴酸
HCl:盐酸
HOAc:冰乙酸
TFA:三氟乙酸
MsOH:甲磺酸
TsOH:对甲苯磺酸
Cs
2CO
3:碳酸铯
tBuOK:叔丁醇钾
KOH:氢氧化钾
NaOH:氢氧化钠
LiOH:氢氧化锂
ACN/MeCN:乙腈
DCM:二氯甲烷
DCE:二氯乙烷
DMF:N,N-二甲基甲酰胺
DMSO:二甲亚砜
Et
2O:二乙醚
EA:乙酸乙酯
PE:石油醚
THF:四氢呋喃
TBME:甲基叔丁基醚
Me:甲基
Et:乙基
Pr:丙基
iPr:异丙基
cPr:环丙基
Ph:苯基
根据上述所示的有关合成方法,分别合成了本发明中关键的三卤代胺基苯酚化合物SM2-01和式IIIb的系列化合物IIIb-01至IIIb-65:
实施例1
化合物SM2-01的合成:
SM2-01的合成方法一:
对氨基苯磺酸的重氮盐的制备:1L三口瓶中加入对胺基苯磺酸(60g,1.00eq)、水(500mL)和Na2CO3(20.0g),搅拌至澄清,控制内温0℃,滴入NaNO2(25.0g)的水(75mL)溶液,滴完后,滴入浓盐酸(86mL),控制内温<5℃,然后搅拌40分钟(冷藏备用)。
1L三口反应瓶中加入3-氯-2,6-二氟苯酚(44.2g),水(516.0g),NaOH(5mol/L,70mL)水溶液和Na2CO3(27.6g),冰水浴冷却至0-5℃时,滴入对氨基苯磺酸的重氮盐溶液,滴完,搅拌至反应结束后,加浓盐酸调节PH~5.0,然后加入甲酸铵(108.0g),加入Zn粉(65.0g),室温反应。至反应结束,加入EA(1.0L),搅拌,过滤,滤液EA萃取(500m×2),合并有机相,经水洗,无水硫酸钠干燥,浓缩,加二氯甲烷(120mL),搅拌,过滤,干燥,得产物4-胺基-3-氯-2,6-二氟苯酚(SM2-01,40.0g),收率:83%。
经NMR分析确证,产物SM2-01盐酸盐的核磁共振氢谱数据:1H NMR(400MHz,d
4CD
3OD)δ:7.30/7.273(m,1H)。
产物SM2-01盐酸盐的核磁共振碳谱数据:13C-NMR(100MHz,d4CD3OD)δ:153.51(m),151.95(m),137.45(m),120.98(m),113.68(m),109.00(m)。
产物SM2-01盐酸盐的核磁共振氟谱数据:19F-NMR(377MHz,d4CD3OD) δ:-132.36/-132.40/-133.09/-133.13。
经质谱分析确证,产物SM2-01的ESI-MS[(M+H)+]:m/z理论值:180.0,实测值:180.1。
SM2-01的合成方法二:
将3-氯-2,6-二氟苯酚(1000g)和DCM(4L)加入至10.0L三口反应瓶中,冰水浴下搅拌溶解,冰水浴冷却至0℃,滴加浓硝酸(600g),控温<10℃,滴完,搅拌至反应结束,加水(2.0L),搅拌0.5小时,分液,滤液经DCM(2.0L×2)粗去,合并有机相,水洗,浓缩,得3-氯-2,6-二氟-4-硝基苯酚1.35kg。
10.0L三口瓶中加入3-氯-2,6-二氟-4-硝基苯酚(665g)和水(5.0L),加热至85℃,缓慢加入铁粉(500.0g),控制内温不高于95℃,滴加浓盐酸(100mL)。滴完后搅拌反应分钟,补加铁粉(40.0g),至反应结束,冷却至低于40℃,加EA(2.5L),搅拌过滤,滤液经EA萃取,合并有机相,经水洗,无水硫酸钠干燥,浓缩,加DCM(600mL),搅拌,过滤,干燥得产物4-胺基-3-氯-2,6-二氟苯酚(SM2-01,393g),二步合计收率:72%。
经NMR分析确证,产物SM2-01的核磁共振氢谱数据:1H NMR(400MHz,d4CD3OD)δ:7.30/7.273(m,1H)。
经质谱分析确证,产物SM2-01的ESI-MS[(M+H)+]:m/z理论值:180.0,实测值:180.1。
核磁共振和质谱分析确证,上述二种合成方法均能可靠得到本发明创新中关键的三卤代胺基苯酚化合物SM2-01。
实施例2
化合物IIIb-01的合成:
按照合成方法一所示方法进行
第一步:
向50mL的单口瓶中,加入原料SM1-01(2.52g,10mmol),SM2-01(2.34g,13mmol)、叔丁醇钾(1.46g,13mmol)和DMSO(20mL),氮气保护,85℃下反应,HPLC显示反应结束后,将反应液冷却到室温,缓慢倒入至100mL冰水中,有固体析出,过滤,水洗涤滤饼,充分干燥,得到中间体RM1-23(3.28g),收率:83%;
第二步:
向100mL的三口瓶中,加入中间体RM1-23(3.95g,10mmol)、DMF(20mL)和吡啶(30mmol),冰水浴控制不超过10℃,滴入氯甲酸苯酯(30mmol),滴完以后室温反应,HPLC显示反应结束后,将反应液冷,缓慢倒入至100mL水中,有固体析出,过滤,水洗涤滤饼,干燥,经柱层析纯化,得到中间体RM2-23(3.45g),收率:67%;
第三步:
向100mL的单口瓶中,加入中间体RM2-23(5.15g,10mmol)、MeCN(50mL)和SM3-01(30mmol),60℃下反应,HPLC显示反应结束后,有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物RM3-01(2.91g),收率:61%。
第四步:
向100mL的单口瓶中,加入中间体RM3-01(4.78g,10mmol)、THF(10mL)、MeOH(10mL)和氢氧化钠(30mmol),40℃下反应,HPLC显示反应结束后,经3N-盐酸调节至pH至约6后,有固体析出,过滤,洗涤干燥后,得到固体产物RM4-01(3.94g),收率:85%。
第五步:
向100mL的单口瓶中,加入中间体RM4-01(464mg,1.0mmol)、DMF(5mL)、HATU(1.3mmol)和SM4-01(1.5mmol),滴入DIEA(3.0mmol),20℃反应,HPLC显示反应结束后,加水有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物IIIb-01(386mg),收率:81%。
经分析确证,化合物IIIb-01的1H NMR(400MHz,DMSO+1.0eq甲磺酸)δ:9.06-9.05(d,1H),8.68(s,1H),8.54(m,1H),8.43(s,1H),8.36-8.32(dd,1H),7.69(s,1H),7.48(d,1H),7.33-7.31(d,1H),4.09(s,3H),2.85-2.84(d,3H),2.61(m,1H),2.39(s,3H),0.70-0.69(m,2H),0.46(m,2H).
