WO2020135442A1 - 一种fak抑制剂及其联合用药物 - Google Patents

一种fak抑制剂及其联合用药物 Download PDF

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WO2020135442A1
WO2020135442A1 PCT/CN2019/128030 CN2019128030W WO2020135442A1 WO 2020135442 A1 WO2020135442 A1 WO 2020135442A1 CN 2019128030 W CN2019128030 W CN 2019128030W WO 2020135442 A1 WO2020135442 A1 WO 2020135442A1
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hydrogen
cancer
compound
inhibitors
drug
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PCT/CN2019/128030
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English (en)
French (fr)
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杜武
李宇
温坤
李兴海
陈元伟
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成都海创药业有限公司
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Priority to US17/418,678 priority Critical patent/US20220125788A1/en
Priority to JP2021537154A priority patent/JP2022515273A/ja
Priority to AU2019414550A priority patent/AU2019414550B2/en
Priority to BR112021012682-1A priority patent/BR112021012682A2/pt
Priority to CA3125058A priority patent/CA3125058C/en
Priority to KR1020217023858A priority patent/KR20210110846A/ko
Priority to EP19902488.6A priority patent/EP3904351A4/en
Publication of WO2020135442A1 publication Critical patent/WO2020135442A1/zh

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Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a FAK inhibitor and its combined medicine.
  • FAK Focal adhesion kinase
  • V-Src chicken embryo fibroblasts Focal adhesion kinase
  • FAK is a non-receptor tyrosine kinase in cells and was first discovered in transfected V-Src chicken embryo fibroblasts.
  • FAK is highly expressed in most tissues, and its protein sequence has high homology in many species (mouse, toad, human, etc.).
  • FAK is the junction of multiple signal transduction pathways in the cell and participates in multiple biological processes such as tumor formation, proliferation, metastasis and apoptosis, cardiovascular disease, etc. It is one of the anti-tumor targets that has received widespread attention.
  • FAK can be activated by a variety of factors, including integrins, G protein-coupled receptors, etc.
  • FAK regulates intracellular P53, PI3K-AKT-mTOR and other signals through kinase-dependent and kinase-independent pathways Pathways, participate in biological processes such as survival, proliferation, and metastasis of tumor cells.
  • the initial attempt was to suppress the tumor by down-regulating the expression of FAK in tumor cells.
  • Silencing FAK through transfection of carboxyl-terminally inactivated FAK (FAK-CD) reduces cell adhesion and proliferation, and achieved the effect of inhibiting the growth of breast cancer cells in vivo.
  • FAK-siRNA By transfecting a plasmid containing FAK-silenced RNA (FAK-siRNA), cancer is suppressed in vivo. Simultaneously inhibiting the expression of FAK and FAK downstream signaling molecules (such as SRC) can enhance the anti-tumor effect.
  • Deuterated drugs refer to replacing part of the hydrogen atoms in the drug molecules with deuterium.
  • Deuterium (D) is a stable isotope of hydrogen. Since the form and volume of deuterium in the drug are basically the same as hydrogen, part of the hydrogen atoms in the drug molecule Substituted for deuterium, the drug molecule activity remains basically unchanged. In addition, since the deuterium atom has twice the mass of hydrogen, the carbon-deuterium bond (CD) has a lower vibrational zero energy than the carbon-hydrogen bond (CH), and the carbon-deuterium bond is more stable.
  • the present invention provides a deuterated compound and its use as a FAK inhibitor, and also provides a scheme in which the aforementioned deuterated compound is used in combination with other anti-cancer drugs.
  • the present invention provides a compound represented by formula (I) or its optical isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate:
  • S ring is selected from aromatic ring or five-membered heterocyclic ring;
  • A, B, X, Y, Z are independently selected from carbon or nitrogen;
  • E is no or methylene;
  • R 6 is selected from hydrogen or none;
  • R 7 is selected from hydrogen, nitrogen or none;
  • R 8 is selected from haloalkyl or halogen, or R 7 and R 8 are connected to form a ring;
  • R 9 is selected from —NMeSO 2 Me, —CONHOMe, —CONHMe, amide, hydrogen or none;
  • R 10 is selected from hydrogen or none;
  • R 11 is selected from —NHSO 2 Me, halogen, substituted piperazine or hydrogen , The substituent on the piperazine is ethanolyl;
  • R 12 is selected from -SO 2 Me or hydrogen;
  • R 13 is selected from -CONHMe, -CONHOMe, N-alkylsulfonamide, hydrogen or none, or, R 11 and R 13 is connected to form a ring;
  • Dx shown in formula (I) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-A):
  • A, B, X, Y, Z are independently selected from carbon or nitrogen; E is no or methylene;
  • R 1 , R 5 are selected from hydrogen or methoxy;
  • R 2 , R 4 are selected from hydrogen or methoxy,
  • R 3 is selected from hydrogen, -CONHMe, alkoxyamide, morpholine, methoxy, ethylamine Or sulfonamide, or R 2 and R 3 are connected to form a ring, or R 3 and R 4 are connected to form a ring;
  • R 6 is selected from hydrogen or none;
  • R 7 is selected from hydrogen, nitrogen or none,
  • R 8 is selected from haloalkyl or halogen, or R 7 and R 8 are connected to form a ring;
  • R 9 is selected from —NMeSO 2 Me, —CONHOMe, —CONHMe, amide, hydrogen or none;
  • R 10 is selected from hydrogen or none;
  • R 11 is selected from —NHSO 2 Me, halogen, substituted piperazine or hydrogen , The substituent on the piperazine is ethanolyl;
  • R 12 is selected from -SO 2 Me or hydrogen;
  • R 13 is selected from -CONHMe, N-alkylsulfonamide, hydrogen or none, or, R 11 and R 13 are connected Forming a ring, or R 13 and R 3 and R 4 are connected to form a ring;
  • Dx shown in formula (I-A) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-B):
  • A, X, Y are selected from carbon or nitrogen; E is none;
  • R 14 , R 15 and R 16 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, methyl, ethyl or isopropyl;
  • R 9 and R 13 are selected from -CONHOMe, -CONHMe or hydrogen; R 10 and R 12 are hydrogen;
  • R 11 is selected from halogen, hydrogen or substituted piperazine, and the substituent on the piperazine is ethanolyl;
  • Dx shown in formula (I-B) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-C):
  • A, X, Y are selected from carbon or nitrogen; E is selected from methylene or none;
  • R 9 and R 13 are selected from hydrogen, -NMeSO 2 Me, -CONHOMe or -CONHMe; R 10 and R 12 are hydrogen; R 11 is selected from hydrogen, substituted piperazine or halogen, and the substituent on the piperazine is Ethanol group
  • R 6 is selected from hydrogen;
  • R 7 is selected from hydrogen,
  • R 8 is selected from haloalkyl or halogen, or R 7 and R 8 are connected to form a ring;
  • R 1 , R 4 , R 5 are selected from hydrogen or methoxy;
  • R 2 is selected from hydrogen or methoxy,
  • R 3 is selected from hydrogen, —CONHMe, alkoxyamide, morpholine, methoxy , Ethylamine or sulfonamide, or, R 2 and R 3 are connected to form a ring;
  • Dx shown in formula (I-C) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-D):
  • R 9 and R 13 are selected from -CONHOMe, -CONHMe or hydrogen;
  • R 10 and R 12 are hydrogen;
  • R 11 is selected from halogen, hydrogen or substituted piperazine, and the substituent on the piperazine is ethanolyl;
  • A, X, Y are selected from carbon or nitrogen; E is none;
  • R 6 is selected from hydrogen; R 7 is selected from hydrogen; R 8 is halogen
  • R 14 is selected from methyl, ethyl or isopropyl;
  • R 15 is selected from methyl or hydrogen;
  • R 16 is hydrogen;
  • Dx shown in formula (I-D) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-E):
  • B and Z are selected from carbon or nitrogen;
  • E is methylene;
  • Y is nitrogen;
  • X and A are carbon;
  • R 6 is none;
  • R 7 is hydrogen;
  • R 8 is haloalkyl;
  • R 1 and R 2 are hydrogen;
  • R 3 is -CONHMe,
  • R 4 is hydrogen, or R 3 and R 4 are connected to form a ring;
  • Dx shown in formula (I-E) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-F):
  • Dx represented by formula (I-F) means that the hydrogen in at least one carbon atom of the compound in parentheses is replaced by deuterium, and x is an integer greater than or equal to 1.
  • the compound has the structure represented by formula (I-G):
  • R 1 , R 5 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are substituted with deuterium.
  • the compound is selected from but not limited to one of the following compounds substituted by deuterium:
  • the compound is selected from but not limited to one of the following compounds or one of the following compounds substituted with deuterium:
  • the present invention also provides the use of the aforementioned compound or its optical isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate in the preparation of FAK inhibitors; preferably, the FAK inhibitors are drugs used to treat cancer.
  • the cancer is a solid tumor
  • the solid tumors include mesothelioma, pancreatic cancer, soft tissue tumor, metastatic tumor, non-solid cancer, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal cancer, urogenital cancer, prostate cancer, ovarian cancer
  • the gastrointestinal cancer includes colon cancer
  • the urogenital system cancer includes kidney, urothelial or testicular tumors
  • the ovarian cancer includes advanced ovarian cancer;
  • the mesothelioma includes neurofibromas, renal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma , Neuroma, adenoid cystic carcinoma, ependymoma, ependymoma, malignant pleural tumor, malignant pleural mesothelioma, triad, negative breast cancer, non-hematological malignant tumor, melanoma, colorectal Cancer, leukemia, adenocarcinoma, solid tumors;
  • the melanoma includes locally advanced melanoma, melanoma caused by locally mutated N-Ras, metastatic malignant cutaneous melanoma, the colorectal cancer includes metastatic colorectal cancer, and the leukemia includes acute myeloid
  • the adenocarcinoma includes adenocarcinoma
  • the solid tumor includes locally advanced solid tumors, metastatic solid tumors, and hepatocellular carcinoma.