经质谱分析确证,化合物IIIb-01的ESI-MS[(M+H)+]:m/z理论值:477.1, 实测值:477.2。
实施例3
化合物IIIb-02的合成:
按照合成方法一所示方法进行:
第一步:向50mL的单口瓶中,加入原料SM1-01(2.52g,10mmol),SM2-01(2.12g,13mmol)、叔丁醇钾(1.46g,13mmol)和DMSO(20mL),氮气保护,85℃下反应,HPLC显示反应结束后,将反应液冷却到室温,缓慢倒入至100mL冰水中,有固体析出,过滤,水洗涤滤饼,充分干燥,得到中间体RM1-24(2.95g),收率:78%;
第二步:向100mL的三口瓶中,加入中间体RM1-24(3.78g,10mmol)、DMF(20mL)和吡啶(30mmol),冰水浴控制不超过10℃,滴入氯甲酸苯酯(30mmol),滴完以后室温反应,HPLC显示反应结束后,将反应液冷,缓慢倒入至100mL水中,有固体析出,过滤,水洗涤滤饼,干燥,经柱层析纯化,得到中间体RM2-24(3.64g),收率:73%;
第三步:向100mL的单口瓶中,加入中间体RM2-24(4.98g,10mmol)、MeCN(50mL)和SM3-01(30mmol),60℃下反应,HPLC显示反应结束后,有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物RM3-02(2.63g),收率:57%。
第四步:向100mL的单口瓶中,加入中间体RM3-02(4.61g,10mmol)、THF(10mL)、MeOH(10mL)和氢氧化钠(30mmol),40℃下反应,HPLC显示反应结束后,经稀酸调节至pH至约6后,有固体析出,过滤,洗涤干燥后,得到固体产物RM4-02(3.53g),收率:79%。
第五步:向100mL的单口瓶中,加入中间体RM4-02(447mg,1.0mmol)、DMF(5mL)、HATU(1.3mmol)和SM4-01(1.5mmol),滴入DIEA(3.0mmol),20℃下反应,HPLC显示反应结束后,加水有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物IIIb-02(308mg),收率:67%。
经质谱分析确证,化合物IIIb-02的ESI-MS[(M+H)+]:m/z理论值:461.1,实测值:461.2。
实施例4
化合物IIIb-03的合成:
按照合成方法一所示方法进行:
制备化合物IIIb-03的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-02(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-03(329mg),收率:67%。
经质谱分析确证,化合物II1-03的ESI-MS[(M+H)+]:m/z理论值:491.1,实测值:491.1。
实施例5
化合物IIIb-04的合成:
按照合成方法一所示方法进行:
制备化合物IIIb-04的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-03(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-04(345mg),收率:68%。
经质谱分析确证,化合物IIIb-04的ESI-MS[(M+H)+]:m/z理论值:505.1,实测值:505.0。
实施例6
化合物IIIb-05的合成
按照合成方法一所示方法进行
制备化合物IIIb-05的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-11(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-05(401mg),收率:77%。
经分析确证,化合物IIIb-05的1H NMR(400MHz,DMSO+1.0cq甲磺酸)δ:8.97(m,1H),8.78-8.75(t,1H),8.63(s,1H),8.41(s,1H),8.36-8.32(dd,1H),7.63(s,1H),7.46-7.45(d,1H),7.19(m,1H),4.65-4.63(t,1H),4.54-4.51(t,1H),4.07(s,3H),3.68-3.64(t,1H),3.62-3.58(t,1H),2.61(m,1H),2.33(m,3H),0.72-0.67(m,2H),0.45(m,2H).
经分析确证,化合物IIIb-05的19F NMR(377MHz,DMSO+1.0eq甲磺酸)δ:-126.67(s),-127.72(s).
经质谱分析确证,化合物IIIb-05的ESI-MS[(M+H)+]:m/z理论值:521.1,实测值:521.2。
实施例7
化合物IIIb-06的合成
按照合成方法一所示方法进行
制备化合物IIIb-06的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-04(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-06(407mg),收率:80%。
经质谱分析确证,化合物IIIb-06的ESI-MS[(M+H)+]:m/z理论值:509.1,实测值:509.1。
实施例8
化合物IIIb-07的合成
按照合成方法一所示方法进行
制备化合物IIIb-07的合成方法与实施例3相同,其中在第五步反应中采用化合物SM4-05(1.5mmol)与中间体RM4-02反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-07(424mg),收率:83%。
经分析确证,化合物IIIb-07的1H NMR(400MHz,DMSO+1.0eq甲磺酸)δ:9.12-9.10(d,1H),8.98-8.95(t,1H),8.85(s,1H),8.67(s,1H),8.25-8.22(m,1H),7.72(s,1H),7.39-7.37(d,1H),7.03(m,1H),6.33-6.05(m,1H),4.09(s,3H),3.79-3.70(m,2H),2.61(m,1H),2.39(s,3H),0.68-0.65(m,2H),0.46-0.42(m,2H).
经分析确证,化合物IIIb-07的19F NMR(377MHz,DMSO+1.0eq甲磺酸)δ:-121.56(s),-132.15(s),-132.18(s),-150.58(s),-150.64(s).
经质谱分析确证,化合物IIIb-07的ESI-MS[(M+H)+]:m/z理论值:511.1,实测值:511.1。
实施例9
化合物IIIb-08的合成
按照合成方法一所示方法进行
制备化合物IIIb-08的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-05(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-08(453mg),收率:86%。
经分析确证,化合物IIIb-08的1H NMR(400MHz,DMSO)δ:8.82-8.79(t,J=6.0Hz,1H),8.72-8.71(d,J=5.3Hz,1H),8.60(s,1H),8.36(s,1H),8.32-8.28(dd,1H),7.59(s,1H),7.43-7.42(d,1H),6.78-6.77(d,J=5.3Hz,1H),6.33-6.05(tt,1H),4.04(s,3H),3.79-3.70(m,2H),2.61(m,1H),0.70-0.67(m,2H),0.45(m,2H).
经分析确证,化合物IIIb-08的19F NMR(377MHz,DMSO)δ:-121.62(s),-127.11(m),-127.88(s).
经质谱分析确证,化合物IIIb-08的ESI-MS[(M+H)+]:m/z理论值:527.1,实测值:527.1。
实施例10
化合物IIIb-09的合成
按照合成方法一所示方法进行
制备化合物IIIb-09的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-06(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-09(441mg),收率:81%。
经分析确证,化合物IIIb-09的1H NMR(400MHz,DMSO)δ:9.04-9.01(t,1H),8.73-8.72(d,J=5.2Hz,1H),8.53(s,1H),8.35(s,1H),8.32-8.28(dd,1H),7.60(s,1H),7.43(d,1H),6.79-6.77(d,J=5.2Hz,1H),4.18-4.13(m,2H),4.03(s,3H),2.61(m,1H),0.70-0.68(m,2H),0.45(m,2H).
经分析确证,化合物IIIb-09的19F NMR(377MHz,DMSO)δ:-70.29(s),-127.07/-127.08(d),-127.84(s).
经质谱分析确证,化合物IIIb-09的ESI-MS[(M+H)+]:m/z理论值:545.1,实测值:545.1。
实施例11
化合物IIIb-10的合成
按照合成方法一所示方法进行
制备化合物IIIb-10的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-07(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-10(368mg),收率:69%。
经质谱分析确证,化合物IIIb-10的ESI-MS[(M+H)+]:m/z理论值:534.2,实测值:534.1。
实施例12
化合物IIIb-11的合成
按照合成方法一所示方法进行
制备化合物IIIb-11的合成方法与实施例3相同,其中在第五步反应中采用化合物SM4-08(1.5mmol)与中间体RM4-02反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-11(424mg),收率:87%。
经质谱分析确证,化合物IIIb-11的ESI-MS[(M+H)+]:m/z理论值:487.2,实测值:487.2。
实施例13
化合物IIIb-12的合成
按照合成方法一所示方法进行
制备化合物IIIb-12的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-08(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-12(392mg),收率:78%。
经质谱分析确证,化合物IIIb-12的ESI-MS[(M+H)+]:m/z理论值:503.1,实测值:503.1。
实施例14
化合物IIIb-13的合成
按照合成方法一所示方法进行
制备化合物IIIb-13的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-09(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-13(402mg),收率:74%。
经质谱分析确证,化合物IIIb-13的ESI-MS[(M+H)+]:m/z理论值:543.2,实测值:543.0。
实施例15
化合物IIIb-14的合成
按照合成方法一所示方法进行
制备化合物IIIb-14的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-10(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-14(317mg),收率:63%。
经质谱分析确证,化合物IIIb-14的ESI-MS[(M+H)+]:m/z理论值:503.1,实测值:503.0。
实施例16
化合物IIIb-15的合成
按照合成方法一所示方法进行
制备化合物IIIb-15的合成方法与实施例3相同,其中在第五步反应中采用化合物SM4-12(1.5mmol)与中间体RM4-02反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-15(236mg),收率:48%。
经质谱分析确证,化合物IIIb-15的ESI-MS[(M+H)+]:m/z理论值:491.1,实测值:491.3。
实施例17
化合物IIIb-16的合成
按照合成方法一所示方法进行
制备化合物IIIb-16的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-12(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-16(294mg),收率:58%。
经质谱分析确证,化合物IIIb-16的ESI-MS[(M+H)+]:m/z理论值:507.1,实测值:507.1。
实施例18
化合物IIIb-17的合成
按照合成方法一所示方法进行
制备化合物IIIb-17的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-13(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-17(245mg),收率:47%。
经质谱分析确证,化合物IIIb-17的ESI-MS[(M+H)+]:m/z理论值:521.1,实测值:521.2。
实施例19
化合物IIIb-18的合成
按照合成方法一所示方法进行
制备化合物IIIb-18的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-14(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-18(422mg),收率:81%。
经分析确证,化合物IIIb-18的1H NMR(400MHz,DMSO)δ:8.71-8.69(d,J=5.2Hz,1H),8.57(s,1H),8.35(s,1H),8.32-8.28(dd,1H),8.26-8.24(d,1H),7.56(s,1H),7.43-7.42(d,1H),6.76-6.75(d,J=5.2Hz,1H),4.85(m,1H),4.03(m,4H),3.45(m,1H),3.42(m,1H),2.60(m,1H),1.18-1.16(d,J=6.6Hz,3H),0.70(m,2H),0.45(m,2H).
经分析确证,化合物IIIb-18的19F NMR(377MHz,DMSO)δ:-127.09/127.10(d),-127.84(s)。
经质谱分析确证,化合物IIIb-18的ESI-MS[(M+H)+]:m/z理论值:521.1, 实测值:521.2。
实施例20
化合物IIIb-19的合成
按照合成方法一所示方法进行
制备化合物IIIb-19的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-15(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-19(305mg),收率:57%。
经质谱分析确证,化合物IIIb-19的ESI-MS[(M+H)+]:m/z理论值:535.1,实测值:535.2。
实施例21
化合物IIIb-20的合成
按照合成方法一所示方法进行
制备化合物IIIb-20的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-16(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-20(242mg),收率:45%。
经质谱分析确证,化合物IIIb-20的ESI-MS[(M+H)+]:m/z理论值:537.1,实测值:537.2。
实施例22
化合物IIIb-21的合成
按照合成方法一所示方法进行
制备化合物IIIb-21的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-17(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-21(295mg),收率:55%。
经分析确证,化合物IIIb-21的1H NMR(400MHz,DMSO)δ:8.72-8.70(d,J=5.2Hz,1H),8.69(s,1H),8.51(t,1H),8.35(s,1H),8.32-8.28(dd,1H),7.59(s,1H),7.46(d,1H),6.77(d,J=5.2Hz,1H),4.95(d,1H),4.68(t,1H),4.05(s,3H),3.67-3.66 (m,1H),3.48(m,1H),3.42-3.37(m,2H),3.31-3.28(m,2H),2.61(m,1H),0.70-0.68(m,2H),0.45(m,2H).
经质谱分析确证,化合物IIIb-21的19F NMR(377MHz,DMSO)δ:-127.10/127.11(d),-127.86(s)。
经分析确证,化合物IIIb-21的ESI-MS[(M+H)+]:m/z理论值:537.1,实测值:537.2。
实施例23
化合物IIIb-22的合成
按照合成方法一所示方法进行
制备化合物IIIb-22的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-18(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-22(258mg),收率:48%。
经质谱分析确证,化合物IIIb-22的1H NMR(400MHz,DMSO)δ:8.72-8.71(d,J=5.3Hz,1H),8.69(s,1H),8.51(t,1H),8.36(s,1H),8.32-8.28(dd,1H),7.59(s,1H),7.46(d,1H),6.77-6.76(d,J=5.3Hz,1H),4.95(d,1H),4.68(t,1H),4.05(s,3H),3.67-3.66(m,1H),3.48(m,1H),3.42-3.37(m,2H),3.31-3.28(m,2H),2.61(m,1H),0.70-0.68(m,2H),0.45(m,2H).
经质谱分析确证,化合物IIIb-22的19F NMR(377MHz,DMSO)δ:-127.10/127.11(d),-127.86(s)。
经质谱分析确证,化合物IIIb-22的ESI-MS[(M+H)+]:m/z理论值:537.1,实测值:537.2。
实施例24
化合物IIIb-23的合成
按照合成方法一所示方法进行
制备化合物IIIb-23的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-19(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-23(219mg),收率:41%。
经质谱分析确证,化合物IIIb-23的ESI-MS[(M+H)+]:m/z理论值:533.1,实测值:533.2。
实施例25
化合物IIIb-24的合成
按照合成方法一所示方法进行
制备化合物IIIb-24的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-20(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-24(296mg),收率:57%。
经质谱分析确证,化合物IIIb-24的ESI-MS[(M+H)+]:m/z理论值:519.1,实测值:519.2。
实施例26
化合物IIIb-25的合成
按照合成方法一所示方法进行
制备化合物IIIb-25的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-21(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-25(277mg),收率:52%。
经质谱分析确证,化合物IIIb-25的ESI-MS[(M+H)+]:m/z理论值:533.1,实测值:533.2。
实施例27
化合物IIIb-26的合成
按照合成方法一所示方法进行
制备化合物IIIb-26的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-22(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-26(314mg),收率:59%。
经质谱分析确证,化合物IIIb-26的ESI-MS[(M+H)+]:m/z理论值:533.1,实测值:533.0。
实施例28
化合物IIIb-27的合成
按照合成方法一所示方法进行
制备化合物IIIb-27合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-23(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-27(300mg),收率:55%。
经质谱分析确证,化合物IIIb-27的ESI-MS[(M+H)+]:m/z理论值:546.2,实测值:546.0。
实施例29
化合物IIIb-28的合成
按照合成方法一所示方法进行
制备化合物IIIb-28合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-24(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-28(465mg),收率:83%。
经质谱分析确证,化合物IIIb-28的ESI-MS[(M+H)+]:m/z理论值:560.2,实测值:560.0。
实施例30
化合物IIIb-29的合成
按照合成方法二所示方法进行
第一步:
向50mL的单口瓶中,加入原料SM1-12(2.19g,10mmol),SM2-01(2.34g,13mmol)、叔丁醇钾(1.46g,13mmol)和DMSO(20mL),氮气保护,85℃下反应,HPLC显示反应结束后,将反应液冷却到室温,缓慢倒入至100mL冰水中,有固体析出,过滤,水洗涤滤饼,充分干燥,得到中间体RM1-25(2.10g),收率:58%;
第二步:
向100mL的三口瓶中,加入中间体RM1-25(3.62g,10mmol)、DMF(20mL) 和吡啶(30mmol),冰水浴控制不超过10℃,滴入氯甲酸苯酯(30mmol),滴完以后室温反应,HPLC显示反应结束后,将反应液冷,缓慢倒入至100mL水中,有固体析出,过滤,水洗涤滤饼,干燥,经柱层析纯化,得到中间体RM2-25(4.10g),收率:85%;
第三步:
向50mL的单口瓶中,加入中间体RM2-25(482mg,1mmol)、MeCN(10mL)和SM3-01(3mmol),60℃下反应,HPLC显示反应结束后,有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物IIIb-29(280mg),收率:63%。
经质谱分析确证,化合物IIIb-29的ESI-MS[(M+H)+]:m/z理论值:445.1,实测值:444.8。
实施例31
化合物IIIb-30的合成
按照合成方法二所示方法进行
第一步:
向50mL的单口瓶中,加入原料SM1-12(2.19g,10mmol),SM2-11(2.49g,13mmol)、叔丁醇钾(1.46g,13mmol)和DMSO(20mL),氮气保护,85℃下反应,HPLC显示反应结束后,将反应液冷却到室温,缓慢倒入至100mL冰水中,有固体析出,过滤,水洗涤滤饼,充分干燥,得到中间体RM1-26(2.43g),收率:65%;