  • the present invention also provides a combined drug for treating tumors, which contains the aforementioned compound and anticancer drug for simultaneous or separate administration of unit preparations of the same or different specifications, and a pharmaceutically acceptable carrier.
  • the anticancer drug is a drug for immunotherapy, a drug for chemotherapy or a drug for radiation therapy.
  • the drug for immunotherapy is selected from checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibiting antibodies, TIM3 inhibiting antibodies, LAG3 inhibiting antibodies, TIGIT inhibiting antibodies, and blocking inspections Targeted antibody, costimulatory antibody or CAR-T therapy cell.
  • the PD-1 inhibitor or PD-L1 inhibitor including but not limited to: nivolumab, CT-011; AMP-224, pembrolizumab, pidilizumab, MK-3475, BMS936559, MEDI4736, MSB001071 8C, MPDL-3280A, SHR -1210, IBI308, BGB-A317, JS001, GLS-010, GB226 zenomab, HLX10, AK103, AK104, AK105, AK112, SSI-361, JY034, KN035, SHR1316, TQB2450, KL-A167, CS1001, STI -A1014, JS003, AK106, HLX-09, mPD-1 antibody;
  • the antibodies that block checkpoint targets include IMP321, MGA271;
  • the costimulatory antibodies include anti-4-lBB antibody, anti-OX40 antibody, anti-GITR antibody, anti-CD27 antibody, and anti-CD40 antibody.
  • the chemotherapeutic drugs are toxic drugs, alkylated drugs, antimetabolite drugs, antibiotics, hormone therapy drugs, natural product anticancer drugs, topoisomerase inhibitor drugs, immune drugs, platinum complex drugs, kinase inhibition Agents, anti-proliferative drugs, antibodies, interferons or drugs that regulate androgen signaling pathways.
  • the toxic drugs include but are not limited to gemcitabine, paclitaxel, docetaxel;
  • the kinase inhibitors include, but are not limited to, MEK kinase inhibitors, cMet inhibitors, VEGFR2 inhibitors, EGFR inhibitors;
  • the drugs that regulate androgen signaling pathway include but are not limited to: androgen synthesis inhibitors, CYP17A inhibitors, androgen receptor inhibitors, BET inhibitors, BRD4 inhibitors, ROR ⁇ inhibitors, CBP/P300 inhibitors, BMX inhibitor, PARP inhibitor; preferably, the androgen receptor inhibitor includes but is not limited to: Enzalutamide, Apalutamide, Bicalutamide, Abiraterone, ODM-201, EPI-001, ONC1-13B, EM-5854, JNJ -63576, TAS-3681, HC-1119, prokamide, SHR3680.
  • the invention also provides the use of the aforementioned combined medicine in the preparation of a medicine for treating cancer.
  • the cancer is a solid tumor
  • the solid tumors include mesothelioma, pancreatic cancer, soft tissue tumor, metastatic tumor, non-solid cancer, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal cancer, urogenital cancer, prostate cancer, ovarian cancer
  • the gastrointestinal cancer includes colon cancer
  • the urogenital system cancer includes kidney, urothelial or testicular tumors
  • the ovarian cancer includes advanced ovarian cancer;
  • the mesothelioma includes neurofibromas, renal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma , Neuroma, adenoid cystic carcinoma, ependymoma, ependymoma, malignant pleural tumor, malignant pleural mesothelioma, triad, negative breast cancer, non-hematological malignant tumor, melanoma, colorectal Cancer, leukemia, adenocarcinoma, solid tumors;
  • the melanoma includes locally advanced melanoma, melanoma caused by locally mutated N-Ras, metastatic malignant cutaneous melanoma, the colorectal cancer includes metastatic colorectal cancer, and the leukemia includes acute myeloid
  • the adenocarcinoma includes adenocarcinoma
  • the solid tumor includes locally advanced solid tumors, metastatic solid tumors, and hepatocellular carcinoma.
  • alkyl includes a linear or branched alkyl group.
  • the term "compound of the present invention” refers to a compound represented by formula (I).
  • the term also includes various crystalline forms of compounds of formula (I), pharmaceutically acceptable salts, hydrates or solvates, optical isomers, tautomers, prodrugs.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base, which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with alkali metals.
  • Alkali metals suitable for salt formation include, but are not limited to: lithium, sodium, potassium, calcium, magnesium, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • the present invention provides a deuterated compound. Compared with the pre-deuterated compound, it shows better pharmacokinetics, higher maximum blood drug concentration, higher exposure and longer half-life. More excellent metabolic performance. Moreover, the deuterated compound of the present invention can effectively inhibit FAK activity, and has very good application prospects in the preparation of FAK inhibitors and/or drugs for treating cancer. At the same time, the combined use of the deuterated compound of the present invention and anti-cancer drugs (such as PD-1 inhibitors) can exert a synergistic effect, significantly improve the tumor suppression effect, and provide a better choice for clinical treatment of cancer.
  • anti-cancer drugs such as PD-1 inhibitors
  • FIG. 1 is a drug efficacy experiment of a deuterated compound of the present invention on an MC38 tumor animal model.
  • FIG. 2 is a test of the efficacy of the deuterated compound of the present invention on the PAN02 tumor animal model.
  • the raw materials and instruments used in the present invention can be purchased through the market.
  • Deuterated methylamine hydrochloride (7.75 g, 109.99 mmol) was placed in a 250 mL single-necked round bottom flask, while adding dichloromethane (120 mL) and stirring at room temperature. Subsequently, the system was transferred to an ice-water bath, cooled and stirred. After 15 min, triethylamine (21.73 g, 214.75 mmol) and DMAP (128 mg, 1.05 mmol) were added in sequence. After completion, the system was further stirred and reacted in an ice-water bath for 10 min. After that, methanesulfonyl chloride (12.0 g, 104.76 mmol) was added to the system.
  • N-trideuterated methyl methanesulfonamide (6.0g, 53.54mmol), 2-chloro-3 cyanopyrazine (6.23g, 44.62mmol) was placed in a 500mL single-necked round bottom flask, while adding acetonitrile (300mL) , Stir at room temperature. Subsequently, cesium carbonate (24.71g, 75.85mmol) was added to the system. After completion, the system was transferred to an oil bath at 80°C and the reaction was continued to be heated and stirred. After 1.5h, the samples were taken and the TLC showed that the raw materials had been consumed. Stop heating and let the system cool to room temperature naturally.
  • Step 3 Synthesis of N-(3-(aminomethyl)pyrazine-2-yl)-N-trideuterated methyl methanesulfonamide (Compound 41-3)
  • Step 4 Synthesis of the compound tert-butyl (4-(methylcarbamoyl)phenyl) carbamate
  • Step 7 Compound N-methyl-4-((4-(((3-(N-deuterated methylmethanesulfonamido)pyrazine-2-yl)methyl)amino)-5-(tri Synthesis of fluoromethyl)pyrimidine-2-yl)amino)benzamide
  • Step 1 Synthesis of (4-(trideuteromethylcarbamoyl)phenyl)carbamic acid tert-butyl ester (Compound 44-1)
  • N-Boc-4-aminobenzoic acid (6.0 g, 25.29 mmol) and EDCI (7.27 g, 37.93 mmol) were weighed into a 250 mL single-necked round bottom flask, and DMF (50 mL) was added at the same time, and stirred at room temperature. Subsequently, triethylamine (6.40 g, 63.22 mmol) and deuterated methylamine hydrochloride (1.96 g, 27.82 mmol) were added to the system. After completion, the system was stirred at room temperature and reacted overnight. The next day, a sample was taken and TLC showed that the reaction was over.
  • Step 3 Synthesis of 4-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-trideuterated methylbenzamide (Compound 44-3)
  • Step 4 Synthesis of N-trideuteromethyl-4-((4-(((((3-(N-trideuteromethylmethanesulfonamide)pyrazine-2-yl)methyl)amino)-5 -(Trifluoromethyl)pyrimidine-2-yl)amino)benzamide (Compound 44)
  • Step 5 Synthesis of N-deuterated methyl-4-((4-(((3-(N-deuterated methylmethanesulfonamide)pyrazin-2-yl)methyl)amino)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)benzamide hydrochloride
  • Step 1 Synthesis of compound N-(3-(aminodideuterated methyl)pyrazin-2-yl)-N-deuterated methyl methanesulfonamide (45-1)
  • the compound 41-2 (100.0 mg, 0.46 mmol) was weighed into a 25 mL single-necked round bottom flask, and 5 mL of deuterated methanol was added, and stirred at room temperature to dissolve and clarify. Subsequently, 20.0 mg of wet palladium carbon (treated with heavy water) and triethylamine (188.2 mg, 1.86 mmol) were sequentially added to the system, and the system was subjected to deuterium gas replacement operation, repeated ten times. After completion, the system was stirred at room temperature for reaction. After 72h, the monitoring reaction was over. The system was subjected to suction filtration operation. The filter cake was rinsed with deuterated methanol (10 mL) for a few times.
  • Step 2 Synthesis of compound N-deuterated methyl-4-((4-(((3-(N-deuterated methylmethanesulfonamido)pyrazin-2-yl)deuterated methyl)amino) -5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (45)
  • TLC monitors the complete consumption of raw materials. Stop heating, and after the system has cooled to room temperature, remove the solvent by rotary evaporation to obtain a crude product, which is separated and purified by Prep-TLC to obtain an off-white solid N-deuteromethyl-4-((4-(((3-(N-deuterium Methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide 8.1 mg. Yield: 15.6%. MS (ESI) m/e 519.2 (M+H) + .
  • Step 2 Synthesis of compound 4-((4-(((3-(N-trideuteromethylmethanesulfonamide)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl) Pyrimidin-2-yl)amino)benzamide (52)
  • Test Example 1 Inhibitory activity of the deuterated compound of the present invention on FAK
  • test compound is diluted to 1000 nM, and then diluted 1:3 with DMSO to take 0.1L solution and put it into a 384-well plate. Each concentration is set with 2 duplicate wells.
  • Add 5L of 2X FAK enzyme solution centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes.