第二步:
向100mL的三口瓶中,加入中间体RM1-26(3.74g,10mmol)、DMF(20mL)和吡啶(30mmol),冰水浴控制不超过10℃,滴入氯甲酸苯酯(30mmol),滴完以后室温反应,HPLC显示反应结束后,将反应液冷,缓慢倒入至100mL水中,有固体析出,过滤,水洗涤滤饼,干燥,经柱层析纯化,得到中间体RM2-26(3.95g),收率:80%;
第三步:
向50mL的单口瓶中,加入中间体RM2-26(494mg,1mmol)、MeCN(10mL),吡啶(3mmol)和SM3-01(3mmol),60℃下反应,HPLC显示反应结束后,有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物IIIb-30(274mg),收率: 60%。
经质谱分析确证,化合物IIIb-30的ESI-MS[(M+H)+]:m/z理论值:457.1,实测值:457.0。
实施例32
化合物IIIb-31的合成
按照合成方法一所示方法进行
制备化合物IIIb-31的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-25(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理后,经柱层析纯化得固体。
所得固体经THF/MeOH体系碱性水解,反应结束后调节pH至约6,析出固体,过滤、洗涤,干燥后到固体产物IIIb-31(290mg),收率:53%。
经质谱分析确证,化合物IIIb-31的ESI-MS[(M+H)+]:m/z理论值:547.1,实测值:547.2。
实施例33
化合物IIIb-32的合成
按照合成方法一所示方法进行
制备化合物IIIb-32合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-26(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-32(259mg),收率:48%。
经质谱分析确证,化合物IIIb-32的ESI-MS[(M+H)+]:m/z理论值:539.1,实测值:538.9。
实施例34
化合物IIIb-33的合成
制备化合物IIIb-33合成方法与实施例1的前四步相同。
第五步:
向50mL的单口瓶中,加入中间体RM4-01(478mg,1.0mmol)、DMF(5mL) 和CDI(1.5mmol),滴入DIEA(3.0mmol),20℃下反应,HPLC显示转化为中间体反应结束后,加入SM4-27(3.0mmol),HPLC显示反应结束后,加水有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物IIIb-33(151mg),收率:28%。
经质谱分析确证,化合物IIIb-33的ESI-MS[(M+H)+]:m/z理论值:541.1,实测值:540.9。
实施例35
化合物IIIb-34的合成
制备化合物IIIb-34合成方法与实施例1的前四步相同。
第五步:
向50mL的单口瓶中,加入中间体RM4-01(478mg,1.0mmol)、DMF(5mL)和CDI(1.5mmol),滴入DIEA(3.0mmol),20℃下反应,HPLC显示转化为中间体反应结束后,加入SM4-28(3.0mmol),HPLC显示反应结束后,加水有固体析出,过滤,洗涤干燥后,经柱层析纯化得到固体产物IIIb-34(130mg),收率:23%。
经质谱分析确证,化合物IIIb-34的ESI-MS[(M+H)+]:m/z理论值:567.1,实测值:567.0。
实施例36
化合物IIIb-35的合成
按照合成方法一所示方法进行
制备化合物IIIb-35合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-29(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-35(409mg),收率:73%。
经质谱分析确证,化合物IIIb-35的ESI-MS[(M+H)+]:m/z理论值:560.1,实测值:559.8。
实施例37
化合物IIIb-36的合成
按照合成方法一所示方法进行
制备化合物IIIb-36合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-30(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-36(387mg),收率:69%。
经质谱分析确证,化合物IIIb-36的ESI-MS[(M+H)+]:m/z理论值:560.1,实测值:559.8。
实施例38
化合物IIIb-37的合成
按照合成方法一所示方法进行
制备化合物IIIb-37合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-31(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-37(178mg),收率:31%。
经质谱分析确证,化合物IIIb-37的ESI-MS[(M+H)+]:m/z理论值:573.1,实测值:573.0。
实施例39
化合物IIIb-38的合成
按照合成方法一所示方法进行
制备化合物IIIb-38合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-32(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-38(167mg),收率:29%。
经质谱分析确证,化合物IIIb-38的ESI-MS[(M+H)+]:m/z理论值:575.1,实测值:575.2。
实施例40
化合物IIIb-39的合成
按照合成方法一所示方法进行
制备化合物IIIb-39合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-33(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理 干燥后,经柱层析纯化得到固体产物IIIb-39(408mg),收率:73%。
经质谱分析确证,化合物IIIb-39的ESI-MS[(M+H)+]:m/z理论值:559.1,实测值:558.9。
实施例41
化合物IIIb-40的合成
按照合成方法一所示方法进行
制备化合物IIIb-40合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-34(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-40(400mg),收率:70%。
经质谱分析确证,化合物IIIb-40的ESI-MS[(M+H)+]:m/z理论值:573.1,实测值:572.9。
实施例42
化合物IIIb-41的合成
按照合成方法一所示方法进行
制备化合物IIIb-41合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-35(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-41(383mg),收率:67%。
经质谱分析确证,化合物IIIb-41的ESI-MS[(M+H)+]:m/z理论值:571.1,实测值:570.9。
实施例43
化合物IIIb-42的合成
按照合成方法一所示方法进行
制备化合物IIIb-42合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-36(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-42(334mg),收率:58%。
经质谱分析确证,化合物IIIb-42的ESI-MS[(M+H)+]:m/z理论值:575.1, 实测值:574.9。
实施例44
化合物IIIb-43的合成
按照合成方法一所示方法进行
制备化合物IIIb-43的合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-37(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-43(224mg),收率:39%。
经质谱分析确证,化合物IIIb-43的ESI-MS[(M+H)+]:m/z理论值:575.1,实测值:575.2。
实施例45
化合物IIIb-44的合成
按照合成方法一所示方法进行
制备化合物IIIb-44合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-38(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-44(132mg),收率:27%。
经质谱分析确证,化合物IIIb-44的ESI-MS[(M+H)+]:m/z理论值:488.1,实测值:487.8。
实施例46
化合物IIIb-45的合成
按照合成方法一所示方法进行