  • Table 1 shows the FAK inhibitory activity of each compound. It can be seen that the compounds prepared by the present invention can effectively inhibit the activity of FAK enzymes, and the deuterated compounds 41 and 45 of the present invention have higher inhibitory activity against FAK enzymes compared to the defactinib compounds which are not deuterated.
  • the deuterated compounds 25 and 44 prepared by the present invention show better pharmacokinetics.
  • the compounds of the present invention have a higher maximum blood concentration Cmax and higher exposure AUC, and longer half-life. Therefore, the deuterated compounds prepared by the present invention will have better application prospects as FAK inhibitors or drugs for treating cancer.
  • Test Example 3 The efficacy test of the deuterated compound of the present invention combined with PD-1 inhibitor in tumor animal model
  • MC-38 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS). The MC-38 cells in the logarithmic growth phase were collected, and HBSS was resuspended to a suitable concentration for subcutaneous tumor inoculation of C57BL/6 mice.
  • FBS fetal bovine serum
  • mice C57BL/6 mice, female, 6-8 weeks old, weighing about 18-20g, 96, purchased from Beijing Viton Lihua Experimental Animal Technology Co., Ltd.
  • Tumor cell inoculation Collect tumor cells in logarithmic growth phase, adjust the cell concentration to 5 ⁇ 10 6 /mL with HBSS, inoculate 0.1 mL with a 1 mL syringe to the right side of each mouse, close to the back of the back, that is, 5 ⁇ 10 5 /mouse . After that, observe and measure the tumor volume. When the average tumor volume of the mice reaches 50-100 mm 3 , the tumor-bearing mice are randomly grouped and administered according to the tumor volume. The details are as shown in Table 3 below. The day of group administration is defined as day 0 .
  • N the number of animals used; i.p.: intraperitoneal injection; p.o.: intragastric administration; BID: twice daily; QD: once daily; BIW: twice weekly.
  • Compound 44 compared with Compound 44 alone (Group 4) or mPD-1 antibody alone (Group 2), Compound 44 combined with mPD-1 antibody administration (Group 5) achieved a significantly improved tumor suppression effect, Played a synergistic effect.
  • PAN-02 cells in the logarithmic growth phase were taken, washed twice with PBS, and then resuspended in pre-chilled PBS for inoculation.
  • the experimental animal was a C57BL/6 mouse, female, and was purchased from Beijing Viton Lihua Experimental Animal Technology Co., Ltd. C57BL/6 mice were adapted to the laboratory environment for 3 days, and PAN-02 cells were inoculated subcutaneously in the right flank. The amount of inoculated cells was 1 ⁇ 10 6 per mouse. When the tumors grew to about 100 mm 3 , they were screened and randomly divided into groups. Eight animals were administered according to the grouping and administration schedule in Table 4 below. The day of group administration is defined as the first day, and the administration period is 33 days.
  • N number of animals used; i.p.: intraperitoneal injection; i.g.: intragastric administration; BID: twice daily; BIW: twice weekly.
  • the present invention provides a deuterated compound, which shows better pharmacokinetics, higher maximum blood concentration, higher exposure and longer Half-life, with more excellent metabolic properties. Moreover, the deuterated compound of the present invention can effectively inhibit FAK activity, and has very good application prospects in the preparation of FAK inhibitors and/or drugs for treating cancer. At the same time, the combined use of the deuterated compound of the present invention and anti-cancer drugs (such as PD-1 inhibitors) can exert a synergistic effect, significantly improve the tumor suppression effect, and provide a better choice for clinical treatment of cancer.
  • anti-cancer drugs such as PD-1 inhibitors

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Abstract

一种式(I)所示的氘代化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物。与氘代前的化合物相比，氘代化合物显示了更优的药代动力学，更高的最高血药浓度，更高的暴露量和更长的半衰期，具有更加优异的代谢性能。而且，氘代化合物能够有效抑制FAK活性，在制备FAK抑制剂和/或治疗癌症的药物中具有非常好的应用前景。同时，氘代化合物与抗癌药物(比如PD-1抑制剂)联合使用能够发挥协同增效的作用，显著提高肿瘤抑制效果，为临床治疗癌症提供了更好的选择。 (I)

Description

一种FAK抑制剂及其联合用药物 技术领域
本发明属于药物化学领域，具体涉及一种FAK抑制剂及其联合用药物。
背景技术
黏着斑激酶(focal adhesion kinase，FAK)是一种细胞内的非受体酪氨酸激酶，在转染的V-Src鸡胚成纤维细胞中被首次发现。FAK在多数组织中都有较高的表达，其蛋白序列在很多物种(鼠、蟾蜍、人等)中具有较高的同源性。FAK在细胞内是多条信号传导通路的交汇处，参与肿瘤形成、增殖、转移和凋亡、心血管疾病等多个生物过程，是目前受到广泛关注的抗肿瘤靶点之一。
近年来的研究发现，FAK可经多种因素激活，包括整合素、G蛋白偶联受体等，同时FAK经激酶依赖和非激酶依赖2种途径调控细胞内P53、PI3K-AKT-mTOR等信号通路，参与肿瘤细胞的生存、增殖、转移等生物过程。最初的尝试是通过下调FAK在肿瘤细胞中的表达以达到抑制肿瘤的目的。通过转染羧基端失活的FAK(FAK-CD)沉默FAK，减少细胞黏着和增殖，在活体实验中实现了抑制乳腺癌细胞生长的作用。通过转染含有FAK-silenced RNA(FAK-siRNA)的质粒，在活体内抑制了癌症。同时抑制FAK和FAK下游信号分子(如SRC)的表达，能够使得抗肿瘤效应增强。
考虑到FAK在肿瘤细胞中的重要功能、基因转染的可靠性和病毒载体的安全性，基于FAK信号通路的小分子抑制剂开始出现，并且近年来取得较好的成果。目前有多种FAK抑制剂作为抗肿瘤药物，处于临床前研究或临床试验阶段。有文献报道(抗肿瘤新靶点黏着斑激酶FAK及其抑制剂研究进展，陈瑛等)，TAE226又称NVP-226可以通过阻滞FAK与ATP的连接位点以及FAK的Y397和Y861磷酸化位点，起到抑制FAK活性的作用。然而，本领域仍需要开发具有更佳的抑制活性或更好药效学性能的FAK抑制剂。