制备化合物IIIb-45合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-39(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-45(236mg),收率:47%。
经质谱分析确证,化合物IIIb-45的ESI-MS[(M+H)+]:m/z理论值:502.1,实测值:501.9。
实施例47
化合物IIIb-46的合成
按照合成方法一所示方法进行
制备化合物IIIb-46合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-40(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-46(289mg),收率:56%。
经质谱分析确证,化合物IIIb-46的ESI-MS[(M+H)+]:m/z理论值:516.1,实测值:515.9。
实施例48
化合物IIIb-47的合成
按照合成方法一所示方法进行
制备化合物IIIb-47合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-41(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-47(419mg),收率:79%。
经质谱分析确证,化合物IIIb-47的ESI-MS[(M+H)+]:m/z理论值:530.1,实测值:529.9。
实施例49
化合物IIIb-48的合成
按照合成方法一所示方法进行
制备化合物IIIb-48合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-42(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-48(322mg),收率:61%。
经质谱分析确证,化合物IIIb-48的ESI-MS[(M+H)+]:m/z理论值:528.1,实测值:527.9。
实施例50
化合物IIIb-49的合成
按照合成方法一所示方法进行
制备化合物IIIb-49合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-43(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-49(396mg),收率:73%。
经质谱分析确证,化合物IIIb-49的ESI-MS[(M+H)+]:m/z理论值:542.1,实测值:541.9。
实施例51
化合物IIIb-50的合成
按照合成方法一所示方法进行
制备化合物IIIb-50合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-44(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-50(356mg),收率:69%。
经质谱分析确证,化合物IIIb-50的ESI-MS[(M+H)+]:m/z理论值:516.1,实测值:515.9。
实施例52
化合物IIIb-51的合成
制备化合物IIIb-51的合成方法与实施例1的前面四步相同,其中在第五步反应中采用化合物SM4-45(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理后,经柱层析纯化得固体。
所得固体经THF/MeOH体系酸性脱除胺基的保护基,反应结束后调节pH至约10,析出固体,过滤、洗涤,干燥后到固体产物IIIb-51(172mg),收率:34%。
经质谱分析确证,化合物IIIb-51的ESI-MS[(M+H)+]:m/z理论值:506.1,实测值:505.9。
实施例53
化合物IIIb-52的合成
制备化合物IIIb-52合成方法与实施例2相同,其中在第五步反应中采用化 合物SM4-46(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-52(228mg),收率:43%。
经质谱分析确证,化合物IIIb-52的ESI-MS[(M+H)+]:m/z理论值:529.1,实测值:528.8。
实施例54
化合物IIIb-53的合成
制备化合物IIIb-53合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-47(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-53(337mg),收率:62%。
经质谱分析确证,化合物IIIb-53的ESI-MS[(M+H)+]:m/z理论值:543.1,实测值:543.0。
实施例55
化合物IIIb-54的合成
制备化合物IIIb-54合成方法与实施例2相同,其中在第五步反应中采用化合物SM4-48(1.5mmol)与中间体RM4-01反应,形成酰胺键产物,经相同后处理干燥后,经柱层析纯化得到固体产物IIIb-54(358mg),收率:66%。
经质谱分析确证,化合物IIIb-54的ESI-MS[(M+H)+]:m/z理论值:543.1,实测值:543.0。
实施例56
化合物IIIb-55的合成:
按照合成方法三所示方法进行
2-氯-3,5-二氟-4-羟基苯氨甲酸苯酯的制备:
5L三口瓶中加入SM2-01(100g,0.56mol)、吡啶(58g,0.73mol)和DMF(1L),搅拌,冰水浴冷却,不超过10℃,滴入氯甲酸苯酯(96g,0.61mol),加完15分钟取样检测至SM2-01转化结束后,直接进入下一步。
经分析确证,该中间体:2-氯-3,5-二氟-4-羟基苯氨甲酸苯酯的的核磁共振氢谱,1H-NMR(400MHz,DMSO)δ:10.71(s,1H),9.78(s,1H),7.44-7.36(m,3H),7.27-7.19(m,3H);该中间体的核磁共振氟谱,19F NMR(377MHz,DMSO)δ:-131.38/-131.42(d),-132.79/-132.81(d)。
控制温度不高于10℃滴加入环丙胺(127g,2.24mol),搅拌半小时,检测转化结束后,加入乙腈(2L),搅拌半小时,过滤,乙酸乙酯(300mL)淋洗,干燥,得1-(2-氯-3,5-二氟-4-羟基苯基)-3-环丙基脲环丙铵盐(143g)。
将此中间体:1-(2-氯-3,5-二氟-4-羟基苯基)-3-环丙基脲环丙铵盐(143g)加入5L三口瓶中,加入甲醇中(600mL),搅拌均匀,滴入6N-盐酸(80mL),搅拌至全溶,加入水(3L),约搅拌1小时,过滤,水洗(1.0L),干燥得RM1b-01(117g),收率80%。
经分析确证,中间体RM1b-01的核磁共振氢谱,1H-NMR(400MHz,DMSO)δ:10.13(s,1H),7.90(s,1H),7.86-7.82(dd,1H),7.11(d,1H),2.56(m,1H),0.67-0.62(m,2H),0.43-0.39(m,2H);中间体RM1b-01的核磁共振碳谱,13C-NMR(100MHz,DMSO)δ:155.47(s),151.82(m),149.74(m),129.04(m),128.87-128.67(m),105.54 (m),103.54(m),22.27(s),6.19(s);中间体RM1b-01的核磁共振氟谱,19F-NMR(377MHz,DMSO)δ:-132.09(m)。经质谱分析确证,化合物RM1b-01的ESI-MS[(M+H)+]:m/z理论值:263.0,实测值:263.1。
50mL单口瓶中加入SM1-02(269mg,1.0mmo1)、RM1b-01(342mg,1.3mol)、叔丁醇钾(146mg,1.3mmol)和二甲亚砜(3mL),升温至65℃下反应,反应结束后,冷切后滴入冰水(30mL)中,充分搅拌,过滤,水洗,经柱层析纯化后得到目标化合物IIIb-55:312mg,收率63%。
经质谱分析确证,化合物IIIb-55的ESI-MS[(M+H)+]:m/z理论值:495.1,实测值:494.9。
实施例57
化合物IIIb-56的合成
制备化合物IIIb-56合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-03(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到IIIb-56(323mg),收率:60%。
经质谱分析确证,化合物IIIb-56的ESI-MS[(M+H)+]:m/z理论值:513.1,实测值:512.8。
实施例58
化合物IIIb-57的合成
制备化合物IIIb-57合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-04(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-57(276mg),收率:52%。
经质谱分析确证,化合物IIIb-57的ESI-MS[(M+H)+]:m/z理论值:531.1,实测值:530.8。
实施例59
化合物IIIb-58的合成
制备化合物IIIb-58的合成方法与实施例55相同,其中在第三步反应中采用 化合物SM1-05(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-58(259mg),收率:53%。