氘代药物是指将药物分子中的部分氢原子替换为氘，氘(D)是氢的一种稳定同位素，由于氘在药物中的形态和体积与氢基本相同，将药物分子中部分氢原子替代为氘，药物分子活性基本保持不变。此外，由于氘原子质量是氢的两倍，碳氘键(C-D)比碳氢键(C-H)的振动零点能要低，碳氘键更稳定，将药物分子中部分氢原子替代为氘，会延缓药物的分解过程，使氘代药物在体内作用时间更长，达到改变药物代谢速度或代谢途径的目的，以此提高药代动力学、降低药物代谢毒性。鉴于FAK抑制剂在肿瘤治疗领域的重要用途和其局限性，将其与氘代药物技术结合，发现新的分子实体，降低其对肝肾功能的影响、提升药物安全性和有效性是促进这一种类药物进一步发展的研究趋势，具有巨大的应用价值。
药物联合使用是有效提高药物疗效的方式，未见将氘代FAK抑制剂与其他的抗癌药物或者抗癌方法联合使用的报道。
发明内容：
为了解决上述问题，本发明提供了一种氘代化合物及其作为FAK抑制剂的用途，还提供了前述氘代化合物与其他抗癌药物联合使用的方案。
本发明提供了式(I)所示的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物：
Figure PCTCN2019128030-appb-000001
其中，S环选自芳环或五元杂环；A、B，X、Y，Z分别独立地选自碳或氮；E为无或亚甲基；
和/或，R 6选自氢或无；R 7选自氢，氮或无；R 8选自卤代烷基或卤素，或者，R 7和R 8连接成环；
和/或，R 9选自-NMeSO 2Me、-CONHOMe、-CONHMe、酰胺、氢或无；R 10选自氢或无；R 11选自-NHSO 2Me、卤素、取代的哌嗪或氢，所述哌嗪上的取代基为乙醇基；R 12选自-SO 2Me或氢；R 13选自-CONHMe、-CONHOMe、N-烷基磺酰胺、氢或无，或者，R 11和R 13连接成环；
式(I)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-A)所示结构：
Figure PCTCN2019128030-appb-000002
其中，A、B，X，Y，Z分别独立地选自碳或氮；E为无或亚甲基；
R 1、R 5选自氢或甲氧基；R 2、R 4选自氢或甲氧基，R 3选自氢、-CONHMe、烷氧基酰胺、吗啉、甲氧基、乙基胺或磺酰胺，或者，R 2和R 3连接成环，或者，R 3和R 4连接成环；
和/或，R 6选自氢或无；R 7选自氢，氮或无，R 8选自卤代烷基或卤素， 或者，R 7和R 8连接成环；
和/或，R 9选自-NMeSO 2Me、-CONHOMe、-CONHMe、酰胺、氢或无；R 10选自氢或无；R 11选自-NHSO 2Me、卤素、取代的哌嗪或氢，所述哌嗪上的取代基为乙醇基；R 12选自-SO 2Me或氢；R 13选自-CONHMe、N-烷基磺酰胺、氢或无，或者，R 11和R 13连接成环，或者，R 13和R 3和R 4连接成环；
式(I-A)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-B)所示结构：
Figure PCTCN2019128030-appb-000003
其中，A、X、Y选自碳或氮；E为无；
R 14，R 15，R 16独立地选自氢，C 1-6烷基，C 3-6环烷基，甲基、乙基或异丙基；
和/或，R 6为氢；R 7为氢；R 8为卤素；
R 9、R 13选自-CONHOMe、-CONHMe或氢；R 10、R 12为氢；
R 11选自卤素、氢或取代的哌嗪，所述哌嗪上的取代基为乙醇基；
式(I-B)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-C)所示结构：
Figure PCTCN2019128030-appb-000004
其中，A、X、Y选自碳或氮；E选自亚甲基或无；
R 9、R 13选自氢、-NMeSO 2Me、-CONHOMe或-CONHMe；R 10、R 12为氢；R 11选自氢、取代的哌嗪或卤素，所述哌嗪上的取代基为乙醇基；
和/或，R 6选自氢；R 7选自氢，R 8选自卤代烷基或卤素，或者，R 7和R 8连接成环；
和/或，R 1、R 4、R 5选自氢或甲氧基；R 2选自氢或甲氧基，R 3选自氢、-CONHMe、烷氧基酰胺、吗啉、甲氧基、乙基胺或磺酰胺，或者，R 2和R 3 连接成环；
式(I-C)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-D)所示结构：
Figure PCTCN2019128030-appb-000005
其中，R 9、R 13选自-CONHOMe、-CONHMe或氢；R 10、R 12为氢；R 11选自卤素、氢或取代的哌嗪，所述哌嗪上的取代基为乙醇基；
A、X、Y选自碳或氮；E为无；
和/或，R 6选自氢；R 7选自氢；R 8为卤素
和/或，R 14选自甲基、乙基或异丙基；R 15选自甲基或氢；R 16为氢；
式(I-D)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-E)所示结构：
Figure PCTCN2019128030-appb-000006
其中，B、Z选自碳或氮；E为亚甲基；Y为氮；X、A为碳；
和/或，R 6为无；R 7为氢；R 8为卤代烷基；
和/或，R 1、R 2为氢；R 3为-CONHMe，R 4为氢，或者，R 3与R 4连接成环；
式(I-E)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-F)所示结构：
Figure PCTCN2019128030-appb-000007
其中，式(I-F)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
优选地，所述化合物具有式(I-G)所示结构：
Figure PCTCN2019128030-appb-000008
其中，R 1、R 5、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24中的一个或多个被氘取代。
优选地，所述化合物选自但不局限于氘取代的如下化合物之一：
Figure PCTCN2019128030-appb-000009
Figure PCTCN2019128030-appb-000010
优选地，所述化合物选自但不局限于如下化合物之一或氘取代的如下化合物之一：
Figure PCTCN2019128030-appb-000011
Figure PCTCN2019128030-appb-000012
本发明还提供了前述化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物在制备FAK抑制剂中的用途；优选地，所述FAK抑制剂是治疗癌症的药物。
其中，所述癌症为实体瘤；
所述实体瘤包括间皮瘤，胰腺癌，软组织肿瘤，转移瘤，非固体癌，肉瘤，腺癌，肺癌，乳腺癌，淋巴瘤，胃肠道癌，泌尿生殖系统癌，前列腺癌，卵巢癌；所述胃肠道癌包括结肠癌，所述泌尿生殖系统癌包括肾，尿路上皮或睾丸肿瘤，所述卵巢癌包括晚期卵巢癌；
所述间皮瘤包括神经纤维瘤，肾癌，肺癌，小细胞肺癌，非小细胞肺癌，KRAS突变体非小细胞肺癌，肝癌，甲状腺癌，乳腺癌，神经系统肿瘤，神经鞘瘤，脑膜瘤，神经瘤，腺样囊性癌，室管膜瘤，室管膜肿瘤，恶性胸膜瘤，恶性胸膜间皮瘤，三联体瘤，阴性乳腺癌，非血液恶性肿瘤，黑素瘤，，结直肠癌，白血病，腺癌，固体肿瘤；
所述黑素瘤包括局部晚期黑素瘤，局部突变的N-Ras引起的黑素瘤，转移性恶性皮肤黑色素瘤，所述结直肠癌包括转移性结直肠癌，所述白血病包括急性髓性白血病，所述腺癌包括腺癌，所述固体肿瘤包括局部晚期实体瘤，转移性实体瘤，肝细胞癌。
本发明还提供了一种用于治疗肿瘤的联合用药物，它含有相同或不同规格单位制剂的用于同时或者分别给药的前述化合物与抗癌药物，以及药学上可接受的载体。
所述抗癌药物为免疫疗法用药物、化学疗法用药物或辐射疗法用药物。
所述免疫疗法用药物选自检查点抑制剂、PD-1抑制剂、PD-L1抑制剂、抑制CTLA-4的抗体、抑制TIM3的抗体、抑制LAG3的抗体、抑制TIGIT的抗体、阻断检查点靶点的抗体、共刺激抗体或者CAR-T疗法用细胞。
所述PD-1抑制剂或PD-L1抑制剂，包括但不局限于：nivolumab，CT-011；AMP-224，pembrolizumab，pidilizumab，MK-3475，BMS936559，MEDI4736，MSB001071 8C，MPDL-3280A，SHR-1210,IBI308，BGB-A317，JS001，GLS-010，GB226杰诺单抗，HLX10，AK103,AK104,AK105,AK112,SSI-361,JY034,KN035,SHR1316,TQB2450,KL-A167,CS1001，STI-A1014,JS003,AK106,HLX-09，mPD-1抗体；
所述阻断检查点靶点的抗体包括IMP321,MGA271；
所述共刺激抗体包括anti-4-lBB抗体,anti-OX40抗体,anti-GITR抗体,anti-CD27抗体,anti-CD40抗体。
所述化学疗法用药物为毒性药物，烷基化药物，抗代谢产物药物，抗生素，激素疗法药物，天然产物抗癌药物，拓扑异构酶抑制剂药物，免疫药物，络合铂药物，激酶抑制剂，抗增生药物，抗体，干扰素或调控雄激素信号通路的药物。
所述毒性药物为包括但不局限于gemcitabine，paclitaxel，docetaxel；
所述激酶抑制剂包括但不局限于,MEK激酶抑制剂，cMet抑制剂，VEGFR2抑制剂，EGFR抑制剂；
所述调控雄激素信号通路的药物包括但不局限于：雄激素合成抑制剂，CYP17A抑制剂，雄激素受体抑制剂，BET抑制剂，BRD4抑制剂，RORγ抑制剂，CBP/P300抑制剂，BMX抑制剂，PARP抑制剂；优选地，所述雄激素受体抑制剂包括但不局限于：Enzalutamide,Apalutamide,Bicalutamide,Abiraterone,ODM-201，EPI-001，ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119,普克鲁胺，SHR3680。
本发明还提供了前述联合用药物在制备治疗癌症的药物中的用途。
其中，所述癌症为实体瘤；
所述实体瘤包括间皮瘤，胰腺癌，软组织肿瘤，转移瘤，非固体癌，肉瘤，腺癌，肺癌，乳腺癌，淋巴瘤，胃肠道癌，泌尿生殖系统癌，前列腺癌，卵巢癌；所述胃肠道癌包括结肠癌，所述泌尿生殖系统癌包括肾，尿路上皮 或睾丸肿瘤，所述卵巢癌包括晚期卵巢癌；
所述间皮瘤包括神经纤维瘤，肾癌，肺癌，小细胞肺癌，非小细胞肺癌，KRAS突变体非小细胞肺癌，肝癌，甲状腺癌，乳腺癌，神经系统肿瘤，神经鞘瘤，脑膜瘤，神经瘤，腺样囊性癌，室管膜瘤，室管膜肿瘤，恶性胸膜瘤，恶性胸膜间皮瘤，三联体瘤，阴性乳腺癌，非血液恶性肿瘤，黑素瘤，，结直肠癌，白血病，腺癌，固体肿瘤；
所述黑素瘤包括局部晚期黑素瘤，局部突变的N-Ras引起的黑素瘤，转移性恶性皮肤黑色素瘤，所述结直肠癌包括转移性结直肠癌，所述白血病包括急性髓性白血病，所述腺癌包括腺癌，所述固体肿瘤包括局部晚期实体瘤，转移性实体瘤，肝细胞癌。