经质谱分析确证,化合物IIIb-58的ESI-MS[(M+H)+]:m/z理论值:488.1,实测值:487.8。
实施例60
化合物IIIb-59的合成
制备化合物IIIb-59的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-06(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-59(354mg),收率:68%。
经质谱分析确证,化合物IIIb-59的ESI-MS[(M+H)+]:m/z理论值:520.1,实测值:519.9。
实施例61
化合物IIIb-60的合成
制备化合物IIIb-60的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-07(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到得到固体产物。
所得固体经/MeOH体系,加四丁基溴化铵去除羟基的硅醚保护基,反应结束后脱溶除去THF,加水析出固体,过滤、洗涤,干燥后到固体产物IIIb-60(192mg),收率:38%。
经质谱分析确证,化合物IIIb-60的ESI-MS[(M+H)+]:m/z理论值:493.1,实测值:492.9。
实施例62
化合物IIIb-61的合成
制备化合物IIIb-61的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-08(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到固体产物。
所得固体经THF/MeOH体系酸性脱除胺基的保护基,反应结束后调节pH至约10,析出固体,过滤、洗涤,干燥后到固体产物IIIb-61(233mg),收率:45%。
经质谱分析确证,化合物IIIb-61的ESI-MS[(M+H)+]:m/z理论值:518.1,实测值:517.9。
实施例63
化合物IIIb-62的合成:
制备化合物IIIb-62的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-09(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-62(305mg),收率:59%。
经质谱分析确证,化合物IIIb-62的ESI-MS[(M+H)+]:m/z理论值:517.1,实测值:516.9。
实施例64
化合物IIIb-63的合成
制备化合物IIIb-63的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-09(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-63(274mg),收率:53%。
经质谱分析确证,化合物IIIb-63的ESI-MS[(M+H)+]:m/z理论值:517.1,实测值:516.9。
实施例65
化合物IIIb-64的合成
制备化合物IIIb-64的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-11(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-64(331mg),收率:64%。
经质谱分析确证,化合物IIIb-64的ESI-MS[(M+H)+]:m/z理论值:517.1,实测值:516.9。
实施例66
化合物IIIb-65的合成
制备化合物IIIb-65的合成方法与实施例55相同,其中在第三步反应中采用化合物SM1-16(1.0mmol)与中间体RM1b-01(1.3mmol)反应,经相同后处理后柱层析纯化得到产物IIIb-65(286mg),收率:57%。
经质谱分析确证,化合物IIIb-65的ESI-MS[(M+H)+]:m/z理论值:502.1,实测值:501.9。
实施例67
化合物IIIb-08的合成方法二:
1.0L三口瓶中加入SM1-13(10.0g,33mmol)、RM1b-01(11.3g,43mmol)、叔丁醇钾(4.8g,43mmol)和二甲亚砜(100mL),升温至65℃下反应,反应结束后,冷切后滴入冰水(1L),搅拌,过滤,适量水洗涤,干燥,得IIIb-08(13.0g),收率:75%。
实施例68
化合物IIIb-50的合成方法二:
也可以按照合成方法三所示方法进行
1.0L三口瓶中SM1-14(10.0g,35mmol)、RM1b-01(11.8g,45mmol)、叔丁醇钾(5.0g,45mmol)和二甲亚砜(100mL),升温至65℃下反应,反应结束后,冷 切后滴入冰水(1L),搅拌,过滤,适量水洗涤,干燥,得IIIb-50(12.8g),收率:71%。
实施例69:体外抑制活性药效实验
本发明所制备的化合物可藉由下列临床前体外抑制活性测试实验初步测定筛选其对胰腺癌(BXPC3)、肺癌(A549)、肾癌(Caki-1)、肝癌(Hep3B 2.1-7)、胃癌(SNU16)、宫颈癌(Hela)、和白血病(K562)等7种肿瘤细胞株靶点抑制的效果,并且进一步通过对VEGFR1、VEGFR2(KDR)、VEGFR3、FGFR2、RET等多种RTK靶点抑制活性的测定筛选更好的抗癌新药,然后藉由临床试验最终对新药的疗效加以确认。其它方法对本领域中具一般技术之人员而言亦是显而易见的。
本实施例研究化合物(IIIb-01~IIIb-65)对多种肿瘤细胞的增殖抑制作用。
1.第一天进行细胞铺板实验,在96-孔细胞培养板(Corning 3917板)上,均匀铺设每孔100ul含有5000个细胞[例如:胰腺癌(BXPC3)、肺癌(A549)、肾癌(Caki-1)、肝癌(Hep3B 2.1-7)、胃癌(SNU16)、宫颈癌(Hela)、前列腺癌细胞株(PC-3)和白血病(K562)等],然后将细胞板放置于细胞培养箱中。
2.第二天进行化合物加药实验,准备化合物,每个待测化合物及阳性参考药准备10个浓度点,以1∶3的浓度梯度稀释于培养液中,复孔。添加5ul待测化合物或者阳性参考药至细胞板中,待测化合物终浓度最高为10uM,阳性参考药终浓度最高为3uM,DMSO浓度控制在0.2%以下,然后将细胞板放置于细胞培养箱中培养72小时。
3.第五天,在治疗72后小时后,根据试剂说明书配制CTG试剂(Promega G7573),并将配置完的CTG试剂以及细胞板同时放置于室温环境下30分钟进行热平衡。然后每个细胞板的孔中加入50ul CTG试剂,将细胞板低速震荡混匀后置于室温下20分钟,避光保存。然后将细胞培养板放置于读板仪(Envision或者Viewlux)记录数据并且分析计算增殖抑制率,曲线中50%抑制率对应的化合物浓度即为此化合物在该肿瘤细胞系上增殖抑制作用的IC
50。
五种激酶抑制活性(IC
50)评价的实验:
本实验通过利用荧光微流体迁移率检测技术(Mobility-Shift Assay),检测小分子化合物抑制剂对17种激酶的抑制作用。
1.缓冲液配置:50mM HEPES,pH 7.5,0.00015%Brij-35。
2.化合物在100%DMSO中配置成浓度梯度,并用缓冲液稀释成10%DMSO,加入384孔板。化合物起始浓度为500nM,则用100%DMSO配制成25μM,并梯度稀释10个浓度,再用缓冲液稀释10倍,配成含10%DMSO的化合物中间稀释体,转移5μl到384孔板。
3.激酶用以下缓冲液稀释成最佳浓度:50mM HEPES,pH 7.5,0.00015%Brij-35,2mM DTT(酶反应终浓度:VEGFR-1(FLT1):2nM;VEGFR-2(KDR):1.2nM;VEGFR-3(FLT4):1.5nM;FGFR1:2nM;FGFR2:9nM;FGFR3:8nM;FGFR4:10nM;PDGFRα:3.5nM;c-MET:10nM;RET:7nM;EGFR:6nM)。转移10μl到384孔板中,与化合物孵育10分钟。
4.底物用以下缓冲液稀释成最佳浓度:50mM HEPES,pH 7.5,0.00015%Brij-35。其中反应终浓度如下:
VEGFR1(FLT1):3μM Peptide30(5-FAM-KKKKEEIYFFFCONH
2),278μM ATP,10mM MgCl
2;
VEGFR2(KDR):3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH
2),92μM ATP,10mM MgCl
2;
VEGFR3(FLT4):3μM Peptide30(5-FAM-KKKKEEIYFFFCONH
2),84μM ATP,10mM MgCl
2;
FGFR2:3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH
2),1.9μM ATP,10mM MgCl
2;
RET:3μM Peptide22(5-FAM-EEPLYWSFPAKKKCONH
2),23μM ATP,10mM MgC
l2
5.用Caliper Reader读取转化率,计算转化率为抑制,公式Percent inhIcition=(maxConversion)/(max-min)*100.。
6.用XL-fit5.4.0.8软件拟合计算IC50公式Y=Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)。