本发明中，“烷基”包括直链或支链的烷基。
本发明中，术语“本发明化合物”指式(Ⅰ)所示的化合物。该术语还包括式(Ⅰ)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物、光学异构体、互变异构体、前药。
本发明中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与碱金属形成的盐。适合形成盐的碱金属包括但并不限于：锂、钠，钾、钙、镁等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明提供了一种氘代化合物，与氘代前的化合物相比，其显示了更优的药代动力学，更高的最高血药浓度，更高的暴露量和更长的半衰期，具有更加优异的代谢性能。而且，本发明的氘代化合物能够有效抑制FAK活性，在制备FAK抑制剂和/或治疗癌症的药物中具有非常好的应用前景。同时，本发明的氘代化合物与抗癌药物(比如PD-1抑制剂)联合使用能够发挥协同增效的作用，显著提高肿瘤抑制效果，为临床治疗癌症提供了更好的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明氘代化合物在MC38肿瘤动物模型上的药效实验。
图2为本发明氘代化合物在PAN02肿瘤动物模型上的药效实验。
具体实施方式
本发明所用原料和仪器均可通过市场购买得到。
实施例1、合成N-三氘代甲基-4-((4-(((3-(N-甲基甲磺酰胺基)吡嗪-2-基)甲基) 氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酸酰胺(化合物25)
Figure PCTCN2019128030-appb-000013
第一步：合成化合物25-2
将25-1(200mg，0.39mmol)，DMAP(1.29g，10.57mmol)加入到10mL二氯甲烷中，再滴加(Boc) 2O(1.71g，7.83mmol)。体系在油浴中回流反应24h。翌日，冷却至室温，加入二氯甲烷和0.1N HCl溶液，萃取，后静置分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤后旋蒸除去溶剂，柱层析分离粗品，得类白色固体25-2，136mg，收率：42.8％。MS(M+1)：811.2。
第二步：合成化合物25-3
将25-2(136mg，0.17mmol)，氘代甲胺盐酸盐(189mg，2.68mmol)加入到5mL乙腈中，室温搅拌。再向其中加入DBU(613mg，4.03mmol)，逐渐溶解澄清。随后将体系置于油浴中回流反应过夜。翌日，冷却至室温，旋蒸除去溶剂后，向体系中加入二氯甲烷以及0.1N HCl溶液，剧烈搅拌，静置分层，有机相分别用纯净水以及饱和食盐水洗涤，无水硫酸钠干燥，旋蒸除去溶剂，Pre-TLC分离纯化(PE/EA＝2:1)，得白色固体25-3(42mg，收率35.3％)。MS(M-Boc+1)：614.2。
第三步：合成化合物25
将25-3(42mg，0.06mmol)加入到2mL二氯甲烷中，室温搅拌(未能溶解澄清)。随后向其中加入0.1mL三氟甲磺酸，体系逐渐呈现透明澄清状，任其在室温搅拌反应过夜。翌日，旋蒸除去溶剂，向体系中加入乙酸乙酯以及饱和NaHCO 3溶液，剧烈搅拌，后静置分层，测得水相的pH值约为7-8左右。有机层分别用水以及饱和食盐水洗涤各2次，无水硫酸钠干燥，旋蒸除去溶剂，得白色固体化合物25(24mg，收率：80.0％)。
1HNMR(400Hz,DMSO-d 6):δ9.863(1H,s),8.688(1H,d,J＝2.4Hz),8.581(1H,d,J＝2.8Hz),δ8.316(1H,s),δ8.180(1H,s),7.665-7.594(4H,dd，J 1＝19.6Hz，J 2＝8.8Hz),7.476-7.450(1H,t，J＝5.2Hz),δ5.001(2H,d,J＝4.8Hz),3.221(3H,s),3.199(3H,s).LC-MS(M+H +)：514.2。
采用与化合物相对应的原料和类似于化合物25的制备方法，制备得到化合物26-40。
实施例2、合成N-甲基-4-((4-(((3-(N-三氘代甲基甲磺酰胺基)吡嗪-2-基)甲基) 氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酸酰胺(化合物41)
Figure PCTCN2019128030-appb-000014
第一步：合成N-三氘代甲基甲磺酰胺(化合物41-1)
氘代甲胺盐酸盐(7.75g，109.99mmol)置于250mL单颈圆底烧瓶中，同时加入二氯甲烷(120mL)，室温搅拌。随后将体系移置于冰水浴中降温冷却搅拌，15min后依次加入三乙胺(21.73g，214.75mmol)以及DMAP(128mg，1.05mmol)，完毕，体系在冰水浴中继续保温搅拌反应10min。尔后，向体系中加入甲基磺酰氯(12.0g，104.76mmol)，完毕，撤去冰浴，让体系在室温搅拌反应过夜。翌日，TLC检测反应结束，对体系进行抽滤操作，滤饼用乙酸乙酯少量多次淋洗，合并滤液，旋蒸除去溶剂，再向体系中加入乙酸乙酯(90mL)，剧烈搅拌，10min后，再次对体系进行抽滤操作，滤饼亦用乙酸乙酯少量多次淋洗，合并滤液，真空浓缩得N-三氘代甲基甲磺酰胺(11.16g)无色透明油状液体，不经进一步纯化，直接用于下步反应中。收率：94.9％。LC/MS(ESI+)Calcd for C2H4D3NO2S(M+H+)m/z,113.1；Found:113.3。
第二步：合成N-(3-氰基吡嗪-2-yl)-N-三氘代甲基甲磺酰胺(化合物41-2)
N-三氘代甲基甲磺酰胺(6.0g，53.54mmol)，2-氯-3氰基吡嗪(6.23g，44.62mmol)置于500mL单颈圆底烧瓶中，同时加入乙腈(300mL)，室温搅拌。随后向体系中加入碳酸铯(24.71g，75.85mmol)，完毕，将体系移置于80℃的油浴中继续加热搅拌反应。1.5h后，取样点板，TLC显示原料已经消耗完毕。停止加热，让体系自然冷却至室温。对体系进行抽滤操作，滤饼用乙腈少量多次淋洗，尔后，合并滤液，旋蒸除去溶剂。再向体系中加入乙酸乙酯(150mL)和水(150mL),剧烈搅拌，静置分层，水相用乙酸乙酯反萃(50mL*3)，合并有机相，依次用纯净水(30mL x 3)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，真空浓缩得粗品，并通过柱层析分离纯化得N-(3-氰基吡嗪-2-yl)-N-氘代甲基甲磺酰胺(5.29g)浅棕红色油状液体。收率：55.1％。LC/MS(ESI+)Calcd for C7H5D3N4O2S(M+H+)m/z,216.1；Found:233.1(M+H2O)。1H NMR(400MHz,DMSO-d6)δ8.65–8.63(dd,J＝6.0,2.4Hz,2H),3.26(s,3H).
第三步：合成N-(3-(氨甲基)吡嗪-2-yl)-N-三氘代甲基甲磺酰胺(化合物41-3)
称取N-(3-氰基吡嗪-2-yl)-N-氘代甲基甲磺酰胺(2.0g，9.30mmol)置于500mL的单颈圆底烧瓶中，并向其中加入甲醇(270mL)，室温搅拌溶解澄 清。随后，向体系中加入湿钯碳(1g)，以及氨水(20mL)。尔后对体系进行抽真空，通氩气的操作反复5次，确保体系中的惰性气体氛围。再对体系进行氢气置换操作，完毕，仍体系在室温搅拌反应。5h后，取样点板，TLC显示原料已经消耗完毕。停止反应，撤去加氢装置。对体系进行抽滤操作，滤饼用甲醇反复淋洗数次，合并滤液，旋蒸除去溶剂，并使用甲醇多次旋带除去体系中残留的水分，得N-(3-(氨甲基)吡嗪-2-yl)-N-氘代甲基甲磺酰胺浅黄棕色透明油状液体，不经进一步纯化，直接用于下步反应中。LC/MS(ESI+)Calcd for C7H9D3N4O2S(M+H+)m/z,220.1；Found:220.1。
第四步：化合物叔丁基(4-(甲基氨甲酰)苯基)氨基甲酸酯的合成
称取4-((叔丁氧羰基)氨基)苯甲酸(3.0g，12.65mmol)置于250mL单颈圆底烧瓶中，并向其中加入50mL DMF，室温搅拌。随后向体系中依次加入EDCI(4.8g，25.29mmol)，TEA(4.5g，44.28mmol)，甲胺盐酸盐(1.3g，18.98mmol)，DMAP(16.0mg，0.13mmol)。完毕，体系在室温搅拌反应过夜。翌日，监测原料消耗完毕，向体系中加入乙酸乙酯(70mL)和水(50mL)，剧烈搅拌，静置分层后，水相用乙酸乙酯反萃(20mL*3)，合并有机层，分别用水(20mL*3)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，旋蒸除去溶剂得粗品，后经柱层析分离得类白色固体叔丁基(4-(甲基氨甲酰)苯基)氨基甲酸酯2.1g。收率：66.5％。MS(ESI)m/e 251.2(M+H) +。
第五步：化合物4-氨基-N-甲基苯甲酰胺三氟乙酸盐的合成
称取叔丁基(4-(甲基氨基甲酰)苯基)氨基甲酸酯(500.0mg，2.00mmol)置于50mL单颈圆底烧瓶中，并向其中加入10mL二氯甲烷，室温搅拌。尔后，向体系中加入三氟乙酸(1mL)，完毕，体系在室温搅拌反应过夜。翌日，TLC显示反应结束。浓缩除去溶剂以及过量的三氟乙酸，并使用二氯甲烷多次旋带除去体系中残留的三氟乙酸直到体系中呈现完全固状为止，得类白色固体4-氨基-N-甲基苯甲酰胺三氟乙酸盐(510.0mg)，不经进一步纯化，直接用于下步反应中。
第六步：化合物4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-甲基苯甲酰胺的合成
称取2,4-二氯-5-(三氟甲基)嘧啶(499.0mg，2.30mmol)于50mL单颈圆底烧瓶中，并向体系中加入1,2-二氯乙烷(5mL)和叔丁醇(5mL)，室温搅拌溶解澄清。后将体系移置于冰水浴中继续降温冷却搅拌，15min后，向体系中加入溴化锌(1.4g，6.00mmol)。完毕，体系在冰水浴中继续保温搅拌30min。然后向体系中加入前步合成的4-氨基-N-甲基苯甲酰胺三氟乙酸盐以及三乙胺(648.0mg，6.40mmol)。加毕，撤去冰浴，体系在室温搅拌反应过夜。翌日，监测反应结束，旋蒸除去溶剂后，向体系中加入乙酸乙酯(30mL)和水(20mL)，剧烈搅拌，静置分层后，水层用乙酸乙酯反萃(10mL*3)，合并有机相，依次用水(15mL*3)，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，减压浓缩得粗品，后经柱层析分离得类白色固体4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-甲基苯甲酰胺280.0mg。收率：42.3％。MS(ESI)m/e 331.0 (M+H) +。
第七步：化合物N-甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-yl)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰胺的合成
向装有N-(3-(氨甲基)吡嗪-2-yl)-N-氘代甲基甲磺酰胺(化合物41-3，65.8mg，0.30mmol)的25mL单颈圆底烧瓶中加入5mL 1,2-二氯乙烷，5mL叔丁醇，室温搅拌溶解澄清。随后，向体系中依次加入4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-甲基苯甲酰胺(100.0mg，0.30mmol)，二异丙基乙胺(116.3mg，0.90mmol)，加毕，将体系移置于80℃的油浴中回流反应。8h后，TLC监测原料消耗完全。停止加热，待体系冷却至室温后，旋蒸除去溶剂得粗品，后经Pre-TLC分离纯化得类白色固体N-甲基-4-((4-(((3-(N-三氘代甲基甲磺酰胺基)吡嗪-2-yl)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰胺(化合物41)12mg。收率：7.8％。MS(ESI)m/e 514.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.69(s,1H),8.59(s,1H),8.32(s,1H),8.20(d,J＝4.0Hz,1H),7.68-7.61(dd,J＝14.4,8.4Hz,4H),7.41-7.39(t,J＝4.4Hz,1H),5.01(d,J＝3.6Hz,2H),3.20(s,3H),2.76(d,J＝4.0Hz,3H)。
采用与化合物相对应的原料和类似于化合物41的制备方法，制备得到化合物42和43。
实施例3、合成N-三氘代甲基-4-((4-(((3-(N-三氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酸酰胺(化合物44)及其盐酸盐
Figure PCTCN2019128030-appb-000015
第一步：合成(4-(三氘代甲基氨基甲酰)苯基)氨基甲酸叔丁酯(化合物44-1)
分别称取N-Boc-4-氨基苯甲酸(6.0g，25.29mmol)，EDCI(7.27g，37.93mmol)置于250mL单颈圆底烧瓶中，同时加入DMF(50mL)，室温搅拌。随后向体系中加入三乙胺(6.40g，63.22mmol)，氘代甲胺盐酸盐(1.96g，27.82mmol)，完毕，体系在室温搅拌反应过夜。翌日，取样点板，TLC显示反应已经结束。向体系中加入乙酸乙酯(50mL)，水(50mL)剧烈搅拌，后静置分层，水相用乙酸乙酯反萃(50mL*3)，合并有机相，依次用水(30mL*3)，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，真空浓缩得粗品，并通过柱层析分离纯化得(4-(氘代甲基氨基甲酰)苯基)氨基甲酸叔丁酯(4.92g)类白色固 体。收率：76.8％。LC/MS(ESI+)Calcd for C13H15D3N2O3(M+H+)m/z,254.2；Found:254.2。
第二步：合成4-氨基-N-三氘代甲基苯甲酰胺三氟乙酸盐(化合物44-2)
称取(4-(氘代甲基氨基甲酰)苯基)氨基甲酸叔丁酯(3.0g，11.84mmol)置于100mL单颈圆底烧瓶中，同时加入二氯甲烷(15mL)，室温搅拌。随后向体系中加入三氟乙酸(7mL)，完毕，体系在室温搅拌反应。5h后，取样点板，TLC显示反应已经结束。旋蒸除去溶剂以及过量的三氟乙酸，并使用二氯甲烷反复旋带除去残留的三氟乙酸，得类白色固体4-氨基-N-氘代甲基苯甲酰胺三氟乙酸盐。不经进一步纯化，直接用于下步反应中。
第三步：合成4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-三氘代甲基苯甲酰胺(化合物44-3)
称取2,4-二氯-5-三氟甲基嘧啶(2.83g，13.02mmol)置于100mL单颈圆底烧瓶中，同时加入1,2-二氯乙烷(30mL)和叔丁醇(30mL)，室温搅拌溶解澄清。随后将体系移置于冰水浴中继续降温冷却搅拌，待体系内温降至约0℃时，向体系中加入溴化锌(8.0g，35.52mmol)，完毕，体系在冰水浴中继续保温反应30min。随后，向体系中加入前步反应制得的4-氨基-N-氘代甲基苯甲酰胺三氟乙酸盐以及三乙胺(3.83g，37.89mmol)，尔后，撤去冰水浴，让体系在室温搅拌反应过夜。翌日，取样点板，TLC显示原料已经消耗完毕，停止反应。旋蒸除去溶剂，向体系中加入乙酸乙酯(50mL)，水(30mL)剧烈搅拌，后静置分层，水相用乙酸乙酯反萃(30mL*3)，合并有机相，依次用水(30mL*3)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，真空浓缩得粗品，并通过柱层析分离纯化得4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-氘代甲基苯甲酰胺(3.23g)类白色固体。第二～第三两步反应的收率：81.8％。LC/MS(ESI+)Calcd for C13H7D3ClF3N4O(M+H+)m/z,334.0；Found:334.0。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.87(s,1H),8.31(s,1H),7.84–7.77(m,4H).
第四步：合成N-三氘代甲基-4-((4-(((3-(N-三氘代甲基甲磺酰胺)吡嗪-2-yl)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰胺(化合物44)
称取4-((4-氯-5-(三氟甲基)嘧啶-2-yl)氨基)-N-氘代甲基苯甲酰胺(3.1g，9.29mmol)，N-(3-氰基吡嗪-2-yl)-N-氘代甲基甲磺酰胺(2.0g，9.29mmol)于250mL单颈圆底烧瓶中，随后向其中加入1,2-二氯乙烷(80mL)和叔丁醇(80mL)，室温搅拌溶解澄清。尔后，向体系中加入二异丙基乙胺(3.6g，27.87mmol)，完毕，将体系移置于80℃的油浴中回流搅拌反应过夜。翌日，取样点板，TLC显示反应结束。旋蒸除去溶剂，向体系中加入乙酸乙酯(100mL)，水(50mL)剧烈搅拌，后静置分层，水相用乙酸乙酯反萃(50mL*3)，合并有机相，依次用水(30mL*3)，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，真空浓缩得粗品，并通过柱层析分离纯化得目标化合物(2.36g)类白色固体。后将该固体置于250mL单颈圆底烧瓶中，加入乙酸乙酯(75mL)，室温搅拌打浆。3h后，对其进行抽滤操作，滤饼用乙酸乙酯 (45mL)少量多次淋洗，后置于真空干燥箱中低温干燥，得N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺)吡嗪-2-yl)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰胺(2.11g)白色固体。收率：44.0％。LC/MS(ESI+)Calcd for C20H15D6F3N8O3S(M+H+)m/z,517.2；Found:517.2。1H NMR(400MHz,DMSO)δ9.83(s,1H),8.69(d,J＝2.8Hz,1H),8.58(d,J＝2.4Hz,1H),8.31(s,1H),8.17(s,1H),7.67–7.61(dd,J＝15.4,8.6Hz,4H),7.41(t,J＝5.0Hz,1H),5.00(d,J＝4.8Hz,2H),3.20(s,3H).
第五步：合成N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺盐酸盐
称取化合物44(500mg，0.97mmol)置于100mL单颈圆底烧瓶中，并向其中加入甲醇(25mL)，室温搅拌均匀。随后向体系中缓慢地滴加氯化氢的乙醇溶液(2.25mL，2.0M)，完毕，体系继续在室温搅拌反应。1.5h后，对体系进行抽滤操作，滤饼用甲醇(15mL)少量多次淋洗，后置于真空干燥箱中低温干燥，得N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺)吡嗪-2-yl)甲基)氨基)-5-(三氟甲基)嘧啶-2-yl)氨基)苯甲酰盐酸盐(517mg)，为类白色固体。收率：96.6％。LC/MS(ESI+)Calcd for C20H16D6ClF3N8O3S(M+H+)m/z,517.2；Found:517.2。1H NMR(400MHz,DMSO)δ10.02(s,1H),8.68(d,J＝2.8Hz,1H),8.58(d,J＝2.4Hz,1H),8.35(s,1H),8.21(s,1H),7.67–7.57(m,5H),5.26(br,6H)5.00(d,J＝4.8Hz,2H),3.19(s,3H).
实施例4、合成N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)氘代甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物45)
Figure PCTCN2019128030-appb-000016
第一步：合成化合物N-(3-(氨基二氘代甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺(45-1)
称取化合物41-2(100.0mg，0.46mmol)置于25mL单颈圆底烧瓶中，并加入5mL氘代甲醇，室温搅拌溶解澄清。随后向体系中依次加入湿钯碳(使用重水处理)20.0mg，三乙胺(188.2mg，1.86mmol)，对体系进行氘气置换操作，反复十次。完毕，体系在室温搅拌反应。72h后，监测反应结束。对体系进行抽滤操作，滤饼用氘代甲醇(10mL)少量多次淋洗，合并滤液，旋蒸除去溶剂，得浅黄褐色油状液体N-(3-(氨基氘代甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺，不经进一步纯化，直接用于下步反应中。MS(ESI)m/e 222.2(M+H) +。
第二步：合成化合物N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2- 基)氘代甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(45)
向装有N-(3-(氨基氘代甲基)吡嗪-2-基)-N-氘代甲基甲磺酰胺(22.1mg，0.10mmol)的25mL单颈圆底烧瓶中加入2mL 1,2-二氯乙烷，2mL叔丁醇，室温搅拌溶解澄清。随后，向体系中依次加入化合物44-3(33.4mg，0.10mmol)，二异丙基乙胺(30.6mg，0.30mmol)，加毕，将体系移置于80℃的油浴中回流反应。8h后，TLC监测原料消耗完全。停止加热，待体系冷却至室温后，旋蒸除去溶剂得粗品，后经Prep-TLC分离纯化得类白色固体N-氘代甲基-4-((4-(((3-(N-氘代甲基甲磺酰胺基)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺8.1mg。收率：15.6％。MS(ESI)m/e 519.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.69(d,J＝2.0Hz,1H),8.58(d,J＝2.4Hz,1H),8.31(s,1H),8.17(s,1H),7.67-7.61(dd,J＝15.2,8.8Hz,4H),7.39(s,1H),3.20(s,3H)。