hERG(钾离子通道)是新药研究过程中涉及化合物安全性的一个重要参数,钾离子(K+)通道在心脏中高表达,是心肌动作电位三期快速复极化电流(IKr)的主要组成部分。hERG突变引起的功能缺失常伴随一些遗传性长QT综合症(LQTS)并且会增加发生严重的室性心律失常,扭转性实行心动过速的风险。钾离子(K
+)通道被抑制引起的副作用是近年来新药研究失败和撒市的主要原因之一,如果一个化合物的hERG的体外抑制效应IC
50<30uM,则该化合物可能存在上述的隐患和风险。因此药物的hERG通道的体外抑制效应(IC
50)评价已被国际药品注册协调会议推荐作为临床前安全性评价工作的一部分(ICHS7B Expert Working Group,′02)。
hERG的体外抑制效应(IC
50)评价的实验:
将稳转的细胞滴于圆形玻片上并置于培养皿中,细胞密度低于50%,培养过夜。将实验用细胞转移到一个嵌于倒置显微镜平台的约1ml的浴槽中,灌流细胞外液,灌流速度为2.7ml/分钟。稳定5分钟后即可开始实验。采用HEKA EPC-10膜片钳放大器和PATCHMASTER采集系统记录膜电流(HEKA Instruments Inc.,D-67466 Lambrecht,Pfalz,Germany)。所有实验均在室温(22-24℃)下完成。实验中使用P-97微电极拉制仪(Sutter Instrument Company,One Digital Drive,Novato,CA 94949)拉直电极(BF150-110-10)。电极内径为1-1.5mm,充满内液后的入水电阻为2-4MΩ。hERG钾通道的电生理刺激方案,是首先将膜电压钳制在-80mV,给予细胞持续2s、+20mV电压刺激,激活hERG钾通道,再复极化至-50mV、持续5s,产生外向尾电流,刺激频率每15s一次。电流值为尾电流的峰值。
实验中采用全细胞记录模式记录通道电流。首先灌流细胞外液(大约每分钟2毫升)并持续记录,并等待电流稳定(5分钟内电流衰减(Run-Down)小于5%),此时尾电流峰值即为对照电流值。接着灌流含待测药物的细胞外液并持续记录直到药物对hERG电流的抑制作用到达稳定状态,此时尾电流峰值即为加药后电流值。稳定状态的标准以最近的连续3个电流记录线是否重合来判断。达到稳定态势以后如果以细胞外液灌流冲洗后hERG电流回复或接近加药物之前的大小,则可以继续灌流测试其它浓度或药物。30μM Quinidine(奎尼丁)被用于实验中作 为阳性对照以保证所使用的细胞反应正常。
部分优选的式IIIb等化合物(如:IIIb-06、IIIb-08、IIIb-09、IIIb-21、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65)抑制各种肿瘤细胞株[如:胰腺癌(BXPC3)、肺癌(A549)、肾癌(Caki-1)、肝癌(Hep3B 2.1-7)、胃癌(SNU16)、宫颈癌(Hela)、前列腺癌(PC-3)、和白血病(K562)等]和酪氨酸激酶(如:VEGFR1、VEGFR2(KDR)、VEGFR3、FGFR2、RET)的活性测试结果分别列于以下表6、表7和表8。
每个化合物抑制胰腺癌细胞株(BXPC3)的活性效果范围(IC
50)在<5.0uM标示为“A”,活性范围在5.0-10.0uM标示为“B”,活性范围>10.0uM标示为“C”;
每个化合物抑制肺癌细胞株(A549)的活性效果范围(IC
50)在<2.5uM标示为“A”,活性范围在2.5-5.0uM标示为“B”,活性范围>5.0uM标示为“C”;
每个化合物抑制肾癌细胞株(Caki-1)的活性效果范围(IC
50)在<2.5uM标示为“A”,活性范围在2.5-5.0uM标示为“B”,活性范围>5.0uM标示为“C”;
每个化合物抑制肝癌细胞株(Hep3B 2.1-7)的活性效果范围(IC
50)在<2.5uM标示为“A”,活性范围在2.5-5.0uM标示为“B”,活性范围>5.0uM标示为“C”;
每个化合物抑制胃癌细胞株(SNU16)的活性效果范围(IC
50)在<5.0uM标示为“A”,活性范围在5.0-10.0uM标示为“B”,活性范围>10.0uM标示为“C”;
每个化合物抑制宫颈癌细胞株(Hela)的活性效果范围(IC
50)在<5.0uM标示为“A”,活性范围在5.0-10uM标示为“B”,活性范围>10uM标示为“C”;
每个化合物抑制白血病细胞株(K562)的活性效果范围(IC
50)在<5.0uM标示为“A”,活性范围在5.0-10uM标示为“B”,活性范围>10uM标示为“C”;
每个化合物抑制前列腺癌细胞株(PC-3)的活性效果范围(IC
50)在<5.0uM标示为“A”,活性范围在5.0-10uM标示为“B”,活性范围>10uM标示为“C”。
表6:一些式IIIb化合物的三种细胞株抑制活性试验结果
表7:一些式IIIb优选化合物抑制肝癌、胃癌、宫颈癌、白血病四种细胞株的活性结果
现将式IIIb中一些优选的化合物,分别用于抑制VEGFR1-3、FGFR2、RET等RTK靶点的活性结果分别列于下列表8中;其中,每个化合物抑制各种酪氨酸激酶VEGFR1、KDR(VEGFR2)、VEGFR3的活性效果范围(IC
50)在<5nM标示为“A”,活性范围在5-10nM标示为“B”,活性范围>10nM标示为“C”;每个化合物抑制各种酪氨酸激酶FGFR2的活性效果范围(IC
50)在<50nM标示为“A”,活性范围在50-100nM标示为“B”,活性范围>100nM标示为“C”;每个化合物抑制各种酪氨酸激酶RET的活性效果范围(IC
50)在<5nM标示为“A”,活性范围在5-10nM标示为“B”,活性范围>10nM标示为“C”。
表8:一些式IIIb优选化合物抑制三种酪氨酸激酶的活性结果
化合物 | VEGFR1 | KDR | VEGFR3 | FGFR2 | RET |
IIIb-08 | A | A | A | A | A |
IIIb-09 | B | A | A | B | B |
IIIb-21 | A | A | A | B | B |
IIIb-45 | A | A | A | A | A |
IIIb-50 | A | A | A | A | A |
IIIb-55 | A | A | A | A | B |
IIIb-56 | A | A | A | A | A |
IIIb-57 | A | A | A | A | A |
IIIb-58 | A | A | A | A | A |
IIIb-60 | A | A | A | A | A |
IIIb-61 | A | A | A | A | A |
IIIb-65 | A | A | A | A | A |
索拉非尼 | C | C | C | C | C |
瑞戈非尼 | C | C | C | B | C |
仑伐替尼 | B | B | A | B | B |
表9:一些优选化合物的hERG抑制效应检测结果
从上述表6、表7、表8、表9中的各种测试结果可以发现,本发明在上述表中所列的化合物“IIIb-08、IIIb-09、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65”对于多种肿瘤细胞株和酪氨酸激酶均具有较好的抑制效果,其抑制活性、以及hERG>30uM等安全性参数明显优于已经临床上市的仑伐替尼、瑞戈非尼、索拉非尼3个脲类对照药物。
实施例70:化合物毒性筛选试验
为了测试上述表7-9中活性较高优选的新化合物“IIIb-08、IIIb-09、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65”的毒性,本发明分别进行大鼠的MTD毒性试验(150mg/kg,QD),连续14天内服药无死亡等异常情况发生。大鼠解剖结果也无发现体内心、肝、肺、肾、胃、肠等各种脏器有任何异常变化,一般认定所测试的化合物在适当剂量以内为安全无毒。
目前正在使用这些优选化合物(如:IIIb-08、IIIb-09、IIIb-45、IIIb-50、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65)分别对裸鼠皮下移植胰腺癌细胞株(BXPC3)、胃癌细胞株(SNU16)、肝癌细胞株(Hep3B 2.1-7)等肿瘤进行体内抑制作用试验,己经观察到较好的抑瘤效果,3~4周内裸鼠皮下肿瘤的抑瘤率能够达到80-110%,结果表明这些优选化合物具有较好的抗肿瘤活性药效。因此,本发明设计合成的优选化合物“IIIb-08、IIIb-09、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65”不仅具有更好的抑制活性效果,而且具有较好的安全性和成药性,具有进一步进行药毒理等临床前研究和临床试验的应用价值。
综上所述,本发明在多靶点抗肿瘤创新药物研究中发现的化合物“IIIb-08、IIIb-09、IIIb-45、IIIb-50、IIIb-55、IIIb-56、IIIb-57、IIIb-58、IIIb-60、IIIb-61、IIIb-65”不仅具有更好的抑制活性效果,并且大鼠的MTD毒性试验(150mg/kg, QD),连续14天内服药无死亡等异常情况发生,安全性较好(优于对照药物“仑伐替尼”公开报导的MTD为40mg/kg,有关抑制活性和安全性结果均优于目前已知的仑伐替尼等同类对照药物。