实施例5、合成4-((4-(((3-(N-三氘代甲基甲磺酰胺)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(化合物52)
Figure PCTCN2019128030-appb-000017
第一步：合成化合物4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(52-2)
称取2,4-二氯-5-(三氟甲基)嘧啶(434mg，2.00mmol)于50mL单颈圆底烧瓶中，并向体系中加入1,2-二氯乙烷(5mL)和叔丁醇(5mL)，室温搅拌溶解澄清。后将体系移置于冰水浴中继续降温冷却搅拌，15min后，向体系中加入溴化锌(1.2g，5.22mmol)。完毕，体系在冰水浴中继续保温搅拌30min。然后向体系中加入前步合成的4-氨基苯甲酰胺(237mg，1.74mmol)以及三乙胺(564mg，5.57mmol)。加毕，撤去冰浴，体系在室温搅拌反应过夜。翌日，监测反应结束，旋蒸除去溶剂后，向体系中加入乙酸乙酯(30mL)和水(20mL)，剧烈搅拌，静置分层后，水层用乙酸乙酯反萃(10mL*3)，合并有机相，依次用水(15mL*3)，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，减压浓缩得粗品，后经柱层析分离得类白色固体4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺294mg。收率：53.4％。MS(ESI)m/e 317.0(M+H) +。第二步：合成化合物4-((4-(((3-(N-三氘代甲基甲磺酰胺)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺(52)
向装有前述制得的化合物52-2的25mL单颈圆底烧瓶中加入5mL 1,2-二氯乙烷，5mL叔丁醇，室温搅拌溶解澄清。随后，向体系中依次加入化合物44-3(63.0mg，0.20mmol)，二异丙基乙胺(78mg，0.60mmol)，加毕，将体系移置于80℃的油浴中回流反应。翌日，TLC监测原料消耗完全。停止加热，待体系冷却至室温后，旋蒸除去溶剂得粗品，后经Prep-TLC分离纯化 得类白色固体4-((4-(((3-(N-氘代甲基甲磺酰胺)吡嗪-2-基)甲基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯甲酰胺22mg。收率：22.0％。MS(ESI)m/e 500.1(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.69(s,2H),8.60(s,1H),8.31(s,1H),8.20(d,J＝4.0Hz,1H),7.68-7.60(dd,J＝15.4,8.4Hz,4H),7.41-7.39(t,J＝4.4Hz,1H),5.03(d,J＝3.6Hz,2H),3.20(s,3H)。
用已知化合物4-氨基-3,5-二氘代苯甲酸，4-氨基-2,6-二氘代苯甲酸(Journal of Labelled Compounds and Radiopharmaceuticals,53(11-12),668-673；2010)为原料，参照上述实施例的方法制备得到化合物48-50，53-55。用已知化合物4-氨基-2,3,5,6-四氘代苯甲酸(Journal of Natural Products,79(6),1532-1537；2016)为原料，参照上述实施例的方法制备得到化合物59-61。
以下通过试验例证明本发明的有益效果。
试验例1、本发明氘代化合物对FAK的抑制活性
(1)试验方法
参照文献方法(Cancer Res.2008,68,1935)进行FAK酶抑制活性实验。具体如下：待测化合物稀释至1000nM,然后用DMSO按1：3逐级稀释取0.1L溶液放入384孔板中，每个浓度设置2个复孔。加入5L 2倍FAK酶溶液，在1000rpm离心1分钟，在25℃孵化15分钟。加入5L 2倍底物溶液在25℃孵化60分钟。再加入5L Sa-XL665溶液和5μL TK抗体-Eu3+，在1000rpm离心1分钟，在25℃孵化60分钟，最后用Envision 2104读板机读取荧光信号，并计算出各化合物对FAK酶的半数抑制浓度IC50。以已知的FAK抑制剂defactinib为对照。
(2)试验结果
各化合物对FAK抑制活性如表1所示。可以看出，本发明制得的化合物能够有效抑制FAK酶的活性，并且，与未氘代的化合物defactinib相比，本发明的氘代化合物41、45对FAK酶的抑制活性更高。
表1、本发明化合物对FAK酶的抑制活性
化合物 defactinib 41 44 45 46
IC50(nM) 0.24 0.20 0.47 0.15 0.37
试验例2、本发明氘代化合物的大鼠药代动力学测试
(1)试验方法
精密称取适量待测药物(10mg)，先加入N,N-二甲基乙酰胺(DMA)0.25ml使之溶解，然后缓慢加入0.5％羧甲基纤维素钠(CMC-Na)至5ml，超声、涡漩混匀。取上述配制的终溶液0.2ml，于-20℃保存，用于浓度测定。
健康成年雄性SD大鼠3只(180-250g，购自成都达硕实验动物有限公司)，禁食过夜(自由饮水)后，灌胃给药，给药体积5ml/kg；于给药前及给药后0.5,1,2,4,6,8,12,24h由眼眶后静脉丛采血0.1ml，4℃离心5min分离 血浆，于-20℃保存待测。然后采用LC/MS/MS法测定血浆中的待测化合物浓度。以已知的FAK抑制剂defactinib为对照。
(2)试验结果
表2、本发明化合物的药代动力学参数
Figure PCTCN2019128030-appb-000018
如表2所示，与defactinib相比，本发明制得的氘代化合物25、44显示了更优的药代动力学，本发明的化合物具有更高的最高血药浓度Cmax，更高的暴露量AUC，和更长的半衰期。所以，本发明制得的氘代化合物在作为FAK抑制剂或治疗癌症的药物中将具有更优的应用前景。
试验例3、本发明氘代化合物联合PD-1抑制剂在肿瘤动物模型上的药效实验
1.MC38肿瘤模型：
(1)试验方法
细胞培养：MC-38细胞培养在含10％胎牛血清(FBS)的DMEM培养液中。收集对数生长期的MC-38细胞，HBSS重悬至适合浓度用于C57BL/6小鼠皮下肿瘤接种。
实验动物:C57BL/6小鼠，雌性，6-8周龄，体重约18-20g，96只，购自于北京维通利华实验动物技术有限公司。
肿瘤细胞接种：收集对数生长期肿瘤细胞，用HBSS将细胞浓度调整为5×10 6/mL，用1mL注射器接种0.1mL于每只小鼠右侧靠近背部皮下，即5×10 5/只。之后观察和测量肿瘤体积，待小鼠平均瘤体积长至50-100mm 3时，根据肿瘤体积对荷瘤鼠进行随机分组并给药，详细信息如下表3，分组给药当天定义为第0天。
计算肿瘤体积：于第18天处死小鼠，取出肿瘤，测量肿瘤体积，并计算各组抑瘤率。
表3、MC38肿瘤模型分组，给药信息及抑瘤率
Figure PCTCN2019128030-appb-000019
Figure PCTCN2019128030-appb-000020
注：N：使用动物数量；i.p.：腹腔注射；p.o.：灌胃给药；BID：每天两次；QD：每天一次；BIW：每周两次。
(2)试验结果
动物给药18天后的药效如图1所示，计算出的抑瘤率见表3。可以看出本发明化合物44单用的药效比mPD-1抗体单用的药效更佳，说明本发明化合物单独给药对MC38肿瘤模型小鼠有治疗效果。
此外，与化合物44单用(第4组)或mPD-1抗体单用(第2组)相比，化合物44联合mPD-1抗体给药(第5组)取得了显著提高的肿瘤抑制效果，发挥了协同增效的作用。
另外，与Defactinib(50mg/kg,每天2次给药)联合mPD-1抗体给药(第3组)相比，本发明化合物44(50mg/kg,每天一次给药)联合mPD-1抗体给药(第5组)后的肿瘤抑制效果更佳，取得了更优异的肿瘤抑制效果。也就是说，在与PD-1抑制剂联用时，采用Defactinib一半剂量的本发明化合物，却能取得更佳的肿瘤抑制效果，说明本发明化合物与PD-1抑制剂联合用药对MC38肿瘤模型的抗肿瘤效果显著优于Defactinib与PD-1抑制剂联合用药。
2.PAN02肿瘤模型
(1)试验方法
取处于对数生长期的PAN-02细胞，用PBS洗两次，然后重悬于预冷PBS中用于接种。实验动物为C57BL/6小鼠，雌性，购自北京维通利华实验动物技术有限公司。C57BL/6小鼠实验室环境适应3天，于右肋部皮下接种PAN-02细胞，接种细胞量为1×10 6/只，待肿瘤生长至100mm 3左右时进行筛选、随机分组，每组8只，按下表4分组和给药方案给药。分组给药当天定义为第1天，给药周期为33天。
表4、PAN-02肿瘤模型分组，给药信息及抑瘤率
Figure PCTCN2019128030-appb-000021
Figure PCTCN2019128030-appb-000022
注：N：使用动物数量；i.p.：腹腔注射；i.g.：灌胃给药；BID：每天两次；BIW：每周两次。
(2)试验结果
动物给药33天后的药效如图2所示，计算出的抑瘤率见表4。可以看出，与化合物44单用(第4组)或mPD-1抗体单用(第2组)相比，化合物44联合mPD-1抗体给药(第5组)取得了显著提高的肿瘤抑制效果。
同时，与Defactinib(50mg/kg,每天2次给药)联合mPD-1抗体给药(第3组)后的肿瘤抑制效果相比，本发明化合物44(25mg/kg,每天两次给药)联合mPD-1抗体给药(第5组)后的肿瘤抑制效果显著提高。也就是说，在与PD-1抑制剂联用时，采用比Defactinib更低剂量的本发明化合物，反而能取得更加优异的肿瘤抑制效果，说明本发明化合物与PD-1抑制剂联合用药对PAN-02肿瘤模型的抗肿瘤效果显著优于Defactinib与PD-1抑制剂联合用药。
综上，本发明提供了一种氘代化合物，与氘代前的化合物相比，其显示了更优的药代动力学，更高的最高血药浓度，更高的暴露量和更长的半衰期，具有更加优异的代谢性能。而且，本发明的氘代化合物能够有效抑制FAK活性，在制备FAK抑制剂和/或治疗癌症的药物中具有非常好的应用前景。同时，本发明的氘代化合物与抗癌药物(比如PD-1抑制剂)联合使用能够发挥协同增效的作用，显著提高肿瘤抑制效果，为临床治疗癌症提供了更好的选择。

Claims (19)

  1. 式(I)所示的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物：
    Figure PCTCN2019128030-appb-100001
    其中，S环选自芳环或五元杂环；A、B，X、Y，Z分别独立地选自碳或氮；E为无或亚甲基；
    和/或，R 6选自氢或无；R 7选自氢，氮或无；R 8选自卤代烷基或卤素，或者，R 7和R 8连接成环；
    和/或，R 9选自-NMeSO 2Me、-CONHOMe、-CONHMe、酰胺、氢或无；R 10选自氢或无；R 11选自-NHSO 2Me、卤素、取代的哌嗪或氢，所述哌嗪上的取代基为乙醇基；R 12选自-SO 2Me或氢；R 13选自-CONHMe、-CONHOMe、N-烷基磺酰胺、氢或无，或者，R 11和R 13连接成环；
    式(I)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