总体而言,权利要求中所用的术语应不被认为是将权利要求限制到本说明书和权利要求中公开的具体的实施方式,而应认为是包括遵循与所列权利要求等同的完全范围的所有可能的实施方式和其它化学上合理的改变。因此,权利要求并不受本公开内容限制。
Claims (13)
- 一种式IIIb所示的化合物,及其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、或药学上可接受的盐或水合物、以及氘代或其它同位素取代的化合物:其中,E是氮(N)、或CH;G 1是氢、氘(D)、卤素、-CN、C 1-20烷基、C 1-20烷氧基、或C 1-20烷基胺基;G 2是卤素、-CN、C 1-20烷基胺基、C 1-20羟基亚烷基胺基、C 1-20腈基亚烷基胺基、C 1-20胺基亚烷基胺基、C 3-20胺基环亚烷基胺基、C 1-20羧基亚烷基胺基、C 3-20羧基环亚烷基胺基、3-6元的杂环基胺基、或-OR 6;其中,R 6选自:氢、氘、C 1-20烷基、C 1-20卤代烷基、C 1-20氰基亚烷基、C 3-20氰基环亚烷基、C 2-20羟基亚烷基、C 2-20胺基亚烷基、C 3-20胺基环亚烷基、C 2-20羧基亚烷基、C 3-20羧基环亚烷基、C 3-6环烷基、C 3-6胺基环亚烷基、C 1-20胺基(C 3-20环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;G 3是-CN、-C(O)OR、-C(O)NH 2、氘代-C(O)ND 2、C 1-20烷氧基、C 1-20烷基胺基、或-C(O)NR 4R 5;其中,R是氢、或C 1-20烷基,R 4和R 5各自独立地选自:氢、氘、C 1-20烷基、C 1-20卤代烷基、C 1-20腈基亚烷基、C 3-20氰基环亚烷基、C 2-20羟基亚烷基、C 3-20羟基环亚烷基、C 2-20胺基亚烷基、C 3-20胺基环亚烷基、C 2-20羧基亚烷基、C 3-20羧基环亚烷基、C 3-20环烯基、C 3-20环烷基、3-6元的杂环基、3-6元的杂环基亚烷基、C 6-20芳基、C 3-20杂环芳基、C 1-20烷基磺酰基、C 3-20环烷基磺酰基、或C 2-20杂环烷基磺酰基;R 4和R 5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;G 4和G 5各自独立地选自:氢、氘(D)、卤素、-CN、C 1-20烷基、C 1-20烷氧基、或C 1-20烷基胺基;R 1选自:氢、氘、C 1-20烷基、C 3-20环烷基、或C 3-20氘代环烷基;R 2和R 3各自独立地选自:氢、氘、C 1-20烷基、C 3-20环烷基、C 3-20氘代环烷基、或3-6元的杂环基;X 1、X 2和X 3各自独立地选自:卤素、-CN、-NH 2、C 1-20烷氧基、或C 1-20烷基胺基;X 4选自:氢、氘、卤素、-CN、-NH 2、C 1-20烷氧基、或C 1-20烷基胺基。
- 如权利要求1所述的化合物,其特征在于,E是氮(N)、或CH;G 1是氢、氘(D)、卤素、-CN、C 1-6烷基、C 1-6烷氧基、或C 1-6烷基胺基;G 2是卤素、-CN、C 1-6烷基胺基、C 1-6羟基亚烷基胺基、C 1-6腈基亚烷基胺基、C 1-6胺基亚烷基胺基、C 3-6胺基环亚烷基胺基、C 1-6羧基亚烷基胺基、C 3-6羧基环亚烷基胺基、3-6元的杂环基胺基、或-OR 6;其中,R 6选自:氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基亚烷基、C 3-6氰基环亚烷基、C 2-6羟基亚烷基、C 2-6胺基亚烷基、C 3-6胺基环亚烷基、C 2-6羧基亚烷基、C 3-6羧基环亚烷基、C 3-6环烷基、C 3-6胺基环亚烷基、C 1-6胺基(C 3-6环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;G 3是-CN、-C(O)OR、-C(O)NH 2、氘代-C(O)ND 2、C 1-6烷氧基、C 1-6烷基胺基、或-C(O)NR 4R 5;其中,R是氢、或C 1-6烷基,R 4和R 5各自独立地选自:氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6腈基亚烷基、C 3-6氰基环亚烷基、C 2-6羟基亚烷基、C 3-6羟基环亚烷基、C 2-6胺基亚烷基、C 3-6胺基环亚烷基、C 2-6羧基亚烷基、C 3-6羧基环亚烷基、C 3-6环烯基、C 3-6环烷基、3-6元的杂环基、3-6元的杂环基亚烷基、C 6-10芳基、C 3-10杂环芳基、C 1-6烷基磺酰基、C 3-6环烷基磺酰基、或C 2-6杂环烷基磺酰基;R 4和R 5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;G 4和G 5各自独立地选自:氢、氘(D)、卤素、-CN、C 1-6烷基、C 1-6烷氧基、或C 1-6烷基胺基;R 1选自:氢、氘、C 1-6烷基、C 3-6环烷基、或C 3-6氘代环烷基;R 2和R 3各自独立地选自:氢、氘、C 1-6烷基、C 3-6环烷基、C 3-6氘代环烷基、或3-6元的杂环基;X 1、X 2和X 3各自独立地选自:卤素、-CN、-NH 2、C 1-6烷氧基、或C 1-6烷基胺基;X 4选自:氢、氘、卤素、-CN、-NH 2、C 1-6烷氧基、或C 1-6烷基胺基。
- 如权利要求2所述的化合物,其特征在于,E是CH;G 1是氢;G 2是-OR 6,其中R 6选自:氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基亚烷基、C 3-6氰基环亚烷基、C 2-6羟基亚烷基、C 2-6胺基亚烷基、C 3-6胺基环亚烷基、C 2-6羧基亚烷基、C 3-6环烷基、C 3-6胺基环亚烷基、C 1-6胺基(C 3-6环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;G 3是-C(O)OR、-C(O)NH 2、或-C(O)NR 4R 5;其中,R是氢、或C 1-6烷基,R 4和R 5各自独立地选自:氢、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基亚烷基、C 3-6氰基环亚烷基、C 2-6羟基亚烷基、C 2-6胺基亚烷基、C 2-6羧基亚烷基、C 3-6环烷基、3-6元的杂环基、C 1-6亚烷基(3-6元的杂环基)、C 3-6杂环芳基、C 1-6烷基磺酰基、C 3-6环烷基磺酰基、或C 2-6杂环烷基磺酰基;R 4和R 5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;G 4和G 5各自独立地选自:氢;R 1选自:氢;R 2选自:氢;R 3各自独立地选自:C 3-6环烷基;X 1、X 2和X 3各自独立地选自:卤素;X 4选自:氢。
- 如权利要求1-4任一项所述的式IIIb化合物的制备方法,其中,E是CH;G 1、G 4和G 5各自是氢;R 1是氢;R 2是氢;R 3是C 3环烷基;X 1是F;X 2是Cl;X 3是F;X 4是氢;G 2是-OR 6,其中R 6选自:氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基亚烷基、C 3-6氰基环亚烷基、C 2-6羟基亚烷基、C 2-6胺基亚烷基、C 3-6胺基环亚烷基、C 2-6羧基亚烷基、C 3-6环烷基、C 3-6胺基环亚烷基、C 1-6胺基(C 3-6环烷基)亚烷基、3-6元的杂环基、或3-6元的杂环基亚烷基;G 3是-C(O)OR、-C(O)NH 2、或-C(O)NR 4R 5;其中,R是氢、或C 1-6烷基,R 4和R 5各自独立地选自:氢、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基亚烷基、C 3-6氰基环亚烷基、C 2-6羟基亚烷基、C 2-6胺基亚烷基、C 2-6羧基亚烷基、C 3-6环烷基、3-6元的杂环基、C 1-6亚烷基(3-6元的杂环基)、C 3-6杂环芳基、C 1-6烷基磺酰基、C 3-6环烷基磺酰基、或C 2-6杂环烷基磺酰基;R 4和R 5之间或相互连接成含1-3个杂原子的3-8元的杂环基或杂环芳基;其特征在于:通过下述二种方法的任一种方法制得:方法一包括下述五个步骤,反应方程式如下:方法二包括下述三个步骤,反应方程式如下:
- 一种组合物,其包含如权利要求1-4中任一项所述的化合物或其药学上可以接受的盐以及药学上可接受的稀释剂和/或赋形剂。
- 权利要求1-4中任一项所述的化合物在制备用于预防或治疗血液系统疾病的药物中的应用。
- 权利要求1-4中任一项所述的化合物在制备用于治疗癌症的药物中的应用。
- 如权利要求11所述的应用,其中,所述癌症选自:胰腺癌、肺癌、肾癌、肝癌、胃癌、宫颈癌和白血病。
- 一种联合药物产品,其包含如权利要求1-4中任一项所述的化合物,以及选自以下的另外药学上的活性剂:(1)免疫调节剂;(2)PD-1;(3)PD-L1;或(4)不属于上述(1)-(3)的其他化合物。
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