  2. 根据权利要求1所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-A)所示结构：
    Figure PCTCN2019128030-appb-100002
    其中，A、B，X，Y，Z分别独立地选自碳或氮；E为无或亚甲基；
    R 1、R 5选自氢或甲氧基；R 2、R 4选自氢或甲氧基，R 3选自氢、-CONHMe、烷氧基酰胺、吗啉、甲氧基、乙基胺或磺酰胺，或者，R 2和R 3连接成环，或者，R 3和R 4连接成环；
    和/或，R 6选自氢或无；R 7选自氢，氮或无，R 8选自卤代烷基或卤素，或者，R 7和R 8连接成环；
    和/或，R 9选自-NMeSO 2Me、-CONHOMe、-CONHMe、酰胺、氢或无； R 10选自氢或无；R 11选自-NHSO 2Me、卤素、取代的哌嗪或氢，所述哌嗪上的取代基为乙醇基；R 12选自-SO 2Me或氢；R 13选自-CONHMe、N-烷基磺酰胺、氢或无，或者，R 11和R 13连接成环，或者，R 13和R 3和R 4连接成环；
    式(I-A)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
  3. 根据权利要求1所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-B)所示结构：
    Figure PCTCN2019128030-appb-100003
    其中，A、X、Y选自碳或氮；E为无；
    R 14，R 15，R 16独立地选自氢，C 1-6烷基，C 3-6环烷基，甲基、乙基或异丙基；
    和/或，R 6为氢；R 7为氢；R 8为卤素；
    R 9、R 13选自-CONHOMe、-CONHMe或氢；R 10、R 12为氢；
    R 11选自卤素、氢或取代的哌嗪，所述哌嗪上的取代基为乙醇基；
    式(I-B)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
  4. 根据权利要求2所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-C)所示结构：
    Figure PCTCN2019128030-appb-100004
    其中，A、X、Y选自碳或氮；E选自亚甲基或无；
    R 9、R 13选自氢、-NMeSO 2Me、-CONHOMe或-CONHMe；R 10、R 12为氢；R 11选自氢、取代的哌嗪或卤素，所述哌嗪上的取代基为乙醇基；
    和/或，R 6选自氢；R 7选自氢，R 8选自卤代烷基或卤素，或者，R 7和R 8连接成环；
    和/或，R 1、R 4、R 5选自氢或甲氧基；R 2选自氢或甲氧基，R 3选自氢、-CONHMe、烷氧基酰胺、吗啉、甲氧基、乙基胺或磺酰胺，或者，R 2和R 3连接成环；
    式(I-C)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
  5. 根据权利要求3所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-D)所示结构：
    Figure PCTCN2019128030-appb-100005
    其中，R 9、R 13选自-CONHOMe、-CONHMe或氢；R 10、R 12为氢；R 11选自卤素、氢或取代的哌嗪，所述哌嗪上的取代基为乙醇基；
    A、X、Y选自碳或氮；E为无；
    和/或，R 6选自氢；R 7选自氢；R 8为卤素
    和/或，R 14选自甲基、乙基或异丙基；R 15选自甲基或氢；R 16为氢；
    式(I-D)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
  6. 根据权利要求1所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-E)所示结构：
    Figure PCTCN2019128030-appb-100006
    其中，B、Z选自碳或氮；E为亚甲基；Y为氮；X、A为碳；
    和/或，R 6为无；R 7为氢；R 8为卤代烷基；
    和/或，R 1、R 2为氢；R 3为-CONHMe，R 4为氢，或者，R 3与R 4连接成环；
    式(I-E)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代， x为大于或等于1的整数。
  7. 根据权利要求6所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-F)所示结构：
    Figure PCTCN2019128030-appb-100007
    其中，式(I-F)所示Dx表示括号内的化合物至少1个碳原子上的氢被氘取代，x为大于或等于1的整数。
  8. 根据权利要求7所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物具有式(I-G)所示结构：
    Figure PCTCN2019128030-appb-100008
    其中，R 1、R 5、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24中的一个或多个被氘取代。
  9. 根据权利要求1～8任一项所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物，其特征在于：所述化合物选自但不局限于氘取代的如下化合物之一：
    Figure PCTCN2019128030-appb-100009
    Figure PCTCN2019128030-appb-100010
    优选地，所述化合物选自但不局限于如下化合物之一或氘取代的如下化合物之一：
    Figure PCTCN2019128030-appb-100011
    Figure PCTCN2019128030-appb-100012
  10. 权利要求1～9任一项所述的化合物或其光学异构体、互变异构体、药学上可接受的盐、前药、水合物或溶剂合物在制备FAK抑制剂中的用途；优选地，所述FAK抑制剂是治疗癌症的药物。
  11. 根据权利要求10所述的用途，其特征在于：所述癌症为实体瘤；
    所述实体瘤包括间皮瘤，胰腺癌，软组织肿瘤，转移瘤，非固体癌，肉瘤，腺癌，肺癌，乳腺癌，淋巴瘤，胃肠道癌，泌尿生殖系统癌，前列腺癌，卵巢癌；所述胃肠道癌包括结肠癌，所述泌尿生殖系统癌包括肾，尿路上皮或睾丸肿瘤，所述卵巢癌包括晚期卵巢癌；
    所述间皮瘤包括神经纤维瘤，肾癌，肺癌，小细胞肺癌，非小细胞肺癌， KRAS突变体非小细胞肺癌，肝癌，甲状腺癌，乳腺癌，神经系统肿瘤，神经鞘瘤，脑膜瘤，神经瘤，腺样囊性癌，室管膜瘤，室管膜肿瘤，恶性胸膜瘤，恶性胸膜间皮瘤，三联体瘤，阴性乳腺癌，非血液恶性肿瘤，黑素瘤，，结直肠癌，白血病，腺癌，固体肿瘤；
    所述黑素瘤包括局部晚期黑素瘤，局部突变的N-Ras引起的黑素瘤，转移性恶性皮肤黑色素瘤，所述结直肠癌包括转移性结直肠癌，所述白血病包括急性髓性白血病，所述腺癌包括腺癌，所述固体肿瘤包括局部晚期实体瘤，转移性实体瘤，肝细胞癌。
  12. 一种用于治疗肿瘤的联合用药物，其特征在于：它含有相同或不同规格单位制剂的用于同时或者分别给药的权利要求1～9任一项所述的化合物与抗癌药物，以及药学上可接受的载体。
  13. 根据权利要求12所述的联合用药物，其特征在于：所述抗癌药物为免疫疗法用药物、化学疗法用药物或辐射疗法用药物。
  14. 根据权利要求13所述的联合用药物，其特征在于：所述免疫疗法用药物选自检查点抑制剂、PD-1抑制剂、PD-L1抑制剂、抑制CTLA-4的抗体、抑制TIM3的抗体、抑制LAG3的抗体、抑制TIGIT的抗体、阻断检查点靶点的抗体、共刺激抗体或者CAR-T疗法用细胞。
  15. 根据权利要求14所述的联合用药物，其特征在于：
    所述PD-1抑制剂或PD-L1抑制剂，包括但不局限于：nivolumab，CT-011；AMP-224，pembrolizumab，pidilizumab，MK-3475，BMS936559，MEDI4736，MSB001071 8C，MPDL-3280A，SHR-1210,IBI308，BGB-A317，JS001，GLS-010，GB226杰诺单抗，HLX10，AK103,AK104,AK105,AK112,SSI-361,JY034,KN035,SHR1316,TQB2450,KL-A167,CS1001，STI-A1014,JS003,AK106,HLX-09，mPD-1抗体；
    所述阻断检查点靶点的抗体包括IMP321,MGA271；
    所述共刺激抗体包括anti-4-lBB抗体,anti-OX40抗体,anti-GITR抗体,anti-CD27抗体,anti-CD40抗体。
  16. 根据权利要求13所述的联合用药物，其特征在于：所述化学疗法用药物为毒性药物，烷基化药物，抗代谢产物药物，抗生素，激素疗法药物，天然产物抗癌药物，拓扑异构酶抑制剂药物，免疫药物，络合铂药物，激酶抑制剂，抗增生药物，抗体，干扰素或调控雄激素信号通路的药物。
  17. 根据权利要求16所述的联合用药物，其特征在于：
    所述毒性药物为包括但不局限于gemcitabine，paclitaxel，docetaxel；
    所述激酶抑制剂包括但不局限于,MEK激酶抑制剂，cMet抑制剂，VEGFR2抑制剂，EGFR抑制剂；
    所述调控雄激素信号通路的药物包括但不局限于：雄激素合成抑制剂，CYP17A抑制剂，雄激素受体抑制剂，BET抑制剂，BRD4抑制剂，RORγ抑制剂，CBP/P300抑制剂，BMX抑制剂，PARP抑制剂；优选地，所述雄激素受体抑制剂包括但不局限于：Enzalutamide,Apalutamide,Bicalutamide, Abiraterone,ODM-201，EPI-001，ONC1-13B,EM-5854,JNJ-63576,TAS-3681,HC-1119,普克鲁胺，SHR3680。
  18. 权利要求12～17所述联合用药物在制备治疗癌症的药物中的用途。
  19. 根据权利要求18所述的用途，其特征在于：所述癌症为实体瘤；
    所述实体瘤包括间皮瘤，胰腺癌，软组织肿瘤，转移瘤，非固体癌，肉瘤，腺癌，肺癌，乳腺癌，淋巴瘤，胃肠道癌，泌尿生殖系统癌，前列腺癌，卵巢癌；所述胃肠道癌包括结肠癌，所述泌尿生殖系统癌包括肾，尿路上皮或睾丸肿瘤，所述卵巢癌包括晚期卵巢癌；
    所述间皮瘤包括神经纤维瘤，肾癌，肺癌，小细胞肺癌，非小细胞肺癌，KRAS突变体非小细胞肺癌，肝癌，甲状腺癌，乳腺癌，神经系统肿瘤，神经鞘瘤，脑膜瘤，神经瘤，腺样囊性癌，室管膜瘤，室管膜肿瘤，恶性胸膜瘤，恶性胸膜间皮瘤，三联体瘤，阴性乳腺癌，非血液恶性肿瘤，黑素瘤，，结直肠癌，白血病，腺癌，固体肿瘤；
    所述黑素瘤包括局部晚期黑素瘤，局部突变的N-Ras引起的黑素瘤，转移性恶性皮肤黑色素瘤，所述结直肠癌包括转移性结直肠癌，所述白血病包括急性髓性白血病，所述腺癌包括腺癌，所述固体肿瘤包括局部晚期实体瘤，转移性实体瘤，肝细胞癌。
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